FitSugar

8 Habits of the Super Healthy

FitSugar — Tue, 03 Nov 2009 07:00:10 -0800

If you are looking to keep colds and flu bugs at arm's length, I researched habits of healthy women. Here are eight habits that will help keep you well over the following months.

First, start by upping your vitamin C intake. While the vitamin won't prevent you from catching a cold, it will boost your immune system. And if you do happen to catch a cold, vitamin C will decrease the duration of runny nose time. Try to eat foods naturally high in the vitamin, like citrus fruits and red bell peppers.

To see the other seven habits, just start the slideshow.
Source: Getty

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Another Reason to Exercise: Boost Your Immune System

FitSugar — Wed, 19 Mar 2008 04:00:00 -0700

We're nearing the end of flu season and heading into allergy season, but that doesn't mean we should get complacent about fighting off illness. Since I am always looking for new reasons to exercise and new ways to avoid getting sick, I was excited to find this research suggesting that consistent exercise can boost your immune system.

Moderate exercise temporarily increases your body's production of macrophages, the cells designed to fend off bacteria, and allows them to travel more efficiently through the body. Though these are temporary responses to working out, new research suggests that the more often you exercise, the more permanent the health benefits become. According to Dr. David Nieman of Appalachian State University, moderate exercise on a regular basis also strengthens your immune system in the long run.

But for super-serious athletes like marathoners, exercise can actually make the body more susceptible to illness, so be sure to give yourself plenty of recovery days if you're training for a big event.

Do you exercise daily? If so, do you think it helps you avoid getting sick?

Source

Give your Immune System a Boost

FitSugar — Fri, 01 Dec 2006 03:00:00 -0800

I am paranoid about the flu, I'll admit it. So I'm putting my paranoia to good use and figuring out simple ways to boost my immune system and I would like to share them with you.

One of the easiest ways is to sleep at least 7 - 9 hours a night. For me, this might mean going to bed a little early since I am not always in control of my wake up time. My 20 month old daughter IS my alarm clock.

Or course exericise is beneficial too - it is my answer for all the ills of the world. Working out helps to strengthen your immune system and increases the body’s natural virus-killing cells. This is why if you have a little cold it is good to do a light work out.

Eating nuts and sunflower seeds also gives your immune system a little boost since they are high in Vitamin E. Vitamin C might get all the press, but Vitamin E is the unsung hero of your immune system since it helps stimulate the production of natural killer cells that seek out and destroy germs. It helps you fight the good fight.

I'm going to chomp on some seeds right now.

Came Down With a Cold? Eat These Foods

FitSugar — Wed, 28 Oct 2009 07:00:57 -0700

A balanced diet can boost your immune system and prevent you from getting sick, but if you happen to catch a cold or worse, the flu, a healthy diet is essential in helping you recover faster. Here are some foods you should eat when you're sick.

Source: Getty

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Immunizations

FitSugar — Wed, 08 Oct 2008 17:35:29 -0700

In This Report

Highlights
Introduction
Diphtheria, Tetanus, and Pe...
Measles, Mumps, and Rubella...
Varicella-Zoster Virus (Chi...
Varicella-Zoster Virus (Shi...
Hepatitis A
Hepatitis B
Pneumococcal Pneumonia
Poliomyelitis
Viral Influenza
Haemophilus Influenzae Type...
Human Papillomavirus (HPV)...
Rotavirus
Smallpox
Other Vaccinations
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Vaccines

The Centers for Disease Control and Prevention now recommends that children receive 2 doses of the varicella-zoster (Chickenpox) vaccine: the initial vaccine between ages 12 - 15 months, and a booster between 4 - 6 years. Children aged 12 and older and adults who have not had the vaccine should receive 2 doses. Immunization guidelines were changed following research that indicated the effectiveness of the vaccine declines over time. A 2007 study indicated that children who were vaccinated 5 or more years earlier were 2.6 times more likely to have a moderate-to-severe breakthrough case of chickenpox than those who had been vaccinated more recently.
A study finds that the conjugate pneumococcal vaccine, which was introduced for children in 2000, has reduced hospital admissions for pneumonia in children under age 2 by about 39%. The vaccine has also caused hospital admissions to drop 26% among adults aged 18 - 39. Another study found that recurrent ear infections have fallen by 28% since the introduction of the vaccine.
In April 2007, the U.S. Food and Drug Administration approved the first vaccine against the avian flu virus. The avian flu vaccine is designed for people ages 18 - 64 who are at risk for exposure to the virus. The vaccine is given in 2 shots, spaced about 1 month apart. The U.S. government is stockpiling the vaccination in case of an avian influenza outbreak, but the vaccine is not available to the general public.
Research finds that the human papillomavirus (HPV) vaccine (Gardisil) is 100% effective against cervical, vaginal, and vulvar diseases caused by 4 types of HPV (6, 11, 16, and 18).

Introduction

Immunizations against childhood diseases have saved millions of lives. American vaccination rates are now at an all-time high. Disease and death from diphtheria, pertussis, tetanus, measles, mumps, rubella, and Haemophilus influenzae (H. influenzae) type b are at or near record lows. In adults, immunizations against influenza (the flu), pneumococcal pneumonia, hepatitis, and other ailments have likewise saved many lives and prevented many more cases of serious illness. A new vaccine has been shown to be highly effective for preventing the virus that leads to cervical cancer.

More than 70 bacteria, viruses, parasites, and other infectious microbes cause major human disease. Fortunately, vaccines are either available or being developed against many of them. With the advent of new or newly feared biological threats, emerging infections, and bacterial resistance to common antibiotics, immunizations are assuming an increasingly important role in maintaining the health of billions of people worldwide.

Immunizations (vaccinations) are given to initiate or augment resistance to an infectious disease. Immunizations provide a specialized form of immunity that provides long-lasting protection against specific antigens, which cause disease.

Routine Childhood Vaccines. Experts recommend that all children be routinely vaccinated against the following diseases:

Measles
Mumps
Rubella (German measles)
Diphtheria
Tetanus
Pertussis (whooping cough)
Poliomyelitis (polio)
Varicella (chickenpox)
Hepatitis B
Hepatitis A
H. influenzae type B (a cause of meningitis)
Influenza (children aged 6 - 59 months)
Pneumococcal disease
Meningococcal disease (for selected populations)
Rotavirus (children aged 6 - 32 weeks)

Many vaccinations are first given during infancy. Even premature infants can, in most cases, be given vaccinations on a normal schedule. There is even some evidence that doing so may offer some slight protection against sudden infant death syndrome. Note: These facts pertain to children in the United States. Children from other countries have not been well studied. Parents who adopt internationally may want to have their children's immunity assessed by a physician. Some evidence suggests that their medical records may not correctly reflect immunization status and that many adopted children, such as those from China, have not had many important vaccinations.

Click the icon to see an animation about vaccines.

Common Adult Vaccines. Vaccinations against the following disorders are also recommended routinely for certain adults:

Influenza (flu). Every year in high-risk adults under 49 and everyone over 50. When supplies are limited, as with the 2004 - 2005 flu season, the vaccine should be administered preferentially to adults only over age 65 and to individuals with heart disease, lung disease, and other significant chronic illnesses. Health care providers with direct patient contact, child care providers, and residents of long-term care facilities should also be vaccinated.
Pneumococcal pneumonia. One dose in high-risk adults under 64 and a first dose or a revaccination in everyone over 65.
Hepatitis A and B and Meningococcal vaccine. Given to high-risk individuals.
Tetanus. Adults need a booster shot every 10 years.
Measles, mumps, rubella. Typically given to adults under 56 who are unsure of their vaccination history. High-risk individuals may receive two doses.
Diphtheria and pertussis are now recommended with tetanus (Tdap vaccine) booster every 10 years until age 65.
Herpes zoster (shingles) vaccine. One dose for adults 60 and older.
Human papillomavirus (HPV). Three doses in young women aged 11 - 26.

Vaccines are currently taken by mouth (orally) or given by a shot (injection). Vaccines are usually made of one of two agents that cause the body to produce antibodies that attack a specific disease. A vaccine may contain:

A live but weakened virus. Live-virus vaccines provide longer immunity than inactivated ones, but they can cause serious infection in people with weakened immune systems and have also been associated with severe medical disorders in rare instances.
Inactivated bacteria, viruses, or toxoids. Inactivated vaccines are safe even in people with impaired immune systems.

Click the icon to see an image of antibodies.

The weakened or inactivated agent in the vaccine teaches the immune system to recognize the real, harmful substance and attack it when the person becomes exposed to the infection. The antibodies remain in the body, preventing future illness from the disease. This is called immunity.

Combination Vaccines. The American Academy of Pediatrics and American Academy of Family Physicians recommend that health care providers use, whenever possible, combination vaccines instead of individual components. Combination shots containing vaccines for diphtheria, tetanus, and pertussis (DTaP), and for measles, mumps, and rubella (MMR), have been available for years. New combinations that cover up to 5 vaccinations are being developed and are proving to be safe and well tolerated in infants as young as 2 months. For example, one that combines DTaP, hepatitis B, and the polio vaccine (Pediarix) has been approved and should simplify the immunization process.

There is some concern that increasing use of combinations may reduce the potency of some of the vaccines. Some parents are also worried about increased side effects. Studies to date, however, are reporting that combinations are effective and safe.

Passive Immunity. Another form of protection against disease is called passive immunity. This approach uses immune globulin, which are blood products containing antibodies. Immune globulin is generally used for people who cannot be vaccinated, when immediate protection is required, or to prevent severe complications of the disease. In some circumstances, passive immunity can interfere with active vaccinations, particularly live-virus vaccines, so, if possible, they should not be administered within weeks or even months of each other.

General Information on Side Effects. Vaccines can have side effects, such as swelling at the injection site or fever, which are nearly always mild. There have been a number of reports in the popular press about alarming side effects in many vaccines. Anti-vaccine groups vocally oppose immunizations in children. Although it is true that no vaccine is 100% safe, childhood infections have not been wiped out. Without immunization, children risk diseases that have in the past killed millions of young children.

Thimerosal is a preservative used in many vaccines. It has been in use since the 1930s. The preservative contains small amounts of mercury. Some people are concerned about possible neurologic consequences from cumulative doses of mercury contained in vaccines given to infants. A 2003 study did report an association between thimerosal in DTaP vaccines and a higher risk for problems in neurologic development, including autism and speech problems.

In 2004, the Institute of Medicine (IOM) Safety Review Committee reported the results of studies in the U.S. and several European countries evaluating a possible association between thimerosal and autism. They concluded that scientific studies did not find that thimerosal caused autism.

In any case, manufacturers have been removing this preservative from vaccines. At the time of this report, all vaccines recommended for children age 6 or younger contain either no thimerosal or only trace amounts, with the exception of the inactivated influenza vaccine (although a limited supply of a version of the vaccine containing only trace amounts of thimerosal is available for use in infants, children, and pregnant women). A trace amount means that a given dose of vaccine contains less than 1 part per million.

Inactivated-virus and toxoid vaccines are usually safe in pregnant women, although any vaccination should be delayed, if possible, until the second or third trimester. Because of a possible risk to the fetus, live-virus vaccines should not be given to pregnant women or those likely to become pregnant within 28 days unless such women need immediate protection against life-threatening diseases, such as yellow fever, that are only prevented using live-virus vaccines. The live-virus MMR combination, which vaccinates against measles, mumps, and rubella, is not given to pregnant women because of the theoretical risk of the live-rubella vaccine on the fetus.

Click the icon to see an image of rubella syndrome.

Live-virus vaccines are not usually given to people whose immune system has been compromised by illness or the use of medication such as long-term corticosteroids. They include:

Click the icon to see an image of HIV.

Persons who have immune deficiency diseases (such as HIV or AIDS).
Patients with active leukemia or lymphoma.
Patients who are taking treatments that suppress the immune system, such as corticosteroids, alkylating drugs, antimetabolites, or radiation. (There are important exceptions, however, which are noted in the discussion of individual vaccinations below.) Short-term corticosteroids (given for less than 2 weeks) do not suppress the immune system and so should not affect any live-virus vaccination. It should be noted that some topical corticosteroids are suppressive. Patients who need vaccinations and who take long-term or high-dose topical steroids should check with their physicians.

In general, vaccines are not completely effective for patients whose immune systems are compromised by disease or medications. Often, such patients are given immune globulin if they are exposed to infection. It may take 3 months to 1 year before a person who has stopped taking immunosuppressant drugs regains the full ability to be successfully immunized against disease.

People who are traveling to developing countries should check with the US Centers for Disease Control (www.cdc.gov/travel) for up-to-date information on immunization requirements for their destination.

Below are some general guidelines for vaccinations, immunizations, and other preventive steps for travel:

Everyone should be up-to-date on any recommended vaccinations for childhood diseases, regardless of their age. Booster shots may be required for travelers to developing countries even if they have completed the initial series. Vaccinations may include polio, H. influenzae, the series for diphtheria, pertussis, and tetanus (DTaP), hepatitis B, rotavirus, measles, and varicella-zoster (chickenpox). If children have not completed their DTaP series, parents should consider having it completed while overseas.
Pregnant women should have vaccinations that are appropriate to their trimester. Not all vaccinations are safe during pregnancy.
Older adults may not respond to a vaccination as quickly as younger people or they may have a higher risk for side effects. They should check with their physicians.
Upper respiratory infections are very common after foreign travel. The flu vaccine may be recommended when traveling to any country during flu season, particularly for the elderly and people at risk for serious illness. This group may also need the pneumococcal vaccine.
Travelers to areas where there are tuberculosis (TB) outbreaks should have skin tests before traveling; those with negative tests should have a repeat test 2 - 4 months after they return.
Vaccination against hepatitis A is recommended for all travelers to developing countries. Some expert groups believe that such travelers should have hepatitis B vaccinations as well, but the CDC does not generally recommend them at this time except under certain circumstances.
Travelers to countries with malaria should take preventive agents.
Some countries may require vaccinations against yellow fever, meningitis, typhoid, cholera, Japanese encephalitis, and rabies under certain circumstances. Some of these vaccinations are covered in this report.
Studies indicate that multiple vaccines may be given at the same time to most adults without significantly increasing adverse effects.

[For more information, see In-Depth Report #1: Travel to developing countries.]

Childhood Immunization Schedule**
Age	Chickenpox (Varicella Zoster)	Diphtheria, Tetanus, Pertussis (DTaP)*	Haemophilus influenzae type (Hib)	Hepatitis A	Rotavirus
Birth
2 months		DTaP*	Hib		Rotavirus
4 months		DTaP*	Hib		Rotavirus
6 months		DTaP*	Hib (Depending on brand. For example, no third dose is required for PedvaxHIB or ComVax.)		Rotavirus
12 to 15 months	Varicella	DTaP* (Typically between 15 and 18 months. May be given as early as 12 months in high-risk children as long as 6 months have passed since the third dose.)	Hib (Sometime between 12 and 15 months.)	HepA (In 2 does, between 12 and 23 months)
2 years old				In children who have not been fully vaccinated.
4 to 6 years	Varicella	DTaP
11 to 12 years	Varies. (If previously missed, two doses should be given at least four weeks apart.)			In adolescents through age 18 in selected areas.

Age	Hepatitis B (Hep-B)*	Measles, Mumps, Rubella (MMR)	Pneumococcal Vaccine (PCV7)	Polio (Inactive virus) (IPV)*	Human Papillomavirus (HPV)
Birth	Hep-B immediately after birth. (This is very important when mothers are infected.) No later than 2 months in children of noninfected mothers. *
2 months	Hep-B some time between 1 and 4 months depending on risk. *		PCV7	IPV*
4 months			PCV7	IPV*
6 months	Hep-B some time between 6 and 18 months. *		PCV7	IPV* (Advised at some point between 6 and 18 months.) *
12 to 15 months	Varies.	MMR (Some time between 12 and 15 months.)
2 years old			PCV7 -- 1 dose for children not previously vaccinated.
4 to 6 years		MMR	PCV7 -- 1 dose in high-risk children.	IPV*
11 to 12 years	Hep-B (If vaccinations were previously missed). Two or 3 doses a few months apart.	MMR (If vaccinations were previously missed).			HPV (Females)
* A one-shot combination vaccine (Pediarix) has been approved that covers polio, hepatitis B, diphtheria, pertussis, and tetanus (DTaP) and should simplify the immunization process. It would be given as a single injection at 2, 4, and 6 months with booster shots given at 12 to 15 months and 4 to 6 years. **All children aged 6 - 59 months should receive an annual flu shot. Children older than 5 years of age who have chronic medical conditions should also receive the influenza vaccination. The flu shot is not approved for children younger than 6 months of age.

Of great concern are anti-immunization organizations and websites, which were formed mostly because of unsubstantiated reports linking small numbers of serious problems to some vaccines. The following watchdog systems are now in effect to monitor side effects from vaccination:

VAERS (Vaccine Adverse Event Reporting System) is a government service that registers all adverse events reported after vaccination, including those not related to the vaccine. It is useful for surveillance but has limitations. For example, the service may record the same case more than once. In addition, more serious events that occur after a vaccination are more likely to be reported than later and milder events, and such events are not necessarily linked to the vaccine.
VSD (Vaccine Safety Datalink) is a linked database that analyzes the records of more than 5 million patients each year. It is more accurate than VAERS, although the information it contains is not as timely.
The CDC has established the national network of Clinical Immunization Safety Assessment (CISA) Centers. It will provide services to physicians to help them evaluate and manage patients who may have had a side effect.

Studies using these systems are ongoing and none to date have confirmed reports of any significant association between most vaccines and severe side effects that would outweigh the benefits of these important and lifesaving agents.

No vaccine is 100% safe. Allergic and serious reactions are possible. In 2 cases, the early polio vaccine and the rotavirus vaccine, problems did occur, and some were serious. It is important to note, however, that even in these cases, the vaccines were withdrawn and the severe events still were far fewer than the number of lives saved.

The focus on vaccination side effects is ironic due to the fact that reports of such adverse effects outnumber the number of actual infections. Because vaccinations have been in existence for so long, today's parents have no direct knowledge of the consequences of these dreaded infections, which killed or severely sickened millions of children in the past.

It should be noted that studies are reporting that the risk for infection increases significantly in children who are not vaccinated. There is also a rise in infections among immunized children, suggesting resistance to the vaccines.

Infants often accept the first injection easily, since they are not expecting it. It gets more difficult, however, with each additional shot. Simply providing love and warmth can help children of all ages tolerate immunizations.

Additional tips:

Do not lie and tell an older child that a shot will be painless. Some health care providers suggest telling them that it stings a little and to count to 5 while it is being administered.
Ask the doctor if it is OK to give the child a dose of acetaminophen (Tylenol) before or after a shot. Ibuprofen (Motrin, Advil) or other non-aspirin pain relievers may be acceptable alternatives. (Children should NEVER take aspirin after vaccinations.)
Ask the doctor about EMLA cream, a topical anesthetic containing lidocaine and prilocaine. This product can be applied about an hour before the injection. (Note: EMLA may interact with acetaminophen and certain vaccinations, so be sure to check with the doctor first.)
A cooling spray may work as well as EMLA and have fewer side effects.
Longer needles, rather than shorter ones, may help reduce pain. One study reported that using longer needles decreased redness at the injection site by about two-thirds. Parents may want to ask their doctor about this study.
Have your child take a deep breath right before the shot and blow out very hard while it is being given. One study reported very good results with this breathing technique.
Give a sweet fluid before the shot and a little reward, such as a lollipop, immediately after the shot. Sugar actually has mild pain relieving properties for infants.

Diphtheria, Tetanus, and Pertussis

Diphtheria. Diphtheria is caused by the bacterium Corynebacterium diphtheriae, which can occur as either a toxic or nontoxic strain. When only the skin is involved, it is known as cutaneous diphtheria, and is likely to be a nontoxic strain. If the toxic strain affects the mucus linings in the body, such as the throat, diphtheria becomes life threatening. Between 1900 and 1925, diphtheria infected 200,000 people every year and killed between 5 - 10% of them, mostly the very young and very old. Because of immunizations, only one case was reported in 2000.

Tetanus. Tetanus is a disease that causes severe muscular contractions and convulsions. It is caused by a powerful toxin secreted by the bacterium Clostridium tetani. The bacterium is anaerobic, which means it lives without oxygen. People become infected by this dangerous bacterium through wounds in the skin. It is fatal in 15 - 40% of cases. Only 35 cases were reported in the U.S. in 2000, mostly in adults. One case, however, occurred in a 12-year-old boy whose parents refused to vaccinate him.

Pertussis. Pertussis (whooping cough) was a very common childhood illness throughout the first half of the 1900s. The disease is very easily spread from one person to another, and it is most severe in babies. Because of immunizations, which began in the 1940s, cases of whooping cough reached an all-time low of 1,010 in 1976 in the U.S. The incidence has risen recently, with almost 25,837 cases reported in 2004. Many more cases are reported worldwide. Nearly half of pertussis cases now occur in people 10 years of age or older, perhaps due to waning immunity in adolescents and adults. Such cases may be greatly underreported. One study suggested that as many as 25% of adults who see a doctor for persistent cough may actually have pertussis, but it may go undiagnosed because symptoms are usually mild and adults are unlikely to have the classic whooping cough. This is of some concern, because such adults may unknowingly infect unvaccinated children. The younger the patient, the higher the risk for severe complications, including pneumonia, seizures, and even death. Children younger than 6 months are at particular risk because even with vaccination, protection is incomplete.

The Initial Vaccination. Diphtheria, tetanus, and pertussis (DTaP) are very different disorders, but a combination injection has been routinely given to children since the 1940s. Since the early 1990s, the standard vaccine is DTaP, which uses a form of the pertussis component known as acellular pertussis that consists of a single weakened toxoid. (The older vaccine, DTP, includes a pertussis vaccine that contains multiple toxins against different variants of the disease. DTaP is just as effective but has fewer side effects than DTP.)

Pertussis is increasing among adults; the Centers for Disease Control data indicate that there were more than 25,000 cases of pertussis in 2004.

The Booster. Protection against diphtheria and tetanus from the vaccine lasts about 10 years. At that point a booster may be given against tetanus and diphtheria (Td). The Td vaccine contains the standard dose against tetanus and a less potent one against diphtheria and does not contain the pertussis component. In April 2005, the FDA approved the first pertussis booster shot ("Boostrix") for kids aged 10 - 18. Boostrix is a lower dose of infant pertussis vaccine. The infant pertussis vaccine can start to wear off after about 5 years, and some previously immunized teens and adults can get a mild form of the disease. The booster shot may help reduce the number of pertussis cases in adolescents and adults. The FDA also approved in 2005 another novel booster vaccine called Adacel for protection against tetanus, diphtheria and pertussis from adolescence through adulthood.

DTaP Schedule in Childhood. All children younger than 7 years old should receive the DTaP vaccine. In general, the vaccinations are given as follows:

Infants receive a series of three vaccinations at 2, 4, and 6 months of age (doctors may delay a vaccination in infants with suspected neurologic problems until their neurologic situation is clarified, but no later than their first birthday). Children with neurologic problems that have been corrected can be vaccinated.
A fourth dose is given between 15 and 18 months. (Infants at higher risk, such as those exposed to an outbreak of pertussis, may be given this vaccination earlier.) Of note, children who receive their third shot late in the schedule are at higher risk for skipping the fourth dose than children who were on schedule. Parents should be sure to adhere to a schedule that includes the fourth shot, even if they were late on the third.
A fifth dose is given at 4 - 6 years. This fifth shot now usually includes a vaccine against H. influenzae as well.
Children between the ages of 11 and 15 years old should receive a tetanus and diphtheria (Td) booster shot.
Boostrix is a single-dose booster that can be given to children age 10 - 18 years.
Adacel is a single-dose booster Tdap for people age 11 - 64 years.

If a child has a moderate or severe current or recent fever-related illness, vaccinations should be postponed until after recovery. Colds or other mild respiratory infections are no cause for delay. Parents should not be unduly concerned if the interval between shots is longer than that recommended. The immunity from any previous vaccinations persists, and the doctor does not have to start a new series from scratch.

Recommendations for Adults. All vaccinated adults should have a Td booster at least every 10 years throughout their lifetimes. One study reported that fewer than half of adult Americans ages 20 and older were protected against both tetanus and diphtheria, and immunity rates were even lower in those over 70. The results indicate that many people are not getting routine boosters.

Other recommendations for adults are as follows:

Adults who did not receive the primary childhood vaccinations should have the tetanus, diphtheria, and pertussis (Tdap) vaccine, approved in 2005, every 10 years.
Unvaccinated pregnant women should receive two doses of Td, properly spaced, and previously vaccinated women should have a booster.

Preventing Tetanus in Individuals with Wounds. Wounds that put patients at highest risk for tetanus are puncture wounds or wounds contaminated with dirt, feces, or saliva. However, any patient who requires medical care for any wound is a candidate for tetanus immunity.

Some considerations for tetanus vaccinations in wounded people are as follows:

A booster is needed if the last shot was 5 or more years before the injury.
Children under 7 are usually given DTP if they are not fully vaccinated.
Most individuals are given the Td vaccination if they have been vaccinated.
Older patients who had experienced an allergic response to a previous tetanus booster may be given the tetanus immune globulin (TIG).

Allergic Reactions. In rare cases, people may be allergic to the older diphtheria, tetanus, and pertussis vaccine, DTP. Parents should tell their doctor if their children have any allergies. The newer vaccine, DTaP, may pose a slightly higher risk for an allergic reaction than the older vaccine, DTP. Children who have severe responses should not be given further vaccinations. A rash that occurs after a dose of DTP is of little consequence. In fact, it does not usually indicate an allergic response but only a temporary immune reaction and does not usually recur with subsequent shots. It should be noted that no deaths have been reported from allergic reactions, even severe (anaphylactic) ones, to the DTP vaccine.

Pain and Swelling at the Injection Site. Children may feel pain at the injection site. In some cases, a small lump may remain at the site for several weeks. Placing a clean, cool washcloth over any swollen, hot, or red area can help. Children should not be covered or wrapped tightly in clothes or blankets.

The risk for swelling, including of the whole arm or leg, increases with subsequent injections, particularly the fourth and fifth doses. If possible, parents should request that their children receive the same vaccine brand each time to help reduce the risk of side effects.

Feverand Other Symptoms. A child may develop a mild fever, irritability, drowsiness, and loss of appetite after a shot.

The following remedies may be helpful:

Acetaminophen (for example, Children's Tylenol) and a sponge bath in lukewarm -- NOT cold -- water may help relieve fever and pain.
The doctor may suggest that children who have had previous high fevers or other reactions to the shot be given acetaminophen at the time of the vaccination and every 4 hours afterward for 24 hours. (The doctor will determine the dosage according to the weight of the child.)
Children should NEVER be given aspirin.

Fevers that should cause concern include the following:

The older DTP vaccine posed some risk for fever-related seizures on the day of vaccination. The newer DTaP has significantly reduced this side effect. Any very high fever in children (over 105° F) that causes convulsions should be reported immediately to the doctor. Although frightening, such fever-related seizures are uncommon and rarely have any long-term effect, and a recurrence after a subsequent vaccination is very unlikely.
A new fever that develops 24 hours after the vaccination, a fever that persists for longer than 24 hours, or seizures without fever are most likely due to other causes.

Hypotonic-Hyporesponsive Episode (HHE). HHE is an uncommon response to the pertussis component and occurs within 48 hours of the injection in children under 2. The child usually starts out feverish and irritable and then becomes pale, limp, and unresponsive. Breathing is shallow, and the child's skin may turn bluish. The reaction lasts an average of 6 hours and, although it is frightening, virtually all children return to normal. This side effect is less common since the introduction of the DTaP vaccine, but it can still occur.

Neurologic Effects in Pertussis Component. Of concern have been a few reports of permanent neurologic abnormalities that have occurred after children have been vaccinated. Such reports include attention deficit disorder, learning disorders, autism, brain damage (encephalopathy), and even death.

It is well known that the diphtheria and tetanus components cause no adverse neurologic effects, so some people suspect the pertussis component. However, many major studies, including an important statistically sound analysis in 2002, found no causal relationship between neurologic problems and the pertussis vaccination. In fact, one study indicated that children who received pertussis vaccine had fewer problems in school than those who were not vaccinated, regardless of family income levels. Studies on the newer DTaP have reported no safety concerns to date.

There may be some exceptions. Studies now suggest that in cases where neurologic problems have been strongly linked to the vaccination, high fevers -- not immunization -- are responsible. Children with known neurologic abnormalities may also be at risk for an outbreak of symptoms 2 or 3 days after the vaccination. Such a temporary worsening of their disease rarely poses a danger to the child. (Some experts suggest that children who have new neurologic events following their shot may already have a preexisting impairment, such as epilepsy, which is revealed -- but not caused -- by the vaccine.) To date, there is no proof that the pertussis vaccine causes these neurologic events, which, in any case, are so infrequent as to be nearly statistically unmeasurable.

Important Note: Unwarranted fears of side effects from vaccinations can be dangerous. In England such fears have caused a significant decline in immunization rates since the 1970s. Outbreaks of whooping cough have occurred as a result, causing a number of deaths and brain damage in many children. Small babies are particularly endangered if they become infected from older unvaccinated children (who usually have a mild disease).

Call the doctor immediately if a child has any of the following symptoms.

Extremely High Fever. A rectal temperature of 105° F or higher. (Temperatures taken under the arm or by mouth often register lower than actual temperatures.)
Inconsolable Crying. The child has been crying for over 3 hours without stopping or has a cry that isn't normal, such as being high-pitched.
Convulsions. The child's body starts shaking, twitching, or jerking. This is usually in response to a high fever. Place the child face down with the head to one side, protecting the head from hitting anything hard. Be sure the child can breathe freely. Seizures caused by fevers usually last less than 15 minutes.
Shock. The child collapses, turns pale, and becomes unresponsive.
Severe Allergic (Anaphylactic) Reaction. Swelling in the mouth and throat, wheezing and breathing difficulties, dizziness. The child collapses or is pale and limp.

Call the doctor if the following symptoms persist for more than 24 hours:

The injection site is still red and tender.
Fever does not go down.
The child is still fussy.

Measles, Mumps, and Rubella

Measles. Measles, one of the most contagious of all human infections, used to be a very common childhood disease. Most cases go away without serious complications. In severe cases, however, measles can cause pneumonia, and in about 1 out of 1,000 cases it can lead to encephalitis (inflammation in the brain) or death. The risk for these severe complications is highest in the very young and very old. In pregnant women, measles increases the rates for miscarriage, low birth weight, and birth defects.

Measles outbreaks still occur in the United States, usually among groups of people who do not believe in immunizations or in areas where immunization levels have fallen below the critical level. It is a fairly serious childhood infection that is recognized by the rash (as seen here), Koplik spots (small white spots on red background), red eyes, photophobia (sensitivity to light), and coughing.

Aggressive vaccination programs have reduced the incidence of measles in the U.S., to a low of 86 cases in 2000, most imported from other countries. Full-blown measles cases among unvaccinated children still remain a serious international problem, with 42 million cases and over 1 million deaths in small children each year.

Mumps. Mumps is at record lows in the US, with only 338 cases reported in 2000. In about 15% of cases, mumps affects the lining of the brain and spinal cord, although this is usually not ultimately harmful. Swelling of the testicles occurs in between 20 - 30% of males who have reached puberty, although sterility is rare. Deafness in one ear occurs in one patient out of 20,000 with mumps.

Click the icon to see an image of the meninges of the brain.

Rubella (German Measles). When rubella, commonly known as German measles, infects children or adults, it causes a mild illness that includes a rash, enlarged lymph nodes, and sometimes a fever. If a pregnant woman is infected during her first trimester, however, her baby has a 80% chance for developing birth defects, including heart abnormalities, cataracts, mental retardation, and deafness.

Click the icon to see an image of a cataract.

Before the vaccine became available, about 56,000 cases of rubella occurred annually in the U.S. Vaccination programs have dramatically reduced the number of cases to a low of 176 in 2000, but between 6 - 11% of adults are still susceptible, particularly unvaccinated Hispanic Americans who were born outside of the U.S.

Click the icon to see an image of rubella.

Safe and effective live-virus vaccines for measles, mumps, and rubella have been developed over recent decades. They are usually combined in children as the measles, mumps, and rubella (MMR) vaccine. Individual live-virus vaccines or the combined MMR may be given to adults, depending on their risk factors.

Measles-Mumps-Rubella (MMR) Vaccine in Early Childhood. The combined MMR vaccine should be given in two doses:

Between ages 12 and 15 months for the first dose. (Some doctors believe that the vaccine may be effective and safe in children younger than 9 months who are in areas of measles outbreaks. It should be noted that there were only 86 reported cases of measles in the U.S. in 1999.)
Between ages 4 and 6 years for the second dose. (Children who receive only one dose at 15 months or older have five times the risk of measles compared to those who had two doses.)

Measles-Mumps-Rubella (MMR) Vaccine in Adolescents and Adults. The general recommendations for adult MMR vaccinations are as follows:

Most people born before 1957 have experienced these once-common childhood diseases and do not require vaccination.
All unvaccinated people born after 1956 who did not already have measles and mumps should be given two doses of the live MMR vaccine administered at least 1 month apart.
Many people received an inactivated measles-virus vaccine in the early 1960s or an inactivated mumps-virus vaccine between 1950 and 1978; such people need revaccination with two doses of the live MMR vaccine. (This will cause no harm even if someone had a previous live-virus-mumps vaccination.)
The American Academy of Pediatrics now recommends the live-virus MMR vaccine for HIV-infected children, teenagers, and young adults, except for those who are severely immunocompromised. At this time, however, the vaccine appears to be safe in HIV-infected children, and it should be stressed that measles is very dangerous in this population.

Rubella Vaccinations During Pregnancy. It is particularly important for any unvaccinated nonpregnant woman who wants children to be vaccinated against rubella. It is recommended that women wait at least 28 days after vaccination to start trying to conceive. Except under very special circumstances, no live-virus vaccine, especially MMR, is given to an already pregnant woman, since there is a theoretical risk for birth defects from the rubella vaccine. Fortunately, the risk is low. In fact, studies have reported no increase in birth defects in women who were inadvertently vaccinated for rubella early in their pregnancy.

Common side effects from the MMR vaccination include fever, rash, and joint pain. Children are more likely to experience such side effects from the second dose (at 10 - 12 years) than from the first (at 4 - 6 years).

Fever. About 5 - 15% of people who are vaccinated with any live measles virus vaccine develop a fever of 103° F or greater, usually between 5 and 15 days after the vaccination. It usually lasts 1 or 2 days but can persist up to 5 days. In very young children, seizures can occur from high fever 8 - 14 days after vaccination, but they are rare and almost never have any long-term effects.

Swollen Glands. The live-mumps vaccine can cause mild swelling in the glands that are situated near the ears.

Joint Pain. Up to 25% of women have joint pain 1 - 3 weeks after a vaccination with a live-rubella virus; it lasts for 1 day to 3 weeks. Such pain does not usually interrupt daily activities. Rarely, it recurs or becomes persistent.

Allergic Reaction. People who have known anaphylactic allergies (very severe reactions) to eggs or neomycin are at high risk for a severe allergic response to the MMR vaccine. People with allergies that do not cause anaphylactic shock to these substances are not at higher risk for a serious allergic reaction to the vaccine. Mild allergic reactions may occur in some people, including rash and itching. A rash occurs in about 5% of people who are vaccinated with a live-measles vaccine. A live-mumps vaccination has caused rash and itching, but these symptoms are usually mild.

Interaction with Tuberculosis Test. The live-measles vaccine may interfere with a tuberculosis test, so the two should be administered at least 4 - 6 weeks apart. No evidence exists that the vaccine has an adverse effect on tuberculosis itself.

Mild Infection. One study suggests that a mild form of measles that has no symptoms may develop in previously immunized people who are exposed to the virus, although this mild infection may not be significant.

Idiopathic Thrombocytopenic Purpura (ITP). In about 1 in 22,300 doses, MMR can cause a rare bleeding disorder called idiopathic thrombocytopenic purpura (ITP). This can cause a purple, bruise-like discoloration that can spread across the body, nose bleeds, or tiny red spots. It is nearly always mild and temporary. (Of note, the risk for ITP is much higher with the actual infections, particularly rubella.)

Note: Unsubstantiated Reports of Neurologic Side Effects and Decline in Immunization. Much controversy has arisen over unsubstantiated reports of neurologic side effects attributable to MMR. This is of great concern since such reports have resulted in a decline in immunizations in certain areas, notably affluent areas in England where the vaccination rate has dropped from 92% in 1996 to 84% currently. Here, measles outbreaks are now climbing, and doctors fear that unless immunization rates increase rapidly, case numbers will significantly increase. In these and other regions, some parents mistakenly believe that the dangers of immunization outweigh a dangerous childhood illness that only older people remember. It should be strongly noted that measles still cause about 745,000 deaths in unvaccinated children who live in underdeveloped countries, primarily in Africa.

Most publicity has centered on a possible link between the MMR vaccine, which was introduced in 1988, and a variant of autism that includes inflammatory bowel disease (IBD) and impaired behavioral development. Such findings have been rigorously reviewed and refuted in a number of well-conducted studies. Of special note, a 2002 analysis of vaccination records of children born between 1979 and 1998 found no higher incidence in autism, with or without behavioral problems and gastrointestinal disorders. In the study, there was a link between impaired behavioral development and bowel problems, but they were not related to the vaccine.

Despite considerable publicity, there is no evidence linking MMR vaccination with the development of autism. The Centers for Disease Control & Prevention website provides extensive information on this matter. The popular media has incorrectly reported the possible link between autism and MMR as causing a split in the scientific community, but virtually all experts refute any association. In fact, reports of symptoms related to autism increased only after widespread publicity of this supposed side effect.

The potential benefits from receiving the MMR vaccine far outweigh the potential adverse effects. Measles, mumps, and rubella are all very serious illnesses and each may have complications resulting in lifetime disabilities or even death. The incidence of such complications, related to having the actual diseases, is far greater than the potential of developing serious, or even moderate, adverse effects due to the MMR vaccine.

Click the icon to see an image of inflammatory bowel disease.

Varicella-Zoster Virus (Chickenpox)

Chickenpox (caused by the varicella-zoster virus) is one of the most contagious childhood diseases. Nearly every unvaccinated child becomes infected with it. The affected child or adult may develop hundreds of itchy, fluid-filled blisters that burst and form crusts.

The infection rarely causes complications in healthy children, but it is not always harmless. Five out of every 1,000 children are hospitalized and, in rare cases, it can be fatal. Before the vaccination became widespread, chickenpox resulted in about 11,000 hospitalizations and 100 deaths a year.

This is a close-up picture of chickenpox. Early chickenpox lesions consist of small red papules that quickly fill with a yellowish or straw colored fluid to form small blisters (vesicles), as seen in this photograph. Later, these vesicles will rupture, forming shallow erosions that crust over and then ultimately heal.

Click the icon to see an x-ray of pneumonia following exposure to chickenpox.

Chickenpox can be especially severe in adults and very serious in anyone with a compromised immune system. In addition, the varicella virus (which persists after the childhood disease) erupts as a painful and distressing condition called herpes zoster (shingles) in about 20% of adults with a history of chickenpox. Chickenpox itself usually occurs only once, although a few cases of mild second infections, marked by the telltale rash, have been reported in older children years after their first infection.

Click the icon to see an image of the shingles.

A live-virus vaccine (Varivax) produces persistent immunity against chickenpox. Data show that the vaccine can prevent chickenpox or reduce the severity of the illness even if it is used within 3 days, and possibly up to 5 days, after exposure to the infection.

Recommendations for the Vaccine in Children. The vaccine against chickenpox is now recommended in the U.S. for all children between the ages of 18 months and adolescence who have not yet had chickenpox. Children are given one dose of the vaccine. Two doses 1 - 2 months apart are given to people over 13 years of age. To date, more than 75% of children have been vaccinated.

Doctors recommend that the chickenpox vaccine be given at the same time as the measles-mumps-rubella (MMR) vaccine or that there is a delay of at least 1 month between the two vaccinations. (If the chickenpox vaccination is given within that 30-day period -- but not at the same time -- there is a higher risk for a breakthrough infection later on.)

A chickenpox vaccine is part of the routine immunization schedule. It is about 100% effective against moderate or severe illness, and 85 - 90% effective against mild chickenpox. Parents often express concern that the immunity from the vaccine might not last. The chickenpox vaccine, though, is the only routine vaccine that does not require a booster.

Recommendations for the Vaccine in Adults.

Some doctors suggest that every healthy adult without a known history of chickenpox be vaccinated. In general, however, the following adults should consider vaccinations:

Older people without a history of chickenpox and who are at high risk of exposure or transmission (such as hospital or day care workers and parents of young children)
People who live or work in environments in which viral transmission is likely
Nonpregnant women of childbearing age
Adolescents and adults living in households with children
International travelers

As with other live-virus vaccines, the chickenpox vaccine is not recommended for the following:

Pregnant women (including the 3 months prior to pregnancy). Of note, an encouraging study suggested that pregnant women who were inadvertently vaccinated did not face a higher risk for birth defects in their offspring.
People whose immune systems are compromised by disease or drugs (such as after organ transplantation). The vaccine is being studied, however, for its safety in some of these patients, particularly children with cancer or other high-risk conditions. Experts report that it is safe in children with acute lymphoblastic leukemia (ALL), who should receive two doses. Certain children who are HIV positive may be candidates for the vaccine. An inactivated varicella vaccine may be safe and effective in patients undergoing bone marrow transplants, when given before and after the operation.
Most patients who cannot be vaccinated but are exposed to chickenpox are given immune globulin antibodies against varicella virus. This helps prevent complications of the disease if they become infected.

Discomfort at the Injection Site. About 20% of vaccine recipients have pain, swelling, or redness at the injection site.

Mild Rash and Risk of Transmission. The vaccine may produce a mild rash within about a month of the vaccination, which has been known to transmit chickenpox to others. Individuals who have recently been vaccinated should avoid close contact with anyone who might be susceptible to severe complications from chickenpox until the risk for a rash has passed.

Severe Side Effects. Between 1995 and 2001, 759 serious adverse effects were reported. Such events included seizures, pneumonia, anaphylactic reaction, encephalitis, Stevens-Johnson syndrome, neuropathy, herpes zoster, and blood abnormalities. Anecdotal reports have found a higher association of side effects when varicella vaccine is given at the same time as the measles, mumps, and rubella (MMR) vaccination. Because combined vaccinations are being developed, such effects should be closely studied.

There is intense debate over the long-term protection of the vaccine. The incidence of breakthrough infections after vaccination stimulates the controversy. It should be noted, however, that evidence is showing improvements in quality of life and better survival rates since the introduction of the vaccine. Any negative studies to date on long-term effectiveness simply raise the question of the need for booster or higher doses -- not the elimination of the vaccine altogether.

Long-Term Protection in Vaccinated Children. Most studies suggest that the vaccine is not wholly effective in up to 30% of vaccinated children. However, they also report if chickenpox occurs, more than 95% of the cases are mild. It is also usually less contagious. In such people, the infection appears to be caused by a wild virus, not a reactivation of the vaccine. (Of concern was a 2002 study of a day care center reporting a much higher rate -- 56% -- of break-through infection, with only 86% of cases being mild. The implications of this study are unclear.) The longer the interval since vaccination occurs, the higher the risk for a breakthrough infection.

This does not necessarily mean, however, that children who are vaccinated eventually lose total immunity. A breakthrough infection is often due to issues with the primary vaccine (improper storage, low potency, the duration between the chickenpox and measles, mumps, and rubella vaccines being less than a month) or the child's history (having asthma, being less than 14 months at the time of vaccination). Nevertheless, there is also some evidence that either having the vaccination or even having chickenpox itself is not as protective against a later infection as experts have thought.

Long-Term Protection in Vaccinated Adults. The protective effects for adults are even less clear. An encouraging 2002 study of adults vaccinated between 1979 and 1999 reported that 9% developed chickenpox months to years after their last vaccination. The length of time since the vaccination did not seem to affect whether the adults would catch chickenpox or not. (Nearly half of those had been exposed to the disease in their homes.) In all cases, infection was mild, with none of the serious complications of adult chickenpox.

Vaccine's Effect on Shingles. A primary concern is whether the vaccine protects against shingles later on, particularly in people who have breakthrough infections -- however mild. As more and more children get vaccinated, the actual protection of the vaccine and the implication of the breakthrough infection will become clearer.

[For more information, see In-Depth Report #82: Shingles and chickenpox (Varicella-zoster virus).]

In September, 2005, the Food and Drug Administration approved a combination vaccine to protect against measles, mumps, rubella, and chickenpox. Proquad, produced by Merck & Co., protects against all four infections with one shot, thus sparing young children from multiple painful injections. Proquad is approved for use in children from 12 months to 12 years of age. Proquad was studied in four randomized trials involving 5,446 healthy children aged 12 - 23 months received Proquad. Proquad’s immune response rates were 97.4% for measles, 95.8 - 98.8% for mumps, 98.5% for rubella, and 91.2% for chickenpox, similar to the rates induced by the concomitant administration of single doses of M-M-R II and Varviax at separate injection sites in 2,038 children.

Varicella-Zoster Virus (Shingles)

Shingles is a painful infection caused by the varicella zoster virus, the same virus responsible for chickenpox. Once a person has chickenpox, the virus lies dormant in the body. It can emerge years later as shingles.

Shingles causes a painful, red, and sometimes blistery rash to form on the body or face. The disease can cause intense pain, called post herpetic neuralgia. Other symptoms include fever, headache, and chills. In rare cases, complications, such as pneumonia, blindness, and brain inflammation (encephalitis), can occur. Shingles is most common in adults over age 50.

In May 2006, the U.S. Food and Drug Administration licensed the herpes zoster vaccine (Zostavax) for the prevention of shingles. The vaccine can reportedly cut the incidence of shingles in half for adults over age 60.

Recommendations for the Vaccine in Adults. All adults age 60 or older should get a single dose of the herpes zoster vaccine, regardless of whether they have previously had shingles.

The following people should not receive the herpes zoster vaccine:

Anyone who has a weakened immune system due to HIV/AIDS or cancer of the lymph, bone, or blood, or due to treatments such as radiation or corticosteroid drugs
Women who are pregnant, or anyone who is in close contact with a pregnant woman who has not had chickenpox
Children -- they should receive only the chickenpox vaccine

Redness, pain, and swelling. About 1 out of every 3 people who get the vaccine have mild redness, soreness, swelling, or itching at the injection site.

Headache. About 1 in 70 people experience headache after taking the vaccine.

There have been no serious side effects reported with the shingles vaccine.

Research has found that the herpes zoster vaccine reduces the incidence of shingles by about 50%. The benefit is as high as 64% in people ages 60 - 69. In people who are vaccinated but still develop shingles, the vaccine reduces the duration of the pain involved with the disease.

One 2007 study found that doing tai chi might boost the immune response to the vaccine. According to the study, people aged 59 - 86 who took part in a 16-week tai chi program had immunity similar to that of 30- and 40-year-old adults who had been vaccinated. Combining tai chi with the vaccine increased the effects of the vaccine by about 40%.

Hepatitis A

The hepatitis A virus infected an estimated 56,000 people in 2004. Hepatitis A, formerly called infectious hepatitis, is always acute and never becomes chronic. The virus is excreted in feces and transmitted by contaminated food and water. Eating shellfish taken from sewage-contaminated water is a common means of contracting hepatitis A. It can also be acquired by close contact with individuals infected with the virus. It is estimated that 11 - 16% of reported cases occur among children or employees in daycare centers or among their contacts. The hepatitis A virus does not directly kill liver cells, and experts do not yet know how the virus actually injures the liver.

A fly may act as a mechanical vector of diseases such as hepatitis A. The fly may carry the infective organism on its feet or mouth parts and contaminate food or water, which a person then consumes. A biological vector actually develops an infective organism in its body and passes it along to its host, usually through its saliva. A fly can be a biological vector, as in the transmission of leishmaniasis by the sandfly.

All children should get 2 doses of the hepatitis A vaccine starting at 1 year, according to CDC recommendations. The doses should be given at least 6 months apart. Others who should be vaccinated against hepatitis A include travelers to developing countries, people living in communities where outbreaks occur, people with blood-clotting disorders, sexually active homosexual men, and health care workers exposed to the virus. People with chronic liver disease, including those with hepatitis C, should also be vaccinated, particularly if they have not been exposed to hepatitis A, since the infection can cause liver failure in these patients.

The hepatitis A vaccine can be given along with immune globulin and other vaccines. Individuals should also receive immune globulin if they are exposed within 4 weeks of the vaccination. A combined vaccine against both hepatitis A and B is now available as well for those at high risk for both these infections. People should get 3 doses of this vaccine, and the last dose should be given 6 months after the first dose.

Side Effects. The vaccine is very safe and effective, although allergies can occur. The most common side effects reported are soreness at the injection site, headache, and general malaise.

Click the icon to see an image about hepatitis A immunization.

Hepatitis B

About 2 billion people have been infected with the hepatitis B virus (HBV) worldwide, and each year 1 million people die, mostly due to cirrhosis and liver cancers that develop in the chronic form of this disease. In the U.S., about 1.25 million people have chronic hepatitis B.

Hepatitis B is also known as serum hepatitis. It spreads through blood and sexual contact. The infection is seen with increased frequency among intravenous drug users who share needles and among the homosexual population. This photograph is an electronmicroscopic image of hepatitis B virus particles. (Courtesy of the CDC.)

Pregnant women with hepatitis B can transmit the virus to their babies. Even if they are not infected at birth, unvaccinated children of infected mothers run a 60% risk of developing hepatitis B before age 5. Although hepatitis B infections have dropped 95% since routine immunization began in the early 1990s, there are still children who aren't immunized, and the disease persists. Universal vaccination against this disease during childhood is very important.

Several inactivated virus vaccines, including Recombivax HB, GenHevac B, Hepagene, and Engerix-B, can prevent hepatitis B. Twinrix is a vaccine against both hepatitis A and B. They are safe, even for infants and children. Vaccination programs are proving to reduce the risk for liver cancer.

Click the icon to see an image of hepatitis B.

Hepatitis B Vaccine for Early Childhood. Experts now recommend that all infants and children not previously vaccinated be immunized by the time they reach seventh grade. Typical schedules for hepatitis B vaccinations in childhood are as follows:

All infants should receive the hepatitis B vaccine soon after birth and before hospital discharge. (The first dose may be delayed if the mother has no evidence of infection, but only with the doctor's permission.) The second dose should be given at 1 - 2 months; and the third between 6 and 18 months (at least 16 weeks after first dose and 8 weeks after second dose). (A fourth dose may also be given if any of the previous doses was a combination vaccine.) This is a safe vaccine, even in newborns, and parents should be sure their infants are immunized.
Infants of mothers infected with hepatitis B should be treated with immune globulin plus the hepatitis vaccine within 12 hours of birth. The second dose should be given at 1 - 2 months and the third at 6 months. Infants should be tested for antibody status at 9 - 18 months to see if they are chronic virus carriers or need to be revaccinated. Immunization rates are still too low in this group.
When it is not known if a mother is infected, the infant should receive the vaccine within 12 hours of birth. The mother's blood should then be tested right away. If she is infected, the infant should receive immune globulin within 1 week of birth.
Children who are 11 - 12 and who have not been immunized should receive 2 or 3 doses of the vaccine (depending on the brand) given over a few months.

Hepatitis B vaccine protection may wane over time. According to a 2007 study, 40% of adolescents who had received a first dose of the vaccine as newborns had declining immunity to the disease by age 14. As of now, routine booster shots are not recommended because more research is needed on the subject. Booster shots may be recommended for those at risk, such as from sexual exposure.

Hepatitis B Vaccine for Adults. The following adults are at very high risk and should be vaccinated:

Health care and public safety workers who may be exposed to blood products. Such individuals have a risk for hepatitis B that ranges from 15 - 30%.
People in the same household ashepatitis B-infected individuals. (Unvaccinated people who have had intimate exposure to people with hepatitis B may be protected with immune globulin, which is sometimes administered with the vaccine.)
Travelers to countries with a high incidence of hepatitis B infection.
Patients who require transfusions and have not been infected with hepatitis B. (Those with blood clotting disorders should have the vaccination administered under the skin, not injected in the muscle.)
Sexually active individuals with multiple partners.
People with any sexually transmitted diseases.

Other people at risk who would benefit from vaccinations include:

Patients and workers in mental institutions
Morticians
Patients undergoing hemodialysis. (These people may need larger doses or boosters; they also may need to be revaccinated if blood tests indicate they are losing immunity.)
People who use injected drugs
Pregnant women at risk for the virus. (There is no evidence that the vaccine is dangerous to the fetus.)
People receiving treatments or who have conditions that suppress the immune system may need the vaccination, although its benefits for this group are unclear except for those at high risk, such as people with HIV or spleen abnormalities.

Click the icon to see an image of the immune system structures.

The regimen in adults is typically 3 doses given over 6 months. One study reported that older adults would benefit from a fourth dose without incurring serious side effects. People who abuse alcohol may need higher doses.

A small percentage of people do not develop immunity, even after a vaccine has been given repeatedly. A more potent vaccine is proving to be effective for these people; it loses its effect after 5 years in about one-third of those who receive it.

Soreness. Soreness at the injection site is the most common side effect.

Nerve Inflammation. There have been some reports of nerve inflammation after vaccinations for hepatitis B, and some questions about multiple sclerosis. A review article published in 2006 found no evidence that hepatitis B vaccine is associated with multiple sclerosis, sudden infant death syndrome, or chronic fatigue syndrome. Earlier studies also found no evidence linking the vaccine to multiple sclerosis. A 2007 study found that the vaccine doesn't increase the risk for rheumatoid arthritis.

Because of even a small theoretical risk of nerve damage in infants, some groups oppose the vaccination in children who are not in high-risk groups. Worldwide, 65 million people with chronic hepatitis are expected to die from liver disease and vaccinations are saving lives. For example, in Taiwan, where infection rates are high and infants are at risk for hepatitis B from infected mothers, vaccination programs have significantly reduced the risk for liver cancer. [For more information see In-Depth Report #59: Hepatitis.]

Pneumococcal Pneumonia

The pneumococcal bacterium (also called Streptococcus pneumoniae or S. pneumoniae ) is responsible for many respiratory infections in the upper and lower airways. This bacterium is dangerous for people with serious underlying chronic medical conditions and illnesses and is the leading cause of ear infections and sinusitis in children. The most serious complication is pneumonia.

More than 200,000 people in the U.S. are hospitalized each year for pneumonia-related complications. Although the majority of pneumonias respond well to treatment, the infection can still be a very serious problem. It kills approximately 36,000 people each year. Together with influenza, pneumonia is the eighth leading cause of death in the U.S.

Of particular concern is the increasing prevalence of pneumococcal bacteria that are resistant to many standard antibiotics. This has created a great sense of urgency in the medical community to find effective measures for preventing infection.

This picture shows the organism pneumococci. These bacteria are usually paired (diplococci) or appear in chains. Pneumococci are typically associated with pneumonia, but may cause infection in other organs, such as the brain (pneumococcal meningitis) and bloodstream (pneumococcal septicemia). (Courtesy of the CDC.)

The pneumococcal vaccine protects against S. pneumoniae (also called pneumococcal) bacteria, the most common cause of respiratory infections. There are 2 effective vaccines available: The 23-valent polysaccharide vaccine (Pneumovax, Pnu-Immune) for adults and the 7-valent conjugate vaccine Prevnar (PCV7) for infants and young children. Experts are now recommending that more people, including healthy elderly people, be given the pneumococcal vaccine, particularly in light of the increase in antibiotic-resistant bacteria.

The 7-valent conjugate vaccine Prevnar (PCV7) is very effective in children. Research finds that the vaccine, which was introduced in 2000, has reduced hospital admissions for pneumonia in children under age 2 by about 39%. The vaccine has even lowered hospital admissions 26% among adults aged 18 - 39 the study found, likely because they are parents of young children who might otherwise have developed the disease. Another study found that the vaccine also has benefited children who regularly get ear infections. Recurrent ear infections have fallen by 28% since the introduction of the vaccine.

Click the icon to see an image of pneumococcal pneumonia.

The pneumococcal vaccine is now recommended by many experts for the following groups:

Children up to age 2. The vaccine is very effective in children. In one study, a similar vaccine under investigation not only protected children in day care from serious respiratory infections, but their younger unvaccinated siblings had fewer infections as well.
Children up to age 5 who are at risk for pneumonia or complications of influenza, such as children with sickle cell disease, those with immune deficiencies, a damaged spleen or no spleen, or children with chronic medical conditions. One study has found that the rate of pneumococcal disease among children with sickle cell disease has dropped 90% since the vaccine was introduced.
Other children ages 2 - 5 who are at higher risk for serious pneumococcal infections should be considered for vaccinations. They include African- or Native Americans, children in group child care, socially or economically disadvantaged children, or those who have had frequent or complicated acute middle ear infections within the past year.

Pneumococcal Vaccine in Older Children and Adults. The vaccine is proving to be effective in reducing the rate of pneumonia in young adults, although not to the degree that it protects young children. The benefit for the elderly -- other than protection against bloodstream infection -- is unclear. Still, pneumonia is declining among adults, which may be due to fewer infections being transmitted from vaccinated young children. Many experts now recommend the vaccine for the following older children or adults:

All people over 65 years old. Some experts believe that all adults 50 - 64 should also be vaccinated. Unfortunately, although the vaccination is protective against pneumococcal bacteremia (invasive infection) in people over 65, evidence suggests that it does not appear to protect against community-acquired pneumonia.
Adults with any chronic condition that increases the risk for pneumonia. This includes patients with heart disease (such as congestive heart failure), chronic lung disease (COPD or emphysema, but not asthma), or diabetes.
Individuals with immune deficiencies (such as HIV) or those undergoing treatments that suppress the immune system.
Patients with autoimmune diseases, such as rheumatoid arthritis and lupus. Unfortunately, studies show the vaccine may not be as effective in these patients as in those with healthy immune systems. Nevertheless, they are at high risk for serious respiratory infections and should be vaccinated.
Patients with kidney disease or kidney transplants. Older people who have had transplant operations or those with kidney disease may require a revaccination after 6 years.
Patients with problems in the spleen.
Alcoholics, especially those with cirrhosis.
People living in long-term care facilities.
Alaska Natives or American Indians, who may be at increased risk for pneumonia.

The safety of the pneumococcal vaccine hasn't been proven during the first trimester of pregnancy; however, there have been no adverse effects reported. When the vaccine is administered to pregnant women, it may actually protect their infants against certain respiratory infections.

Protection lasts for more than 6 years in most people, although the protective value may be lost at a faster rate in elderly people than in younger adults. Anyone at risk for serious pneumonia should be revaccinated 6 years after the first dose, including those who were vaccinated before age 65. Subsequent booster doses, however, are not recommended.

The recommended schedule of immunization for Prevnar (PCV7) is 4 doses, given at 2, 4, 6, and 12 - 15 months of age. Infants starting immunization between 7 and 11 months should have 3 doses. Children starting their vaccinations between 12 and 23 months only need 2 doses. Those who are over 2 years old need only 1 dose.

Side effects include pain and redness at the injection site, fever, and joint aches. Children are more likely to have fever within 48 hours if they receive other vaccines at the same time, and also after the second dose. Fortunately, severe reactions are very rare, even if a person is mistakenly revaccinated before the effects of the first vaccination have worn off. Allergic reactions are also very rare.

Poliomyelitis

Poliomyelitis, more commonly known as polio, is a disorder caused by a virus and marked by potentially paralyzing nerve-related damage, which can be fatal. Fifty years ago it was a major killer of children, and it remains a threat in parts of Asia and Africa today. Vaccination programs eliminated the disease in the Americas in 1994, with the last case of wild poliovirus in the U.S. reported in 1979. As of 2004, polio has been eradicated in the Americas, the Western Pacific, and Europe.

Poliomyelitis is a communicable disease caused by viral infection and occurs through direct contact with infected secretions. Polio is found worldwide, but immunization has reduced the incidence. Clinical polio affects the central nervous system (brain and spinal cord). Disability is more common than death.

Two poliovirus vaccines have been available in the U.S.: oral poliovirus vaccine (OPV), a live-virus vaccine, and inactivated poliovirus vaccine (IPV), a killed vaccine that is administered by a shot. Both produce immunity in more than 95% of people. The live-virus used in the vaccine, however, has, in some cases, reverted to a form that can cause polio in unvaccinated people. This is a particular danger in developing countries where vaccination rates are low. The Centers for Disease Control and Prevention now recommends only the inactivated IPV vaccine for children. The schedule is 4 doses of IPV at ages 2 months, 4 months, 6 - 18 months, and 4 - 6 years.

Poliovirus Vaccine in Older Children and Adults. The poliovirus vaccine is not usually recommended for people over 18. Exceptions are unvaccinated health care workers, laboratory technicians, or others exposed to polioviruses. Travelers to developing countries where outbreaks of poliovirus have been reported should be vaccinated. Adults should also be given the inactivated poliovirus vaccine (IPV).

Allergic Reactions. The inactivated poliovirus vaccine (IPV) contains small amounts of streptomycin and neomycin, so people allergic to these antibiotics can also have an allergic response to this vaccine. Patients should report any allergies to their physician.

Paralysis. Rare cases of paralysis have occurred in people taking the oral live poliovirus vaccine or in those exposed to recipients of this vaccine. It should be stressed the risk is very small, with only 1 case occurring out of 2.4 million doses. Since the introduction of the current recommended series that uses only IPV, no cases have been reported.

Contamination by Simian Virus 40. The public was alarmed by reports of contamination of polio vaccines given between 1955 and 1963 by a virus known as SV40. The virus has been detected in certain rare cancers, including mesothelioma (a lung cancer normally associated with asbestos exposure), osteosarcoma, some brain tumors, and non-Hodgkin's lymphoma.

Click the icon to see an image of a brain tumor.

Still, about 98 million people may have been exposed, and most of these cancers are very rare (although some, including non-Hodgkin's lymphoma, are increasing). At least 40 years of observation have raised no red flags that indicate any serious problem. However, polio, once a major killer of children, has nearly been wiped out worldwide.

Viral Influenza

Influenza, commonly called the flu, is always caused by a virus.

Influenza, also known as the flu, is caused by a virus.

There are different strains of influenza:

Influenza A is the most widespread and most severe strain. It can affect both animals and humans. Influenza A is the cause of the worldwide epidemics (pandemics) of the flu that have occurred. More than 200,000 hospitalizations per year are due to this strain of the flu. Influenza A is usually further categorized by 2 subtypes based on 2 substances that occur on the surface of the viruses: hemagglutinin (H) and neuraminidase (N).
Avian Influenza A (called “bird flu”) was first detected in humans in 1997 in China and the region of Hong Kong. Bird flu is spread easily from bird to bird. Humans usually contract the flu from contact with infected domesticated birds, such as chickens, turkeys, and ducks. The World Health Organization confirms that there were, as of the publishing of this report, 331 cases of bird flu in humans and 203 deaths. The greatest number of cases have occurred in Indonesia, followed by Vietnam, Egypt, Thailand, and China. In April 2007, the U.S. Food and Drug Administration approved the first vaccine against the avian flu virus.
Influenza B infects only humans. It is less common than type A, but is often associated with specific outbreaks, such as in nursing homes. Flu caused by this strain tends to be milder than that caused by Influenza A.

Based on a final analysis of the 2005 - 2006 flu season, nearly 80% were type A and about 20% were type B. Influenza A usually causes more severe disease than type B. However, because influenza B has been less common in the past few years, there is concern that some people -- particularly small children -- may have fewer antibodies to it and so may be at higher risk for severe infection. (See Flu Vaccines in this report.)

Complications of the Flu. In general, the flu is usually self-limited and not serious. It is responsible, however, for 15 - 30% of the excess number of hospitalizations that occur in winter. More than 200,000 people who contract the flu end up in the hospital, and an estimated 36,000 people currently die each year of flu-related complications. The highest risks for serious complications occur in people age 65 and older and in those who are already sick with another disease. There have also been reports of flu-related deaths in very young children.

Pneumonia is the major serious complication of the flu and can be very serious. It can develop about 5 days after viral influenza. It is an uncommon event, however. It nearly always occurs in high-risk individuals, such as the very young or very old, and hospitalized or immunocompromised patients.

Note on Pandemics. Every year, flu strikes millions of people worldwide. Influenza epidemics are most serious when they involve a new strain against which most people are not immune. Such so-called pandemics can infect more than one fourth of the world's population within a 3-month period. For example, the Spanish flu in 1918 and 1919 killed 20 million people in the U.S. and Europe, and 17 million people in India. Although pandemics are still of great concern, there have been major improvements in private and public health since then, including the discovery of antibiotics to treat bacterial complications, new antiviral agents and vaccines, and intensive worldwide surveillance of outbreaks.

Description of Vaccines. Vaccines against the flu use inactivated (not live) viruses. The influenza vaccine is commonly called a "flu shot." It is designed to provoke the immune system to attack antigens contained on the surface of the virus. (Antigens are foreign molecules that the immune system specifically recognizes as alien and so targets for attack.)

Click the icon to see an image of antigens.

Unfortunately, the antigens in these influenza viruses undergo genetic alterations (called antigenic drift ) over time, so they are likely to become resistant to a vaccine that worked in the previous year. Vaccines are redesigned annually to match the current strain.

Influenza A. The influenza A virus is further categorized by primary molecular antigens (hemagglutinin and neuraminidase), which serve as the targets for the vaccines. Influenza A is a particular problem because it can infect other species, such as pigs or chickens, and undergo major genetic changes.
Influenza B viruses tend to be more stable than influenza A viruses, but they, too, vary. Although influenza B has been far less common than A, a vaccine for type B is important because experts are concerned that small children will not have developed any immunity to the virus and will experience severe flu if they are exposed to type B.

Until recently the vaccine has been administered only by injection. A vaccine (FluMist) that can be delivered in a nasal spray has now been approved for people aged 5 - 49. The vaccine contains live viruses that have been engineered to replicate in the cool temperatures of the nasal passages, but not in the warmer lungs and lower airways. Its presence in the nasal passages boosts the specific immune factors in the mucous membranes that fight off the epidemic viruses. Studies in 2003 reported protection against the flu that ranged from 66 - 92%, depending on whether the flu was type A or type B. (The lower rates were those observed for influenza B, particularly a new variant.) A 2007 study found that children aged 6 months - 5 years who had the nasal spray had 55% fewer cases of the flu than those given the injection. However, the vaccine is not approved for children in this age group. A preservative-free intramuscular injectable vaccine (Fluzone) is also now available.

The avian flu vaccine is designed for people aged 18 - 64 who are at risk for exposure to the avian H5N1 virus. The vaccine is given as 2 shots, spaced about 1 month apart. In studies, the vaccine appeared to be effective and well tolerated. Currently, the government is stockpiling the vaccination in case of an avian influenza outbreak. The vaccine is not available to the general public.

Ideally, appropriate candidates should be vaccinated every October or November. However, it may take longer for a full supply of the vaccine to reach certain locations. In such cases, the high-risk groups should be served first.

Antibodies to the flu virus usually develop within 2 weeks of vaccination, and immunity peaks within 4 - 6 weeks, then gradually wanes.

Because children under age 9 do not develop strong immune responses to 1 dose, the CDC recommends 2 vaccinations given 1 month apart.
Early research also suggests that it may be equally effective to administer children’s vaccinations in the spring and fall, rather than 1 month apart; further study is ongoing.
It should be noted that if an individual develops flu symptoms and is accurately diagnosed in time, vaccination of the other members of the household within 36 - 48 hours affords effective protection to those individuals, according to a 2004 Canadian analysis of multiple studies.

In healthy adults, immunization typically reduces the chance of getting the flu by about 70 - 90%. The current flu vaccines may be slightly less effective in certain patients, such as the elderly and those with certain chronic diseases. Some evidence suggests, however, that even in people with a weaker response, the vaccine is usually protective against serious flu complications, particularly pneumonia. The major outstanding question is whether the vaccination prevents complications of serious illness. One 2003 study, for instance, reported no reduction in severity of chronic lung diseases among vaccinated patients with asthma, emphysema, or chronic bronchitis. Some evidence suggests, on the other hand, that among the elderly, a flu shot may help protect against stroke, adverse heart events, and death from all causes.

Children Who Should Be Vaccinated. The following children over 6 months should be vaccinated against the flu:

The American Academy of Pediatrics (AAP) and the CDC recommend flu shots for all healthy children ages 6 - 23 months. In addition, any child over age 2 years who has a condition that requires regular medical care or who has been hospitalized for a serious illness (particularly lung or kidney disease, diabetes, sickle cell disease, or immune deficiencies).
Children who are receiving long-term aspirin therapy should also receive a flu shot. Children who get the flu are at higher risk for Reye syndrome, a life-threatening disease.
Some doctors now advocate flu shots for all school-age children. Research indicates that children are responsible for transmitting the vast majority of cases of the flu, and that routine vaccination of school-age children would considerably reduce transmission rates throughout communities.

There has been some question concerning flu shots because of some reports that vaccines may worsen asthma. Recent and major studies have been reporting, however, that the vaccination is safe for children with asthma. It is also very important for these patients to reduce their risk for respiratory diseases. Yet many children with asthma are not vaccinated. One study by the CDC found that fewer than one-third of children with asthma were vaccinated during the 2004-2005 flu season.

Older Children and Adults Who Should Be Vaccinated. The following, in order of priority, are the population groups who should be vaccinated each year. The first 2 groups have the highest need for flu shots and are given top priority:

All adults 65 years and older. Older adults who get a flu shot have lower hospitalization rates than those who do not. Evidence now suggests that vaccination may help protect against adverse heart events (including after heart surgeries), stroke, and death from all causes in the elderly. Still, studies suggest that only two-thirds of people in this group are vaccinated, mostly because of unwarranted fears of ineffectiveness or adverse effects.
People of any age at high risk for serious complications from the flu. Such people include those with heart disease, lung problems, immune deficiencies, diabetes, kidney disease, or chronic blood disease. Those with any condition that may compromise respiratory function or the handling of respiratory secretions, including people with cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders, are included in this group. (There have been concerns about the safety of the vaccinations in certain high-risk patients, such as those with HIV or asthma. Studies now suggest that the vaccine is generally safe in these patient groups. Furthermore, their risk for serious complications from the flu outweighs any potential adverse effects from the vaccines.)
Adults aged 50 - 64 who have chronic medical conditions. The U.S. Advisory Committee on Immunization Practices (ACIP) suggests that all adults over age 50 should be vaccinated, although this is not a recommendation of the CDC.
All health care workers should be vaccinated, according to the ACIP’s 2005 recommendations.
Household members in contact with individuals who are at high risk for complications from the flu should be vaccinated.

Other adults who should consider flu shots include:

People at risk for complications of the flu who are traveling to the tropics at any time or to the Southern Hemisphere between April and September.
Pregnant women who are at risk for complications of the flu and who will be in their second or third trimester during flu season. Women who are pregnant should receive only the inactivated flu vaccine. (Vaccinations should usually be given after the first trimester. Exceptions may be women who are in their first trimester during flu season, because their risk from complications of the flu is higher than any theoretical risk to the baby from the vaccine.)
People such as firemen or policemen who are critical for public safety.

Possible side effects of the flu vaccine include:

Allergic Reaction. Newer vaccines contain very little egg protein, but an allergic reaction still may occur in people with strong allergies to eggs.
Soreness at the Injection Site. Up to two-thirds of people who receive the influenza vaccine develop redness or soreness at the injection site for 1 or 2 days afterward.
Flu-like Symptoms. Some people actually experience flu-like symptoms, called oculo-respiratory syndrome, which include conjunctivitis, cough, wheeze, tightness in the chest, sore throat, or a combination. Such symptoms tend to occur 2 - 24 hours after the vaccination and generally last for up to 2 days. It should be noted that these symptoms are not the flu itself but an immune response to the virus proteins in the vaccine. (Anyone with a fever at the time the vaccination is scheduled, however, should wait to be immunized until the ailment has subsided.)
Guillain-Barre Syndrome. Isolated cases of a paralytic illness known as Guillain-Barre syndrome have occurred, but if there is any higher risk, it is very small (one additional case per 1 million people), and does not outweigh the benefits of the vaccine.

Haemophilus Influenzae Type B

Haemophilus influenzae (H. influenzae) type B is a bacterium, which, despite its name, is entirely different from the viruses that cause influenza (the flu). Before vaccination, H. influenzae type B (Hib) was the most common cause of childhood bacterial meningitis, killing 600 American children every year and leaving others deaf, mentally retarded, or epileptic. It is rarely troublesome for adults, although it can be dangerous for anyone with chronic lung disease and those susceptible to infections.

This is a Gram stain of spinal fluid from a person with meningitis. The rod-like organisms seen in the fluid are Haemophilus influenza, one of the most common causes of childhood meningitis (prior to the widespread use of the H. influenza vaccine). The large red-colored objects are cells in the spinal fluid. A vaccine to prevent infection by Haemophilus influenza type B is available as one of the routine childhood immunizations (Hib), typically given at 2, 4, and 12 months.

Three equally effective inactivated bacterial vaccines (commonly called Hib vaccines) are available for H. influenzaetype B. All children under 5 should be vaccinated against H. influenzae type B. The vaccine is administered as an injection at 2 and 4 months. Depending on the vaccination preparation, a third shot in the series is administered at 6 months. A booster is required at some time between 12 and 15 months of age.

Click the icon to see an image of Hib immunization.

In children older than 12 months, the Hib and DTaP vaccines are being combined in a single injection. This combined injection can be given as a booster, but not as the initial Hib immunization.

Evidence suggests that in infants, this combined vaccine using acellular pertussis (the current DTaP standard) is less effective in protecting against Hib than one that uses the older form with whole-cell pertussis. The booster at 1 year should help maintain protection, however.

The Hib vaccine may benefit older people who have had their spleen removed or illnesses that put them at risk for pneumonia, including sickle cell disease, leukemia, and HIV infection.

Click the icon to see an image of sickle cells.

Side effects of the Hib vaccine include redness and pain at the injection site, moderate fever, and, in rare cases, weakness, nausea, and dizziness.

Human Papillomavirus (HPV)

In 2006, the U.S. Advisory Committee on Immunization Practices( ACIP) voted to recommend the use of the first vaccine (Gardasil) to protect against human papillomavirus (HPV). This group of 100 viruses includes some 40 sexually transmitted viruses. Some HPV viruses can significantly increase the risks of cervical cancer, as well as cancers of the vulva, vagina, anus, and penis.

HPV is a very common virus; an estimated 20 million people in the U.S. have it. At least half of all sexually active men and women will eventually develop the virus.

A 2007 study indicated that the Gardasil vaccine is 100% effective against cervical, vaginal, and vulvar diseases caused by 4 types of HPV (6, 11, 16, and 18); however, it does not protect against the other types of the virus. It is less effective in women who were exposed to the virus before they were vaccinated. A 2007 study indicated that the vaccine is effective for 5 years after women receive the initial dose. The manufacturer has applied to the FDA for approval of the vaccine to also help prevent cancers of the vagina and vulva.

A new experimental vaccine, called Cervarix, has been shown in research to be effective for 5 1/2 years against the 2 most prevalent strains of HPV. Research is also indicating that the vaccine might be effective against more types of infections than the Gardasil vaccine. Researchers are studying the vaccine further, and they're looking at whether Cervarix is effective in women over age 25.

Girls ages 11 - 12 should get the vaccine, but they can get it as early as age 9. Adolescents and women ages 13 - 26 also should get the vaccine if they haven't already received it. Young women should ideally get the vaccine before they are sexually active, but it is still effective in sexually active women who haven't yet been infected with HPV. Currently there is no research to confirm the vaccine's effectiveness in women over 26, so there is no recommendation yet for this age group. Gardasil is not recommended for pregnant women.

Young women should get 3 doses of the vaccine. They should get the second dose 2 months after the first dose, and the third dose 6 months after the first dose.

Studies have shown no significant side effects from the HPV vaccine. The most common side effect was soreness at the injection site.

Rotavirus

Rotavirus is the most common cause of diarrhea, cramps, and vomiting in infants, and affects about 3.5 million children in the U.S. each year. As many as 80% of small children become infected with the virus. Although most cases in this country are mild, more than 50,000 American children are hospitalized and as many as 125 die from severe diarrhea every year. Worldwide the virus can be devastating, causing more than 600,000 infant deaths annually. There is also some strong evidence that the virus can lead to childhood diabetes.

An oral vaccine (Rotashield) has been withdrawn after reports of a severe and even life-threatening condition called intussusception following use of the vaccine. Intussusception occurs when the bowel slips inside itself like a telescope and obstructs the intestine. The risk was very small and occurred within a week or two of the vaccination. Any child who previously had the vaccination no longer incurs any increased risk. Preliminary reports suggest that newer rotavirus vaccines may be highly effective in preventing infection among infants, although more research is needed to confirm these findings and to determine their safety record in a large number of children. The association between diabetes and the virus itself raises some alarm that the vaccine might also increase the risk in children who are genetically susceptible to type 1 diabetes.

The U.S. Food and Drug Administration (FDA) approved a new oral rotavirus vaccine (Rotavirus, Live, Oral, Pentavalent vaccine -- trade name RotaTeq) early in 2006, and the Advisory Committee on Immunization Practices (ACIP) recommended that all infants should be immunized (3 liquid doses by mouth at 2, 4, and 6 months of age). In February 2007, the FDA announced there had been 28 reports of intussusception in infants who received the vaccine. After carefully monitoring cases of intussusception and other adverse effects associated with RotaTeq the FDA announced in March 2007 that the vaccine does not pose an increased risk of intussusception.

Because this is a deadly virus for many children worldwide, international groups believe that the few cases of intussusception do not warrant withdrawing its use, at least for countries where the infection is so common and deadly.

Click the icon to see an x-ray of intussusception.

Smallpox

Vaccination against smallpox used to be routine in the U.S. until 1972, and most older Americans bear the telltale small round smallpox vaccination scar on their upper arms. Immunity may last 10 years or longer. The last case of smallpox, a highly contagious and deadly disease caused by the variola virus, occurred in a laboratory worker in the U.K. in 1978.

However, the growing threat of bioterrorism has raised fears that smallpox could be used as a biological weapon, and in 2002 the US government issued plans for vaccinating every citizen against the disease in the event of an outbreak. The vaccination, however, carries some risks. Currently, then, vaccination continues to be recommended only for laboratory workers and scientists who work with the virus.

If an outbreak occurs, guidelines from the CDC call for a so-called "ring vaccination" approach. This involves identifying anyone who comes into contact with an infected person and vaccinating them and their contacts with a single dose of vaccine. This includes people of all ages and even those at risk for vaccine complications. The vaccine may work even if given within the first few days of infection.

Those at increased risk of vaccine complications but who should still be immunized if they are actually exposed to an outbreak include the following:

Children younger than a year. About 42 infants out of a million will develop brain swelling that may result in retardation or death. A severe, body-wide rash may also occur, especially if children touch the vaccination site.
Pregnant women. There is a small risk of miscarriage or premature delivery, although smallpox itself in pregnant mothers has more serious implications.
People with skin conditions, particularly eczema. They may develop a widespread blistering rash called eczema vaccinatum, which is fatal in 1 - 6% of cases, and they should not be vaccinated unless they've been exposed to the disease. They should also avoid others who have been vaccinated until those persons' vaccination scabs heal and fall off. People with non-chronic skin conditions, such as allergic rashes, severe burns, or chickenpox, may be vaccinated once their skin condition clears up.
People with suppressed immunity due to HIV, organ transplants, high-dose steroids, cancer chemotherapy, or other conditions.
Should a severe rash or other complication develop, patients should notify their doctors immediately. Two investigational medications, vaccine immune globulin (derived from the blood of people who have been vaccinated against smallpox) and an antiviral drug called cidofovir (Vistide), may be administered intravenously in the hospital should serious complications arise.
In the event of an outbreak, current plans specify that vaccination against smallpox will remain voluntary, although unvaccinated people who are exposed to the disease may be quarantined for 18 days to help contain the spread of disease.

Other Vaccinations

Many other types of vaccinations are available.

Rabies is a frequently fatal, acute viral infection that is transmitted to humans by infected animals (often dogs or bats) via a bite or exposing broken skin to an infected animal's saliva. In the past, human cases in the U.S. usually resulted from a dog bite, but more cases of human rabies have been linked to bats. Meanwhile, there have not been any rabies cases caused by dog bites for a number of years. Few cases occur in the U.S. because of extensive animal vaccination programs.

Anyone who is exposed to bats or to secretions of an animal suspected of having rabies should receive the rabies vaccine. Exposed individuals should also receive immune globulin unless they were previously vaccinated. Veterinarians and animal handlers should be vaccinated. This does not eliminate the need for treatment if they are exposed to rabies, but it reduces the intensity of the treatment.

Side effects include pain, redness, swelling at the injection site, headache, nausea, stomach pain, muscle aches, and dizziness. Allergic response can occur after the first shot and as many as 21 days after a booster shot. Rare cases of neurologic disorders that cause pain and paralysis in the legs and arms have also been reported. These neurologic disorders usually clear up in about 12 weeks.

Click the icon to see an image of rabies.

Plague is a severe, and potentially deadly, infection. It is caused by the organism Yersinia pestis. Wild rodents, like rats, spread the disease to humans. Plague is spread among rodents by a flea bite. Humans may get the plague when they touch or eat the infected animal, or when they come in contact with its feces. Certain forms of the plague can be spread from human to human. Plague is rare in the United States, but has been known to occur in parts of California, Utah, Arizona, Nevada, and New Mexico.

Veterinarians and assistants in the western U.S. or anyone who works with potentially plague-infected animals and travelers to developing countries where outbreaks have occurred should be vaccinated. The plague vaccine is not 100%y protective; it may only lessen severity of the disease. Preventive antibiotics are needed for anyone exposed. Side effects include headache, malaise, fever, swollen lymph nodes, and, occasionally, non-infected abscesses. Allergic reactions may occur, particularly in those sensitive to beef, soy, milk, and phenol.

Anthrax is an infectious disease caused by the spore-forming bacteria called Bacillus anthracis. Infection in humans most often involves the skin, the gastrointestinal tract, or the lungs.

Anthrax commonly affects hoofed animals such as sheep and goats, but humans who come in contact with the infected animals can get sick from anthrax, too. Historically, the populations most at risk for anthrax included farm workers, veterinarians, and tannery and wool workers. Anthrax is a potential agent for use as a biological weapon or for bioterrorism. In 2001, bioterrorist activities involving the U.S. Postal Service infected 22 people with anthrax; 7 survivors had confirmed cutaneous anthrax disease.

Military personnel and vaccine researchers, as well as people who work with imported animal hides, furs, bone meal, wool, animal hair (especially goat hair), and bristles, should receive an anthrax vaccine. The anthrax vaccine appears to be safe and effective, even after exposure, but requires 6 shots over 18 months. Up to half of recipients develop temporary soreness; some develop fever. Pregnant women should not get the anthrax vaccine.

Click the icon to see an image of cutaneous anthrax.

Click the icon to see an image of tuberculosis.


Disease	Who Should Get It?	Additional Information
Adenovirus	Military personnel.	Vaccine given orally for the prevention of respiratory illness.
Yellow Fever	Travelers to developing countries where outbreaks have occurred, currently parts of Africa and Central and South America. Residents of these areas, particularly children.	Vaccinations safe and effective for the prevention of jaundice and kidney and liver failure. Anaphylactic reactions in those allergic to eggs. Very rarely, may cause a potentially fatal illness resembling yellow fever, with fever and diarrhea, particularly in seniors. Lower immunity when given with cholera vaccine; the vaccines should be given three weeks apart.
Cholera	Travelers to developing countries where outbreaks have occurred.	Recently developed vaccines (Dukoral, Mutacol) are more effective than previous ones, which provided little protection. Not recommended or available, however, in the US.
Typhoid	Travelers to developing countries where outbreaks have occurred.	Oral vaccines include: (Ty21a, Vivotif). The oral vaccines are not effective against parathyroid fever. One-shot vaccine (Typhim Vi). Can be taken as early as two weeks before travel. Vi-rEPA is a newer injected vaccine that is safe in children and may be more effective-than other vaccines to date. No vaccine is 100% effective. The response to the typhoid vaccine tends to be lower in older people.
Tuberculosis	Individuals exposed to infected people.	Bacille Calmette-Guerin vaccine has been the standard vaccine, but its effectiveness has been questioned. No longer recommended in US except for certain high-risk children. A new recombinant BCG vaccine, shown in early trials to be more effective, is now licensed for use and is undergoing continued study.
Meningitis caused by meningococcal bacteria	U.S. Advisory Committee on Immunization Practices (ACIP) recommendations now call for routine vaccination of all young adolescents (aged 11 - 12) as well as those previously defined as at increased risk: People exposed to single cases or outbreaks; freshmen college students living in dorms; military recruits; travelers to developing countries where outbreaks have occurred; patients with problems in the spleen.	Vaccines are available against four subtypes of meningococcal bacteria but not for serogroup B, which causes up to 40% of meningococcal disease in the U.S. Among young people, fatalities have been higher in 15- to 24-year-olds than those younger than 15.

Resources

www.immunize.org -- Immunization Action Coalition
www.cdc.gov/vaccines/ -- The National Immunization Program
www.fda.gov/cber/vaers/vaers.htm -- Vaccine Adverse Event Reporting System
www.909shot.com/Issues/Injury_Compensation.htm -- National Vaccine Injury Compensation Program
www.immunizationinfo.org -- The National Network for Immunization Information
www.vaccine.chop.edu -- Vaccine Education Center, Children's Hospital of Philadelphia
www.vaccinesafety.edu -- Institute for Vaccine Safety, Johns Hopkins School of Public Health
www.whathealth.com -- National Partnership for Immunization
www.immunofacts.com -- Information on vaccinations
www.vaccines.org -- The Vaccine Page

References

American Academy of Pediatrics Committee on Infectious Diseases. Recommended childhood and adolescent immunization schedule: United States, 2005. Pediatrics. 2005 Jan;115(1):182.

Centers for Disease Control and Prevention. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). Mor Mortal Wkly Rep. June 2007;56:1-40.

Centers for Disease Control and Prevention. Recommended Immunization Schedule for Ages 0-6 Years, United States, 2007.

Chaves SS, Gargiullo P, Zhang JX, Civen R, Guris D, Mascola L. Loss of vaccine-induced immunity to varicella over time. NEJM. March 15, 2007;356:1121-1129.

Garland SM, Hernandez-Avila M, Wheeler CM, Perez G, Harper DM, Leodolter S, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. NEJM. May 10, 2007;356:1928-1943.

Grijalva CG, Nuorti JP, Arbogast PG, Martin SW, Edwards KM, Griffin MR. Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis. Lancet. April 7, 2007;369:1179-1186.

Harper SA, Fukuda K, Uyeki TM, Cox NJ, Bridges CB. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2005 Jul 29;54(RR-8):1-40.

Poehling KA, Szilagyi PG, Crijalva CG, Martin SW, LaFleur B, Mitchel E, et al. Reduction of frequent otitis media and pressure-equalizing tube insertions in children after introduction of pneumococcal conjugate vaccine. Pediatrics. April 4, 2007;119:707-715.

Prevention of influenza in the general population: Recommendation statement from the Canadian Task Force on Preventive Health Care. CMAJ. 2004;171:10.

American Academy of Pediatrics Committee on Infectious Diseases. Prevention and control of meningococcal disease: recommendations for use of meningococcal vaccines in pediatric patients. Pediatrics. 2005 Aug;116(2):496-505.

Pneumococcal vaccine cuts severe bacterial disease in US. Mor Mortal Wkly Rep CDC Surveill Summ 2005;54:893-896.

Wise R, Iskander J, Pratt D, et al. Postlicensure Safety Surveillance for 7-Valent Pneumococcal Conjugate. JAMA. 2004; 292:1702-1710.

Krym VF, MacDonald RD. Global efforts to eradicate polio. CMAJ. 2004 Jan 20;170(2):189-90.

Zuckerman JN. Protective efficacy, immunotherapeutic potential, and safety of hepatitis B vaccines. J Med Virol. 2006 Feb;78(2):169-77.

Review Date:
10/1/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

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HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Warning

Chemotherapy can cause anemia, a drop in red blood cell (hemoglobin) levels. Erythropoiesis-stimulating drugs, which boost the production of red blood cells, are administered to counteract this complication. However, these drugs, which include epoietin alfa (Epogen, Procrit) and darbepoietin alfa (Aranesp), can also cause serious side effects and adversely affect survival when hemoglobin levels are raised too high.

In 2007, the U.S. Food and Drug Administration (FDA) made several changes to the prescribing labels for erythropoiesis-stimulating drugs. The new labels have stronger warnings and updated dosing-related safety information.

The FDA advises that for treating anemia associated with chemotherapy, dosing should increase hemoglobin levels to no more than 12 g/dL. Treatment with these drugs should stop as soon as the chemotherapy course is completed. Erythropoiesis-stimulating drugs are not safe or appropriate for all patients undergoing chemotherapy. Patients should discuss the risks and benefits with their oncologists. The FDA is currently reviewing additional data concerning the safety of these drugs.

Positron Emission Tomography (PET) Scans and Lymphoma

PET scans are used to help diagnose and stage lymphoma, and they may also be helpful in assessing treatment outcomes for some types of lymphoma. In 2007, an international team of cancer specialists drew up new guidelines for evaluating how well lymphoma responds to treatment in clinical trials. The guidelines now recommend that PET scans be used to help determine if a patient has achieved remission.

Introduction

Lymphomas are malignancies of the lymph system that are generally subdivided into two groups, Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Hodgkin's disease accounts for about 15% of all lymphomas. [For more information, see In-Depth Report #83: Hodgkin's disease.]

Non-Hodgkin's lymphomas is a term for malignancies that range from a very slow disease to an extremely aggressive but curable condition. They have certain features in common.

The lymphatic system filters fluid from around cells. It is an important part of the immune system. When people refer to swollen glands in the neck, they are usually referring to swollen lymph nodes. Common areas where lymph nodes can be easily felt, especially if they are enlarged include the groin, armpits (axilla), above the clavicle (supraclavicular), in the neck (cervical), and the back of the head just above hairline (occipital).

Lymphomas, such as non-Hodgkin's lymphomas and Hodgkin's disease, represent tumors of the lymphatic system. This system is a network of organs, ducts, and nodes. The system interacts with the blood's circulatory system to transport a watery clear fluid called lymph throughout the body. The lymphatic system contains lymphocytes, important cells involved in defending the body against infectious organisms. This system also restores 60% of the fluid that leaks out from blood capillaries back into circulation, and its ducts provide transportation for fats, proteins, and other substances collected from the body's tissues.

Lymphocytes. The lymphatic system is involved in the production and transportation of lymphocytes, white blood cells that are a primary component of the immune system. Among other vital functions, certain lymphocytes are responsible for producing antibodies, factors that can target and attack specific foreign proteins (antigens). To understand the lymphatic system, it is helpful to track part of the life cycle of these lymphocytes:

Lymphocytes develop in the bone marrow or thymus gland and are therefore categorized as either B cells (bone marrow-derived cells) or T cells (thymus gland-derived cells).
B cells complete their structural growth and definition (known as differentiation) and mature in the bone marrow.
T cells also start out in the bone marrow but differentiate and mature in the thymus gland, located beneath the breastbone (sternum). This small gland is active mostly in the fetal stage through the first 10 years of life, after which it atrophies (shrinks).
B-cell and T-cell lymphocytes leave these organs through the bloodstream, which eventually branches out into the tiny blood vessels called capillaries.
Some lymphocytes, along with fluid, proteins, and other substances, migrate out of the capillaries into the surrounding tissues. A proportion of these lymphocytes and other substances then enter the lymphatic vessels.
Lymphatic vessels begin as tiny, blind-ended tubes and lead to larger lymphatic ducts and branches until they drain into two ducts in the neck, where the fluid re-enters the bloodstream.
Along the way, the fluid passes through lymph nodes, oval structures composed of lymph vessels, connective tissue, and white blood cells. Here, the lymphocytes are either filtered out or added to the contents of the node.

Lymph Nodes. In the lymph node, lymphocytes receive their initial exposure to foreign substances (antigens), such as bacteria or other microorganisms, activating the lymphocytes to perform their immune functions. The size of a lymph node varies generally from that of a pinhead to a bean. Most nodes are in clusters located throughout the system. Important node clusters are found in the neck, lower arm, armpit, and groin.

Other Structures in the Lymphatic System. The tonsils and adenoids are secondary organs composed of masses of lymph tissue that also play a role in the lymphatic system. The spleen is another important organ that processes lymphocytes from incoming blood.

Click the icon to see an animation about lymph nodes.

Click the icon to see an image of lymph nodes in the head and neck.

Click the icon to see an image of the immune system structures.

Non-Hodgkin's lymphomas occur most often in lymph nodes in the chest, neck, abdomen, tonsils, and the skin. NHLs may also develop in sites other than lymph nodes such as the digestive tract, central nervous system, and around the tonsils.

About 85% of non-Hodgkin's lymphomas (NHLs) arise in B cells; the rest occur in T cells. Activation of a gene called BCL-2 is believed to be partly responsible for many B-cell lymphomas. This defect prevents apoptosis (a natural process whereby cells self-destruct) in the lymphoma cells.

There are more than 20 distinct types of non-Hodgkin's lymphomas. Most first arise in the lymph nodes, but about 20 - 30% of cases are now found outside the nodes, most often in the stomach, small intestine, skin, and brain.

Even experts disagree about the exact groupings. Lymphomas are categorized in a number of ways.

Classification by Cell Type, Appearance, and Genetic Make-up: The REAL System. Different classification systems for lymphoma have been proposed. The system used in this report is called REAL (Revised European-American Lymphoma Classification). It classifies all lymphomas by appearance, cell type, and genetic make-up:

Non-Hodgkin's lymphomas are first grouped as B cell or T cell.
Next, they are categorized by whether the B-cell and T-cell lymphomas were derived from immature (precursor) cells or mature (peripheral) cells.
The peripheral B and T cells are then classified by their appearance, genetic make-up, and specific chemical "markers," which further identify them.

T-cell lymphomas, Hodgkin's disease, and certain leukemias and aggressive lymphomas are covered in the REAL classification but are not discussed in any depth in this report.

Groups by Slow or Fast Growth. Each non-Hodgkin's lymphoma is further defined by its grade, or how aggressive it is:

Indolent (slow-growing), also called low-grade
Aggressive (fast-growing), also called intermediate- or high-grade

According to one report, half of new cases are now intermediate-grade lymphomas. Low-grade makes up 30%, while high-grade makes up 10% of all lymphomas.

Groups by Properties. Lymphomas are also grouped by certain properties:

Size (large versus small)
Shape (round versus irregular)
Whether they are or resemble blood plasma cells
Whether they are follicular (organized in round clusters) or diffuse (spread evenly throughout the lymph node)

Staging. Staging the disease is the next important step in classifying lymphomas. The stage (I - IV) of an NHL is determined by the number of tumors and whether they are still localized or have spread beyond the lymph node. In general, the higher the stage, the poorer the outcome, but other factors are important for a precise prognosis.

Indolent (Slow-Growing) Lymphomas (also Called Low-Grade Lymphomas)

Follicular lymphomas (FLs). Follicular small cleaved cell lymphoma (grade I) and follicular mixed small and large cell lymphoma (grade II). FLs account for 70% of indolent tumors and 20% of all NHLs in industrialized countries. It is very rare in developing countries and in Asia.

Lymphoplasmacytoid/Waldenstrom's macroglobulinemia. Often found in bone marrow, lymph nodes, and spleen. Can cause blood to become viscous and "sticky."

Marginal zone lymphomas (MZL). MZLs often occur as a result of a pre-existing disorder such as hepatitis C, bacterial infection in the stomach (H. pylori ), or an autoimmune disorder (Sjögren syndrome in the salivary glands or Hashimoto's thyroiditis in the thyroid gland). They may be classified as:

Monocytoid B-cell lymphoma, which involves only lymph nodes
Splenic marginal zone lymphoma, which affects the spleen, blood, and bone marrow
Mucosa-associated lymphoid tissue (MALT) lymphoma, which usually involves the gastrointestinal tract, thyroid, lung, breast, or skin

There is some controversy over whether MALT is a variation of MZL or a completely separate type of lymphoma that is more suitably classified as a separate low-grade lymphoma. At this time, it is classified as an MZL.

Aggressive Lymphomas (also Called Intermediate- and High-Grade Lymphomas)

Diffuse large-cell lymphomas (DL). DLs are the most common NHLs, accounting for about 40% of all cases. Subtypes include the following:

Primary mediastinal large B-cell lymphoma
Follicular large cell lymphoma
Anaplastic large cell lymphoma
T-cell lymphomas (not covered in this report)

In about 40% of cases, these DL lymphomas appear in areas outside lymph nodes, including digestive tract, skin, bone, thyroid, and testes.

Burkitt's lymphoma/diffuse, small noncleaved cell lymphoma. This is the most common childhood NHL. In African children, it often involves facial bones and is associated with Epstein-Barr infection.

Mantle cell lymphoma. Mantle cell lymphomas are found in lymph nodes, the spleen, bone marrow, blood, and sometimes the gastrointestinal system (lymphomatous polyposis). This lymphoma is similar to indolent lymphomas at the time of diagnosis, but it is more aggressive.

Lymphoblastic lymphoma. This lymphoma often occurs in young people. It is associated with a large mediastinal mass (occurring in chest cavity between the lungs) and carries a high risk for spreading to bone marrow and central nervous system.

Risk Factors

About 63,000 Americans were diagnosed with non-Hodgkin's lymphomas in 2007, and nearly 19,000 people died of the disease. For the past 25 years, the incidence in NHL has increased continuously. Most of this increase has occured in people over age 65.

Part of the reason for the dramatic rise was AIDS, which increases the risk for high-grade lymphomas. However, even after eliminating changes in diagnosing NHLs and known causes (such as AIDS), the incidence over the past 40 years is 40% higher. The number of cases in which lymphomas first occur outside the lymph nodes has also increased compared to those limited to the nodes. (This observed increase, however, may in large part be due to different methods of diagnosing lymphomas).

The cancer can develop in people at all ages, including children, although it is most common in those ages of 45 - 60. In general, the incidence of NHL is 50% higher in men than in women. This higher rate has been observed in many countries. Nevertheless, recent reports suggest that the rate is leveling off or even declining in men, but is increasing in women, particularly African-American women. Overall, the risk is slightly higher in Caucasians than in African-Americans.

The risks for NHL among men versus women and among African-Americans versus Caucasians may vary by lymphoma subtype. For example, follicular lymphomas were significantly higher in Caucasians than in African-Americans, and there was little gender difference. High-grade lymphomas were the most rapidly increasing type, particularly among men, with follicular lymphomas increasing most rapidly in African-American men.

Other studies have also reported ethnic differences by specific lymphoma subtypes. For example, follicular lymphomas constitute 20% of all NHLs in Western nations but are very uncommon in Asia and in developing countries.

The brother or sister of a person with the disease has more than twice the risk of developing NHL than the general population. Some cases of NHL in such cases are due to inherited disorders of the immune system. Studies suggest, however, that such family clusters are more likely to be due to environmental conditions that trigger the genetic factors.

Because of the rapid rise in NHL, investigators are looking for lifestyle factor that may contribute to this increase. No real association between lymphomas and body weight or shape or amounts of exercise has been found.

A number of reports suggest an influence of diet in the development of non-Hodgkin's involvements. However, for the most part a strong association remains speculative. Some of the possible dietary risk factors include:

A number of studies have observed an association between an increased risk for non-Hodgkin's lymphomas and high consumption of red meat (beef, pork, and lamb).
A higher risk for lymphoma has also been suggested for trans fatty acids (hydrogenated polyunsaturated fats, which are contained in hard margarines and commercial baked goods and fast foods). There appears to be no higher risk with natural polyunsaturated fats (found in most vegetable and fish oils).
Fish may be protective.
Some evidence suggests that milk may also be protective.
One major study observed a reduction in risk with high intake of vegetables. Another found no protection from vegetables, but did with diets rich in fruit.
Vitamin supplements have no effect on NHL.

Despite these kinds of reports, the influence of diet on the development of non-Hodgkin's lymphomas remains speculative.

Alcohol Use. Studies on alcohol have been mixed, with some showing a higher risk, some a lower risk, and some no difference at all.

Smoking. There is no evidence that smoking increases the risk for NHL itself, although it has been linked with high-grade and follicular NHLs in people with lymphomas.

Viruses or other microorganisms also play a role in some lymphomas. A number are being investigated:

Epstein-Barr virus, the cause of mononucleosis, is highly associated with Burkitt's disease and NHLs associated with immunodeficiency diseases. It is also a risk factor for Hodgkin's disease
Adult T-cell leukemia-lymphoma, which appears to be caused by a virus known as HTLV-I, has been found in southwestern Japan, the Caribbean, and the southeastern United States.
People who have stomach inflammation due to Helicobacter pylori or H. heilmannii bacteria are at increased risk for mucosa-associated lymphoid tissue lymphomas (MALT). (The use of antibiotics to get rid of the bacteria may cause remission in some patients who have an early stage form of lymphoma in an early stage.)
Human herpes virus 8 has been associated with NHL.
Borrelia burgdorferi, the bacteria that causes Lyme disease, has been associated with primary B-cell lymphoma.
Heavy antibiotic use during adulthood may increase risk. A 2005 study found that adults who used antibiotics more than 10 times had 1.8 times the risk of developing NHL than nonusers. However, researchers were not certain if antibiotics themselves, or the underlying infections they treated, were responsible for the increased risk.

Click the icon to see an image of Lyme disease.

Studies are reporting a higher prevalence of viral hepatitis C and B in patients with lymphomas, although such viruses do not appear to play a major role in triggering lymphoma.

Patients with diseases or conditions that affect the immune system may be at higher risk for lymphomas:

HIV-positive patients and those with full-blown AIDS are at higher risk for NHL, and the disease is more likely to be widespread in these patients than in those without the immune disease. Most AIDS-related NHLs are high-grade lymphomas. Burkitt's lymphoma is often seen in patients with AIDS. Although these patients have had a very poor prognosis, advances in antiviral therapy for HIV now allow better management of NHL with some success in achieving favorable outcomes. Part of the dramatic increase in NHL incidence over the past decades can be traced to AIDS.
Patients with a history of autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus, Hashimoto's thyroiditis, Crohn's disease, and Sjögren syndrome, are at an increased risk for certain NHLs, such as marginal zone lymphomas.
People who have organ transplants are at higher risk for NHL, probably due to multiple factors, including the drugs used to suppress the immune system and the transplanted organ itself.
Patients who have had high-dose chemotherapy with stem-cell transplantation are at higher risk.
Other immunodeficiency syndromes that put people at risk for NHL include Chediak-Higashi syndrome, ataxia-telangiectasia, B-cell lymphoproliferative syndrome, Bruton agammaglobulinemia, common variable immunodeficiency, and Wiskott-Aldrich syndrome.

Note on Allergies: There appears to be no association between NHL and allergies, overactive responses of the immune system. Allergies are the most common immune disorder.

Overexposure to a number of industrial and agricultural chemicals has been frequently linked to an increased risk for lymphomas. The data, however, are not consistent.

Organochlorines are chemicals produced when solid waste is burned. These by-product chemicals include dioxin, polychlorinated biphenyls (PCBs), and furans. Many studies have indicated that exposure to these chemicals increases the risk of developing NHL.
A number of studies have found an association between NHL and certain pesticides and herbicides, although more research is needed to confirm any definitive risk.
White spirits, thinners, phenoxy herbicides, wood preservative, aviation gasoline, plastic, and rubber chemicals have been associated with a higher risk for lymphomas. Specifically, in one study, painters and lumberjacks had a higher risk for NHL, while office and house workers had a lower risk.
Some studies have found an association with long duration and early use of permanent dark hair dyes. There is no consistent evidence, however, that hair dye increases the risk for lymphomas.

Symptoms

The most common first sign of lymphomas is painless enlargement of one or more lymph node, usually in the neck, armpits, or groin. Patients should see their doctors if these symptoms do not go away within 2 - 3 weeks.

The most common lumps or swellings in the neck are enlarged lymph nodes. They can be caused by bacterial or viral infections, cancer, and other rare causes.

Lymphomas sometimes cause systemic symptoms -- symptoms that affect the whole body, rather than a specific location. Some systemic symptoms are referred to as B symptoms. Patients who have B symptoms have a more severe condition than asymptomatic patients with the same cancer stage or tumor location or size.

B systemic symptoms include:

Drenching night sweats and weight loss
Fever (may occur sporadically and only at night)

Other systemic symptoms include:

Itching all over the body caused by the release of histamines, substances ordinarily triggered by an allergic response. In the case of NHL, this is due to abnormalities in the immune system. Although this is a systemic symptom, it is not usually considered a B symptom if other systemic symptoms are not also present.
In late stages, some patients develop a skin rash.
Tumor masses in the chest can cause coughing or breathlessness.
Lymphomas in the stomach can cause nausea and vomiting.

Many patients seek medical help for abnormally swollen lymph nodes (commonly referred to as "swollen glands"). Swollen glands can be caused by many conditions, most often infections, and are rarely serious.

Infections. In the great majority of cases, swollen glands are caused by an infection:

Enlarged lymph nodes in the neck are much more likely to be a sign of strep or other throat infection than NHL.
Infectious mononucleosis (caused by the Epstein Barr virus) is a common cause of swollen lymph nodes in young people.
Travel, particularly to countries with a high incidence of tropical diseases, can trigger similar symptoms.
Other infections that cause swollen glands include cat scratch fever, Lyme or other tick-borne disease, HIV, tularemia, tuberculosis, syphilis, herpes simplex virus, cytomegalovirus, and hepatitis.

Hodgkin's Disease. Although both Hodgkin's disease and non-Hodgkin's lymphomas are malignancies of the lymph nodes, they can usually be distinguished by certain characteristics. It is extremely important to differentiate between Hodgkin's lymphomas and non-Hodgkin's lymphomas, since the treatments for these two conditions differ. In particular, a subtype of lymphoma called anaplastic large-cell lymphoma (ALCL) might be confused with Hodgkin's disease under some circumstances. [For more information, see In-Depth Report #83: Hodgkin's disease.]


Characteristics	Hodgkin's Disease	Non-Hodgkin's Lymphomas
Age and Prevalence	Average age is 28 with two age peaks, the major one occuring between 15 - 24, anda lesser peak after age 55. It is less common than NHL.	Average age is about 67. It is more common than HD.
Location	In both malignancies, the disease occurs most often in lymph nodes above the collarbone. However, in HD it is also more likely to appear in the chest cavity between the lungs (the mediastinum), particularly in younger patients. Only about 15 - 20% of cases are found in areas below the diaphragm. Disease occurs outside the nodes in about 4% of cases.	In both malignancies, the disease occurs most often in lymph nodes above the collarbone. In NHL, however, it is also more likely to appear in the nodes in the abdomen (called the mesenteric nodes). The disease occurs in the chest cavity in less than 40% of patients. (An exception, lymphoblastic lymphoma, which is seen most often in young people, is likely to first appear in the chest.) Disease occurs outside the nodes in about 23% of patients. Slow-growing lymphomas are common in the liver and bone marrow.
Symptoms	More likely than NHL (40%) to have systemic symptoms (such as fever and night sweats) at the time of diagnosis.	Less likely to have systemic symptoms (27%) at the time of diagnosis.
Progression	Less likely than NHL to be diagnosed in stage IV (10%). Hodgkin's disease usually progresses in an orderly way from one lymph node region to the next. This process may be slow, particularly in younger people, or very aggressive. The disease typically spreads downward from the initial site. If it spreads below the diaphragm, it usually reaches the spleen first; the disease then may spread to the liver and bone marrow. If the disease starts in the nodes in the middle of the chest, it may spread outward to the chest wall and areas around the heart and lungs.	More likely than HD to be diagnosed in stage IV (36%). The lymphomas are less predictable in their course than Hodgkin's disease and they are more apt to spread.

Other Cancers or Serious Conditions in the Lymphatic System. Other cancers that can travel to lymph nodes include breast cancer and leukemia.

Very serious causes of enlarged lymph nodes include disorders of the lymph system, such as Castleman's disease, lymphomatoid granulomatosis, and angioimmunoblastic lymphadenopathy. These lymph system disorders, although noncancerous, involve abnormal lymph cells. They are often fatal and can be very difficult to distinguish from lymphomas. Many of the other serious illnesses involving diseased lymph nodes develop simultaneously at multiple sites, while Hodgkin's nearly always starts at one location before spreading to nearby nodes. [For more information, see In-Depth Report #83: Hodgkin's disease or Report #86: Acute lymphocytic leukemia.]

Exposure to Medications. Exposure to certain medications such as phenytoin (Dilantin) may cause enlarged nodes. Other drugs, such as cephalosporins, penicillins, or sulfonamides, can cause enlarged nodes and other symptoms, including fever and rash, which may resemble Hodgkin's disease.

Diagnosis

The doctor will first ask questions about the patient's medical history and perform a physical examination to detect any node enlargements. If these steps point to lymphoma, additional tests will be done to rule out other diseases or to confirm the diagnosis and extent of the lymphoma.

It is sometimes reasonable to wait a little while for the swelling and symptoms to go away before deciding that additional testing is necessary. In some cases, lymph node swelling may be due to a temporary infection. However, some lymphomas cause off and on lymph node swelling. This is particularly true with small cleaved cell lymphoma (the most common NHL). Lymph nodes should be checked periodically for any return of swelling.

The doctor will examine not only the affected lymph nodes but also the surrounding tissues and other lymph node areas for signs of infection, skin injuries, or tumors. The consistency of the node sometimes indicates certain conditions. For example, a stony, hard node is often a sign of cancer, usually one that has metastasized (spread to another part of the body). A firm, rubbery node may indicate lymphoma. Soft nodes suggest infection or inflammatory conditions.

Blood tests help rule out infection and other diseases. Such tests include those blood counts and blood chemistries for kidney and liver function, uric acid, calcium, and phosphate levels. In a patient already diagnosed with lymphoma, blood tests that measure the enzyme lactate dehydrogenase are important in determining the prognosis. High levels indicate bulkier tumors. The presence of anemia may indicate specific NHLs, such as diffuse, small lymphocytic lymphoma.

A biopsy is the most important test for diagnosing lymphomas and can be used to tell the difference between non-Hodgkin's and Hodgkin's disease. A biopsy has risks and should be performed only by a qualified and experienced doctor. Sometimes a doctor may choose to wait and observe the involved lymph nodes, which will usually go away on their own if a temporary infection is causing the swelling. (However, some lymphomas may go away and appear to be benign, only to reappear at a later time.)

The Procedure. The doctor removes the node and checks the surrounding areas. The tissue in the node is then examined under a microscope for signs of infection and abnormalities indicating cancer or other conditions.

Results. Even if biopsies do not show any problems, disease may still be present in some cases. The doctor should continue to observe the patient until swelling or other signs of disease are gone. Biopsied tissue samples should be frozen in case special tests are later required. Such tests may include detection of particular antibodies, genetic and immune factors, and certain markers (substances that may indicate disease) located on the surface of the cells. If lymphoma has been diagnosed, the tissue will be examined for its histology, the cellular structures that will determine the lymphoma type.

Bone marrow aspirate and biopsy are routinely performed to determine whether the disease has spread. With bone marrow aspirate, bone marrow cells are sucked out through a special needle. A biopsy may be performed before or after the aspiration. In this procedure, a special needle removes a core of the marrow that is structurally intact.

Click the icon to see an image of bone marrow aspiration.

Chest X-Ray. A chest x-ray shows the lymph nodes in the chest and neck area. It is particularly useful in detecting Hodgkin's disease and enlarged lymph nodes.

Click the icon to see an image of an x-ray machine.

Computer Tomography. Computed tomography (CT) scans are more accurate than x-rays. They can detect abnormalities in the chest and neck area, as well as revealing the extent of the cancer and whether it has spread. CT scans are used to evaluate symptoms and help diagnose lymphomas, help with staging of the disease, monitor response to treatment, and evaluate when the symptoms occur. A CT scan is also often used in detecting lymphomas in the abdominal and pelvic areas, the brain, and chest area.

Click the icon to see an image of a CT machine.

Magnetic Resonance Imaging (MRI). MRIs may be used to detect the spread of the disease to the brain, spine, chest, pelvis, and abdomen.

Click the icon to see an image of a MRI machine.

Positron Emission Tomography (PET). PET scans can help tell whether or not an enlarged lymph node is benign or cancerous. PET scans are more accurate than CT scans or other imaging tests for staging lymphomas. PET scans may also help doctors determine how well a patient has responded to treatment, if any residual cancer exists, and if a patient has achieved remission.

Tests of lymphoma's DNA are in use or are being developed to detect particular genetic abnormalities that help determine outlook and may eventually lead to new treatments. Examples of such abnormal genetic arrangements are those that affect normal cell death, resist chemotherapy, or trigger aggressive cancer growth.

An advanced approach called the microarray technique uses chips that contain up to thousands of DNA sequences that represent specific normal and abnormal genes. Such sequences have been compiled for lymphomas. Eventually, experts may be able to match a patient's DNA to these patterns and identify specific subtypes.

Biologic markers, also called biomarkers, are high levels of substances released by tumors. They indicate the level of cancer activity. Biomarkers can be found in sputum, blood, and tissue samples. Biomarkers can be enzymes, hormones, amino-acid compounds, antigens (identified by antibodies that specifically target them), and growth factors. Some under investigation include:

CD44. This molecule binds to the surface of cells and may be involved in metastasis. High levels of this molecule may suggest a more aggressive disease.
BCL-6. This cancer gene is implicated in diffuse large B-cell lymphoma. High levels of this gene in these patients indicate a better outlook after treatment.

Outlook

Five-year survival rates for NHL range from 20 - 95%, depending on the lymphoma type, stage, age of the patient, and other variables. Because the outlook varies so widely, making a definite prognosis is very difficult. For example, patients with very slow growing (indolent) lymphomas can live many years. However, they are usually diagnosed at a late stage, after the cancer has spread, thus reducing the survival rate. Aggressive lymphomas are more likely to cause rapid death, but they are also often curable. New drugs that target specific factors in the tumor cells are improving survival rates.

Follicular lymphomas, the most common indolent (slow-growing) NHLs, are potentially curable in early stages I and II. Unfortunately, however, these slow-growing malignancies produce no symptoms until they are in advanced stages. In most cases, these lymphomas are not diagnosed until they have spread to other sites, including the spleen and bone marrow. In such cases, they are difficult to cure. Predicting outcome for indolent follicular lymphomas is more difficult than for aggressive lymphomas. Even if treatment achieves a response, these tumors almost always recur. Even after relapse, however, the tumors can be treated again if they are still very slow-growing.

In general, the average survival rate for follicular lymphoma is 7 - 10 years, depending on other risk factors. New drug treatments, particularly monoclonal antibodies, have significantly improved survival rates. According to a 2005 study, 91% of patients with follicular lymphoma now survive the first 4 years after diagnosis, compared with 69% of patients treated in the past with older types of drugs. The research team found the best 4-year survival rates for patients treated with the CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy regimen followed by monoclonal antibody biologic drugs (rituximab or iodine-131 tositumomab).

Factors for Predicting Outlook in Indolent Lymphomas. Six risk factors are proving to be useful for predicting outlook:

Being male
Being older
Having stage III or IV disease
Elevated levels of the enzyme lactate dehydrogenase (LDH)
The presence of B symptoms
Erythrocyte sedimentation rate over 30

Patients with a good chance for a positive outcome (65% chance for survival rates of 10 years or greater) have one or none of these factors. Those with intermediate risk (23%) have two factors, and those likely to have a poor outcome (11%) have three or more factors. MALT lymphomas generally have a good prognosis. Primary gastric lymphomas have a 3-year survival rate of 89%.

High-grade aggressive lymphomas are often symptomatic early on and are potentially curable with aggressive treatments. Diffuse large-cell lymphomas, the most common aggressive non-Hodgkin's lymphomas, while fatal if not treated, are often curable with intensive chemotherapy combinations. If relapse occurs after chemotherapy, it usually does so within 2 years.

Most other aggressive lymphomas respond to aggressive chemotherapy. Mantle cell lymphoma is less responsive to chemotherapy. The average survival time is 3 - 5 years.

Factors for Predicting Outlook in Aggressive Lymphomas: A scoring system called the International Prognostic Index has proved to be fairly accurate for predicting outcome in patients with most aggressive B-cell lymphomas. It uses five risk factors to help predict whether the disease will be aggressive:

Being older than 60 -- this age group tends to have other medical conditions, which contribute to the poorer prognosis
Having a disseminated tumor (stage III or IV)
Disease that has spread to more than one site beyond the lymph nodes
A poor performance status
Having elevated levels of lactate dehydrogenase (LDH)

Having one or none of these risk factors indicates the best outlook. Two factors indicate a low-to-intermediate likelihood of a poor outlook. Three factors predict an intermediate-to-high likelihood of poor outlooks. Finally, four or five factors pose the highest likelihood of poor survival.

Lymphoma can spread to the central nervous system, or it can appear there first. Called primary CNS lymphomas (PCNSL), this condition is a very serious, particularly if it occurs at relapse.

The central nervous system is comprised of the brain and spinal cord. The peripheral nervous system includes all peripheral nerves.

Risk Factors for CNS Involvement After a Diagnosis of NHL. AIDS-related lymphomas often involve the central nervous system (CNS), including the brain and spinal column. CNS involvement also occurs with aggressive lymphomas, such as Burkitt’s lymphoma.

Risk Factors of Primary CNS Lymphomas. PCNSL used to account for only about 2% of lymphomas, but the incidence is on the rise in all age groups and in both. The reason for the increase is not known.

Medical Problems. The radiation and chemotherapies used in treating NHL can have long-term effects on many organs in the body and can increase the risk for serious illnesses, including heart disease and certain cancers.

Negative Emotional Problems. Depression and anxiety are common in survivors, particularly those who suffer additional medical conditions. Many patients also suffer from fatigue and aches and pains, called somatic symptoms, which have no apparent physical basis. In one study, such symptoms were more highly associated with intensive chemotherapy. Women and people in lower social and economic groups are at higher risk for depression and somatic symptoms -- just as they are in the general population.

Staging and Treatment Guidelines

Treatment for non-Hodgkin's lymphoma is highly specific for each patient and is determined by the tumor classification. It includes the following factors:

Stage
Grade
Histologic type (cellular structure)
Location
Other factors, such as blood levels of lactate dehydrogenase

Treatment for lymphomas has been primarily dependent on chemotherapy (particularly intensive regimens using several drugs) or a combination of chemotherapy and radiation. For advanced or refractory lymphomas and for relapse, patients may undergo bone marrow or stem cell transplantation. New treatments, especially those known as immunotherapies, or biological response modifier (BRM) therapies, are showing promise. Some experts recommend that patients ask their doctors about getting into well-designed clinical trials as early as possible.

Click the icon to see an illustrated series detailing bone marrow transplant surgery.

In assessing the success of a clinical trial, experts often refer to the tumor response. A complete response, for example, means that there is no longer any evidence at all of the disease by examination, blood tests, or x-ray studies. It does not necessarily mean, however, that the disease is cured. It may still recur later on.

In judging the success of a treatment for NHL, the most important criteria are overall survival and the duration of time until the disease progresses or the patient dies.

In Stage I, lymphoma is found in only one lymph node area or in only one area or organ outside the lymph nodes. Either of the following indicates stage II:

Lymphoma is found in two or more lymph node areas on the same side of the diaphragm.
Lymphoma is found in only one area or organ outside the lymph nodes and in the lymph nodes around it. Other lymph node areas on the same side of the diaphragm may also have lymphoma.

Early Stage Indolent (Low-Grade) Lymphoma. Below are the general treatment options:

Radiation therapy. Radiation to local areas can achieve a cure in 40 - 50% of patients.
Chemotherapy. Chemotherapy uses drugs to kill cancer cells.
Watchful waiting. Patients who choose watchful waiting must be aware of signs and conditions indicating the need for treatment. These include B symptoms, endangered organs, massive bulky tumors, or a steady progression that lasts at least 6 months.
Investigative treatments, such as conjugated and unconjugated monoclonal antibodies or radiation plus chemotherapy. In one study, a combination of therapies worked better than radiation alone.

The following are treatment options for some specific low-grade lymphomas:

Mucosa-associated lymphoid tissue (MALT) lymphoma. When disease is in the stomach (gastric MALT) and the patient is infected with H. pylori bacteria, antibiotics can cause regression in a significant number of patients with stage I lymphoma. In certain patients where antibiotics fail, or are not appropriate, radiation alone can achieve significant cure rates. Surgery with or without radiation, or chemotherapy with or without radiation, are possible options. Treatment options for patients with MALT localized in other sites depend on the location of the specific disease and range from radiation to chemotherapy to biologic therapies, such as interferon.
Primary gastric lymphoma (indolent). Radiation is the typical treatment for this lymphoma, which is located only in the stomach, small intestine, or other nearby regions. Surgery is being reconsidered since it seems to offer no advantage.

Click the icon to see an image of the digestive system.

Early Stage Aggressive (Intermediate- to High-Grade) Lymphomas. Treatment options include:

Chemotherapy alone
Combinations of chemotherapy (usually CHOP) plus radiation therapy
Radiation alone (rarely)
Chemotherapy alone or with surgery for lymphoma in the gastrointestinal region
Immunotherapies (rituximab, Bexxar) with or without chemotherapy (usually CHOP), or high dose chemotherapy and bone marrow or stem cell transplantation

In stage III, lymphoma is found in lymph node areas on both sides of the diaphragm (for instance, in both the chest and the abdomen). The lymphoma may also have spread to the spleen. In stage IV, lymphoma has spread via the bloodstream to organs outside the lymph system, such as the bone marrow or brain. Lymphoma cells may or may not be in the lymph nodes near these organs.

Advanced Stage Indolent (Low-Grade Lymphomas). Treatment options are controversial because of the low-cure rate and yet slow-growing nature of these lymphomas. Patients without symptoms are often managed by watchful waiting, in which the disease is monitored closely for development of symptoms or bulky tumor masses, particularly if they threaten major organs. At such times, treatment is started. Treatment may include:

Chemotherapy combinations (CHOP, CVP, CMOPP)
Nucleoside analogs (for example, fludarabine) alone or with chemotherapy
Oral alkylating chemotherapy drugs such as cyclophosphamide or chlorambucil with or without steroids
Monoclonal antibodies (MAbs) such as rituximab alone or in combinations with CHOP or nucleoside analogs
Chemotherapy plus interferon
Clinical trials involving intensive chemotherapy and radiation followed by bone marrow or stem cell transplantation

Advanced Stage Aggressive (Intermediate- to High-Grade) Lymphomas. Treatment options may include:

Doxorubicin-based combination chemotherapy with or without rituximab
Chemotherapy plus radiation therapy
Immunotherapies with or without chemotherapy
Treatments to prevent disease from spreading to the central nervous system in high-risk patients
Clinical trials for patients at high risk for relapse, involving intensive chemotherapy, high dose chemotherapy, and bone marrow or stem cell transplantation

Indolent-Lymphomas Relapses. Nearly all patients with indolent lymphomas relapse after initial treatment, with length of remission after a first treatment averaging 18 - 50 months. Successful retreatment is often possible, but disease-free periods become increasingly shorter with each subsequent treatment.

Older patients may choose watchful waiting. Other treatment options may include:

Radiation alone or with chemotherapy -- in one study low-dose involved-field radiotherapy was very effective in recurring indolent lymphoma
Chemotherapy
High-dose chemotherapy with autologous stem cell transplant
Clinical trials involving monoclonal antibodies, radioimmunotherapy, nucleoside analogues alone or in combination with other drugs, or stem cell transplantation followed by biologic therapies

Aggressive Lymphomas Relapse. After initial treatment, more than half of patients with aggressive lymphomas are cured, while about 20% progress, and the other 30% relapse after a disease-free period. Among those who relapse, many can still be cured with aggressive treatments.

Treatment options:

Bone marrow or peripheral stem cell transplantation
Bone marrow transplantation with radiation
Clinical trials that involve continuous infusion chemotherapy, biologic therapies (monoclonal antibodies) alone or in combination with transplantation

Click the icon to see an illustrated series detailing bone marrow transplant surgery.

Treating Lymphoma Restricted to the Central Nervous System. Treatment options may include:

High-dose methotrexate regimens alone or in combination with radiation
Corticosteroids and radiation
Clinical trials that involve biologic therapies, such as rituximab or interferon alpha administered directly into the spinal fluid (intrathecal administration) for meningitis related to central nervous system lymphoma

Preventing (Prophylactic Treatment) Lymphomas in High-Risk Patients. Treatment to prevent the spread of NHL to the central nervous system may be appropriate in some patients. It is not recommended for patients with low-grade NHL. Preventive treatment may be appropriate for certain patients with high-grade NHL, such as those with lymphoblastic and Burkitt's lymphoma or if they have 4 - 5 of the following risk factors: Elevated levels in the blood of the enzyme acetate dehydrogenase and albumin (a common protein), being older than 60, and having lymph nodes beyond the peritoneum (the lining of the abdomen) and involvement of more than one site outside a lymph node.

Chemotherapy

Chemotherapy plays a role in the treatment of nearly all lymphoma patients and has achieved remarkable results, even in late stages. It uses drugs to kill cancer cells. Such drugs are called cytotoxic drugs. Chemotherapy is referred to as bodywide or systemic therapy because the drugs travel throughout the bloodstream to the entire body.

Studies indicate that chemotherapy as sole treatment is adequate for most children and young adults in early, and perhaps in many advanced, stages. (Radiation has been commonly used for these patients but can be particularly dangerous for children.)

A chemotherapy cycle is usually 21 - 28 days. Patients take the drugs for a few days, then have a period of rest. The drugs may be taken by mouth or given by injection. Chemotherapy is injected into the spinal fluid if the cancer has spread to the brain. This is called intrathecal chemotherapy. Intrathecal chemotherapy is also used as a preventive measure in patients at high risk for central nervous system involvement. Chemotherapy may be administered at a medical center or in a doctor's office. Some patients receiving chemotherapy need to remain in the hospital for several days so the effects of the drug can be monitored. Patients with lymphoblastic lymphoma may need long-term maintenance chemotherapy. Such therapy does not seem to benefit patients with small-noncleaved-cell and large-cell lymphomas.

CHOP. The current standard chemotherapy regimen for NHL is CHOP. CHOP is a combination of cyclophosphamide, doxorubicin hydrochloride (Adriamycin), vincristine (Oncovin), and prednisone. It is proving to be particularly effective for many stages of lymphoma when used in combination with rituximab (Rituxan), a monoclonal antibody. (See Biologic Therapy section.) Some studies of this combination in low-grade lymphomas have reported response rates of 70 - 100%. CHOP alone is still preferred for HIV patients, who tend to have a toxic response to rituximab.

CVP. This stands for cyclophosphamide, vincristine, and prednisone. It may be used with CHOP in certain cases.

Fludarabine and Nucleoside Analogues. Fludarabine (Fludara) is a type of drug called a nucleoside analogue. It is one of the most active drugs for treating low-grade lymphomas and may be effective for other NHLs, including mantle cell lymphomas. Promising regimens containing fludarabine are under investigation. For example, FND (fludarabine, mitoxantrone, and dexamethasone) may be helpful in combination with rituximab for certain patients, including those with indolent NHL. Other nucleoside analogues include gemcitabine and cladribine. Toxicities and infection rates from high dose nucleoside analogues have been high. Fludarabine also has been associated with a risk for leukemia.

Bendamustine. This potent drug has shown to be effective for indolent NHLs and possibly aggressive lymphomas. One study suggested that a single dose of low-dose etoposide, taken by mouth, may be beneficial for elderly patients.

Antibiotics. Antibiotics, such as doxycycline, may cure or put into complete remission about half of mucosa-associated lymphoid tissue (MALT) lymphoma cases. MALT lymphoma is a type of lymphoma that sometimes affects the eyes. It is associated with the bacterium Helicobacter pylori (H. pylori ), which also causes stomach ulcers. Recent studies indicate that antibiotics are a good alternative to chemotherapy or radiation for patients with this type of lymphoma. Patients most likely to respond positively to antibiotics are those with MALT lymphoma in its early stages.

Vorinostat. Vorinostat (Zolinza) was approved in 2006 for treatment of cutaneous T-cell lymphoma (CTCL), a rare form of NHL.

Side effects and complications of any chemotherapeutic regimen are common. They are more severe with higher doses. Side effects may increase over the course of treatment.

Common Side Effects. Common side effects include:

Nausea and vomiting -- Drugs known as serotonin antagonists, such as ondansetron (Zofran) or granisteron (Kyril), can relieve these side effects in nearly all patients given moderate drugs and in most patients who take more powerful drugs.
Diarrhea
Hair loss
Weight loss
Depression

These side effects are nearly always temporary. Most patients are able to continue with normal activities for all but perhaps a few days a month.

Serious Side Effects. Serious chemotherapy side effects can also occur and may vary depending on the specific drugs used. They include:

Neutropenia is a severe drop in white blood cells. Neutropenia increases the chance for infection from suppression of the immune system and is a potentially life-threatening condition. Drugs known as granulocyte colony stimulating factor (G-CSF) are used to help boost white blood cell count. These drugs, which include filgrastim (Neupogen) and pegfilgrastim (Neulasta), can help lessen the risk for neutropenia occurrence and, if neutropenia does occur, to reduce its length and severity.
Anemia is a lack of red blood cells. Erythropoietin stimulates red blood cell (hemoglobin) production and can help reduce or prevent this side effect. It is available as epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). In 2007, the FDA released strict dosing guidelines for these drugs. In patients with cancer, they should be used to treat only anemia associated with chemotherapy and to increase hemoglobin levels to no more than 12 g/dL. Treatment should stop as soon as chemotherapy is complete. These drugs may not be safe or appropriate for all patients.
Liver and kidney damage
Abnormal blood clotting (thrombocytopenia)
Allergic reaction

Long-Term Complications.

Fatigue and Somatic Symptoms. Chemotherapy has been associated with long-term somatic symptoms, which are general conditions, such as fatigue and aches and pains that have no apparent physical basis. Fatigue is especially common after chemotherapy and can even last for years.
The most serious long-term complications from chemotherapy are secondary cancers, particularly in people over age 40.
Infertility is a risk, particularly with the use of cyclophosphamide.
Some patients get osteoporosis (bone thinning) and damage in bone cells.
Regimens containing certain drugs, particularly doxorubicin or mitoxantrone, increase the risk for future heart failure.

Click the icon to see an image of the uterus and ovaries.

In general, these serious late side effects are dependent on the cumulative drug dose and rate of administration.

Doctors are particularly concerned about the effects of combinations of chemotherapy with radiation, especially leukemia and heart problems. Interestingly, in one study on patients with intermediate- and high-grade NHL, those on chemotherapy alone had more toxic effects than those on combined modality, most likely because it employed fewer cycles of chemotherapy. Better radiation techniques are also reducing the risks of combined modality treatments.

Biologic Therapy (Immunotherapy)

Biological response modifier therapy, also called immunotherapy, uses the body's own immune system to fight cancer using natural or laboratory-developed factors. These drugs are often combined with other treatments.

Monoclonal antibodies (MAbs) are designed in the laboratory to produce the same effects as natural antibodies and are exciting new weapons in the anti-cancer armament. They bind to specific proteins called antigens and make them vulnerable to attack by other factors in the immune system. Lymphomas carry antigens that provoke strong immune responses and so are believed to be particularly good candidates for MAb therapy.

MAbs are called either unconjugated or conjugated, depending on how they are designed to destroy the cancer cell.

Unconjugated monoclonal antibodies rely on a strong natural immune system. The antibody builds up at the tumor site until it is able to trigger an immune response against the cancer. A possible downside to this form is the potential development of tolerance to the antibody so that it loses its effectiveness. Rituximab is an unconjugated form and the first MAb to be approved for any cancer.
Conjugated monoclonal antibodies are linked to a plant or bacterial toxin or radioisotope. The antibody specifically attacks the antigen on the lymphoma cell, and the toxin or radioactive material from the isotope kills it.

Unconjugated MAbs (Rituximab). Rituximab (Rituxan) was the first monoclonal antibody approved for cancer. This drug targets the CD-20 antigen, which is found on most B-cell lymphomas.

First approved in 1997 for treatment of relapsed or refractory NHL, rituximab has received several expanded indications since that time. As of 2006, rituximab is approved for:

Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell, NHL
First-line treatment of diffuse large B-cell (DLBC), CD20-positive, NHL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens
First-line treatment of follicular, CD20-positive, B-cell NHL in combination with CVP (cyclophosphamide, vincristine and prednisolone) chemotherapy
Low-grade, CD20-positive, B-cell NHL in patients with stable disease or patients who have been partially or completely helped by first-line treatment with CVP chemotherapy

Rituximab in combination with CHOP (a regimen called R-CHOP, or CHOP-R) is used for first-line treatment for aggressive lymphomas, with studies reporting 3-year event-free survival of 53% compared to 35% with CHOP alone. A 2006 study also indicated that rituximab provides benefits when used as maintenance treatment after CHOP or R-CHOP induction therapy. Rituximab plus CHOP is also showing promise as a first-line treatment for mantle cell lymphoma.

Rituximab is given by infusion. The treatment has mild-to-moderate short-term side effects, including nausea, fever, chills, hives, dizziness, and headache. Uncommon and more serious side effects are severe allergic reactions, very low blood pressure, blood abnormalities, wheezing, infections, and sudden heart events.

Rituximab has also been associated with cases of progressive multifocal leukoencephalopathy (PML), a rare and potentially deadly brain infection. Patients who experience any of the following symptoms should immediately contact their doctors:

Vision problems or unusual eye movements
Confusion
Dizziness or loss of balance
Difficulty talking or walking

Patients who have previously had hepatitis B, or who are at high-risk for this viral infection, should be tested before taking rituximab because the drug has been linked to reactivation of the hepatitis B virus. Patients who are HIV-positive may experience more adverse effects from rituximab than with CHOP.

Conjugated Monoclonal Antibodies with Radioimmunotherapy. Conjugated MAbs with radioimmunotherapy contain tiny amounts of radioactive materials. When the drug is injected, the monoclonal antibody targets an antigen (protein) on the surface of the tumor. The radioisotope is then delivered directly into the tumor where it kills the cancer. Ibritumomab and tositumomab both target the CD-20 antigen. Treatment with these drugs takes about 7 - 9 days to complete, compared to several months for traditional chemotherapy treatments.

Ibritumomab (Zevalin) is approved for patients with relapsed or refractory low-grade, follicular or transformed B-cell NHL. It is also approved for patients with follicular NHL who have not responded to rituximab (Rituxan). Research indicates it may also be safe for patients with advanced NHL who have had stem cell transplantation. Zevalin uses an yttrium-90 (90-Y) radioactive isotope.
Tositumomab and Iodine I-131 (Bexxar) combines the monoclonal antibody tositumomab with the radioisotope I-131. The Bexxar treatment is approved for treatment of relapsed or refractory low-grade, follicular, or transformed B-cell NHL. Overall response rates of 56% have been reported with Bexxar, with up to 30% being complete responses (no evidence of cancer). Recent studies suggest that when Bexxar is used as a first treatment, it may produce long-term complete remission in patients with advanced stage follicular lymphoma. In a 2005 New England Journal of Medicine study, 95% of previously untreated patients with advanced follicular lymphoma responded to Bexxar, and 75% had complete responses. Seventy percent who had complete responses from Bexxar treatment were still disease-free 4 - 7 years later.

In general, these drugs cause fewer side effects than traditional chemotherapy. However, serious complications may include skin infections, severe allergic reactions, and temporary lowering of blood counts.

Other Monoclonal Antibodies. Other MAbs are being developed that target other antigens on lymphomas. For example, epratuzumab targets CD-22 and is showing promise in early studies. Some are being studied in both conjugated and unconjugated forms and also in combination with MAbs that target different antigens.

Interferon alpha (Intron A) is used as an antiviral drug that also has properties that are effective against some common forms of NHL, particularly low-grade, follicular NHL in advanced stages. It is usually combined with chemotherapy regimens such as CHOP that contain an anthracycline drug (usually doxorubicin). The combination is toxic, however, and outcomes vary. Interferon is also being studied for lymphomas in the central nervous system. It may be useful after autologous stem cell transplantation.

Side Effects. Side effects of interferon include flu-like symptoms, severe depression, irritability, weight loss, vomiting, general weakness and loss of strength, and fever. About a third of patients have a severe drop in white blood cells. About 10% of patients cannot tolerate the drug's side effects.

Cytotoxic Deoxyguanosine Analogue Prodrugs. Nelarabine (Arranon) is approved for treating T-cell lymphoblastic lymphoma (T-LBL). T-LBL is a rare form of lymphoma that accounts for less than 2% of all cases of NHL.

Proteasome Inhibitors. In 2006, bortezomib (Velcade) was approved for treatment of mantle cell lymphoma in patients who have received at least one prior therapy.

Cyclin-Dependent Kinase Inhibitors. Flavopiridol, a drug known as a cyclin-dependent kinase inhibitor, is showing some effect in patients with mantle-cell lymphoma. This drug is designed to block enzymes that regulate cell cycles and help block their growth.

Vaccines. Although still experimental, lymphoma vaccines are used to treat -- not prevent -- cancer. They are part of an immunotherapy approach called personalized medicine; each vaccine is individually tailored to the genetic composition of the patient’s tumor. The vaccine is usually given a few months after a patient receives chemotherapy. Several different vaccines, including the BiovaxID and MYVax, are in late-stage clinical trials.

Radiation

Radiation is commonly used to treat indolent lymphomas. The dose administered ranges from 35 - 50 Gy and depends on a number of factors: The type of lymphoma, the age of the patient, whether the intent is to cure or relieve symptoms, how close sensitive organs are to the diseased area, and whether radiation is being combined with chemotherapy.

Radiation is tailored to the individual and usually limited to the diseased areas and possibly nearby regions:

If the lymphoma is confined to tissues above the diaphragm, radiation is delivered to the neck, chest, and under arms (called the mantle-field) and sometimes to lymph nodes in the upper abdomen or spleen or both.
If the lymphoma is below the diaphragm, subtotal nodal radiation may be used, which is directed to other regions, including lymph nodes in the upper abdomen, spleen, and pelvis, in addition to the mantle-field.
Radiation to the brain is called cranial radiation.
Total body irradiation is sometimes performed, although it is not clear whether its high toxicity outweighs any advantages.

Devices called planning simulators allow doctors to plan x-ray treatments that accurately conform to the patient's anatomy so that protective shields can be created to precisely protect the regions outside the treatment areas.

Side effects and complications of radiation generally depend on the target site in the body. They include:

Dental problems
Inflammation in the lungs -- with carefully conducted therapy, the risks for lung complications are small. Lung impairment may not even be evident, and the lungs usually recover after 2 - 3 years.
Hypothyroidism
Infections
Long-term risk for heart disease
Long-term risk for certain cancers -- of particular concern is a possible increased risk for breast cancer. Studies indicate that young women and adolescent girls are at highest risk, with the incidence increasing significantly 15 years after treatment. The risk is greater in those who had higher radiation doses. Radiation may also increase the risk over time for other cancers, including lymphoma and thyroid, lung, and colon cancers, although the risk is still low. Smoking, of course, increases the risk for lung cancer. Radiation of bone marrow increases the risk for leukemia.
Impaired bone growth -- children and adolescents are at special risk for bone problems caused by radiation. Experts are finding that radiation for many children and young adults in early stages or NHL is no more effective and has more serious long-term effects than chemotherapy. Some believe that radiation should play no role in the treatment of young people, except in special cases, such as lymphomas that require radiation to the brain.
Infertility -- the negative effects on fertility may be worse in women than in men; sperm usually recover within 5 years. To protect the ovaries, a technique called ovarian transposition is sometimes used. Transposition may sometimes be performed through a laparoscope, a thin tube containing tiny instruments and cameras, which is introduced through a small incision. The doctor uses the laparoscope to move the ovaries out of the range of areas being treated with radiation.

Click the icon to see an image of the lungs.

Click the icon to see an image of hypothyroidism.

Click the icon to see an image of the uterus and ovaries.

Transplantation

Stem cell procedures have proven to produce long-term survival and even cures in some patients with intermediate- and high-grade non-Hodgkin's lymphomas.

Stem cell transplantation involves removing and replacing stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments harm growing cells as well as cancer cells, and so the healthy stem cells must be replaced by transplanting them from the donor into the patient.

Sources of Cells. Stem cells must first be collected in one of the following ways:

Directly from blood, called peripheral blood stem cell transplantation
From bone marrow, called bone marrow transplantation
From umbilical cords or placentas -- this procedure uses donor cells, but has a lower risk for immune system rejection of the cells than with a standard donor transplant. It takes longer to restore blood cells with this process, so it is generally used for children and sometimes adults with low weight.

Some evidence suggests that both stem cell and bone marrow procedures produce similar benefits in terms of response rates and duration of remission. However, in one study, stem cell transplantation was associated with better overall survival rates. It also seems to be superior in terms of cost, quality of life, and the need for less supportive care.

Donor or Patient Cells. The marrow or blood stem cells can be taken from the patient (autologous) or from a matched donor (allogeneic):

In an autologous transplant, the marrow or blood cells used for replacement are taken from the patient. There is some danger, however, that these cells may contain tumor cells, and that the cancer can regrow. It is unclear if this approach improves survival compared to standard chemotherapy for newly diagnosed disease. However, it clearly has benefits in the treatment of some forms of relapsed non-Hodgkin's lymphomas. There is also a higher risk for leukemia. (This risk is lower in peripheral stem cells transplants than in bone marrow transplants.)
In an allogeneic transplant, bone marrow or stem cells are taken from a donor. Siblings are the best donors. Relapse rates can be very low with this approach, and cure may be possible in some cases. However, it is highly toxic and donor and recipient must be matched as closely as possible to avoid rejection by the immune system, a serious complication called graft-versus-host disease. Advances in techniques are reducing the toxicities associated with this approach. Older patients who cannot tolerate the preparatory treatment required for a standard allogeneic transplant may be able to receive a non-myeloblative transplant (“mini-transplant), which uses lower doses of chemotherapy and radiation.

The Blood Stem Cell Collection Procedure. With peripheral blood stem cell transplantation:

The donor is usually given a drug called granulocyte colony-stimulating factor, or G-CSF (filgrastim, lenograstim, pegfilgrastim) to stimulate stem cell growth.
The patient (or donor in an allogeneic procedure) then undergoes apheresis. With this process the blood is withdrawn from one of the patient's veins, then passes through a machine that filters out the white cells and platelets, which contain the stem cells. The blood is returned through another vein. The entire procedure takes 3 - 4 hours but needs to be repeated several times.
The stem cells are treated to remove contaminants and then are frozen to keep them alive until the patient is ready to receive them back.

Blood is the only fluid tissue in the body. Blood transports oxygen and nutrients to body tissues, and returns waste and carbon dioxide. Blood distributes nearly everything that is carried from one area in the body to another place within the body. For instance, blood helps transport hormones from the endocrine organs to their target organs. Blood also helps maintain body temperature. The protective functions of blood include clot formation and the prevention of infection.

Allogeneic transplants are preceded by chemotherapy treatment known as conditioning. The point of this treatment is to inactivate the immune system and to kill any residual malignant cells. It is extremely toxic since it also destroys non-malignant marrow cells. Drugs used are typically cyclophosphamide, carmustine, and etoposide. Alternative conditioning to reduce toxicity includes total-body radiation plus drugs. Monoclonal antibodies, such as rituximab, are promising drugs, since they have low toxicity and may add benefits for all stages of transplantation.
A few days after treatment, the patient given the stored stem cells, which are administered through a vein. This may take several hours. Patients may have a fever, chills, hives, shortness of breath, or a fall in blood pressure during the procedure.
The patient may be treated with granulocyte colony-stimulating factor after chemotherapy. The goal is to stimulate the growth of infection-fighting white blood cells. Adding thrombopoietin may help enhance stem cell production.
The patient is kept in a protected environment to minimize infection. Patients who have received an allogeneic transplant may need blood cell replacement, nutritional support, and drugs to treat graft-versus host disease. They usually can leave the hospital within 3 - 5 weeks.

Candidates. These procedures are typically used for patients with relapsed aggressive lymphoma who are still sensitive to the effects of chemotherapy. The procedures do not work for patients whose tumors are not responsive to drugs. Some evidence suggests that certain primary (non-relapsed) lymphomas initially unresponsive to a first round of chemotherapy but who respond to a second round may benefit from combination of high-dose chemotherapy and radiation followed by transplantation. Transplantation is also being investigated as first-line therapy for patients with aggressive lymphomas, although at this time evidence does not support its use.

Success Rates. Success rates vary depending on many factors. The following are survival rates reported by a few studies of patients with different lymphomas:

In patients with refractory or relapsed intermediate grade NHL who received autologous transplantation, 5-year survival rates averaged 34%.
In a study of allogeneic bone marrow transplantation, 58% of patients with late-stage low-grade lymphoma had survived after an average of 29 months.
Patients with anaplastic large-cell lymphoma were treated with autologous stem cell transplantation with intensified chemotherapy as first line-therapy. Survival rates were 87% at 5 and more years afterward. (Survival was much lower with other lymphomas.)
Patients with diffuse aggressive NHL who did not achieve a first remission but who are still sensitive to chemotherapy achieved a 5-year survival rate of up to 37% after autologous stem cell transplantation.
In one study, 35% of patients with an initial poor prognosis were still alive 5 years after an allogeneic stem cell transplantation, although mortality probability from the treatment itself was very high (48%).

Common side effects include nausea, vomiting, fatigue, mouth sores, and loss of appetite.

The procedures themselves are fairly dangerous and carry a small risk for death. When it was first used, transplantation procedures had 10 - 25% morality rates. Now mortality rates are below 5%.

Infection resulting from a weakened immune system is the most common side effect. Because the stem cell procedure is done more swiftly, the risk period is shorter than with bone marrow transplantation. The risk for infection is most critical during the first 6 weeks following the transplant, but it takes 6 - 12 months post-transplant for a patient’s immune system to fully recover. Immune systems of patients with graft-versus-host disease can take even longer to function normally.

Many patients develop severe herpes zoster virus infections (shingles) or have a recurrence of herpes simplex virus infections (cold sores and genital herpes). Pneumonia, cytomegalovirus, aspergillus (a type of fungus), and Pneumocystis carinii (a protozoan) are among the most important life-threatening infections.

It is very important that patients take precautions to avoid infections. Guidelines for post-transplant infection prevention include:

Discuss with your doctor what vaccinations you need and when you should get them.
Avoid crowds, especially during cold and flu season.
Be diligent about handwashing and make sure that visitors wash their hands.
Avoid eating raw fruits and vegetables -- food should be well cooked. Do not eat foods purchased at salad bars or buffets. In the first few months after the transplant, be sure to eat protein-rich foods to help restore muscle mass and repair cell damage caused by chemotherapy and radiation.
Boil tap water before drinking it.
Dental hygiene is very important, including daily brushing and flossing. Schedule regular visits with your dentist.
Do not sleep with pets. Avoid contact with pets’ excrement.
Avoid fresh flowers and plants as they may carry mold. Do not garden.
Swimming may increase exposure to infection. If you swim, do not submerge your face in water. Do not use hot tubs.
Report to your doctor any symptoms of fever, chills, cough, difficulty breathing, rash or changes in skin, and severe diarrhea or vomiting. Fever is one of the first signs of infection. Some of these symptoms can also indicate graft-versus-host disease.
Report to your ophthalmologist any signs of eye discharge or changes in vision. Patients who undergo radiation or who are on long-term steroid therapy have an increased risk for cataracts.

Graft-versus-host disease (GVHD) is a serious attack by the patient's immune system triggered by the donated new marrow in allogeneic transplants. Mild cases of GVHD can actually be helpful as they can cause graft-versus-lymphoma where the immune system kills remaining lymphoma cells. Still, severe GVHD can pose serious complications.

To reduce the risk for GVHD, doctors remove some immune T-cells from the donor’s stem cells before the transplant. Researchers are investigating new techniques to refine this process of T-cell depletion.

Acute GVHD occurs in 30 - 50% of allogeneic transplants, usually within 25 days. Its severity ranges from very mild symptoms to a life-threatening condition (more often in older patients). The first sign of acute GVHD is a rash, which typically develops on the palms of hands and soles of feet and can then spread to the rest of the body. Other symptoms may include nausea, vomiting, stomach cramps, diarrhea, loss of appetite and jaundice (yellowing of skin and eyes). To prevent acute GVHD, doctors give patients immune-suppressing drugs such as steroids, methotrexate, cyclosporine, tacrolimus, and monoclonal antibodies.

Chronic GVHD can develop 70 - 400 days after the allogeneic transplant. Initial symptoms include those of acute GVHD. Skin, eyes, and mouth can become dry and irritated, and mouth sores may develop. Chronic GVHD can also sometimes affect the esophagus, gastrointestinal tract and liver. Bacterial infections and chronic low-grade fever are common. Chronic GVHD is treated with similar medicines as acute GVHD.

Too much sun exposure can trigger GVHD. Be sure to always wear sunscreen (SPF 15 or higher) on areas of the skin that are exposed to the sun. Stay in the shade when you go outside.

Secondary cancers. There is a small long-term risk for leukemia after transplantation in young people. Use of newer chemotherapeutic drugs, however, may not pose as high a danger as older treatments.

Other potentially serious complications include:

Bleeding because of reduced platelets (highest risk within the first 4 weeks); blood transfusions may be required
Infertility
Organ complications to the liver, heart, kidney, or lungs
Failure of the transplant
Muscle problems including stiffness, cramps, and joint pain
Frequent urination and bladder control problems
Older patients should be screened for osteoporosis (bone thinning) and hypothyroidism (underactive thyroid)

Surgery

Surgery is sometimes used to remove as much malignant tissue as possible before administering chemotherapy. This is particularly useful for bulky tumors that occur in the stomach.

Surgery is sometimes performed for primary gastric lymphoma, but its advantages are uncertain. Some studies indicate that chemotherapy alone or with radiation may be sufficient and could spare many patients from surgery.

Resources

www.cancer.gov -- National Cancer Institute
www.cancer.org -- American Cancer Society
www.leukemia.org -- The Leukemia and Lymphoma Society
www.canceradvocacy.org -- National Coalition for Cancer Survivorship
www.marrow.org -- National Marrow Donor Program
www.asco.org -- American Society of Clinical Oncology
www.lymphoma.org -- Lymphoma Research Foundation
www.plwc.org -- People Living with Cancer
www.oncolink.org -- Cancer information
www.fhcrc.org/science/clinical/ltfu/patient -- Fred Hutchinson Cancer Research Center -- Transplant Infection Guidelines for Patients
www.lymphomainfo.net -- Lymphoma Information Network
www.cancer.gov/clinicaltrials -- Find clinical trials

References

Boffetta P, de Vocht F. Occupation and the risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2007: 16(3):369-72.

Ferrara JL. Novel strategies for the treatment and diagnosis of graft-versus-host-disease. Best Pract Res Clin Haematol. 2007. 20(1):91-7.

Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol. 2007 Feb 10;25(5):571-8. Epub 2007 Jan 22.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphoma. V.3.2007.

Seam P, Juweid ME, Cheson BD. The role of FDG-PET scans in patients with lymphoma. Blood. 2007 Nov 15;110(10):3507-16. Epub 2007 Aug 20.

Review Date:
1/21/2008
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A.D.A.M. Copyright

adam.com

Shingles and chickenpox (Varicella-zoster virus)

FitSugar — Wed, 08 Oct 2008 17:35:12 -0700

In This Report

Highlights
Introduction
Symptoms
Risk Factors
Complications
Vaccination
Diagnosis
Treatment for Chickenpox...
Treatment for an Acute Shin...
Treatment for Postherpetic ...
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

New Chickenpox Immunization Schedule

In 2007, the U.S. Centers for Disease Control (CDC) updated the immunization schedule for the chickenpox vaccine. The CDC now recommends that children receive two doses of the vaccine. Children should receive:

The first dose when they are 12 – 15 months old
The second dose when they are 4 – 6 years old

If your child has been previously vaccinated, make sure that the pediatrician administers a second “catch-up” dose. It is clear that one dose of chickenpox vaccine does not provide complete protection against chickenpox. Adults who are at high risk of contracting chickenpox should also receive two doses of the chickenpox vaccine.

Shingles Vaccine

In 2006, the FDA approved the first shingles vaccine (Zostavax). The CDC now recommends that all adults with intact immune systems who are age 60 years and older receive this vaccine to help prevent herpes zoster (shingles). This includes adults who have previously had a shingles attack. Evidence indicates that Zostavax can help prevent the occurrence of shingles by about 50%. The vaccine can also help prevent the development of post-herpetic neuralgia (the nerve pain that can follow shingles) by 67%.

Scientists Identify Varicella-Mediating Protein

The varicella-zoster virus causes both chickenpox and shingles. After a chickenpox attack, the virus can lie dormant in the body for many years. Once reactivated, the virus quickly travels through nerve cells, causing rash and nerve pain. In 2006, scientists at the U.S. National Institutes of Health identified a specific protein that causes the virus to spread throughout cells in the body. Researchers hope that this important discovery may lead to new drug treatments for shingles.

Investigational Treatments for Postherpetic Neuralgia

Intravenous antiviral drug treatment, followed by oral antiviral drugs, may help reduce postherpetic neuralgia pain, according to a small study published in the Archives of Neurology.

Introduction

Shingles and chickenpox were once considered separate disorders. Researchers now know that they are both caused by a single virus of the herpes family known as varicella-zoster virus (VZV). The word herpes is derived from the Greek word "herpein," which means "to creep," a reference to a characteristic pattern of skin eruptions. VZV is still referred to by separate terms:

Varicella: The primary infection that causes chickenpox
Herpes zoster: The reactivation of the virus that causes shingles

Varicella (Chickenpox). When patients with chickenpox cough or sneeze, they expel tiny droplets that carry the virus. If a person who has never had chickenpox or been vaccinated inhales these particles, the virus enters the lungs. From here it passes into the bloodstream. When it is carried to the skin it produces the typical rash of chickenpox.

Chickenpox is caused by the varicella-zoster virus, a member of the herpes virus family. The same virus also causes herpes zoster, shingles, in adults. Chickenpox is extremely contagious, and can be spread by direct contact, droplet transmission, and airborne transmission. Symptoms range from fever, headache, stomach ache, or loss of appetite before breaking out in the classic pox rash. The rash can consist of several hundred small, itchy, fluid-filled blisters over red spots on the skin. The blisters often appear first on the face, trunk, or scalp and then spread to other parts of the body

Herpes Zoster (Shingles). The varicella virus also travels to nerve cells called dorsal root ganglia. These are bundles of nerves that transmit sensory information from the skin to the brain. Here, the virus can hide from the immune system for years, often for a lifetime. This inactivity is called latency.

Click the icon to see an image of shingles.

If the virus becomes active after being latent, it causes the disorder known as shingles. The virus in this later form is referred to as herpes zoster. The virus spreads in the ganglion and to the nerves connecting to it. Nerves most often affected are those in the face or the trunk. The virus can also spread to the spinal cord and into the bloodstream. In 2006, scientists at the U.S. Institutes of National Health identified a specific protein, called insulin-degrading enzyme, which causes the varicella-zoster virus to spread throughout cells in the body. The scientists hope that this discovery may eventually help in developing new drug therapies for treating shingles.

It is not clear why the varicella virus reactivates in some people but not in others. In many cases, the immune system has become impaired or suppressed from certain conditions such as AIDS, other immunodeficient diseases, or certain cancers or drugs that suppress the immune system. Aging itself increases the risk for shingles.

The varicella-zoster virus belongs to a group of herpes viruses that includes eight human viruses (it also includes animal viruses as well). Herpes viruses are similar in shape and size and reproduce within the structure of a cell. The particular cell depends upon the specific virus. The human herpes viruses are:

Herpes Simplex Virus 1 (HSV-1; causes cold sores and sometimes genital herpes)
Herpes Simplex Virus 2 (HSV-2; causes genital herpes and sometimes cold sores)
Varicella-zoster Virus (VZV; causes chickenpox and shingles)
Cytomegalovirus (CMV; causes mononucleosis and retinitis)
Epstein-Barre Virus (EBV; causes mononucleosis
Human Herpesvirus 6 (HHV6; causes roseola)
Human Herpesvirus 7 (HHV7; causes roseola)
Human Herpesvirus 7 (HHV8; causes Kaposi's sarcoma)

All herpes viruses share some common properties, including a pattern of active symptoms followed by latent inactive periods that can last for months, years, or even for a lifetime. [See In-Depth Report #52: Herpes simplex.]

Symptoms

The time between exposure to the virus and eruption of symptoms is called the incubation period. For chicken pox, this period is 10 - 20 days. The patient often develops fever, headache, swollen glands, and other flu-like symptoms before the typical rash appears. While fevers are low grade in most children, some can reach up to 105° F.

These symptoms subside once the rash breaks out. One or more tiny raised red bumps appear first, most often on the face, chest, or abdomen. They become larger within a few hours and spread quickly, eventually forming small blisters on a red base. The numbers of blisters vary widely. Some patients have only a few spots, others can develop hundreds. Each blister is filled with clear fluid that becomes cloudy in several days. It takes about 4 days for each blister to dry out and form a scab. During its course, the rash itches, sometimes severely. Usually separate crops of blisters occur over 4 - 7 days, and the entire disease process lasts 7 - 10 days.

Chickenpox itself usually occurs only once, although mild second infections, marked by the telltale rash, have been reported in older children years after their first infection.

Shingles nearly always occurs in adults. It develops on one side of the body. Usually two, and sometimes three, identifiable symptom stages occur:

The first is known as the prodrome, a cluster of warning symptoms that appear before the outbreak of the infection.
The second stage comprises the symptoms of the active infection itself.
In many patients, a third syndrome known as postherpetic neuralgia develops.

One form of shingles is known as zoster sine herpes, in which pain occurs first without a rash. Pain is so common to all stages of herpes zoster that doctors often refer to all syndromes with a single term: Zoster-Associated Pain (ZAP).

Prodrome (Pain).

Pain is the primary early symptom for shingles, and it occurs in all patients. The pain most often occurs in the skin at the site of the re-activated virus. The pain may be experienced as sharp, aching, piercing, tearing, or similar to an electric shock.
The affected skin may itch, feel numb, and be unbearably sensitive to touch. Often the patient experiences a combination of these sensations along with pain.
In addition, some patients may have flu-like symptoms such as muscle aches. (Some people have fever, but it is uncommon.)

The prodrome stage lasts 1 - 5 days before the infection becomes active and the skin rash erupts. Occasionally, the pain can last weeks or even months before the rash erupts.

Active Shingles. The rash that marks the active infection follows the same track of inflamed nerves as the prodrome pain. Between 50 - 60% of cases occur on the trunk. The second most common site is the head, particularly on one side of the face. It may also erupt on the neck or lower back. If the face is affected, there is a danger that the infection can spread to the eye or mouth. A rash that follows the side of the nose is a warning that the cornea of the eye is in danger.

This is a picture of herpes zoster (shingles) on the neck and cheek. The same virus that causes chickenpox is responsible for outbreaks of shingles. Outbreaks of shingles often follow the distribution of nerves in the skin. This distribution pattern is called a dermatome (see the "dermatomes" picture).

The active infection is typically marked by the following sequence:

A rash appears, starting as well-defined, small, red, clear spots.
Within 12 - 24 hours, these pimples develop into small fluid-filled blisters.
The blisters grow, merge, and become pus-filled.
Pain is common during the active infection.
Within about 7 - 10 days (as with chickenpox), the blisters form crusts and heal. In some cases it may take as long as a month before the skin clears completely. Healing takes even longer in patients who have impaired immune systems, and, in such cases, the blisters may persist for months.

Zoster Sine Herpete. Sometimes pain develops without a rash, a condition known as zoster sine herpete. This usually occurs in elderly patients. Symptoms include burning or shooting pain, numbness, tingling, itching, headache, fever, chills, and nausea. An accurate early diagnosis of shingles in such cases is often difficult. Some evidence suggests that some cases of Bell's palsy (in which part of the face becomes paralyzed) might actually be an indication of zoster sine herpete.

Postherpetic Neuralgia. Postherpetic neuralgia (PHN) is pain that persists for longer than a month after the onset of herpes zoster. (Some experts define persistent pain as subacute herpetic neuralgia if it lasts between 1 - 3 months, and as PHN if it lasts beyond 3 months.) PHN occurs in approximately 10 - 20% of patients who have shingles.

Risk for Recurrence of Shingles. Shingles can recur, but the risk is low (1 - 5%). Some evidence suggests that a first zoster episode boosts the immune system to ward off another attack. To support this theory, some elderly people with zoster who are exposed to children with chickenpox appear to have extra protection against a second zoster attack. In people with impaired immune systems, such as those with AIDS, a booster effect does not occur. These patients are at particular risk for multiple recurrences of shingles.

Risk Factors

The varicella-zoster virus is responsible for both chickenpox and herpes zoster, but its method of infection is different in both diseases.

Both the active varicella and zoster form of the virus can cause chickenpox.
The shingles virus in its latent (inactive) form is never infectious.

Catching Chickenpox. Most people get chickenpox from exposure to other people with chickenpox. It is most often spread through sneezing, coughing, and breathing. It is so contagious that few nonimmunized people escape this common disease when they are exposed to someone else with the disease.

People can also catch chickenpox from direct exposure to a shingles rash if they have not been immunized by vaccination or a previous bout of chickenpox. In such cases, transmission happens during the active phase when blisters have erupted but have not formed dry crusts. Herpes zoster spreads only from the rash. A person with shingles cannot transmit the virus by breathing or coughing.

Developing Shingles. Shingles itself can develop only from a reactivation of the varicella-zoster virus in a person who has previously had chickenpox. In other words, shingles itself is never transmitted from one person to another either in the air or through direct exposure to the blisters.

Between 75 - 90% of chickenpox cases occur in children under 10 years of age. Before the introduction of the vaccine, about 4 million cases of chickenpox were reported in the U.S. each year. Since a varicella vaccine became available in the U.S. in 1995, however, the incidence of disease and hospitalizations due to chickenpox has declined by nearly 90%.

The disease usually occurs in late winter and early spring months. It can also be transmitted from direct contact with the open sores. (Clothing, bedding, and such objects do not usually spread the disease.)

A patient with chickenpox can transmit the disease from about 2 days before the appearance of the spots until the end of the blister stage. This period lasts about 5 - 7 days. Once dry scabs form, the disease is unlikely to spread.

Most schools allow children with chickenpox back 10 days after onset. Some require children to stay home until the skin has completely cleared, although this is not necessary to prevent transmission.

About 500,000 cases of shingles occur each year in the U.S. Anyone who has had chickenpox has risk for shingles later in life, which means that 90% of adults in the U.S. are at risk for shingles. Shingles occurs, however, in 10 - 20% of these adult over the course of their lives, so certain factors must exist to increase the risk for such outbreaks.

The Aging Process. The risk for herpes zoster increases as people age, and the overall number of cases will undoubtedly increase as the baby boomer generation gets older. One study estimated that a person who reaches age 85 has a 50% chance of having herpes zoster. The risk for postherpetic neuralgia (PHN) is also highest in older people with the infection and increases dramatically after age 50. PHN is persistent pain and is the most feared complication of shingles.

Immunosuppression. People whose immune systems are impaired from diseases such as AIDS or childhood cancer have a risk for herpes zoster that is much higher than those with healthy immune systems. Herpes zoster in people who are HIV-positive may be a sign of full-blown AIDS. Certain drugs used for HIV, called protease inhibitors, may also increase the risk for herpes zoster.

Cancer. Cancer places people at risk for herpes zoster. At highest risk are those with Hodgkin's disease (13 - 15% of these patients develop shingles). About 7 - 9% of patients with lymphomas, and between 1 - 3% of patients with other cancers, have herpes zoster. Chemotherapy itself increases the risk for herpes zoster.

Immunosuppressant Drugs. Patients who take certain drugs that suppress the immune system are at risk for shingles (as well as other infections). They include:

Azathioprine (Imuran)
Chlorambucil (Leukeran)
Cyclophosphamide (Cytoxan)
Cyclosporine (Sandimmune, Neoral)
Cladribine (Leustatin)

These drugs are used for patients who have undergone organ transplantation and are also used for severe autoimmune diseases caused by the inflammatory process. Such disorders include rheumatoid arthritis, systemic lupus erythematosus, diabetes, multiple sclerosis, Crohn's disease, and ulcerative colitis.

Lack of Exposure to Children Infected with Chickenpox. Interestingly, one study suggested that previously infected adults who are exposed to children with chickenpox may receive an extra boost in antibody production, which can actually help them fight off herpes zoster. This means that as more children are vaccinated against chickenpox, more adults may be at risk for herpes zoster.

Risk Factors for Shingles in Children. Although most common in adults, shingles occasionally develops in children. One study reported that only 5% of cases occur in those under age 15. Children with immune deficiencies are at highest risk. Children with no immune problems but who had chickenpox before they were 1 year old also have a higher risk for shingles.

Complications

Chickenpox (varicella) rarely causes complications, but it is not always harmless. It can cause hospitalization and, in rare cases, death. Fortunately, since the introduction of the vaccine in 1995, hospitalizations have declined by nearly 90%, and there have been few fatal cases of chickenpox.

Adults have the greatest risk for dying from chickenpox, with infants having the next highest risk. Males (both boys and men) have a higher risk for a severe case of chickenpox than females. Children who catch chickenpox from family members are likely to have a more severe case than if they caught it outside the home. The older the child the higher the risk for a more severe case. But even in such circumstances, chickenpox is rarely serious in children. Other factors put individuals at specifically higher risk for complications of chickenpox.

Recurrence of Chickenpox. Recurrence of chickenpox is possible, but uncommon. One episode of chickenpox usually means lifelong immunity against a second attack. However, people who have had mild infections may be at greater risk for a breakthrough infection later on.

Reactivation of the Virus as Shingles (Herpes Zoster). The major long-term complication of varicella is the later reactivation of the herpes zoster virus and the development of shingles. Shingles occurs in about 20% of people who have had chickenpox.

Aside from itching, the complications described below are very rare.

Itching. Itching, the most common complication of the varicella infection, can be very distressing, particularly for small children. Certain home remedies are available that can alleviate the discomfort (see Treatment for Chickenpox section).

Secondary Infection and Scarring. Small scars may remain after the scabs have fallen off, but they usually clear up within a few months. In some cases, a secondary infection may develop at sites which the patient has scratched. The infection is usually caused by the bacteria Staphylococcus aureus or Streptococcus pyogenes. Permanent scarring may occur as a result. Children with chickenpox are at much higher risk for this complication than adults are, possibly because they are more likely to scratch.

Ear Infections. Some children are at higher risk for ear infections from chickenpox. Hearing loss is a very rare result of this complication.

A middle ear infection is also known as otitis media. It is one of the most common of childhood infections. With this illness, the middle ear becomes red, swollen, and inflamed because of bacteria trapped in the eustachian tube.

Bacterial Superinfection. Bacterial superinfection of the skin caused by group A streptococcus is the most common serious complication of chickenpox (but it is still rare). The infection is usually mild, but if it spreads in deep muscle, fat, or in the blood, it can be life-threatening. Infection can cause serious conditions such as necrotizing fasciitis (the so-called flesh-eating bacteria) and toxic shock syndrome (TSS).

Symptoms include:

A persistent or recurrent high fever
Redness, pain, and swelling in the skin and the tissue beneath

Pneumonia. Pneumonia is suspected if coughing and abnormally rapid breathing develop in patients who have chickenpox. Adults and adolescents with chickenpox are at some risk for serious pneumonia. Pregnant women, smokers, and those with serious medical conditions are at higher risk for pneumonia if they have chickenpox. Oxygen and intravenous acyclovir are key treatments for this condition. Pneumonia that is caused by varicella can result in lung scarring, which may impair oxygen exchange over the following weeks, or even months.

Click the icon to see an image of pneumonia.

Effects on the Brain and Central Nervous System.

Inflammation in the Brain. Encephalitis and meningitis, infections or inflammation in the central nervous systems, have occurred in a few varicella patients, both children and adults. This condition can be very dangerous, causing coma and even death. Fortunately, it is extremely rare. Symptoms vary. The patient may become over-agitated or may exhibit loss of coordination and poor balance.
Stroke. Although stroke in children is extremely rare, a condition called cerebral vasculitis, in which blood vessels in the brain become inflamed, has been associated with varicella-zoster. Varicella may be a factor in some cases of stroke in young adults.

Effects During Pregnancy. The risk for chickenpox in a pregnant woman is very low (1 - 7 cases in 10,000). However, chickenpox places the woman at risk for life-threatening pneumonia. Infection in the pregnant woman in the first trimester also poses a 1 - 2% chance for infecting the developing fetus, which is an extremely serious condition. (Herpes zoster is even rarer in pregnant women, and there is almost no risk for the unborn child in such cases.)

Disseminated Varicella. Disseminated varicella, chickenpox that spreads to organs in the body, is extremely serious and is a major problem for patients with compromised immune systems. An immune system may become compromised as a result of diseases such as AIDS, inherited conditions, or certain drugs. For example, disseminated varicella occurs in up to 35% of children with chickenpox who are taking cancer chemotherapy. In such cases, mortality rates are between 7 - 30%.

Reye Syndrome. Reye syndrome, a disorder that causes sudden and dangerous liver and brain damage, is a complication of chickenpox and other viruses in children who take aspirin. The disease can lead to coma and is life-threatening. Symptoms include rash, vomiting, and confusion beginning about a week after the onset of the disease. Because of the strong warnings against children taking aspirin, this condition is, fortunately, nearly nonexistent.

Other Rare Complications of Chickenpox. Other extremely rare complications of varicella include problems in blood clotting, and inflammation of the nerves in the hands and feet. Inflammation can also occur in other areas of the body, such as the heart, testicles, liver, joints, or kidney. Children should never be given aspirin when they have a viral infection.

Pain. The pain and discomfort of the active herpes zoster infection is the primary symptom and complication of herpes zoster. The pain usually takes one of these forms:

Continuous burning or aching pain
Periodic piercing pain
Spasm similar to electric shock

Such experiences may also be more intense than even normal responses, defined in the following ways:

Allodynia is pain caused by factors, such as a light touch of clothing or a cold wind, which occurs from very little stimulation.
Hyperalgesia is a more intense painful response to a normally painful experience.

The pain tends to be more severe at night. Temperature changes can also affect pain. The pain may extend beyond the areas of the initial zoster attack. In most cases, it does not affect daily life. Rarely, however, the pain of herpes zoster affects sleep, mood, work, and overall quality of life. This can lead to fatigue, loss of appetite, depression, social withdrawal, and impaired daily functioning.

Itching. Many patients report itching (postherpetic itch) as the primary symptom, rather than pain. In rare cases, it can be disabling.

Postherpetic Neuralgia (PHN). Postherpetic neuralgia (PHN) is pain that persists for longer than a month after the onset of herpes. It is the most common severe complication of shingles. It is not clear why PHN occurs. Some theories for its development are:

The herpes zoster virus appears to produce persistent inflammation in the spinal cord that causes long-term damage, including nerve scarring.
Nerves that are injured in the initial attack may regrow abnormally and provoke an exaggerated response in the brain that signals intense sensitivity or pain.

In people with herpes zoster, the risk of developing PHN ranges from 10 - 70%. In general, however, the risk is likely to be in the lower range. People with impaired immune systems do not seem to be at any higher risk for persistent PHN than those with normal immune systems.

The following are risk factors for PHN:

Age. PHN affects about 25% of herpes zoster patients over 60 years old. The older a person is, the longer PHN is likely to last. It rarely occurs in people under age 50.
Gender. Some studies suggest that women may be at slightly higher risk for PHN than men.
Severe or Complicated Shingles. People who had prodromal symptoms or a severe attack (numerous blisters and severe pain) during the initial shingles episode are also at high risk for PHN. The rate is also higher in people whose eyes have been affected by zoster.

In most cases, PHN resolves within 3 months. Some experts define persistent pain after a herpes zoster attack as subacute herpetic neuralgia if it lasts between 1 - 3 months and as PHN only if it lasts beyond 3 months. Studies report that only about 10% of patients experience pain after a year. Unfortunately, when PHN is severe and treatments have not been very effective, the persistent pain and abnormal sensations can be profoundly frustrating and depressing for patients.

Secondary Infection in the Blisters. If the blistered area is not kept clean and free from irritation, it may become infected with Streptococcus A or Staphylococcus bacteria. If the infection is severe, scarring can occur.

Guillain-Barre Syndrome. Guillain-Barre syndrome is caused by inflammation of the nerves and has been associated with a number of viruses, including herpes zoster. The arms and legs become weak, painful, and, sometimes, even paralyzed. The trunk and face may be affected. Symptoms vary from mild to severe enough to require hospitalization. The disorder resolves in a few weeks to months. Other viruses ( C. jejuni, cytomegalovirus, and Epstein-Barr) may have a stronger association to this syndrome than herpes zoster. One study, in fact, found no higher incidence of herpes zoster virus in patients with Guillain-Barre than in the general population.

Effects on Face and Ears.

Ramsay Hunt Syndrome. Ramsay Hunt syndrome occurs when herpes zoster causes facial paralysis and rash on the ear (herpes zoster oticus) or in the mouth. Symptoms include severe ear pain and hearing loss, ringing in the ear, loss of taste, nausea, vomiting, and dizziness. Ramsay Hunt syndrome may also cause a mild inflammation in the brain. The dizziness may last for a few days or even for weeks, but usually resolves. Severity of hearing loss varies from partial to total; however, this too usually always goes away. Facial paralysis, on the other hand, may be permanent.
Bell's Palsy. Bell's palsy is partial paralysis of the face. There is some indication that this syndrome may suggest a reactivation of herpes zoster, even if no rash appears.

In some cases, it is difficult to distinguish between Bell's palsy and Ramsay Hunt syndrome, particularly in the early stages. Ramsay Hunt syndrome tends to be more severe than Bell's palsy. Although evidence is weak on treating facial involvement of herpes zoster, some experts recommend oral prednisone (a corticosteroid) and an antiviral drug within 7 days of symptom onset. Even though nearly all cases of Bell's palsy and the majority of Ramsay Hunt syndrome resolve without problems, the possibility of residual symptoms with Ramsay Hunt and the early resemblance between the two syndromes warrants this treatment.

Effects on the Brain. Inflammation of the membrane around the brain (meningitis) or in the brain itself (encephalitis) is a rare complication in people with herpes zoster. The encephalitis is generally mild and resolves in a short period. In rare cases, particularly in patients with impaired immune systems, it can be severe and even life-threatening.

Click the icon to see an image of the meninges of the brain.

Effects in the Urinary Tract. In rare situations, herpes zoster can infect the urinary tract and cause difficulty in urination. The condition is temporary but may require a catheter for patients who have trouble urinating.

Click the icon to see an image of the male urinary tract.

Infections in the Eye. If shingles occurs in the face, the eyes are at risk, particularly if the path of the infection follows the side of the nose. If the eyes become involved (called herpes zoster ophthalmicus), a severe infection can occur that is difficult to treat and can threaten vision. AIDS patients may be at particular risk for a chronic infection in the cornea of the eye.

Click the icon to see an image of the eye.

Herpes zoster can also cause a devastating infection in the retina called imminent acute retinal necrosis syndrome. In such cases, visual changes develop within weeks or months after the herpes zoster outbreak has resolved. Although this complication usually follows a herpes outbreak in the face, it can occur after an outbreak in any part of the body. Prompt treatment with acyclovir can often halt its progress, at least in people with healthy immune systems. Either acyclovir or valacyclovir, a similar drug, may prevent other eye complications, such as conjunctivitis (pink eye), inflammation of the cornea, and pain.

Disseminated Herpes Zoster. As with disseminated chickenpox, disseminated herpes zoster, which spreads to other organs, can be serious to life-threatening, particularly if it affects the lungs. People with compromised immune systems are at greatest danger, with risk of 5 - 25%. It is very rare in people with healthy immune systems.

In very rare cases, herpes zoster has been associated with Stevens-Johnson syndrome, an extensive and serious condition in which widespread blisters cover mucous membranes and large areas of the body.

Elderly people. The older the patient, the higher the risk for complications from either chickenpox or shingles. Adults who smoke are at particularly higher risk for pneumonia from chickenpox.

Patients with Compromised Immune Systems. People with suppressed immune systems from diseases such as AIDS, leukemia, or those who take immunosuppressive drugs, are at the highest risk for severe and even unusual forms of VZV. Examples include chronic chickenpox with persistent sores, or disseminated varicella-zoster (in which the infection spreads to internal organs).

Patients with Serious Illnesses. People with serious illnesses may be at risk for complications of the varicella-zoster virus. Patients with diseases, such as Hodgkin's disease, who receive bone marrow or stem cell transplants are at higher risk for herpes zoster and its complications. An inactivated vaccine given before the procedure may be helpful.

Pregnant Women. Pregnant women who become infected with the varicella-zoster virus, whether in the form of chickenpox or shingles, are at increased risk for serious pneumonia.

The risk for the infant is lower or higher depending on when the mother became infected.
Chickenpox in the mother during early pregnancy poses a slightly increased risk for birth defects in the infant, but it is not usually viewed as grounds for terminating a pregnancy.
The highest risk for birth defects is about 2%, which usually occurs if the mother has chickenpox between the 13th and 20th week. Even in such cases, birth defects may only result in minor skin abnormalities. More serious defects include a smaller than normal head, eye problems, low birth weight, and mental retardation.
If women develop chickenpox (not shingles) within 5 days before and 2 days after delivery, their newborns are at risk for life-threatening varicella.

Newborns and Infants. Chickenpox in newborns is a life-threatening condition. Although chickenpox can still be very dangerous in older infants, most are protected by antibodies in breast milk from mothers who have had chickenpox. Children under age 1 who develop chickenpox are at higher risk for childhood shingles. All infants should have as little exposure as possible to people with chickenpox.

Vaccination

There are two types of varicella vaccines:

A chickenpox vaccine for vaccinating children, adolescents, and some adults
A shingles vaccine for vaccinating adults age 60 years and older

A live-virus vaccine (Varivax) produces persistent immunity against chickenpox. [A vaccine (Proquad) for children ages 1 - 12 years now combines measles, mumps, rubella, and varicella in one product.] The vaccine can prevent chickenpox or reduce the severity of the illness if it is used within 3 days, and possibly up to 5 days, after exposure to the infection.

In 2007, the U.S. Centers for Disease Control’s Advisory Committee on Immunization Practices (ACIP) revised the immunization schedule for the chickenpox vaccine. The new schedule recommends that children receive TWO doses of the chickenpox vaccine with:

The first dose administered when the child is 12 – 15 months years of age, and
The second dose administered when the child is 4 – 6 years of age

As of 2007, all children should routinely receive these vaccinations. For children who have previously received one dose of the chickenpox vaccine, the ACIP recommends that they receive a “catch-up” second dose during their regular doctor’s visit. This second dose can be given at any time as long as it is at least 3 months after the first dose. Experts pushed for the new second-dose policy due to a number of recent chickenpox outbreaks among previously vaccinated schoolchildren.

A 2007 study in the New England Journal of Medicine also found that one dose of the vaccine may not be enough to provide complete immunity. Among 350,000 patients researchers studied over 10 years, 11,356 were reported to have chickenpox. A total of 1,080 of the patients had breakthrough disease, a modified form of chickenpox with a mild rash that can occur in some vaccinated people. According to the study, those most at risk were children ages 8 - 12 years who had been vaccinated at least 5 years before their current chickenpox infection.

The U.S. Centers for Disease Control and Prevention (CDC) recommends that every healthy adult without a known history of chickenpox be vaccinated. Adults in the following groups should strongly consider vaccination:

Those with high risk of exposure or transmission (hospital or day care workers, parents of young children)
People in contact with those who have compromised immune systems
Nonpregnant women of childbearing age
International travelers

As with other live-virus vaccines, the chickenpox vaccine is not recommended for:

Women who are pregnant or who may become pregnant within 30 days of vaccination.
People whose immune systems are compromised by disease or drugs (such as after organ transplantation). Experts report that the vaccine is safe in children with acute lymphoblastic leukemia (ALL). Certain children who are HIV-positive may be candidates for the vaccine. An inactivated chickenpox vaccine may be safe for patients undergoing bone marrow transplants when given before and after the operation.

Patients who cannot be vaccinated but who are exposed to chickenpox receive immune globulin antibodies against varicella virus. This helps prevent complications of the disease if they become infected.

Discomfort at the Injection Site. About 20% of vaccine recipients have pain, swelling, or redness at the injection site.
Severe Side Effects. Only about 5% of adverse reactions are serious. Such events include seizures, pneumonia, anaphylactic reaction, encephalitis, Stevens-Johnsons syndrome, neuropathy, herpes zoster, and blood abnormalities.
Risk of Transmission. The vaccine may produce a mild rash within about a month of the vaccination, which can transmit chickenpox to others. Individuals who have recently been vaccinated should avoid close contact with anyone who might be susceptible to severe complications from chickenpox until the risk for a rash passes.
Later Infection. Months or even years after the vaccination, some people develop a mild infection termed modified varicella-like syndrome (MVLS). The condition appears to be less contagious and has fewer complications than naturally acquired chickenpox.

In 2006, a shingles vaccine was approved for use in the United States. The zoster vaccine (Zostavax) is a stronger version of the chickenpox vaccine. Study results published in 2005 suggested that the zoster vaccine can prevent about half of all shingles cases and two-thirds of postherpetic neuralgia cases. The CDC recommends that all adults age 60 years and older who have intact immune systems should receive this vaccine

Varicella-zoster immune globulin (VariZIG) is a substance that triggers an immune response against the varicella-zoster virus. It is used to protect high-risk patients who are exposed to chickenpox, or those who cannot receive a vaccination of the live virus. Such groups include:

Pregnant women with no history of chickenpox
Newborn infants whose mothers had signs or symptoms of chickenpox around the time of delivery (5 days before to 2 days after)
Premature infants
Immunocompromised children and adults with no antibodies to VZV
Recipients of bone-marrow transplants (even if they have had chickenpox)
Patients with a debilitating disease (even if they have had chickenpox)

For these patients, VariZIG should be given within 96 hours of exposure to someone with chickenpox. (Note: VariZIG is a new formulation of an older drug called VZIG, which is no longer being produced.)

Diagnosis

Both chickenpox (varicella) and shingles (zoster) can usually be diagnosed by symptoms alone. If a diagnosis is still unclear after a physical examination, diagnostic tests may be required.

Either variation of the virus may be confused with other disorders.

Ruling out Disorders that Resemble Chickenpox. Chickenpox, particularly in early stages, may be confused with herpes simplex (the disorder more commonly referred to as "herpes"), or impetigo, insect bites, and scabies.

Ruling out Disorders that Resemble Shingles. The early prodrome stage of shingles can cause severe pain on one side of the lower back, chest, or abdomen before the rash appears. It therefore may be mistaken for disorders, such as gallstones, that cause acute pain in internal organs.

In the active rash stage, shingles may be confused with herpes simplex, particularly in young adults if the blisters occur on the buttocks or around the mouth. Herpes simplex, however, does not usually generate chronic pain.

A diagnosis may be difficult if herpes zoster takes a non-typical course, such as with Bell's palsy or Ramsay Hunt syndrome in the face, or if it affects the eye, or causes fever and delirium.

In most cases of chickenpox and shingles, the symptoms alone are sufficient to make a diagnosis. In some patients, such as those who are immunosuppressed, if the symptoms are not straightforward the doctor performs one or more additional tests to detect the virus itself. The tests usually aim to distinguish between varicella-zoster and herpes simplex viruses.

Virus Culture. A viral culture uses specimens taken from the blister, fluid in the blister, or sometimes spinal fluid. They are sent to a laboratory, where it takes 1 - 14 days to detect the virus in the preparation made from the specimen. It is also sometimes used in vaccinated patients to determine if a varicella-like infection is caused by a natural virus or by the vaccine. This test is useful, but it is sometimes difficult to recover the virus from the samples.

Immunofluorescence Assay. Immunofluorescence is a diagnostic technique used to identify antibodies to a specific virus. In the case of herpes zoster, the technique uses ultraviolet rays applied to a preparation composed of cells taken from the zoster blisters. The specific characteristics of the light as seen through a microscope will identify the presence of the antibodies. This test is less expensive than a culture, more accurate, and results are faster.

Polymerase Chain Reaction (PCR). Polymerase chain reaction (PCR) techniques use a piece of the DNA of the virus, which is then replicated millions of times until the virus is detectable. This technique is expensive but is useful for unusual cases, such as identifying infection in the central nervous system.

Treatment for Chickenpox

Acetaminophen. Patients with chickenpox do not have to stay in bed unless fever and flu symptoms are severe. To relieve discomfort, a child can take acetaminophen (Tylenol), with doses determined by the doctor. A child should never be given aspirin, or medications containing aspirin, as aspirin increases the risk for a dangerous condition called Reye syndrome.

Soothing Baths. Frequent baths are particularly helpful in relieving itching, when used with preparations of finely ground (colloidal) oatmeal. Commercial preparations (Aveeno) are available in drugstores, or one can be made at home by grinding or blending dry oatmeal into a fine powder. Use about 2 cups per bath. The oatmeal will not dissolve, and the water will have a scum. A 1/2 - 1 cup of baking soda in a bath may also be helpful.

Lotions. Calamine lotion and similar over-the-counter preparations can be applied to the blisters to help dry them out and soothe the skin.

Antihistamines. For severe itching diphenhydramine (Benadryl) is useful and may help children sleep.

Preventing Scratching. Small children may have to wear mittens so that they don't scratch the blisters and cause a secondary infection. All patients with varicella, including adults, should have their nails trimmed short.

Acyclovir is an antiviral drug that may be used in adult varicella patients or those of any age with a high risk for complications and severe forms of chickenpox. The drug may also benefit smokers with chickenpox, who are at higher than normal risk for pneumonia. Some experts recommend its use for children who catch chickenpox from other family members because such patients are at risk for more serious cases. To be effective, oral acyclovir must be taken within 24 hours of the onset of the rash. Early intravenous administration of acyclovir is essential treatment for chickenpox pneumonia.

Treatment for an Acute Shingles Attack

The treatment goals for an acute attack of herpes zoster include:

Reduce pain
Reduce discomfort
Hasten healing of blisters
Prevent the disease from spreading

Over-the-counter (OTC) remedies are often effective in reducing the pain of an attack. Antiviral drugs (acyclovir and others), oral corticosteroids, or both are sometimes given to patients with severe symptoms, particularly if they are older and at risk for postherpetic neuralgia (PHN). In addition, psychological therapies aimed at coping and reducing the effects of pain may be useful.

Applied Cold. Cold compresses soaked in Burrow's solution (an OTC remedy) and cool baths may help relieve the blisters. It is important not to break blisters as this can cause infection. Experts advise against warm treatments, which can intensify itching. Patients should wear loose clothing and use clean loose gauze coverings over the affected areas.

Itch Relief. In general, to prevent or reduce itching, home treatments are similar to those used for chickenpox. Patients can try antihistamines, (particularly Benadryl), oatmeal baths, and calamine lotion.

Over-the-Counter Pain Relievers. For an acute shingles attack, patients may take over-the-counter pain relievers:

Children should take acetaminophen. (Shingles is very rare in children.)
Adults may take aspirin or other nonsteroidal anti-inflammatory drugs, such as ibuprofen (Advil). Such remedies, however, are not very effective for postherpetic neuralgia.

Nucleoside Analogues. The best class of drugs developed against varicella-zoster are those known as nucleoside, or guanosine, analogues, which are able to block viral reproduction. None of these drugs can actually destroy the virus and cure the disease, but they can significantly reduce the severity of the attack, hasten healing, and reduce the duration. There is some evidence that early treatment with these drugs can reduce the risk for postherpetic herpes.

These anti-viral drugs are usually taken for 7 days. Ideally they should be started within 72 hours of the onset of infection. The earlier they are given the more effective these drugs are, but they can be helpful even if treatment is started after 3 days. Combinations of antiviral therapy with other drugs, such as tricyclic antidepressants or anticonvulsant drugs, are under investigation

Acyclovir (Zovirax), famciclovir (Famvir), and valacyclovir (Valtrex) are approved for shingles. Acyclovir is the oldest, most studied of these drugs, but either famciclovir (Famvir) or valacyclovir (Valtrex), which are both metabolized into acyclovir, are now preferred to treat herpes zoster in most patients. They relieve symptoms better than acyclovir and require fewer daily doses (typically three) than the five doses needed with acyclovir.

Because herpes zoster tends to resolve fairly quickly in young adults, these drugs are generally reserved for patients at greatest risk for complications or persistent pain. They include:

Elderly people
Those with infections that threaten the eye
Patients who are HIV positive or immunocompromised in other ways
Patients whose infection covers a larger-than-average surface area of the skin
Those with very severe pain

These drugs appear to have little or no harmful effect on healthy cells and can penetrate most body tissues, including cerebrospinal fluid. Evidence to date suggests that they are safe during pregnancy.

Possible side effects of nucleoside analogues include rash, headache, fatigue, tremor, nausea and vomiting. Seizures are a very rare side effect. Patients with AIDS or other diseases that compromise the immune system are at increased risk for kidney damage and blood clots. Patients with suppressed immune systems are also more likely to have viral resistance to these drugs. These drugs are safe to take during pregnancy.

Foscarnet. Foscarnet (Foscavir) is a powerful antiviral drug known as a pyrophosphate analogue. It is used in cases of VZV strains that have become resistant to acyclovir and similar drugs. Administered intravenously, the drug can have toxic effects. It can impair kidney function (which is reversible) and cause seizures. Fever, nausea, and vomiting are common side effects. It can also cause ulcers on genital organs. As with other drugs, it does not cure shingles.

Brivudin. Brivudin (Helpin, Zostex) is another anti-viral drug, but it is not available in the U.S. It needs to be taken only once a day.

Oral corticosteroids, including prednisolone or prednisone, are powerful anti-inflammatory medications. They have some benefit for reducing pain and accelerating healing in acute attacks when used with acyclovir. (They are not recommended without acyclovir.) They also may be helpful for improving symptoms of Bell's palsy and Ramsay Hunt syndrome. Corticosteroids do not appear to prevent a further shingles attack or reduce the risk for PHN. Side effects of corticosteroids can be severe, and patients should take oral steroids at as low a dose and for as short a time as possible. (Injected or intravenous steroids, however, may offer specific relief for PHN without significant side effects.)

Epidural blocks are injections of local anesthetics and steroids outside the tough membrane surrounding the spinal cord (the dura matter). The injected drugs block the nerves and may offer relief from acute herpes zoster pain for some people. A 2006 study found that a single epidural injection helps slightly to relieve shingles pain for a month, but the effect does not last any longer. The injection does not help prevent postherpetic neuralgia.

Treatment for Postherpetic Neuralgia

Postherpetic neuralgia (PHN) is difficult to treat. Once PHN develops, a patient may need a multidisciplinary approach that involves a pain specialist, psychiatrist, primary care physician, and other health care providers.

In 2004, the American Academy of Neurology (AAN) issued treatment guidelines for postherpetic neuralgia based on an extensive review of published studies. The AAN recommends:

Tricyclic antidepressants (amitriptyline, nortriptyline, desipramine, maprotiline)
Anticonvulsants (gabapentin and pregabalin)
Lidocaine skin patches
Opioids (oxycodone, methadone, morphine)

Topical Pain Relievers. Creams, patches, or gels containing various substances can provide some pain relief.

Lidocaine and Other Anesthetic Patches. A patch that contains the anesthetic lidocaine (Lidoderm) is approved specifically for postherpetic neuralgia (PHN). One to four patches can be applied over the course of 24 hours. Another patch (EMLA) contains both lidocaine and prilocaine, a second anesthetic. The most common side effects are skin redness or rash.
Capsaicin (Zostrix) is prepared from the active ingredient in hot chili peppers. An ointment form has been approved for postherpetic neuralgia. Its benefits are limited, however. A patch form that uses a higher than standard dose may work better. In one study, it reduced pain by 33% in nearly half of patients. Capsaicin should not be used until the blisters have completely dried out and are falling off the skin. Capsaicin ointment should be handled using a glove, and applied to affected areas three or four times daily. The patient will usually experience a burning sensation when the drug is first applied, but this sensation diminishes with use. It may take up to 6 weeks for the patient to experience its full effect, and about a third of patients cannot tolerate the burning sensation.
Topical Aspirin. Topical aspirin, known chemically as triethanolamine salicylate (Aspercreme), may bring relief.
Menthol-Containing Preparations. Topical drugs containing menthol, such as high-strength Flexall 454, may be helpful.

Skin Coolants. Ethyl chloride (Chloroethane) and fluori-methane are chemicals that cool the blood vessels in the skin. Sprays that contain these chemicals are not anesthetics, but are used to inactivate the sensitive areas. To use the spray, the patient must be in a comfortable position. The spray bottle is held upside-down, about 12 - 18 inches from the targeted area, and the face must be covered if the spray is being used near the head.

Tricyclic antidepressants relieve pain in up to two-thirds of patients. These drugs not only relieve depression, which can be common in PHN sufferers, but certain tricyclics specifically block sodium channels, which play a role in causing pain in PHN. Nortriptyline (Pamelor, Aventyl), amitriptyline (Elavil, Endep), and desipramine (Norpramin) are standard drugs.

According to one study, two-thirds of patients obtain pain relief if they take tricyclics within 3 months to a year after a herpes zoster attack. The drugs are less successful when taken after that. It may take several weeks for the drugs to become fully effective. They do not work as well in patients who experience burning pain or allodynia (pain that occurs with normally non-painful stimulus, such as a light touch or wind).

Unfortunately, tricyclics have side effects that are particularly severe in the elderly, who are also more likely to have PHN. Desipramine and nortriptyline have fewer side effects than amitriptyline and are preferred for older patients. Side effects include dry mouth, blurred vision, constipation, dizziness, difficulty urinating, disturbances in heart rhythms, and an abrupt drop in blood pressure when standing up.

Certain anticonvulsant drugs have effects that block over-excitation of nerve cells and may be helpful for PHN patient. (Anticonvulsant drugs are also known as anti-seizure drugs.)

Gabapentin. Gabapentin (Neurontin) was the first anticonvulsant drug approved for PHN. Studies suggest significant pain relief in patients with PHN and reduction in the use of opioids. Many patients also report improved quality of life, including better sleep. Gabapentin is also showing promise in combination with valacyclovir for reducing pain from an acute herpes zoster attack.

Side effects include skin rashes, increased risk for infection, headache, dizziness, sleepiness, swelling, and upset stomach. Some people experience visual disturbances, ringing in the ears, agitation, or odd movements when drug levels are at their peak. These side effects may limit their value in older people who are at risk of falling. In general, however gabapentin is safer than tricyclic antidepressants for elderly patients.

Pregabalin. Pregabalin (Lyrica) is similar to gabapentin. Like gabapentin, side effects can include sleepiness and dizziness

Other Anticonvulsant Drugs. The AAN guidelines found insufficient evidence to recommend carbamazepine (Tegretol).

Opioids. Patients with severe pain that does not respond to tricyclic antidepressants may need powerful painkilling opioid drugs. They may be taken by mouth or delivered through a skin patch. Oxycodone is the standard opioid for PHN. Morphine is also used. Methadone (Dolophine) may also be helpful. A 2005 study found that morphine worked best when combined with the anticonvulsant gabapentin. Constipation, drowsiness, and dry mouth are common side effects of opioids.

Tramadol. Tramadol (Ultram) is a pain reliever that has been used as an alternative to opioids. It has opioid-like properties but is not as addictive. (Dependence and abuse have been reported, however.) It can cause nausea but not severe gastrointestinal problems, as NSAIDs can. Studies suggest it might be very helpful for PHN patients, particularly those with heart problems or other conditions that restrict tricyclic antidepressants.

Intrathecal Corticosteroid Injections. Epidural (also called intrathecal) injections of corticosteroids are administered within the the tough membrane surrounding the spinal cord. The corticosteroids are sometimes combined with anesthetics. Some older studies indicated that these injections may relieve PHN pain, but this treatment is still under investigation and is not common medical practice. A 2006 study reported that epidural injections may provide slight temporary relief for acute shingles attacks, but they do not prevent PHN.

Antiviral Drugs. Researchers are investigating whether treatment with antiviral drugs may help reduce the pain associated with postherpetic neuralgia. A small 2006 study suggested that a 2-week course of therapy with intravenous acyclovir, followed by 1-month treatment with oral valacyclovir, may help relieve pain.

Surgery. Certain surgical techniques in the brain or spinal cord attempt to block nerve centers associated with postherpetic neuralgia. These methods carry risk for permanent damage, however, and should be used only as a last resort when all other methods have failed and the pain is intolerable. Most studies indicate that surgery does not relieve PHN pain.

Stress Reduction Techniques. A number of relaxation and stress-reduction techniques may be helpful for managing chronic pain. They include meditation, deep breathing exercises, biofeedback, and muscle relaxation. Such techniques may apply to those with severe pain from acute infection and from persistent long-term postherpetic neuralgia. [See In-Depth Report #31: Stress.]

Behavioral Cognitive Therapy. Behavioral cognitive therapy is showing benefit in enhancing patients' beliefs in their own abilities for dealing with pain. Using specific tasks and self-observation, patients gradually shift their fixed ideas that they are helpless against the pain that dominates their lives to the perception that it is a manageable experience. The skill of the therapist is very important to its success.

Many people with chronic pain such as PHN turn to alternative treatments for relief. Aside from hypnosis, little evidence indicates that these treatments work for PHN. Remedies include:

Hypnosis
Topical use of diluted apple cider vinegar
Acupuncture
Colostrum (a pre-milk fluid produced by mammals)
Pantothenic acid (Vitamin B5)

Resources

www.cdc.gov -- Centers for Disease Control and Prevention
www.niaid.nih.gov -- National Institute of Allergy and Infectious Diseases
www.ninds.nih.gov -- National Institute of Neurological Disorders and Stroke
www.aan.com -- American Academy of Neurology
www.neuropathy.org -- Neuropathy Association

References

American Academy of Pediatrics Committee on Infectious Diseases. Recommended immunization schedules for children and adolescents--United States, 2007. Pediatrics. 2007 Jan;119(1):207-8.

Centers for Disease Control and Prevention (CDC). A new product (VariZIG) for postexposure prophylaxis of varicella available under an investigational new drug application expanded access protocol. MMWR Morb Mortal Wkly Rep. 2006 Mar 3;55(:209-10.

Centers for Disease Control and Prevention (CDC). Varicella outbreak among vaccinated children--Nebraska, 2004. MMWR Morb Mortal Wkly Rep. 2006 Jul 14;55(27):749-52.

Chaves SS, Gargiullo P, Zhang JX, Civen R, Guris D, Mascola L, et al. Loss of Vaccine-Induced Immunity to Varicella over Time. N Engl J Med. 2007 Mar 15;356(11):1121-9.

Davis MM, Marin M, Cowan AE, Guris D, Clark SJ. Physician attitudes regarding breakthrough varicella disease and a potential second dose of varicella vaccine. Pediatrics. 2007 Feb;119(2):258-64.

Li Q, Ali MA, Cohen JI. Insulin degrading enzyme is a cellular receptor mediating varicella-zoster virus infection and cell-to-cell spread. Cell. 2006 Oct 20;127(2):305-16.

Lopez AS, Guris D, Zimmerman L, Gladden L, Moore T, Haselow DT, et al. One dose of varicella vaccine does not prevent school outbreaks: is it time for a second dose? Pediatrics. 2006 Jun;117(6):e1070-7.

Quan D, Hammack BN, Kittelson J, Gilden DH. Improvement of postherpetic neuralgia after treatment with intravenous acyclovir followed by oral valacyclovir. Arch Neurol. 2006 Jul;63(7):940-2.

Review Date:
3/15/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Multiple sclerosis

FitSugar — Wed, 08 Oct 2008 17:35:12 -0700

In This Report

Highlights
Introduction
The Autoimmune Disease Proc...
Symptoms
Causes
Risk Factors
Complications
Diagnosis
Treatment
Drug Treatment
Other Treatments
Treating the Complications...
Lifestyle Changes
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Gender and Multiple Sclerosis (MS)

MS is increasingly affecting women, according to research presented at the 2007 annual conference of the American Academy of Neurology. Researchers found that in the 1940s, women were twice as likely as men to be diagnosed with MS. By 2000, women were about four times more likely than men to develop MS. Experts are uncertain why this ratio is growing.

Family History

If MS runs in your family, there’s a chance you may develop the disease at the same age that other family members did, suggests a 2007 Neurology study. However, family history does not predict disease course or severity.

Vitamin D

Higher blood levels of vitamin D may reduce the risk for MS, at least among Caucasians, indicates a 2007 study in the Journal of the American Medical Association. (The researchers found no protective effect for African-Americans or Hispanics.) However, until further research is conducted, doctors do not recommend taking vitamin D supplements for MS prevention.

Infections and Symptom Relapse

Both viral and bacterial systemic infections can trigger relapses, according to a study in Neurology. Researchers found that relapses and new brain lesions appeared within 2 weeks after an infection.

Drug Research

Natalizumab (Tysabri) may help reduce vision loss in patients with relapse-remitting MS, indicates a 2007 Neurology study. In 2006, the FDA enforced safety restrictions on the use of this drug due to cases of progressive multifocal leukoencephalopathy (PML), a rare brain disorder. Since the restrictions were put in place, no new cases of PML have been reported.
Glatiramer acetate (Copaxone) shows little benefit for primary progressive MS, according to a 2007 study in Annals of Neurology.
Testosterone gel may help men with relapse-remitting MS, suggests a small study published in 2007 in the Archives of Neurology.

Introduction

Multiple sclerosis (MS) is a disease of the central nervous system (CNS), the nerves that comprise the brain and spinal cord. It has two major features:

Destruction of myelin, a fatty insulation covering the nerve fibers, is the main characteristic of MS. The end results of this process, called demyelination, are multiple patches of hard, scarred tissue called plaques. (Multiple sclerosis is well named. Sclerosis comes from the Greek word skleros, which means hard.)
Destruction of axons, the long filaments that carry electric impulses away from a nerve cell, is also a major factor in the permanent disability that occurs with MS.

Myelin is the layer that forms around nerves. Its purpose is to speed the transmission of impulses along nerve cells.

The symptoms, severity, and course of MS vary widely depending partly on the sites of the plaques and the extent of the demyelination. Experts generally group multiple sclerosis into two major symptom categories:

Relapsing-remitting
Chronic-progressive

Chronic-progressive MS is often subcategorized as primary-progressive, secondary-progressive, and progressive-relapsing.

Recent evidence suggests that the disease process starts long before symptoms begin. By the time symptoms appear, there are often already signs of brain and spinal cord atrophy. The cause of MS is unknown, and it cannot be prevented or cured. It is not fatal, however, and great progress is being made in treating it and identifying underlying mechanisms that trigger this disease.

Relapsing-remitting multiple sclerosis generally occurs in younger people and is the most common form of MS. It generally follows this course:

Most patients first experience a single attack of symptoms called a clinical isolated syndrome, which typically occurs between the ages of 20 - 40 years. Once a second attack occurs, the patient is considered to have relapsing-remitting multiple sclerosis.
The characteristic feature of relapsing-remitting MS is the attack (also referred to as relapse, flare-up, or exacerbation), which is a bout of specifically MS symptoms (facial pain, Lhermitte’s sign, or bladder instability) that lasts at least 24 hours and typically several days. Such attacks are fairly mild in about half of patients with this form of MS.
The disease then goes into remission (when symptoms improve or disappear), usually for about 4 - 8 weeks. To be considered in remission, attacks need to be separated by at least 30 days. Remission periods may be spontaneous or induced by immunosuppressive drugs. A person with multiple sclerosis in remission may have subtle attacks and not realize it. For example, hands may be a little numb for a few days, or there may be slight awkwardness in gait or coordination.
Remissions are almost always followed by relapses, in which symptoms flare-up or the patient experiences a period of deteriorating ability.

About 20% of patients with relapsing-remitting MS experience little or no progression after a first attack for long periods of time, although by 25 years most patients have converted to a progressive phase.

The term chronic-progressive multiple sclerosis is used to describe cases in which symptoms continue to worsen slowly without remission. About 20% of multiple sclerosis patients (usually those whose first symptoms occur after age 45) have the chronic-progressive form without first developing relapsing-remitting MS. Chronic-progressive MS generally follows a downhill course, but its severity varies widely. Three variants are commonly used to define this patient group:

Secondary-Progressive MS (SPMS). SPMS is the natural evolution of relapsing-remitting MS and develops in about half of patients during the first 10 years and nearly all of them within 25 years. It follows a progressive course of nerve and muscle deterioration with occasional acute flare-ups, remissions, and plateaus.
Primary-Progressive MS (PPMS). PPMS progresses continuously and gradually from the first onset of symptoms and has no remissions. It occasionally levels off, and minor improvement is even possible. This occurs in about 10% of patients, who tend to be older than average at the time of diagnosis.
Progressive-Relapsing MS (PRMS). PRMS is progressive from the start with acute symptom flare-ups, but may have some relapses with continued deterioration between them. It occurs in less than 5% of patients.

Because the natural courses of primary-progressive and progressive-relapsing MS are similar, some experts believe this distinction is unnecessary.

Click the icon to see an image depicting multiple sclerosis.

The Autoimmune Disease Process

Multiple sclerosis is referred to as an autoimmune disease. The general theory for the development of MS is that a genetically damaged immune system is unable to distinguish between virus proteins and the body’s own myelin and so produces antibodies that attack. In other words, the body becomes allergic to itself, a condition known as autoimmunity.

Autoimmunity may develop when the body's immune system is damaged by genetic or environmental factors or both, causing it to attack its own tissues. In the case of MS, the immune system attacks the tissues that make up myelin:

Myelin is made from layers of cell membranes that are produced in the brain and spinal cord by specialized cells called oligodendrocytes. The destruction of this myelin sheath during the disease process is the hallmark for multiple sclerosis.
The myelin coat is distributed in segments along the axons, the long filaments that carry electric impulses away from a nerve cell.
The segments are separated from each other by tiny clusters called nodes of Ranvier, which house channels for sodium ions. These sodium ions are important for boosting the electrical charge required to pass signals from one nerve to another.
As the myelin insulation is destroyed, signals transmitted from nerve cell to nerve cell throughout the central nervous system are disrupted.
Experts once believed that axons themselves were spared during the disease process. Research, however, has shown that many are severed in MS and, in fact, axon destruction appears to start at an early stage in the disease and may be a major cause of its irreversibility.

The body often makes corrective actions to offset the effects of the nerve cell destruction:

For example, researchers have observed an increase in the density of the sodium channels, which carry electric charges. By increasing their numbers, the nerve cells can continue to communicate, in spite of the loss of myelin.
The nerves also retain some capacity to remyelinate (to restore the insulating myelin).

Such processes are probably responsible for the remissions that most patients experience. Unfortunately, the disease process nearly always eventually outpaces these corrective actions.

The Normal Immune Response.

The most important critical immune factors in the disease process are white blood cells called lymphocytes, which consist of T cells and B cells. These cells are the warriors in the immune defense system.
Receptors on T cells acquire the ability to recognize specific molecules called antigens. Antigens are typically proteins from infecting organisms, such as bacteria or viruses, and perceived as a threat to the body.
Once the antigen is identified, specific T cells, called helper T cells, trigger the B cells to release antibodies. These molecules are designed to attach to and destroy the targeted antigen.

Autoimmunity.

Multiple sclerosis, and probably all autoimmune diseases, involves an error in the education of T cells, which makes them unable to distinguish self from non-self.
In multiple sclerosis, the miseducated T cells mistake molecules in the body's own myelin as a foreign antigen. Such targets are referred to as self-antigens.
In response to detection of these self-antigens, the T cells set off the usual cascading immune events, including the release of B lymphocytes, to rid the body of the perceived threat.
The B lymphocytes fire off antibodies as usual, but in this case they are referred to as autoantibodies, because they are attacking antigens that belong to the body's own self.
In MS, the immune system is tricked into targeting self-antigens that are myelin proteins, the fatty insulation covering the nerve fibers. Another autoantibody target may be the oligodendrocytes themselves -- the specialized cells that make up myelin.
To make matters worse, the process perpetuates through a cascading series of events in which the B cells and T cells continue to interact, creating numerous different self-antigens. The attacks continue and, in the process, the original self-antigen is unrecognizable.

Cytokines and the Inflammatory Response. The inflammatory response is the product of an overactive immune system and is a major destructive force in an autoimmune disease.

Once the lymphocytes have launched a response to an antigen, they also release masses of other white blood cells to gather at the injured or infected site.
The major players in this response are white blood cells called leukocytes. Researchers are particularly interested in leukocytes called cytokines. These are small powerful proteins that, in tiny amounts, are indispensable for healing. When they are overproduced, however, which occurs in MS, they play a major role in the destructive process.
Their intensive convergence on the affected area causes it to become inflamed and injurious to the very cells they are designed to protect. Under normal conditions, this inflammatory process is controlled and self-limiting, but in people with autoimmune diseases such as multiple sclerosis, the process persists and damage occurs in the surrounding tissues.

Important cytokines in MS appear to be tumor necrosis factors, interleukin-12, and interferon-gamma. Other cytokines, including interleukin-10 and transforming growth factor beta, may play a protective role and help block inflammatory activity.

The inflammatory response may trigger the disease, but afterward a progressive course takes over that does not appear to be related to inflammation. Experts have found that destruction of axons, the long filaments that carry electric impulses away from a nerve cell, is a major feature of multiple sclerosis. In fact, it may be the major cause of permanent disability that occurs with this disease. Microscopic studies reveal that axons are injured early on as "bystanders" while myelin is being peeled off. As the disease progresses, these weakened and exposed axons degenerate further. Most of the damage occurs early in the disease process and decreases over time, although some destruction can still be observed years and decades afterward. Such evidence is having significant effect on approaches to treatment and research.

Symptoms

Most patients first experience multiple sclerosis as a single attack of symptoms called a clinical isolated syndrome, which typically occurs between the ages of 20 - 40 years. Once a second attack occurs, the patient is considered to have relapsing-remitting multiple sclerosis. Much less commonly, the disease is progressive from the start and symptoms are more or less continuous.

Early symptoms may include the following:

Optic neuritis and other problems in the eye. Optic neuritis, which is inflammation of the nerves in the eye, affects over 50% of patients and is the first symptom in about 16% of patients. Symptoms include unclear or doubled vision, usually in one eye. Some people see a shimmering effect. Patients may also experience pain or involuntary jerking or movement of the eye (called nystagmus). In 20% of people with this condition, MS develops within 2 years after the onset. In 45 - 80%, MS develops within 15 years. About 17% of people eventually experience impaired eye movement.
Fatigue. Fatigue is typically worse in the afternoon and may be accompanied by an increase in body temperature. At the onset, this occurs in about 20% of patients, but as the disease progresses, this is a significant symptom in nearly all patients.
Changes in sensations in the arms and legs. Patients can experience heaviness, weakness, or clumsiness in the limbs. Tingling or loss of sensations can also occur, most commonly in the legs. The first symptoms for patients with primary progressive MS often develop slowly in the upper legs.
Muscle weakness in the legs and poor coordination.
Lhermitte’s sign. This is an electrical sensation that runs down the back and into the legs, which is produced by bending the neck forward.
Spasticity. Spasticity is the inability to control muscle tone and leads to spasms and stiffness. It is very common in MS.
Disturbances in the bladder.

In addition to the persistence of early symptoms, some patients experience the following symptoms as the disease progresses:

Imbalance and dizziness.
Tremors.
Facial pain.
Spasm-related symptoms. They include burning, itching, aching, quivering sensations. They usually occur in the extremities and last seconds to minutes.
Speech difficulties.
Difficulty swallowing.
Symptoms in the gastrointestinal, urinary, and genital tracts. Possible sexual dysfunction and loss of bowel and bladder control in severe cases.
Emotional mood swings. Depression is very common. About 10% of patients suffer from psychosis (manic depression and paranoia). About 5% of patients with severe MS experience uncontrolled and extreme mood swings called the laughing/weeping syndrome.
Problems in concentration and memory.
Hearing loss.

Infections. Viral infections have long been known to worsen MS symptoms. An important 2006 study indicated that bacterial infections can also trigger MS relapses. In the study, relapses appeared within 2 weeks of a viral or bacterial infection.

Heat. Heat, whether generated by ambient temperature, infection, or physical activity, worsens MS symptoms in about 60% of patients.

Stress. There is a strong correlation between severe stress and exacerbation of MS symptoms. For example, in one study, 85% of instances of MS exacerbations were associated with stressful events that occurred within an average of 14 days before the episode. Stress is not a cause of MS, however.

Trauma. Some experts believe that injury (trauma) to the head, neck, or upper back may trigger new or recurrent symptoms by disrupting the blood-brain barrier and allowing immunological attacks on the brain. This is a highly controversial theory, however, with very little supporting evidence.

Causes

The cause, or causes, of multiple sclerosis remains a mystery. Genetic factors certainly play a role in MS. No single gene, however, is likely to be responsible for causing MS. Rather, the current theory is that the disease occurs in people with a genetic susceptibility who are exposed to some environmental assault (a virus or a toxin) that disrupts the blood-brain barrier. Immune factors converge in the nerve cells and trigger inflammation and an autoimmune attack (a self-attack) on myelin and axons. Still, a number of disease patterns have been observed in patients, and some experts believe that MS may prove to be not a single disorder, but may represent several diseases with different causes.

Some research suggests that all autoimmune diseases are basically due to the same genetic error. A 2001 study found, for example, that the T cell immune factors in type 1 diabetes target the same self-antigens as in multiple sclerosis (MS). Many questions are unanswered, however. It is not known why the diseases develop in different locations to cause separate disorders. Nor, why some autoimmune events occur in everyone but not everyone develops an autoimmune disease.

Genetic factors probably play some role in making a person susceptible to the disease process leading to multiple sclerosis. In particular, abnormalities in the human leukocyte antigen (HLA) region located on chromosome 6 appear to be more prevalent among people with MS. Researchers theorize, however, that a combination of genes (not a single gene) is implicated in the development of MS, and the risk for someone inheriting all of these genetic factors is less than 5%. Advanced techniques called microarray technologies are now making it possible to scan hundreds of genes and identify those most likely to be contributors to MS. Genetic research may also pave the way for the development of new drugs to treat this disease. For example, researchers have recently identified the Olig1 gene as a key regulator in repairing damaged myelin-producing cells.

Infectious organisms, most likely viruses, are the top suspects for triggering the autoimmune response in people genetically susceptible to MS. There are a number of reasons for this belief:

The geographical distribution of the disease. The number of MS cases increases the further one gets from the equator in either direction.
Multiple sclerosis clusters. Four separate clusters of multiple sclerosis outbreaks occurred between 1943 - 1989 in the Faroe Islands, located between Iceland and Scandinavia. During World War II, this region was occupied by British troops. The incidence of MS increased each year for 20 years after the war, leading some researchers to think that the troops might have brought with them some disease-causing organism. In fact, one theory suggests that these findings offer evidence that MS is a sexually transmitted infection that occurs during adolescence. For example, the disease clusters observed in the Faroe Islands could be related to high sexual activity between the troops and local young women. A high incidence of MS is found in countries with a high degree of sexual permissiveness. MS is very rare in traditional cultures, but increases in people from these regions when they immigrate to industrialized Western nations.
Viral similarity to myelin. Some viruses are strikingly similar to the myelin protein and may therefore cause confusion in the immune system, causing the T cells to continue to attack their own protein rather than the viral antigen. More than one antigen may be involved; some may trigger the disease, and others may keep the process going.

Infectious Organisms Under Suspicion. Although many infectious microorganisms have been investigated, no one organism has emerged as a proven trigger. It is possible that different patients may be affected by different organisms, and that infections cause some, but not all, cases of MS. Organisms that are at the top of the suspect list are those that can affect the central nervous system. The following are three primary suspects:

HHV-6. Herpesvirus 6 (a form of herpesvirus that causes roseola, a benign disease in children) is also known to cause encephalitis (brain inflammation) in patients with impaired immune systems. A number of studies have reported higher than normal rates of HHV-6 infection in patients, and some experts believe that may be important in MS. Other experts argue, however, that nearly everyone harbors this virus and there is still no evidence of a causal relationship. Other herpes viruses can also infect brain cells. They include herpes simplex 1 and 2 (the causes of oral and genital herpes), varicella-zoster virus (the cause of chicken pox and shingles), and cytomegalovirus.
Epstein-Barr virus (EBV). Evidence suggests an association between EBV, the cause of mononucleosis, and MS. EBV is an extremely common virus and another member of the herpes virus family. Nearly all people have been exposed to EBV. However, researchers have discovered that people who are especially sensitive to the virus and have unusually high levels of EBV antibodies may have a greater risk of developing MS. Scientists are still uncertain if EBV is a cause of MS. EBV has also been linked to other autoimmune diseases such as lupus.
Chlamydia Pneumoniae. This atypical bacterium has been associated with persistent inflammation. A few studies have reported significantly higher rates of previous Chlamydia infection in patients with MS than in individuals without MS. An important group of 2000 studies reported no connection at all between Chlamydia and MS, and any experts now believe there is no strong evidence linking the microbe to MS. It is still possible, however, that the infection, which can cause widespread inflammation, plays a role early in the course of the disease in some individuals.

Other viruses that have been investigated include measles virus, adenovirus, and the retroviruses (HIV, HTLV-I, and HTLV-II), but none have emerged as having any importance.

Note on Vaccinations: Concerns about a link between the hepatitis B vaccine and MS led France to halt a major vaccination program in 1998. Subsequent research investigating whether the hepatitis B vaccine is indeed associated with an increased risk of MS has yielded mixed results. It appears that the vaccine would be, at most, a contributing -- but not the sole -- factor in MS development. At present, the evidence has not warranted any change in American immunization policies. Research has ruled out a link between any other vaccinations, such as or influenza or tetanus, and relapses of MS.

Risk Factors

An estimated 400,000 Americans and 2.5 million people worldwide suffer from MS.

Age. Onset occurs between the ages of 20 - 40 years in 70% of patients with the average age being 30 and the peak incidence occurring in the mid-twenties. The disease can still occur in both younger and older individuals. It rarely develops before age 15 or after age 60, however.

Gender. MS is more common among women than men. The gender gap is strongest among people who develop MS at a younger age. According to research presented at the 2007 American Academy of Neurology annual conference, the ratio between women to men has been growing. Researchers found that in the 1940s, the ratio of women to men with MS was 2 to 1. By 2000, the ratio had grown to 4 to 1. However, some research indicates that men may be more disabled by the disease than women.

Ethnicity. Multiple sclerosis occurs worldwide but is most common in Caucasian people of northern European origin, especially those of Scottish descent. It is extremely rare among Asians, Africans, and Native Americans. Specific groups (gypsies, Eskimos, Bantus) have never reported a case. While the risk of MS for African-Americans is around half of that for Caucasians, a recent study suggested that African-Americans are more likely to develop a more aggressive form of the disease and to suffer impaired mobility.

Geography. The risk for MS is higher in different regions of the world. In general, MS is more prevalent in temperate regions than in the tropics. Specifically, prevalence is highest in northern and central Europe (except northern Scandinavia), Italy, southern Australia, and northern regions of North America. Middle-risk areas include southern Europe (except Italy), southern US, northern Australia, and northern Scandinavia. Low-risk areas include parts of Africa and Asia, the Caribbean, Mexico, and possibly northern South America. It is unclear whether this pattern is attributable to environmental factors, genetics, or both.

Family History. A family history of the disease also puts people at risk for MS, although the risk for someone inheriting all the genetic factors contributing to MS is only about 2 - 4%. A 2007 study indicated that family members who have MS tend to develop the disease at around the same age. However, family history does not predict whether one family member will experience the same disease severity as another family member.

Cow's Milk During Early Infancy. Breast milk contains factors that may help regulate the immune response, and there is some evidence that infants fed only on cow's milk may have a higher risk for either diabetes type 1 (another type of autoimmune disease) or multiple sclerosis later in life. Studies on national differences in diabetes suggest that the risk may vary with different milk proteins, suggesting that not all cow's milk is the same and that some proteins carry higher risks than others.

The Hygiene Theory: Early Infections as Protection Against Allergies and Autoimmune Diseases. Over the past decades, there has been a dramatic increase in asthma, allergies, and autoimmune diseases, such as multiple sclerosis, Crohn's disease, and type 1 diabetes. One theory blames this rise on the reductions in childhood infections that have occurred with modern hygiene and antibiotic use. Studies supporting this have observed a higher incidence of allergies and autoimmune diseases, including MS, among populations with good hygiene and in animals that have been raised in a germ-free environment. The basic theory rests on the idea that early infections stimulate production of specific immune factors that protect against allergies and autoimmune diseases. The exact mechanisms of these effects are as yet unknown.

Vitamin D. Higher blood levels of vitamin D have been associated with a lower risk for MS, at least among Caucasians. (Studies have not shown that vitamin D has a protective effect for other racial groups.) However, there is not yet enough evidence to indicate that taking vitamin D supplements can help prevent MS.

Exposure to Sunlight. In a 2003 study, higher exposure to sunlight during childhood and early adolescence was associated with a lower risk for MS, perhaps because UV radiation produces higher levels of vitamin D, which has been associated with protection against MS. The effect of sunlight during winter seemed to be more protective than summer light. Unfortunately, higher exposure to sunlight also coincides with a higher risk for skin cancer, which is far more common than MS.

Estrogen and Oral Contraceptives. Higher estrogen levels may temporarily lower the risk of developing multiple sclerosis. Studies indicate that oral contraceptives (which contain estrogen) and pregnancy delay the onset of multiple sclerosis. The risk for a first clinical attack increases, however, in the 6 months after a woman gives birth.

Complications

Multiple sclerosis is not a fatal disease. Some data suggest that it shortens the average life span by only about 6 or 7 years. Still, in about half of MS cases, patients die of complications of the disease, and the disease has significant negative emotional and physical consequences. Suicide rates among patients with MS are higher than average.

The severity of the disease varies widely from patient to patient and is unpredictable. About 20% of patients remain asymptomatic or become only mildly symptomatic after an initial clinical event. Another 20% experience a rapidly progressive condition. Most patients, however, will experience some degree of progression.

Women tend to have a better outlook than men. Factors the determine a higher risk for a severe condition include:

Age over 40 years at the time of onset of symptoms
Initial symptoms that affect motor control, mental functioning, or urinary control, or initial symptoms affect multiple regions
Attacks in the first years that are frequent or interval between the first two attacks is short
Incomplete remissions
Rapid progression to disability
MS that is progressive from the beginning or becomes progressive shortly after the onset

Doctors and researchers often use a scale called the Kurtzke Disability Status Scale to assess and predict future disability. The system uses a score of 1 to 10 to rate the degree of walking disability. Experts have used the scale to attempt to predict average times for progression from one stage to the next depending on whether patients have relapsing-remitting or chronic progressive MS.


Score	Disability Description	Relapsing-Remitting MS: Average time until onset of symptoms*	Chronic Progressive MS: Average time until onset of symptoms*
1	No disability and minimal neurologic symptoms.	11.4 years from Score 1 to Score 4	0 years from Score 1 to Score 4
2	Minimal disability in one or two functional areas. Slight weakness or stiffness, mild walking impairment or visual disturbances
3	Moderate disability in one functional area, such as vision or the urinary tract, and possibly more than one minimal disability in several others. Either a part of one of the limbs or a whole side can be partially paralyzed. May stagger at times.
4	Disability is relatively severe but there is full ability to walk without aid. Patients are self-sufficient and can be active 12 hours a day and carry on normal activities. Can walk without aid or rest for 300 to 500 meters.
5	Disability is severe enough to impair or even preclude a full day's activities. Able to walk unaided and without rest for 100 to 200 meters.	23.1 years from Score 1 to Score 6	7.1 years from Score 1 to Score 6
6	Can walk unaided for about 100 meters only with assistance or devices, such as two canes, crutches, or braces.	23.1 years from Score 1 to Score 6	7.1 years from Score 1 to Score 6
7	Mostly restricted to wheelchair, although can manage the wheelchair and leave it unassisted. Can walk with aids no further than about five meters.	33.1 years from Score 1 to Score 7	13.4 years form Score 1 to Score 7
8	Mostly restricted to wheelchair or even bed, but still has effective use of arms remains and able to perform many self-care functions.	(Data not available)	(Data not available)
9	Bedridden. Patient can communicate or eat.
10	Fatality occurs from complications.
* Data taken from Relapses and Progression of Disability in Multiple Sclerosis, The New England Journal of Medicine, November 16, 2000, Vol. 343, No. 20

Because the effects of nerve injury are widespread, complications can be very severe and affect all parts of the body. Although not all patients experience all of the following problems, any of them can negatively impair quality of life.

Fatigue. Fatigue is one of the most common and debilitating MS symptoms and affects at least two-thirds of patients with MS. Fatigue specifically attributed to MS and not to other causes is defined as abnormal fatigue that lasts at least half of the time or more than 6 weeks. It causes a general lack of energy that significantly limits daily functioning regardless of any neurologic symptoms or specific muscle weaknesses. Up to 40% of patients describe fatigue as the most disabling MS symptom, which is higher than weakness, spasticity, motor control, or bowel or urinary problems. Many conditions that are common in MS (sleep disorders, depression, hypersensitivity to sensation, hypothyroidism, medications, heat) may contribute to fatigue. None fully explain the consistent presence or severity of this problem in MS. Researchers using imaging techniques have identified possible changes in part of the brain in MS that may play a role in the fatigue of MS.

Loss of Mobility and Spasticity. Nearly every patient loses some mobility, which may take the form of less or impaired motor control, muscle weakness, impaired balance, and, importantly, spasticity. Spasticity is one of the primary symptoms of MS. It is characterized by weakness, loss of dexterity, and the inability to control specific movements. It is usually more severe in the legs and torso. (Ironically, mild spasticity actually helps improve muscle tone in the legs, which is important in supporting the patient’s weight when walking.) Mobility can be affected by many non-physical factors, including mental well-being, social networks, fatigue, and even the weather.

Pain. About two-thirds of patients experience pain at some point during the course of the disease, and 40% are never pain free. MS causes many pain syndromes; some are acute while others are chronic. Some worsen with age and disease progression. Pain syndromes associated with MS are trigeminal (facial) pain, powerful spasms and cramps, optic neuritis (pain in the eye), pressure pain, stiffened joints, and a variety of sensations, including feelings of itching, burning, and shooting pain.

Bowel Dysfunction. Bowel dysfunction, which can include constipation or fecal incontinence, is a serious problem for many patients. Constipation may be caused by the disorder itself or by medications used to treat spasms or other symptoms.

Sexual Dysfunction. Sexual dysfunction is a common problem, occurring in over 70% of patients. Men are likely to have impotence and women, problems with vaginal lubrication. It appears to be highly associated with urinary dysfunction.

The nerves that branch off the central nervous system (CNS) provide messages to the muscles and organs for normal function. When there is CNS damage, the function of these organs and tissues may be compromised. In multiple sclerosis, the demyelinization of nerve cells may lead to bowel incontinence, bladder problems and sexual dysfunction.

Urinary Dysfunction. Urinary problems from bladder dysfunction occur in two-thirds of patients. Some patients have difficulties in urinating at will, called urinary retention. Often it takes the form of urge incontinence (also called hyperactive or irritable bladder). People with urge incontinence need to urinate frequently or are unable to reach the bathroom before leakage. In such cases, the bladder is overactive. Complications in the urinary tract also produce a high rate of urinary tract infections.

Difficulty Swallowing. A third to a half of patients experience difficulty in chewing or swallowing, problems that may be caused or made worse by many MS medications.

Speech and Hearing Problems. Problems in speech may occur because of difficulty in controlling the quality of the voice and articulating words. (Problems with language itself, however, are very rare in MS.) Hearing problems also occur in MS and may affect speech.

Problems in the Lungs. As the muscles that control breathing weaken, the ability to cough is impaired and the patient is at higher risk for pneumonia and other complications in the lungs.

Osteoporosis. Osteoporosis (loss of bone density) and subsequent fractures are common and under-recognized problems among patients. Osteoporosis is caused and worsened by immobility and by some MS medications. Fractures caused by falls can be far more serious in patients than in the normal population, leading to problems, including deconditioning or even inability to walk, obstruction of the intestines (from pain-relieving medications), and respiratory complications.

Cognitive problems, such as having trouble concentrating and solving problems, affect about half of patients. More people with MS leave work because of such cognitive difficulties than because of physical problems, according to a 2000 study. In about 10% of cases, mental dysfunction may be severe and resemble dementia. The severity of such mental changes appears to be associated with the degree of loss of brain tissue. This offers another argument for early treatment as interferon medications may improve these symptoms.

Between 40 - 60% of patients suffer from depression at some point over the course of the illness, and studies have reported risks for suicide ranging from 3 - 15%. Some evidence suggests that depression in multiple sclerosis is not only due to the social and psychologic impact of MS but also to the disease process itself. Depression may have biologic effects, such as increasing production of inflammatory cytokines, that could exacerbate the disease itself. Doctors should assess patients for depression, even if there are no obvious signs of it. The risk for suicide may be present even in patients who are not obviously depressed. People at highest risk for suicide are those who live alone, those with a history of an emotional disorder (depression, anxiety, alcohol abuse), a family history of mental illness, and people with high social stress.

Diagnosis

Multiple sclerosis is characterized by recurring neurologic episodes that are due to multiple lesions (injured areas) in different locations in the central nervous system. The diagnostic challenges in multiple sclerosis are two-fold:

Making an initial diagnosis as early as possible in order to slow down the disease progression. Most patients first seek medical help after an initial inflammatory event (known as a clinically isolated syndrome) originating from demyelination in the eye, the spinal cord, or the brain. About 30% of these individuals will develop progressive MS within the year. At this time, however, experts cannot predict who among these patients are at highest risk for rapid progression.
Predicting the severity of the disease. Once MS has been diagnosed, the pattern of the disease is uncertain. It can be very benign to rapidly progressive and severe. Magnetic resonance imaging (MRI) is able to detect lesions in the brain indicating MS. But, the severity of the disease does not appear related to the number of lesions, the rate of their appearance, or their location. Researchers are hoping to identify some biologic marker, possibly certain antibodies, that will enable doctors to accurately determine the onset and severity of the problem once a diagnosis has been made.

The McDonald Criteria. There is no single test that can accurately diagnose MS, and a number of other conditions may mimic its symptoms. Some doctors use a set of factors, called the McDonald criteria, for diagnosing multiple sclerosis in early stages. The criteria include the presence of specific symptoms, spinal fluid evaluation, and magnetic resonance imaging techniques for detecting lesions within the central nervous system and tracking them over time. The criteria show high reliability in identifying MS in patients with a variety of disease stages or states, including having only one episode, a typical relapsing-remitting course, or a slow insidious progression without clear attacks or remissions. Depending on the MRI and other findings, the patient is then categorized as having MS, possible MS, or no MS.

The symptoms of MS are similar to a number of other diseases, which must be ruled out. These include stroke, alcoholism, emotional disorders, Lyme disease, chronic fatigue syndrome, fibromyalgia, AIDS, and certain other autoimmune disorders (hypothyroidism, scleroderma, Sjögren syndrome, and systemic lupus erythematosus).

Doctors and investigators generally use a test called the Expanded Disability Status Scale (EDSS) to rate the severity of symptoms. It is also used after a diagnosis to gauge the status of the disease, and score the effectiveness of treatments. The scale ranges from 0 to 10 with higher scores indicating more severe symptoms. These are subjective ratings that require doctor observation skills.

Objections to the use of the EDSS are that it assesses only limp and walking problems and does not assess other important complications, including fatigue, sexual function, and mental function.

No reliable single laboratory procedure or test can establish the diagnosis of multiple sclerosis. Several are necessary before a diagnosis can be made.

Analysis of Cerebrospinal Fluid (CFS). Obtaining a sample of spinal fluid requires a lumbar puncture, or spinal tap. Testing spinal fluid is becoming increasingly important for detecting abnormal proteins, tiny fragments of myelin, or specific white blood cells that can help in making a diagnosis. For example, high levels of the immunoglobulin IgG is useful for making a diagnosis and may be a marker for disease progression. (Immunoglobulins are protein chains that are part of the immune system.)

A lumbar puncture, or spinal tap, is a procedure to collect cerebrospinal fluid to check for the presence of disease or injury. A spinal needle is inserted, usually between the 3rd and 4th lumbar vertebrae in the lower spine. Once the needle is properly positioned in the subarachnoid space (the space between the spinal cord and its covering, the meninges), pressures can be measured and fluid can be collected for testing.

Evoked Potential (EP) Test. This is a simple and painless electrical test of nerve function that assesses how long it takes nerve impulses from the eye, ear, or skin to reach the brain.

Magnetic resonance imaging (MRI) scans are important diagnostic tools in MS and are used for diagnosing multiple sclerosis, tracking changes over time, and helping to determine treatment effectiveness.

Click the icon to see an image of a brain MRI.

Making a Diagnosis and Tracking the Disease. Magnetic resonance imaging (MRI) scans can detect bright patches that indicate injured tissue (lesions) caused by MS. Such lesions may also indicate other conditions, such as infections, migraines, or clots. Importantly, a very sensitive MRI technique using enhancement by a contrast material called gadolinium can indicate recent activity by showing if the blood-brain barrier has been broken down (the first step in the development of MS lesions). Detecting lesions and treating MS early in the disease process may help reduce progression. Many experts therefore now advocate performing a brain MRI as soon as symptoms appear.

Once diagnosed, periodic follow-up MRIs can be used to track the disease and effectiveness of treatments in two ways:

By distinguishing new lesions from old ones
Revealing increasing or decreasing numbers of lesions within the central nervous system over time

Unfortunately, neither the rate nor the number of new or growing lesions necessarily predicts whether symptoms will worsen or if the patient will develop secondary progressive MS.

Measuring Atrophy in Brain and Spinal Cord. As myelin, axons, oligodendrocytes, and neurons are destroyed, the brain begins to shrink. Processing MRI images to determine brain volume may be a useful way to monitor progression and treatment effects. MRI can also detect shrinkage in the spinal cord, which is proving to be a very strong marker of disease progression. A variation of MRI, magnetic resonance spectroscopy (MRS), provides information on the biochemistry of the brain, and may be particularly helpful in detecting this destructive aspect of MS.

Detecting Black Holes.Severe disease progression can be gauged by the presence of so-called "black holes.” These are lesions in the brain that emit very low signals on an MRI scan. Some evidence suggests that they may represent iron deposits in the brain.

Researchers are continuously searching for biologic markers that might help make an accurate diagnosis, predict outcome, or both. Promising markers are antibodies that target two key protein components of myelin: Myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP). If future studies confirm the predictive value of these antibodies, scientists may be able to develop a blood test for MOG and MBP.

Treatment

Patients diagnosed with multiple sclerosis face great uncertainty, since the course of the illness varies so widely among patients. Experts recommend a multidisciplinary approach to the disease, which might involve a neurologist, a nurse or social worker expert in MS, and possibly a specialist in mental health (since depression is so common and the suicide rate is higher than average).

Evidence now strongly suggests that the most destructive changes from multiple sclerosis in the brain occur very early on in the disease process -- and may cause considerable damage even before symptoms begin.

Many experts are now urging treatment after a first episode of relapsing MS (a clinically isolated syndrome) using medication called disease-modifying drugs. They include three interferons -- IFN1b (Betaseron) and IFN1a (Avonex, Rebif) -- and glatiramer (Copaxone). These drugs are all effective and may help slow down or even prevent progression in some patients. Definitive studies comparing them are ongoing.

The best current approach is to use specific findings from advanced MRI techniques to help determine which patients are at highest risk for progression and would be likely candidates for early treatment with disease modifying drugs.

Interferons and other disease-modifying drugs can have significant side effects and are expensive. Furthermore, a significant number of patients have a mild course that can be managed with less toxic drugs. Nevertheless, strong evidence suggests that delaying treatment in most patients increases the risk for severe disability.

Corticosteroids are the standard drugs for treating an acute relapse and hastening recovery. Typically, intravenous methylprednisolone (IVMP) is given once a day for 3 days. Sometimes this is followed by oral prednisolone for a few days.

Disease Modifying Drugs. Since the introduction of disease modifying drugs -- interferons beta (Betaseron) and alpha (Avonex, Rebif) and glatiramer (Copaxone) -- relapsing-remitting multiple sclerosis is now considered a treatable disease. In patients with very active MS, some experts start with Betaseron or Rebif. For patients with possible or probable MS, they begin with Avonex. This drug is slightly less effective than Rebif and Betaseron but has fewer side effects. Copaxone is also a reasonable choice for early mild MS. It appears to have the fewest side effects, longer relapse-free rates than interferons, and its benefits persist for years.

The newest drug, the monoclonal antibody natalizumab (Tysabri), was approved in November 2004 for treatment of relapsing forms of MS. The FDA withdrew it from the market, however, in February 2005 following reports of serious neurological events. In June 2006, the FDA allowed natalizumab back on the market but with special restrictions (see Drug Treatment section).

Other Approaches. Some research has reported benefits from the use of pulsed administration of intravenous methylprednisolone (IVMP) or intravenous immunoglobulin, although there is not enough evidence for either approach to recommend them as first-line choices. Other drugs showing promise include azathioprine (an immunosuppressant) and laquinimod (an oral immune-modulating drug).

Treating Secondary Progressive Multiple Sclerosis (SPMS). Interferons and other standard treatments for relapsing-remitting MS may be helpful for patients with SPMS who are still experiencing relapses. It is not clear if they help those whose condition has become continuously progressive.

Mitoxantrone (Novantrone) was the first drug approved for SPMS. The drug is an immunosuppressant and is proving to delay relapse and progression. Side effects, however, can be serious in some cases. Some experts recommend using mitoxantrone when evidence suggests progression to SPMS, and continuing the interferons Betaseron or Rebif for maintenance.

Other immunosuppressants, such as cyclophosphamide, methotrexate, and cladribine, may help some patients with SPMS. They can have very toxic side effects, however, and there must be clear treatment indications for patients who take these drugs.

Treating Primary Progressive Multiple Sclerosis. No treatments have been proven yet to slow progressive multiple sclerosis. Studies using interferons and glatiramer are under way.

A number of treatments are available for managing symptoms and complications.

Drug Treatment

Corticosteroids (commonly called steroids) are mainstay treatments for acute relapses patients with relapse-remitting MS. High-dose methylprednisolone given intravenously (IVMP) is typically administered for major relapse, often followed by oral prednisone for a few days. Steroids reduce inflammation in the central nervous system and may help suppress the immune system's attack on myelin and even improve electrical conduction.

Steroids, in general, do not improve the long-term course of the disease and can lose effectiveness if overused. They are not generally used for maintenance therapy. Some research, however, is reporting benefits from the use of pulsed administration of intravenous methylprednisolone. Such an approach typically administers the steroid daily for 5 days every 4 months for 3 years, then every 6 months for 2 years. Some research suggests that this approach might reduce destruction in central nervous system, although more evidence is needed before it can be recommended. They can also have considerable adverse effects when used over time.

Side Effects. Side effects of long-term use of steroids include weight gain and facial fullness, hypertension, diabetes, osteoporosis, cataracts, intestinal bleeding, and increased susceptibility to infections. In addition, side effects of steroids on the central nervous system (sleeplessness, memory loss, anxiety, and depression) can be particular problems for patients. It is extremely important to taper withdrawal very carefully after continuously taking steroids for a prolonged period of time. This gives the body time to recover its own ability to produce natural steroids. A serious condition known as adrenal insufficiency can otherwise develop.

Interferons (so-called because they “interfere” with viral replication) both suppress important inflammatory factors in the immune system and have anti-viral properties. Interferons specifically block immune factors known as class II MHC molecules, which are associated with the attack on myelin and the breach in the blood-brain barrier that allows the destructive T cells to pass through.

Specific Interferons Used for MS. Interferon drugs used for MS are IFN1b (Betaseron) and IFN1a (Avonex, Rebif). They are now the treatments of choice for relapsing-remitting MS. Expert organizations urge that they be used early in the course of the disease and continued indefinitely, unless they produce no benefits or have severe side effects.

Successes and Drawbacks. Interferons can reduce flare-ups overall by 30% and have an even greater effect on reducing major relapses. Disease activity, as measured by MRI scanning, is reduced by over 80%. They appear to be about equal in reducing disability. To date, only Avonex has demonstrated slowing progression of mental impairment. It also appears to be better tolerated than other interferons. Studies on their effects on quality of life are limited. None of the interferons are a cure, in any case, and when the drug is discontinued, disease activity may increase. All of these drugs need to be injected. (Oral forms are under investigation.)

Side Effects and Complications. Side effects include:

Pain at the injection site. Many patients taking Betaseron complain of severe pain at the injection site caused by damaged tissue. Experts recommend taking acetaminophen (Tylenol) before the injection and then every 6 hours after each injection for 24 hours during the first 6 months of treatment.
Skin injury at the injection site. Black dead tissue may form around the site, and many patients taking Betaseron have reported severe skin eruptions. These skin injuries heal after the drug is withdrawn, but scarring can occur. This side effect is least severe with Avonex, followed by Rebif.
Other physical side effects. Both drugs cause flu-like symptoms, nausea, vomiting, headaches, and dizziness. Such side effects usually fade after 2 - 3 months.
Depression. Early studies associated taking interferon with a higher risk for depression during the first 2 - 6 months following initial therapy. More recent studies, however, have reported no greater risk for depression in patients taking any of these drugs. MS itself, in any case, is highly associated with depression.
Thyroid abnormalities. Interferon has been associated with autoimmune thyroiditis, a cause of hypothyroidism. Some experts recommend monitoring for thyroid function, particularly in the first year and in those with a history of thyroid problems. If there is no evidence of the condition during that period, the risk for its occurrence appears to be very low.
Liver damage. Interferon may cause liver damage and, in rare cases, liver failure. Patients should avoid alcohol and have regular liver function tests while taking this drug

Neutralizing Antibodies That Reduce Effectiveness. Over time, people taking interferons develop antibodies to the drugs, some of which can neutralize their effects. The risk for neutralizing antibodies (NAbs) increases with higher doses and greater frequency of use. Interferons injected under the skin (Betaseron, Rebif) are more likely to produce neutralizing antibodies than Avonex, which is injected into a muscle. Patients who experience this, however, often can be effectively treated with an alternative interferon or with glatiramer, which has an extremely low risk, for NAbs. In many cases, after switching drugs, NAb levels decline, and the patient may be able to return to the original interferon.

Glatiramer acetate (Copaxone) is a synthetic molecule that resembles a basic protein found in myelin. It is used as a decoy to trick white blood cells into attacking it instead of myelin. It is approved to help reduce the frequency of relapses in patients with relapse-remitting MS. The best results are in patients in early stages, but the longer patients remain on the drug, the greater the improvement. Benefits have persisted for years. Glatiramer acetate can also help reduce the number of new brain lesions.

Glatiramer acetate is also being studied for its effects in patients with primary progressive MS. A 2007 study indicated that while the drug had little benefit for most patients with this type of MS, it may help slow disease progression and delay disability in men with primary progressive MS.

Side Effects. Side effects occur in about 15% of patients, usually right after the injection. They include pain at the injection site, chest pain, rapid heartbeat, flushing, anxiety, and shortness of breath.

Monoclonal antibodies (MAbs) are drugs that target specific antibodies involved with the immune response. In 2004, natalizumab (Tysabri) became the only MAb approved for treatment of MS. Shortly afterwards, reports emerged of progressive multifocal leukoencephalopathy (PML) occurring among patients who took natalizumab for more than 2 years. PML is a rare neurological disease that can affect people with compromised immune systems. Based on these reports, the FDA suspended marketing of natalizumab in February 2005 and recommended that patients discontinue its use.

In June 2006, the FDA allowed natalizumab to return to the market with certain safety restrictions. Doctors can prescribe the drug only to patients who have failed to respond to or who cannot tolerate other MS treatments. Natalizumab can only be taken alone, not in combination with other immune-modifying drugs. Patients who take natalizumab must enroll in a special program called TOUCH, which is run by the drug’s manufacturer. Patients need to get magnetic resonance imaging (MRI) brain scans before they begin taking the drug, and they are evaluated regularly during drug treatment to make sure they are not at risk of developing PML. In the year after these restrictions were implemented, no new cases of PML were reported.

Clinical trials indicate that natalizumab’s benefits may outweigh its risks. Several studies published in 2006 in the New England Journal of Medicine showed that natalizumab, alone or in combination with IFN1a (Avonex) can help prevent disability in patients with multiple sclerosis. Another study suggested that the risk of PML is very low if patients use natalizumab for less than 18 months.

Natalizumab is also being studied for treating complications associated with MS. In a 2007 study, natalizumab helped reduce vision loss in patients with relapsing MS. Vision loss is one of the most common symptoms associated with MS.

Other MAbs under investigation for MS include daclizumab (Zenapax), alemtuzumab (Campath), and rituximab (Rituxan). Results from a 2005 phase II trial for alemtuzumab indicated that the drug helped prevent relapse but also caused serious side effects. Patients who took the drug had a high risk for developing a serious bleeding disorder caused by a low blood platelet count. Daclizumab is currently in phase II trials as is rituximab. Unlike other MAbs, which affect T cells, rituximab targets and depletes B cells. In several studies presented at the 2007 meeting of the American Academy of Neurology, rituximab showed promising results in reducing relapse frequency and number of brain lesions in patients with relapse-remitting MS.

Intravenous immunoglobulin treatments are monthly infusions of natural antibodies. They appear to have some modest benefits for relapsing-remitting MS. Studies suggests that intravenous immunoglobulin reduces relapse rates and occurrences of new lesions and slows disease progression in relapsing-remitting MS. It does not appear to reduce disability. It is extremely expensive and does not appear to have any benefits for patients with secondary progressive MS.

Many drugs being investigated for chronic progressive multiple sclerosis are immunosuppressants, which block certain factors in the immune system that contribute to the inflammatory process. Each of these drugs can produce serious side effects, including susceptibility to infection. Evidence on benefits is uncertain, mainly because of high toxicity or study limitations. Still, some immunosuppressants may help certain patients with severe MS. Among immunosuppressant drugs or procedures that have been investigated with little or no obvious benefits or unacceptably high side effects are total lymphoid irradiation, sulfasalazine, cyclosporine, acyclovir, and oral bovine myelin.

Mitoxantrone. Mitoxantrone (Novantrone) was the first drug approved specifically for secondary progressive MS. Studies suggest that it may help reduce progression and relapse rates. Cumulative doses can have toxic effects on the heart, however, so the drug is only used for a limited period. Mitoxantrone is also being studied in combination with glatiramer acetate. In one preliminary study, initial treatment with mitoxantrone, followed by maintenance treatment with glatirimer acetate, helped reduce relapses for up to 5 years.

Methotrexate. In some patients, low doses of the immunosuppressant methotrexate may slow the course of chronic-progressive MS, particularly in those with secondary progressive MS. To date, studies have found beneficial effects only on the upper body, however. Although this drug, like all immunosuppressants, can have toxic side effects, it may be taken in low doses for MS and so side effects are generally minimal.

Cyclophosphamide. Cyclophosphamide (Cytoxan) blocks cell growth and also suppresses the immune system. Some studies, but not all, have reported benefits for patients with chronic progressive MS. Small studies suggest that monthly intravenous administration or a combination with interferon-beta may help some patients with rapidly deteriorating MS. Cyclophosphamide has many side effects, including hair loss, nausea, vomiting, infertility, lung scarring, and blood abnormalities, and should be used for patients who do not respond to methotrexate.

Azathioprine. Azathioprine (Imuran) is designed to suppress the immune system and reduce the number of cells attacking the CNS myelin. It is used with or without steroids and is sometimes used as an alternative to patients with relapsing-remitting MS who do not respond to either interferon beta or glatiramer acetate. One study reported that 40% of patients had not experienced a relapse after taking the drug for 3 years, although others report only modest benefits. The drug has no effect on progression of disability.

Cladribine. Cladribine (Leustatin) may be effective in delaying progression in patients with chronic progressive MS. It has no significant effect on relapsing-remitting MS.

A number of treatments are under investigation that may prove to be helpful for multiple sclerosis. Those discussed below are only some of them.

Immune-Modulating Drugs. Most MS drugs are injected, but researchers are developing several new drugs that can be taken by mouth. Four of the most promising candidates are cladibrine (Mylinax), fingolimod (FTY720), teriflunomide, and fumarate (BG00012). In late-stage clinical trials, these drugs have shown positive results in the treatment of relapse-remitting MS.

Sex Hormones. Women with MS have a reduced risk of experiencing relapses during pregnancy, probably because of their high levels of the female sex hormones estrogen and progesterone. Because of this association, researchers have investigated whether oral estrogen therapy (estriol) can help prevent relapses. Some small studies have indicated that estriol treatment may help reduce lesions and disease activity, but the overall evidence is still inconclusive. The male sex hormone testosterone is also being studied as a treatment for men with relapse-remitting MS. A small 2007 pilot study suggested that treatment with testosterone gel is safe and may help improve cognitive function, slow brain degeneration, and increase muscle mass.

Cannabinoids. Cannabinoids are compounds in marijuana (cannabis), which may have properties that protect nerve cells. Cannabis has been found to improve pain, mobility, tremor, mood, appetite, fatigue, vision, sexual and urinary function, and memory. In a 2003 study, patients reported less pain and improved mobility (although spasticity itself did not improve). Not all patients respond. The drug may also worsen balance and posture in patients with spasticity. Synthetic versions are being investigated that allow rapid delivery without the unwanted side effects of natural cannabis.

Potassium Channel Blockers. Aminopyridines are potassium-blocking compounds that appear to improve nerve conduction through demyelinated areas. In small, preliminary trials, 4–aminopyridine (also called AP) was associated with mild-to-marked improvement in vision, strength, and coordination and was well tolerated. Beneficial effects, however, lasted only a few hours. A related compound, 3,4–diaminopyridine, or DAP, is being studied for relieving fatigue associated with MS.

Statins. Statins are currently the most important drugs for lowering cholesterol. They are also showing additional possible benefits, including anti-inflammatory and nerve protecting properties, which may help patients with neurologic conditions, including multiple sclerosis.

Plasmapheresis. Plasmapheresis with plasma exchange is a procedure in which blood is removed from the body. Blood cells are separated from plasma (the liquid portion of blood) and mixed with replacement plasma, which is then returned to the body. The replacement plasma is thought to dilute antibodies and other immunologically active substances that may trigger MS. Small studies suggest this procedure may have significant benefits for some patients with severe MS, particularly if they are younger and have an early response to this treatment. Side effects include risk of infection and blood clotting problems.

Stem Cell Transplantation. Investigators are studying the benefits of stem-cell transplantation procedures. Stem cells are produced in the bone marrow and are the early forms for all blood cells in the body (including red, white, and immune cells). Early studies indicate that stem cell transplantation may slow progression, although at this point it is not a cure.

Oligodendrocyte Implants. A newly developed, minimally invasive method to transplant modified oligodendrocyte cells directly into the brain is under investigation. Such cells stimulate nerve and axon growth. If feasible, this approach might be helpful in patients whose MS is not caused by an autoimmune response (where the new cells would be attacked, just as the patient's own cells were).

Other Treatments

Nearly 60% of patients try some form of nontraditional remedies. Research on any benefits is slim, and there may be some danger with many remedies commonly used by patients. The following are a few alternative remedies sometimes used for MS.

Relaxation and Meditation Techniques. Generally harmless, and possibly helpful, nontraditional therapies for MS are relaxation and meditation techniques and Eastern martial art exercises. Such techniques include biofeedback, music therapy, yoga, tai chi, and massage therapy.

Acupuncture. Some patients report benefit from acupuncture, which does carry a very small risk, usually for infection.

Acupuncture, hypnosis, and biofeedback are all alternative ways to control pain. Acupuncture involves the insertion of tiny sterile needles, slightly thicker than a human hair, at specific points on the body.

Electromagnetic Stimulation. A few centers have studied pulses of weak electromagnetic fields applied to the brain. Very small studies have reported improvement in fatigue, tremors, depression, and other symptoms in patients who were severely affected by MS. In one controlled study, this approach relieved symptoms more effectively than placebo. The effect was small however and more research is needed.

Linoleic Acid. Linoleic acid, commonly known as evening primrose oil, is a polyunsaturated fatty acid believed by some people to be helpful because myelin is composed of fatty acids. No study has proven that it is beneficial, but supplements sold in health food stores do not appear to be harmful.

Oral Enzymes. Oral drugs containing various natural enzymes, including bromelain, trypsin, papain, and rutin, have been used overseas to treat arthritic pain. They appear to reduce inflammation and are also being studied in patients with MS. Such enzymes have been marketed alone and in combinations (Wobenzym, Phlogenzym). In one small study, Phlogenzym was associated with a decline in complications and longer remission. They are not painkillers; any benefits derived from them may take several weeks. As with any natural remedy, there are few clinical studies on these products and no U.S. regulation of quality, safety, or effectiveness.

Generally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Patients should check with their doctor before using any herbal remedies or dietary supplements

The following warnings are of particular importance for people with multiple sclerosis:

Antioxidants. Some patients use antioxidant vitamins or supplements (A, E, C, Q10, pycnogenol, OPC, grape seed extract), since the destruction in the MS disease process may be partly due to oxidation (chemical damage from particles called oxygen-free radicals). Theoretically, however, antioxidants can trigger T cells and macrophages (inflammatory components of the immune system) and, therefore, may pose some danger to patients. Small studies to date have not found any worsening of the disease from taking vitamin supplements, but patients should be cautious. No vitamins studied for MS, including carotenoids, vitamin C, vitamin E, B12 injections or vitamin D, have been proven to be beneficial.

Gingko. Although the risks for gingko appear to be low, there is an increased risk for bleeding at high doses. Ginkgo can also interact with high doses of vitamin E, anti-clotting medications, aspirin, and NSAIDs. Large doses have also been known to cause convulsion. Commercial gingko preparations may contain colchicine, a drug that can be harmful in pregnant women and people with kidney or liver problems.

Bee Venom. For years, anecdotal reports have claimed that bee stings relieve some MS symptoms, although a study on mice indicated that it may worsen MS. Bee venom contains many chemicals, some of which can cause severe and sometimes deadly allergic reactions in some people.

Other Remedies. Herbal or natural remedies that supposedly boost the immune system (echinacea, ginseng, garlic, zinc) may worsen MS. Melatonin has been associated with worsening of some autoimmune diseases. Toxic effects have also been reported with herbal remedies such as borage seed oil, chaparral, and comfrey.

Treating the Complications

Fatigue affects at least two-thirds of patients. It is among the most disabling problems in MS and is difficult to treat. Treating any problem (depression, hypothyroidism) that may be causing fatigue is important. Aerobic exercise programs scheduled early in the day have been helpful for patients who can participate. Preventing overheating can improve fatigue.

Modafinil (Provigil, Alertec) is a promising drug that promotes long-lasting wakefulness and is currently used in narcolepsy. Small studies report that it is effective in reducing fatigue and sleepiness, with lower doses (200 mg) being more effective than higher ones. Studies also suggest that the antiviral drug amantadine (Symmetrel) may be helpful.

Managing pain and spasticity in the lower limbs can be difficult. Although many drugs are used to reduce spasticity and lower-limb pain, most studies investigating these drugs have been poorly designed and no treatment has emerged as a front-runner.

Exercise. Mild spasticity actually helps improve muscle tone in the legs, which is important in supporting the patient’s weight when walking. This benefit can be lost with drug treatment. Mild spasticity, then, should be treated with exercises several times a day that improve range of motion.

Drugs Used for Spasticity.

Baclofen (Lioresal) has long been the drug of choice to alleviate more severe spasticity. It is available both orally and infused through an implanted pump. Distressing side effects include confusion, drowsiness, and a rubbery-like sensation in the legs that makes it hard to stand.
Antiseizure medications, such as gabapentin (Neurontin) or levetiracetam (Keppra), may help reduce spasticity without increasing fatigue or impairing concentration. Studies on gabapentin also suggest that it also have other specific benefits for patients, including reducing facial pain and improving vision.
Tizanidine (Zanaflex) is an oral drug that works after one week. In one study, 75% of patients taking tizanidine reported improvement without the leg-muscle weakness experienced using baclofen. The drug does not appear to be any more effective than baclofen, however. Side effects include dizziness, drowsiness, dry mouth, and fatigue. Liver function must be monitored.
Diazepam (Valium) is also used for spasticity and may be particularly useful for patients who also experience anxiety. Drug dependence is the primary problem with diazepam, as well as dizziness, drowsiness, and confusion. The medication should not be used by people who are seriously depressed.
Botulinum toxin (Dysport) injections are being investigated for spasticity in specific regions such as the hip.
Dantrolene (Dantrium) may be an effective alternative for patients who cannot tolerate diazepam or baclofen. Because dantrolene causes muscle weakness, however, it is best suited for either patients who are wheelchair bound but still suffer from spasticity, or for those whose muscles are still strong so that the drug-induced weakness isn't unduly debilitating. It also causes nausea, vomiting, and anorexia, and with high dosages it can cause dangerous liver damage.

Surgery. In very severe cases where medication and exercise are not helpful, surgery may be considered. In such cases, the surgeon cuts the tendons that are involved with spasticity.

Spinal Injections. In very severe cases, administering phenol using spinal injections in the lower back may reduce pain and spasms for some patients with severe conditions. Most patients are not appropriate candidates for this approach.

Other Treatments. Researchers are also investigating non-drug treatments for spasticity. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method that uses a magnet placed on the scalp to generate a magnetic field that stimulates the cortex of the brain. In a small 2007 study, rTMS showed promise in improving lower-limb spasticity in patients with relapse-remitting MS.

Urge Incontinence. Urge incontinence (the need to urinary frequently) is common in patients. To help reduce social difficulties, patients should not drink fluids before going to places where restrooms are not easily available. When possible, they should urinate every 3 - 4 hours. A number of medications are available for urge incontinence, including anticholinergic drugs, such as propantheline bromine (Pro-Banthine), tolterodine (Detrol), or oxybutynin (Ditropan). Sacral nerve stimulation (InterStim) sends electrical pulses to help retrain nerves in the pelvic area, and is also proving to be helpful. Botulinum toxin injection into the urinary tract muscles is being investigated and may be helpful for incontinence caused by spasticity. [See In-Depth Report #50: Urinary incontinence.]

Urinary Retention. Urinary retention occurs in some patients. Sometimes urination can be stimulated simply by pressing the bladder area with the fist or hand, by tapping against it, or by straining. Drugs being tried with some success for this problem are desmopressin (DDAVP), ordinarily used for bed wetting in children, and maprotiline (Ludiomill), an antidepressant. If medication is ineffective, a catheter may be needed, either one used intermittently by the patient or placed in the urinary tract. Various new surgical procedures that reconstruct the bladder or divert urine flow may be effective in severe cases of bladder dysfunction. Because urinary symptoms usually remain intermittent for years, treatment approaches for bladder dysfunction should be limited to medications and other reversible therapies, for as long as possible.

Urinary Tract Infections. Urinary tract infection is common in patients, and a urinalysis should be performed with any symptom flare-ups, fever, or change in bladder symptoms. Treatment uses appropriate antibiotic regimens. Some evidence suggests that cranberry juice may help prevent infections. [See In-Depth Report #36: Urinary tract infection.]

In addition to maintaining a high-fiber diet and drinking plenty of fluids, bulk fiber such as psyllium (Metamucil), with or without a stool softener, may be needed. Going to the bathroom the same time every day, particularly after a meal and waiting there for a movement, reduces the risk of losing control later in the day. Exercise helps patients avoid becoming dependent on laxatives, enemas, or colonic irrigation, which can eventually slow down the bowel and cause imbalances in electrolytes. Biofeedback techniques may be helpful in some patients with limited multiple sclerosis.

Major tremors can be very distressing and are particularly hard to treat. Carbamazepine and glutethimide have some possible benefits, but in general drug therapy has been disappointing. Weight applied to the affected limb has been beneficial in about 20% of cases. Surgery is very controversial.

Trigeminal neuralgia is facial pain, usually on one side, that can be very severe and may be triggered by an event as mild as a breeze or teeth brushing. If nonprescription painkillers fail to alleviate facial pain, it can be treated with anticonvulsive medications. Carbamazepine (Tegretol) is currently the drug of choice. Carbamazepine is also effective on other types of MS pain and spasm-related symptoms, including itching and aching. Another antiseizure drug, gabapentin (Neurontin), however, may be particularly effective for MS. This drug also appears to improve blurred vision associated with MS and may help spasticity in general.

Other drugs used for this symptom include phenytoin (Dilantin), diazepam (Valium), or pimozide (Orap), and the antidepressant amitriptyline (Elavil). If severe pain persists and interferes with function, some patients elect to have a section of a nerve surgically removed or blocked. This relieves pain but causes numbness. Before patients commit to such a procedure, they should ask the doctor to temporarily block the nerve with an anesthetic in order to experience the effect of numbness before undergoing irreversible surgery.

A small percentage of patients suffer from pseudobulbar affect (uncontrollable laughing or crying). Neurodex is an investigative drug that is showing promise in controlling these symptoms. The drug combines dextromethorphan (an ingredient contained in many cough suppressants) and the enzyme inhibitor quinidine.

Sildenafil (Viagra) may help improve sexual dysfunction in some patients. Corticosteroids, which are sometimes used for other MS symptoms, also improve sexual function. Other treatments are available that might be very beneficial. Patients should not be shy about discussing sexuality with their doctor. [See In-Depth Report # 15: Erectile dysfunction.]

Techniques for helping patients with swallowing problems include using specific head and tongue positions to assist swallowing, and preparing pureed food. Patients may need to work with otolaryngologists (doctors specializing in ear, nose, and throat disorders) to address swallowing problems. Left untreated, swallowing problems can increase a patient's risk of aspiration pneumonia, malnutrition, dehydration, and other problems.

MS is a strong risk factor for osteoporosis. In addition to calcium and vitamin D supplements, a number of drugs are now available to help prevent bone loss and reduce the risk of fractures due to osteoporosis. [See In-Depth Report #18: Osteoporosis.]

Treating Depression. Treating depression may not only improve mood but may also have direct benefits for patients.

Antidepressants known as tricyclics may have specific benefits for MS in addition to managing severe depression. Amitriptyline (Elavil), for example, may be effective in alleviating the extreme mood swings that frequently occur in patients. This “emotional incontinence,” the inability to control emotions, can distress some patients more than physical symptoms. Other tricyclics include desipramine (Norpramin, Pertofrane) and imipramine (Tofranil), which have additional effects that improve bladder symptoms in some patients. These drugs, however, can have severe side effects.
Newer antidepressant drugs, known as SSRIs (serotonin-reuptake inhibitors), which include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil), may be better tolerated. A study on sertraline suggested that it may also reduce the immune system's inflammatory response.

Stress Reduction and Supportive Measures. Stress can worsen symptoms, and may worsen the disease itself. Reducing stress is an important part of general health maintenance. Studies on methods for reducing stress report improved well-being in patients. A sense of control and connection appears to be extremely important for patients. Relaxation or meditation exercises can be beneficial, although cognitive-behavioral methods may be more effective in these patients. [See In-DepthReport # 31: Stress.]

Support for Caregivers. Many patients require long-term physical, financial, and psychological support from family and friends. The physical and mental health of the caregiver are critical. In one study, caregivers reported that among the most distressing aspects were the psychological impact of MS on the patient and the incurability of the disease. Most caregivers identified the best form of support to be practical help, cooking, cleaning, and better availability of medical and financial advice. Therapeutic help for family members may also be helpful.

Interferon, used to treat MS, may improve mental function. Other medications and therapies may also be helpful. For example, drugs called cholinesterase inhibitors, such as donepezil (Aricept), which are used for Alzheimer's disease, may help improve mental functioning. Vocational programs for the patient may also be helpful. Therapeutic programs for both patients and their families can help them better understand and cope with cognitive weaknesses such as concentration and problem solving.

Lifestyle Changes

People with multiple sclerosis should make every effort to preserve their general health. A healthy diet, sufficient rest, establishing priorities to conserve energy, and developing emotional support networks can all be very helpful.

Some dietary suggestions for patients with MS include:

Drink two quarts of water a day and avoid caffeine-containing beverages, which are actually dehydrating. This helps avoid constipation (although may cause difficulties in patients who also have urge incontinence).
Eat a diet rich in fiber, particularly from whole grains (especially bran, oats, or flax), fruits (particularly prunes), and vegetables.
Low-fat diets have not proven to have much effect on MS but are, in any case, generally healthy.
Fish and fish oil. Omega-3 fatty acids, which are found in oily fish, have been associated with protection against inflammation and some reduction in symptoms in people with various autoimmune conditions. Such fatty acids are also available in supplements as docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids. Standards for optimal amounts and forms of omega-3 fatty acids have not yet been established, however. Some experts recommend that people with MS eat three fish meals a week.

Special diets, such as those that are gluten- or yeast-free, have not shown to have any direct effect on the symptoms or course of MS.

Exercise is an important component in managing MS. An active patient with MS is less likely to develop certain complications, such as bladder and bowel dysfunction, osteoporosis, permanent muscle contractions, ulcerations of the skin, or abnormal blood clotting. MS symptoms can temporarily worsen during physical activity, however, so any program must be planned carefully. A health professional should be consulted to determine the best form of physical activity. One study reported that physical rehabilitation for 3 weeks in a hospital setting was significantly more effective in achieving functional independence than home exercise. It is not known if the same benefits can be achieved with a similar program outside the hospital.

Some suggestions include:

Exercise programs must be designed to stimulate working muscles, but at the same time avoid overload and overheating, which can block nerve conduction.
Stretching and range-of-motion exercises are important because they can relieve muscle spasticity.
Pool exercises are particularly helpful. Water supports the body, and cool water dissipates heat.
Specific exercises that strengthen and increase the endurance of muscles that control breathing functions may be helpful. However, it is unclear if such exercises reduce lung complications over the long-term.
Gradually, patients may be able to build up to more complex exercise programs.

Body overheating causes demyelinated nerves to function less efficiently than usual. Although this effect is resolved within a few hours of regaining normal body temperature, active cooling can help reduce fatigue and improve stability. As a result, researchers are studying the effectiveness of cooling suits.

The following measures may be helpful:

Use air conditioners in the summer.
Keep the home slightly cool in winter.
Avoid swimming in heated pools.
A portable helmet that uses cold liquid to cool the head and neck and therefore lower core body temperatures may help MS symptoms during daily activities.

MS symptoms worsen during a cold or the flu, probably because of increased immune system activity. Experts recommend that patients with MS receive a flu shot in the fall. However, experts warn that patients should not take the nasal spray version of the flu vaccine (FluMist Intranasal). Unlike the flu injection vaccine, which uses an inactivated virus, FluMist contains a live virus. Live virus vaccinations may be harmful for people with MS, especially those who take immune-suppressing drugs.

Resources

www.ninds.nih.gov -- National Institute of Neurological Disorders and Stroke
www.aan.com -- American Academy of Neurology
www.msaa.com -- Multiple Sclerosis Association of America
www.nmss.org -- National Multiple Sclerosis Society
www.msfacts.org -- Multiple Sclerosis Foundation
www.www.fda.gov/cder/drug/infopage/natalizumab -- FDA information on natalizumab (Tysabri)
www.myelin.org -- The Myelin Project
www.abledata.com -- National database of assistive devices and rehabilitation equipment

References

Balcer LJ, Galetta SL, Calabresi PA, Confavreux C, Giovannoni G, Havrdova E, et al. Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Neurology. 2007 Apr 17;68(16):1299-304.

Boggild M. .Rationale and experience with combination therapies in multiple sclerosis. J Neurol. 2006 Nov;253 Suppl 6:vi45-vi51.

Centonze D, Koch G, Versace V, Mori F, Rossi S, Brusa L, et al. Repetitive transcranial magnetic stimulation of the motor cortex ameliorates spasticity in multiple sclerosis. Neurology. 2007 Mar 27;68(13):1045-50.

Correale J, Fiol M, Gilmore W. The risk of relapses in multiple sclerosis during systemic infections. Neurology. 2006 Aug 22;67(4):652-9. Epub 2006 Jul 26.

Hensiek AE, Seaman SR, Barcellos LF, Oturai A, Eraksoi M, Cocco E, et al. Familial effects on the clinical course of multiple sclerosis. Neurology. 2007 Jan 30;68(5):376-83.

Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006 Sep 14;355(11):1124-40.

Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006 Dec 20;296(23):2832-8.

Sicotte NL, Giesser BS, Tandon V, Klutch R, Steiner B, Drain AE, et al. Testosterone treatment in multiple sclerosis: a pilot study. Arch Neurol. 2007 May;64:683-688.

Wolinsky JS, Narayana PA, O'Connor P, Coyle PK, Ford C, Johnson K, et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol. 2007 Jan;61(1):14-24.

Review Date:
5/26/2007
Reviewed By:
Harvey Simon, M.D., Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

A.D.A.M. Copyright

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Colds and the flu

FitSugar — Wed, 08 Oct 2008 17:35:26 -0700

In This Report

Highlights
Introduction
Diagnosis
Complications
Risk Factors
Prevention
Treatment
Medications
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Vaccine News:

On September 28, 2007, the U.S. Food and Drug Administration (FDA) approved a new brand of inactivated influenza ("flu") vaccine, Alfuria, for adults aged 18 years or older. This vaccine is given by injection.
On September 19, 2007, the FDA approved the use of the live flu vaccine (FluMist) in healthy children as young as 2 years of age. This vaccine, given in the form of a nose spray, was previously approved for healthy children and non-pregnant adults aged 5 - 49.

Drug Resistance:

The World Health Organization reports that resistance to the anti-viral drug oseltamivir (Tamiflu) can develop with extensive use. Oseltamivir is one of two drugs the CDC recommends for treating the flu. It is also the current recommended treatment for the H5N1 avian flu virus.

Drug Recalls:

In October 2007, drug manufacturers voluntarily withdrew from the market all oral cough and cold products, including decongestants, aimed at children under 2, due to potential harm from misuse. The U.S. Food and Drug Administration (FDA) recommends against using these products to treat children under age 2. The FDA is currently reviewing the safety of cough and cold medicines in children ages 2 - 11 years.

Emerging Virus:

A new, more virulent strain of adenovirus has reportedly emerged in the United States in 2006. The adenovirus family causes upper respiratory infections, pneumonia, and several other diseases. The new strain of adenovirus 14 causes severe respiratory illness that has resulted in several deaths.

Introduction

Upper respiratory tract infections affect the airways in the nose, ears, and throat.

Structures of the throat include the esophagus, trachea, epiglottis, and tonsils.

The infections can be caused by viruses, bacteria, or other microscopic organisms. In most cases, these infections lead to colds or mild influenza (flu) and are temporary and harmless. In rare cases, flu can be severe, or the infections may turn into pneumonia.

Organisms that cause these upper respiratory tract infections are generally spread by:

Direct contact (such as hand-to-mouth)
Coughing or sneezing

The common cold (medically known as infectious nasopharyngitis) is the most common upper respiratory tract infection. More than 200 viruses can cause colds. The most common cause is the rhinovirus, which is responsible for about half of all colds. Symptoms usually develop 1 - 3 days after being exposed to the virus.

A cold usually progresses in the following manner:

It nearly always starts rapidly with throat irritation and stuffiness in the nose.
Within hours, full-blown cold symptoms usually develop, which can include sneezing, mild sore throat, fever, minor headaches, muscle aches, and coughing.
Fever is low-grade or absent. In small children, however, fever may be as high as 103°F for 1 or 2 days. The fever should go down after that time, and be back to normal by the 5th day.
Nasal discharge is usually clear and runny the first 1 - 3 days. It then thickens and becomes yellow to greenish.
The sore throat is usually mild and lasts only about a day. A runny nose usually lasts 2 - 7 days, although coughing and nasal discharge can persist for more than 2 weeks.

A new, more virulent strain of adenovirus has reportedly emerged in the United States in 2006. The adenovirus family causes upper respiratory infections (it is one of the many viruses that cause the common cold). It also causes pneumonia, conjunctivitis, and several other diseases. The new strain of adenovirus 14 causes severe respiratory illness that has resulted in several deaths. Some patients who contracted this new viral disease had to be hospitalized, sometimes in intensive care units.

Every year, influenza strikes millions of people worldwide. Influenza epidemics are most serious when they involve a new strain, against which most people around the world are not immune. Such global epidemics (pandemics) can rapidly infect more than one fourth of the world's population. For example, the Spanish flu in 1918 and 1919 killed an estimated 20 million people in the U.S. and Europe and 17 million people in India. With modern society's dependence on air travel, an influenza pandemic could potentially inflict catastrophic damage on human lives, and disrupt the global economy.

The influenza virus mutates (changes) rapidly as it moves from species to species. Most Type A influenza strains (the most common strains) first develop in migratory waterfowl populations. While most avian influenza (bird flu) virus strains are relatively harmless, a few develop into "highly pathogenic avian influenza," which can be very deadly for domesticated poultry and livestock. As recent events have shown, these strains can also be deadly to humans. People can become infected by these bird flu strains through contact with contaminated chickens and pigs. The medical community is now greatly concerned about the H5N1 bird flu virus, which has infected and even killed people in several countries.

Symptoms of influenza. Patients usually feel sick 1 - 4 days after exposure to the influenza (flu) virus. The flu usually involves:

Abrupt onset of severe symptoms, which include headache, muscle aches, fatigue, and high fever (up to 104°F).
Cough (which is usually dry but can be severe) and sometimes a runny nose and sore throat.
Children may experience vomiting, diarrhea, and ear infections, as well as other flu symptoms.
The symptoms usually resolve in 4 - 5 days, although some people can experience coughing and feelings of illness for more than 2 weeks. In some cases, flu can become more severe or make other conditions worse.

Transmitting the Virus. The flu virus is spread primarily when a person with the flu coughs or sneezes near someone else. Adults with flu typically spread it to someone else from 1 day before symptoms start to about 5 days after symptoms develop. Children can spread the infection for more than 10 days after symptoms begin, and young children can transmit the virus 6 days or even earlier before the onset of symptoms. People with severely compromised immune systems can transmit the virus for weeks or months.

Flu Strains. A virus is a cluster of genes wrapped in a protein membrane, which is coated with a fatty substance that contains molecules called glycoproteins. Strains of the flu are identified according to the number of membranes and type of glycoproteins present.

Click the icon to see an image of a virus.

The two major flu strains are referred to as A and B:

Influenza A is the most widespread and can infect animals and humans. Influenza A is the cause of the major pandemics (worldwide epidemics) of influenza that have occurred so far. It is usually further categorized by two subtypes based on two substances that occur on the surface of the viruses: hemagglutinin (H) and neuraminidase (N).
Influenza B infects only humans. It is less common than type A, but is often associated with specific outbreaks, such as in nursing homes.

The vast majority of flu cases are type A. Influenza A usually causes more severe disease than type B. There is some concern, however, that since influenza B has been less common in the past few years, some people, particularly small children, may have fewer antibodies to it and so may be at higher risk for severe infection.

Although the risk of lethal viruses is generally low, scientists are greatly concerned about a particular virus called H5N1, which causes avian influenza. Since 1997, the H5N1 virus has triggered deadly outbreaks in poultry across Southeast Asia. As of Janaury 15, 2008, 350 people had been infected with the bird flu in 12 countries. Of these people, 217 have died, according to the World Health Organization. No cases have been seen in the United States.

So far, the virus has spread from birds to humans. The virus does not seem to be easily spread from person to person. However, scientists and public health officials are monitoring the spread of H5N1 and working to contain it. Efforts include slaughtering infected birds, developing new vaccines, and stockpiling antiviral drugs such as oseltamivir (Tamiflu). Many poor nations have limited resources and already contend with other serious health problems, including HIV-AIDS. If H5N1 does mutate and spread, the consequences could be especially severe for these countries.

In April 2007, the FDA approved a vaccine to protect humans from avian influenza. Currently this vaccine is not being used for routine immunization. However, if the avian flu develops the ability to spread fairly easily from human to human, this vaccine may be made available.

Diagnosis

Differentiating between a cold and flu may be difficult. Cold symptoms are nearly always less severe than those of the flu.


Symptoms	Cold	Flu
Fever	Rare	Common and high (102-104°F); lasts 3 - 4 days
Headache	Rare	Almost always present
General aches and pains	Mild, if they occur at all	Often severe
Fatigue, exhaustion, and weakness	Mild, it they occur at all	Extreme exhaustion is early and severe; can last 2 - 3 weeks
Stuffy nose	Nearly always	Sometimes
Sneezing	Very common	Sometimes
Sore throat	Common	Sometimes
Chest discomfort and cough	Mild-to-moderate, hacking cough	Common, can be severe
Source: National Institute of Allergy and Infectious Disease

Several available tests can isolate and identify the viruses responsible for some respiratory infections. They are generally not needed, since most cases of the flu are self-evident. However, such tests can be very helpful in confirming or ruling out the flu. If a doctor believes a diagnosis would help, samples using a swab should be taken from the nasal passages or throat within 4 days of the first symptoms.

A nasopharyngeal culture is a test used to identify disease-causing organisms in nasal secretions. Nasopharyngeal cultures are useful in identifying Bordetella pertussis and Neisseria meningitidis (types of bacteria). The culture may help determine appropriate antibiotic therapy.

Several rapid tests for the flu can produce results in less than 30 minutes, but vary on the specific strain or strains that they can detect. They are not as accurate as a viral culture, however, in which the virus is reproduced in the laboratory. Culture results can take 3 - 10 days. Blood tests can also document the infection several weeks after symptoms appear.

In February 2006, the U.S. Food and Drug Administration approved a new, faster test for diagnosing H5 strains of avian influenza in people suspected of having the virus. The test is called the Influenza A/H5 (Asian lineage) Virus Real-time RT-PCR Primer and Probe Set. The test gives preliminary results within 4 hours. Older tests required 2 - 3 days. It checks for the presence of the Influenza A H5 strain. If the presence of this strain is confirmed through the rapid test, further testing will be needed to determine the exact subtype of the virus. For example, the current strain of concern is H5, subtype N1, designated as H5N1 for short.

Ruling out Allergic Rhinitis. Symptoms of allergic rhinitis include nasal obstruction and congestion, which are similar to the symptoms of a cold. People with allergies, however, are likely to have the following:

Thin, clear, and runny nasal discharge
An itchy nose, eyes, or throat
Recurrent sneezing

There are two forms of allergic rhinitis:

Symptoms that appear only during allergy season are called allergic rhinitis, commonly known as hay or rose fever. [For more information, see In-Depth Report #77: Allergic rhinitis.]
Allergens in the house, such as house dust mites, molds, and pet dander, can cause year-long allergic rhinitis, referred to as perennial rhinitis.

Click the icon to see an image of common allergens.

Ruling out Sinusitis. The signs and symptoms suggestive of true acute sinusitis include the following:

A return of congestion and discomfort after initial improvement in a cold (called double sickening)
Purulent (pus-filled) nasal secretion
A lack of response to decongestant or antihistamine
Pain in the upper teeth or pain on one side of the head
Pain above or below both eyes when leaning over

Children with sinusitis are less likely to have facial pain and headache and may only develop a high fever or prolonged upper respiratory symptoms (such as a daytime cough that does not improve for 11 - 14 days). When the diagnosis is unclear or complications are suspected, further tests may be required. [For more information, see In-Depth Report #62: Sinusitis.]

Acute Bronchitis. Acute bronchitis is usually caused by a virus and in most cases is self-limiting. The cough it causes typically lasts for about 7 - 10 days, but in about half of patients, coughing can last for up to 3 weeks, and 25% of patients continue to cough for over 1 month.

Atypical Pneumonia. Pneumonia caused by atypical organisms (for example, Mycoplasma pneumonia, chlamydia, Legionella) can cause symptoms similar to the flu. Only laboratory tests can diagnose the difference. [For more information, see In-Depth Report #64: Pneumonia.]

Ruling out More Serious Viral Infections. Respiratory syncytial virus (RSV) and, possibly human parainfluenza viruses (HPV), are proving to be important causes of serious respiratory infections in infants, the elderly, and people with damaged immune systems. (Both also cause mild conditions.) RSV may be a much more common cause of flu-like symptoms than previously thought.

Pertussis. Pertussis (whooping cough) was a very common childhood illness throughout the first half of the century. Although immunizations caused a decline in cases to only 1,700 in the U.S. in 1980, the incidence has risen recently, with almost 30,000 cases reported between 1997 and 2000 (17 infants died of the disease in 2000). Many more cases are reported worldwide.

Nearly half of pertussis cases now occur in people 10 years of age or older, perhaps due to waning immunity in adolescents and adults. Such cases may be greatly underreported. Up to 25% of adults who see a doctor for persistent cough may actually have pertussis. It may go undiagnosed, however, because symptoms are usually mild, and adults are unlikely to have the classic "whooping" cough. This is of some concern because such adults may unknowingly infect unvaccinated children. The younger the patient, the higher the risk for severe complications, including pneumonia, seizures, and even death. Children younger than 6 months are at particular risk because protection is incomplete, even with vaccination.

In addition to common cold viruses, other, less frequent causes of sore throat include the following:

Strep throat
Foodborne and waterborne infections (Streptococcus C and G)
An uncommon organism called Arcanobacterium haemolyticum (infection with this bacterium can mimic strep throat and may even cause a rash)
Infectious mononucleosis ("mono")
Herpesvirus 1

Group A Streptococcal bacteria is the most common bacterial cause of the severe sore throat known commonly as "strep throat." It occurs mostly in school age children, but people of all ages are susceptible. (Strep throat constitutes about 12% of all sore throat cases seen by doctors.)

The symptoms of strep throat include the following:

A sudden onset of severe sore throat
Difficulty in swallowing
Fever
Headache
Stomach pain
Vomiting

Only about half of patients with strep throat have such clear-cut symptoms. Furthermore, half of people who have these symptoms do not actually have strep throat.

How Is Strep Throat Diagnosed? Most cold-related sore throats are caused by viruses and require no treatment. They usually do not last more than a day. When the sore throat persists and is very painful the doctor will want to rule out or confirm the presence of the strep bacteria.

The doctor will look for redness and pus-filled patches on the tonsils and back of the throat. Enlarged tonsils are less likely to indicate a strep throat.
The doctor will feel the sides of the neck for swollen lymph nodes. If the lymph nodes are not swollen, it is less likely to be a strep throat.
A cotton swab is used to take a sample of pus in the throat for a throat culture.

A throat culture is the most effective and least expensive test for confirming the presence of strep throat. It takes 24 - 48 hours to obtain a result.

Rapid Antigen-Detection Test for Strep Throat. A faster test, called the rapid strep antigen test, uses chemicals to detect the presence of bacteria in a few minutes. A positive result nearly always means that streptococcal bacteria is the cause of the infection. The test, however, fails to detect 10 - 20% of cases, so a culture may still be necessary to catch any missed infections, particularly in children.

How Serious is Strep Throat? The use of antibiotics has removed the threat of most complications from streptococcus infection in the throat (strep throat). However, untreated strep throat could lead to the following complications:

Abscess in the tonsils
Scarlet fever
Rheumatic fever (rare in the U.S.)

How Is Strep Throat Treated? Strep throat infections require antibiotics. Antibiotics prevent a serious complication called rheumatic fever, which can result in permanent damage to the heart. Fortunately, this complication occurs rarely in United States anymore. If started on time, antibiotic treatment of strep throat will almost always prevent this complication. In addition, antibiotics shorten the recovery time from strep throat.

The following antibiotics are generally used to treat strep throat:

Penicillin is usually the antibiotic of choice unless the patient is allergic. A full 10 days may be necessary. Amoxicillin, a form of penicillin, is proving to be effective when taken in a single daily dose for 10 days.
Macrolide antibiotics. Erythromycin is known as a macrolide antibiotic and is the first choice for patients with penicillin allergies. A 10-day regimen is needed. Another macrolide, azithromycin, can be given as a single daily dose and may be effective in 5 days. It is expensive, however, and bacterial resistance to macrolides is growing, so it should not be given as a first choice.
Cephalosporins are very effective in eradicating the bacteria.

Antibiotics are very commonly inappropriately prescribed for non-strep sore throats. One study reported that an estimated 6.7 million American adults visited their doctors because of sore throat between 1989 and 1999, with 73% of them receiving antibiotics. Studies indicate, however, that fewer than half of adults and far fewer children with even strong signs and symptoms for strep throat actually have strep infections.

Parents should be comforted that a delay in antibiotic treatment while waiting for lab results does not increase the risk that the child will develop serious long-term complications, including acute rheumatic fever. If a patient is severely ill, however, it is reasonable to begin administering antibiotics before the results are back. If the culture is negative (there is no evidence of bacteria), the doctor should call the family to make certain the patient stops taking the antibiotics and any remaining pills are discarded.

Children who have a sore throat and who have had rheumatic fever in the past should receive antibiotics immediately, even before culture results are back. Children with a sore throat who have a family member with strep throat or rheumatic fever should also receive immediate antibiotic treatment.

Complications

Colds rarely cause serious complications. In about 1% of cases, a cold can lead to other complications, such as sinus or ear infections. It can also aggravate asthma and, in uncommon situations, increase the risk for lower respiratory tract infections.

Ear Infections. The rhinovirus infection, a major cause of colds, also commonly predisposes children to ear infections, possibly by obstructing the Eustachian tube, which leads to the middle ear. Viruses may even attack the ear directly.

Sinusitis. Between 0.5 - 5% of people with colds develop sinusitis, an infection in the sinus cavities (air-filled spaces in the skull). Sinusitis is usually mild, but if it becomes severe, antibiotics generally eliminate further problems. In rare cases, however, sinusitis can be serious.

Lower Respiratory Tract Infections. The common cold poses a risk for bronchitis and pneumonia in nursing home patients, and in other people who may be vulnerable to infection. Some experts believe that the rhinovirus may play a more significant role than the flu in causing lower respiratory infections in the vulnerable population.

Aggravation of Asthma. Rhinovirus infections can aggravate asthma in both children and adults. In fact, rhinovirus has been reported to be the most common infectious organism associated with asthma attacks. Colds may promote allergic inflammation of the airways, and increase the intensity their responsiveness for weeks.

The flu is usually self-limited and not serious. However, each year in the United States, more than 200,000 people are hospitalized due to complications of the flu. An estimated 36,000 people die each year of influenza-related complications. People at highest risk for serious complications are those over 65 years old and those with chronic medical conditions. Influenza A is the most severe strain. Influenza B tends to be milder.

Pneumonia. Pneumonia is the major serious complication of influenza and can be very serious. It can develop about 5 days after viral influenza. More than 90% of the deaths caused by influenza and pneumonia occur among older adults. Flu-related pneumonia nearly always occurs in high-risk individuals, such as the following:

People with weakened immune systems, such as AIDS patients
Elderly patients, particularly patients in nursing home
Very young children -- [it may be difficult to tell whether pneumonia is related to influenza or caused by respiratory syncytial virus (RSV)]
Hospitalized patients and anyone with serious medical conditions, such as diabetes, heart, circulation, or lung disorders, particularly chronic lung disease
Drug abusers who use needles

Combinations of these factors further increase the risk. It should be noted that pneumonia is an uncommon outcome of influenza in healthy adults.

Complications in the Central Nervous System in Children. Influenza increases the risk for complications in the central nervous system of small children. Febrile seizures are the most common neurologic complication in children The risks decline after a child turns 1 year old, but are still high in children aged 3 - 5 years old.

Risk Factors

The very young and the very old are at higher risk for upper respiratory tract infections and their associated complications.

Children. Young children are prone to colds and may have 8 to 12 of them every year. Millions of cases of influenza develop in American children and adolescents each year.

Before the immune system matures, all infants are susceptible to uppper respiratory infections, with a possible frequency of one cold every 1 - 2 months. Smaller nasal and sinus passages also make younger children more vulnerable to colds than older children and adults. Upper respiratory infections gradually diminish as children grow, until at school age their rate of such infections is about the same as an adult's. There is almost never cause for concern when a child has frequent colds, unless the colds become unusually severe or more frequent than usual.

The Elderly. The elderly have diminished cough and gag reflexes, and their immune systems are often weaker. They are therefore at greater risk for serious respiratory infections than the young and middle-aged adults.

The risk of respiratory infections is increased by exposure to cigarette smoke, which can injure airways and damage the cilia (tiny hair-like structures that help keep the airways clear). Toxic fumes, industrial smoke, and other air pollutants are also risk factors. Parental smoking increases the risk of respiratory infections in their children.

People with AIDS and other medical conditions that damage the immune system are extremely susceptible to serious infections.

Cancers, especially leukemia and Hodgkin's disease, put patients at risk. Patients who are on corticosteroid (steroid) treatments, chemotherapy, or other medications that suppress the immune system are also prone to infection.

People with diabetes are at a higher risk for the flu.

Certain genetic disorders predispose people to respiratory infections. They include sickle-cell disease, cystic fibrosis, and Kartagener syndrome (which results in malfunctioning cilia).

Much evidence suggests that stress increases one's susceptibility to a cold. In one study, people with high stress levels averaged 2.7 upper respiratory infections during a 6-month period and those reporting low stress averaged 1.5 infections. Another study found the duration of colds in children with chronic, year-round colds decreased with help of a stress management program. Stress appears to increase the risk for a cold regardless of lifestyle or other health habits. And once a person catches a cold or flu, stress can make symptoms worse.

It is not clear why these events occur. Some experts believe that stress alters specific immune factors, which cause inflammation in the airways. One study reported that the only people who got sick after experiencing short stress were those whose body responded to stress with high levels of cortisol, a stress hormone, coupled with a low immune response.

In people who already have colds, exercise has no effect on the illness' severity or duration of the infection. High-intensity or endurance exercises, however, appear to suppress the immune system while they are being performed. Some highly trained athletes, for instance, report being susceptible to colds after strenuous events. People should avoid strenuous physical activity when they have high fevers or widespread viral illnesses. Note: Very low fat diets appear to worsen this dampening effect on the immune system. A higher fat-diet may help correct this imbalance (omega-3 fatty acids, found in fish and canola oil, are preferred). Whether carbohydrate loading provides much additional value is not clear.

Colds and flus occur predominantly in the winter. Flu season typically starts in October and lasts into mid March.

The reasons for this seasonal bias are not due to the cold itself, but to other factors. Certainly, flus and colds are more likely to be transmitted in winter because people spend more time indoors and are exposed to higher concentrations of airborne viruses. Dry winter weather also dries up nasal passages, making them more susceptible to viruses. Some experts theorize that the high rates of viral infections in winter may be due to certain immune factors, which react to light and dark and affect a person's susceptibility to viruses.

Traveling in close contact with people, whether on trains, planes, or buses, can increase the risk for respiratory infections.

Children who attend day care may have an increased risk of colds. However, one study suggested that although children in day care centers incur higher rates of the common cold in the preschool years, they have lower cold rates in their first years of regular school. The colds they catch in day care, then, may bestow some immunity to future colds for a few years. By age 13, such protection has worn off. There is also some evidence that frequent colds in young children may help protect against future allergies and asthma.

Prevention

Because colds and flus are easily spread, everyone should always wash their hands before eating and after going outside. Ordinary soap is sufficient. Waterless hand cleaners that contain an alcohol-based gel are also effective for every day use and may even kill cold viruses. (They are less effective, however, if extreme hygiene is required. In such cases, alcohol-based rinses are needed.)

Antibacterial soaps add little protection, particularly against viruses. In fact, one study suggests that common liquid dish washing soaps are up to 100 times more effective than antibacterial soaps in killing respiratory syncytial virus (RSV), which is known to cause pneumonia. Wiping surfaces with a solution that contains one part bleach to 10 parts water is very effective in killing viruses.

Colds are not caused by insufficiently warm clothes or by going outside with wet hair.

Foods Containing Lactobacilli (Good Bacteria). Researchers are also studying the possible protective value of certain strains of lactobacilli bacteria found in the intestines. Some of these strains, particularly acidophilus, are used to make yogurt. According to one Finnish study, children attending day care who ate milk containing the strain lactobacilli GG 10 - 20% fewer respiratory infections. (The strain used was not the kind found in most commercial yogurt products.)

Vitamins. Studies are mixed whether vitamin supplements protect against upper respiratory infections. Large doses of vitamin C, for example, may help reduce the duration of a cold, but they do not appear to protect against one in the first place, even after exposure to a cold virus. Two studies on multivitamins reported opposite results, with one finding fewer infections and one finding no difference. It is possible that vitamin C or multivitamin supplements may be helpful in specific people, such those who are vitamin deficient or have medical problems that impair their immune systems.

Treatment

The following are some food and fluid recommendations. Most will not cure a cold, but they may help a person deal better with the symptoms:

Drinking plenty of fluids and getting lots of rest when needed is still the best bit of advice to ease the discomforts of the common cold. Water is the best fluid and helps lubricate the mucous membranes. (There is no evidence that drinking milk will increase or worsen mucus, although milk is a food and should not serve as fluid replacement.)
Chicken soup does indeed help congestion and body aches. The hot steam from the soup may be its chief advantage, although laboratory studies have actually reported that ingredients in the soup may have anti-inflammatory effects. In fact, any hot beverage may have similar soothing effects from steam. Ginger tea, fruit juice, and hot tea with honey and lemon may all be helpful.
Spicy foods that contain hot peppers or horseradish may help clear sinuses.
Foods rich in vitamins A and C are always recommended and may be helpful during a respiratory infection. They include oranges, kiwi, and tomatoes for vitamin C, and sweet potatoes, spinach, and broccoli for vitamin A.

Different studies have found that large doses of vitamin C may reduce the duration of a cold. Some precautions against taking high doses of vitamin C include the following:

High doses of vitamin C may cause headaches, intestinal and urinary problems, and even kidney stones.
Because vitamin C increases iron absorption, people with certain blood disorders, such as hemochromatosis, thalassemia, or sideroblastic anemia, should avoid high doses of this vitamin.
Large doses of vitamin C can also interfere with anticoagulant medications ("blood thinners"), blood tests used in diabetes, and stool tests.
Vitamin E or multivitamin supplements do not appear to be helpful in reducing symptoms of the cold.

Zinc appears to have certain important effects on the immune system and it may have a direct effect on viruses. How it works is not entirely clear, however. Zinc preparations in lozenge or nasal gel form are now available as cold treatments. Studies are very mixed on the effects of zinc on colds. The variance may be due to different zinc preparations. A review of available studies comparing zinc treatment to placebo ("sugar pill") found only one high-quality study, which showed that zinc nasal gels might provide a benefit. The overall benefit of zinc in the prevention of colds remains unproven. In any case, no one with an adequate diet and a healthy immune system should take zinc for prolonged periods, for the purpose of preventing colds.

Side Effects. Side effects, particularly of the lozenges form, include the following:

Dry mouth
Constipation
Nausea
Bad taste (possibly only with zinc gluconate lozenges)
Severe vomiting, dehydration, and restlessness (signs of overdose, seek medical help)
Allergic response (rare)

Food and Drug Interactions. Zinc may also interact with drugs or other elements:

It may reduce absorption of certain antibiotics.
Foods high in calcium or phosphorus may reduce zinc absorption.
In high doses and for long periods of time, zinc can cause copper deficiencies.

Many people take medications to reduce mild pain and fever. Adults most often choose aspirin, ibuprofen (Advil), or acetaminophen (Tylenol).

The following are recommendations for children:

Acetaminophen (Tylenol) or ibuprofen (usually Advil or Motrin) are the typical pain-relievers parents give their children. Most pediatricians advise such medications for children who run fevers over 101°F. Some suggest alternating the two agents, although there is no evidence that this regimen offers any benefits, and it might be harmful.
Aspirin and aspirin-containing products are virtually never recommended for children or adolescents. Reye syndrome, a very serious condition, has been associated with aspirin use in children who have flu symptoms or chicken pox.

Nasal strips (such as Breathe Right) are placed across the lower part of the nose and pull the nostrils open. These strips may open the nasal passages and ease congestion due to a cold, sinusitis, or hay fever. As of yet, there is no scientific evidence that they offer such benefits.

A nasal wash can be helpful for removing mucus from the nose. A saline solution can be purchased at a drug store or made at home. One study reported that neither a homemade solution (using one teaspoon of salt and one pinch of baking soda in a pint of warm water) nor a commercial hypertonic saline nasal wash had any effect on symptoms. Further, one preliminary study found that over-the-counter saline nasal sprays that contain benzalkonium chloride as a preservative may actually worsen symptoms and infection.

Some physicians, however, advocate a traditional nasal wash that has been used for centuries and is different from that used in most studies. It contains no baking soda and uses more fluid for each dose and less salt. The nasal wash should be performed several times a day.

A simple method for administering a nasal wash:

Lean over the sink head down.
Pour some solution into the palm of the hand and inhale it through the nose, one nostril at a time.
Spit the remaining solution out.
Gently blow the nose.

The solution may also be inserted into the nose using a large rubber ear syringe, available at a pharmacy. In this case, the process is the following:

Lean over the sink head down.
Insert only the tip of the syringe into one nostril.
Gently squeeze the bulb several times to wash the nasal passage.
Then press the bulb firmly enough so that the solution passes into the mouth.
The process should be repeated in the other nostril.

Nasal-delivery decongestants are applied directly into the nasal passages with a spray, gel, drops, or vapors. Nasal forms work faster than oral decongestants and have fewer side effects. They often require frequent administration, although long-acting forms are now available. Ingredients and brands of nasal decongestants include the following:

Long Acting Nasal-Delivery Decongestants. They are effective in a few minutes and remain so for 6 - 12 hours. The primary ingredient in long-acting decongestant is:

Oxymetazoline: Brands include Vicks Sinex (12-hour brands), Afrin (12-hour brands), Dristan 12-Hour, Good Sense, Nostrilla, Neo-Synephrine 12-Hour
Xylometazoline: Inspire, Otrivin, Natru-vent

Short-Acting Nasal-Delivery Decongestants. The effects usually last about 4 hours. The primary ingredients in short-acing decongestants are:

Phenylephrine: Neo-Synephrine (mild, regular, high-potency), 4-Way, Dristan Mist Spray, Vicks Sinex
Naphazoline (Naphcon Forte, Privine)

Dependency and Rebound. The major hazard with nasal-delivery decongestants, particularly long-acting forms, is a cycle of dependency and rebound effects. The 12-hour brands pose a particular risk for this effect. This effect works in the following way:

With prolonged use (more than 3 - 5 days), nasal decongestants lose effectiveness and even cause swelling in the nasal passages.
The patient then increases the frequency of their dose. The congestion worsens, and the patient responds with even more frequent doses, in some cases as often as every hour.
Individuals then become dependent on them.

Tips for Use. The following precautions are important for people taking nasal decongestants:

When using a nasal spray, spray each nostril once. Wait a minute to allow absorption into the mucosal tissues, and then spray again.
Keep the nasal passages moist. All forms of nasal decongestants can cause irritation and stinging. They also may dry out the affected areas and damage tissues.
Do not share droppers and inhalators with other people.
Use decongestants only for conditions requiring short-term use, such as before air travel or for a single-allergy attack. Do not take them more than 3 days in a row. With prolonged use, nasal decongestants become ineffective and result in the so-called rebound effect and dependence.
Discard sprayers, inhalators, or other decongestant delivery devices when the medication is no longer needed. Over time, these devices can become reservoirs for bacteria.
Discard the medicine if it becomes cloudy or unclear.

Oral decongestants also come in many brands, which mainly differ in their ingredients. The most common active ingredient is pseudoephedrine (Sudafed, Actifed, Drixoral).

Side Effects of Decongestants. Decongestants have certain adverse effects, which are more apt to occur in oral than nasal decongestants and include the following:

Agitation and nervousness
Drowsiness (particularly with oral decongestants and in combination with alcohol)
Changes in heart rate and blood pressure

Avoid combinations of oral decongestants with alcohol or certain drugs, including monoamine oxidase inhibitors (MAOI) and sedatives

Individuals at Risk for Complications from Decongestants. People who may be at higher risk for complications are those with certain medical conditions, including disorders that make blood vessels highly susceptible to contraction. Such conditions include the following:

Heart disease
High blood pressure
Thyroid disease
Diabetes
Prostate problems that cause urinary difficulties
Migraines
Raynaud's phenomenon
High sensitivity to cold
Emphysema or chronic bronchitis

Anyone with the above conditions should not use either oral or nasal decongestants without a doctor's guidance. In addition, people taking medications that increase serotonin levels, such as certain antidepressants, anti-migraine agents, diet pills, St. John's wort, and methamphetamine, should avoid decongestants. The combinations can cause blood vessels in the brain to narrow suddenly, causing severe headaches and even stroke.

Others who should use these drugs with caution are the following (consult your health care provider):

Anyone who is pregnant.
Children: Children appear to metabolize decongestants differently than adults. Decongestants should not be used at all in infants and small children under the age of 2, according to a new recommendation from an advisory panel of the Food and Drug Administration. These children are at particular risk for side effects that depress the central nervous system. Such symptoms cause changes in blood pressure, drowsiness, deep sleep, and, rarely, coma. Studies have also shown that these cough and cold products generally are not effective in the treatment of children under 6 years of age.

In October 2007, drug manufacturers voluntarily withdrew from the market all oral cough and cold products, including decongestants, aimed at children under 2, due to potential harm from misuse.

Major studies have indicated that over-the-counter cough medicines are not very effective, but they are also not harmful.

For thick phlegm, patients may try cough medications that contain guaifenesin (Robitussin, Scot-Tussin Expectorant), which loosens mucus. Patients should not suppress coughs that produce mucus and phlegm. It is important to expel this substance. To loosen phlegm, patients should drink plenty of fluids and use a humidifier or steamer.
For patients with a dry cough, a suppressant may be useful, such as one that contains dextromethorphan (Drixoral Cough, Robitussin Maximum Strength Cough Suppressant).

Medications that contain both a cough suppressant and an expectorant are not useful and should be avoided. Medicated cough drops that contain dextromethorphan are not very useful. A patient is just as likely to find relief from hard candy or lozenges.

Prescription cough medications with small doses of narcotics are available. They are usually reserved for lower respiratory infections with significant coughs.

Sore throats that are associated with colds are generally mild. The following may be helpful:

Cough drops, throat sprays, or gargling warm salt water may help relieve sore throat and reduce coughing.
Throat sprays that contain phenol (for example, Vicks Chloraseptic) may be particularly helpful. Phenol has antibacterial properties. In one study, patients with sore throat who used the spray experienced faster resolution of the cold itself, including fever, headache, and other symptoms compared to a placebo. The patients were not taking antibiotics.
Cough drops that contain menthol and mild anesthetics, such as benzocaine, hexylrescorincol, phenol, and dyclonine (the most potent), may soothe a mild sore throat.
People with sore throats from postnasal drip might try taking a teaspoon of liquid antacid. They shouldn't drink anything afterward, since the intention is to coat the throat and help neutralize the acid in the mucus that might be causing pain.

If soreness in the throat is very severe and does not respond to mild treatments, the patient or parent should check with the physician to see if a strep throat is present, which would require antibiotics. [See What is Strep Throat? in the Diagnosis section.]

Dozens of remedies are available that combine ingredients aimed at more than one cold or flu symptom. In general, they do no harm, but they have the following problems:

Some ingredients may produce side effects without even helping a cold.
In some cases, the ingredients conflict (such as a cough expectorant and a cough suppressant).
In other cases, a patient may wish to increase the dosage to improve one symptom, which serves to increase other ingredients that do no good and, in higher doses, may cause side effects.

Note on Antihistamines. Many combination remedies contain antihistamines. Antihistamines are used for allergies and are not generally recommended to relieve the symptoms of the common cold. Some evidence suggests, however, that they may have some value.

First-generation antihistamines may reduce cold symptoms. Their benefits for the cold are likely to be due to the drowsiness they cause. Such antihistamines include Benadryl, Tavist, and Chlor-Trimeton. The newer, second-generation antihistamines (Claritin, Allegra, Zyrtec) do not have these effects and also appear to have no benefits against colds.

Herbal remedies and dietary supplements are not regulated by the FDA. This means that manufacturers and distributors do not need FDA approval to sell their products. In addition, any substance that affects the body's chemistry can, like any drug, produce side effects that may be harmful. There have been numerous reported cases of serious and even deadly side effects from herbal products.

The following are special concerns for people taking natural remedies for colds or influenza:

Echinacea is commonly taken to prevent onset and ease symptoms of cold or flu. A rigorous study, published in 2005 in the New England Journal of Medicine, determined that this herb does not help to prevent or treat colds. In addition, some people are allergic to echinacea. People who have autoimmune diseases or plant allergies should avoid it. There have been a few reports of people experiencing a skin reaction called erythema nodosum, which is characterized by tender, red nodules under the skin.
Chinese herbal cold and allergy products can contain trace amounts of aristolochic acid, a chemical that causes kidney damage and cancer. Many herbal remedies imported from Asia may contain potent pharmaceuticals, such as phenacetin and steroids, as well as toxic metals.

Medications

Vaccines are available to prevent influenza (See section on Viral Influenza Vaccines).

For mild influenza, symptom relief is similar to that for colds.

Two classes of antiviral agents have been developed to treat influenza: neuraminidase inhibitors and M2 inhibitors.

Brands and Benefits. Zanamivir (Relenza) and oseltamivir (Tamiflu) are neuraminidase inhibitors. They are newer agents that have been designed to block a key viral enzyme, neuraminidase, which is involved with viral replication. According to a major review of over 50 studies published in 2006, these drugs are effective against the flu in about 60% of cases.

Important points about the use of these drugs:

Neuraminidase inhibitors are effective for treating both A and B strains of influenza. (M2 inhibitors are effective only against type A.) However, their main benefit has been to reduce the length of symptoms by about one day, and only when started within 48 hours after symptoms become evident.
They may help reduce transmission of the virus.
They have a lower risk than M2 inhibitors for emerging viral strains that are resistant to their effects. However, The World Health Organization reports that viral resistance to oseltamivir (Tamiflu) can develop with extensive use. The level of resistance averaged 0.3% over 3 flu seasons surveyed in Japan (2003 - 2006). During that time, 35 million Japanese patients used the drug.
They have fewer serious side effects than the M2 inhibitors.
Both show some benefits for preventing influenza. Only oseltamivir has been approved for this purpose, however, and only in people over 13.
They may reduce complications of influenza, although this needs to be confirmed. It is not yet known if they have any effect on overall survival rates.
Oseltamivir is the only drug studied in avian flu cases. Although it is active in lab experiments, it has not been successful clinically. Experience is very limited, however, and it is not clear whether people infected with avian flu received the drug in time for it to be useful.

Limitations and Side Effects. Although they have many advantages compared to the M2 inhibitors, neuraminidase inhibitors are much more expensive. They also need to be taken within 2 days of the start of symptoms to be effective. Neither neuraminidase inhibitor is effective against influenza-like illness (one that is not caused by an influenza virus). There are also some differences between the two drugs that could be significant for some individuals:

Zanamivir is administered as a nasal spray or inhaler. People with asthma or other lung disorders may experience airway spasms and should use this drug with caution. Side effects are generally minor in most patients. It is important to make sure that elderly patients are able to properly use the zanamivir inhaler device.
Oseltamivir comes in capsule and liquid form. Side effects are also minor, but about 10 - 15% of patients experience nausea and vomiting. Patients with kidney dysfunction should take lower doses.

The current use of neuraminidase inhibitors in different age and patient groups is as follows:

Adults: Both drugs are approved for treatment in adult patients.
Children: Oseltamivir is approved for use in children age one and older. Studies report significant reduction in symptoms and in the incidence of ear infections in this population. However, studies from Japan point to the possibility of psychiatric side effects in children under 16 using oseltamivir. Zanamivir is approved for children over age 7, and studies are currently underway to determine its safety in younger children.
High-Risk Patients. Recent studies indicate neuraminidase inhibitors are safe and effective in patients with serious medical problems or other conditions that put them at risk for complications of flu.

Brands and Benefits. Amantadine (Symmetrel) and rimantadine (Flumadine) are M2 inhibitors. The following benefits may apply to the minority of strains of influenza A that remain sensitive to the drugs:

Both offer protection against influenza A and prevent severe illness if a person contracts the infection. (To be effective it must be administered within 2 days of onset.)
They may shorten the duration and lessen the severity of the flu if given within 48 hours of onset of symptoms.

Limitations. Drawbacks of M2 inhibitors include:

Viral resistance to these agents is rapidly emerging. For this reason, the Centers for Disease Control and Prevention Does not recommends M2 inhibitors for use during the 2007 - 2008 flu season in the United States.
M2 inhibitors are not effective against influenza B.
Neither drug has proven to reduce the risk for complications of the flu, including pneumonia and bronchitis.

Side Effects. Both M2 inhibitors occasionally cause nausea, vomiting, indigestion, insomnia, and hallucinations. Amantadine affects the nervous system and about 10% of people experience nervousness, depression, anxiety, difficulty concentrating, and lightheadedness. Rimantadine is less likely to do so. Rarely, amantadine can cause seizures, usually in elderly people already at risk for psychiatric symptoms.

Note: Amantadine is a standard treatment for Parkinson's disease and should be continued for that condition.

Flu Shots. These vaccines use inactivated (not live) viruses. They are designed to provoke the immune system to attack antigens contained on the surface of the virus. (Antigens are foreign molecules that the immune system specifically recognizes as alien and targets for attack.)

Unfortunately, the antigens in these influenza viruses undergo genetic changes (called antigenic drift) over time, so they are likely to become resistant to a vaccine that worked in the previous year. Vaccines are then redesigned annually to match the current strain.

Influenza A. The influenza A virus is further categorized by primary molecular antigens (hemagglutinin and neuraminidase), which serve as the targets for the vaccines. Influenza A is a particular problem, because it can infect other species, such as pigs or chicken, and undergo major genetic changes.
Influenza B viruses tend to be more stable than influenza A viruses, but they too vary. Although influenza B has been far less common than A, a vaccine for type B is important because experts are concerned that small children will not have developed any immunity to the virus, and will experience severe flu if they are exposed to type B viruses.

Intranasal (inside the nose) vaccine. A live but weakened intranasal vaccine (FluMist) is proving to be effective and safe in healthy, non-pregnant people aged 2 - 49 years and has been approved by the FDA. It is known as a live, attenuated, intranasal influenza vaccine (LAIV). The vaccine is engineered to grow only in the cooler temperatures of the nasal passages, not in the warmer lungs and lower airways. It boosts the specific immune factors in the mucous membranes of the nose that fight off the actual viral infections. FluMist is given using a nasal spray.

Timing and Effectiveness of the Vaccine. Ideally, people should be vaccinated every October or November. However, it may take longer for a full supply of the vaccine to reach certain locations. In such cases, the high-risk groups should be served first.

Antibodies to the influenza virus usually develop within 2 weeks of vaccination, and immunity peaks within 4 - 6 weeks, then gradually wanes.

Because children under age 8 do not develop strong immune responses to one dose, the CDC recommends two vaccinations given 1 month apart on the first year they receive the vaccine. If children under 8 received only 1 dose of the vaccine on their first immunization year, they should receive 2 doses the following year. Children under 8 who have received single doses for 3 or more years should continue to receive single doses.
It should be noted that if an individual develops influenza symptoms and is accurately diagnosed in time, vaccination of the other members of the household within 36 - 48 hours affords effective protection to those individuals.

In healthy adults, immunization typically reduces the chance of illness by about 70 - 90%. The current flu vaccines may be slightly less effective in certain patients, such as the elderly and those with certain chronic diseases. Even in people with a weaker response, however, the vaccine is usually protective against serious flu complications, particularly pneumonia. In fact, among the elderly, interesting studies are now suggesting that influenza vaccination may help protect against stroke, adverse heart events, and death from all causes.

Children Who Should Be Vaccinated. The following children over 6 months should be vaccinated against influenza:

The American Academy of Pediatrics (AAP) and the CDC recommend influenza vaccination in all healthy children between 6 and 59 months old.
In addition, any child over the age of 2 years with a condition that requires regular medical care or who has been hospitalized for a serious illness (particularly lung or kidney disease, diabetes, sickle-cell, or immune deficiencies). If parents are concerned about vaccines that contain the mercury preservative thimerosal, they can ask their doctor about reduced-thimerosal flu vaccine.
Children who come in direct contact with a person vulnerable to complications from influenza should also be vaccinated.
Children who are receiving long-term aspirin therapy should also be immunized against the flu because they are at higher risk for Reye syndrome, a life-threatening disease, if they get the flu.
Some experts now advocate flu shots for all school-age children. Emerging research indicates that children are responsible for transmitting the vast majority of cases of seasonal flu, and that routine vaccination of school-age children would considerably reduce transmission rates throughout communities.

Older Children and Adults Who Should Be Vaccinated. The following, in order of priority, are the population groups who should be vaccinated each year. The first two groups have the highest need for influenza vaccinations and are given top priority:

All adults 50 years and older. Vaccinated older adults have lower hospitalization rates than unvaccinated peers. Evidence now suggests that vaccination may help protect against adverse heart events (including those after heart surgeries), stroke, and death from all causes in the elderly. Still, studies suggest that only two thirds of the people in this group are vaccinated, mostly because of unwarranted fears of ineffectiveness or adverse effects.
People of any age at high risk for serious complications from influenza. Such people include those with heart disease, lung problems, immune deficiencies, diabetes, kidney disease, or chronic blood disease. Those with any condition that may compromise respiratory function or the handling of respiratory secretions, including people with cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders, are included in this group. (There have been concerns about the safety of the vaccinations in certain high-risk patients such as those with HIV or asthma. Studies now suggest that the vaccine is generally safe in these patient groups. Furthermore, their risk for serious complications from influenza outweighs any potential adverse effects from the vaccines.)
All health care workers should be vaccinated, according to the ACIP's recommendations.
Household members in contact with individuals who are at high-risk for complications from influenza should be vaccinated.

Other adults who should consider influenza vaccinations include:

People at risk for complications for influenza and who are traveling to the tropics at any time or to the Southern Hemisphere between April and September.
Pregnant women who are at risk for complications of influenza, and who will be in their second or third trimester during flu season. (Vaccinations should usually be given after the first trimester. Exceptions may be women who are in their first trimester during flu season and their risk from complications of the flu is higher than any theoretical risk to the baby from the vaccine.)
Police officers, firefighters, and other public safety officials.

Negative Effects. Possible negative responses to the vaccines include:

Allergic Reaction. Newer vaccines contain very little egg protein, but an allergic reaction still may occur in people with strong allergies to eggs.
Soreness at the Injection Site. Up to two thirds of people who receive the influenza vaccine develop redness or soreness at the injection site for 1 - 2 days afterward.
Flu-like Symptoms. Some people actually experience flu-like symptoms, called oculo-respiratory syndrome, which include cough, wheezing, tightness in the chest, sore throat, or a combination. Such symptoms tend to occur 2 - 24 hours after the vaccination and generally last up to 2 days. These symptoms are not influenza itself but an immune response to the virus proteins in the vaccine. (Anyone with a fever at the time the vaccination is scheduled, however, should wait to be immunized until the ailment has subsided.)
Guillain-Barre Syndrome. Although iIsolated cases of a paralytic illness known as Guillain-Barre syndrome occurred in about one of every 100,000 people vaccinated with the swine-flu vaccine in 1976, it has not been a problem with subsequent vaccines.
There has been some question concerning influenza vaccinations because of some reports that vaccines may worsen asthma. Recent and major studies have been reporting, however, that the vaccination is safe for children with asthma. It is also very important for these patients to reduce their risk for respiratory diseases.

The FDA approved the first vaccine for humans against H5NI influenza virus in April 2007. The vaccine, which is made from a human strain of the virus, could be used in people ages 18 - 64 to prevent the spread of the virus from human to human. The vaccine requires two shots, given about a month apart. It will not be sold commercially, but instead is being purchased by the U.S. government to be stockpiled and distributed to public health officials in the event of an outbreak of avian flu.

In a study, 103 healthy adults received two g shots of the virus, 28 days apart. An additional group of 300 adults received the vaccine at a lower dose, while 48 people received placebo injections. The study showed that 45% of those who received the higher dose developed antibodies that may reduce their risk of getting the avian flu. The most common side effects reported were pain at the injection site, headache, and muscle pain. Research on the vaccine is continuing.

The intense and widespread use of antibiotics is leading to a serious global problem of antibiotic resistance. The inappropriate use of powerful newer antibiotics for conditions such as colds or sore throats poses a particular risk for resistant strains of bacteria. For example, the number of cases of methicillin-resistant Staphylococcus aureus (MRSA) is increasing in people who have no known risk factors. (MRSA causes sometimes-fatal skin infections.) In 2006, rates of Neisseria gonorrhoeae resistance to the fluoroquinolone antibiotics family exceeded 10%. The CDC no longer recommends treating gonorrhea infections with fluoroquinolone first.

When Antibiotics Are Needed for Upper Respiratory Infections.

Antibiotics do not affect viruses and, in healthy individuals, these drugs are almost never necessary or helpful for influenza or colds, even with persistent cough and thick, green mucus. In one disturbing study, antibiotics were prescribed for nearly half of children who went to the doctor for a common cold.

Antibiotics may be required for upper respiratory tract infections only under certain situations, such as the following:

Patients, particularly small children or elderly people, who have medical conditions that put them at high risk for complications from any respiratory tract infections, should usually be given antibiotics.
Patients with severe sinusitis that does not clear up within 7 days (some experts say 10 days) and whose symptoms include one or more of the following: green and thick nasal discharge, facial pain, or tooth pain or tenderness.
Some children with middle ear infections, although experts differ on who will benefit. Some experts recommend that only children under the age of 2 years should be treated with antibiotics, and children over 2 should be treated on a case-by-case basis.
Patients with strep throat or severe sore throat that involves fever, swollen lymph nodes, and absence of cough. (Strep throat makes up only 10 - 15% of all sore throat cases.)
Patients who have an acute cough that is caused by pneumonia (but in few other cases, regardless of the duration of the cough). Experts estimate that, outside the hospital setting, less than 20% of prescriptions for persistent coughing are necessary.

Patients at Highest Risk for Infection with Resistant Bacteria Strains. Some patients are at greater risk for developing an infection resistant to common antibiotics. At this time, the average person is not endangered by this problem. Risk factors include:

Very old or very young age
Exposure to patients with drug-resistant infection
Hospitalization in intensive care
History of an invasive surgical procedure
Staying in the hospital
Prolonged course of antibiotics, particularly within the past 4 - 6 weeks
Serious wounds
Tubes down the throat, catheters, or intravenous (I.V.) lines
Immunosuppression

Children at higher risk for antibiotic resistance are those who attend day care, who are exposed to cigarette smoke, who were bottle-fed, and who had siblings with recurrent ear infections.

What the Health Care Community Is Doing. Prescribing antibiotics only when necessary is the most important step in restoring bacterial strains that are susceptible to antibiotics. Encouraging studies are reporting that inappropriate antibiotic prescriptions are on the decline. Prescriptions for other common respiratory infections, such as otitis media, sore throat, acute bronchitis, and colds and flus have been decreasing.

What Patients and Parents Can Do. Patients and parents can also help with the following tips:

Use home or over-the-counter remedies to relieve symptoms of mild upper respiratory tract infections.
Realize that antibiotics will not shorten the course of a viral infection. It is important for patients and parents to understand that although antibiotics may bring a sense of security, they provide no significant benefit for a person with viral infection, and overuse can contribute to the growing problem of resistant bacteria.
Don't pressure a doctor into prescribing an antibiotic if it is clearly inappropriate. The doctor very often will give in.
If a child needs an antibiotic, ask the doctor whether it is appropriate to use high-dose short-term antibiotics, which may lower the risk for developing resistant strains.
If an antibiotic is prescribed, take the full course, even if you feel better before finishing it.

Resources

www.cdc.gov/flu -- U.S. Centers for Disease Control and Prevention
www.niaid.nih.gov -- National Institute for Allergy and Infectious Diseases
www.who.int/csr/disease/influenza/en -- World Health Organization
www.cdc.gov/vaccines -- National Immunization Program
www.immunize.org -- Immunization Action Coalition
www.entnet.org -- American Academy of Otolaryngology -- Head and Neck Surgery
www.cdc.gov/flu/avian -- Avian Influenza Information

References

American Academy of Pediatrics Committee on Infectious Diseases. Recommended childhood and adolescent immunization schedule: United States, 2005. Pediatrics. 2005 Jan;115(1):182.

Caruso TJ, Prober CG, Gwaltney JM Jr. Treatment of naturally acquired common colds with zinc: a structured review. Clin Infect Dis. 2007;45(5):569-74.

Centers for Disease Control and Prevention. Key Facts About Seasonal Influenza (Flu). Available online.

Centers for Disease Control and Prevention. 2007-08 Influenza Prevention & Control Recommendations: Vaccination of Specific Populations. Available online.

Centers for Disease Control and Prevention. Acute Respiratory Disease Associated with Adenovirus Serotype 14 -- Four States, 2006-2007. MMWR. 2007;56(45):1181-84.

Centers for Disease Control and Prevention. FDA Approves New Laboratory Test To Detect Human Infections With Avian Influenza A/H5 Viruses. February 3, 2006.

Hayden GF, Turner RB. Acute Pharyngitis. In: Behrman RE, Kliegman RM, Jenson HB, eds. Behrman: Nelson Textbook of Pediatrics, 17th ed. Philadelphia, Pa: Saunders; 2004.

Interagency Task Force on Antimicrobial Resistance. Executive Summary: 2006 Annual Report on Progress on "A Public Health Action Plan to Combat Antimicrobial Resistance." Draft release, June 2007. Available online.

Jefferson T, Demichelli V, Rivetti D, Jones M, Di Pietrantonj C, Rivetti A. Antivirals for influenza in healthy adults: systematic review. Lancet 2006 Jan 28;367(9507):303-13.

Morantz CA. ACIP Updates Guidelines on Prevention and Control of Influenza. Am Fam Physician. 2005; 72(6); 1119-1127.

Reveiz L, Cardona AF, Ospina EG. Antibiotics for acute laryngitis in adults. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD004783.

Sasazuki S, Sasaki S, Tsubono Y, Okubo S, Hayashi M, Tsugane S. Effect of vitamin C on common cold: randomized controlled trial. Eur J Clin Nutr. 2006;60(1):9 - 17.

Shah SA, Sander S, White CM, Rinaldi M, Coleman CI. Evaluation of echinacea for the prevention and treatment of the common cold: a meta-analysis. Lancet Infect Dis. 2007;7(7):473-80.

Simasek M, Blandino DA. Treatment of the common cold. Am Fam Physician. 2007;75(4):515-20.

Taverner D, Latte J. Nasal decongestants for the common cold. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD001953.

U.S. Food and Drug Administration: Nonprescription Drugs and Pediatric Advisory Committee Meeting. Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18-19, 2007. Available online.

World Health Organization: Neuraminidase Inhibitor Susceptibility Network. Monitoring of neuraminidase inhibitor resistance among clinical influenza virus isolates in Japan during the 2003-2006 influenza seasons. Weekly epidemiological record. 2007;82(17):149-50.

World Health Organization. Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO. January 15, 2008. Available online.

Review Date:
1/18/2008
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A.D.A.M. Copyright

adam.com

Hodgkin's disease

FitSugar — Wed, 08 Oct 2008 17:35:06 -0700

In This Report

Highlights
Introduction
Risk Factors
Symptoms
Diagnosis
Outlook
Staging and Treatment Guide...
Treatment Options by Stage...
Radiation Treatments
Chemotherapy
Transplantation
Immunotherapy
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Warning

Chemotherapy can cause anemia, a drop in red blood cell (hemoglobin) levels. Erythropoiesis-stimulating drugs, which boost the production of red blood cells, are administered to counteract this complication. However, these drugs, including epoietin alfa (Epogen, Procrit) and darbepoietin alfa (Aranesp), can also cause serious side effects and adversely affect survival when hemoglobin levels are raised too high.

In 2007, the U.S. Food and Drug Administration (FDA) made several changes to the prescribing labels for erythropoiesis-stimulating drugs. The new labels contain stronger warnings and updated dosing-related safety information.

Preventing Infection after Cancer Treatment

Both chemotherapy and stem cell transplants increase the risk for serious infections. Patients must take precautions to avoid exposure to germs. Ways to prevent infection include:

Practice good hygiene, including regular handwashing and dental care (brushing, flossing)
Avoid crowds, especially during cold and flu season
Eat only well-cooked foods (no raw fruits or vegetables)
Boil tap water before drinking it
Do not keep fresh flowers or plants in your house as they may carry mold

Introduction

Hodgkin's disease is a type of lymphoma. Lymphomas are cancers of the lymphatic system. They are generally subdivided into two groups: Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). NHL is discussed in another report. [For more information, see In-Depth Report #84: Non-Hodgkin's lymphomas.]

The lymphatic system filters fluid from around cells. It is an important part of the immune system. When people talk about swollen glands in the neck, they are usually referring to swollen lymph nodes. Common areas where lymph nodes can be easily felt, especially if enlarged, are: the groin, armpits (axilla), above the clavicle (supraclavicular), in the neck (cervical), and the back of the head just above hairline (occipital).

HD is the major tumor in a group known as malignant lymphomas. Most often HD starts in B cell lymphocytes located in lymph nodes in the neck area, although any lymph node may be the site of initial disease.

Click the icon to see an image of the lymph nodes in the head and neck.

The following is a possible description of the process leading to HD:

In early development, B cells normally undergo a series of genetic rearrangements until they create immunoglobulins, proteins that act as antibodies.
Antibodies are produced by the immune system. They contain receptors that match and bind to a wide array of foreign substances (such as viral proteins) called antigens. Antibodies help launch an immune attack against antigens.
B cells normally undergo limited cycles of genetic rearrangement that result in immunoglobulin production. In rare cases, however, the genetic arrangements create a mutation that does produce immunoglobulins. The results are large, abnormal cells referred to as Reed-Sternberg cells.
Without immunoglobulin, Reed-Sternberg cells can be infected by certain viruses (notably the Epstein-Barr virus -- the cause of infectious mononucleosis). Genetic byproducts of these viruses appear to inhibit a natural process of self-destruction (called apoptosis) that would normally kill off these natural cells. Instead, the abnormal B cells grow non-stop, causing most forms of HD.

Click the icon to see an image of an antibody.

Only a very small percentage (about 1%) of cells found in the affected lymph tissues of HD are actually Reed-Sternberg cells. Researchers are unable to completely explain why so few cells can cause such severe symptoms. One explanation is that these cells trigger production of very powerful immune system proteins called cytokines (including those known as interleukin-1, interleukin-6, and tumor necrosis factor). These cytokines produce an inflammatory response that can cause local pain, fever, and other symptoms typical of HD. The dominance of different kinds of cytokines may also explain why HD takes different forms.

Classical Hodgkin's Lymphoma. Based on the variations and numbers of Reed-Sternberg cells, as well as other features, four major subtypes of classical HD have been identified:

Nodular Sclerosis. Nodular sclerosis is the most common subtype, representing almost 60% of HD cases. Younger patients are more likely to have this type. The nodes first affected are often those located in the center of the chest (the mediastinum).
Mixed Cellularity. Mixed cellularity is the next most common HD form, occurring in about 25% of patients, mostly in older patients, children, and those with immune disorders, such as AIDS. It usually indicates a more severe condition.
Lymphocyte Depleted. Lymphocyte-depleted HD occurs in about 4% of patients, nearly always in elderly people. It indicates extensive disease and a poor outlook. It can easily be confused with non-Hodgkin's lymphoma.
Lymphocyte-Rich Classical Hodgkin's Lymphoma. This form is similar to nodular lymphocyte predominant HD, but has more cell characteristics that conform to classical HD.

Nodular Lymphocyte-Predominant Hodgkin's Disease. Nodular lymphocyte-predominant Hodgkin's disease (LPHD) occurs in about 5% of patients. The cells in LPHD known as lymphocytic and histolytic cells are proving to be distinctly different from classic Reed-Sternberg B cells. Patients with lymphocyte predominance are usually young men, who often have no symptoms. LPDH is very slow growing and may be associated with long survival. There is a 3% risk, however, that LPDH will transform to non-Hodgkin's lymphoma. In fact, lymphocyte-predominant HD may eventually be defined as a non-Hodgkin's lymphoma.

Lymphomas represent tumors of the lymphatic system. This system is a network of organs, ducts, and nodes. The system interacts with the blood's circulatory system to transport a watery clear fluid called lymph throughout the body. The lymphatic system contains lymphocytes, which are important cells involved in defending the body against infections. This system also restores 60% of the fluid that leaks out from blood capillaries back into circulation. Its ducts provide transportation for fats, proteins, and other substances collected from the body's tissues.

Lymphocytes. The lymphatic system helps produce and transport lymphocytes, white blood cells that are a primary component of the immune system. Some lymphocytes produce antibodies that can target and attack specific foreign substances (antigens).

Lymphocytes develop in the bone marrow or thymus gland. They are categorized as either B cells (bone marrow-derived cells) or T cells (thymus gland-derived cells).
B cells complete their structural growth and definition (known as differentiation) and mature in the bone marrow.
T cells also start out in the bone marrow, but differentiate and mature in the thymus gland, located beneath the breastbone (sternum). This small gland is active mostly in the fetal stage through the first 10 years of life, after which it shrinks.
B-cell and T-cell lymphocytes leave these organs through the bloodstream, which eventually branches out into the tiny blood vessels called capillaries.
Some lymphocytes, along with fluid, proteins, and other substances, move out of the capillaries into the surrounding tissues. Some enter the lymphatic vessels.
Lymphatic vessels begin as tiny, blind-ended tubes. They lead to larger lymphatic ducts and branches, and drain into two ducts in the neck, where the fluid re-enters the bloodstream.
Along the way, the fluid passes through lymph nodes, which are oval structures composed of lymph vessels, connective tissue, and white blood cells. Here, the lymphocytes are either filtered out or added to the contents of the node.

Lymph Nodes. In a lymph node, lymphocytes typically receive their initial exposure to foreign substances, such as bacteria. This exposure prompts the lymphocytes to perform their immune functions. The size of a lymph node varies generally from that of a pinhead to a bean. Most nodes are clustered throughout the body. Important node clusters are found in the neck, lower arm, armpit, and groin.

Other Structures in the Lymphatic System. The tonsils and adenoids are secondary lymphatic organs. They are composed of masses of lymph tissue that also play a role in the lymphatic system. The spleen is another important organ that processes lymphocytes from incoming blood.

Click the icon to see an animation about lymph nodes.

Click the icon to see an image of an antibody.

Click the icon to see an image of the immune system structures.

Risk Factors

Hodgkin’s disease accounts for about 11.5% of all types of lymphomas. According to the American Cancer Society, about 8,200 new cases of Hodgkin's disease (HD) were diagnosed in the United States in 2007 and about 1,000 people died of the disease. Experts believe that the malignant process leading to Hodgkin's disease is triggered by a combination of environmental and genetic factors along with a susceptible immune system. The exact triggers, however, are unknown.

Hodgkin's disease occurs most often in people between the ages of 15 - 40, (especially in the 20s), and in people over age 55. About 10 - 15% of Hodgkin’s disease cases are diagnosed in children and teenagers.

Hodgkin's disease is slightly more common among males than females. Women who get Hodgkin's disease appear to have a slightly lower risk for relapse after treatment than men.

Infectious mononucleosis (“mono”), which is caused by the Epstein-Barr virus (EBV), appears to increase the risk for Hodgkin’s disease. Research suggests that the virus activates some pathway within the lymphocyte cell that leads to cell proliferation. However, only 1 in 1,000 patients with mononucleosis develops Hodgkin's disease. The Epstein-Barr virus itself is present in 90% of the population and, in the great majority of these cases, causes a mild infection or none at all. Very few people who have had mononucleosis go on to develop HD. Other factors must be present to trigger the malignancy.

Hodgkin's disease runs in families in about 5% of cases. Siblings have three times more risk than the general population.

Symptoms

The onset of Hodgkin's disease symptoms is highest during late winter months, with lymph node enlargement usually being the first sign. Lymph nodes may be enlarged in the following regions:

The most common first sign of Hodgkin's disease is painless enlargement of one or more lymph nodes above the diaphragm, most often those in the neck, chest, or armpits.
Enlarged lymph nodes are often detected in the chest cavity between the lungs (the mediastinum), particularly in younger patients.
Only about 15% of cases occur exclusively below the diaphragm.

Hodgkin's disease usually progresses in an orderly way from one lymph node region to the next. This process may be slow, particularly in younger people, or very aggressive. The disease typically spreads downward from the initial site.

If it spreads below the diaphragm, it usually reaches the spleen first; the disease may then spread to the liver and bone marrow.
If the disease starts in the nodes in the middle of the chest, it may spread outward to the chest wall and areas around the heart and lungs.

Symptoms in or around the Lymph Nodes. Occasionally, patients may have a cough or chest pain if the disease is located in the middle of the chest, but usually the enlarged nodes produce no symptoms. Sometimes patients experience pain in the diseased lymph nodes after drinking alcohol.

Systemic (B) Symptoms. Between 20 - 40% of patients have systemic symptoms that affect the whole body rather than just the specific location of the disease. Some of systemic symptoms are referred to as B symptoms. Patients who have B symptoms have a more severe condition than asymptomatic patients with the same cancer stage or tumor location or size.

Systemic symptoms include:

Drenching night sweats and weight loss (B symptoms)
Fever -- may occur only at night in episodes that come and go (B symptoms)
Itching all over the body -- caused by the release of histamines, substances ordinarily triggered by an allergic response. In the case of Hodgkin's disease, histamine release is due to abnormalities in the immune system. Although itching is a systemic symptom, it is not usually considered a B symptom if other systemic symptoms are not also present.
Rash (late stages)

Many patients seek medical help for abnormally swollen lymph nodes (commonly referred to as “swollen glands”). Swollen glands can be caused by many conditions, most often infections, and are rarely serious.

Infections. In the great majority of cases, swollen glands are caused by an infection:

For example, although Hodgkin's often first appears in the neck, enlarged lymph nodes in that location are much more likely to be a sign of strep throat, or other throat infections.
Infectious mononucleosis (caused by the Epstein Barr virus) is a common cause of swollen lymph nodes in young people.
Recent travel, particularly to countries with a high incidence of tropical diseases, can trigger similar symptoms.
Other infections that cause similar symptoms include cat scratch fever, Lyme or other tick-borne disease, HIV, tularemia, tuberculosis, syphilis, herpes simplex virus, cytomegalovirus, and hepatitis.

Lymph nodes play an important part in the body's defense against infection. Swelling might occur even if an infection is small or not apparent.

Non-Hodgkin's Lymphomas. Although both Hodgkin's disease and non-Hodgkin's lymphomas are malignancies of the lymph nodes, they can usually be distinguished by certain characteristics. It is extremely important to differentiate between Hodgkin's lymphomas and non-Hodgkin's lymphomas, since the treatments for these two conditions differ. In particular, a subtype of lymphoma called anaplastic large-cell lymphoma (ALCL) might be confused with Hodgkin’s disease under some circumstances. [For more information, see In-Depth Report #84: Non-Hodgkin's lymphomas.]


Characteristics	Hodgkin's Disease	Non-Hodgkin's Lymphomas
Age and Prevalence	Average age is 27.7 with two age peaks, the major one between 15 - 24 with a lesser peak after age 55. It is less common than NHL.	Average age is about 67. It is more common than HD.
Location	In both malignancies, the disease occurs most often in lymph nodes above the collarbone. However, in HD it is also more likely to appear in the chest cavity between the lungs (the mediastinum), particularly in younger patients. Only about 15 - 20% of cases are found in areas below the diaphragm. Disease occurs outside the nodes in about 4% of cases.	In both malignancies, the disease occurs most often in lymph nodes above the collarbone. In NHL, however, it is also more likely to appear in the nodes in the abdomen (called the mesenteric nodes). The disease occurs in the chest cavity in less than 40% of patients. (An exception, lymphoblastic lymphoma, which is seen most often in young people, is likely to first appear in the chest.) Disease occurs outside the nodes in about 23% of patients. Slow-growing lymphomas are common in the liver and bone marrow.
Symptoms	More likely than NHL (40%) to have systemic symptoms (such as fever and night sweats) at the time of diagnosis.	Less likely to have systemic symptoms (27%) at the time of diagnosis.
Progression	Less likely than NHL to be diagnosed in stage IV (10%). Hodgkin's disease usually progresses in an orderly way from one lymph node region to the next. This process may be slow, particularly in younger people, or very aggressive. The disease typically spreads downward from the initial site. If it spreads below the diaphragm, it usually reaches the spleen first; the disease then may spread to the liver and bone marrow. If the disease starts in the nodes in the middle of the chest, it may spread outward to the chest wall and areas around the heart and lungs.	More likely than HD to be diagnosed in stage IV (36%). The lymphomas are less predictable in their course than Hodgkin's disease and they are more apt to spread.

Other Cancers or Serious Conditions in the Lymphatic System. Other cancers that can travel to lymph nodes include breast cancer and leukemia.

Very serious causes of enlarged lymph nodes include disorders of the lymph system that include Castleman's disease, lymphomatoid granulomatosis, and angioimmunoblastic lymphadenopathy. These lymph system disorders, although noncancerous, involve abnormal lymph cells. They are often fatal and can be very difficult to distinguish from lymphomas. Many of the other serious illnesses involving diseased lymph nodes develop simultaneously at multiple sites, while Hodgkin's nearly always starts at one location before spreading to nearby nodes. [For more information, see In-Depth Report #84: Non-Hodgkin's lymphomas or Report #86: Acute lymphocytic leukemia.]

Exposure to Chemicals. Exposure to industrial chemicals or certain medications, such as phenytoin (Dilantin), may cause enlarged nodes. In addition, other drugs, such as cephalosporins, penicillins, or sulfonamides, can cause enlarged nodes and other symptoms, including fever and rash that may resemble Hodgkin's disease.

Diagnosis

The doctor will take a medical history and perform a physical examination. If these simple procedures point to Hodgkin's disease, a number of additional tests may be needed to either rule out other diseases or confirm HD and determine the extent of the cancer.

The doctor will examine not only the affected lymph nodes but also the surrounding tissues and other lymph node areas for signs of infection, skin injuries, or tumors. The consistency of the node is sometimes indicative of certain conditions. For example, a stony, hard node is often a sign of cancer, usually one that has metastasized (spread to another part of the body). A firm, rubbery node may indicate lymphoma (including Hodgkin's). Soft nodes suggest infection or inflammatory conditions.

Blood tests are performed to measure white and red blood cells, blood protein levels, the uric acid level, blood proteins, and the liver's function. Another blood test is the erythrocyte sedimentation rate (ESR), which is sometimes elevated in Hodgkin's disease (although it is not specific for this condition).

Click the icon to see an image of the formed elements of blood.

Chest X-Ray. A chest x-ray shows the lymph nodes in the chest and neck area, where Hodgkin's disease usually starts. It a useful step for detection of enlarged lymph nodes.

Click the icon to see an image of an x-ray machine.

Click the icon to see an image of a CT machine.

Positron Emission Tomography (PET). PET scans combined with CT scans can help doctors clarify the location of the cancer. PET scans can also provide information on whether or not an enlarged lymph node is benign or cancerous and are more accurate than CT scans or other imaging tests for staging lymphomas. PET scans may also help doctors determine how well a patient has responded to treatment, if any residual cancer exists, and if a patient has achieved remission.

A biopsy of the suspicious lymph node is the most definitive way to diagnose Hodgkin's disease. A biopsy has risks, and should be performed only by a qualified and experienced doctor. Sometimes a doctor may choose to wait and observe the involved lymph nodes, which will usually regress on their own if a temporary infection is causing the enlargement. However, some lymphomas may regress and appear to be benign, only to reappear at a later time.

The Procedure. During a biopsy, the doctor usually removes the node and checks the surrounding areas. The tissue in the node is then examined for signs of infection and blood cell or other abnormalities. Biopsies of bone marrow may also be performed in patients with existing Hodgkin's disease if the doctor suspects that it may have spread to the marrow.

Biologic markers, called biomarkers for short, are high levels of substances that are released by tumors and indicate the level of cancer activity. Biomarkers can be found in sputum, blood, and tissue samples. Biomarkers can be enzymes, hormones, amino-acid compounds, antigens (identified by antibodies that specifically target them), growth factors, and other chemicals. Some under investigation include:

CD44 is a molecule that binds to the surface of cells and may be involved in metastasis. High levels of this molecule may suggest a more aggressive disease.
Interleukin (IL) 10 is another immune factor that may indicate a poor outlook when it occurs in high levels.

Outlook

Hodgkin’s disease is considered one of the most curable forms of cancer, especially if it is diagnosed and treated early. Unlike other cancers, Hodgkin's disease is even potentially curable in late stages. About 85% of patients with Hodgkin’s disease survive at least 5 years after cancer treatment. Five-year survival rates for patients diagnosed with stage I or II Hodgkin’s disease are 90 - 95%. Patients who survive 15 years after treatment are more likely to later die from other causes than Hodgkin’s disease.

Survival rates are poorest for:

Those who relapse within a year of treatment
Patients who do not respond to the first-line therapy and have signs of disease progression

The good news about Hodgkin's disease is that treatment can cure the disease. The bad news is that survivors face a higher than average risk for long-term complications of these treatments, some very serious.

Many patients may experience chronic fatigue that could persist for years. One study indicated that aerobic exercise may significantly improve fatigue; in doing so it could have a positive effect on mood as well.

The most serious complications are secondary cancers and heart disease, which occur over the 2 - 3 decades following treatments. Secondary cancers include non-Hodgkin's lymphoma, leukemia, melanoma, stomach and lung cancers, and breast and uterine cancers. Heart disease complications include coronary artery disease, stroke, heart valve problems, and cardiomyopathy (weakening of the heart muscle). Thyroid disorders are also a potential complication. Combinations of radiation and chemotherapies are especially associated with these problems.

A 2006 study in the New England Journal of Medicine evaluated the long-term health status of adult survivors of various childhood cancers. The study found that, 30 years after treatment, patients with Hodgkin’s disease had among the highest risk of developing serious health problems. Female survivors had a significantly greater risk than male survivors. In particular, women who received chest radiation are at very high risk for developing breast cancer. Still, in a 2000 study, 20 years after treatment, 90% of patients who had survived treatments were still living.

Patients with Hodgkin’s disease should get a written record of the treatments they received as children, and the potential risks of these treatments. These records can help the doctors who later oversee their care monitor for potential health problems. Survivors of Hodgkin’s disease should receive regular screening tests for cancer and heart disease. They may need to get these tests at a younger age than most patients. In particular, patients who were treated with chest radiation should get blood tests every 5 years to measure their cholesterol levels. Female patients who received chest radiation should get early and frequent mammograms.

Although HD is highly curable, it can have many psychologic consequences. Depression and anxiety are common in survivors, particularly those who suffer additional medical conditions. Fatigue persists in the majority of patients for years. Still, many survivors have an excellent quality of life.

Staging and Treatment Guidelines

Multiple treatment approaches are available for patients with Hodgkin's disease at nearly every stage, often resulting in similar rates of cure. Ultimately, the choice of treatment is based on a consideration of various prognostic factors as well as treatment side effects, both short and long term. Treatment decisions are individualized, and patients should discuss the pros and cons of various approaches with their doctors.

Staging the disease according to how far the cancer has spread (I through IV) is a primary method for determining both treatment options and prognosis. There are two levels of staging: Clinical staging and pathological staging.

Clinical stages are determined by conducting a thorough examination, which may include blood tests and different kinds of x-rays.
Pathologic staging is conducted after a laparotomy and biopsy of the tissue to help determine treatment options. It involves a much more detailed examination, but is not required as often as in the past for making treatment decisions.

In general, the prognosis according to stage is as follows:

If the disease is treated in stages I or II, the cure rates are as high as 90%. (Slightly more than half of all patients are diagnosed in these stages.)
Patients in stages III or IV are usually diagnosed with advanced Hodgkin's disease. (Even in such stages, survival at 5 years can be as high as 85%.)

The staging system can be further refined according to other features or factors that indicate a more or less severe condition and can help determine whether treatments should be more or less aggressive.

Presence or Absence of B Symptoms. For example, stages I through III are further categorized as either A or B according to whether certain widespread symptoms are absent (A) or present (B). The presence of B symptoms increases the risk of relapse.

The patient is classified as B if they have unexplained weight loss of more than 10% within 6 months, unexplained fever, and drenching night sweats. Fever and weight loss are the most important indications of B symptoms; night sweats alone do not always mean that such symptoms are present. Itching by itself is not considered a reliable B symptom.
If the patient has none of these symptoms, the disease is considered at A, which is less severe than the B form at any stage.
Another letter used to further refine a stage is E, which indicates that the malignancy is still local but has gone beyond the lymph node into surrounding tissue.

Indicators for Aggressive Treatments. Certain factors are indicators of a more serious case at any stage and the need for aggressive treatment:

The malignancy is "bulky" (a large mass)
Blood tests show high levels of erythrocyte sedimentation rates
Multiple tumors in the spleen
Greater involvement in the abdomen

Even if a patient has stage II disease, the presence of a bulky tumor or multiple tumors in the spleen indicates the patient may be treated as if they had advanced Hodgkin's disease.

Cell Types. The cell type of Hodgkin's disease may also influence treatment. For example, those with mixed cellularity type might require more aggressive therapy in certain cases than those with a slower-growing form, such as lymphocyte-predominant Hodgkin's disease (LPHD). In fact, some studies suggest that LPHD is the mildest form of Hodgkin's disease and that patients with LPHD are more likely to die of treatment-related disease than from Hodgkin's itself. Some experts are investigating the role of limiting radiation doses in such patients, although the most optimal approach is not yet known.

Other Prognostic Risk Factors. The International Prognostic Factors Project on Advanced Hodgkin’s Disease has developed seven factors that help determine which patients with advanced Hodgkin's disease would benefit from more or less aggressive chemotherapy. They are also useful to help determine success in patients with relapsed or persistent HD who are undergoing stem cell transplantation. The score is determined by the number of yes answers to the following questions. The more yes answers, the more likely the patient needs to be treated aggressively:

Is the patient male?
Is the patient older than 45?
Does the patient have stage IV disease?
Does the patient have blood tests showing lower than normal albumin levels? (Albumin is a protein found throughout the body.)
Does the patient have abnormally low hemoglobin levels? (Hemoglobin is the oxygen-carrying compound in red blood cells, so low levels suggest anemia.)
Does the patient have an abnormally high white blood cell count (15,000 or more)?
Does the patient have abnormally low levels of lymphocytes?

To avoid putting patients through unnecessary treatments that may actually be as or even more lethal than the disease itself over time, doctors are attempting to identify more specifically those patients who would or would not benefit from aggressive therapy.

Preventing Infection. Both the disease and some of the treatments suppress the immune system, increasing the risk for infections. Widespread, life-threatening infection is a particular danger if the spleen has been removed and both radiation and chemotherapy are administered. A week before any treatment, patients are often vaccinated against three bacteria: pneumococcus, meningococci, and Haemophilus influenza.

Measures for Infertility. People who wish to have children should discuss the possibility for receiving treatments that may lessen the risk for infertility. Examples include the following:

Men with Hodgkin's disease may want to consider sperm freezing and assisted reproductive techniques. One encouraging study on male survivors of childhood Hodgkin's disease, reported that although treatments had reduced their sperm count and quality, the actual genetic material was healthy. Such men, then, would still be good candidates for assisted reproductive techniques.
Women should ask their doctors about the possibility for preserving fertility by taking hormonal drugs called GnRH analogs before and during chemotherapy.

[For more information on fertility preservation treatments, see In-Depth Report #67: Male infertility and In-Depth Report #22: Female infertility.]

Considerations During Pregnancy. Women who are pregnant need special preparation and treatments.

Periodic examination for recurrent Hodgkin's disease is necessary for years after treatment, since relapse is not uncommon, even after treatment for early stages, and can occur a decade or more after treatment. Chest x-rays and CT scans of the abdomen are useful for detecting relapsed disease. Relapse is more likely to occur in early-stage disease, probably because limited radiation normally used in such cases did not destroy all malignancies. Patients who had large tumors in the chest are also at higher risk for recurrence. Patients also need to be monitored for long-term effects of the treatments themselves. Conditions to watch for include inflammation in the lungs and thyroid disease from radiation in the chest and heart disease and cancers from combined treatments, chemotherapy (particularly the use of MOPP), and blood stem cell transplantation.

Because Hodgkin's disease often occurs in young adults, treatment for pregnant women is of particular concern. Therapy must be effective enough to protect the mother without hurting the fetus. Treatment choice must be individualized, taking into consideration the mother's wishes, the severity and pace of the disease, and the length of the remaining pregnancy. The treatment plan may need to be changed as the pregnancy progresses.

Early in the Term. Unfortunately, an abortion may sometimes be the most prudent approach if the disease occurs in the first trimester. Chemotherapy is rarely used during that period, because it poses a risk for birth defects. Deciding on a course of action when Hodgkin's disease occurs in the first trimester is very difficult and emotionally wrenching. Prospective parents should not be shy about consulting with more than one doctor if they are uncertain about how to proceed.

Later in the Term. If the disease develops in the second half of the pregnancy, it may be possible to postpone therapy until after an early induced delivery. Alternatively, some evidence suggests that chemotherapy in pregnant women after the first trimester may be beneficial without harming the fetus. If full-dose standard chemotherapy is not deemed possible, vinblastine alone may be beneficial; this drug is not usually associated with fetal abnormalities in the second half of pregnancy.

Steroids may also be used late in the pregnancy both because of their antitumor effect and their effect in hastening fetal lung maturity. As an alternative, a short course of radiation (with extensive shielding of the fetus) can sometimes be considered prior to delivery if the mother is experiencing lung problems because of a rapidly enlarging mass in the chest. Combination chemotherapy may also be safe in the second half of pregnancy.

In one study, the 20-year survival rate of pregnant women with Hodgkin's disease was no different from that of nonpregnant women matched for similar stage of disease and age at diagnosis.

Treatment Options by Stage

Treatment is guided by the stage of the disease and usually relies on the location and extent of the disease. Treatment may vary within a stage, depending on whether it is categorized as either A or B. (Systemic symptoms are absent in "A" and present in "B.”) The presence of B symptoms increases the risk of relapse, and so may require more aggressive treatments for that stage.

Early Stages (I or II). For disease in stages I or II, the following treatments may be used:

Treatment in Adults. Doctors usually recommend radiation first for adults with HD. It provides excellent remission rates, although studies have reported a number of serious long-term complications in some patients. Selected patients in early stages may also be candidates for radiation limited only to areas above the diaphragm (called the mantle field), which can also have excellent results although still pose a considerable risk for late serious complications.
Treatment in Children. Chemotherapy and low-dose radiation is the standard treatment for most children and adolescents who have not reached full growth. Specific chemotherapy combinations have been developed to reduce the risks for infertility, leukemia, and toxic effects on the heart and lungs. Researchers are studying the use of chemotherapy alone in this group.

Later Stages. For stage III disease, chemotherapy, often with radiation, is a standard treatment. For stage IV disease, chemotherapy alone is generally recommended. The latest chemotherapy regimens are achieving survival rates that reach 90%.

Relapse. Relapse after treatment occurs in 20 - 35% of patients. Treatments for relapse include chemotherapy, radiation, and bone marrow or blood stem cell transplantation. Many patients respond favorably to such treatments, although another relapse is still possible.

Click the icon to see an illustrated series detailing bone marrow transplant surgery.

Disease is limited to a single node region (I) or has involved one neighboring area or a single nearby organ (IE). The standard treatment for stage I disease is usually radiation for adult patients who have determined the stage using pathologic staging with laparotomy. Chemotherapy with low-dose radiation is now the standard approach for children and adolescents. Cure rates can be greater than 90%.

Stage IA. Treatments depend on location. For a malignancy above the diaphragm, which does not involve a large part of the chest, the following may be used:

Radiation therapy to the mantle field (chest, neck, and arm pits) and to the lymph nodes in the upper abdomen and spleen
Radiation therapy to a mantle field in certain patients -- best candidates are females with nodular sclerosis or lymphocyte predominant cell types, who are no older than 40 years, have no "B" symptoms, and have erythrocyte sedimentation rate (ESR) levels less than 50
Radiation therapy to a mantle field, the lymph nodes in the upper abdomen, and the spleen (subtotal node irradiation)
Chemotherapy alone is under investigation

If the malignancy is bulky, above the diaphragm, and involves a large part of the chest, chemotherapy plus radiation therapy is commonly used.

If the malignancy is below the diaphragm, treatment includes chemotherapy with or without radiation. Radiation therapy may be directed to the lymph nodes in the upper abdomen and pelvis, and sometimes the spleen or groin. Total nodal irradiation is an option which includes these regions plus the mantle field.

Stage IB. Treatments depend on location. For a malignancy above the diaphragm, which does not involve a large part of the chest, the following may be used:

Chemotherapy plus radiation therapy to a mantle field (in patients who have severe symptoms and did not undergo laparotomy to determine the extent of the disease below the diaphragm)
Radiation therapy to the mantle field and to the lymph nodes in the upper abdomen is sometimes considered, but relapse rate can be high if significant B symptoms are present
Chemotherapy alone under investigation for children

If the malignancy is bulky, above the diaphragm, and involves a large part of the chest, chemotherapy plus radiation therapy is commonly used.

If the malignancy is below the diaphragm, treatment includes chemotherapy with or without radiation to the upper abdomen and pelvis, to the areas that contain cancer, or to the spleen. Total nodal irradiation or radiation to lymph nodes in the upper abdomen and pelvis is another option.

Disease is limited to two or more lymph nodes on the same side of the diaphragm (II) or involvement of a single neighboring organ or area and one or more nearby lymph nodes; other lymph nodes on the same side of the diaphragm may be involved (IIE).

There are few differences between treatments for stage IIA and IIB, and the approach for both depends on the extent and location of the disease:

Non-bulky disease:

Radiation alone for adult and possibly adolescent (especially male) patients
Chemotherapy with low-dose radiation is used for children

For a malignancy above the diaphragm, which does not involve a large part of the chest, the following may be used:

Radiation therapy to a mantle field and to the lymph nodes in the upper abdomen
Radiation therapy to a mantle field only (See Stage I Hodgkin's Disease section above)

Chemotherapy alone or with radiation therapy (combined modality) is being evaluated for those with non-bulky stage IIA. Also under investigation is radiation therapy to a mantle field only in patients with lymphocyte predominant cell types, who are no older than 40 years.

If the malignancy is above the diaphragm and does involve a large part of the chest, chemotherapy plus radiation therapy to a mantle field is the common approach.

If the malignancy is below the diaphragm, treatment includes chemotherapy with or without radiation to the upper abdomen and pelvis, and possibly the spleen. Total nodal irradiation is another option.

Disease is in lymph nodes on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an associated organ or site outside the lymph node (IIIE), by involvement of the spleen (IIIS), or by both (IIIE+S). In addition, stage III may be further categorized by the extent of its spread into the spleen or where it has spread in the abdominal area. Survival rates in some cases can be as high as 90%.

Stage IIIA. Chemotherapy is the most common treatment approach for most adults and children. Radiation may be added under certain circumstances, especially to provide localized treatment of bulky areas. (Radiation does not appear to offer any survival advantage for patients whose disease is in complete remission after chemotherapy.)

For a malignancy above the diaphragm, which does not involve a large part of the chest, the following may be used:

Chemotherapy alone
Chemotherapy with radiation therapy (combined modality)
Total or subtotal nodal radiation therapy alone -- for adults if disease is only in the upper abdomen and fewer than five nodes in the spleen are affected

If the malignancy involves a large part of the chest, the following may be used:

Standard chemotherapy alone
Chemotherapy plus radiation therapy (combined modality)
Investigative treatments

Stage IIIB. Chemotherapy alone is the standard treatment for most adults and children. Radiation is often added to treat areas of bulky tumor.

Disease has spread to organs outside the lymph system, such as liver, lung, or bone marrow. Even in this population, high long-term survival rates of over 85% are possible, including in children.

Treatment may include:

Chemotherapy alone
Chemotherapy with limited radiation to places of bulky disease
A clinical trial of investigational chemotherapy regimens or of stem-cell transplantation

Click the icon to see an image of liver involvement in Hodgkin's disease.

When disease recurs or persists after initial treatment either in the same area or in another part of the body, the next round of therapy depends on where the disease returns and the previous treatment used.

If the previous treatment was radiation therapy without chemotherapy, salvage chemotherapy is the usual choice.
If the patient was previously treated with chemotherapy, the choice may be radiation therapy to the lymph nodes with or without salvage chemotherapy.
In some patients, if the disease has persisted or if relapse has occurred after chemotherapy with or without radiation, high-dose chemotherapy and stem cell transplantation may be given.

Radiation Treatments

High-dose radiation therapy, which shrinks the tumors, has been used for more than 50 years for treating Hodgkin's disease. High-dose radiation is generally reserved for adults. Radiation treatments are highly toxic for children and appear to add little benefit. In such young age groups radiation is mostly used if there are large areas of disease in the chest; otherwise, chemotherapy with possibly low-dose radiation is the best option with excellent survival rates.

Radiation is directed to specific areas depending on the location of the disease:

If HD is above the diaphragm, “extended field radiation” is delivered to the neck, chest, and under arms (called the mantle field). Extended-field radiation is sometimes expanded to include lymph nodes in the upper abdomen.
If cancer is below the diaphragm, an "inverted Y" field is sometimes used, in which radiation is directed at lymph nodes in the upper abdomen, spleen, and pelvis.
Inverted Y-field radiation therapy combined with mantle-field radiation is called “total nodal radiation.”
"Involved field radiation" targets only lymph node regions that are known to have cancer. By contrast, extended-field radiation targets lymph node regions with cancer as well as adjacent, uninvolved lymph node regions. Involved-field radiation is usually given after several rounds of chemotherapy.

A 2006 study indicated that radiation therapy alone, without chemotherapy, may help older patients with early-stage Hodgkin’s disease. If chemotherapy is given, another 2006 study suggested that involved-field is a better option than extended-field radiation for elderly adults with early-stage unfavorable Hodgkin’s lymphoma.

In general, recent research suggests that extended-field radiation adds little survival advantage and carries a greater risk of serious side effects. Involved-field radiation is now becoming the preferred method. Some researchers recommend that involved-field radiation therapy plus chemotherapy should become the standard treatment for patients with early-stage Hodgkin’s disease who have a good prognosis. More research is needed before standard practice guidelines can be implemented.

It is very important that radiation treatments cover the entire diseased area and that the radiation therapy be powerful enough to destroy the malignant cells' capacity to grow and divide. Unfortunately, this means that normal cells are also affected, which can cause serious side effects. Different approaches may be used to prevent complications.

Devices called planning simulators allow doctors to plan x-ray treatments that accurately conform to the patient's anatomy so that protective shields can be created to precisely protect the regions outside the treatment areas.
Long-term complications generally occur at higher radiation doses (over 35 Gy). Investigators are studying the doses as low as 20 Gy (in children). Studies indicate that radiation alone in doses under 35 Gy can control the disease as well as higher doses in most stage I and II patients, although some patients may require more aggressive treatment.
To protect ovaries, a technique called ovarian transposition may sometimes be performed. The procedure uses a laparoscope (a thin tube containing tiny instruments and cameras) that is introduced through a small incision. The doctor uses the laparoscope to move the ovaries out of the range of areas being treated with radiation.

The uterus is a hollow muscular organ located in the female pelvis between the bladder and rectum. The ovaries produce the eggs that travel through the fallopian tubes. Once the egg has left the ovary it can be fertilized and implant itself in the lining of the uterus. The main function of the uterus is to nourish the developing fetus prior to birth.

Infections. Infections may be a particular problem with radiation combined with chemotherapy. All patients should be vaccinated against pneumonia and influenza.

Inflammation in the Lungs. With carefully conducted therapy, the risks for lung complications are small. Lung impairment may not even be evident, and the lungs usually recover after 2 - 3 years.

Click the icon to see an image of the lungs.

Infertility. Radiation therapy to the pelvic area can adversely affect later fertility in women and men. Such negative effects may be worse in women; sperm usually recover within 5 years.

Heart Disease and Stroke. Radiation is associated with a future risk of heart disease, which includes atherosclerosis (hardening of the arteries) and diseases of the heart valves. Lower doses pose less risk. Recent research suggests that adults who survived childhood Hodgkin’s disease have a four times higher risk of having a stroke than healthy patients.

Fatigue. Fatigue is significant and chronic in many survivors. It is more highly associated with intensive chemotherapy, but it also may be a late response to radiation treatment.

Secondary Cancers. Second cancers (such as breast, stomach, lung, melanoma) may develop later in areas within or at the edge of the radiation area. Thyroid, respiratory tract, and digestive tract secondary cancers may affect patients who were treated as children. The risks are twice as high with treatments that are combined with chemotherapy.

Lung cancer in survivors is highly associated with smoking after treatment, and no survivor should smoke. The risk for breast cancer increases significantly in young women after treatment, particularly with high radiation doses and combined chemotherapy and radiation. The risk can persist for 25 years or more after radiotherapy, and lifetime monitoring (including frequent mammograms) is essential.

Thyroid Disorders. Hypothyroidism (underactive thyroid) occurs in a number of patients treated with radiation treatments. There is also a 5% chance for hyperthyroidism (overactive thyroid).

Click the icon to see an image of hypothyroidism.

Click the icon to see an image of hyperthyroidism.

Impaired Growth in Children. Children and adolescents are at special risk for impaired bone growth.

Chemotherapy

Chemotherapy uses drugs to kill cancer cells. The drugs are called cytotoxic medications. Chemotherapy is referred to as body-wide, or systemic, therapy because the drugs travel throughout the entire body.

Cytotoxic drugs may be taken by mouth or given by injection. Treatment may be administered at a medical center, doctor's office, or even a patient's home. Some patients receiving chemotherapy may need to remain in the hospital for several days so the effects of the drug can be monitored.

Patients may receive 4 - 8 cycles of chemotherapy, depending on the stage. A cycle is usually 28 days and consists of several doses of drug administration followed by a period of rest.

The standard chemotherapy regimens for Hodgkin’s disease are ABVD and Stanford V.

ABVD consists of a 4-drug combination:

Doxorubicin (Adriamycin)
Bleomycin
Vinblastine
Dacarbazine

Stanford V consists of a 7-drug combination:

Doxorubicin (Adriamycin)
Mechlorethamine (nitrogen mustard)
Vincristine
Vinblastine
Bleomycin
Etoposide
Prednisone

BEACOPP (bleomycin, etoposide, Adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) is a chemotherapy regimen reserved for high-risk patients. This regimen is proving to be extremely effective, particularly in advanced stages, with studies reporting remission rates of over 95% in patients with advanced Hodgkin's. However, this regimen also increases the risk for developing secondary cancers such as leukemia. Patients who are treated with BEACOPP should receive long-term follow-up care to monitor for side effects from this therapy.

Side effects and complications of any chemotherapeutic regimen are common, are more severe with higher doses, and increase over the course of treatment, though some trials suggest that toxicities can be reduced by administering the drugs for shorter duration without loss of cancer-killing effects.

Common Side Effects. Common side effects include the following:

Nausea and vomiting -- drugs known as serotonin antagonists, including ondansetron (Zofran) or granisteron (Kyril), can relieve these side effects in nearly all patients given moderate drugs and most patients who take more powerful drugs.
Diarrhea
Hair loss
Weight loss
Depression

These side effects are nearly always temporary. Most patients are able to continue with normal activities for all but perhaps 1 or 2 days a month.

Serious Side Effects. Serious side effects can also occur and may vary depending on the specific drugs used. They include:

Neutropenia is a severe drop in white blood cells. Neutropenia increases the chance for infection from suppression of the immune system and is a potentially life-threatening condition. Drugs known as granulocyte colony stimulating factor (G-CSF) are used to help boost white blood cell count. These drugs, which include filgrastim (Neupogen) and pegfilgrastim (Neulasta) can help lessen the risk for neutropenia occurrence and, if neutropenia does occur, to reduce its length and severity.
Anemia is a lack of red blood cells. Erythropoietin stimulates red blood cell (hemoglobin) production and can help reduce or prevent this side effect. It is available as epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). In 2007, the FDA released strict dosing guidelines for these drugs. In patients with cancer, they should be used to only treat anemia associated with chemotherapy and to increase hemoglobin levels to no more than 12 g/dL. Treatment should stop as soon as chemotherapy is complete. These drugs may not be safe or appropriate for all patients.
Infection. Patients must take precautions against infections (see "Infection Prevention" in Transplant section).
Liver and kidney damage
Abnormal blood clotting (thrombocytopenia)
Allergic reaction

Long-Term Complications.

Fatigue and general aches and pains are called somatic symptoms. Fatigue is especially common after chemotherapy and can even last for years.
Many women stop menstruating after chemotherapy. The risk for infertility is highest for women with advanced stage Hodgkin’s disease who are treated after age 30. Studies indicate that the risk for infertility is higher with BEACOPP than with ABVD. Researchers are studying whether taking oral contraceptives during chemotherapy can reduce the risk.
Bone thinning (osteoporosis) may be related to steroid treatments such as prednisone.
Heart failure may occur with the use of anthracyclines (such as doxorubicin).
Bleomycin (Blenoxane), an antibiotic, is particularly toxic to the lungs. Vinblastine may also pose a risk when used in combination with radiation therapy.

In general, these serious late side effects are dependent on the cumulative drug dose and rate of administration.

Regimens. Chemotherapy (usually ABVD) plus radiation, referred to as combined modality, is a common treatment approach for patients with more advanced-stage disease and for those who have early-stage bulky (large mass) disease.

Chemotherapy with low-dose radiation is being used in children with excellent results, even for late stage cancer. In one study, 82% of the children were still disease free at 5 years. Some chemotherapy drugs or high doses of radiation may be more deleterious to a boy's future fertility than to a girl's. A gender-specific combined regimen for pediatric Hodgkin's reduces the amount of radiation given to boys and also substitutes etoposide for procarbazine in the chemotherapy mixture (procarbazine, vincristine, prednisone, and doxorubicin).

Side Effects and Long-Term Complications. Side effects of combination treatments can be very serious. Examples include:

Combined modality poses a higher risk for secondary cancers than the use or radiation or chemotherapy alone. They include breast, lung, thyroid, melanoma, and gastrointestinal cancers, which usually develop in near or in the areas treated with radiation. Of note, the risk for breast cancer is lower when chemotherapies using alkylated drugs or radiation treatments damage the ovaries, suggesting that hormone stimulation plays a role in this higher risk. Newer drugs used in combined modalities may reduce the risk, at least for breast cancer.
ABVD and other regimens containing bleomycin increase the risk for severe effects on the lungs when used before or after mantle-field radiation. EVA (etoposide, vinblastine, and doxorubicin) is considered to be an effective substitute in patients with lung disease for whom bleomycin and radiation present an unacceptable risk.

Transplantation

Patients with relapsed or progressive HD are often treated with high-dose chemotherapy followed by stem cell transplantation procedures. (Transplantation does not appear to offer an advantage compared to standard chemotherapy as initial treatment for patients with high-risk advanced HD.)

This treatment involves removal and replacement of stem cells, which are produced in the bone marrow. This allows the patient to receive high-dose chemotherapy without destroying these important cells. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments harm growing cells as well as cancer cells, and so the healthy stem cells must be replaced by transplanting them.

For Hodgkin’s disease, the most common type of transplant is an autologous procedure, using the patient’s own cells. An allogeneic transplant, using cells from a donor, is more risky for patients with Hodgkin’s disease and is generally used only when an autologous transplant has failed. (This section provides information pertinent to autologous procedures. Detailed information on allogeneic transplants, including such complications as graft-versus-host-disease, can be found in In-Depth Report #84: Non-Hodgkin’s Lymphoma.)

Stem cells must first be collected in one of the following ways:

Directly from blood (peripheral blood stem cell transplantation)
From bone marrow (bone marrow transplantation)

Click the icon to see an illustrated series detailing bone marrow transplant surgery.

Stem cells are collected several weeks before the procedure. They are frozen and stored while the patient undergoes high-dose chemotherapy. Some patients receive high-dose whole body radiation therapy along with chemotherapy.

After the patient completes the pre-transplant therapy, the frozen cells are thawed and then infused into the patient. Within a few weeks, these cells start to generate new white blood cells and then new red blood cells.

The risk for infection greatest during the first 6 weeks following the transplant. During this period, a patient usually remains in isolation and receives antibiotics and intravenous nutrition. It takes 6 - 12 months post-transplant for a patient’s immune system to fully recover.

It is very important that patients take precautions to avoid infections. Guidelines for infection prevention include:

Discuss with your doctor what vaccinations you need and when you should get them.
Avoid crowds, especially during cold and flu season.
Be diligent about handwashing, and make sure that visitors wash their hands.
Avoid eating raw fruits and vegetables -- food should be well cooked. Do not eat foods purchased at salad bars or buffets. In the first few months after the transplant, be sure to eat protein-rich foods to help restore muscle mass and repair cell damage caused by chemotherapy and radiation.
Boil tap water before drinking it.
Dental hygiene is very important, including daily brushing and flossing. Schedule regular visits with your dentist.
Do not sleep with pets. Avoid contact with pets’ excrement.
Avoid fresh flowers and plants as they may carry mold. Do not garden.
Swimming may increase exposure to infection. If you swim, do not submerge your face in water. Do not use hot tubs.
Report to your doctor any symptoms of fever, chills, cough, difficulty breathing, rash or changes in skin, and severe diarrhea or vomiting. Fever is one of the first signs of infection.
Report to your ophthalmologist any signs of eye discharge or changes in vision. Patients who undergo radiation or who are on long-term steroid therapy have an increased risk for cataracts.

Common side effects of stem cell transplants include nausea, vomiting, fatigue, mouth sores, and loss of appetite.

The procedures themselves are fairly dangerous and carry a small risk for death. When it was first used, transplantation procedures had 10 - 25% morality rates. Now mortality rates are below 5%.

There is a small long-term risk for leukemia after transplantation in young people. Chemotherapy itself increases the risk of secondary cancers. Recent studies suggest that transplantation after chemotherapy does not add any additional risks. In addition, use of newer chemotherapeutic drugs may not pose as high a danger as older treatments.

Other serious potential complications include:

Bleeding because of reduced platelets (highest risk within the first 4 weeks); blood transfusions may be required
Infertility
Organ complications to the liver, heart, kidney, or lungs
Failure of the transplant
Muscle problems including stiffness, cramps, and joint pain
Frequent urination and bladder control problems
Older patients should be screened for osteoporosis (bone thinning) and hypothyroidism (underactive thyroid)

Immunotherapy

Investigational approaches to Hodgkin's disease include immunotherapies, which are drugs that take advantage of the patients' own immune factors to attack the disease.

One important approach uses genetically designed immune factors called monoclonal antibodies (MAb) that recognize and attack specific molecules found on the surface of cells associated with HD.

Rituximab (Rituxan) was the first monoclonal antibody to be approved for any cancer. It is an unconjugated MAb that targets the CD-20 antigen, which is found on most B-cell lymphomas and normal mature B cells (although not stem cells). It is used in non-Hodgkin's lymphomas, but it may have benefits for some patients with Hodgkin's disease as well.

Resources

www.cancer.gov -- National Cancer Institute
www.cancer.org -- American Cancer Society
www.lymphoma.org -- Lymphoma Research Foundation
www.leukemia.org -- Leukemia and Lymphoma Society
www.canceradvocacy.org -- National Coalition for Cancer Survivorship
www.asco.org -- American Society of Clinical Oncology
www.plwc.org -- People Living with Cancer
www.marrow.org -- National Marrow Donor Program
www.oncolink.org -- Cancer information
www.lymphomainfo.net -- Lymphoma Information Network
www.cancer.gov/clinicaltrials -- Find clinical trials

References

Fermé C, Eghbali H, Meerwaldt JH, et al. Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med. 2007 Nov 8;357(19):1916-27.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Hodgkin Disease / Lymphoma. V.1.2007.

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