(Page 81)
The air we breathe, the food we eat, the hands we shake, the items we touch - everything we contact in daily life is a potential source of bacteria, viruses or fungi that can cause infection. For a normal, healthy individual these daily encounters with sources of infection are not a major problem. The body and its immune system work to protect the body from infections or efficiently destroy them if they enter the body.
For BMT patients, however, it's a different story. The chemotherapy and/or radiation administered prior to a BMT cannot distinguish between cancerous and normal cells, and thus attacks not only the cancer or diseased bone marrow, but disrupts the patient's immune system as well. Skin and mucous membranes, the body's first line of defense against infection, may be damaged. White blood cells, part of the body's internal defense team, are destroyed. Special proteins called "antibodies" that normally help destroy bacteria and viruses such as measles or chicken pox are depleted. Until the transplanted bone marrow engrafts and produces new white blood cells, BMT patients are extremely vulnerable to infections that in some cases can be life threatening.
The first two to four weeks after the transplant is a particularly critical time as the transplanted bone marrow migrates to the cavities of the large bones and begins producing new white blood cells. Although the risk of infection steadily declines once the transplanted marrow begins producing new white blood cells, most patients' immune systems remain "compromised" (not functioning at 100 percent efficiency) for six months to a year after the transplant, and often longer for patients with graft- versus-host disease.
During the first month post-BMT, the risk of infection is the same for both autologous and allogeneic BMT patients. Thereafter, allogeneic BMT patients, especially those with GVHD, are more likely to developinfections than autologous BMT patients. GVHD prolongs the period of time during which the immune system is compromised and the patient remains susceptible to infection.
Although post-transplant infections are a serious cause for concern, great strides have been made over the past ten years to better manage and prevent infections, and deaths from infections have declined significantly.
The immune system is the body's defense network against infection and disease. Many organs, tissues, cells, and proteins make up the immune system, each with a specific role to play in the body's defense.
Skin and the mucous membranes lining the mouth and nose provide the body's first line of defense against invading organisms and foreign substances, and repel millions of harmful organisms daily. If a cut occurs, infectious organisms can invade the body, causing white blood cells or "leukocytes" to spring into action.
Leukocytes patrol the body via the bloodstream or the lymph system and take up residence in tissues, seeking out and destroying foreign matter that invades the body. (The lymph system is a network of vessels running alongside the bloodstream, which transport cells and waste products of the immune system.)
Leukocytes evolve from "stem cells," which are produced in the bone marrow. Those that play a key role in protecting the body against infection, disease, and other foreign substances are lymphocytes, macrophages, monocytes, neutrophils, and natural killer cells.
There are two kinds of lymphocytes: "T - cells and T- cells." T-cells recognize foreign particles in the body, orchestrate their destruction, and shut down the "immune system response" or attack once the foreign matter has been
Viruses, parasites and bacteria that invade the body are composed of cells. On the surface of each cell are genetic markers called "antigens." The immune system knows which antigens belong in a person's body and which do not. When "helper" T-cells spot a foreign antigen in the body, they stimulate the production of "killer" T-cells, which engulf and destroy the invading cell. "Suppressor" T-cells shut down the immune system attack once the foreign cell is destroyed.
Helper T-cells can also order the second type of lymphocytes-B-cells- into action. Helper T-cells point out foreign antigens to the B-cells which, in turn, manufacture a Y-shaped protein called an "immunoglobulin" or "antibody." The antibody zeroes in on the antigen and attaches to the surface of the invading cell. The antibody then summons the ''complement system"-a group of proteins circulating in the bloodstream-to surround the cell and dissolve a hole in it. This process is called cell lysis. When the dissolution is completed, other white blood cells clean up the remains of the destroyed cell, and suppressor T-cells shut down the B-cell activity.
Over the course of a lifetime, millions of antibodies are produced by B-cells. Once an antibody has been produced, it circulates through the body for many years, making the body "immune" to further attacks by that particular antigen.
Monocytes, macrophages, and neutrophils are often referred to collectively as "phagocytes." These scavenger cells engulf and destroy some invading particles, and clean up the remains of others that have been destroyed by T-cells or B-cells. Natural killer cells are another type of leukocyte that can recognize and destroy some tumor cells.
To function properly, the immune system needs all types of white blood cells in sufficient quantity and in the proper ratio in the bloodstream. If the bone marrow, which produces white blood cells, malfunctions or is destroyed, the body can no longer fight off serious and sometimes fatal infections.
Bacteria are microscopic organisms that invade tissues and multiply rapidly. Bacteria can cause infections anywhere in the body, and are the usual cause of ear and sinus infections, as well as bronchitus.
Bacteria secrete poisonous chemicals called "toxins" that interfere with normal organ functions. Toxins can, among other things, cause shock or low blood pressure that can lead to death if insufficient oxygen is provided to the heart or brain.
Bacteria can also disrupt normal organ functions by their sheer number. Some pneumonias, for example, are caused by rapidly multiplying bacteria which fill up the spaces in lungs where air is normally absorbed into the body.
Bacterial infections are most common during the first two to four weeks following a BMT, occurring in 50 percent of patients. The chemotherapy and/or radiation administered prior to the transplant impair a patient's ability to fight bacterial infections in three ways.
First, the skin and mucous membrane barriers which normally prevent bacteria from entering the body are damaged. Second, neutrophils-the white blood cells responsible for fighting bacteria-are destroyed, making patients "neutropenic." Third, antibodies that once made the patient immune to certain bacterial infections are depleted.
Post-BMT bacterial infections occur most often in intestines, on the skin (especially around the central line), and in the mouth. They also occasionally occur in the bladder and can cause pneumonia in the lungs.
To combat bacterial infections, large doses of antibiotics such as aminoglycosides, penicillins, cephalosporins or vancomycin are usually administered during the first few weeks post-transplant if the patient's temperature rises above 101. Patients bathe or shower daily to remove bacteria from their skin. Careful oral hygiene to destroy bacteria in the mouth is generally required. Soft toothbrushes or sponges are used to clense the gums and teeth so that cuts through which bacteria, fungi and viruses may enter can be avoided.
Hospital staff and visitors carefully wash their hands with antiseptic soap prior to touching the patient (since hands are a primary carrier of infectious agents), and may also wear protective masks, gowns or gloves while in the patient's room. Flowers and plants (both live and dried) which can harbor harmful bacteria or fungi are not permitted in the room while the patient is neutropenic. Similarly, fresh fruits and vegetables are eliminated from the patient's diet until the immune system begins functioning properly.
When detected promptly and treated with antibiotics, bacterial infections are usually not fatal.
Fungi are primitive life forms that we encounter daily. Bread mold is an example of a common fungus. Most are harmless and some, such as the fungus called Candida, normally reside inside our bodies.
Fungal infections are common in BMT patients during the first three months post-transplant, particularly among allogeneic BMT patients with graft-versus-host disease. Ironically, while the widespread use of antibiotics post-transplant has successfully reduced the incidence of harmful bacterial infections, these antibiotics may also destroy beneficial bacteria in the body that keep fungi in check.
Fungal infections are very difficult to detect and treat. Candida and Aspergillus infections are the most common post- transplant fungal infections.
Candida fungi live in the intestines, mouth and vagina and are normally kept in check by bacteria. When bacteria are destroyed by antibiotics, however, the fungus can multiply and spread, infecting many parts of the body.
Aspergillus infections occur most often in the sinus passages or lungs, and can cause pneumonia. Aspergillus fungi are frequently found around construction sites or where buildings are being remodeled.
At some BMT centers, special air-filtering equipment is installed in patients' rooms to remove fungi from the air. Eliminating fresh plants, fruits and vegetables from the patient's environment also reduces the risk of fungal infections.
MONTHS 2-3
MONTHS 4-12
* More common following allogeneic BMTs than autologous BMTs, particularly in patients with graft- versus-host disease.
Amphotericin B, an anti-fungal medication, is usually given to patients who have continuous fevers after taking antibiotics in an attempt to control the develope ment of fungal infections. Research is underway for other anti-fungal treatments since amphotericin B may be toxic and can interfere with the effectiveness of drugs given to control
graft-versus-host disease. A drug called fluconazole has been shown to be effective in treating Candida infections in clinical trials and is now often used as a preventive medication.
Historically, Aspergillus infections have been difficult to treat and infected patients have often died. New techniques used to diagnose Aspergillus infections earlier, as well as the use of amphotericin B have helped reduce the number of deaths from Aspergillus infections.
Viruses are tiny parasites, smaller than bacteria, that are not self-sufficient. They must invade other organisms, such as human cells, in order to survive and multiply. Viruses tinker with the genetic machinery of the "host" cell, turning it into a factory for the production of more of the virus. The virus eventually destroys or cripples the host cell and moves on to neighboring cells to continue its reproduction and destruction.
Infections caused by viruses are very difficult to treat. Because few effective anti-viral medications are available, healthy individuals rely on T-cells and antibodies produced by B-cells to keep invading viruses in check. Several anti-viral agents such as acyclovir and ganciclovir are useful, but the number of viruses they effectively treat is small.
Viral infections following a BMT can occur either as a result of exposure to a new virus or reactivation of an old virus dormant in the patient's body. The chemotherapy and/or radiation administered to the patient prior to the transplant destroys T-cells and depletes antibodies responsible for keeping viruses in check.
Viral infections are most common during the first 12 months following a BMT, but may occur as late as two years post- transplant. Those most commonly seen in BMT patients are caused by the herpes simplex virus (HSV), cytomegalovirus (CMV), and varicella zoster virus (VZV).
Herpes simplex infections are caused by two separate viruses: Herpes 1 and Herpes 2. "Oral herpes" (the Herpes 1 virus) causes painful fever blisters around and in the mouth. "Genital herpes" (the Herpes 2 virus) causes painful blisters on the genitalia and/or rectum.
An estimated 70 percent of Americans are exposed to the Herpes 1 virus, usually during childhood. The virus is highly contagious and is usually transmitted through contact with persons having active herpes sores on their mouths. Herpes 2, on the other hand, is usually transmitted through sexual intercourse with an infected partner.
Herpes infections often recur after the initial episode. The virus can lay dormant in the body for many years, flaring up at predictable or unpredictable intervals. Even if a person does not recall having had an active case of herpes, the virus may nonetheless be present in the body.
Herpes infections usually occur during the first month following a BMT. They're almost always caused by a herpes virus present in the body prior to the transplant.
In addition to the usual mouth sores associated with a Herpes 1 infection, skin lesions are sometimes associated with a Herpes 1 infection in BMT patients. In rare cases, a Herpes 1 infection can occur in the brain.
Herpes simplex is one of the viruses that responds well to treatment with anti-viral agents. Acyclovir taken orally or administered intravenously is the usual treatment. Most centers now administer prophylactic (preventive) doses of acyclovir, which has greatly reduced the incidence of post-transplant herpes infections.
CMV or cytomegalovirus is a common cause of infection in BMT patients. Approximately 30 percent of patients undergoing a BMT develop a CMV infection, usually during the second or third month following the transplant.
CMV infections can develop in several different organs including the liver, colon, eye, and lungs. Although all CMV infections are cause for concern, CMV pneumonia is particularly worrisome because it's usually fatal. A CMV infection in the intestines is often fatal as well.
Approximately half the general population is exposed to CMV during their lifetime, particularly urban dwellers. Doctors can test a patient's blood prior to transplant to determine whether or not CMV is present in their body. If it is not, the patient is "CMV-negative" and care is taken to prevent exposure to CMV before, during and after the transplant. If possible, a CMV-negative bone marrow donor is used. Blood products given to patients are often screened to ensure they are CMV-negative before being infused into patients. Alternatively, some BMT centers administer intravenous immunoglobulin when CMV-negative blood products are not available.
Patients who test positive for CMV prior to transplant are twice as likely to develop a CMV infection post-transplant than those who test negative. Patients undergoing an allogeneic BMT are more likely to develop a CMV infection than autologous BMT patients, particularly if they receive bone marrow from a mismatched donor.
Some two to four percent of autologous BMT patients, and approximately 10 to 20 percent of allogeneic BMT patients develop CMV pneumonia. The risk of developing CMV pneumonia increases with age and among patients with graft-versus-host disease.
Recent studies suggest that a new drug called ganciclovir used in combination with intravenous immunoglobulin can effectively treat CMV pneumonia. Other studies are underway to determine whether ganciclovir is an effective preventive therapy for CMV infections.
Varicella Zoster virus (VZV) is sometimes referred to as "shingles" or "herpes zoster." It is the same virus that causes chicken pox. Twenty to 40 percent of BMT patients develop a VZV infection during the first year post-transplant, usually after the third month. VZV infections occur most frequently in allogeneic BMT patients with graft-versus-host disease, but are common among autologous BMT patients as well.
VZV infections manifest themselves in one of two ways. The first involves an itching, blistering skin rash extending along any one of the body's nerve branches. The nerve endings under the skin at the site of the rash are infected and can cause great pain.
The second involves the ophthalmic nerve or nerve to the eye. A painful rash may occur along the nerve path on the forehead and eyelids and, if not treated promptly, can damage the eye.
VZV infections are usually treated with acyclovir intravenously over a seven-day period. They are quite contagious, and a hospital stay is usually required for treatment. While in the hospital, medications such as Tylenol, codeine or morphine may be administered to control pain. Early treatment can reduce the pain associated with VZV infections. VZV infections are not fatal if treated promptly.
A VZV infection can occur more than once post-transplant. The itching and/or pain associated with a VZV infection continue long after all clinical signs of the disease disappear.
Acyclovir given to prevent herpes and CMV infections can also be effective in the prevention of VZV infections. Since VZV infections are highly contagious, patients who have never had chicken pox or who've had a negative blood test for VZV should avoid people with chicken pox or VZV infections for the first year following a BMT.
Other viruses such as adenovirus, papovavirus, Epstein-Barr virus (EBV), respiratory syncitial virus (RSV), and human papilloma virus (HPV) can also create problems post-transplant, although the incidence of these infections is quite low. Adenovirus and RSV infections can cause fatal pneumonia. Adenovirus can also cause infections in the kidneys or gastrointestinal tract and bleeding in the urine. In rare cases, the Epstein-Barr virus infects the lymph system of allogeneic BMT patients, creating a lymphoma-like condition which is often fatal. The likelihood of developing these viral infections can be greatly reduced by limiting contact with the public post-transplant, wearing face masks, and meticulous hand washing.
There are several steps BMT patients can take to minimize the risk of infections:
Protozoa are single cell parasites that feed on organisms such as human cells to survive. T-cells provide the primary defense against protozoan infections. Although infections from protozoa are less common than bacterial or viral infections, they can pose serious problems for BMT patients who are T-cell deficient.
One protozoan called Pneumocystis carinii often lurks harmlessly in the trachea or windpipe of healthy human beings. When a person's immune system becomes suppressed, however, this protozoan may enter the lungs and grow into tiny cysts which cause pneumonia. Bactrim or Septra and pentamidine are highly effective in preventing and treating Pneumocystis carinii pneumonia.
Another infection called toxoplasmosis occasionally develops in patients post-BMT. Toxoplasmosis is caused by a protozoan called Toxoplasma gondii, which is often transmitted in the feces of cats. Toxoplasmosis may infect the brain, eyes, musdes, liver and/or lungs. A painful, inflamed retina in the eye is a common manifestation of the disease, which, without prompt treatment can result in damage to the eye. With early diagnosis and proper treatment, toxoplasmosis is seldom fatal.
It's tempting to throw caution to the wind after a BMT and ignore the threat of infections. Keep in mind, however, that bacteria, viruses and fungi that are harmless to most people can cause very serious and sometimes fatal infections in BMT patients whose immune systems are not fully recovered post-transplant. Don't take chances.
Avoiding sources of infection post-BMT can be inconvenient and frustrating, but a few months of caution are well worth saving your life.
Click for "Bone Marrow Transplants" table of contents
This document was created by NYSERNet, Inc. through a grant funded by the New York State Science and Technology Foundation as part of the Breast Cancer Infomation Clearinghouse.