Cancer patients are at risk for various viral, bacterial, and fungal infections, but there are preventive measures that can reduce the possibility of such complications.
Patients with cancer can experience multiple levels of immunodeficiency, explained Brahm Segal, MD, Chief of the Division of Infectious Disease at Roswell Park Cancer Institute. “There are different infection prevention recommendations for different patients. There are differences in which people require antibiotics and which require precautions involving their lifestyle. Some patients will require one type of prophylaxis, while others may require simultaneous agents—It's a matter of assessing the level of risk in the individual patient.”
Infection risk among patients with cancer depends on the type of malignancy they have and the treatment they receive, noted Jeremy Young, MD, MPH, an infectious disease specialist at the James Cancer Hospital and Solove Research Institute at Ohio State University.
For example, patients with leukemias such as acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and chronic lymphocytic leukemia (CLL) are at an increased risk of infection because of low counts of healthy white blood cells, and AML, in particular, results in prolonged neutropenia, putting patients at an especially high risk of infection.
Disease treatments such as chemotherapy and bone marrow transplant can also lower white blood cell counts, further immunocompromising patients.
Moreover, Dr. Young said, graft-versus-host disease (GVHD), a common side effect of allogeneic transplantation, as well as medications such as prednisone and tacrolimus used to decrease the effects of GVHD lead to a compromised immune system.“We see many infections, such as invasive mould infections, several months to years after stem cell transplants due to ongoing GVHD.”
The immune system recovers more quickly with an autologous transplant because it uses the patient's own stem cells, noted Steve Devine, MD, also at the James, where he is Director of the Blood and Marrow Transplant Program. Patients who receive an autologous transplant may need to use precautions to avoid infection for about a month, while those with allogeneic transplants may need to be careful for three to six months or even longer if they remain on immunosuppressive drugs, especially if they have GVHD.
Patients with solid tumors such as those of the lung, breast, and colon have a slightly higher risk of infection than someone with a normal immune system because chemotherapy can lower white blood cell counts. Still, the counts tend to improve after treatment, Dr. Young noted.
Because of the lower degree of immunocompromise, the screening process and infection prophylaxis in patients with solid tumors isn't quite as rigorous as that for individuals with blood cancers, he explained.
Comprehensive Control Plans Vital
The most important component of preventing infection in patients is a comprehensive infection-control program, said Corey Casper, MD, MPH, Medical Director of Infection Control at the Seattle Cancer Care Alliance/ Fred Hutchinson Cancer Research Center (FHCRC) and Assistant Member of the Vaccine and Infectious Disease Institute at FHCRC. “If you're a single practicing physician, it makes no sense to have an entire program, but the same infection control concepts apply.”
Generally, larger institutions have comprehensive programs that can track infections by the day or month, he noted. This lets physicians know what types of infection to anticipate, whether it's a severe outbreak of a respiratory illness in transplant patients or seasonal influenza.
Bone marrow transplant programs take a number of precautions to help patients avoid infection. Although these precautions may vary somewhat from center to center, several offer prophylactic antiviral, antibacterial, and antifungal treatments to prevent infection, Dr. Devine said.
For example, said John Greene, MD, Section Chief of the Division of Infectious and Tropical Diseases at H. Lee Moffitt Cancer Center and Research Institute and the hospital's epidemiologist, patients there are primed months in advance of their transplant to be infection free. All patients scheduled to undergo an allogeneic transplant get an infectious disease consult.
Eighty to 90 percent of individuals are able to go through a standard infection prevention protocol, he said. About 10% to 20% may need different antibiotics tailored to specific active infections or to prevent infections that developed during prior episodes of neutropenia and that may likely recur after the transplant. Examples include prior neutropenic enterocolitis, Clostridium difficile colitis, and disseminated Candida or mould infections, which may resurface after the transplant.
Physicians can also prevent life-threatening infections with judicious use of prophylactic and empiric antibiotics, Dr. Greene added, noting that overall, infection prevention should be tailored to the individual.
Physicians usually screen immunocompromised patients for viral infections and prescribe prophylactics when needed, said Lindsey Robert Baden, MD, Clinical Research Director in the Division of Infectious Disease at Brigham and Women's Hospital in Boston.
For example, Dr. Devine said, patients at the James set to receive an allogeneic or autologous transplant are screened for prior exposure to herpes simplex virus (HSV), cytomegalovirus (CMV), hepatitis B and C, and varicella. Some transplant programs monitor patients for signs of reactivation of these infections or will offer upfront prophylactic treatment—for example, acyclovir is used to prevent HSV reactivation.
At Moffitt, Dr. Greene said, patients are screened for CMV on a weekly basis shortly after allogeneic bone marrow transplantation and given preemptive oral valganciclovir if the polymerase chain reaction (PCR) CMV test detects more than 1,000 copies of CMV/cc of blood. During further follow-up patients are tested once a week for CMV DNA by PCR or other antigen-detection systems.
Another prophylactic option, Dr. Young said, is the antiviral drug maribavir (Camvia), granted Orphan Drug status last year for prevention of CMV disease.
Even if allogeneic bone marrow recipients are CMV negative, they can acquire a new CMV infection from their donors.“This is actually the highest risk category for acquiring CMV—those who have undergone allogeneic transplants where the donor is CMV positive and the recipient is CMV negative,” he said.
While donors for allogeneic transplant are screened for viral infections, they may not automatically be prohibited from donating bone marrow if they test positive, Dr. Devine said. Unless a CMV-negative donor is found, CMV-positive donors may be allowed to give bone marrow, and because donors are often difficult to match to recipients, exclusion may not be an option.
“We do not exclude for HSV or varicella but might if the donor had hepatitis B,” Dr. Devine said. “It would depend on whether the donor had active virus growing in their blood.” If donors test positive for HIV, they are excluded.
Progress has been made in screening and preventing the spread of fungal infections over the last several years.
For instance, Dr. Greene and his colleagues use a baseline computed tomography (CT) scan of the chest to see if immunocompromised patients, namely those with acute leukemia, many of whom are scheduled for bone marrow transplant, have a mould infection that is not causing a lot of symptoms or is left over from prior chemotherapy treatments.
Because CT scans that are performed about every two weeks during the neutropenic period can pick up early small fungal nodules such as Aspergillus or Fusarium, physicians can provide prompt antifungal treatment, allowing the patient to receive a clinically indicated transplant as soon as possible.
Treatment with the newer, more effective and less toxic antifungals can help to shrink larger infections down to small sizes in shorter amounts of time, he said.
Five to 10 years ago, fungus might not have been detected until it was much larger and required one to three months of treatment. During this time, leukemia might relapse, disqualifying the patients as a candidate for bone marrow transplant. Some larger growths would require resection.
“We also perform CT scans when indicated after transplant and compare them with the baseline scan to detect new nodules that are suspicious for mould infections,” said Dr. Greene, adding that surveillance can continue for six to 12 months after transplant.
Physicians also use antifungals to prevent infection in immunocompromised patients, who can readily pick up fungi from the environment, Dr. Young said. For example, the drug posaconazole is indicated to prevent infection with Aspergillus and Candida and is also active against Histoplasma capsulatum.
Patients who have undergone allogeneic transplantation and have GVHD are at particular risk of developing fungal infections and GVHD itself, and the steroids used to decrease the effects of GVHD lead to a compromised immune system.
And Dr. Greene said that individuals who receive high-dose corticosteroids for acute GVHD should be placed on the antifungal voriconazole to prevent mould infections.
Hospitals and bone marrow transplant centers also actively seek to prevent bacterial infections in immunocompromised patients.
Some physicians may give prophylactic gram-positive drugs upfront depending on the rates of infection in their center, Dr. Devine said. For example, if a center has problems with Streptococcus or Staphylococcus aureus, they may choose this route. “Others may not treat patients until they develop fevers—which is empirical therapy,” he explained.
A major problem plaguing bone marrow patients with neutropenia is central venous catheter infection, Dr. Greene said. Consequently, patients receive prophylactic doxycycline, which kills skin bacteria, during the one to two weeks when the catheter is new, and this reduces infection some five- to 10-fold.Dr. Greene said he and his colleagues almost never have to remove catheters due to infections now that this change in practice has been implemented.
To prevent gram-negative infections such as Escherichia coli, Klebsiella and Pseudomonas, prophylactic levofloxacin (Levaquin) can be helpful, he said.
However, he added, Moffitt Cancer Center is seeing increasing breakthroughs of resistant E coli bacteremia in neutropenic leukemia patients receiving levofloxacin prophylaxis.
“We're losing the quinolones, because the susceptibility of gram-negative rods, especially E coli, to Levaquin has been dropped from about 95% 10 years ago to about 50% currently. It's not a good fight.”
Patients who develop neutropenic fever despite prophylaxis with doxycycline and levofloxacin receive empiric therapy with vancomycin and cefepime.
The cancer center also screens all patients going into induction chemotherapy, whether for acute leukemia or allogeneic or autologous transplant, for methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococci (VRE) colonization, Dr. Greene noted.
If patients are colonized with MRSA, the doxycycline they have been taking to prevent central line infections will likely be effective against MRSA central venous catheter infections or bacteremia, he added. “No one really knows what to do with patients colonized with VRE.”
Some centers will give prophylactic daptomycin for VRE coverage, while others will give empiric daptomycin therapy in patients colonized with VRE to prevent bacteremia.“We're investing whether daptomycin should be given prophylactically with neutropenia to prevent breakthrough infections,” he said.
Still, Dr. Baden cautioned, while hospital infection control precautions can help prevent MRSA and VRE, the antibiotics administered to treat these infections today may not work years from now.
Dr. Young and his colleagues do not use prophylactic antibiotics in immunocompromised patients as much as they used to due to antibiotic resistance, he said.
However, to help combat bacterial infections, the bone marrow transplant unit at the James Cancer Hospital has a pilot project that screens patients at admission and on a weekly basis for MRSA and VRE, whether or not the patient has symptoms.
If patients test positive for colonization with no signs or symptoms of infection, they are put into contact isolation, and health care workers take typical precautions, such as frequent hand washing and putting on a gown and gloves before entering the room and removing these items when they leave. If patients have active infection they are also given antibiotics.
Infections such as Pseudomembranous colitis caused by Clostridium difficile may also require putting patients into isolation, he said.
Another important part of preventing infection is to ensure that patients are vaccinated for certain illnesses.
Generally, patients should be up to date on their vaccines before treatment—“although if the vaccine consists of a live virus, such as with Yellow fever, we won't give it,” Dr. Young said.
Varicella zoster vaccine is another live vaccine that should be avoided because of the risk of vaccine-associated infection, noted Dr. Segal.
Flu shots are strongly recommended in patients with cancer, and family members and health care workers should also be immunized because they can transmit the disease to the patient, he said.
The actual antibody response to an influenza vaccine may be reduced in immunocompromised individuals, although some protection is better than no protection. Patients undergoing chemotherapy may not experience a protective response with a flu shot because of suppressed white blood cell counts, he said.
Getting vaccinated between rounds of chemotherapy is sometimes effective because the patient is more likely to have some sort of antibody response, Dr. Greene said. Aggressive bone marrow transplant protocols call for vaccination of all allogeneic patients one to two years after transplantation when they are able to mount an immune response.
Other vaccinations may also be needed to reduce a patient's infection risk, Dr. Segal said. Individuals with an impaired ability to mount antibody responses—for example, those with multiple myeloma and CLL, or those without a spleen—are at particularly high risk for infection with Pneumococcus and other encapsulated bacteria, he explained. Allogeneic stem cell transplant recipients with chronic GVHD are also at high risk for pneumococcal disease.
The Centers for Disease Control and Prevention recommends pneumococcal immunization for patients with impaired immunity, which includes those receiving cancer treatment.
“It's best to immunize at least two weeks prior to starting treatment or having a splenectomy,” he said. “If this is not feasible, I would administer pneumococcal immunization with the understanding that the protection may be incomplete and repeat immunization may be required.”
In addition to immunization, penicillin prophylaxis is commonly administered toasplenic patients and allogeneic stem cell transplant recipients, particularly those with chronic GVHD.
What Patients Can Do to Avoid Infection
After transplantation, immunocompromised patients are given a series of recommendations to help them avoid infection, said Corey Casper, MD, MPH.“Assuming there aren't complications, it can take one to two years for the patient's immune system to fully restore itself.”
Common sense can help outpatients avoid infection, said Lindsey Robert Baden, MD, noting, for example, that some of the best precautions are hand washing and minimizing contact with people who are sick.
People with significant levels of immunocompromise should follow CDC guidelines and avoid unpasteurized dairy; undercooked poultry, meat, and fish; and be aware of local outbreaks of foodborne illnesses such as E coli and Salmonella, said Brahm Segal, MD.
Most patients are on low bacterial diets during the time of transplant, said Steven Devine, MD. “We provide instructions to wash food thoroughly and avoid raw or uncooked foods, in addition to avoiding well water,” he said.“They drink bottled water instead.”
Patients can also take precautions to avoid fungal infection. Because Histoplasma capsulatum, which causes Histoplasmosis, and Aspergillus, which causes Aspergillosis, are both found in soil and decaying organic matter, Jeremy Young, MD, MPH, advises his patients not to garden or do other yard work.
Patients should also know the typical signs and symptoms of infection: fever, chills, and sweats are of concern, especially if the patient just had chemotherapy, he said.
All other signs and symptoms of infection are particular to the organ infected. For example, painful urination could be a sign of a urinary tract infection, a bad cough could be a symptom of pneumonia, and profuse diarrhea could be a symptom of Clostridium difficile, he explained.
Such patient precautions in addition to screening and administering prophylactic treatments can help to reduce the overall risk of infection.