Risk Assessment in the Immunocompromised Traveler

The main risk for the immunocompromised traveler is a complication or exacerbation of the underlying disease. In addition, endemic infectious diseases that may be acquired at the destination(s) may cause disease of increased severity in the traveler. Each proposed preventive intervention must be examined from two perspectives: 1) safety in the context of the underlying illness and the medication(s) being taken; and 2) the possibility of decreased effectiveness of the intervention (1,2). The medical provider should ensure that the traveler under-stands the risks involved of the proposed itinerary, based on his/her medical needs and the traveler’s individual tolerance for the risks of the proposed interventions and of the travel itself.

Specific Immunocompromising Conditions

The degree to which a person is immunocompromised should be determined by a health-care provider. For practical purposes, immunocompromised travelers can be categorized into one of four groups, each with a general approach.

Severe Immunocompromise (Non-HIV)

Persons considered as having severe immunosuppression include those who have active leukemia or lymphoma, generalized malignancy, aplastic anemia, graft versus host disease or congenital immunodeficiency, or persons who have received current or recent radiation therapy, solid organ transplant, or bone marrow transplant within 2 years of transplantation; or persons whose transplants are of longer duration but who are still taking immunosuppressive drugs. For solid organ transplants, much higher risk of infection occurs within the first year of transplant, so high-risk travel might be postponed until after that time.

Medications that cause severe immunosuppression include high-dose corticosteroids, alkylating agents (e.g., cyclophosphamide), antimetabolites (e.g., azathioprine, 6-mercaptopurine), transplant-related immunosuppressive drugs (e.g., cyclosporine, tacrolimus, sirolimus, and mycophenolate mofetil), mitoxantrone (used in multiple sclerosis), and most cancer chemotherapeutic agents (excluding tamoxifen). Methotrexate, including low-dose weekly regimens, is classified as severely immunosuppressive, as evidenced by increased rates of opportunistic infections and blunting of responses to killed vaccines (1-3). The immunosuppressive effects of steroid treatment vary, but the majority of clinicians consider a dose equivalent to either >2 mg/kg of body weight or 20 mg/day of prednisone or equivalent for persons who weigh >10 kg when administered for ≥2 weeks as sufficiently immunosuppressive to raise concern about the safety of vaccination with live-virus vaccines. Corticosteroids used in greater than physiologic doses also can reduce the immune response to vaccines. Vaccination providers should wait at least 1 month after discontinuation of high dose systemically absorbed corticosteroid therapy administered for more than 2 weeks before administering a live-virus vaccine. (4). Tumor necrosis factor (TNF)-blocking agents such as etanercept, adalimumab, and infliximab are known to activate latent mycobacterial infection as well as to increase overall susceptibility to other serious infec-tions. (5) Although the benefits of live viral and bacterial vaccines in persons receiving TNF-blocking agents need to be carefully weighed against potential risk, most practicing clinicians would be reluctant to use such vaccines in this situation. The safety of using live vaccines is unknown for persons taking TNF-alpha blocking agents or interleukin-1 receptor antagonist (IL-1ra) (6).

Severe Immunocompromise Due To Symptomatic HIV/AIDS

Knowledge of a current CD4 lymphocyte count is necessary before consultation with the HIV-infected traveler (7). HIV-infected persons with CD4 counts lower than 200, history of an AIDS-defining illness, or clinical manifestations of symptomatic HIV are considered to have severe immunosuppression (see Chapter 4.) In newly diagnosed, treatment-naïve patients with CD4 counts lower than 200, travel should be delayed pending reconstitution of CD4 counts with antiretroviral therapy. This delay will minimize risk of infection and avoid immune-reconstitution illness during the travel (8).

Asymptomatic HIV Infection

Asymptomatic HIV-infected persons with CD4 counts from 200 to 500 are considered to have limited immune deficits (9). CD4 counts increased by antiretroviral drugs, rather than nadir counts, should be used in categorizing HIV-infected persons. The exact time at which reconstituted lymphocytes are fully functional is not well defined. To achieve maximal vaccine response with minimal risk, if possible, many clinicians advise a delay of 3 months post-reconstitution before immunizations are administered (8).

Chronic Diseases with Limited Immune Deficits

These chronic diseases include asplenia, chronic renal disease, chronic hepatic disease (cirrhosis and alcoholism), diabetes, and nutritional deficiencies. Patients taking ribavirin and interferon for hepatitis C infection are at risk for neutropenia, although no clinically apparent increase in opportunistic infections has been described. No information on possible decreased vaccine efficacy or increased adverse events with live viral antigens is available for this group.

Persons Considered To Have No Immunologic Compromise

For the purpose of pre-travel preparation, travelers with the following conditions are not considered to be immunocompromised and should be prepared as any other traveler, although the nature of the previous or underlying disease needs to be kept in mind:

1. Corticosteroid therapy under the following circumstances: short or long term daily or alternate day therapy with 20 mg or less of prednisone or equivalent; long-term, alternate day treatment with short-acting preparations; maintenance physiologic doses (replacement therapy); steroid inhalers; topical steroids (skin, ears, or eyes); intra-articular, bursal, or tendon injection of steroids; or if longer than 1 month has passed since high-dose steroids (greater than 20 mg per day of prednisone or equivalent for longer than 2 weeks) have been used (9). Some experts will wait 2 weeks prior to the administration of measles vaccine following short-term (less than 2 weeks) of therapy with daily or alternate day dosing of greater than 20 mg of prednisone or equivalent (see Chapter 4).
2. HIV patients with >500 CD4 lymphocytes (9).
3. Longer than 3 months since chemotherapy for leukemia/lymphoma or cancer, and the malignancy is in remission. Although some clinicians suggest waiting only 1 month since a last dose of immunosuppressive medications (including TNF-blockers) that are not being used for the chemotherapy of cancer, data are inconclusive. This recommendation may primarily refer to corticosteroids, but it remains unknown exactly how long is safest.
4. Bone marrow transplant, if longer than 2 years post-transplant, not on immunosuppressive drugs and without graft versus host disease.
5. Definitive data do not exist with respect to autoimmune diseases in the absence of any overlay of immunosuppressive drugs (e.g., systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, or multiple sclerosis). The ACIP’s advice for the normal use of all live-virus as well as killed vaccines in multiple sclerosis (MS) patients who are not undergoing a current exacerbation of disease is reinforced by the National MS Society (http://www.nationalmssociety.org/Sourcebook-vaccinations.asp), a source well respected by MS patients and their physicians. In the past, many practicing neurologists have strongly advised their MS patients against the use of live-virus vaccines at any time. If possible, MS patients should not receive any vaccine for 6 weeks after the onset of a disease exacerbation. Immunomodulatory agents com-monly used in MS patients, such as interferons and glatiramer acetate, are not thought to affect vaccine response or safety, but definitive data are lacking. In these special circumstances, travel health advisors should confer with the traveler’s other physicians in developing an appropriate plan.

Vaccine Administration

Travelers with symptomatic HIV or severe non-HIV immunocompromise 1) cannot be given live-virus or live bacterial vaccines; 2) may require additional vaccines when compared with the healthy traveler; and 3) may receive decreased protection from some or all vaccines administered. Use of vaccines for different categories of immunocompromised adults is shown in Table 9-1 (10,11). Overall considerations for travel-related vaccines, such as destination and risk behavior, are the same as for other travelers, although the consequences of not administering an indicated vaccine may be more severe. A high risk for acquiring infections should prompt discussion of trip deferral or consideration of an alternate itinerary.

Vaccine Considerations for Certain Hosts

1. Transient increases in HIV viral load, which return quickly to baseline, have been observed after administration of several different vaccines to HIV-infected persons. The clinical significance of these increases is not known, but they do not preclude the use of any vaccine.
2. Patients receiving any vaccines while receiving immunosuppressive therapy or in the 2 weeks before starting therapy because of imminent travel are not considered to have received valid vaccine doses. At least 3 months after therapy is discontinued, these patients should be revaccinated with all vaccines that are still indicated at that time.
3. Vaccine doses received by HIV-infected individuals while CD4 counts are less than 200 should be ignored, and the individual should be revaccinated at least 3 months after immune reconstitution with antiretroviral therapy.
4. Complete revaccination with standard childhood vaccines should begin 12 months after bone marrow transplantation (BMT). However, MMR vaccine should be administered at 24 months after BMT if the recipient is presumed to be immunocompetent. Influenza vaccine should be administered at 6 months after BMT and annually thereafter.
5. Persons with chronic lymphocytic leukemia have poor humoral immunity even early in the disease course and rarely respond to vaccines.
6. Household contacts of severely immunocompromised patients may be given live-virus vaccines such as yellow fever, MMR, or varicella vaccine but should not be given live intranasal influenza vaccine.

Considerations for Certain Vaccines

Yellow Fever Vaccine

Severely immunosuppressed travelers should be strongly discouraged from travel to destinations that present true risk of yellow fever. If travel to a yellow fever-endemic zone (see Chapter 4) by such individuals is unavoidable and the vaccine is not given, travelers should be instructed carefully in methods to avoid mosquito bites and should be provided a vaccination waiver letter. If international travel requirements and not true exposure risk are the only reasons to vaccinate an asymptomatic HIV-infected person or a person with a limited immune deficit, the physician should provide a waiver letter on letterhead stationery. Travelers should be warned that vaccination waiver documents may not be accepted by some countries and that if the waiver is rejected, the option of deportation might be preferable to yellow fever vaccination at the destination. Patients with limited immune deficits or asymptomatic HIV should be offered the choice of vaccination and monitored closely for possible adverse effects. As vaccine response may be suboptimal, such vaccinees are candidates for serologic testing 1 month post-vaccination. (For information about serologic testing, contact a state health department or the CDC Division of Vector-Borne Diseases [970] 221-6400.) Diligent insect precautions are similarly recommended in this situation. Despite the theoretical risk for neuroinvasion and encephalitis due to vaccine, there are no reports of clinical or epidemiologic studies to evaluate the risk of yellow fever vaccination among severely immunocompromised recipients.

Hib Vaccine

This vaccine is recommended or should be considered for many categories of compromised host. Normally only one dose is recommended for persons older than 5 years of age. This dose may be insufficient to induce immunity in immunosuppressed persons, but the data are insufficient to recommend more than one dose.

Meningcoccal Vaccines

Either one of the two vaccines should be considered for individuals who have a variety of compromising conditions, such as asplenia or complement deficiencies. The traveler’s primary health-care provider should participate in the decision making in such situations.

Pneumococcal Polysaccharide Vaccine

This vaccine is recommended for many categories of compromised host, followed by a single booster. Data are insufficient on the use of pneumococcal conjugate vaccine to recommend its use in compromised older children and adults.

Influenza Vaccine

Influenza is a year-round infection in the tropics, and in the Southern Hemisphere the influenza season is April through September. Immunocompromised patients should be protected according to influenza risk at the destination; they should not be given live intranasal influenza vaccine (see Chapter 4).

Prevention and Self-Treatment of Infections

Travelers with symptomatic HIV or severe non-HIV immunocompromise are at risk for increased severity of some diseases.

Enteric Infections

The risk for foodborne and waterborne infections among immunosuppressed persons is amplified during travel to developing countries. Many enteric infections, such as those caused by Salmonella, Campylobacter, and Cryptosporidium, can be very severe or become chronic in immunocompromised persons.

Foods and beverages, specifically raw fruits and vegetables, raw or undercooked seafood or meat, tap water, ice made with tap water, unpasteurized milk and dairy products, and items purchased from street vendors, may be contaminated. Immunocompromised travelers need to be extraordinarily diligent in adhering to the food and water precautions recommended for all travelers (see Chapter 2). Waterborne infections might result from swallowing water during recreational activities. To reduce the risk for cryptosporidiosis and giardiasis, patients should avoid swallowing water during swimming and should not swim in water that might be contaminated (e.g., with sewage or animal waste). Attention to hand hygiene, including frequent and thorough hand washing, is the best prevention against gastroenteritis and is especially important on cruise ships (see Chapters 4 and 7). Hands should also be washed after any contact with animals, particularly young ones, or their living areas. Since diarrhea is a frequent complication of highly active antiretroviral therapy for HIV, such patients should receive counseling regarding the symptoms of enteric infections. Travelers’ diarrhea is a frequent problem of immunosuppressed travelers, as it is in the general traveling population; however antibiotic prophylaxis is not routinely recommended (see Chapter 4).

Malaria

Meticulous malaria prevention should always be advised, as for immunocompetent travelers (see Chapter 4). Risk of malaria acquisition and severity of malaria are increased in HIV-infected individuals. Malaria infection increases HIV viral load and thus may exacerbate disease progression (12,13). Both atovaquone and mefloquine have theoretical potential for competition with protease inhibitors for metabolic enzymes (e.g., cytochrome P450) in the liver, but published evidence for clinically significant interaction is lacking (14). For malaria treatment, the use of quinidine (and by implication quinine) in patients taking nelfinavir or ritonavir is contraindicated because of potential cumulative cardiotoxicity. However, if a patient has severe and complicated malaria, there may be no choice. In these circumstances, as in others, quinidine should be used only with close monitoring. In addition, very careful monitoring should accompany quinidine therapy in those taking amprenivir, delaviridine, or the lopinavir/ritonavir combination. Ritonavir and ritonavir-containing combination drugs that do not require refrigeration are now available. Several protease inhibitors have been shown in laboratory testing to inhibit the growth of malaria parasites (15). Asplenic individuals may be at greater risk of acquisition and complications of malaria.

Reducing Risk for Other Diseases

Travelers should be informed about other region-specific risks and instructed in ways to reduce those risks. Sexual activity increases during travel. Safer sex should be reinforced. HIV-infected individuals may still acquire Hepatitis B or C, or, rarely, a superinfection with a nonclade B HIV strain. Geographically focal infections that pose an increased risk of severe outcome for immunocompromised persons include visceral leishmaniasis (a protozoan infection transmitted by the sandfly) and several inhalationally acquired fungal infections (e.g., Penicillium marneffei infection in Southeast Asia and coccidioidomycosis in the Americas). Many developing areas have high rates of tuberculosis, and obtaining a baseline tuberculin skin test should be considered. Patients with advanced HIV and transplant recipients are frequently taking either primary or secondary prophylaxis for one or more opportunistic infections (e.g., pneumocystis, mycobacteria, and toxoplasma). Complete adherence to all indicated regimens should be confirmed before travel (see Chapter 2).

General Preparation: Practical Considerations

• Identify specific sources of medical care at the destination before departure and seek medical attention promptly when ill.
• Avoid changes in the medication regimen shortly before travel to ensure that no side effects or complications of a new regimen occur while traveling.
• Verify medical insurance coverage, purchase additional travel insurance if necessary and possible, and understand that many policies will not cover preexisting conditions such as HIV.
• Carry an oversupply of medications, along with copies of prescriptions. Medications should be divided between carry-on and checked baggage, as either one can be lost or stolen (see Chapter 2). Long-stay travelers should ensure the availability of adequate medication at the destination or a reliable source for its importation.
• HIV-positive travelers should be informed that many countries restrict entry of travelers with HIV infection. Antiretroviral drugs found in baggage at customs may lead to exclusion. Many countries require HIV antibody testing for students, workers, and others applying for long-term entry permits (seehttp://travel.state.gov/law/info/info_621.html for an unofficial list of requirements). Travelers should ascertain whether tests conducted in their home countries before travel will be accepted.
• Seek medical assistance early in case of any febrile illness while in a developing country. Asplenic or functionally asplenic patients are predisposed to rapidly overwhelming sepsis with encapsulated bacteria. If competent medical help is not readily available, febrile asplenic patients should carry a broad-spectrum antibiotic such as levofloxacin to initiate self-therapy immediately. Widespread bacterial resistance now precludes most clinicians from recommending oral penicillins.

References

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DAVID O. FREEDMAN