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The Immunocompromised Traveler

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 that traveler. Each proposed preventive intervention must be examined from two perspectives:

1. safety in the context of the underlying immunocompromise and ongoing medication; and
2. the possibility of decreased effectiveness of the intervention in that context.

Before proceeding, the medical provider should ensure a complete understanding by the traveler of the wisdom 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 for that patient.

Severe Immunocompromise (non-HIV)

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

Medications that cause severe immunosuppression include high-dose corticosteroids, alkylating agents (e.g., cyclophosphamide), antimetabolites (e.g., methotrexate in any dose, 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 (not tamoxifen). The immunosuppressive effects of steroid treatment vary, but most clinicians consider a dose of greater than or equal to20 mg/day of prednisone or equivalent administered for greater than or equal to2 weeks as causing severe immunocompromise. Tumor necrosis factor (TNF)-blocking agents such as etanercept and infliximab are known to activate latent mycobacterial infection, but the degree of overall susceptibility to other microorganisms is unclear. 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.

Severe Immunocompromise Due to Symptomatic HIV/AIDS

Consultation with the HIV-infected traveler cannot be performed without knowledge of a current CD4 lymphocyte count. HIV-infected persons with CD4 counts <200, history of an AIDS-defining illness, or clinical manifestations of symptomatic HIV are considered to have severe immunosuppression.

Asymptomatic HIV Infection

Asymptomatic HIV-infected persons with CD4 counts from 200 to 500 are considered to have limited immune deficits. Antiretroviral drug-induced increased CD4 counts and not 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, a wait of 3 months post-reconstitution before immunization is advised by many clinicians.

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

1. Corticosteroid therapy under the following circumstances: short-term (i.e., <2 weeks); less than or equal to20 mg per day 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 >1 month has passed since high-dose steroids (>20 mg/day prednisone equivalent for >2 weeks) have been used.
2. HIV patients with >500 CD4 lymphocytes.
3. >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 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 >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., lupus, inflammatory bowel disease, rheumatoid arthritis, or multiple sclerosis). The ACIP advice for the normal use of live-virus vaccines in multiple sclerosis (MS) patients who are not undergoing a current exacerbation of disease is reinforced by the National MS Society (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 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 such as interferons and glatiramer acetate commonly used in MS patients are not thought to impact 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 bacterial vaccines; 2) may require additional vaccines when compared with the healthy traveler; and 3) may have decreased protection from some or all vaccines administered. Use of vaccines for different categories of immunocompromised adults is shown in Table 9-1. Overall destination and risk behavior considerations for travel-related vaccines are the same as for other travelers, although the consequences of not administering an indicated vaccine may be more severe. Sufficiently high risk for acquiring infections should prompt discussion of trip deferral or consideration of an alternate destination.

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. They should be revaccinated >3 months after therapy is discontinued with all vaccines that are still indicated at that time.
3. Complete revaccination with standard childhood vaccines should begin 12 months after bone marrow transplantation. However, MMR vaccine should be administered at 24 months of age if the recipient is presumed to be immunocompetent. Influenza vaccine should be administered at 6 months of age and annually thereafter.
4. Persons with chronic lymphocytic leukemia have poor humoral immunity even early in the disease course and rarely respond to vaccines.
5. 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 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. Travelers should be warned that vaccination waiver documents may not be accepted by some countries and that if this 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. (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, clinical or epidemiologic studies to evaluate the risk of yellow fever vaccination among severely compromised recipients have not been reported. If international travel requirements and not true exposure risk are the only reasons to vaccinate an asymptomatic HIV-infected person or person with a limited immune deficit, a waiver letter should be given.

Hib Vaccine

This vaccine is recommended or should be considered for many categories of compromised host. Normally only one dose is recommended for persons >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.

Pneumococcal Polysaccharide Vaccine

This vaccine is recommended for many categories of compromised host, followed by a single booster at 5 years of age. 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.

Prevention and Self-Treatment of Infections

The risk for foodborne and waterborne infections among immunosuppressed persons is magnified 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. 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. Since diarrhea is a frequent complication of highly active antiretroviral therapy for HIV, such patients should receive counseling regarding the symptoms of enteric infections.

Antimicrobial prophylaxis for travelers' diarrhea is not recommended routinely for immunocompromised persons traveling to developing countries because of the potential for adverse effects. Nonetheless, many studies (none involving an immunocompromised population) have reported that prophylaxis can reduce the risk for travelers' diarrhea. In circumstances in which the risk for infection is high, the period of travel brief, and the patient severely immunocompromised, the health-care provider and patient may opt for antibiotic prophylaxis with a quinolone antibiotic once a day (e.g., 500mg ciprofloxacin).

Loperamide can be used to treat mild diarrhea. As for immunocompetent travelers, antimicrobial agents (e.g., fluoroquinolones or azithromycin should be provided to travelers before their departure, to be taken for self-treatment if diarrhea occurs. Severely immunocompromised travelers should have a lower threshold than other travelers for initiating self-therapy.

Malaria

Meticulous malaria prevention should always be advised, as for immunocompetent travelers. Malaria does not appear to occur more frequently or pose a greater risk for adverse outcomes in immunocompromised travelers (including those with advanced HIV or asplenia), except in travelers who are both HIV infected and pregnant. 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. For malaria treatment, the use of quinidine (and by implication quinine) in patients on nelfinavir or ritonavir is contraindicated because of potential cumulative cardiotoxicity. This drug should be used only with close monitoring in those taking amprenivir, delaviridine, or the lopinavir/ritonavir combination.

Reducing Risk for Other Diseases

Travelers should be informed about other region-specific risks and instructed in ways to reduce those risks. Geographically focal infections that pose an increased risk of severe outcome to 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.

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 pre-existing conditions.
• 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. 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. (See http://travel.state.gov/travel/tips/brochures/brochures_1230.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 as in the past.

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