Elaine C. Jong, David O. Freedman

Approach to the Immunocompromised Traveler

The pre-travel preparation of travelers with immune suppression due to any medical condition, drug, or treatment, must address several categories of concern:

• Is the traveler’s underlying medical condition under stable control? The travel health advisor may need to contact the traveler’s primary and specialty care providers (with the patient’s permission) to gain a comprehensive medical overview and to verify the drugs and doses composing the usual maintenance regimen.
• Do the conditions, medications, and treatments of the traveler constitute contraindications to or decrease the effectiveness of any of the disease-prevention measures recommended for the proposed trip? Most importantly, these measures include immunizations against vaccine-preventable diseases and drugs used for malaria chemoprophylaxis and management of travelers’ diarrhea.
• Do any of the disease-prevention measures recommended for the proposed trip itinerary present a risk for destabilization of the underlying medical condition through direct pathophysiology or drug–drug interactions?
• Are there specific health hazards at the destination that would cause exacerbation of the underlying condition, or an illness of increased severity in the immunocompromised traveler? If so, can specific interventions be recommended to mitigate these risks?

The traveler’s immune status is particularly relevant to the administration of travel-related immunizations. Overall considerations for vaccine recommendations, such as destination and the likely risk of exposure to various modes of disease transmission, are the same for immunocompromised travelers as for other travelers, although the consequences of not administering an indicated vaccine may be more severe. In some complex cases when travelers cannot tolerate recommended immunizations and/or malaria chemoprophylaxis drugs, a change of itinerary, an alteration of activities planned during travel, or even deferral of the proposed trip must be considered—depending on the traveler’s personal tolerance for risk.

Medical Conditions without Significant Immunologic Compromise

With regard to travel immunizations, travelers whose health status places them in one of the following groups are not considered significantly 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. Travelers receiving corticosteroid therapy under any of the following circumstances:
   • Short- or long-term daily or alternate-day therapy with <20 mg 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
   • If >1 month has passed since high-dose steroids (≥20 mg per day of prednisone or equivalent for >2 weeks) have been used. Some experts will wait 2 weeks prior to the administration of measles vaccine following short-term (<2 weeks) of therapy with daily or alternate-day dosing of ≥20 mg of prednisone or equivalent.
2. HIV patients with >500 CD4 lymphocytes.
3. Travelers who received their last chemotherapy treatment at least 3 months previously and whose malignancy is in remission. However, when patients are on immunosuppressive medications (including TNF-blockers) for conditions other than hematologic malignancies and cancer, some clinicians suggest waiting only 1 month since a last dose of such medications before immunization. This recommendation may refer primarily to corticosteroids; it remains unknown exactly what duration off other drugs is optimal for immunization of such patients.
4. Bone marrow transplant recipients who are >2 years post-transplant, not on immunosuppressive drugs, and without graft-versus-host disease.
5. Travelers with autoimmune disease not being treated with immunosuppressive drugs (e.g., systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, or multiple sclerosis), although definitive data are lacking.
   • The ACIP advises the normal use of all live-virus and killed vaccines in multiple sclerosis (MS) patients who are not undergoing a current exacerbation of disease. This advice concurs with that of the National MS Society (www.nationalmssociety.org/), 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 commonly used in MS patients, such as interferons and glatiramer acetate, are not thought to affect vaccine response or safety, but definitive data are lacking.

Medical Conditions Associated with Immune Suppression

For purposes of clinical assessment and approach to immunizations, immunocompromised travelers fall into one of four groups, based on mechanism and level of immune suppression.

Vaccine use recommendations for different categories of immunocompromised adults are shown in Table 8-1.

Asymptomatic HIV Infection

Asymptomatic HIV-infected persons with CD4 cell counts of 200–500/mm³ are considered to have limited immune deficits. 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 a maximal vaccine response with minimal risk, many clinicians advise a delay of 3 months after reconstitution, if possible, before immunizations are administered. While seroconversion rates and geometric mean titers of antibody in response to vaccines may be less than those measured in healthy controls, seroprotective levels of antibody following immunization with most vaccines studied can be elicited in the majority of HIV-infected patients in this category.

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.

Chronic Conditions Associated with Limited Immune Deficits

Chronic conditions associated with limited immune deficits include asplenia, chronic renal disease, chronic liver disease (including chronic hepatitis C), diabetes mellitus, and complement deficiencies. No information on possible decreased vaccine efficacy or increased adverse events with administration of live attenuated viral or bacterial antigen vaccines is available for this group.

• A blunted response to hepatitis B vaccine has been reported in patients with chronic liver disease; a decreased response to hepatitis B vaccine has also been observed in patients with diabetes. Additional doses of hepatitis B vaccine beyond the primary three-dose series may be necessary.
• Double-dose hepatitis B vaccine preparations are used to promote optimal immunization of persons with chronic renal failure and other patient groups with absent or suboptimal response to standard hepatitis B vaccine doses.
• Adjuvanted hepatitis B candidate vaccines currently undergoing clinical trials look to be more effective for immunization of liver transplant patients and patients with renal insufficiency.
• Persons with asplenia have increased susceptibility to overwhelming sepsis with encapsulated bacterial pathogens. Although response to vaccines may be suboptimal compared with hosts with a functioning spleen, many clinical guidelines recommend immunization with meningococcal vaccine, pneumococcal vaccine, and Haemophilus influenzae conjugate vaccine in this patient category, regardless of travel plans. Limited data show that vaccine response in persons who have had a splenectomy was relatively more impaired if splenectomy was performed because of hematologic malignancy rather than for splenic trauma.
• Persons with terminal complement deficiencies appear to have increased susceptibility to meningococcal infections and should be immunized against meningococcal disease.

Severe Immunocompromise (Non-HIV)

Severely immunocompromised persons include those who have active leukemia or lymphoma, generalized malignancy, aplastic anemia, graft-versus-host disease, or congenital immunodeficiency; persons who have received current or recent radiation therapy, solid organ transplant, or bone marrow transplant recipients within 2 years of transplantation; or persons whose transplants occurred >2 years ago but who are still taking immunosuppressive drugs.

• Persons with chronic lymphocytic leukemia have poor humoral immunity even early in the disease course and rarely respond to vaccines.
• 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.
• For solid organ transplants, a higher risk of infection occurs within the first year of transplant than later, so travel to high-risk destinations might best be postponed until after that time.

Vaccine doses received while concurrently receiving immunosuppressive therapy, or during the 2 weeks before starting therapy because of imminent travel, are not considered 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. Persons taking any of the following categories of medications are considered severely immunocompromised:

• High-dose corticosteroids. Most clinicians consider a dose of either >2 mg/kg of body weight or ≥20 mg/day of prednisone or equivalent in 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. Furthermore, the immune response to vaccines may be impaired. Vaccine providers should wait at least 1 month after discontinuation of high-dose systemically absorbed corticosteroid therapy before administering a live-virus vaccine.
• Alkylating agents (e.g., cyclophosphamide).
• Antimetabolites (e.g., azathioprine, 6-mercaptopurine).
• Transplant-related immunosuppressive drugs (e.g., cyclosporine, tacrolimus, sirolimus, and mycophenolate mofetil) and mitoxantrone (used in multiple sclerosis).
• 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 certain vaccines among patient groups. Limited studies show that methotrexate monotherapy had no effect on the response to influenza vaccine, but it did impair the response to pneumococcal vaccine.
• Tumor necrosis factor (TNF)-blocking agents such as etanercept, adalimumab, and infliximab are known to blunt the immune response to certain vaccines, such as influenza vaccine. When used in combination regimens with methotrexate for treatment of rheumatoid disease, TNF-blocking agents were associated with an impaired response to pneumococcal vaccine as well. Although the potential benefits of live viral and bacterial vaccines in persons receiving TNF-blocking agents need to be weighed carefully against potential risks, most clinicians would be reluctant to use such vaccines in this situation, as the safety of using live vaccines is unknown for these agents and interleukin-1 receptor antagonist (IL-1ra).

Severe Immunocompromise Due to Symptomatic HIV/AIDS

Knowledge of the HIV-infected traveler’s current CD4 lymphocyte count is necessary for pre-travel consultation. HIV-infected persons with CD4 cell counts <200/mm³, history of an AIDS-defining illness, or clinical manifestations of symptomatic HIV are considered to have severe immunosuppression (see the HIV Infection and Acquired Immunodeficiency Syndrome (AIDS) section in Chapter 5) and should not receive live attenuated viral or bacterial vaccines because of the theoretical risk that the vaccine agent may cause serious systemic disease. The response to inactivated vaccines also will be suboptimal; thus, vaccine doses received by HIV-infected individuals while CD4 cell counts are <200/mm³ should be ignored, and the individual should be revaccinated at least 3 months after immune reconstitution with antiretroviral therapy.

In newly diagnosed treatment-naïve patients with CD4 cell counts <200/mm³, travel should be delayed pending reconstitution of CD4 cell counts with antiretroviral therapy. This delay will minimize risk of infection and avoid immune-reconstitution illness during the travel.

Household Contacts

Household contacts of severely immunocompromised patients may be given live-virus vaccines such as yellow fever, measles–mumps–rubella, or varicella vaccines but should not be given the live attenuated influenza vaccine (LAIV).

Special Considerations for the Immunocompromised Traveler

Yellow Fever Vaccine

Travelers with severe immune compromise should be strongly discouraged from travel to destinations that present a true risk of yellow fever (YF). If travel to a YF-endemic zone (see Maps 2-3 and 2-4) by such individuals is unavoidable and the vaccine is not given, they should be carefully instructed in methods to avoid mosquito bites and should be provided with a vaccination medical waiver (see the Yellow Fever section in Chapter 2).

Patients with limited immune deficits or asymptomatic HIV going to YF-endemic areas may be offered YF vaccine and monitored closely for possible adverse effects. As vaccine response may be suboptimal, such vaccinees are candidates for serologic testing one month after vaccination. (For information about serologic testing, contact the state health department or CDC’s Division of Vector-Borne Diseases at 970-221-6400.) Data from clinical and epidemiologic studies are insufficient at this time to evaluate the actual risk of severe adverse effects associated with YF vaccine among recipients with limited immune deficits.

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. Travelers should be warned that vaccination waiver documents may not be accepted by some countries; if the waiver is rejected, the option of deportation might be preferable to receipt of YF vaccine at the destination.

Malaria Chemoprophylaxis

When travel destinations are in malaria-endemic areas, immunocompromised travelers should be prescribed appropriate drugs for malaria chemoprophylaxis and receive counseling about avoidance of mosquito bites—the same as for immunocompetent travelers (see the Malaria section in Chapter 2). However, special concerns for immunocompromised travelers include any of the following possibilities:

• Drug-drug interactions between the drugs used for malaria chemoprophylaxis and the drugs in the traveler’s maintenance regimen
• The underlying medical condition will predispose the immunocompromised traveler to more serious disease from malaria
• A malaria infection and the drugs used to treat the malaria infection will cause an exacerbation of the underlying disease.

The severity of malaria is increased in HIV-infected individuals. Malaria infection increases HIV viral load and thus may exacerbate disease progression. Table 8-2 gives some examples of potential drug-drug interactions between drugs used for malaria chemoprophylaxis and drugs used in HAART regimens for treatment of HIV infections. Since new drugs and drug combinations for HIV treatment are under continuous development, travel health advisors are encouraged to review the most current information regarding possible drug interactions. An interactive web-based resource for checking on drug-drug interactions involving HAART drugs is found at the University of Liverpool website at www.hiv-druginteractions.org/.

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. Although the clinical significance, if any, is not known, several protease inhibitors have been shown in laboratory testing to inhibit the growth of malaria parasites.

Some clinical case reports suggest that asplenic individuals may be at greater risk of acquisition and complications of malaria, so asplenic travelers to malaria areas should be counseled to adhere conscientiously to the malaria chemoprophylaxis regimen prescribed for them.

Enteric Infections

Many foodborne and waterborne infections, such as those caused by Salmonella, Campylobacter, Giardia, and Cryptosporidium, can be very severe or become chronic in immunocompromised persons. Enteroaggregative Escherichia coli is an emerging enteric pathogen causing persistent diarrhea among children, adults, and HIV-infected persons.

Safe food and beverage selection guidelines should be followed by all travelers, but travelers’ diarrhea can occur despite strict adherence.

• Selection of antimicrobials to be used for self-treatment of travelers’ diarrhea may require special consideration of potential drug-drug interactions among patients already taking medications for chronic medical conditions. Fluoroquinolones and rifaximin are active against several enteric pathogens and do not have significant interactions with HAART drugs. However, macrolide antibiotics may have significant drug–drug interactions with HAART drugs (Table 8-3). Emerging therapies for diarrhea in HIV/AIDS patients may involve probiotics such as Lactobacillus rhamnosus GR-1, L. reuteri RC-14, and others.
• 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. Hands should be washed after contact with public surfaces and also after any contact with animals or their living areas.

Reducing Risk for Other Diseases

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 fungal infections acquired by inhalation (e.g., Penicillium marneffei infection in Southeast Asia and coccidioidomycosis in the Americas). Many developing areas have high rates of tuberculosis (TB), and establishing the TB status of immunocompromised travelers going to such destinations may be helpful in the evaluation of any travel-associated illness that subsequently develops. Depending on the traveler’s degree of immune suppression, the baseline TB status may be assessed by obtaining a tuberculin skin test, chest radiograph, or Mycobacterium tuberculosis antigen-specific interferon gamma assay.

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 the HIV Infection and Acquired Immunodeficiency Syndrome (AIDS) section in Chapter 5).

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