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Chapter 5 Travelers with Additional Considerations

Immunocompromised Travelers

Camille Nelson Kotton, Andrew T. Kroger, David O. Freedman

APPROACH TO THE IMMUNOCOMPROMISED TRAVELER

Immunocompromised travelers make up 1%–2% of travelers seen in US travel clinics and pursue itineraries largely similar to those of immunocompetent travelers. The pretravel preparation of travelers with immune suppression due to any medical condition, drug, or treatment must take into consideration several issues:

  • What is the cause of the immune suppression? Different conditions and medications produce widely varying degrees of immunocompromise, and there are many unknowns in this field. Guidance regarding vaccination of immunocompromised travelers is less evidence-based than with other categories of travelers; this section provides recommendations based on the best available data and the practices of experienced clinicians.
  • Is the traveler’s underlying medical condition stable? The travel health care provider may need to contact the traveler’s primary or specialty care providers (with the patient’s permission) to discuss the traveler’s fitness to travel, give specific medical advice for the proposed itinerary, verify the drugs and doses composing their usual maintenance regimen, and discuss whether any of the disease-prevention measures recommended for the proposed trip could destabilize the underlying medical condition, directly or through drug interactions.
  • Do the conditions, medications, and treatments of the traveler constitute contraindications to, decrease the effectiveness of, or increase the risk for adverse events of any of the disease-prevention measures recommended for the proposed trip? Depending on the destination, such measures may include immunizations and drugs used for malaria chemoprophylaxis and management of travelers’ diarrhea. Are there specific health hazards at the destination that would exacerbate the underlying condition or be more severe in an immunocompromised traveler? If so, can specific interventions be recommended to mitigate these risks?
  • If an immunocompromised traveler were to become ill while traveling, what are the health care options (see Chapter 6, Obtaining Health Care Abroad)? What would the traveler do should medical evacuation be required? An immunocompromised traveler should have a plan for when and how to seek care overseas and how to pay for it.

The traveler’s immune status is particularly relevant to immunizations. Overall considerations for vaccine recommendations, such as destination and the likely risk of exposure to disease, are the same for immunocompromised travelers as for other travelers. The risk of severe illness or death from a vaccine-preventable disease must be weighed against potential adverse events from administering a live vaccine to an immunocompromised patient. In some complex cases when travelers cannot tolerate recommended immunizations or prophylaxis, the traveler should consider changing the itinerary, altering the activities planned during travel, or deferring the trip.

For purposes of clinical assessment and approach to immunizations, immunocompromised travelers may be thought of as falling into 1 of 3 groups, based on mechanism and level of immune suppression. The 3 groups are people who have 1) medical conditions without significant immunologic compromise, 2) medical conditions and treatments associated with limited immune deficits, and 3) medical conditions or treatments associated with severe immune compromise. Vaccine recommendations for different categories of immunocompromised adults are shown in Table 5-01.

MEDICAL CONDITIONS WITHOUT SIGNIFICANT IMMUNOLOGIC COMPROMISE

With regard to travel immunizations, travelers whose health status places them in any of the following groups are not considered significantly immunocompromised and should be prepared as any other traveler, although the nature of the 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.
    • Maintenance steroids at physiologic doses (replacement therapy).
    • Steroid inhalers or topical steroids (skin, ears, or eyes).
    • Intraarticular, 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. After short-term (<2 weeks) therapy with daily or alternate-day dosing of ≥20 mg of prednisone or equivalent, some experts will still wait 2 weeks or more before administering live vaccines.
  2. HIV patients without severe immunosuppression (for definitions of severe immunosuppression, see www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf).
  3. Travelers with a history of cancer who received their last chemotherapy treatment ≥3 months previously and whose malignancy is in remission. Those who have received immunotherapy with agents such as checkpoint inhibitors may need to wait longer; any vaccination should be discussed directly with their oncologist.
  4. Hematopoietic stem cell transplant recipients or CAR-T cell recipients who are >2 years posttransplant, not on immunosuppressive drugs, with no evidence of ongoing malignancy, and without graft-versus-host disease.
  5. Travelers with autoimmune disease (such as systemic lupus erythematosus, inflammatory bowel disease, or rheumatoid arthritis) who are not being treated with immunosuppressive or immunomodulatory drugs, although definitive data are lacking.

Table 5-01. Immunization of immunocompromised adults

  HIV
INFEC-
TION, CD4 CELLS ≥200/
mm3
SEVERE IMMUNO-
SUPPRES-
SION
(HIV/
AIDS) CD4 CELLS <200/
mm3
SEVERE IMMUNO-
SUPPRES-
SION
(NOT HIV-
RELATED)
ASPLENIA RENAL FAILURE
Live Vaccines
Bacillus Calmette
Guérin (BCG)
X X X U U
Cholera ND1 ND1 ND1 U U
Influenza, live attenuated (LAIV) X X X X P
Measles-mumps-rubella (MMR)2 R2 X2 X2 U U
Typhoid, Ty21a X X X U U
Varicella (adults)3 C3 X3 X3 U U
Yellow Fever4 P4 X4 X U OC5
Zoster-live (ZVL) OC6 X6 X U U
Inactivated Vaccines
DTaP U U U U U
Haemoph-
ilus
influenzae
type b (Hib)
U U OC7 R8 U
Hepatitis A9 U U U U U
Hepatitis B10 R10 R10 U10 U10 R11
Human Papillomavirus U12 U12 U12 U U
Influenza
(inacti-
vated)
R R R R R
Japanese
encepha-
litis13
ND ND ND ND ND
Meningo-
coccal
conjugate
R14 R14 U R14 U
Meningococcal group B U U U R U
PCV13 followed by PPSV2315 R R R R R
Polio (IPV) U U U U U
Rabies U OC16 OC16 U U
Td or Tdap U U U U U
Typhoid, Vi U U U U U
Zoster-recombinant (RZV) OC OC OC U U

Abbreviations: X, Contraindicated (per the Advisory Committee on Immunization Practices [ACIP]); U, Use as indicated for normal hosts; R, Recommended for all in this patient category; P, Precaution (per ACIP); OC, Other considerations; C, Consider; ND, No data; PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23- valent pneumococcal polysaccharide vaccine.
1 No safety or efficacy data exist regarding use of the current formulation of CVD 103- HgR vaccine in HIV-positive adults or people with severe immunosuppression. Limited data from an older formulation of the CVD 103-HgR suggest no association between the vaccine and serious or systemic adverse events, and slightly lower immunogenicity of the vaccine in HIV-positive versus HIV-negative adults.
2 MMR vaccination is recommended for all HIV-infected patients aged ≥12 months with (for patients aged <6 years) CD4 percentage ≥15% or (for patients aged ≥6 years) CD4 percentage ≥15% and CD4 counts ≥200/mm3 for ≥6 months if they are without evidence of measles immunity. Immune globulin may be administered for short-term protection of those facing high risk of measles and for whom MMR vaccine is contraindicated. Additional guidance is available at www.cdc.gov/mmwr/preview/mmwrhtml/rr6204a1.htm.
3 Varicella vaccine should not be administered to people who have cellular immunodeficiencies, but people with impaired humoral immunity (including congenital or acquired hypoglobulinemia or dysglobulinemia) may be vaccinated. HIV-positive adults with CD4 counts ≥200 cells/mm3 should be considered to receive 2 doses of vaccine spaced at 3-month intervals. VariZIG (varicella-zoster–specific immune globulin) is recommended for those exposed to varicella or herpes zoster if they do not have evidence of varicella immunity and have contraindications to vaccination.
4 See details in Chapter 4, Yellow Fever. Yellow fever (YF) vaccination is a precaution for asymptomatic HIV-infected people with CD4 cell counts of 200–499/mm3. YF vaccination is not a precaution for people with asymptomatic HIV infection and CD4 cell counts ≥500/mm3. YF vaccine is also considered contraindicated by ACIP for symptomatic HIV patients without AIDS and with CD4 counts <200/mm3.
5 No data suggest increased risk of serious adverse events after use of YF vaccine in people with these conditions; however, varying degrees of immune deficit might be present, and providers should carefully weigh vaccine risks and benefits before deciding to vaccinate people with these conditions.
6 Also contraindicated by ACIP for symptomatic HIV patients without AIDS and with CD4 counts <200/mm3. No recommendation for asymptomatic HIV patients without AIDS and with CD4 counts ≥200/mm3. Recombinant zoster vaccine is the preferred agent.
7 Recipients of a hematopoietic stem cell transplant should be vaccinated with a 3-dose regimen 6–12 months after a successful transplant, regardless of vaccination history; at least 4 weeks should separate doses.
8 In adults, Hib is recommended for those with asplenia only if they have not previously received Hib vaccine.
9 Routinely indicated for all men who have sex with men, hemophiliacs, patients with chronic hepatitis, injection drug users, and others.
10 Hepatitis B vaccination is indicated for people at risk for infection by sexual exposure, including sex partners of hepatitis B surface antigen (HBsAg)-positive people, sexually active people who are not in a long-term mutually monogamous relationship, people seeking evaluation or treatment for a sexually transmitted disease, men who have sex with men, people at risk for infection by percutaneous or mucosal exposure to blood, current or recent injection-drug users, household contacts of HBsAg-positive people, residents and staff of facilities for developmentally disabled people, health care and public safety workers with reasonably anticipated risk for exposure to blood or blood-contaminated body fluids, people with end-stage renal disease, international travelers to regions with high or intermediate levels (HBsAg prevalence >2%) of endemic HBV infection (see Map 4-04), people with chronic liver disease, and people with HIV infection.
11 Adult patients receiving hemodialysis or with other immunocompromising conditions should receive 1 dose of 40 μg/mL Recombivax HB administered on a 3-dose schedule at 0, 1, and 6 months or 2 doses of 20 μg/mL (Engerix-B) administered simultaneously on a 4-dose schedule at 0, 1, 2, and 6 months. Test for antibodies to hepatitis B virus surface antigen serum after vaccination and revaccinate if initial antibody response is absent or suboptimal (<10 mIU/mL). HIV-infected nonresponders may react to a subsequent vaccine course if CD4 cell counts rise to 500/mm3 after institution of highly active antiretroviral therapy. See text for discussion of other immunocompromised groups.
12 HPV vaccine (3 dose schedule at 0, 1-2, and 6 months) is recommended through age 26 years. Should be administered as indicated for males and females but is additionally recommended for men 22–26 years of age in this patient category (otherwise male indication is through age 21 years). Female indication in each category is through 26 years of age.
13 No safety or efficacy data exist regarding the use of Ixiaro in immunocompromised people. In general, inactivated vaccines can be administered safely to people with altered immunocompetence, using the usual doses and schedules, but the effectiveness might be suboptimal. The inactivated, Vero cell–derived Japanese encephalitis vaccine, Ixiaro, is the only Japanese encephalitis vaccine available in the United States; other types of Japanese encephalitis vaccines, including live vaccines, are available internationally but are not included here.
14 Children aged 2–23 months should receive the vaccine in accordance with the age- appropriate, licensed, multidose schedule. For people aged ≥2 years, 2 doses ≥8 weeks apart are recommended. If the most recent dose was received at age <7 years, a booster dose should be administered 3 years after the primary series and every 5 years thereafter. If the most recent dose was received at age ≥7 years, a booster dose should be administered after 5 years, and every 5 years thereafter. See www.cdc.gov/mmwr/volumes/65/wr/pdfs/mm6543a3.pdf for more information.
15 Previously unimmunized asplenic, HIV-infected, with chronic renal disease or nephrotic syndrome, or immunocompromised adults aged ≥5 years should receive 1 dose of 13-valent pneumococcal conjugate vaccine (PCV13) followed by 1 dose of pneumococcal polysaccharide vaccine (PPSV23) ≥8 weeks later. People with these conditions previously immunized with PPSV23 should follow catch-up guidelines per ACIP.
16 For postexposure prophylaxis, both vaccine (5 doses at day 0, 3, 7, 14, 28) and immune globulin should be given to immunocompromised people, regardless of previous vaccination status.

MEDICAL CONDITIONS AND TREATMENTS ASSOCIATED WITH LIMITED IMMUNE DEFICITS

Asymptomatic HIV Infection

Asymptomatic adults with HIV and CD4 cell counts of 200–499/mm3 are considered to have limited immune deficits and should be vaccinated according to the guidelines in Table 5-01. Meningococcal (MenACWY), pneumococcal, and hepatitis B vaccines are recommended for HIV-positive patients regardless of travel plans. More specific recommendations are available for MMR (measles-mumps-rubella) vaccine (www.cdc.gov/mmwr/preview/mmwrhtml/rr6204a1.htm). CD4 counts while on antiretroviral drugs, rather than nadir counts, should be used to categorize people with HIV.

To achieve a maximal vaccine response with minimal risk, many clinicians advise a delay of 3 months after immune reconstitution (usually 6 months after initiation of antiretroviral therapy), if possible, before immunizations are administered; however, the optimal time to initiate vaccination after starting antiretroviral therapy has been identified as a gap in knowledge by the Infectious Diseases Society of America. For MMR vaccine, the recommendation is ≥6 months on antiretroviral therapy with the age- and CD4-based criteria. Although seroconversion rates and geometric mean titers of antibody in response to vaccines may be less than those measured in healthy controls, most vaccines can elicit protective levels of antibody in many HIV-infected patients in this category.

Single-antigen varicella vaccine should be con­sidered for HIV-infected children aged 1–8 years who have CD4 percentages ≥15%. Vaccine may be considered, after weighing the risk for severe dis­ease from wild virus and potential benefit of vaccination, for HIV-infected children aged >8 years with comparable levels of immune function (CD4 count ≥200 cells/mm3). Eligible children should receive 2 doses 3 months apart, with the first dose administered as soon as possible after the first birthday. Varicella vaccine is not recommended for HIV-infected children who have evidence of severe immunosuppression (CD4 percentage <15% for those 1–8 years of age and CD4 count <200 cells/mm3 for those aged >8 years).

People with HIV may require vaccination with MMR or varicella vaccine. However, they also might receive periodic doses of intravenous immunoglobulin (IVIG), which may interfere with vaccine response. Varicella and MMR vaccines should be considered approximately 14 days before the next scheduled dose of IVIG. MMRV vaccine has not been studied in HIV-infected children and should not be substituted for single-antigen varicella vaccine.

Transient increases in HIV viral load, which return quickly to baseline, have been observed after administration of several different vaccines to asymptomatic HIV-infected people but does not occur in those well controlled on current antiretroviral therapies. The clinical significance of these increases is not known, but they do not preclude the use of any vaccine.

Multiple Sclerosis (MS)

Inactivated vaccines, including influenza, hepatitis B, human papillomavirus, and tetanus vaccines, are generally considered safe for people with MS, although vaccination should be delayed during clinically significant relapses until patients have stabilized or begun to improve from the relapse, typically 4–6 weeks after it began. Published studies are lacking on the safety and efficacy of other vaccines, such as those against hepatitis A, meningococcal disease, pertussis, pneumococcal disease, polio, and typhoid. Inactivated vaccines are theoretically safe for people being treated with an interferon medication, glatiramer acetate, mitoxantrone, fingolimod, or natalizumab, although safety and efficacy data are lacking.

Modern MS therapy often includes aggressive and early immunomodulatory therapy for many MS patients, even those with stable disease. Live vaccines should not be given to people with MS during therapy with immunosuppressants such as mitoxantrone, azathioprine, methotrexate, or cyclophosphamide; during chronic corticosteroid therapy; or during therapy with any immunosuppressive biologic agents including nataluzimab and alemtuzumab. Although definitive study of each medication is lacking, glatiramer acetate and interferon therapy are generally not classified by MS experts as immunosuppressive and do not preclude live vaccine administration.

Published studies suggest that mumps, measles, rubella, varicella, and zoster vaccines are safe in people with stable MS if administered 1 month before starting or at the appropriate interval (see Duration of Iatrogenic Immune Compromise below) after discontinuing immunosuppressive therapy. One study suggests yellow fever vaccine can exacerbate symptoms in MS patients; this risk together with the risk of yellow fever at the destination should be considered in consultation with the patient’s neurologist before administering the vaccine to those at risk of yellow fever.

Other Chronic Conditions

Chronic medical conditions that may be associated with varying degrees of immune deficit include asplenia and chronic renal disease. These patients should be vaccinated according to the guidelines in Table 5-01. Patients with complement deficiencies can receive any live or inactivated vaccine. Factors to consider in assessing the general level of immune competence of patients with chronic diseases include disease severity, duration, clinical stability, complications, comorbidities, and any potentially immune-suppressing treatment (see the next section in this chapter, Travelers with Chronic Illnesses).

Adults aged ≥19 years with most immuno­compromising conditions who have not previously received the 13-valent pneumococcal conjugate vaccine (PCV13) or the 23-valent pneumococcal polysaccharide vaccine (PPSV23) should receive a single dose of PCV13 followed by a dose of PPSV23 ≥8 weeks later.

Those with anatomic or functional asplenia (including sickle cell disease), complement deficiency, or taking eculizumab are susceptible to overwhelming and rapidly progressive sepsis with certain bacterial pathogens despite indicated immunizations. Advise asplenic travelers to seek immediate medical advice if they develop a fever and be prepared to initiate self-treatment in the form of a broad-spectrum antibiotic; they should not travel to destinations where immediate access to high standard medical care is not possible. People with asplenia generally are not considered immunocompromised for the purposes of vaccination, and live vaccines are not contraindicated.

Although response to vaccines may be diminished compared with people who have a functioning spleen, immunization against meningococcal (MenACWY and MenB), pneumococcal (see dosing above), and Haemophilus influenzae type b disease is recommended in these patients, regardless of travel plans. Age-appropriate dosing and schedules differ from competent hosts, and the recommended immunization schedules should be consulted (www.cdc.gov/vaccines/schedules/hcp/index.html).

People with terminal complement deficiencies, including anyone receiving the complement component inhibitor eculizumab, have increased susceptibility to meningococcal infections and should be immunized against meningococcal disease with both MenACWY and, if ≥10 years of age, MenB vaccine and could consider antimicrobial prophylaxis. The recommendations are the same as for patients with asplenia. Patients receiving eculizumab have increased risk of overwhelming meningococcal sepsis even after vaccination.

People with hypogammaglobulinemia or dysgammaglobulinemia may require vaccination with MMR or varicella vaccine. However, many people with these disorders also receive periodic doses of IVIG, which may interfere with vaccine response. Varicella and MMR vaccines should be considered approximately 14 days before the next scheduled dose of IVIG.

MEDICAL CONDITIONS AND TREATMENTS ASSOCIATED WITH SEVERE IMMUNE COMPROMISE

Severe Immune Compromise (Non-HIV)

Severely immunocompromised people include those who have active leukemia or lymphoma, generalized malignancy, aplastic anemia, graft-versus-host disease, or congenital immunodeficiency; others in this category include people who have received recent radiation therapy or checkpoint inhibitor treatment (therapy of autoimmune complications of treatment is immunosuppressive), those who have had solid-organ transplants and who are on active immunosuppression, and both CAR-T cell and hematopoietic stem cell transplant recipients (within 2 years of transplantation or still taking immunosuppressive drugs). The severely immunocompromised should generally not be given live vaccines, and inactivated vaccines are likely to be less effective; these patients should consider postponing travel until their immune function improves. For people likely to travel in the future, usual travel-related vaccines may be recommended before starting immunosuppressive therapies, if feasible. Administer inactivated vaccines ≥2 weeks and live vaccines ≥4 weeks before immunosuppression if possible (minimum 2 weeks before immunosuppression).

Special considerations apply for several common travel-related vaccines. Data indicate that immunocompromised people, notably those being treated with immunosuppressive drugs, may have inadequate seroconversion after a single dose of hepatitis A vaccine. For immunocompromised people (based on a provider guidance risk assessment) of any age who are traveling internationally, hepatitis A vaccine with additional immune globulin (IG) is recommended by the Advisory Committee on Immunization Practices (ACIP). The dose of IG, which varies according to planned duration of travel, is 0.1 mL/kg for travel up to one month; 0.2 mL/kg for travel up to 2 months; and for travel of more than 2 months, repeat doses of 0.2 mL/kg every 2 months. In general, IG should be administered immediately before travel. Immunocompromised travelers should make efforts to receive 2 doses of the hepatitis A vaccine over a 6-month period prior to their trip. Instead of concomitant IG, the approach of giving a second dose of vaccine ≥4 weeks after the first dose for time-constrained travelers who can get both doses before travel has been effective in select studies. For unvaccinated travelers who require postexposure prophylaxis during or after the trip, IG may be administered in addition to hepatitis A vaccine in people older than 40 years, depending on the providers’ risk assessment (for example, patient age, immune status and underlying conditions, exposure type/risk of transmission, and availability of IG).

The humoral immune response to hepatitis B vaccine is reduced in children and adults who are immunocompromised. Limited data indicate that modified dosing regimens might increase response rates. Similar to dialysis patients, a 3-dose series of 40 µg Recombivax HB at 0, 1, and 6 months or a 4-dose series of 40 µg Engerix-B at 0, 1, 2, and 6 months should be used. Heplisav-B (HepB-CpG) is an adjuvanted vaccine and is recommended to be administered as 2 doses, 1 month apart in people ≥18 years of age. Postvaccination serologic testing following any hepatitis B vaccination series is recommended to confirm response to immunization in immunocompromised people.

Immunocompromised people deemed at risk for vaccine-preventable rabies should receive a full intramuscular vaccine course on days 0, 7, and 21 or 28. Abbreviated, low-dose, and intradermal series should not be used. Serologic postvaccination testing may be indicated. For postexposure rabies prophylaxis, all severely immunocompromised people should generally receive rabies vaccine at days 0, 3, 7, 14, and 28, plus human rabies immune globulin, irrespective of previous vaccination history.

Although no extra pretravel indication exists, many travel clinics administer zoster vaccines. Recombinant zoster vaccine (RZV), newly introduced in 2018 as preferential to zoster vaccine live (ZVL) in competent hosts, is not contraindicated in immunocompromised people, but no efficacy data in this population are available to inform a licensed indication by FDA.

People with chronic lymphocytic leukemia have poor humoral immunity, even early in the disease course, and rarely respond to vaccines. After hematopoietic stem cell transplant, complete revaccination with standard childhood vaccines should begin at 6 months, with the caveat that MMR and varicella vaccines should be administered 24 months after transplant and only if the recipient is assumed to be immunocompetent. Inactivated influenza vaccine should be administered beginning ≥6 months after hematopoietic stem cell transplant and annually thereafter; a dose of inactivated influenza vaccine can be given as early as 4 months after transplant if there is a community outbreak.

For solid-organ transplants, the risk of infection is highest in the first year after transplant, so travel to high-risk destinations should be postponed until after that time. For hematopoietic cell transplant (HCT), travel should ideally be delayed ≥2 years after transplant to allow for full revaccination.

Doses of inactivated vaccines received while concurrently receiving potent immunosuppressive therapy (see below) or during the 2 weeks before starting therapy should not be counted toward completing the primary vaccination series or relied upon to induce adequate immune responses. At least 3 months after potent immunosuppressive therapy is discontinued, patients should be revaccinated with all indicated inactivated vaccines.

People 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 per day of prednisone or equivalent in people who weigh >10 kg, when administered for ≥2 weeks, as sufficiently immunosuppressive to raise concern about the safety of vaccination with live vaccines. Furthermore, the immune response to vaccines may be impaired. Clinicians should wait ≥1 month after discontinuation of high-dose systemic corticosteroid therapy before administering a live-virus vaccine.
  • Alkylating agents (such as cyclophosphamide).
  • Antimetabolites (such as azathioprine, 6-mercaptopurine, methotrexate). However, low-dose monotherapy (methotrexate ≤0.4 mg/kg/week, azathioprine ≤3 mg/kg/day, or 6-mercaptopurine ≤1.5 mg/kg/day) with these drugs does not preclude administration of either zoster vaccine.
  • Transplant-related immunosuppressive drugs (such as cyclosporine, tacrolimus, sirolimus, everolimus, azathioprine, and mycophenolate mofetil).
  • Cancer chemotherapeutic agents are classified as severely immunosuppressive, as evidenced by increased rates of opportunistic infections and blunting of responses to certain vaccines among patient groups.1 Vaccination following immunomodulatory therapies, such as checkpoint inhibitors, and CAR-T cell treatments have not been well studied, and until additional data are available, live attenuated vaccine should be avoided for many months after treatment.
  • Tumor necrosis factor (TNF) blockers such as etanercept, adalimumab, certolizumab pegol, golimumab, and infliximab blunt the immune response to certain vaccines and certain chronic infections. When used alone or in combination regimens with other disease-modifying agents to treat rheumatoid disease, TNF blockers were associated with an impaired response to hepatitis A, influenza, and pneumococcal vaccines.
    • Despite measurable impairment of the immune response, postvaccination antibody titers were often sufficient to provide protection for most people; therefore, treatment with TNF blockers does not preclude immunization against hepatitis A, influenza, and pneumococcal disease. When possible, all doses in the hepatitis A and pneumococcal series should be given before travel.
    • The use of live vaccines is contraindicated according to the prescribing information for most of these therapies.
  • Other biologic agents that are immunosuppressive or immunomodulatory may result in significant immunocompromise as outlined in Table 5-02. In particular, lymphocyte-depleting agents (thymoglobulin or alemtuzumab) and B cell–depleting agents (rituximab) are more significantly immunosuppressive. Consideration of the clinical context in which these were given is important, especially in hematologic malignancies.

1 Some of these agents are less immunosuppressive than others, such as tamoxifen or trastuzumab given to breast cancer patients, but clinical data to support safety with live vaccines are lacking.

DURATION OF IATROGENIC IMMUNE COMPROMISE

The period of time clinicians should wait after discontinuation of immunosuppressive therapies before administering a live vaccine is not consistent across all live vaccines. For cancer chemotherapy, radiation therapy, and highly immunosuppressive medications (exclusive of lymphocyte-depleting agents and organ transplant immunosuppression), the waiting period is 3 months. For lymphocyte-depleting (alemtuzumab and rituximab) agents, the waiting period is ≥6 months, although some experts believe the waiting period should be ≥1 year.

For steroid regimens considered immunosuppressive (see above), wait 1 month. The live zoster vaccine (Zostavax) is exceptional and may be given 1 month after any highly immunosuppressive agent, although many experts advocate waiting ≥1 year for anti–B cell antibodies and other lymphocyte-depleting agents. The live zoster vaccine is now no longer preferred and should rarely, if ever, be used. People should instead receive the 2-dose recombinant shingles vaccine.

For agents not considered highly immunosuppressive (Table 5-02), consultation with the prescribing clinician (and possibly a hospital pharmacist) is recommended to manage individual patients and estimate degree of immunosuppression. No basis exists for interpreting laboratory studies of general immune parameters to predict vaccine safety or efficacy. Restarting immunosuppression after live vaccination has not been studied, but some experts would recommend waiting ≥1 month.

Severe Immune Compromise Due to Symptomatic HIV/AIDS

Knowledge of the HIV-infected traveler’s current CD4 T-lymphocyte count is necessary for optimal pretravel consultation. People with HIV and CD4 cell counts <200/mm3, history of an AIDS-defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV are considered to have severe immunosuppression (see Chapter 4, HIV Infection) and should not receive live viral or bacterial vaccines because of the risk that the vaccine could cause serious systemic disease.2

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 and ideally complete suppression of detectable viral replication. Such postponement helps minimize risk of infection and avoid immune reconstitution illness during travel.

2 For MMR vaccine, severe immunosuppression is defined as CD4 percentages <15% at any age in addition to CD4 count <200/mm3 for people aged >5 years. See www.cdc.gov/mmwr/preview/mmwrhtml/rr6204a1.htm.

 

Table 5-02. Immunosuppressive/ immunomodulatory biologic agents that preclude use of live vaccines1

GENERIC NAME TRADE NAME MECHANISM/TARGET OF ACTION
Abatacept Orencia Anti-CD28/CTLA-4
Adalimumab Humira TNF blocker
Alemtuzumab Campath Anti-CD52
Anakinra Kineret IL-1 antagonist
Atezolizumab Tecentriq PD- L1
Avelumab Bavencio PD- L1
Basiliximab Simulect IL-2R/CD25
Belatacept Nulojix CTLA-4
Bevacizumab Avastin VEGF
Certolizumab pegol Cimzia TNF blocker
Cetuximab Erbitux EGFR
Dasatinib Sprycel Bcr-Abl tyrosine kinase inhibitor
Dimethyl fumarate Tecfidera Activates the nuclear erythroid 2-related factor 2 transcriptional pathway
Etanercept Enbrel TNF blocker
Fingolimod Gilenya Sphingosine 1-phosphate receptor modulator
Glatiramer acetate Copaxone Immunomodulatory; target unknown
Golimumab Simponi TNF blocker
Ibritumomab tiuxetan Zevalin CD20 with radioisotope
Ibrutinib Imbruvica Tyrosine kinase inhibitor
Imatinib mesylate Gleevec, STI 571 Signal transduction inhibitor/protein-tyrosine kinase inhibitor
Infliximab Remicade TNF blocker
Interferon alfa Pegasys, PegIntron Block hepatitis C viral replication
Interferon beta-1a Avonex, Rebif Immunomodulatory; target unknown
Interferon beta-1b Betaseron Immunomodulatory; target unknown
Natalizumab Tsabri α4-integrin
Nivolumab Opdivo PD-1
Ofatumumab Arzerra CD20
Panitumumab Vectibix EGFR
Pembrolizumab Keytruda PD-1
Lenalidomide Revlimid Immunomodulatory
Rilonacept Arcalyst IL-1
Rituximab Rituxan CD20
Sarilumab Kevzara IL- 6
Secukinumab Cosentyx IL-17A
Sunitinib malate Sutent Multikinase inhibitor
Tocilizumab Actemra IL-6
Tofacitinib Xeljanz JAK kinase inhibitor
Trastuzumab Herceptin Human EGFR 2 (HER2)
Ustekinumab Stelara IL-12, IL-23
Vedolizumab Entyvio Binds integrin α4β7

Abbreviations: CD, cluster of differentiation; CTLA, cytotoxic T-lymphocyte antigen; TNF, tumor necrosis factor; IL, interleukin; VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor.
1This table is based primarily on conservative expert opinion, given the lack of clinical data. Numerous agents are often given in combination with other agents (especially chemotherapy) and are immunosuppressive when given together. The list provides examples but is not inclusive of all biologic agents that suppress or modulate the immune system. Not all therapeutic monoclonal antibodies or other biologic agents result in immunosuppression; details of individual agents not listed here must be reviewed before determining whether live viral vaccines can be given. Interferon and glatiramer acetate given to multiple sclerosis patients are immunomodulators and are generally not classified by MS experts as immunosuppressive so do not preclude live vaccine administration (except perhaps YF vaccine), but clinical data to support safety with live vaccines are lacking.

SPECIAL CONSIDERATIONS FOR IMMUNOCOMPROMISED TRAVELERS

Household Contacts

The live vaccines MMR, varicella, and rotavirus vaccines should be administered to susceptible household contacts and other close contacts of immunocompromised patients when indicated. Inactive influenza vaccine (IIV) is the preferred agent; however, household and other close contacts of mildly or moderately immunocompromised patients can safely receive LAIV if they are unable to receive IIV. LAIV is contraindicated in close contacts and caregivers of severely immunocompromised people who require a protected environment.

Zoster vaccine live and yellow fever vaccine may be administered when indicated. Smallpox vaccine (mostly for military personnel) is transmissible to immunocompromised household and intimate contacts; infection control measures among family members should be implemented. If a varicella vaccine recipient has a rash after vaccination, direct contact with susceptible household contacts with altered immunocompetence should be avoided until the rash resolves.

Yellow Fever Vaccine

Unvaccinated travelers with severe immune compromise should be strongly discouraged from travel to destinations that present a true risk for yellow fever (YF). Significant immunosuppression is a contraindication to YF vaccination, as there is a risk of developing a serious adverse event, such as life-threatening yellow fever vaccine–associated viscerotropic disease and yellow fever vaccine–associated neurotropic disease. Additionally, YF vaccination is contraindicated in people with a history of a thymus disorder associated with abnormal immune cell function (e.g., thymoma or myasthenia gravis). This applies whether or not they have undergone therapeutic thymectomy (see “Altered Immune Status” under “Contraindications” in Chapter 4, Yellow Fever). There are no data to support IgA deficiency as a contraindication to YF vaccination.

If travel is unavoidable to an area where YF vaccine is recommended (see Maps 4-13 and 4-14) and the vaccine has not been given, these travelers should be informed of the risk of YF, carefully instructed in methods to avoid mosquito bites, and provided with a vaccination medical waiver (see Chapter 4, Yellow Fever). They may wish to travel during periods of lower disease activity. Travelers should be warned that vaccination waiver documents might not be accepted by some countries, and refusal of entry or quarantine is possible.

Patients with conditions that ACIP considers precautions (as opposed to contraindications) to administration of YF vaccine, such as asymptomatic HIV (see “Precautions” in Chapter 4, Yellow Fever) may be offered YF vaccine if travel to YF-endemic areas is unavoidable; recipients should be monitored closely for possible adverse effects. Studies show that higher CD4 cell counts and suppressed HIV viral loads seem to be the key determinants for development of protective neutralizing antibodies. Patients with undetectable viral loads respond well to YF vaccination regardless of CD4 count, although data are limited in those with CD4 counts <200 mm3. As vaccine response may be suboptimal, such vaccinees are candidates for serologic testing 1 month after vaccination. For information about serologic testing, contact your 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 a traveler with asymptomatic HIV infection or a limited immune deficit, the physician should provide a waiver letter.

Booster doses of YF vaccine are no longer recommended for most travelers, because a single dose of yellow fever vaccine provides long-lasting protection. However, additional doses of yellow fever vaccine are recommended for certain populations (such as hematopoietic stem cell transplant recipients and people with HIV) who might not have as robust or sustained immune response to yellow fever vaccine compared with other recipients.

People who received a hematopoietic stem cell transplant after receiving a dose of yellow fever vaccine and who are sufficiently immunocompetent to be safely vaccinated should be revaccinated if travel puts them at risk of yellow fever. People who were infected with HIV when they received their last dose of yellow fever vaccine should receive a dose every 10 years if they continue to be at risk for yellow fever and if there are no precautions or contraindications based on their current CD4 cell counts. Recent data suggest that yellow fever vaccination before solid-organ transplant, even long before transplant, generally provides protective antibody levels after transplant.

Response to Vaccination

Response to vaccination may be muted in severely immunocompromised hosts, and potential travelers should be informed about this. The immunosuppressive regimen does not predict the decrease in response to vaccination. Recent data in solid-organ transplant recipients vaccinated before transplant suggests that a prolonged phase of protective antibody titers can exist after transplant. In general, serologic testing for response to most travel-related vaccines is not clinically recommended.

Malaria Prophylaxis

Immunocompromised travelers to malaria-endemic areas should be prescribed drugs for malaria prophylaxis and receive counseling about mosquito bite avoidance—the same as for immunocompetent travelers (see Chapter 4, Malaria). Special concerns for immunocompromised travelers include any of the following possibilities:

  • Most current first-line regimens for HIV (integrase and entry inhibitors) have few drug interactions, but some older maintenance regimens for HIV may interact with drugs used for malaria prophylaxis. Notably, chloroquine, mefloquine, and primaquine may interact with older maintenance regimens for HIV, particularly those containing protease inhibitors.
  • The underlying medical condition, notably splenectomy, or immunosuppressive regimen may predispose the immunocompromised traveler to more serious disease from malaria infection. Such travelers should be counseled to adhere conscientiously to mosquito avoidance techniques and the malaria prophylaxis.
  • Malaria infection and the drugs used to treat it may exacerbate the underlying disease.
  • The severity of malaria is increased in HIV-infected people; malaria infection increases HIV viral load and thus may exacerbate disease progression.

Commonly used integrase inhibitor (raltegravir, dolutegravir, elvitegravir)/NRTI combinations (brand names include Descovy-Tivicay, Truvada-Tivicay) have no known interactions with CDC-recommended prophylactic drugs, although the cobicistat booster coformulated with elvitegravir (Stribild, Genvoya) may theoretically increase mefloquine levels. The rilpivirine, emtricitabine, TAF/TDF combinations (Odefsey and Complera) similarly have no interactions with antimalarials.

Of older drugs, efavirenz lowers serum levels of both atovaquone and proguanil, but there is no evidence for clinical failure of these agents when used concurrently. Efavirenz could potentially increase the amount of hemotoxic metabolites of primaquine.

Antimalarial treatment regimens, including artemisinin derivatives, quinine/quinidine, lume­fantrine (part of the artemether/lumefantrine combination, Coartem), and atovaquone and proguanil, may have potential interactions with many NNRTIs, PIs, and with the CCR5 receptor antagonist maraviroc. Advice from the CDC or another malaria expert should be sought when treating patients for malaria who are also on antiretrovirals.

Extra care must be taken in researching potential interactions in people with HIV who are receiving antiretroviral therapy. An interactive web-based resource for assessing possible drug interactions is found at the University of Liverpool website (www.hiv-druginteractions.org; a mobile application is available).

In organ transplant recipients, malaria prophylactic drugs may interact with calcineurin inhibitors and mTor inhibitors (tacrolimus, cyclosporine, sirolimus, everolimus). Mefloquine, chloroquine, primaquine, and doxycycline may cause elevated calcineurin inhibitor levels. Mefloquine, chloroquine, and calcineurin inhibitors may interact to prolong the QT interval. Some travel-related medications need to be dose-adjusted according to altered hepatic or renal function.

ENTERIC INFECTIONS

Many foodborne and waterborne infections, such as those caused by Salmonella, Shigella, Campylobacter, Giardia, Listeria, and Cryptosporidium, can be severe or become chronic in immunocompromised people. All travelers should follow safe food and beverage precautions; travelers’ diarrhea can nonetheless occur despite strict adherence. Meticulous hand hygiene, including frequent and thorough handwashing with soap, is the best prevention against gastroenteritis. Hands should be washed after contact with public surfaces, after any contact with animals or their living areas, and before preparing food or eating.

Because enteric pathogens, particularly Shigella, can also be acquired sexually, patients should be counseled about avoiding sex with people who have diarrhea; washing hands, genitals, and anus before and after sex; and using barriers during sex with partners who recently recovered from diarrhea.

To reduce the risk of cryptosporidiosis, giardiasis, and other waterborne infections, patients should avoid swallowing water during swimming and other water-based recreational activities and should not swim in water that might be contaminated (with sewage or animal waste, for example). Travelers with liver disease should avoid direct exposure to salt water that may contain Vibrio spp., and all immunocompromised hosts should avoid raw seafood. Patients and clinicians should be aware of the augmented risk of infection or colonization with multidrug-resistant organisms during travel, and should report recent travel to their doctors if ill afterwards.

Selecting antimicrobials to be used for self-treatment of travelers’ diarrhea, if indicated, may require special consideration of potential drug interactions among patients already taking medications for chronic medical conditions. Fluoroquinolones, rifaximin, and rifamycin SV are active against several enteric bacterial pathogens and are not known to have significant interactions with highly active antiretroviral therapy (HAART) drugs. Macrolide antibiotics may have significant interactions with HAART drugs and sometimes with organ transplant–related immunosuppression. Fluoroquinolones as well as azithromycin in combination with calcineurin inhibitors and mTor inhibitors may cause a prolonged QT interval. Antibiotic prophylaxis for a limited duration may be considered for travelers with severe immune suppression, although it should be used with caution given the risk of selecting for multidrug-resistant organisms.

REDUCING RISK FOR OTHER DISEASES

Geographically focal infections that pose an increased risk of severe outcome for immunocompromised people include visceral leishmaniasis and several fungal infections acquired by inhalation (such as Talaromyces marneffei [formerly Penicillium marneffei] infection in Southeast Asia and histoplasmosis and coccidioidomycosis in the Americas). Establishing the tuberculosis status of immunocompromised travelers going to regions endemic for tuberculosis may be helpful in the evaluation of subsequent illness. Depending on the traveler’s degree of immune suppression, the baseline tuberculosis status may be assessed by obtaining a tuberculin skin test, Mycobacterium tuberculosis antigen–specific interferon-γ assay, or chest radiograph. The need for posttransplant testing (often 3 months after travel) depends on exposure risk during the trip, medical conditions, and other factors.

Patients with advanced HIV and transplant recipients frequently take either primary or secondary prophylaxis for opportunistic infections (such as Pneumocystis, Mycobacterium, and Toxoplasma spp.). Adherence to all indicated prophylactic regimens should be confirmed before travel (see Chapter 4, HIV Infection).

Key points to stress with immunocompromised travelers are summarized in Box 5-01.

Box 5-01. Key patient education points for the immunocompromised traveler

  • Develop plan in case of illness at destination (clinic or hospital that would be able to care for immunocompromised host; how to use embassy resources and medical evacuation insurance).
  • Bring extra medications in case of travel delays; ensure medications are labeled.
  • Avoid taking medications purchased at destination (drug interactions or substandard, spurious, falsely labeled, falsified, and counterfeit medical products).
  • Augmented risk of infection with multidrug-resistant organisms during and after travel; highlight such travel to clinicians if ill afterwards.
  • Vigilant use of sun protection given dramatically elevated rates of skin cancer in immunocompromised hosts, also higher risk of photosensitivity from medications.
  • Vigilant food and water precautions. Antibacterial hand wipes or an alcohol-based hand sanitizer containing at least 60% alcohol may be useful.
  • Bring travel health/first aid kit.

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