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Chapter 8 Advising Travelers with Specific Needs

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. These travelers 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 immune compromise, 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 2, 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 4 groups, based on mechanism and level of immune suppression. Vaccine recommendations for different categories of immunocompromised adults are shown in Table 8-01.

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 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 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/mmwr/preview/mmwrhtml/rr6002a1.htm).
  3. Travelers with a history of cancer who received their last chemotherapy treatment ≥3 months previously and whose malignancy is in remission.
  4. Hematopoietic stem cell transplant 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.

Box 8-01. 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 high 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 kit.

Table 8-01. 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 CHRONIC LIVER DISEASE, DIABETES
Live Vaccines
Bacillus Calmette
Guérin (BCG)
X X X U U U
Cholera ND1 ND1 ND1 U U U
Influenza, live attenuated (LAIV)2 X X X X P P
Measles-mumps-rubella (MMR) R3 X3 X3 U U U
Typhoid, Ty21a X X X U U U
Varicella (adults)4 C4 X4 X4 U U U
Yellow Fever5 P5 X5 X U OC6 OC6
Zoster OC7 X7 X U U U
Inactivated Vaccines
Tdap, DTaP U U U U U U
Haemoph-
ilus
influenzae
type b (Hib)
U U OC8 R9 U U
Hepatitis A10 U U U U U U (diabetes), R (liver disease)
Hepatitis B11 R12 R12 U12 U12 R12 R12,13
Human Papillomavirus U14 U14 U14 U U U
Influenza
(inacti-
vated)
R R R R R R
Japanese
encepha-
litis15
ND ND ND ND ND ND
Meningo-
coccal
conjugate
R16 R16 U R16 U U
Meningococcal group B C C C R C C
PCV13 followed by PPSV2317 R R R R R OC18
Polio (IPV) U U U U U U
Rabies U OC19 OC19 U U U
Td or Tdap U U U U U U
Typhoid, Vi U U U U 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 CDC did not recommend use of LAIV in the 2016–2017 season due to questions about LAIV effectiveness. Readers should consult the most recent guideline for recommendations in subsequent years.
3 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.
4 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.
5 See details in Chapter 3, 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.
6 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.
7 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.
8 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.
9 Only recommended for asplenic adults who have not previously received Hib vaccine.
10 Routinely indicated for all men who have sex with men, people with multiple sexual partners, hemophiliacs, patients with chronic hepatitis, injection drug users, and others.
11 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 3-04), people with chronic liver disease, and people with HIV infection.
12 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.
13 People with diabetes who are younger than 60 years as soon as feasible after diagnosis; people with diabetes who are age 60 years or older at the discretion of the treating clinician based on the likelihood of acquiring HBV infection, including the risk posed by an increased need for assisted blood glucose monitoring in long-term care facilities, the likelihood of experiencing chronic sequelae if infected with HBV, and the likelihood of immune response to vaccination; all people with chronic liver disease not caused by hepatitis B. At present, routine testing of antibody response after vaccination in people with diabetes or chronic liver disease is not recommended.
14 HPV vaccine should be administered as indicated for males and females but is additionally recommended for all in this patient category for men 22 through 26 years of age (otherwise male indication is through age 21 years). Female indication in each category is through 26 years of age.
15 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.
16 Two doses ≥2 months apart recommended for patients with HIV infection if they are aged ≥2 years. If younger than 7 years old at previous dose, a patient should receive an additional dose of Menactra or Menveo 3 years after the primary series. Boosters should be repeated every 5 years thereafter. If aged ≥7 years at previous dose, a patient should receive an additional dose of Menactra or Menveo 5 years after the primary series. Boosters should be repeated every 5 years thereafter.
17 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.
18 This is an indication for PPSV23 only (as opposed to both PCV13 and PPSV23).
19 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 HIV-infected adults with CD4 cell counts of 200–499/mm3 are considered to have limited immune deficits and should be vaccinated according to the guidelines in Table 8-01. Meningococcal (MenACWY), pneumococcal, and hepatitis B vaccines are recommended for HIV-positive patients regardless of travel plans. Many clinicians regard patients with CD4 cell counts ≥200/mm3 who have undetectable viral loads as immunologically normal. 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 HIV-infected people. 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.

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. 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 immunosuppressive biologic agents. Patients on glatiramer acetate and interferon therapy have more limited immune deficits.

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

Other Chronic Conditions

Chronic medical conditions that may be associated with varying degrees of immune deficit include asplenia, chronic renal disease, chronic liver disease (including hepatitis C), and diabetes mellitus. These patients should be vaccinated according to the guidelines in Table 8-01. 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 and some chronic 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 who have previously received ≥1 dose of PPSV23 should receive a dose of PCV13 ≥1 year after the last PPSV23 dose was received. For adults who require additional doses of PPSV23, the first such dose should be given no sooner than 8 weeks after PCV13 and ≥5 years after the most recent dose of PPSV23.

A blunted response to hepatitis B vaccine has been reported in patients with immunosuppressive disease, which may include chronic hepatic or renal disease; a decreased response to hepatitis B vaccine has also been observed in patients with diabetes. Additional or higher doses of hepatitis B vaccine beyond the standard primary series may be necessary or indicated.

Asplenic patients are susceptible to overwhelming sepsis with encapsulated bacterial pathogens. 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.

  • Dosing schedules for meningococcal ACWY conjugate vaccine in asplenic people differ for the 2 available vaccines. Menactra is indicated for both pediatric and adult populations aged ≥2 years, with 2 doses separated by ≥2 months. Menactra is licensed from 9 months through 55 years of age. For people with asplenia, the vaccine should be administered at 2 years through 55 years of age. For children without asplenia aged 9 months through 2 years, Menactra should be administered at 0 months and 3 months, with an 8-week minimum interval between the doses. Booster recommendations vary by age. If younger than 7 years of age at the previous dose, a patient should receive a booster dose of Menactra or Menveo 3 years after the primary series; boosters should be repeated every 5 years thereafter. If 7 years old or older at the previous dose, a patient should receive an additional dose of Menactra or Menveo 5 years after the primary series; boosters should be repeated every 5 years thereafter.
  • Menveo is recommended on a 2-dose schedule for asplenic adults and children aged ≥2 years and schedules of either 4 or 2 doses for children under the age of 2 depending on age at vaccine initiation; booster vaccinations should be repeated every 5 years if risk is ongoing.
  • Serogroup B meningococcal (MenB) vaccine (Bexsero or Trumenba) is indicated for asplenic people ≥10 years of age. Travel itself is not an indication for vaccination with the serogroup B meningococcal vaccines. A booster interval has not been established.
  • Asplenic people should receive a 1-time dose of H. influenzae type b (Hib) conjugate vaccine.

People with terminal complement deficiencies and those receiving 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. The recommendations are the same as for patients with asplenia.

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, those who have had solid-organ transplants and who are on active immunosuppression, and hematopoietic stem cell transplant recipients (within 2 years of transplantation or still taking immunosuppressive drugs). People who are severely immunocompromised should generally not be given live vaccines, and inactivated vaccines are less likely to be 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 considered before starting immunosuppressive therapies, if feasible.

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 12 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. A repeat dose of zoster vaccine may be administered after hematopoietic stem cell transplant if 24 months have passed since the transplant, the patient does not have graft-versus-host disease, and the patient is considered immunocompetent.

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.

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 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 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
  • 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 8-02. 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 rejection prophylaxis), the waiting period is 3 months. For lymphocyte-depleting (alemtuzumab and rituximab) agents, the waiting period is ≥6 months, although many experts believe the waiting period should be ≥1 year. For steroid regimens considered immunosuppressive (see above), wait 1 month. Zoster vaccine 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. For agents not considered highly immunosuppressive (see Table 8-02), 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 immune parameters to evaluate vaccine safety or efficacy. Restarting immunosuppression after live vaccination has not been studied, but some experts would recommend waiting at least 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. HIV-infected people with 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 3, HIV Infection) and should not receive live viral or bacterial vaccines because of the risk that the vaccine could cause serious systemic disease.2 The response to inactivated vaccines also will be suboptimal; thus, vaccine doses received by HIV-infected people while CD4 cell counts are <200/mm3 should be ignored, and the person should be revaccinated ≥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 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.

 

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. Zoster and yellow fever vaccine may be administered when indicated. Live attenuated influenza vaccine should not be administered. Smallpox vaccine (mostly for military personnel) is also transmissible to immunocompromised household and intimate contacts. Immunocompromised hosts should be cautious about contact with infants who have received the live rotavirus vaccine and children who may have received the oral polio vaccine; handwashing should be emphasized for prevention.

Table 8-02. Immunosuppressive 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
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 Aphingosine 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
Ofatumumab Arzerra CD20
Panitumumab Vectibix EGFR
Lenalidomide Revlimid Immunomodulatory
Rilonacept Arcalyst IL-1
Rituximab Rituxan CD20
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: CTLA, cytotoxic T-lymphocyte antigen; TNF, tumor necrosis factor; CD, cluster of differentiation; IL, interleukin; VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor.
1 This 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. Some of these agents are less immunosuppressive than others; specifically, interferon used for hepatitis C and interferon and glatiramer acetate given to multiple sclerosis patients are immunomodulators, but clinical data to support safety with live vaccines are lacking.

SPECIAL CONSIDERATIONS FOR IMMUNOCOMPROMISED TRAVELERS

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.

If travel is unavoidable to an area where YF vaccine is recommended (see Maps 3-14 and 3-15) 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 be provided with a vaccination medical waiver (see Chapter 3, Yellow Fever). 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 the Advisory Committee on Immunization Practices considers precautions (as opposed to contraindications) to administration of YF vaccine, such as asymptomatic HIV (see “Precautions” in Chapter 3, 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 lower 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 decrease in response to vaccination is not particularly predictable based on the immunosuppressive regimen. Encouragingly, 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 Chemoprophylaxis

Immunocompromised travelers to malaria-endemic areas should be prescribed drugs for malaria chemoprophylaxis and receive counseling about mosquito bite avoidance—the same as for immunocompetent travelers (see Chapter 3, Malaria). Special concerns for immunocompromised travelers include any of the following possibilities:

  • Most current first-line regimens for HIV have few drug interactions, but some older maintenance regimens for HIV may interact with drugs used for malaria chemoprophylaxis. Notably, chloroquine, mefloquine, and primaquine may interact with older maintenance regimens for HIV. Potential interactions between a person’s maintenance medication and antimalarial drugs should be considered and researched.
  • The underlying medical condition or immunosuppressive regimen may predispose the immunocompromised traveler to more serious disease from malaria infection.
  • A malaria infection and the drugs used to treat the malaria infection 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 chemoprophylactic 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. A number of older, now less commonly used drugs, especially protease inhibitors, have potential interactions. Extra care must be taken in researching potential interactions in people with HIV who are receiving highly active antiretroviral therapy.

For any patient on antiretroviral drugs, an interactive web-based resource for assessing possible drug interactions is found at the University of Liverpool website (www.hiv-druginteractions.org) and should always be consulted before adding a new drug to a patient on an anti-HIV regimen.

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. Expert advice should be sought when treating patients for malaria who are also on HAART.

In organ transplant recipients, malaria chemo-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.

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

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 hand-washing 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.

Antibiotic prophylaxis for a very limited duration may be considered for travelers with severe immune suppression. 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 and rifaximin are active against several enteric bacterial pathogens and are not known to have significant interactions with 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.

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). 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 subsequent travel-associated illness. Depending on the traveler’s degree of immune suppression, the baseline TB status may be assessed by obtaining a tuberculin skin test, Mycobacterium tuberculosis antigen-specific interferon-γ assay, or chest radiograph.

Patients with advanced HIV and transplant recipients frequently take either primary or secondary prophylaxis for one or more opportunistic infections (such as Pneumocystis, Mycobacterium, and Toxoplasma spp.). Adherence to all indicated prophylactic regimens should be confirmed before travel (see Chapter 3, HIV Infection).

Key points to stress with the immunocompromised traveler are summarized in Box 8-01.

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