ARCHIVED - The Immunocompromised Traveller
Canada Communicable Disease Report Volume 33 • ACS-4 1 April 2007
An Advisory Committee Statement (ACS)
Committee to Advise on Tropical Medicine and Travel (CATMAT)*†
24 Pages -705 KB
The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.
Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer( s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.
An increasing number of Canadians are living with conditions that reduce immune competence, including organ transplantation, HIV infection and treatment with corticosteroids or immunosuppressive agents for a variety of indications. A growing number of these individuals are travelling to tropical and low-income countries1,2 . Some of these travellers are immigrant Canadians who may be less likely to seek pre-travel advice and more likely to be exposed to infectious risks of travel.
A broad range of common medical conditions including diabetes, alcoholism, renal failure and even advancing age can have significant but non-specific effects on susceptibility to infectious diseases, including some of those related to travel. However, this guideline focuses on more specific and more substantial abnormalities of immune function including solid organ or stem cell transplantation, HIV infection, malignant diseases (and their therapies), high-dose corticosteroid or cytotoxic drug therapy and splenectomy. Specific types of immune suppression tend to be associated with specific disease risks. This statement focuses on health risks and interventions that are in addition to those experienced by and recommended for, immunocompetent travellers. It is intended to supplement the standard care, e.g., vaccinations recommended to transplant recipients and other immunocompromised hosts, irrespective of travel.
The main areas of interaction between immune suppression and travel advice are:
- The potential for increased susceptibility to infections and appropriate measures to mitigate this risk
- Concerns regarding vaccine use
- safety of live vaccines
- possible decreased vaccine efficacy
- Problems related to drugs for the underlying condition and for travel-related illness
- reliable supply during travel
- drug interactions
There is some literature and an abundance of recommendations on the HIV-infected traveller in whom the degree of immune compromise can be quantified with modest precision by measuring CD4 lymphocytes. There is little evidence and fewer recommendations with respect to transplant patients. There is very little information relating to other forms of immune suppression3 and no well-validated laboratory measures to quantify the degree of immune suppression in most of these patients.
This document is divided into two main sections: 1) the immunosuppressive conditions and 2) the complicating infections. In order to avoid duplication, recommendations will not appear in both places; in most cases they will appear in the latter section except where the recommendation is very specific to the immunosuppressive condition, e.g., HIV or transplant.
- Physicians and specialty clinics caring for immunocompromised individuals should emphasize the need for expert travel advice, including a review of vaccination status, prior to travel to tropical and low-income countries.
Specific Immune Suppressing Conditions
The traveller with cancer
There is a broad spectrum in the potential immunologic impact of cancer depending on cancer type and treatment used. For most cancers, the main period of immune suppression is during or immediately following chemotherapy and/or radiation therapy when neutropenia and mucosal injury may be present. Most patients are unlikely to travel during this period. Vaccine response is likely to be best if given prior to chemotherapy or radiotherapy, or several months after their completion. Some chronic cancer therapies are hormonal (tamoxifen, gonadotropin release inhibitors) and have no significant immunologic effects.
Specific malignancies, particularly Hodgkin’s and to a lesser degree, non-Hodgkin’s lymphomas, may be associated with significant deficits in cell-mediated immunity which can persist even after cure, accompanied by ongoing risk of the characteristic spectrum of infections4,5 . Some therapies such as purine analogues (e.g., cladribine) may be associated with major suppression of cell-mediated immunity6 . Multiple myeloma and B-cell chronic lymphocytic leukemia are associated with deficiencies in humoral immunity and susceptibility, particularly to infection with encapsulated organisms such as Streptococcus pneumoniae.
- Travellers should be strongly discouraged from travelling during the immediate post-chemotherapy or radio-therapy period, at least until the treatment course is complete, neutrophil counts have stably normalized and the patient is not requiring transfusions.
- No special measures are routinely required prior to travel, for patients with most cancers which are cured or in full remission or who are taking only hormonally-based treatments.
- Specific patients identified by their oncologists as being likely to have relatively profound immune suppression due to their disease or treatment, should be offered advice similar to that provided to HIV-infected individuals with a CD4 cell count < 200 cells/mm3 (see below).
The transplant patient
Guidelines specific to this patient population exist and are evolving; these and input from local transplant programs may be helpful sources of information7,8 .
Among solid organ transplant recipients, immune suppression varies substantially depending on the organ. In general, kidney transplants require less immune suppression followed by heart and liver, with immune suppression most intense in lung and small intestine transplants, although this will vary with individual circumstances. In general, the degree of immune suppression is greatest in the first 3 to 6 months post-transplant and less after a year, but a significant degree of immune suppression persists indefinitely. A minority of transplant recipients who experience chronic rejection, persistent organ dysfunction, or chronic cytomegalovirus (CMV) or other infections, remain more profoundly immune suppressed.
Allogeneic stem cell transplant patients experience profound immune suppression in the early post-transplant period but relatively normal immunity after +/- 2 years if they are off immune suppressant medication and free of graft versus host disease. The differences in response of autologous and allogeneic stem cell transplant recipients are not currently sufficiently well characterized or different to justify a different approach to vaccination.
Travellers’ diarrhea may be associated with greater risk in the transplant patient for reasons over and above the increased susceptibility to infection such as increased risk of compromised renal function from dehydration and altered absorption of transplant immune suppressants. The safety of regular bismuth subsalicylate use in patients with decreased renal function is unknown.
Drug interactions are of particular concern in transplant patients. Chloroquine can increase serum levels of cyclosporine and perhaps sirolimus and tacrolimus. Data are limited regarding other possible interactions between travel-associated drugs and anti-rejection drugs. The effect on cyclosporine levels, of short courses of ciprofloxacin or azithromycin for travellers’ diarrhea is thought not to be a significant risk.
Some vaccine issues, particularly relating to timing of vaccination, are unique to transplant patients9-12 . Vaccine responses in patients with organ failure pre-transplant may be less than normal. However, vaccine response, for example to hepatitis A13,14 and B vaccines, is particularly likely to be depressed posttransplant, especially in the first 6 months. Vaccine response may be greater for some vaccines when the primary vaccination is given pre-transplant and boosted post-transplant15 . A variety of measures including increased vaccine dose, intradermal administration and use of adjuvants have been tried to improve vaccine response in transplant recipients. Theoretical concerns have been raised regarding the possible effect of vaccination on transplant rejection16,17 , but the current consensus of opinion is that risk of the infection being prevented outweighs any possible risk of vaccination. Vaccination of the stem cell donor has been shown to transfer HBV-specific immunity to the recipient18 .
Duration of vaccine efficacy, which in some cases could be monitored by antibody response, may be reduced in transplant recipients19 but limited evidence exists to guide monitoring or re-vaccination in this population, the best support being for hepatitis B vaccine.
- In general, live vaccines should be avoided: a) post-solid organ transplant or b) stem cell transplant recipients in the first 2 years post-transplant or who continue to take immune suppressant drugs. The risks of exposure to the disease must be balanced against the risks of vaccination, and the individual’s degree of immune suppression (see measles and yellow fever vaccine sections).
- Stem cell transplant recipients should have all vaccinations including any appropriate travel-related vaccines, started anew post-transplant when immune reconstitution is likely to have taken place (off immune suppressive medications, no graft versus host disease, usually +/- 2 years post-transplant).
- Live vaccines such as measles and yellow fever, if clearly indicated, can probably be given to stem cell transplant recipients with minimal risk if the patient is off immuno-suppressive medications, does not have graft versus host disease and is considered immunocompetent(11).
- Solid organ transplant recipients need not routinely repeat vaccinations given ≥ 2 weeks prior to transplantation.
- Because of likely low efficacy in the first 6 months post solid organ transplant, where possible, vaccination should be carried out before transplantation or > 6 months after solid organ transplantation when immune suppression has been reduced to a baseline level and the transplantation physician assesses the immune response capacity to be nearly optimally recovered.
- Solid organ transplant recipients or stem cell transplant recipients still receiving immune suppressive drugs, for whom antimalarial prophylaxis is recommended, should consider starting the drug several weeks prior to departure in order to monitor and adjust the effect on serum cyclosporine, and perhaps tacrolimus or sirolimus levels and adjust dosing accordingly. This is particularly important if chloroquine is to be used, but may also apply in the case of mefloquine or atovaquone/proguanil.
The splenectomized traveller
The predominant risk is of overwhelming infection with encapsulated organisms, particularly Streptococcus pneumoniae, but including meningococcus, Haemophilus, Capnocytophaga sp. and other bacterial pathogens. The risk has been estimated at 1/500 person years of observation. Risk is highest in the first 2 years following splenectomy, but remains elevated for life20 . Young children are at highest risk. These risks are not travel-specific although exposure to meningococcus, particularly serotype A and possibly S. pneumoniae, may be greater in some low-income country settings, the prevalence of antimicrobial resistance may be higher and rapid access to expert medical care for sepsis is likely to be more difficult while travelling. The degree of protection against infection following partial splenectomy or autotransplantation as opposed to complete splenectomy is not known21 . Other conditions such as sickle cell disease are associated with an increased risk of infection due to decreased splenic function.
There is no prospective vaccine efficacy data in splenectomized patients but a combination of pneumococcal vaccine and the promotion of early penicillin therapy for febrile illness appeared to reduce the risk of fatal sepsis in splenectomized Danish children22 . The possible advantages of conjugate pneumococcal or meningococcal vaccines have not been established in splenectomized patients. Some authorities23 suggest provision of a course of broad-spectrum antibiotics such as a “respiratory quinolone” or amoxicillin/clavulanate for pre-emptive empiric therapy should an episode of suspected sepsis occur when medical help is not immediately available. Some travel clinics have developed a letter which the traveller can show to local physicians, indicating the history of splenectomy, risks and possible approaches to management.
The spleen plays a role in the response to malaria so that hyposplenic individuals may have reduced ability to clear malaria parasites24-28 . However falciparum malaria is potentially life threatening in any malaria non-immune traveller, regardless of splenic or immune function. The risk of severe illness due to Babesia sp., a rare tick-borne disease which can be acquired in parts of the U.S. and Europe, is increased in splenectomized individuals. Some authorities suggest consideration of standby therapy for malaria in selected splenectomized travellers in addition to chemoprophylaxis.
- Prior to travel, splenectomized individuals should ensure that they are up-to-date for pneumococcal, Haemophilus influenzae and meningococcal vaccines according to prevailing guidelines29 and if recommended by a physician expert in this area, antimicrobial prophylaxis30 . A “standby” course of a broad spectrum antibiotic therapy such as a levofloxacin, moxifloxacin or amoxicillin/ clavulanate, should be considered for travellers who may have limited access to emergent medical care during their travel.
- Splenectomized travellers should seek expert advice regarding malaria risk and prevention before travel and should be particularly attentive to following those recommendations closely.
- Splenectomized travellers should have a low threshold for seeking urgent medical advice if they experience an unexplained febrile illness, either before or after initiating presumptive antimicrobial therapy.
The traveller taking tumour necrosis factor blockers
Patients on Tumour Necrosis Factor (TNF) α blockers for rheumatoid arthritis, Crohn’s disease or other conditions are a recently recognized group at risk for re-activation of tuberculosis31 . Such patients may also have an increased risk of progression of primary TB following a new exposure. An association has also been described with histoplasmosis and several other “granulomatous” infections, to which the risk of exposure may be greater in some tropical settings 32,33 .
- Patients taking TNF-α blockers should be advised of the risk of tuberculosis transmission in high-prevalence countries, particularly in high-risk settings, such as health care work.
- They should undergo testing for latent tuberculosis infection ≥ 8 weeks after return from travel to a TB endemic area and treatment of latent infection (chemoprophylaxis) should be strongly recommended for any patients demonstrating induration of ≥ 5 mm.
- Tuberculosis and endemic fungal infections should be considered early in the differential diagnosis of unexplained illness in these patients, particularly after travel.
The traveller taking corticosteroid therapy and immunesuppressant agents such as cyclophosphamide, methotrexate, azathiaprine
Patients taking these drugs for rheumatic or other conditions may have a clinically significant degree of immune suppression. Longer term therapy (> 2 weeks) and a dose of > 20 mg/day or 2 mg/kg/d in children of prednisone34 is commonly considered to result in clinically significant immunosuppression35 . Rarely, patients on drugs such as cyclophosphamide experience complications similar to those of patients with advanced HIV infection suggesting profoundly depressed cell-mediated immunity36 but no clinical or laboratory marker is known to predict those at higher risk.
- In relation to decisions such as the administration of live vaccines, patients on corticosteroid therapy for > 2 weeks at a dose equivalent to > 20 mg per day of prednisone, should be considered analogous to patients with HIV infection with a CD4 cell count < 200 cells/mm3 (see below). Patients receiving other immunosuppressive drugs should be advised on a case-by-case basis depending on the degree of immune suppression as judged by the prescribing physician.
The traveller with HIV infection
The degree of immune suppression, which particularly affects cell mediated immunity, varies widely among HIV-infected individuals, reflecting disease stage and response to antiretroviral therapy, and is approximately predicted by a recent CD4+ cell count - > 500 cells/mm3: relatively normal, 200 to 500 cells/mm3: mild to moderate immune suppression, < 200 cells/mm3: relatively severe immune suppression, < 50 cells/mm3: profound immune suppression.
The first problem faced by HIV-infected travellers is the risk of exclusion or discrimination on the basis of their infected status. Travellers can determine the legal requirements of specific countries from the website37 .
HIV-infected travellers on antiretroviral (ARV) therapy also need to plan the logistics of drug supply and storage during the trip. Several antiretroviral drugs, particularly in the protease inhibitor (PI) and to a lesser degree the non-nucleoside reverse transcriptase inhibitor (NNRTI) classes have clinically important interactions with other drugs. At present there are very few clinical data on interactions between the two groups of drugs; in most cases, concerns are based on what is known about pharmacokinetics and metabolism of the drugs. Knowledge in this area evolves rapidly. In the case of antimalarial drugs, ritonavir and possibly other protease inhibitors may decrease levels of atovaquone to a degree which might be clinically significant. Atovaquone can also cause a modest increase in zidovudine levels warranting closer monitoring of hemoglobin and neutrophil count and potentially, dose adjustment. Ritonavir increases serum quinine levels and may have a similar effect on artemisinin derivatives. The metabolism of lumefantrine (benflumetol), a drug now widely used in Africa in combination with artemether (Coartem), is inhibited by protease inhibitors such as ritonavir. Pending clinical studies, there are concerns with the administration of lumefantrine or Coartem to patients on protease inhibitors because of a risk of life threatening cardiac arrhythmias associated with prolongation of the QT interval, known to be serious problem with the related drug halofantrine38,39 .
Vaccines may produce a transient increase in HIV replication but this has not been found to be clinically significant.
HIV confers a markedly increased risk, not only of TB reactivation( 40) but of primary progressive disease following acute exposure41 and of re-infection following cure42. Disseminated infection due to non-typhoidal Salmonella species has long been recognized as an AIDS-defining illness. The risk of pneumococcal disease, although not specifically a travel-related infection, may be approximately 50-fold greater in HIV-infected individuals43.
There are important bidirectional interactions between HIV and malaria: HIV increases the frequency and degree of malaria parasitemia and malaria increases the level (viral load) of HIV infection44,45.
- HIV-infected travellers should take the opportunity of preparing for travel to ensure they are up-to-date with their routine vaccinations including pneumococcus and hepatitis A and B.
- HIV-infected travellers should explore any possible legal or administrative problems they might encounter in proposed destination countries and assure a reliable supply of antiretroviral medications if applicable.
- Prior to prescribing an antimalarial drug for either prophylaxis or therapy, to a patient taking antiretroviral medication, check a frequently updated source for possible interactions.
The pre-travel assessment often provides an opportunity to update “routine” vaccinations in all travellers.
- Except in specific circumstances as discussed below, live vaccines should be avoided in immune compromised hosts.
Bacille Calmette-Guérin (BCG) has variable and limited efficacy in immune competent hosts, unknown benefit in immunocompromised hosts and a very limited role at most, in TB protection for travellers. There is a well documented though uncommon risk of dissemination in HIV-infected individuals46 and in patients with some types of congenital immune deficiency.
- BCG is not recommended for any immune compromised patient.
Cholera vaccination is rarely indicated for travellers47 and the settings where its use might be contemplated (e.g., refugee camps) are unlikely destinations for immune compromised travellers. A live attenuated cholera vaccine (Mutacol™) was safe but resulted in a decreased serologic response in 38 HIV-infected individuals who did not have AIDS48. The combined B subunit and killed whole cell vaccine (Dukoral™) was effective against cholera even in a population with high HIV prevalence49. It may result in a temporary increase in HIV viral load50. It may provide some short-term protection against one form of travellers’ diarrhea, E. coli LT toxin-mediated diarrhea47. Because of its limited benefit in the prevention of travel-associated diarrhea, Dukoral™ is not routinely recommended as a priority for travellers but may be considered in those for whom diarrhea would be associated with increased risk47.
- Dukoral™ may be considered for immune compromised travellers or those with compromised renal function, as an adjunctive measure in the prevention of travellers’ diarrhea.
Diphtheria, pertussis, tetanus
The risk of exposure to these diseases may be increased in low-income countries. There does not appear to be a significantly increased risk of these diseases in the immune suppressed. The serologic response to diphtheria and tetanus and possibly pertussis vaccines, have been found to be diminished in children with HIV infection but there is no evidence of increased risk of vaccine adverse effects51 .
- Travellers, including those who are immune suppressed, should ensure their “routine” vaccines including DPT are up-to-date prior to travel.
Hepatitis A is one of the most important preventable risks of travel. Risk and disease severity appear to be similar in immune compromised and immunocompetent individuals. Travellers with coexisting liver disease, e.g., hepatitis C infection, may have a higher risk of hepatic decompensation following acute hepatitis A infection52. Failure of serological response after vaccination is much more common in some groups of immunocompromised patients14. In HIV infected patients, the response rate to hepatitis A correlates inversely with the CD4 cell count without a clearly delineated cut-off level53,54 . The available diagnostic serologic testing for hepatitis A is not sufficiently sensitive to detect a protective vaccine response.
- Hepatitis A vaccine should be recommended for travellers with mild to moderate degrees of immune suppression, as for all travellers to tropical or low-income countries.
- Immune globulin should be recommended for travellers to low income countries, who have more severe degrees of immune suppression (e.g., HIV with CD4 cell count < 200 cells/mm3) and who lack serologic or convincing historical evidence of immunity from natural infection. Immune globulin could be considered as an alternative for hepatitis A vaccine in non-immune travellers with moderate immune suppression (e.g., HIV with a CD4 cell count of 200 to 300) going to a high risk destination.
Hepatitis B disease can be more severe and vaccine efficacy is decreased in the immune compromised51 . Hepatitis B prevalence is high in many tropical and low-income countries and transmission may be associated with blood/body fluid contact, sexual contact and close contact with local children. High dose hepatitis B vaccination has been shown to increase seroconversion rates in groups who have higher rates of vaccine failure such as dialysis and HIV-infected patients55. Immunity may wane even after successful vaccination, in immune suppressed hosts, resulting in a risk of symptomatic hepatitis. The precise role and timing of booster doses in these patients is unclear.
- Immunocompromised adults who lack antibodies to hepatitis B surface antigen (HBsAb), and who are hepatitis B surface antigen (HBsAg) negative, should be given an increased dose (40 micrograms) of hepatitis vaccine at 0, 1 and 6 months 29 and the serologic response checked after completing the course.
- Following vaccine-related seroconversion, periodic monitoring for the presence of anti-HBs should be considered, taking into account the severity of the compromised state and whether the risk for HBV is still present. Should antibody testing show subsequent decline below protective levels, a booster dose and re-testing should be undertaken as necessary.
Travellers who require replacement (intravenous) immune globulin for a congenital or acquired humoral immune deficiency will optimize their protection against travel-acquired infection if they schedule their dose close to departure where as vaccine efficacy is likely to be enhanced by giving vaccines shortly prior to immune globulin doses, at the time when blood levels of “donor” antibodies are at their nadir.
Influenza or its complications may be more severe in immune suppressed patients. The seasonal epidemiology of influenza differs in tropical regions and in the southern hemisphere.
- Injectable, killed influenza vaccine is specifically recommended for immune compromised individuals regardless of travel, 28 and should be included in pre-travel vaccination, taking into account the influenza season at the destination56 . If influenza vaccine is unavailable in Canada at the time of departure or if the circulating strain in the destination country is not a good match with the vaccine available in Canada, consideration should be given to obtaining influenza vaccine from a reliable source on arrival in the destination country.
Japanese B encephalitis
Encephalitis is very rare overall, among travellers to endemic areas. The risk of clinical encephalitis following infection with the Japanese B encephalitis virus (JEV) is estimated at one in hundreds. Although the risk of disease may be greater in the elderly, it is not known to be increased in immune suppressed individuals. The vaccine may be less effective in this group57 .
- The indications for JEV vaccine are the same in the immune suppressed as in immunocompetent travellers.
The risk of exposure may be greatly increased in some lowincome countries. The disease can be much more serious in the immune suppressed58 and HIV-infected59 with reported case fatality rates of 40% to 70%. Vaccine efficacy is markedly reduced in the immune compromised51. Although large numbers of HIV-infected children have received measles vaccine, there is only one case report of fatal vaccine-related disease in a 20 year old with advanced HIV60 and rare reports of dissemination in the setting of other types of immune suppression61. The great majority of travellers are protected against measles through either naturally acquired or vaccine mediated immunity. As with other diseases, measles immunity is commonly lost in recipients following allogeneic stem cell transplantation.
- Stem cell (bone marrow) transplant recipients should receive two doses of measles vaccination 6 to 12 months apart at ~24 months post transplant as long as they are off immune suppressive medications and are not suffering from graft versus host disease.
- In other immunocompromised travellers born after 1970 and lacking a clear history or documentation of measles or of two doses of measles vaccine given prior to their becoming immune suppressed, consideration should be given to testing measles serology.
- Measles vaccine should be recommended to travellers who are believed to be measles nonimmune (no history of measles disease or vaccination, serology negative) who will be travelling in a low-income country with poorly controlled measles, unless they have clinical or laboratory indicators of very severe immune suppression.
- Immune globulin should be considered for profoundly immune suppressed, measles non-immune travellers to high transmission areas 8 .
The risk of meningococcal disease does not clearly differ in most types of immune suppression, the exception being specific complement disorders, but the vaccine is recommended for all splenectomized individuals regardless of travel62 . Although not well studied, it is likely that the protective response may be decreased in relation to the degree of immune suppression. A recently approved quadrivalent conjugate vaccine is the product of choice.
- Quadrivalent conjugate meningococcal vaccine is indicated on the basis of travel itinerary to highly endemic areas and in all splenectomized individuals.
Pneumococcal disease is not typically considered a travelassociated disease, but is much more common in some lowincome country settings. Although the risk of pneumococcal disease varies with the type of immune suppression and the efficacy of the polysaccharide vaccine may be limited in these populations63 most immune suppressed individuals are considered candidates for pneumococcal vaccine regardless of travel plans. A few studies suggest that the serologic response of immunocompromised hosts to conjugate pneumococcal vaccine is better than to the polysaccharide vaccine64 , but the conjugate vaccine contains only seven, rather than 23 serotypes and evidence of protective efficacy in these patients is lacking.
- An initial dose of pneumococcal vaccine, with a booster dose 5 years after the initial dose, should be offered to immune compromised patients according to current guidelines29 , regardless of travel plans.
Live oral polio vaccine can very rarely cause vaccine-associated poliomyelitis with a risk of 1/750,000 first doses. The risk may be higher in the immune compromised, but very few cases have been identified in Africa where millions of HIV-infected children have received the vaccine51 . Spread of vaccine virus between close contacts is common.
- Immune suppressed travellers to endemic areas should ensure that vaccination with inactivated polio vaccine is up to date.
- Oral polio vaccine (not available in Canada) should not be given to immunocompromised individuals nor to their household contacts.
Rabies is a rare risk of travel and almost universally fatal, once established, even in the immune competent. The serologic response to post-exposure vaccination is reduced in HIV-infected patients with CD4 cell counts < 200 cells/mm65 .
- The serologic response should be checked post vaccination in any immune suppressed individual given pre-exposure rabies vaccination.
The response to typhoid vaccine may be reduced in immune compromised patients66. The live attenuated Ty21a organism used in the live vaccine is thought to be incapable of sustained replication in the human host. However, a polysaccharide component vaccine alternative is available.
- The injectable Vi capsular polysaccharide vaccine is preferred in immune compromised travellers who are at risk of typhoid.
Varicella transmission is paradoxically lower in many tropical countries67 so that travel is not likely to be a major factor in the consideration of use of this live attenuated vaccine in an immune compromised patient.
- Varicella vaccination should be given to immune suppressed individuals according to National Advisory Committee on Immunization (NACI) guidelines or the patient’s physicians or transplantation care team, regardless of travel plans.
Yellow fever is a very uncommon illness in travellers and the risk varies widely within recognized areas of transmission68. The risk for travellers to endemic areas of Africa has been estimated as 23.8/100,000/week, in epidemic areas 357/100,000/week. Since these estimates were based on studies in local populations, they may overestimate risk in travellers. Data from US travellers produced an estimate of 0.4 to 4.3 cases/million travellers to yellow fever endemic areas69. Yellow fever has a high mortality rate even in the immune competent.
The live attenuated yellow fever vaccine has been associated with 23 cases of vaccine-associated viscerotropic and neurotropic disease since 1996, of which 61% were fatal. A disproportionate number (4, 17%) were associated with disease involving the thymus70. It has recently been recognized that the risk of yellow fever vaccine is substantially increased in those over age 6069. Only one case has been reported to date in an HIV-infected individual71. The serologic response was significantly decreased in children with HIV infection72. The World Health Organization (WHO) advises withholding yellow fever vaccine in children with symptomatic HIV infection52. Limited experience suggests that yellow fever vaccine can be given safely and produce protective levels of antibody in HIV-infected individuals with CD4 cell counts > 200 cells/mm373.
- Immunocompromised travellers should be made aware of the risk of visiting areas with active yellow fever transmission.
- In general, yellow fever vaccine should be avoided in immune suppressed individuals.
- When the primary reason for vaccination for an immune suppressed traveller is a country-specific vaccine requirement rather than significant epidemiologic risk of infection, a waiver letter should be provided.
- Travellers thought to have mild to moderate degrees of immune suppression, e.g., HIV infection with CD4 cell count > 200 cells/mm3, who will be at significant risk for acquiring yellow fever, for example in an area of documented recent activity, should be offered the vaccine and advised of the theoretical risks.
- Profoundly immune suppressed travellers who, in spite of being informed of the risks, plan a trip to an area of active yellow fever risk, should obtain advice from a travel medicine expert and should adhere rigourously to mosquito protection measures.
The OPPORTUNISTIC Diseases
It is increasingly recognized that travellers’ diarrhea is most often a foodborne illness and is commonly associated with food handling practices in restaurants in low-income countries74.
It does not appear that toxin-mediated forms of travellers’ diarrhea or cholera are more common or severe in the immune compromised.
Some specific bacterial infections, particularly non-typhoidal Salmonella75,76 and to a lesser extent, Campylobacter sp.77, which are strongly associated with travel in low-income countries, are more severe and much more likely to cause bacteremia, in HIV-infected and other immune suppressed hosts78,79. Shigella may produce a more persistent illness in the HIV-infected81.
Giardia infection is not clearly associated with immune suppression except for persistence in patients with IgA deficiency. An association of immune suppression and Entamoeba histolytica has been reported infrequently81,82.
Some protozoan infections, to which exposure is more common in low-income country settings, are more persistent or serious, even life threatening, in the immune compromised host: Cryptosporidia, a self-limiting infection in the healthy host, causes a persistent wasting illness in advanced HIV infection and rarely in other immune suppressive conditions. Treatment with nitazoxanide (currently available only through emergency release in Canada) in the immune suppressed has had some success83. Infection with Cyclospora and Isospora behaves similarly except that long-term treatment with cotrimoxazole is effective. Microsporidia, which is not commonly recognized in the immunocompetent, but can be travel-acquired,84 is an important pathogen in the setting of advanced HIV infection, and has been described in transplant patients85.
Regular prophylactic use of bismuth subsalicylate preparations may reduce the risk of travellers’ diarrhea by at least 50% in immune competent travellers86. There is little experience with immune suppressed individuals and dosing in patients with renal dysfunction is not well established.
- While recognizing the limitations of “food and water precautions”, immunocompromised travellers should be advised to follow them rigourously, specifically in relation to the choice of hot meals in restaurants of all kinds in low-income countries, water precautions (bottled, boiled or filtered), and avoidance of all unpasteurized milk and milk products.
- Prophylactic antimicrobial agents are not recommended routinely but exceptionally may be considered for a limited period of particularly high risk in a very vulnerable host.
- Every immune suppressed traveller, particularly those with any degree of renal dysfunction or taking nephrotoxic agents such as cyclosporine, should be informed about the importance of maintaining hydration and educated as to the means of oral rehydration.
- All immune suppressed travellers to low-income country settings should be prescribed a supply of antibiotic such as ciprofloxacin or azithromycin, depending on resistance patterns at the destination country87 and advised to have a low threshold for taking it for any diarrheal illness other than mild watery diarrhoea.
- Immune suppressed travellers should be advised to have a low threshold for seeking qualified medical advice locally if there is any suggestion of dehydration (decreased urine output, inability to replace fluids orally), persistent fever or if illness is otherwise severe or prolonged.
Documented interactions between malaria and immune suppression are limited to HIV infection44,45 and hyposplenism (see above). Antimalarials for prophylaxis or treatment may interact with some antiretrovirals and transplant-related immunosuppressives.
Tuberculosis is a potentially important risk to the immunocompromised traveller. Management of this risk is further complicated by the fact that the standard test for identifying infection with Mycobacterium tuberculosis, the tuberculin skin test (TST), has reduced sensitivity in individuals with depressed cellmediated immunity. Alternate tests for latent infection such as in vitro lymphocyte stimulation assays have recently been developed but experience is limited with clinical application of these tools, particularly whether they improve sensitivity among the immune compromised.
The risk of travel-related TB exposure can be estimated from WHO incidence figures for the respective country88. Risk is thought to correlate directly with duration of travel or stay in the endemic country and with the degree of contact with local people, work in the health sector carrying the highest risk89. Children of immigrants travelling to their parents’ homeland, (visiting friends and relatives, VFR) constitute a specific risk group90.
- Patients with HIV infection or other conditions associated with significant suppression of cell-mediated immunity should be informed of the risk of travel and of specific activities, particularly health care work or close contact with local people, in high TB prevalence countries.
- Travellers with any significant immune compromise going to medium or high TB prevalence countries should follow the recommendations of CATMAT91,92 with regard to pre- and post-travel testing for latent tuberculosis infection.
- Any individual with HIV infection or other significant suppression of cell-mediated immunity, found to have evidence of latent tuberculosis infection, (> 5 mm of induration of a TST or a positive lymphocyte stimulation test), should be strongly advised to take chemoprophylaxis (treatment of latent TB infection) after assessment to exclude active disease.
- Physicians caring for immune compromised travellers should have a high index of suspicion for TB as a possible cause of unexplained persistent illness, regardless of the TST response.
The course of dengue virus infection has not been found to be altered by HIV infection or other causes of immunosuppression. Paradoxically, one study found that dengue infection decreased HIV viral load93.
With the exception of Strongyloides stercoralis, the course of intestinal or tissue helminth infections including cysticercosis(94) has not been demonstrated to differ in the immunocompromised host.
Strongyloides stercoralis can progress to “hyperinfection” with a very high mortality rate in immune suppressed individuals, particularly those on high dose glucocorticosteroids95. Perhaps surprisingly, these events have rarely been seen in the HIV-infected; indeed there is a stronger association between Strongyloides and HTLV-1 than HIV. Strongyloides may also be a less common than expected complication in transplants because of the anti-helminthic activity of cyclosporine96,97.
- Immune suppressed individuals should be advised against walking barefoot in tropical areas which might be endemic for Strongyloides.
- Screening for Strongyloides or presumptive treatment should be considered prior to transplantation in immigrants from endemic areas.
- It is not clear that interactions between HIV and schistosomiasis would be clinically important for travellers; decreased egg excretion of S. hematobium98 and increased susceptibility to re-infection with S. mansoni99 have been reported in the HIV-infected.
Sexually transmitted infections
Sexually transmitted infections (STI), including diseases uncommon in Canada such as chancroid and lymphogranuloma verereum, drug resistant organisms, syphilis and HIV, may be highly prevalent in many travel destination countries. STIs should be prevention priorities for all travellers; a few such as syphilis may present a more aggressive course of illness in the immune compromised.
- Every traveller, including the immune suppressed (and particularly those with HIV infection), should be advised about the importance and the means of preventing STI and offered testing upon return if they have been at risk100.
Endemic fungal infections
Endemic fungal infections including Cryptococcus sp. (cosmopolitan distribution), Histoplasma (wide patchy global distribution except in cold or dry areas), Coccidioides (south west USA and parts of Mexico), Paracoccidioides (South America) and Penicillium (mainly South East Asia) are important complications of advanced HIV and other immune suppressive conditions in their respective endemic areas. One study showed a protective effect of itraconazole prophylaxis against Cryptococcus and Penicillium in HIV-infected Thai patients with CD4 counts < 200101. There is no specific information on the risk of these infections in travellers or the efficacy of, or indications for, prophylaxis in this group.
- Antifungal prophylaxis with fluconazole or itraconazole 200 mg daily could be considered in unusual circumstances where the risk of exposure to endemic fungi such as Pencillium is thought to be particularly high, in HIV-infected patients with CD4 counts < 50 cells/mm310.
Risk of, or interaction with, other “exotic” diseases which could be encountered by the immune suppressed traveller
There is little evidence103 that the risk, presentation or outcome of brucellosis differs in the immune compromised.
The course of scrub typhus (Rickettsia tsutsugamushi) the only rickettsial species studied in this context was not found to be altered by co-existing HIV infection104.
Several cases of leptospirosis in HIV-infected individuals have been reported105 all clinically severe, but all of which recovered. While infections with species of Bartonella which appear to be cosmopolitan in distribution are well recognized as complications of HIV infection106, Bartonella bacilliformis, the Peruvian species which causes Carrion’s disease (Oroya fever and verruga peruana) is rarely diagnosed in travellers and has not been associated with HIV infection or other immunosuppressive conditions.
Altered forms of Chagas’ disease (Trypanosoma cruzi) resulting in brain abscesses are well recognized as complications of HIV infection and transplantation in endemic areas. This disease could be an important concern in immigrants from endemic areas, but the infection is virtually unknown in travellers.
There is no recognized interaction between immunosuppression and African trypanosomiasis, a very rare infection in travellers, with a very high mortality even in immunocompetent hosts, except that treatment response may be decreased107.
Leishmania is an important complication of HIV108 and other immune suppressed states109,110 in parts of southern Europe, Africa, the Americas and endemic parts of Asia and the Middle East. As of 1999, over 1,400 cases of leishmaniasis in HIV-infected individuals had been reported, > 90% from Europe. Cutaneous leishmaniasis is a well-recognized risk of travel in parts of Asia, Africa and Latin America while visceral leishmainiasis is rarely reported among immunocompetent travellers. HIV-associated leishmaniasis has been seen primarily among injection drug users suggesting that some leishmania transmission may occur through that route. To date, only a small number of cases of leishmaniasis in immunosuppressed travellers have been reported111. Unusual patterns of clinical involvement including gastrointestinal tract, pulmonary and CNS involvement, have been reported frequently in HIV-infected individuals and the “classical” features of visceral leishmaniasis are often not seen. Unusual strains of leishmania have been described causing visceral human disease. Serologic testing is less sensitive and rates of relapse after treatment are much higher in immunosuppressed patients. Personal protective measures including insecticide treated bednets against sandflies and particular care to avoid needle sharing may minimize the risk112.
- CATMAT acknowledges the valuable contribution of Dr. Karen Doucette in regard to transplant patients.
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*Members: Dr. P.J. Plourde (Chair); Dr. C. Beallor; M. Bodie-Collins (Executive Secretary); Dr. K. Gamble; Ms. A. Henteleff; Dr. S. Houston; Dr. S. Kuhn; Dr. A. McCarthy; Dr. K.L. McClean; Dr. J.R. Salzman; Dr. B.Ward.
Liaison Representatives: Dr. C. Greenaway; Mrs. A. Hanrahan; Dr. C. Hui; Dr. R. Saginur; Dr. P. Teitelbaum; Dr. M.Woo.
Ex-Officio Representatives: Dr. J. Given, Dr. F. Hindieh; Dr. J.P. Legault; Dr. P. McDonald; Dr. R. Paradis; Dr. C. Reed; Dr. M. Smith; Dr. M. Tepper
Member Emeritus: Dr. C.W.L. Jeanes. †This statement was prepared by Dr. S. Houston and approved by CATMAT.
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