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Chapter 11 Posttravel Evaluation

Screening Asymptomatic Returned Travelers

Michael Libman, Sapha Barkati

CDC has no official guidelines or recommendations for screening asymptomatic international travelers without other specific risk factors. (For recommendations regarding the screening of newly arrived immigrants and refugees, see Newly Arrived Immigrants & Refugees in this chapter.) Nevertheless, the screening of travelers returning from developing countries represents a substantial portion of the activity of many travel and tropical medicine clinics.

The scientific literature on the cost effectiveness of screening asymptomatic travelers is sparse. It is clear that asymptomatic travelers can harbor many infections acquired during travel, some of which have the potential to cause serious sequelae or have public health implications. In some cases, these will include pathogens rarely found in the traveler’s country of origin. US medical practitioners may have little familiarity with the associated diseases, and specific diagnostic tests may not be readily available or may have poorly defined operating characteristics.

The decision to screen for particular patho­gens partly will depend on the type of travel, itinerary, and exposure history. Screening short-term healthy travelers who do not report a particular exposure is often not necessary. On the other hand, special groups of travelers such as long-term travelers (expatriates, aid workers, and missionaries), travelers visiting friends and relatives, and adventure travelers may have prolonged or heavy exposure to particular pathogens, and specific tests may be considered. Clinicians should be aware that exposure history may be unreliable and may not be predictive of infection. Further, the value of a detailed itinerary can be limited by incomplete information on where pathogens are endemic. Finally, the type of travel may not provide a practical assessment of risk.

Screening traditionally has been viewed as a secondary prevention intervention, that is, an attempt to identify existing occult illnesses or health risks. The cost effectiveness of screen­ing is dependent on the disease of interest and involves several considerations. Before screening asymptomatic travelers, the physician should evaluate the potential outcomes associated with the disease and whether an early intervention may reduce morbidity or mortality.

Evaluate screening tests with respect to sensitivity and specificity, risk to the patient, and cost. The low prevalence of tropical infections in asymptomatic travelers will heavily influence the positive predictive value of the screening tests, leading to an increased likelihood of false-positive results. As a result, the asymptomatic traveler may be subjected to further investigations, generating higher costs, anxiety, and possible other harms related to diagnostic followup, and creating complex considerations when balancing risks and benefits.

Because of convenience and patient susceptibility to suggestion at the time of screening, the screening visit may offer an opportunity to promote primary prevention by discussing behavioral or other risk factors predisposing to ill health, such as exposure to contaminated food and water, arthropods, and fresh water, and behavioral risks such as drug use or high-risk sex. For many long-term travelers, visits for asymptomatic screening may also be their only hiatus from a continuing assignment abroad that allows for a general health evaluation. The usual recommendations for the periodic health exam, which may include screening for hypertension, diabetes, cardiovascular disorders, and malignancy, would apply. These visits also provide an opportunity to review vaccination status, malaria prophylaxis, and health behaviors.

NONPARASITIC ILLNESS

Sexually Transmitted Infections and Bloodborne Pathogens

High rates of sexual activity with new partners, including sex workers, have been documented in overseas volunteers, expatriate workers, backpackers, and military personnel. Of concern are the low rates of reported condom use. Moreover, travelers may engage in high-risk activities such as getting a tattoo or a piercing, using injection or intranasal drugs, or receiving medical or dental care. Returning travelers with acute HIV, hepatitis B, hepatitis C, or syphilis infection pose public health risks and may be hesitant to volunteer a relevant history.

A detailed questionnaire on risk factors for sexually transmitted infections and bloodborne pathogens is recommended for all travelers, and screening according to published guidelines should always be considered. Screening for those with relevant exposures should include HIV and syphilis serologic tests as well as nucleic acid amplification testing for chlamydia and gonorrhea in urine and at sites of contact (rectum, pharynx). Hepatitis B and hepatitis C serology should be performed in travelers for whom a specific risk factor has been identified. All travelers born between 1945 and 1965 should be tested for hepatitis C if testing has not previously been done.

Zika Virus

The prevalence of Zika virus infection in many countries has decreased dramatically since 2017, and, as a result, the likelihood of a false-positive test result has increased. Moreover, evidence of Zika virus IgM antibody persistence well beyond 12 weeks after infection makes it difficult to determine the date of infection. Screening guidelines for travelers, including pregnant women and their partners, can be found in Chapter 4 and at www.cdc.gov/zika/hc-providers/index.html.

Tuberculosis

The incidence of tuberculosis (TB) infection related to travel is difficult to estimate. A history of work in high-prevalence settings such as in health care institutions or refugee camps merits screening. Traditionally performed using pretravel and posttravel TST, this process of screening is somewhat cumbersome, requiring as many as 4 visits (2 pretravel visits for a 2-step test and 2 posttravel visits after potential exposure) to a health care provider. This process can be simplified by using the interferon-γ release assay (IGRA), which is more expensive but also is less subject to false-positive results that can be related to previous bacillus Calmette-Guérin (BCG) vaccination. Studies assessing the use of IGRA for serial testing demonstrated a large variation in the rate of conversion and reversion. Fully investigate any positive TST or IGRA results, assess for symptoms suggestive of active TB disease, and obtain a chest x-ray. For more information, see Chapter 4, Perspectives: Tuberculin Skin Testing of Travelers.

PARASITIC INFECTION

Travelers are often most concerned with the possibility of an occult parasitic infection. Unfortunately, the literature shows that patient questionnaires and common laboratory testing used to screen for parasitic diseases possess poor sensitivity and specificity. Studies have shown that even an exhaustive risk factor history in asymptomatic patients is unable to reliably detect those who would or would not have evidence of parasitic infection. Physical examination is equally unrewarding.

Most commonly, a stool examination is per­formed, typically microscopy. Several molecular assays are commercially available; these detect a panel of viral, bacterial, and parasitic (limited to protozoal) pathogens. In some cases these panels are more sensitive than traditional testing methods, and even asymptomatic people are often found to harbor pathogens. The clinical implications of asymptomatic carriage, sometimes at a low level, are unknown for most of these agents, and the risks and benefits of treatment are not well studied.

A small number of helminthic infections, namely strongyloidiasis, schistosomiasis, and to a lesser extent filariasis, may be present in asymptomatic travelers and can be associated with significant morbidity if not screened and treated. Diagnostic methods to detect eggs and larvae directly may have poor sensitivity. Serologic tests are typically more sensitive, although some have performance limitations related to specificity and are usually preferred for screening asymptomatic travelers for these infections.

Intestinal Protozoa

Symptomatic patients with intestinal protozoa should be treated, particularly in cases of Entamoeba histolytica, in which severe disease and ectopic infections such as liver abscess can develop. The finding of pathogenic protozoa in asymptomatic patients is of questionable significance (with the possible exception of E. histolytica, a rare finding in asymptomatic travelers).

The most common protozoa found in asymptomatic travelers is Giardia duodenalis and Blastocystis species. History of exposure to contaminated food or water has poor predictive value. There is no evidence to suggest that these asymptomatic carriers are likely to develop symptoms at a later time. Certainly, the medications used to treat pathogens may have their own adverse effects. In theory, these “carriers” (true carriers versus transient asymptomatic infection) pose a public health risk, although transmission by asymptomatic travelers appears to be rare. This is further complicated by the fact that stool microscopy for protozoa is expensive, not very sensitive, and not highly reproducible, and many laboratories have limited expertise.

Entamoeba histolytica cannot be distinguished from E. dispar by microscopy. Differentiation requires further specimen collection and testing. Studies reveal that most travelers with Entamoeba on microscopy are carrying E. dispar. Antigen testing for E. histolytica and Giardia (among others) is fairly reliable but lacks the potential to screen for all intestinal parasites with a single test, and only some antigen tests are able to differentiate E. histolytica from E. dispar.

Commercial molecular methods to screen stool specimens for multiple pathogens simultaneously typically include several protozoa, generally with better sensitivity than microscopy. These assays are also able to specifically detect the potentially pathogenic E. histolytica and not E. dispar. They also offer rapid turnaround times of several hours and, although costs remain high, these assays are increasingly being used in returned travelers with suspected protozoal disease. Some of these panels detect organisms for which pathogenicity remains controversial, such as Blastocystis and Dientamoeba. Identifying these may lead to patient anxiety and unnecessary treatment.

Blood- and Tissue-Dwelling Protozoa

There is no justification for screening most asymptomatic travelers for malaria, whether by blood film, serologic tests, or molecular methods. No available tests can detect the latent hepatic forms (hypnozoites) of Plasmodium vivax or P. ovale. Travelers should be reminded to seek evaluation for unexplained fever and notify practitioners of any recent travel. Immigrants with frequent and regular exposure to malaria may gradually develop partial immunity. This may result in low-level parasitemia with few or no symptoms. They may later recrudesce with more severe illness. This phenomenon is rare in non-immigrant travelers. It should be noted that, in rare cases, travelers who have been compliant with prophylaxis may still acquire malaria and often these people will present with low parasitemia infections.

Occult trypanosomiasis in asymptomatic travelers (as opposed to immigrants) appears to be extremely rare. Screening tests, such as serology and molecular diagnostics, are of unknown value. For travelers to endemic areas of Latin America, testing for Trypanosoma cruzi might be considered in cases of prolonged residence in primitive housing, such as mud walls and thatched roofs, especially if reduviid bugs have been seen; in recipients of blood products; or in travelers with a convincing history of acute Chagas disease. East African trypanosomiasis has affected travelers but typically causes acute symptoms. West African trypanosomiasis is generally not reported in travelers. Refer patients suspected of having these infec­tions (in the setting of clinical, biological, or radiologic abnormalities) to an infectious disease specialist.

Helminths

Travelers are often concerned about “worms,” by which they mean intestinal helminths. However, infections of travelers with large numbers of the common nematodes, such as Ascaris, Trichuris, or hookworm, are rare. Questioning returning expatriates infected with intestinal helminths has disclosed no attributable symptoms compared with uninfected controls. The life cycles of almost all helminths preclude any real risk of ongoing transmission from asymptomatic hosts in developed countries. Helminths generally have a natural lifespan of months to a few years, which ensures eventual spontaneous clearance. In addition, low-intensity infections are of limited clinical importance, though in rare cases aberrant migration of Ascaris spp. can result in clinical disease. The exception to this is Strongyloides stercoralis.

For Strongyloides infections, serious compli­cations are well known, nonspecific symptoms may easily be overlooked, duration of carriage after infection is unlimited due to its autoinfection cycle, and the original burden of infection is irrelevant. Specific types of immune suppression, such as corticosteroid therapy, hematologic malignancy, hematopoietic stem cell transplant, solid organ transplant, and human T-lymphotropic virus type 1 infection, are the most important risk factors for a potentially lethal hyperinfection syndrome or disseminated strongyloidiasis. Unfortunately, diagnosis by stool examination is notoriously insensitive, and serologic methods are often required, as discussed below. Molecular detection of helminths is significantly more sensitive and specific compared with microscopy. However, molecular techniques are not widely available outside the reference laboratory and research setting.

Among the helminths capable of eventually causing illness in asymptomatic travelers, most emphasis in the literature has been given to S. stercoralis and the parasites that cause schistosomiasis and filariasis. There is no evidence that the low-burden schistosomal infections typically found in travelers are likely to lead to the types of complications commonly found in endemic areas, such as liver fibrosis or malignancy. Nevertheless, this possibility cannot be entirely ruled out, particularly in those who may have more intense exposures. Even brief exposures to freshwater lakes and rivers in known endemic areas in Africa are associated with substantial seroconversion rates. In addition, complications due to ectopic egg migration can occur in light infections and without warning.

On the other hand, reports of travelers with late complications from asymptomatic filarial infections are virtually nonexistent. Traditional tests for the parasites that cause these infections, including stool examination for S. stercoralis and Schistosoma spp., urine for S. haematobium, and blood or skin snips for microfilaria, all lack sensitivity, particularly in low-burden infection. For this reason, serologic testing has been advocated as the best screening tool. The problems with serologic screening include expense, lack of easy availability, and lack of standardization. Serologic tests are often designed to maximize sensitivity, typically at the expense of specificity. Unfortunately, specificity is almost impossible to define. Seropositivity in the absence of direct pathogen detection is common, and its clinical significance can be difficult to determine.

Fortunately for patients with strongyloidiasis or schistosomiasis, treatment is cheap, easy, and effective. The common antihelminthic agents, such as ivermectin, albendazole, and praziquantel used for a short-course therapy, have excellent safety profiles. Clinicians should be aware of rare but severe adverse events that can occur when using common antihelminthics in patients who have occult, unsuspected coinfection with other parasites: ivermectin and Loa loa (can cause encephalopathy) or albendazole and Taenia solium (can cause seizures, increased intracranial pressure with focal signs, and retinal damage).

While it is not clear who should be screened for helminthic infections, it is logical to at least perform serologic tests on travelers with a high duration and risk of exposure and to treat all those found to be positive. Since asymptomatic filarial infections appear least likely to have sequelae, and treatment is often neither very effective nor easy, the threshold for filarial serology (and antigen testing in the case of Wuchereria bancrofti) should be higher. Serology usually only becomes positive after adult forms have matured, which means waiting for 3 months or so after exposure. Serology for these pathogens is available at the parasitic diseases laboratory at CDC (www.dpd.cdc.gov/dpdx; 404-718-4745; parasites@cdc.gov). Serology for filarial infection is available as well through the NIH laboratory (301-496-5398).

Other helminth parasitic infections rarely seen in returning travelers include neurocysticercosis, fascioliasis, paragonimiasis, and others. Screening asymptomatic travelers for these infections is generally not appropriate. Primary care providers should refer patients suspected of having these infections (in the setting of clinical, biological, or radiologic abnormalities) to an infectious diseases specialist.

Eosinophilia

Screening for eosinophilia is a common test, since it is quick, universally available, and theoretically of value in detecting invasive helminths, if not protozoa. However, multiple studies have shown tests for eosinophilia to have poor sensitivity. Specificity can be high; however, the low prevalence of infection in asymptomatic travelers means positive predictive value is low. In addition, the finding of eosinophilia may lead to an extensive and often fruitless search for a cause, generating patient anxiety and high costs. Many cases of eosinophilia resolve spontaneously, possibly because of infection with nonpathogenic organisms or a noninfectious cause, such as allergy or drug reaction. Eosinophil counts may be repeated after several weeks or months before embarking on an extensive investigation. Counts may be highly variable, even within a single day, and are suppressed by endogenous or exogenous steroids. Evaluation of absolute counts, rather than by percentage of leukocytes, is more reproducible and predictive.

GENERAL GUIDELINES

The following sections and Table 11-02 may serve as a general guideline for screening asymptomatic returned travelers.

Short-Term Travelers (<3–6 months)

In this group of travelers, the yield of screening is low and should be directed by specific risk factors revealed in the history. A history of prolonged (>2 weeks) digestive symptoms during travel can suggest protozoal infection. Exposure to fresh water in a region endemic for schistosomiasis, especially in Africa, may merit serologic screening, with the addition of stool and urine examination in the case of high-intensity exposure. Serology for Strongyloides may be considered in those who have a high risk of skin exposure to soil likely to be contaminated with human feces, usually those with a history of frequently walking barefoot outdoors. A sexual history should be obtained, and screening for sexually transmitted and bloodborne infections may be warranted. Zika virus testing for asymptomatic travelers (including pregnant women) with potential exposure is generally not recommended unless there is ongoing Zika virus exposure (see Chapter 4, Zika). Work in a health care setting or other area at high risk for TB may merit screening.

Long-Term Travelers or Expatriates (>3–6 months)

For longer-stay travelers, as the overall yield of screening increases it becomes less useful to rely on history for selective testing. The emphasis should be on those with the longest stays and the most problematic sanitary conditions. In some cases employers may require certain tests, partly for reasons of liability. Stool examinations are usually done, although they serve mostly to provide psychological reassurance. Perform serologic testing for schistosomiasis and strongyloidiasis in those with recent or remote travel histories to endemic areas who report some level of risk.

A complete blood count with white blood cell differential, including eosinophil counts, liver transaminases, creatinine, and C-reactive protein are usually the basic set of tests performed. Interpret results cautiously as abnormalities may trigger further testing. Zika virus testing for asymptomatic travelers (including pregnant women) with potential exposure is generally not recommended unless there is ongoing exposure to Zika virus. TST or IGRA tests should be limited to those who have worked in a health care or similar setting or who have had intimate and prolonged contact with residents of a highly endemic area for ≥6 months. Any other screening should be guided by exceptional exposures or knowledge about local outbreaks.

Table 11-02. Considerations for screening asymptomatic travelers

RISK FACTOR OR EXPOSURE SUGGESTED SCREENING TESTS
Short stay (<3– 6 months), no identified risk factor/ exposure None
Long- stay (>3– 6 months), poor sanitation or hygiene CBC with eosinophil count, liver transaminases, creatinine, CRP; consider stool ova and parasite
Sexual contact HIV, syphilis, chlamydia, gonorrhea; HBV for men who have sex with men or sex with unknown partners; HCV screening if risk factors present or born between 1945– 1965
Tattoo, piercing, injection or intranasal drug use, medical/ dental care VHIV; HBV for injection drug use; HCV for injection or intranasal drug use or unregulated tattoos
Pregnant woman who traveled in Zika virus– endemic area or had sex with a partner who traveled in these areas Screening asymptomatic female travelers with potential exposure (but without ongoing risk) is generally not recommended
Health care worker TB screening (TST or IGRA)
Prolonged residence (>6 months) with population in a highly TB-endemic area TB screening (TST or IGRA)
Walking barefoot on soil potentially contaminated with human feces or sewage Strongyloides serology
Exposure to freshwater rivers, lakes, or irrigation canals Schistosoma serology

Abbreviations: CBC, complete blood count; CRP, C-reactive protein; HBV, hepatitis B virus; HCV, hepatitis C virus; TB, tuberculosis; TST, tuberculin skin test; IGRA, interferon-γ release assay.

BIBLIOGRAPHY

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