Fever in the Returning Traveler

Background: It is predicted that approximately two billion tourist trips to foreign countries will be taken worldwide each year by 2030. Germany has long been among the most active countries in tourism. The frequency of illness among persons returning from developing and newly industrialized countries is 43–79%. The appropriate diagnosis of fever in returning travelers is a clinically important matter, as it can be a sign of a life-threatening illness.

Methods: This review is based on publications (2001–2022) retrieved by a selective search in PubMed for studies on the epidemiology, diagnosis, and treatment of febrile illnesses in returning travelers, or on specific tropical diseases.

Results: Diarrhea, fever, and skin changes are the most common manifestations of disease after travel to tropical and subtropical areas. The diagnostic evaluation should be performed in a series of steps, beginning with a precise travel history and the identification of specific risk factors. Among travelers returning from sub-Saharan Africa, Plasmodium falciparum malaria is the most common cause of fever on presentation to centers for infectious diseases and tropical medicine, affecting approximately 50 per 1000 travelers. Among persons returning from travel to Southeast Asia, dengue fever is the most common infectious disease, affecting 50–160 per 1000 travelers. Further potentially dangerous diseases include chikungunya and zika fever, typhoid and paratyphoid fever, amoebic liver abscess, visceral leishmaniasis (kala-azar), leptospirosis, and, very rarely, imported cases of viral hemorrhagic fever. COVID-19 and influenza are important differential diagnoses.

Conclusion: The differential diagnosis can be narrowed by thorough history-taking with particular attention to the patient’s travel route, combined with a good knowledge of the geographic spread and incubation times of the main tropical diseases. Algorithms help clinicians to focus the diagnostic work-up and select the appropriate further laboratory tests and diagnostic procedures.

According to the World Tourism Organization (UNWTO), an estimated two billion persons will travel each year by 2030 (1). As a result of the global increase in mobility, travel-related diseases are gaining in importance. Although travel medicine advice can minimize health risks even before a trip begins, physician contacts are common during and after a trip (2). Studies from Europe and the United States have reported that 43% to 79% of travelers fall ill during or after staying in developing and newly industrialized countries (3, 4). According to data from the EuroTravNet clinics, the European surveillance sub-network of GeoSentinel, acute diarrhea, viral syndromes with or without skin manifestation as well as malaria are the most common reasons for clinic visits (5). Furthermore, a significant increase in arbovirus infections (e.g., dengue fever, Chikungunya and Zika fever) was observed over a period of 20 years (1998–2018). The most frequently visited travel regions include sub-Saharan Africa, Southeast Asia and the Indian subcontinent. Among travelers returning from sub-Saharan Africa, P. falciparum malaria (Malaria tropica) is with about 50 cases per 1000 travelers the most common cause of fever in patients seen at centers for infectious disease and tropical medicine. In other tropical and subtropical regions, such as Southeast Asia, dengue fever is the dominant cause of fever (50–160 cases per 1000 travelers with fever) (5, 6). In 2019, 993 malaria cases were reported in Germany; in the previous years, the number of cases was at a similar level of around 1000 per year (7, 8, 9). The number of dengue cases reported in 2019 was 1176, representing a threefold increase in ten years. In the years 2020/2021, a decrease in reported travel-related infectious diseases of 40–90% compared to 2019 occurred as a result of the pandemic-related decrease in long-distance travel (10). Yet, the number of tourist travels and travel-related diseases is expected to rise again (11).

Given its clinical relevance, the differential diagnostic work-up of fever as a sign of a potentially life-threatening disease is at the heart of the diagnostic process. In many cases, there is uncertainty in the management of febrile returning travelers outside of specialized facilities (12). The aim of this article is to support mainly primary care doctors by providing guidance for a structured diagnostic approach focusing on relevant diseases, i.e., conditions with high incidence, high transmissibility and/or high potential to pose a threat to the patient’s life.

Methods

This review is based on pertinent publications retrieved from a selective literature search in the PubMed database for studies on the epidemiology and diagnosis of fever in the returning traveler or specific tropical diseases, published between 2001 and 2022. In the absence of evidence or supporting literature, the management recommendations (including the algorithm in the Box) are based on the authors’ own experiences or best practices in a center for infectious diseases and tropical medicine.

Box

Fever in the returning traveler: Initial assessment and establishing the diagnosis

Structured approach to fever after return from travel

Fever, defined as a body temperature ≥ 38.3 °C, is an important symptom in the returning traveler seeking medical attention, as it leads to hospitalization in about 30 % of cases (13) and may be indicative of severe disease (14). One-third of the fever-related clinic visits are diagnosed with a tropical infectious disease, with malaria accounting for the majority of cases (70%); 38% of the visits are due to non-tropical infections and in 23% of cases the cause is non-infectious or unspecified (13). SARS-CoV-2 infection (COVID-19) as a differential diagnosis is increasing in importance, as is influenza (11). Climate change and environmental changes are causing shifts in vector distribution areas, so that formerly “classic” tropical diseases, for example some arboviral infections, are becoming more likely to occur even during travel within Europe (15). Examples of autochthonous diseases with the potential to become endemic in the future include West Nile fever (also in Germany), dengue fever (Southern Europe) and Chikungunya fever (Southern Europe). In primary care, it is a key concern to identify diseases with high individual and societal health risk and to narrow down the differential diagnostic spectrum, taking a stepwise approach. By no means should rare (“exotic”) diseases be ruled out a priori. Special considerations apply to children, pregnant women and immunocompromised patients (eBox 1).

eBox 1

Special considerations in children, pregnant women and immunocompromised individuals (selection)

Risk assessment for highly contagious diseases and clinical instability

Highly contagious, life-threatening diseases (high consequence infectious diseases, HCID) are very rarely imported from the tropics/subtropics (16, 17). In Germany, the last two cases of a viral hemorrhagic fever (VHF) transmissible from human to human were reported in 2016. One was a US citizen transferred from Togo to Germany for treatment of Lassa fever, which was only diagnosed post-mortem, the other a mortician with additional secondary infection (18, 19). Besides the Lassa virus, the group of highly contagious VHF pathogens include Ebola virus, Marburg virus and Crimean-Congo hemorrhagic fever virus (CCHFV), among others (17, 20). Even though imported VHF cases are very rare, the transmission risk of HCID makes it an important differential diagnosis to consider (eBox 2) (17, 20, 21, 22).

Most notable in the group of severe highly contagious respiratory diseases are the Middle East Respiratory Syndrome (MERS coronavirus; Arabian Peninsula and neighboring countries, mainly Saudi Arabia) and pneumonic plague (mainly Madagascar and East/Central Africa, secondary South/Southeast Asia and South America, sporadic United States) (23, 24). These should be considered in patients with respiratory symptoms/pneumonia, above mentioned geographic exposure and potentially additional contact to animals, animal products or animal excrements (MERS: dromedary camels; pneumonic plague: fleas, rats, cats, guinea pigs and others) or contact with persons with proven or suspected infection (17, 20, 23, 24).

If a highly contagious disease is already suspected based on a patient’s history and clinical findings, the patient should be isolated immediately. The health authorities must be informed instantly pursuant to paragraph 6 of the German Protection against Infection Act (Infektionsschutzgesetz, IfSG). The decision on how to proceed in a case, especially with regard to the initial patient transfer, is made by the local health authority together with the treating physician and the responsible competence/treatment center of the Permanent Working Group of Competence and Treatment Centers for High Consequence Infectious Diseases (STAKOB, Ständiger Arbeitskreises der Kompetenz- und Behandlungszentren für Krankheiten durch hochpathogene Erreger) (eBox 2) as well as the responsible state health authority. Personal protective equipment should be worn while providing patient care until transfer (17, 22).

eBox 2

Management of patients with suspected viral hemorrhagic fever as per standards in the authors’ department, adapted from (17, 22, e11-e13)

To identify patients with a greater risk of a lethal progression, all patients with suspected systemic infectious disease should be assessed using the quick Sequential Organ Failure Assessment“ (qSOFA) score (Box) (4, 21, 25). Apart from fever, clinical findings indicative of severe disease include petechiae/purpura as a sign of hemorrhagic diathesis, cyanosis, meningism, peritonism, oliguria/anuria, and acral necrosis (17, 21). Any identified high-risk patient should be immediately hospitalized and, if necessary, admitted to ICU (4, 21, 26).

According to a systematic review, deaths are rare among febrile migrants and returning travelers (overall lethality, 0.22%; eight studies) (13). Nevertheless, urgent diagnosis is recommended, as delayed treatment may lead to rapid disease progression with poorer prognosis, especially in cases with P. falciparum malaria, the most common cause of death in the returning traveler (21). In Germany, three malaria deaths were reported in 2017 and 2018, respectively, two deaths in 2019 and one death in 2020, all after staying in sub-Saharan Africa (7, 8, 9, 10, 16).

Symptom-focused clinical history and physical examination

When taking a patient’s history, current symptoms as well as symptoms experienced before, during and after the travel should be recorded along the timeline with as much detail as possible. Temporary, self-limiting symptoms, such as a transient rash (e.g., associated with rickettsioses, dengue fever) (eFigure) or a “typical“ biphasic disease course, e.g., with leptospirosis), can provide valuable clues (27). Based on the symptom timeline and familiarity with incubation times (Table 1, eFigure 1), it is already possible to narrow down the diagnosis. For example, if first symptoms occurred ≥ 21 days after the presumed or latest possible exposure (usually corresponds to the day of departure), VHF and dengue fever can be virtually ruled out given their maximum incubation periods (21, 26, 28, 29). Conversely, for example, P. falciparum malaria with a minimum incubation period of six days can be ruled out in the case of a three-day short stay in an endemic area and symptom onset immediately on the day of departure (26, 30). However, due to the highly variable incubation times, malaria infections can manifest after several months or even years (Table 1, eFigure 1). As a rule of thumb, malaria diagnostics should be performed within 24 hours (on an emergency basis) up to four months after a stay in an endemic area (28, 30). Caution should be used when making differential diagnostic discriminations based on incubation periods, as vague or incorrect patient information or lack of awareness of symptoms and their chronological progression may result in incorrect differential diagnostic conclusions. Rarer scenarios that equally thwart this approach are cases of non-endemic transmission of a tropical disease (e.g., airport malaria) (26).

eFigure

Important differential diagnoses

Table 1

Incubation periods of febrile travel-related infectious diseases in detail, adapted from (21, e5, e6, e7)

eFigure 1

Incubation periods of febrile, travelrelated infectious diseases, adapted from (21, e5-e7)

Physical examination of all body systems should be performed with special attention to instability signs, skin and mucosal findings, including the anogenital region, ophthalmological findings (e.g., conjunctivitis, bleeding), swelling of lymph nodes and enlargement of the liver and spleen, as mentioned under step 1. The guiding findings obtained allow for further differentiation (Table 2). Approximately 20% of febrile returning travelers experience undifferentiated fever (fever without concomitant symptoms other than headache, muscle and joint aches, fatigue) (29, 31). In 14–35% of the cases with undifferentiated fever, malaria is the underlying condition; in the subgroup of travelers from sub-Saharan Africa, this proportion is even higher (32–62%) (29). Other tropical disease with undifferentiated fever include dengue fever, typhoid/paratyphoid fever and rickettsioses (21, 28, 29). For some rickettsioses (e.g., African tick bite fever), a thorough inspection for a necrotic skin lesion (so-called eschar or “tache noire“, eFigure) is warranted.

Table 2

Symptom-based overview of travel-related infectious fever syndromes, adapted from (21, e5, e8)

History focused on exposure risk

The travel history comprises information about all countries and regions of countries travelled (including transit countries), mode and duration of travel, reason for travel, activities (including sexual and drug history), contacts with animals/sick persons/health facilities, accommodations, food, potentially sick fellow travelers, and preventive measures (including travel vaccinations, vector protection, malaria chemoprophylaxis).

With the information about the geographical exposure (Table 3, eFigure 2), the differential diagnosis can be further narrowed down. For example, malaria is by far the most common specific diagnosis among travelers returning from sub-Saharan Africa, while among travelers to Asia dengue fever and typhoid fever and to South America dengue fever and leptospirosis are the predominant diagnoses (5, 13). As a rule, the longer the duration of the travel (i.e. with increasing risk of exposure), the greater the risk of contracting an infectious disease (26). The reason for travel, too, has an impact on the evaluation of differential diagnoses: According to a prospective, monocentric study from Antwerpen, P. falciparum malaria was significantly more common among returning travelers who travelled abroad for work (38%), migrants (26%) and VFRs (travelers visiting friends and relatives, migrants or their offspring visiting friends/family in their country of origin) (26%) compared to tourists (14%) (p<0,001, n = 1743), whereas rickettsioses, dengue fever and acute schistosomiasis were almost exclusively diagnosed in tourists and returning travelers who had been abroad for work (31).

Table 3

Overview of infection-related risk exposure, adapted from (21, e9, e10)

eFigure 2

Frequency of occurrence of tropical diseases in the febrile returning traveler by travel region, adapted from (13)

Targeted questions should be asked to identify disease-specific risk factors related to activities, food and contact with animals or people abroad (Table 3). Freshwater exposure may be indicative of schistosomiasis (note endemic areas) or leptospirosis (12), sexual contacts or percutaneous exposure (tattoos, piercings, intravenous application of drugs/medications) of acute HIV or hepatitis B virus infections (12, 21, 29). If a patient denies exposure and reports having taken preventive measures, this should not lead to immediate exclusion of certain diagnoses: for example, some travelers may not have noticed insect bites; likewise, travel vaccinations and malaria chemoprophylaxis are not 100% effective. The protective efficacy of parenteral typhoid Vi capsular polysaccharide vaccines, for example, is only 69% in the first year (systematic review, three studies, n = 99 979) (32) and the efficacy of malaria chemoprophylaxis with atovaquone/proguanil is 95.8% (meta-analysis, ten RCTs, n = 4539) (33). Besides travel-related information, information about present and past illnesses, long-term medication and PRN medication as well as the possibility of pregnancy should be obtained. Special attention should be paid to (iatrogenic) immunodeficiency, as it may be associated with an increased risk of infection/complications of infection (21, 26, 34).

Note cosmopolitan diseases

In the traveler returning from the tropics/subtropics, non-tropical cosmopolitan diseases are sometimes overlooked, a phenomenon which is explained to some extent by so-called anchoring bias: The diagnostic assessment is “anchored” to certain pieces of information, such as the recent travel, and misses other/new facts (35). The share of febrile cosmopolitan infectious diseases after stay in the tropics/subtropics is actually about 30% (13). Therefore, autochthonous infectious diseases with “typical“ spectrum of pathogens should also be taken into account: bacterial pneumonia (e.g., Streptococcus pneumoniae, Legionella, Mycoplasma), urinary tract infections (e.g., Enterobacterales), meningitis (e.g., Neisseria meningitidis, Streptococcus pneumoniae, Listeria), endocarditis (e.g., Staphylococcus, Streptococcus, Enterococcus), systemic viral infections (e.g., cytomegalovirus, Epstein-Barr virus [EBV], human herpes virus-6), and bacterial or viral gastroenteritis (e.g., adenovirus, norovirus, nontyphoidal Salmonella, Campylobacter, Clostridioides difficile) (21, 28, 29, 36).

Finally, globally distributed infectious diseases with a high transmission rate (e.g., COVID-19, measles, varicella, influenza, tuberculosis) should always be considered, as the incidence rates of some of these pathogens are significantly higher in non-European countries (21). In addition, among returning travelers non-infectious causes of fever are also relevant: Fever of unknown origin is the initial presentation in 2% to 25% of all cancers (e.g., lymphoma) as well as 5% to 32% of all autoimmune diseases (e.g., rheumatoid arthritis, giant-cell arteritis) and hereditary febrile syndromes (e.g. familial Mediterranean fever) (36). Likewise, febrile episodes in the general population are related to medicines in 3% to 7% of cases (drug-induced fever) (36). In patients with drug rash with eosinophilia and systemic symptoms (DRESS), eosinophilia and rash can misdirect the diagnostic evaluation, especially in returning travelers (for example, putative parasitic disease or exanthematous flavivirus infection). Furthermore, travel-related venous thrombosis/thromboembolism (incidence rate for flights >4 hours: <0.01%; >8 hours: 0.5%) is also a potential cause of fever (37).

International travel is associated with an increased risk of temporary colonization with multidrug-resistant bacteria (MDRB) (38, 39, 40, e1). A German study (38) and a Finnish study (e1) on intestinal colonization with extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales after overseas travel found colonization rates of about 30%, with the risk of colonization depending on the region of travel (highest for India, 73%) and showing a positive correlation with traveler‘s diarrhea and antibiotic treatment (38, e1). Likewise, hospitalization abroad is a major risk factor for MDRB colonization (e2). Consequently, the MDRB risk should be taken into account in the evaluation of the febrile returning traveler, both when selecting an empirical antibiotic treatment and with regard to the diagnostic workup and necessary hospital hygiene procedures (39, 40, e1-e4).

Paraclinical diagnosis

As a general rule, a definite diagnosis or a well-founded tentative diagnosis should precede the initiation of a specific treatment. Only in a few cases, it is possible to make a visual diagnosis (e.g., African tick bite fever: eschar and fever after a trip to South Africa, memory of a tick bite). Therefore, additional investigations are usually required, and should have a favorable cost-benefit ratio.

Basic testing should at least include differential blood count, serum electrolytes, renal function tests (creatinine, urea), liver function tests (aspartate aminotransferase [ASAT], alanine aminotransferase [ALAT]; gamma-glutamyl transferase [GGT]), coagulation status and markers of inflammation (e.g., C-reactive protein). Depending on the clinical presentation and the suspected diagnosis, this standard laboratory workup is expanded by adding, for example, hemolysis tests (suspected malaria), muscle enzyme tests (suspected trichinellosis) or further special analyzes. Eosinophilia may indicate invasive parasitosis (e.g., strongyloidiasis, filariasis); a low eosinophil count may be indicative of typhoid fever, if the clinical presentation is suggestive of the disease.

Many infectious disease can only be detected once a pathogen-specific incubation period or prepatent period (period between parasitic infection and appearance of larvae/eggs) has ended or after production of antibodies. Thus, performing specific diagnostic tests too early (or too late) may lead to false negative results. It may be necessary to repeat the testing (e.g., in patients with suspected malaria every 24 hours; if required, repetitively over a period of several days). The disadvantage of testing for antibodies is that pathogens can only be detected indirectly and false-positive results may occur (e.g., due to polyclonal B-cell stimulation triggered by EBV infection or due to cross-reaction of related pathogens). Antibody specificity can be increased by follow-up testing or measuring avidity (the strength of the interactions between the antigen and antibody—increases over the course of the immune response). Serology results should always be interpreted in context.

In general, direct testing (e.g., antigen tests, polymerase chain reaction [PCR], culture, microscopy) has a higher specificity. Serological tests are utterly unsuitable for the acute diagnosis of diseases such as malaria and typhoid fever: The gold standard of malaria diagnosis remains the direct microscopic visualization of Plasmodium parasites in the stained “thick drop“/blood smear (eFigure) with determination of the percentage parasite load, complemented by rapid diagnostic testing [RDT]); Salmonella Typhi bacteria can be cultured initially by blood culture and from the second week onwards from urine and stool samples. In the case of culture-based testing with resistance analysis, it must be borne in mind that it takes several days before results become available and indicated treatments (e.g., empirical administration of antibiotics in patients with suspected typhoid fever) should not be delayed. Sampling for blood culture and malaria diagnosis can be performed whether or not the patient has fever. The possibility of double infections must also be taken into account so that relevant coinfections can simultaneously be ruled out (e.g., if dengue fever is suspected, additional malaria testing should be performed in travelers returning from endemic areas).

Further diagnostic workup and management

In about 20% of febrile returning travelers, the cause of the fever cannot be identified despite comprehensive diagnostic evaluation (13). The reasons are many: Examples include low sensitivity of the diagnostic test, post-infectious condition and misinterpretation of available findings. In some cases, it may be helpful to repeat examinations or choose an alternative diagnostic test (e.g., PCR testing in malaria patients with low-level parasitemia). In most cases, the condition is self-limiting and benign, requiring only pragmatic management (e.g., regular follow-up visits and repetition of the basic diagnostic evaluation until all symptoms have resolved). If in doubt, a specialized center should promptly be contacted in case symptoms persist, the patient‘s condition deteriorates or new symptoms appear (eBox 2).

Conflict of interest statement
The authors declare that no conflict of interest exists.

Manuscript received on 10 February 2022, revised version accepted on 1 April 2022

Translated from the original German by Ralf Thoene, MD.

Corresponding author
Prof. Dr. med. Christoph Lübbert, DTM&H
Interdisziplinäres Zentrum für Infektionsmedizin (ZINF)
Bereich Infektiologie und Tropenmedizin;
Klinik und Poliklinik für Onkologie, Gastroenterologie,
Hepatologie, Pneumologie und Infektiologie
Universitätsklinikum Leipzig, AöR
Liebigstraße 20, 04103 Leipzig, Germany

Cite this as:
Paquet D, Jung L, Trawinski H, Wendt S, Lübbert C: Fever in the returning traveler. Dtsch Arztebl Int 2022; 119: 400–7. DOI: 10.3238/arztebl.m2022.0182

►Supplementary material
eReferences, eFigure, eBoxes, eFigures:
www.aerzteblatt-international.de/m2022.0182

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