Fever upon return from a tropical trip: a comprehensive guide for travelers and healthcare professionals

Fever is a universal symptom, but when it occurs after a stay in a tropical region, it takes on a particular significance and requires immediate attention. Although it may signal a benign and self-limiting illness, fever upon return from travel can also be the first sign of a rapidly progressing and potentially fatal pathology. It is therefore crucial to urgently assess any febrile condition in a returning traveler. Healthcare professionals should be aware of the main etiologies, preventive measures, and associated diagnostic and therapeutic approaches. Similarly, travelers should be aware of the potential risks and precautions to take before, during, and after their stay.

Understanding traveler's fever: definitions and the importance of rapid assessment

Fever upon return from a tropical trip is the second most common reason for consultation for travelers, representing 23% of cases, just after digestive disorders (42%) and before dermatological conditions (17%). This statistic highlights the importance of this symptom. A rapid and adequate assessment is essential, as some pathologies can evolve very quickly and threaten the vital prognosis. It is important to note that tropical pathologies can be evoked even in patients who have traveled several years ago, or who have not traveled at all, as in the case of "airport malaria".

Essential knowledge for healthcare professionals includes the ability to assess the patient's general condition, conduct a thorough interview on travel history, and examine potential skin manifestations. Travel recommendations are regularly updated, and it is essential to consult the guidelines of international organizations and national health authorities for travelers and healthcare professionals. In France, the High Council of Public Hygiene and the Institute for Public Health Surveillance (InVS) publish specific recommendations for travelers.

The clinical approach to a febrile state upon return from travel is broken down into four fundamental steps, allowing for an accurate diagnosis and ensuring appropriate management. First, cosmopolitan infections should be considered, i.e., those not specifically related to tropical travel, such as influenza, ENT, pulmonary, or urinary infections. However, it is imperative to systematically screen for malaria in any febrile patient returning from the tropics, regardless of the associated symptoms, as 10 to 30% of patients with malaria may present with cough, nausea, vomiting, diarrhea, or abdominal pain, thus mimicking more common infections.

The second step is to look for acute, life-threatening pathologies requiring emergency treatment. These include malaria, enteric fever (typhoid, paratyphoid), rickettsiosis, amoebic liver abscess, meningitis or meningoencephalitis, African trypanosomiasis (rare) and viral haemorrhagic fever (rare). The third step is to diagnose pathologies which, although rarely acute and dangerous, require specific treatment. These include leptospirosis, borreliosis, brucellosis, schistosomiasis (Katayama fever), leishmaniasis and Chagas disease. Finally, the fourth stage involves considering pathologies that do not require specific treatment, such as viral hepatitis, dengue fever, chikungunya and Zika, as well as other arboviroses.

Pathologies to consider: a broad spectrum of infections

The range of infections to consider in the face of a fever upon return from a trip is vast and varies depending on the destination and activities of the traveler. Cosmopolitan diseases are the most common, but it is always essential to rule out malaria.

Among the pathologies to be aware of are digestive infections and dermatoses, which are also very common upon return from travel. Specifically regarding diarrhea, it can be of bacterial origin (campylobacter, salmonella, shigella, enterotoxigenic E. coli, entero-invasive E. coli, Vibrio cholerae), parasitic (giardia, cryptosporidium, cyclospora, entamoeba histolytica) or viral. As for skin lesions, sources mention dermatophytoses, urticarial lesions (often linked to insect bites), larva migrans, myiases, and dengue exanthema.

Tropical diseases can manifest as a febrile state, often accompanied by less specific symptoms. It is crucial to consider dengue fever, chikungunya, other arboviruses, HIV, rickettsiosis, brucellosis, borreliosis, leptospirosis, visceral leishmaniasis, schistosomiasis and other helminthiases, as well as trypanosomiasis.

Epidemiology is a key factor in guiding diagnosis. For example, Plasmodium falciparum is the most frequently identified pathogen during stays in sub-Saharan Africa, accounting for approximately 30% of fever cases upon return. In contrast, dengue fever is the main etiology in Southeast Asia (13%) and Latin America (8%). Non-P. falciparum malaria is more widespread (around 4-9% depending on the region). Rickettsioses are also present in all these areas (2-5%), and enteric fever is more common in Southeast Asia (3.4%). A significant proportion of cases remain attributed to other causes or are unknown, highlighting the complexity of differential diagnosis.

Medical history and clinical manifestations: essential clues for diagnosis

The medical history is a fundamental step in the evaluation of a febrile patient returning from travel. It must be thorough and include key questions to guide the etiological diagnosis. These questions include:

• Where did the patient travel? It is important to know the countries visited, and whether they were cities or rural areas, as some diseases are endemic in specific regions.
• When did the trip take place? The duration of the stay, the date of return and the season of the trip are crucial information, particularly for determining disease incubation times.
• Who is the patient? The traveler's medical history may influence susceptibility to certain infections.
• How was the trip? This part of the anamnesis is particularly rich in clues:
  • Swimming or Rafting: May point towards schistosomiasis or leptospirosis.
  • Food consumed: Ingestion of unpasteurized milk may suggest brucellosis, while raw meat may indicate trichinellosis. Contaminated food and water are a very common and non-specific mode of transmission for many germs.
  • Insect bites: Mosquitoes are vectors of malaria, dengue fever, and chikungunya. Ticks can transmit African Rickettsiosis or Lyme disease. Fleas are associated with Rickettsia typhi, and the tsetse fly with African trypanosomiasis. It should be noted that many patients do not remember being bitten.
  • Risky sexual contact or blood contact (dentist, tattoo): May suggest HIV or hepatitis B infection.
  • Vaccinations received: Knowing the vaccination status (hepatitis A, hepatitis B, typhoid fever, yellow fever) is important, knowing that 3% of post-travel feverish states are preventable by vaccination.
  • Medications taken: Taking malaria prophylaxis or antibiotics during the stay may alter the clinical presentation or diagnosis of certain diseases.

Les temps d'incubation sont des indices précieux. Par exemple, une dengue ne peut être responsable d'une fièvre débutant 20 jours après le retour, car son incubation est de 3 à 14 jours. De même, une fièvre débutant au lendemain d'un court séjour de 4 jours en Afrique de l'Ouest n'est pas un paludisme, l'incubation minimale étant de 7 jours. Le tableau des temps d'incubation mentionne des périodes pour la dysenterie bactérienne (<7 jours), la dengue (7-14 jours), le paludisme (7-21 jours), la leishmaniose viscérale (>4 semaines), entre autres.

In addition to the anamnesis, a complete clinical examination is crucial. Certain clinical manifestations are particularly contributory to the differential diagnosis:

• Skin rash: May be observed in measles, arboviruses (dengue, Zika), rickettsioses, typhoid fever, or borreliosis. Dengue exanthem is a notable example.
• Cutaneous black spot (eschar): Characteristic of certain rickettsioses (R. africae, R. conorii).
• Conjunctivitis: Associated with leptospirosis, rickettsiosis, measles, and certain arboviruses (Zika).
• Adenopathies: May indicate rubella, toxoplasmosis, CMV or HIV infection, arboviruses, tuberculosis, leishmaniasis or trypanosomiasis.
• Hepatomegaly: Suggests hepatitis, amoebic abscess, flukes (fascioliasis), leishmaniasis, or malaria.
• Splenomegaly: Common in malaria, leishmaniasis, and enteric fever.
• Neurological signs: Involve serious pathologies such as meningitis, encephalitis, trypanosomiasis or malaria.

Paraclinical examinations: confirming the diagnosis

Paraclinical examinations are essential to confirm the etiological diagnosis of a febrile illness upon return from travel. A basic assessment should be performed for each patient, supplemented by additional examinations based on clinical suspicion or initial results.

The basic assessment includes:

• A complete blood count (CBC), which may reveal anemia or thrombocytopenia, common in malaria.
• C-reactive protein (CRP), bilirubin, AST, ALT (liver enzymes) and creatinine (renal function). Elevated transaminases are common in dengue fever, for example.
• Systematic malaria testing, including blood smear, thick drop and rapid test (antigen detection).
• Urinary sediment.

Depending on clinical suspicion, additional tests may be required:

• A stool examination (for leukocytes, parasites, culture) in case of digestive disorders.
• Blood cultures to identify bacteria, especially in cases of suspected enteric fever.
• Specific viral and/or bacterial serologies for infections such as arboviruses (dengue, chikungunya), rickettsioses, leptospirosis, amoebiasis, HIV, and syphilis. For dengue, the rapid test (NS1 antigen detection) is sensitive from the first days of fever, and specific IgMs appear after 5 to 7 days.
• Parasitic serologies, particularly for screening for helminthiasis after a tropical stay.
• PCR (polymerase chain reaction) assays for the direct detection of pathogens, for example, Zika or Ebola.
• Urine culture.
• Lumbar puncture in case of neurological involvement (suspected meningitis or encephalitis).
• A chest X-ray or abdominal ultrasound may be indicated. Abdominal ultrasound is sensitive for amebic liver abscesses, although non-specific.

It is important to note that in case of fever with eosinophilia, the most frequent cause in travelers is acute schistosomiasis. Other helminthiases should also be considered, such as trichinellosis, fascioliasis (flukes), toxocarosis, as well as strongyloidiasis, ascariasis and hookworm disease in the migration phase.

Malaria management: an absolute priority

Malaria is an absolute priority in the evaluation of any fever upon return from a tropical trip. It should be systematically investigated, regardless of the associated symptoms, in any person who has stayed in an endemic area. The diagnosis can be suspected even several months after the return, and in 2% of cases, it can occur more than a year after the trip.

A precise medical history is crucial for malaria:

• Country visited: Three-quarters of cases diagnosed in Switzerland are contracted in Africa, where Plasmodium falciparum is responsible for 85% of cases. In Asia and Latin America, P. falciparum is responsible for 17-22% of cases.
• Date of stay: The minimum incubation period is one week. 95% of malaria attacks occur within two months of return.
• Anti-malarial prophylaxis: It is important to know whether or not adequate prophylaxis was taken, or whether antibiotic treatment (cotrimoxazole, tetracyclines, macrolides, fluoroquinolones) with partial anti-malarial activity was in progress.

Les manifestations cliniques du paludisme sont souvent peu spécifiques, mimant un état grippal avec fièvre, céphalées, frissons, sudations profuses et myalgies. Plusieurs facteurs rendent le diagnostic plus probable : une prophylaxie anti-malarique inadéquate ou absente, une splénomégalie, une anémie (<12 g/dl) et une thrombopénie (<150 G/l). Il est à noter que 40% des patients atteints de paludisme sont afébriles lors de la première consultation, ce qui renforce l'importance de la recherche systématique.

The diagnosis is based on performing a blood smear, a thick drop, and, possibly, a rapid test. Additional blood tests are indicated: CBC, blood glucose, sodium, bilirubin, ALT, creatinine, lactates, and PT, as well as a urine sediment. It is essential to know that cases of malaria due to P. vivax, P. ovale, P. knowlesi, and P. malariae may also present with clinical manifestations that are sometimes severe and require immediate management and treatment.

Management depends on the results of malaria testing:

• If the result is negative, but there is a strong suspicion, it is recommended to repeat two additional tests within 24 hours of each other, especially if the stay took place in an area of high transmission.
• If the result is positive and there are no signs of severity or other criteria for hospitalization, outpatient treatment may be considered, with clinical and parasitaemia monitoring at 24 hours. It is crucial to monitor progress, as the clinical condition can worsen rapidly in 2-3 days in adults and in less than 24 hours in children.

Severity criteria for malaria require immediate hospitalization and intravenous treatment:

• Manifestations cliniques : Prostration, troubles de la conscience, détresse respiratoire (respiration acidosique), convulsions multiples, collapsus cardiovasculaire (TAs <70 mmHg), œdème pulmonaire radiologique, saignement anormal, ictère (bilirubine totale >50 μmol/l), hémoglobinurie.
• Manifestations biologiques : Anémie sévère (Hb <8 g/dl), hypoglycémie (<2.2 mmol/l), acidose métabolique (bicarbonate plasmatique <15 mmol/l), insuffisance rénale aiguë (sans amélioration après réhydratation) avec diurèse <400 ml/24h et créatinine >265 μmol/l, hyperlactatémie (>5 mmol/l), hyperparasitémie (>5%). Une parasitémie peut être faussement basse en cas de traitement antipaludéen récent insuffisant ou de prise d'antibiotiques ayant une activité antipalustre.

Hospitalization criteria include the presence of at least one severity criterion (Table 6) or the presence of elements such as vomiting, parasitemia >2% in a non-immune individual, marked alteration of general condition, pregnancy, immunosuppression, asplenia, age over 60, or being alone at home.

The first-line treatment for uncomplicated malaria is Artemether + lumefantrine (Riamet®), administered as 4 tablets twice daily for 3 days. This treatment is contraindicated in cases of prolonged QT interval (congenital, electrolyte disturbances, drug-induced). Alternatives include Atovaquone + proguanil (Malarone® or Atovaquone Plus Spirig HC®) at a dose of 4 tablets per day for 3 days. Chloroquine (base) can be used for malaria due to P. vivax, P. ovale or P. malariae, unless P. vivax is resistant. It is recommended to keep the patient under observation for at least one hour after the first dose due to the risk of vomiting, and to take Artemether + lumefantrine or Atovaquone + proguanil with a meal or a glass of milk to improve absorption. In case of pregnancy, hospitalization is preferable. If signs of severity or uncontrollable vomiting appear, emergency hospitalization is indicated for intravenous treatment with Artesunate. For infections with P. vivax or P. ovale, the addition of primaquine can be discussed to prevent relapses, taking into account the contraindications (G6PDH deficiency, pregnancy).

Other common pathologies and their management: enteric fever, amoebic abscess and dengue fever

Beyond malaria, other tropical pathologies are frequently encountered and require specific management. Among them, enteric fever, amoebic liver abscess, and dengue fever are particularly noteworthy.

Enteric fever (typhoid or paratyphoid)

The risk of enteric fever is present for travelers in all developing countries, but it is particularly high in South Asia (e.g., India, Nepal). Vaccination (Vivotif® or TyphimVi®) offers an efficacy of 60 to 70%. Typical clinical manifestations include fever, pulse-temperature dissociation, constipation or diarrhea, dry cough, and abdominal pain.

The cardinal diagnosis of enteric fever is blood culture, which has a sensitivity of approximately 80% during the first week of fever, but decreases thereafter. Stool culture is positive in one-third to two-thirds of cases between the second and fourth weeks. Complete blood count (CBC) may show normal or decreased leukocytes, and CRP is elevated. It is important to note that serology is considered unhelpful for diagnosis.

Management varies depending on the patient's general condition:

• If the general condition is marked, or in the event of complications, Ceftriaxone 2 g/d intravenously is administered for 10 to 14 days.
• If general condition is preserved, Ciprofloxacin 500 mg twice daily for 14 days is an option. Azithromycin, with a loading dose of 1g followed by 500 mg once a day for 6 days, is preferred for typhoid or paratyphoid fever acquired in South Asia, due to resistance to fluoroquinolones.

Amebic liver abscess

Amebic liver abscess most often occurs without associated colonic involvement and has a clear male predominance. The main clinical manifestations are pain in the right hypochondrium and hepatomegaly. An accompanying pleuro-pulmonary syndrome of the right base is present in 30% of cases.

The diagnosis is mainly confirmed by positive serology in more than 85% of cases. Abdominal ultrasound, and possibly CT scan, are sensitive but non-specific examinations, revealing the presence of the abscess.

Management involves treatment with Metronidazole, administered at 750 mg intravenously or orally, three times a day for 10 days, followed by Paromomycin at 3x500mg/day for 5 days.

Dengue fever

Dengue fever is a viral disease caused by four distinct serotypes, transmitted by mosquitoes in tropical and subtropical countries. It is increasingly diagnosed in febrile travelers. The classic clinical manifestations of dengue fever are those of a severe flu-like illness, with high fever lasting 1 to 6 days, headaches, myalgia, arthralgia, and a skin rash (present in 50% of patients, often after the febrile episode).

Complications, mainly hemorrhagic, are very rare in travelers. They generally manifest on the last day of fever or the following day, and include intense stomach pains, hypotension and hemorrhagic manifestations. Individuals who have already had an episode of dengue fever are most at risk of developing complicated forms.

The diagnosis of dengue fever is based on serology (specific IgM detectable from the 5th-7th day after the onset of fever) and a rapid test for the detection of circulating NS1 antigen, which confirms dengue fever from the first days with a sensitivity of approximately 80%. Biologically, thrombocytopenia and leukopenia are maximal on the 3rd-4th day of the onset of fever, and an elevation of transaminases, sometimes with frank hepatitis, is observed.

There is no specific treatment or vaccine for dengue fever. Management focuses primarily on ensuring adequate hydration. Paracetamol can be prescribed for fever and pain, but NSAIDs (non-steroidal anti-inflammatory drugs) and especially aspirin should be avoided due to the risk of bleeding.

Viral hemorrhagic fevers: a rare but serious emergency

Viral hemorrhagic fevers, including Ebola, Marburg, Congo-Crimean, and Lassa, are extremely rare diagnoses upon return from travel. However, their potential for person-to-person transmission represents a major health risk, requiring the rapid implementation of specific measures in case of suspicion.

Viral haemorrhagic fever should be suspected in well-defined situations:

• Presence of a fever associated with hemorrhages (epistaxis, rectal bleeding, hematomas).
• History of contact with a suspected or confirmed case of viral hemorrhagic fever.
• Return from an epidemic or highly endemic area for these viruses.

The diagnosis in case of clinical suspicion requires rigorous analysis of samples (routine blood tests, serological analyses, and molecular biology).

Management of a suspected viral hemorrhagic fever is an absolute emergency:

• Immediate hospitalization of the patient.
• Implementing strict isolation measures.
• Specific treatment according to the advice of consultants specializing in tropical medicine and infectious diseases.

These measures aim to protect the patient, healthcare staff, and the community from a high risk of spread, even if the number of imported cases remains very low.

Prevention: traveling safely

The prevention of travel-related illnesses is an essential component of travel medicine, significantly reducing the risk of contracting infections, including those that can cause fever upon return. Before any trip, it is strongly recommended to consult a healthcare professional specializing in travel medicine. This consultation allows for the assessment of specific risks related to the destination, type of travel, and traveler profile, and to provide personalized advice.

General preventive measures are fundamental and must be scrupulously followed:

• Hand hygiene: Frequent hand washing is crucial, especially before meals and after using the toilet. The use of hydroalcoholic solutions is an effective alternative in the absence of soap and water.
• Food and water safety: It is imperative to drink bottled water that is sealed or made potable (boiled, filtered, or disinfected). Raw foods, ice cubes, unwashed vegetables, unpasteurized dairy products, and raw meat should be avoided. "Cook it, boil it, peel it, or forget it" is the golden rule.
• Protection against insect bites: Use of effective skin repellents, insecticide-impregnated mosquito nets for sleeping, covering clothing and air conditioning if available. These measures are vital in areas at risk of malaria, dengue fever, chikungunya, Zika and other arboviroses.
• Sexual safety: Avoid risky sexual contact and use condoms to prevent sexually transmitted infections.
• Blood protection: Avoid contact with blood and non-sterile needles.

Vaccinations play a major role in prevention and are adapted according to the destination and specific risks:

• Hepatitis A and B: Recommended for many destinations, especially in countries where hygiene is precarious.
• Typhoid fever: Recommended for stays in Asia, Africa, and Latin America, especially in rural areas or during extended stays. Efficacy is 60-70%.
• Yellow fever: Mandatory for certain destinations and strongly recommended for others in endemic areas (Africa and South America).
• Meningococcal meningitis: Recommended for pilgrims traveling to Mecca and for extended stays in sub-Saharan Africa.
• Rabies: Recommended for travelers exposed to animals, especially in Asia and Africa.
• Japanese encephalitis: Recommended for extended rural stays in Asia.
• Tick-borne encephalitis: Recommended for forested areas of Central and Eastern Europe.
• COVID-19: Vaccination is recommended and should be up to date for all international travel.

Beyond vector-borne and waterborne diseases, other various risks exist and require vigilance:

• Parasitic diseases: Some parasitic diseases, such as schistosomiasis, are contracted through contact with contaminated fresh water. It is essential to avoid swimming in stagnant fresh water.
• Contact with animals: Bites, scratches, or simple contact can transmit diseases (rabies, brucellosis). It is advisable not to approach or feed animals.
• Accidents and drownings: Leading cause of mortality and morbidity among travelers. Caution is advised, especially during sports activities.
• Envenomations and plant contacts: Some areas present risks of bites from snakes, scorpions, or venomous insects, as well as skin reactions from contact with certain plants.

In summary, although cosmopolitan diseases are the most common, it is imperative to always rule out malaria in case of fever upon return from a tropical trip. In the presence of a first negative malaria test after a stay in an area of high transmission, two additional tests less than 24 hours apart are necessary. If the patient presents with a marked alteration of the general condition and malaria is excluded, presumptive treatment against enteric fever and possibly rickettsioses should be discussed. Careful preparation before departure and increased vigilance during and after the trip are the keys to a safe stay and a healthy return.

Source

https://www.hug.ch/sites/interhug/files/2022-09/strategie_fievre_voyage.pdf