Fever in the Returning Pediatric Traveler

International tourism has been rebounding strongly since the end of the SARS-CoV-2 pandemic. In 2023, international tourist arrivals reached 89% of prepandemic levels.1 Forecasts suggest that international tourism in 2025 will exceed 2019 levels, and families with children constitute a large part of international travelers. In the child returning from travel, fever is one of the predominant reasons for medical consultations.2 While most febrile episodes are self-limiting and most commonly due to viral airway or gastrointestinal infections, fever can also be a sign of a serious condition or infection, which should not be missed. Data of >80,000 returned adult and pediatric travelers collected by the GeoSentinel network documented a serious tropical infection in 4%, most commonly malaria caused by Plasmodium falciparum, followed by enteric fever and leptospirosis.3 Importantly, most of the deaths were due to malaria, with 10 of 13 travelers having died due to P. falciparum malaria. Therefore, the prompt diagnosis and treatment of malaria remain crucial for children returning from malaria-endemic countries. Due to the broadness of differential diagnoses in a febrile child returning from travel, a concise travel history, thorough clinical assessment and knowledge of incubation periods of potential pathogens will help to narrow the list of possible underlying diseases. Based on the provided travel routes and dates, the list of potential pathogens can be further refined by considering their specific incubation periods (Table, Supplemental Digital Content 1, https://links.lww.com/INF/G118). In addition, special considerations need to be given to febrile children returning from travel after visiting friends and relatives (VFRs) and children with known immunosuppression. Finally, ongoing climate change and the rise of global mobility will further shape global infectious disease patterns, leading to shifts in vector distribution, rise of novel health threats and changes in global antimicrobial resistance patterns. These key aspects of fever in a returning pediatric traveler are discussed further in the following. Special Populations Children VFRs Children VFRs who return from travel are at higher risk of serious infection. At the same time, the proportion of VFRs among children with travel-related illnesses is high. In a Swiss cross-sectional analysis on 801 children with travel-related disease presenting at the emergency department, 53% were VFRs.2 The reason for increased morbidity and mortality in VFRs is multifactorial. Preventive measures by seeking pretravel consultation and adhering to the recommendations are suboptimal in VFRs.4 In a retrospective case review from Belgium, only one-third of children who visited a travel clinic for advice after travel reported having taken malaria prophylaxis. Most of these children (68%) who acquired malaria abroad were VFRs.5 Similar results were observed in studies from Spain, Italy and Canada, where 62.5%, 73.6% and 95% of children with malaria acquired the disease as VFRs. Of these, only 6.7%, 33% and 21%, respectively, had received antimalarial chemoprophylaxis, and inappropriate administration was common.6–8 Children who are VFRs are also at an increased risk for tuberculosis (TB). A prospective study aimed to estimate the risk for TB infection and TB disease and showed that incidence rates of TB disease even surpassed that of the visited country. The risk of TB infection in children VFRs in high-incidence TB countries was equal or greater than the risk of the native population.9 Furthermore, children who are VFRs are at risk for developing enteric fever after traveling to high-incidence settings.10 Immunocompromised Children Immunocompromised children face an increased risk of mortality and morbidity when presenting with fever after returning from travel. These children may have a higher susceptibility to acquire certain infections and/or a lower ability to clear them. Furthermore, they face an increased risk of vaccine-preventable diseases such as measles or varicella. Incubation periods might differ in healthy children leading to delayed manifestations. The etiology of fever in children with primary or acquired immunodeficiency and returning from travel is diverse and includes both travel-related and nonrelated causes and opportunistic pathogens. Fever in this risk group remains a significant cause of mortality and morbidity. In a prospective multicenter study with immunocompromised children, no focus was identified in one-third of febrile episodes, and the bacterial infection rate was 13%. Most of the children (82%) received empirical antimicrobial therapy, and mortality was 1.9%.11 Although early and empirical therapy might lead to antimicrobial overuse, it remains effective in this high-risk population and should, therefore, not be withheld. Given that most children show no symptoms beyond fever, early additional testing such as imaging, laboratory tests, lumbar puncture or tissue biopsy may be required. Furthermore, immunocompromised children may have already been on specific medication or have received multiple prior courses of antimicrobial treatment. Therefore, it is important to consider potential drug interactions and the risk of antimicrobial resistance. In addition, these children deserve closer monitoring, and the threshold to consult a pediatric infectious diseases team should be low. The Art of History Taking History taking is the key component for a timely and accurate diagnosis in children who are returning travelers. First, it is crucial to recognize that many migrant families may not perceive visits to friends and relatives as “travel” in the conventional sense, as these trips are often seen more as family or cultural engagements rather than formal travel. This perspective can lead to underreporting or misunderstanding of travel history, which is crucial for accurate health assessments. One option is, therefore, to ask more broadly whether the family has been outside their country of residence or visited their country of origin. Furthermore, VFRs often do not undertake pretravel consultation, including preventative measures such as vaccinations, use of insect repellents or malaria chemoprophylaxis. Special attention to detail when taking the history is required. To ensure a comprehensive approach, we propose the mnemonic TRAVEL DISC to remember all important aspects. T: Timing: Dates of traveling, season, first exposure, return date and date of first onset of symptoms. R: Route: All visited countries and areas with details on region. Urban/rural accommodation and VFR. A: Animal: Exposure to domestic, farm or wild animal and insect bites. V: Vaccination: Routine and travel-specific vaccinations. Check documentation. E: Exposure: Drinking water and food sources including raw dairy products and raw meat, etc. L: Local: Contact to health care system such as hospitalization or dental procedures. D: Drugs: Travel/nontravel related medications, prophylaxis regimen and injection drug use. I: Immune Status: Known immunosuppression. S: Social Activities: Bathing/rafting in fresh water, visiting caves, etc. C: Contacts: Sick contacts or sexual contacts. Pearls for Clinical Examination In a child returning from travel and presenting with fever, the first step in the clinical examination is the assessment for severity and danger signs. Once the child is stabilized, attention should be paid to all organ systems, as each of them can point toward a special infection (Table, Supplemental Digital Content 2, https://links.lww.com/INF/G119). In children presenting with fever alone, the most important tropical infections to consider are malaria, enteric fever and dengue. Laboratory Testing For febrile children returning from a malaria-endemic country, laboratory testing must include a full blood count, a blood smear and a malaria rapid diagnostic test. A blood smear is highly recommended because the sensitivity of rapid diagnostic tests is insufficient for non-falciparum malaria and can additionally reveal the presence of other pathogens not previously included in the diagnostic differential list, such as African trypanosomiasis, tick-borne relapsing fever, babesiosis or leptospirosis.12,13 The complete blood count can give some indications of specific infections. Children with malaria often present with anemia, thrombocytopenia, leukopenia or leukocytosis and in severe or hemorrhagic cases also with unconjugated hyperbilirubinemia, acidosis, hypoglycemia, coagulopathy, increased blood urea nitrogen and elevated creatinine.14 Anemia, leukopenia and thrombocytopenia can also be observed in patients with enteric fever and dengue,15 but thrombocytosis and elevated liver enzymes might be seen in those conditions as well.12,15 Children with enteric fever might be eosinopenic,16 while acute eosinophilia is more commonly seen in parasitic infections with tissue migration, such as in schistosomiasis, ascariasis and strongyloidiasis.17 Blood cultures are essential for the diagnosis of enteric fever but also for the diagnosis of Brucella spp. or Burkholderia pseudomallei infections. In these cases, the laboratory needs to be informed about the travel history and the differential diagnosis.12 Urine analysis and urine culture should be considered in children with fever without focus to rule out travel-unrelated urinary tract infections, especially in younger children who cannot describe their symptoms. Further testing, including serum biochemistry, nasopharyngeal swabs, serology, blood samples for polymerase chain reaction, chest radiology or abdominal ultrasound, should be based on the child’s signs and symptoms. The Traveling Pathogen Climate change can alter the range and density of various species and the risk of pathogen spillover and, consequently, heighten the threat of emerging zoonoses.18 These changes are contributing to the emergence of tropical infections in previously nonendemic regions, highlighting the need for enhanced infectious disease surveillance. In Europe, distribution maps are regularly updated, for example, by the European Centre for Disease Prevention and Control. The US Centers for Disease Control and Prevention website also gives an overview on the epidemiologic features of infections, which might be travel-related.19,20 The World Health Organization also informs about current disease outbreaks (who.int/emergencies/disease-outbreak-news). The most recent update on Aedes albopictus distribution shows that the warming climate, together with changes in transportation, demography and urbanization has facilitated the expansion of this mosquito species.21 While some Aedes species were established in 8 European countries in 2013 with 114 affected regions, this has nearly tripled with 337 affected regions 10 years later, and further spread to previously unaffected European areas is to be expected.22A. albopictus has now become established in 13 European countries and has been introduced into another 7.23 Recent reports show that the regions where A. albopictus mosquitoes have newly established populations include France, Germany, Spain, the Netherlands, Portugal and Slovenia.24 As a result, diseases transmitted by A. albopictus, such as dengue and chikungunya, have been increasingly reported as locally transmitted, particularly in countries like Italy and France.23 West Nile virus is another example of a virus with increasing occurrence in Europe. While the virus is primarily found in wild birds, it can also be transmitted to humans by several mosquito species such as Culex pipens and modestus, as well as Aedes species. By the end of the year 2024, 19 European countries reported cases of West Nile virus infections, and the countries with the highest burden were Italy and Greece.25 While most cases are reported in adults and tend to be mild, severe meningoencephalitis has also been reported in children. Children who received antimicrobial agents to treat their diarrhea during travel and those who were hospitalized while travelling are at increased risk of infection or colonization with drug-resistant pathogens. The risk is further related to the prevalence of resistance in the country that is visited. For instance, travelers returning from East or Northern Africa, South America, the Middle East, South Asia and especially Southeast Asia have an increased risk for colonization with resistant pathogens to extended-spectrum cephalosporins,26 while the risk for carbapenem-resistant Enterobacterales is especially increased in travelers who return from Southeast Asia. In Southeast Asia, the high prevalence of extended-spectrum beta-lactamase has been a major issue for >2 decades, and carbapenem-resistant Acinetobacter baumannii is one of the most common pathogens associated with nosocomial infections in this region.27,28 Recently, it has been showed that travel to tropical regions, especially to Southeast Asia, is further associated with acquisition of colistin-resistant Enterobacterales carrying an mcr gene.29 Resistance and partial resistance against artemisinin, which is the first-line treatment for severe malaria, occur mainly in the Greater Mekong Subregion of Southeast Asia, but the emergence of artemisinin resistance has also been identified in the African regions.30 Surveillance and mapping of resistance patterns remain crucial to address further spread. CONCLUSIONS The approach of a febrile child returning from travel presents a complex and evolving diagnostic challenge. A thorough travel and personal history, comprehensive clinical assessment and understanding of incubation periods remain the cornerstones of the evaluation. Special attention must be given to the children at risk, which includes children who visited friends and relatives and those with immunosuppression, as they are at higher risk for serious infections. Climate and demographic changes, as well as international mobility, led to a rapidly evolving infectious disease landscape. The approach to the febrile child returning from travel must be responsive to these dynamic global health patterns. While malaria remains a key consideration in febrile children returning from endemic areas, health care providers must be aware of other serious infections requiring immediate action, including novel infections with a potential index patient who requires appropriate infection control measures.

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