key: cord-267139-r8rg0iqq
authors: Scaggs Huang, Felicia A.; Schlaudecker, Elizabeth
title: Fever in the Returning Traveler
date: 2018-03-31
journal: Infectious Disease Clinics of North America
DOI: 10.1016/j.idc.2017.10.009
sha: 
doc_id: 267139
cord_uid: r8rg0iqq

Millions of children travel annually, whether they are refugees, international adoptees, visitors, or vacationers. Although most young travelers do well, many develop a febrile illness during or shortly after their trips. Approaching a fever in the returning traveler requires an appropriate index of suspicion to diagnose and treat in a timely manner. As many as 34% of patients with recent travel history are diagnosed with routine infections, but serious infections such as malaria, enteric fever, and dengue fever should be on the differential diagnosis due the high morbidity and mortality in children.

Millions of children travel annually, whether they are refugees, international adoptees, visitors, or vacationers. [1] [2] [3] [4] In 2015, the International Tourism Organization reported 1.2 billion overseas trips. 5, 6 Although most young travelers do well, many develop febrile illnesses during or shortly after their journeys. 7 In a study of European children, 53% of all pediatric patients with travel-related infections were visiting friends and relatives (VFRs), 43.4% were tourists, and 2.4% were immigrants. 8 Most illnesses are selflimited childhood infections that do not require subspecialist consultation. However, 28% of 24,920 ill American travelers sought care at travel clinics after returning home. 9 Additionally, young children with fevers can present a diagnostic dilemma because they may not report symptoms and can be at risk for severe disease, such as malaria. As awareness of tropical illnesses rise in parents, such as the increase in multidrug-resistant bacteria worldwide or the emergence of epidemics with Zika virus in South America, families may be more anxious about serious infections as an etiologic factor of fevers.

Approaching fevers in the returning traveler requires an appropriate index of suspicion to diagnose and treat the child in a timely manner. This article offers a framework on how to address these issues by discussing diseases based on geography, incubation period, and affected organ systems, as well as risk factors, diagnostic techniques, and resources.

A thorough history is an important initial step when evaluating a pediatric traveler with a fever ( Table 1) . Discussing a detailed travel itinerary develops a timeline of exposures that can be unique to an urban or rural setting ( Table 2) .

Many children receive vaccinations and/or antimicrobial prophylaxis, but reported adherence does not preclude an illness with a particular pathogen. Up to 75% of travelers do not adhere to the recommended malaria prophylaxis. 10 Many travel vaccines, including typhoid vaccine, provide only partial protection despite proper administration of these immunizations. 11 A medically complex individual may have sought care outside of the United States due to necessity or medical tourism, which can increase the risk of infection through body fluid exposures. Multidrug-resistant pathogens can also be associated with health care exposure. Up to half of hospitalized children in Zimbabwe are colonized with extended spectrum beta lactamase producing Enterobacteriaceae on admission to the hospital, 12 a problem that is increasingly seen worldwide. Underlying medical conditions, such as asplenia or immunosuppression from chemotherapy, may predispose children to overwhelming infections and sepsis. Refugee children from countries such as Syria are susceptible to vaccine-preventable diseases such as polio due to infrastructure breakdown. 13 

Fever is a common and anxiety-provoking sign for parents that can be exacerbated by overseas travel. Up to 34% of patients with recent travel history are diagnosed with routine infections. 3 Of the 82,825 cases of infection in travelers from 1996 to 2011 reported to GeoSentinel, a worldwide data collection network on travel-related diseases, 4% of cases were considered to be life-threatening. 14 A study in Swiss children showed that 0.45% of emergency room visits were due to travel-related morbidities with fever and gastrointestinal symptoms being the most common complaints in 63% and 50% of patients, respectively. 8 The temporality of travel to the onset of fever can offer important clues to the etiologic factors of fevers ( Table 3) . Because the causes and clinical outcomes associated with fevers in pediatric travelers vary from self-limited to deadly, a systems-based approach can lead to prompt diagnosis and treatment that evaluates for the most likely and serious diseases early in the illness course.

According to GeoSentinel, 91% of patients with an acute, life-threatening illness will present with fever. 14 There are a broad range of potential tropical infections, including malaria, dengue fever, and enteric fever. The incidence of emerging infections such as Zika virus and chikungunya are not yet known. In both adults and children, pneumonia, sepsis, meningococcemia, and urinary tract infections that were acquired at home or overseas should be on the differential diagnosis.

The initial workup of a febrile child without a clear source will be based on the history, physical examination, and risk factors but commonly includes a complete blood count, liver function tests, creatinine, urinalysis, and blood cultures. 1, 3 Malaria smears are also frequently helpful. Other tests to consider include serologies for dengue fever Scaggs Huang & Schlaudecker or other potential etiologic agents, polymerase chain reaction for Zika virus or other pathogens, chest radiographs, and cultures of the urine and stool. Patients with altered mental status may require head imaging and lumbar puncture. The most common and concerning causes of fever in a returning pediatric traveler are highlighted next. [50] [51] [52] Fever in the Returning Traveler 

Plasmodium falciparum malaria is one of the most common tropical infections. Approximately 15% to 20% of all imported malaria cases are diagnosed in the pediatric population in industrialized countries each year. 3 Malaria is transmitted via the nocturnal-feeding Anopheles genus of mosquito. Children who are VFRs are more likely to become infected with malaria than traditional tourists. 3 Nonimmune children are also susceptible to severe malaria from other malaria strains such as Plasmodium vivax 15 and many young patients can present with atypical symptoms such as abdominal pain and vomiting. 16 Older children may present with paroxysmal fever, fatigue, myalgias, headache, abdominal pain, back pain, hepatosplenomegaly, and hemolytic anemia. Additionally, severe malaria is more common in children after the first month of travel due to the incubation period of P falciparum (7-90 days), especially in those who visited sub-Saharan Africa. 17, 18 Overall, sub-Saharan Africa is one of the most common geographic regions for acquisition, comprising 71.5% of cases according to a GeoSentinel study of travelers migrating or returning to Canada from 2004 to 2014. 19 Malaria should remain on the differential diagnosis for up to a year in an acutely ill, febrile child after travel to an endemic area where P vivax and P ovale strains are present. 17 Interestingly, 20% of malaria cases can be acquired during trips as short as 2 weeks with less utilization of pretravel services being a contributing factor. 19 A minimum of 3 thick and thin blood smears must be performed before malaria can be excluded, preferably collected during febrile episodes. The specificity of blood smears is high but the sensitivity can be low depending on the experience of the individual interpreting the slides. 17 Rapid diagnostic tests that detect specific proteins or lactate dehydrogenase are alternatives for diagnosis at medical centers with limited experience in microbiologic evaluation for malaria. 20 The result should be confirmed, however, through the state public health department. In general, a febrile child without a localizing source or splenomegaly, thrombocytopenia, or indirect hyperbilirubinemia, in addition to exposure to an endemic area, should be presumptively approached as having malaria until an alternative diagnosis can be made. 21 Treatment of malaria is well-established by the Centers for Disease Control and Prevention (CDC) guidelines. Children with acidosis, hypoglycemia, hyperparasitemia, end-organ dysfunction, and severe anemia meet the criteria for severe malaria and require prompt administration of parenteral medication. There is a growing body of evidence that artesunate may reduce mortality compared with quinidine and is becoming more common as first-line therapy in pediatric patients. 22, 23 Artesunate must be obtained through the CDC Malaria Hotline (1-770-488-7788) because it is not routinely available in the United States. 24 Quinidine may be initiated until the medication arrives. Completion of therapy with an oral regimen for uncomplicated chloroquine-resistant P falciparum, such as atovaquone-proguanil, can be offered when the child is able to tolerate the medications and the parasite burden has decreased to less than 1%. Severe disease is less common in P vivax and P ovale and infection can be treated with chloroquine or hydroxychloroquine in most areas outside of Indonesia and Papua New Guinea.

Enteric fever accounts for 18% of the 3655 cases with life-threatening tropical diseases reported to GeoSentinel. Most recorded cases were from the Indian subcontinent and in VFRs. 1 Infection with Salmonella typhi and Salmonella paratyphi are clinically indistinguishable with fever, abdominal pain, nausea, vomiting, myalgias, and arthralgias. Diarrhea is greater than 2.5 times more common in infants than older children or adults, 25 although constipation can also be seen. Patients can exhibit a Fever in the Returning Traveler typhoid mask with dull features and confusion, as well as a stepladder fever progression with rising temperatures over time in untreated individuals. Relative bradycardia and rose spots are also classic signs. 25 Complications such as gastrointestinal bleeding are more common in young children who have been ill for 2 weeks or more. 1 Transmission is fecal-oral, and humans, especially adults, may be chronic carriers. Diagnosis of enteric fever is confirmed through cultures. The most sensitive sterile site is bone marrow (80%-95%). Blood culture has the highest yield during the first week of illness (70%), and stool cultures are more sensitive as the duration of illness increases. 26 Stool studies should be performed on all fellow travelers, and they must be monitored for signs of illness. Other abnormal laboratory findings include transaminitis and a normal or decreased white blood cell count.

The antimicrobial of choice for treatment varies based on the area in which the infection was acquired because multidrug resistance is increasing. Empiric treatment with ceftriaxone or fluoroquinolones is typically recommended. Strains in Latin America and the Caribbean can be susceptible to ampicillin and trimethoprimsulfamethoxazole. South and Southeast Asian serovars more frequently require azithromycin or cefixime. 27, 28 Children with multidrug-resistant strains have more complications such as myocarditis and shock than children infected with susceptible strains but case fatality is similar (1.0% vs 1.3%, respectively). 29 Relapse of infection can occur despite appropriate therapy, with the highest mortality in young children (6%). 29 

Dengue remains an important cause of fever in travelers returning from all tropical regions except Africa. 30 The prevalence is rising, even in the United States, with 50 to 100 million global cases reported yearly and 22,000 deaths, primarily in children. 31 Risk factors are dissimilar from those for malaria because transmission occurs in urban areas during the daytime due to the vector Aedes aegypti, whereas malaria transmission is more common in rural areas from dusk to dawn with the Anopheles species mosquito. 32 Some patients may be asymptomatic, whereas others have hemorrhagic fever and shock. The illness presents as 3 distinct phases: (1) febrile phase over 3 to 7 days characterized by myalgias, headache, retroorbital pain, and rash; (2) critical phase of 24 to 48 days with plasma leakage; and (3) convalescent phase. 32 A rising hemoglobin and gallbladder wall thickening due to increased vascular permeability suggests the development of severe dengue in children. Repeat infections with a different strain may lead to more severe disease. 31 Serologies are most commonly used for diagnosis, although some rapid diagnostic tests are available. In cases in which infection is unclear, it may be helpful to repeat serologies 2 weeks after initial testing to monitor for an increase in titers. Other common laboratory findings include leukopenia and thrombocytopenia. 33 Treatment consists of hydration and avoidance of salicylate-containing products to decrease the risk for bleeding. 32 Children who develop severe dengue with hemorrhage and shock may require blood products. No antivirals or vaccines are currently available.

In recent years, arboviral illnesses transmitted via infected Aedes aegypti mosquitos have caused epidemics of Zika virus and chikungunya in South America. A European study of travelers returning from Brazil in 2013 to 2016 reported that of the 29% of patients with travel-related complaints, 6% had dengue fever, 3% had chikungunya, and 3% had Zika virus infection. 34 The prevalence of yellow fever, which is seen throughout low-resource settings and shares the same vector, has remained stable. 35 These infections are difficult to distinguish clinically with fever, retroorbital pain, conjunctivitis, and myalgias. Knowledge on perinatal infection with Zika and the neurodevelopmental sequelae of affected infants is rapidly evolving. 36 A Canadian study found that 5% of travelers developed neurologic complications such as Guillain-Barre syndrome with Zika, suggesting there is much to learn with this disease in nonperinatally acquired infections. 37 At this time, treatment is primarily supportive. Additional tropical diseases associated with fevers are outlined in Table 4 .

Vomiting and diarrhea are common complaints in returning travelers. Up to 40% of children less than 2 years of age may develop diarrhea, with 15% requiring medical services. 38 Fevers, nausea, and vomiting can be seen with norovirus that occurs worldwide and is frequently associated with contaminated food and water on cruise ships. 39 Rotavirus, however, is one of the most frequent causes of diarrheal illnesses worldwide and is a common cause of infant mortality in low-resource settings. 5 The hepatitides present with a broad range of disease from mild abdominal pain and vomiting to fulminant liver failure, although serious complications are uncommon in pediatric travelers. 40 Community-acquired Clostridium difficile is uncommon in children but infection should be considered if the patient received recent antimicrobials. 41 GeoSentinel data reported that 2% of patients diagnosed with Clostridium difficile after travel were 10 to 19 years of age. 42 There are many other causes of both febrile and nonfebrile gastrointestinal illness in children ( Table 5) .

In the pediatric population, common respiratory infections may be seen on return from international trips including pharyngitis, sinusitis, otitis, and pneumonia from pathogens commonly seen in the United States, such as Streptococcus pneumoniae and rhinovirus. 4, 43 Local epidemiology of infections can be helpful in diagnosis and management and is available through the CDC. In some tropical regions, influenza may occur throughout the year and should hence remain on the differential for patients who warrant treatment with oseltamivir. 44 Mycobacterium tuberculosis is an important etiologic factor of lower respiratory tract disease worldwide and should be considered in children with risk factors or who do not recover with antimicrobials for bacterial pneumonia. 26 Of note, children younger than 3 years of age are more likely to present with miliary tuberculosis or neurologic involvement than adult patients. There are also many other less common causes of febrile respiratory tract infections ( Table 6) .

Children who present with dysuria, hematuria, and fevers may require urinalysis and culture to evaluate for urinary tract infection and/or pyelonephritis. Gross hematuria with the passage of clots in an afebrile child with exposure to freshwater in Africa, the Middle East, China, and Southeast Asia should be tested for the helminth parasite from the genus Schistosoma via serologies or microscopic identification of eggs in stool. 45 Praziquantel is the treatment of choice and may improve anemia and nutrition in some children. 46 Patients who may have early disease or a high parasite burden may require a repeat treatment. 45 Children who are at risk for sexual abuse and adolescents should undergo testing for sexually transmitted infections such as Chlamydia trachomatis and Neisseria gonorrheae. 

Rashes are a source of concern for parents without the context of travel and may be even more worrisome after going abroad. The differential diagnosis includes typical childhood illnesses, such as roseola or staphylococcal cellulitis, in addition to tropical infections. A study of Canadian travelers from 2009 to 2012 found that cutaneous larva migrans (13%) and skin and soft tissue infections (12.2%) were some of the most common infectious dermatologic complaints among tourists. 47 In countries where vaccination rates are low, varicella zoster virus or rubella may cause disease, especially in young children who have not completed their immunization series. Measles remains an important risk, with tourists comprising 44% of the 94 cases reported to GeoSentinel from 2000 to 2014, and 13% of patients being younger than 18 years of age, although this may represent underreporting due to the surveillance system's primarily adult focus. 48 Petechiae on the extremities in an illappearing child may indicate a serious systemic process such as meningococcal or rickettsial infection. There are many other infections with primarily dermatologic manifestations that may not cause fevers ( Table 7) . 49 

As the numbers of children who travel abroad continues to increase, clinicians need to remain up-to-date on potential etiologic factors for febrile illnesses on families' return home. After ruling out life-threatening disorders that can be acquired locally or internationally, physicians are able to develop a focused diagnosis and management plan best suited to the patient's clinical picture. There is a growing body of resources to assist clinicians, such as the CDC (www.cdc.gov/travel/) and GeoSentinel (www.istm.org/geosentinel) for data on epidemiology, geography, and other risk factors.

In the future, physicians will need to be prepared to deal with the global epidemic of antimicrobial drug resistance, evolving epidemics and pandemics caused by emerging pathogens, reemerging infections due to vaccine hesitancy or international conflicts, and medical tourism in both healthy and medically complex children.

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