- Correspondence to Dr Jay Halbert, Department of Paediatrics, Lister Hospital, Coreys Mill Lane, Stevenage, Hertfordshire SG1 4AB, UK; J.Halbert@nhs.net
Abstract
During the last half century there has been an exponential increase in international travel including to more exotic and long-haul destinations. The assessment of febrile returning child travellers presents diagnostic challenges and is often performed poorly. A detailed travel and medical history, clinical examination and appropriate first-line investigations are essential. While the majority of children will have a common self-limiting or easily treatable infection, it is important to consider other causes, including imported infections, which may be life-threatening or highly contagious. In this article, we provide guidance on the initial assessment and management of such children with a focus on some of the more important imported infections, including malaria, dengue, typhoid fever, travellers’ diarrhoea, respiratory infections, tuberculosis, schistosomiasis and rickettsial diseases.Introduction
An exponential increase in international travel has resulted in growing numbers of children with fever following recent travel abroad.1 Such patients present diagnostic challenges and their overall assessment is often poorly performed.2 This article describes a systematic approach to their diagnostic work-up and management.
Initial assessment
The seriously ill child is managed immediately according to advanced paediatric life support (APLS) principles in consultation with an infectious disease specialist.
A comprehensive medical and travel history together with clinical examination are essential and should be undertaken as described below.
A comprehensive medical and travel history together with clinical examination are essential and should be undertaken as described below.
Destinations and dates of travel
A detailed history of all travel destinations including transit points within the previous 12 months (not just the most recent trip) enables consideration of infections more prevalent in or limited to certain geographic regions. The risk of exposure may vary from high to non-existent within the same country, from rural to urban areas and from lower to higher altitudes. Several resources are available that can provide guidance on the risk from infections in different regions of the world.3–6
Precise travel dates enable the exclusion of certain infections by virtue of their incubation periods.7 For instance, malaria may be excluded if symptoms occur <7 days after the first possible exposure. Similarly dengue can be excluded if the onset of symptoms occur >14 days after the last possible exposure.8
The season of travel may be important. For example, the risk from malaria is usually highest during the rainy season and from meningococcal disease in the meningitis belt of sub-Saharan Africa during the dry season. Prolonged travel is associated with an increased risk of exposure to infections.
Precise travel dates enable the exclusion of certain infections by virtue of their incubation periods.7 For instance, malaria may be excluded if symptoms occur <7 days after the first possible exposure. Similarly dengue can be excluded if the onset of symptoms occur >14 days after the last possible exposure.8
The season of travel may be important. For example, the risk from malaria is usually highest during the rainy season and from meningococcal disease in the meningitis belt of sub-Saharan Africa during the dry season. Prolonged travel is associated with an increased risk of exposure to infections.
Purpose of travel and activities
The proportion of children visiting friends and relatives (VFR) abroad has increased more than any other reason for travelling.1 They tend to be at increased risk from infections by virtue of living in closer proximity to the local population; consuming locally prepared foods and drinks; travelling for longer periods; and being less likely to take prophylactic precautions and seek pretravel and post-travel health advice.8 ,9Certain activities undertaken while abroad are associated with specific infections.10 Freshwater recreational activities are associated with leptosporosis and schistosomiasis in certain regions. Children have an increased tendency to play with animals including dogs and monkeys predisposing them to zoonotic infections such as rabies.
Living conditions
Camping, budget accommodation and living in close proximity to the local population are associated with an increased risk of malaria, typhus and meningococcal disease.7The risk of food and waterborne infections depends upon how hygienically food is prepared and consumed. Raw, undercooked and reheated food, as well as non-sterilised water, are associated with typhoid fever, travellers’ diarrhoea, viral hepatitis A and E and fascioliasis. Unpasteurised dairy products are associated with brucellosis, salmonellosis and listeriosis.
Prophylaxis
Dates of routine and travel-specific vaccination schedules, including boosters, are important to ascertain whether sufficient protection was provided prior to departure. While certain vaccines, such as hepatitis A and yellow fever provide almost complete protection, others such as typhoid fever are less effective (<70%).11For travel to malaria endemic areas, details on whether malaria chemoprophylaxis was taken including supervision/compliance is important. While Atovaquone/proguanil should be taken daily until 7 days after the last potential exposure, mefloquine should be taken weekly until 4 weeks after the last potential exposure. The use of mosquito nets, long sleeved clothing and N,N-Diethyl-meta-toluamide, and whether the child sustained insect bites, are important when considering arthropod-borne infections.
Past medical, drug and family history
Current comorbidities and medications, especially those that are immunosuppressive, may predispose the child to infections. A child with splenic dysfunction, for example, sickle cell disease, is at increased risk of malaria and encapsulated organisms such as pneumococcus. Medical care received abroad may be inadequate. Incomplete courses of substandard antimalarials and antibiotics may lead to partially treated infections. Details of unwell travel contacts or companions may have diagnostic and public health implications.History of presenting complaint
A complete systems review, including the date of onset and sequence that symptoms present, is important. Associated symptoms, such as a cough or abdominal pain, may help to localise the infection although symptoms may yet manifest in the acute presentation. The pattern and duration of fever may be important, however, the traditional tertian pattern in Plasmodium falciparum malaria is rarely seen in children. Many infections present with a non-specific fever and a variety of associated symptoms. Care must be taken particularly in the acute phase that associated symptoms do not lead to misdiagnosis through inappropriate localisation of the infectionExamination
A complete physical examination is important to elicit signs associated with certain infections. This should include an assessment of the child’s weight and nutritional status. However, the absence of associated signs and symptoms does not necessarily exclude diagnoses. Skin rashes are often non-specific, but may be characteristic of specific infections or indicate potentially serious infection, such as the petechiae/purpura of meningoccocal disease and viral haemorrhagic fevers (VHF). Lymphadenopathy, hepatomegaly, splenomegaly and jaundice are each associated with a variety of infectious and non-infectious causes (table 1).
- Global child health
Fever in the returning child traveller: approach to diagnosis and management
Table 1 Clinical presentation of selected paediatric infectious diseases
| Sign/symptom | Examples |
|---|---|
| Non-specific fever | Malaria, dengue, typhoid fever, schistosomiasis, rickettsiae, leptosporosis, amoebiasis, tuberculosis |
| Jaundice | Malaria, viral hepatitis, leptospirosis, typhoid fever, typhus, VHF |
| Lymphadenopathy | Tuberculosis, rickettsiae, brucellosis, visceral leishmaniasis |
| Hepatomegaly | Malaria, amoebiasis, typhoid, hepatitis, leptosporosis |
| Splenomegaly | Malaria, typhoid, visceral leishmaniasis |
| Rash | |
| Eschar | Scrub and tick typhus, Crimean Congo haemorrhagic fever |
| Petechiae/purpura | Meninogococcal disease, dengue, chikungunya, VHF |
| Rose spots | Typhoid fever |
| Erythema migrans | Lyme disease |
| Bites | Malaria, dengue, African trypanosomiasis (painful tsetse bite) |
| Haemorrhagic | Dengue, meningococcal disease, VHF, Rocky Mountain spotted fever, leptosporosis |
| Respiratory | Influenza, streptococcus pneumoniae, atypical pneumonias (eg, melioidosis), tuberculosis, histoplasmosis, Hantavirus, hydatid cyst, malaria, Loeffler's syndrome |
| Diarrhoea | Viral—rotavirus Bacterial—enterotoxigenic Escherichia coli, typhoid fever; (cholera is extremely rare and usually presents abroad due to its very short incubation period) Protozoal—giardiasis, amoebiasis, cyclosporiasis, malaria Dysentery—shigellosis, amoebiasis |
| Neurological | Cerebral malaria, meningococcal meningitis, African trypanosomiasis, rabies, arboviruses (eg, Japanese encephalitis, West Nile virus encephalitis) |
| Prolonged fever and pyrexia of unknown origin (>7 days) | Unusual presentations of common infections and tropical infectious—tuberculosis, brucellosis, endocarditis, osteomyelitis, histoplasmosis, typhoid fever, rickettsiae, schistosomiasis, leishmaniasis, toxoplasmosis, leptosporosis, amoebic liver abscess Non-infectious diseases—leukaemia, lymphoma, JIA |
- JIA, juvenile idiopathic arthritis; VHF, viral haemorrhagic fevers.
Investigations
Table 2 lists first-line and second-line investigations to consider depending upon the travel history and clinical presentation. Investigations of particular importance to consider in returning child travellers include a malaria blood film, blood culture, stool culture and chest X-ray. Second-line investigations are usually considered after undertaking first-line investigations and in consultation with a microbiology/infectious disease specialist, but may be included with the initial investigations if there is a strong clinical suspicion.
Thick and thin blood films for malaria diagnosis, speciation and parasite count are mandatory for all children who have travelled to a malaria region within the previous 12 months regardless of a presentation suggestive of alternative diagnoses. Malaria chemoprophylaxis is not 100% effective.
Initial investigations may provide supporting evidence of infections.12 For instance, thrombocytopenia, anaemia and hypoglycaemia are associated with malaria, while leucopoenia and thrombocytopenia are associated with dengue.
Eosinophilia is associated with invasive helminth infections, such as schistosomiasis, fascioliasis and echinococcosis. Filarial tropical pulmonary eosinophilia and Loeffler’s syndrome should be considered if there is associated cough and wheeze. Other causes include fungal infections such as coccidioidomycosis and non-infective causes, such as asthma and systemic lupus erythematosus (SLE). Guidelines for the management of eosinophilia are available from the British Infection Society.13
Local microbiologists can provide guidance on appropriate initial investigations (including how and when samples should be taken) and infection control. For instance, dengue IgM serology does not become positive until after the fourth day of illness.
Regional paediatric infectious disease and public health specialists may be consulted for advice on seriously unwell children, specific infections, second-line investigations, interpretation of results, empirical therapy and infection control. They are usually contacted after consultation with local microbiologists and undertaking first-line investigations. They may recommend specific panels of serological/PCR tests based upon the travel history and presentation. Specialist laboratory services may be available through such regional centres or Public Health England
Table 2 Investigations
Fever in the returning child traveller: approach to diagnosis and management
Table 2 Investigations
| First-line | |
| Malaria blood film | Thick and thin blood films for malaria are mandatory in all febrile children who have a history of travel to malaria regions. Results should be obtained urgently within hours (repeat 3 films 12–24 h apart if negative). Malaria rapid diagnostic tests and PCR may provide useful adjuncts. |
| Haematology | Full blood count; blood film; clotting; erythrocyte sedimentation rate |
| Biochemistry | Electrolytes; glucose; renal function; liver function; C-reactive protein |
| Serology | Hepatitis (viral); saved serum (for specific serology or paired convalescent serology); HIV (consider if risk factors) |
| Microbiology | Blood culture; stool (ova, cysts, parasites and culture); urine (microscopy and culture); throat swab (bacterial, viral); nasopharyngeal aspirate (viruses); sputum (microscopy and culture); lumbar puncture; Antistreptolysin O titre |
| Radiology | Chest X-ray; other imaging as indicated |
| Second-line | |
| Repeat first-line | Consider completing/repeating malaria blood film and blood culture |
| Serology | Focused/panel serology and PCR |
| Microbiology | Mantoux; QuantiFERON; bone marrow aspiration and culture; blood for microfilariae (loaiasis (daytime), Wuchereria bancrofti (night time)); skin snips (onchoceriasis); lymph node biopsy |
| Radiology | Abdominal ultrasound; CT/MRI; echocardiogram; white cell and bone scan; other imaging as indicated |
| Document full travel details, clinical presentation and suspected specific infections on request forms | |
- PCR, polymerase chain reaction.
Initial investigations may provide supporting evidence of infections.12 For instance, thrombocytopenia, anaemia and hypoglycaemia are associated with malaria, while leucopoenia and thrombocytopenia are associated with dengue.
Eosinophilia is associated with invasive helminth infections, such as schistosomiasis, fascioliasis and echinococcosis. Filarial tropical pulmonary eosinophilia and Loeffler’s syndrome should be considered if there is associated cough and wheeze. Other causes include fungal infections such as coccidioidomycosis and non-infective causes, such as asthma and systemic lupus erythematosus (SLE). Guidelines for the management of eosinophilia are available from the British Infection Society.13
Local microbiologists can provide guidance on appropriate initial investigations (including how and when samples should be taken) and infection control. For instance, dengue IgM serology does not become positive until after the fourth day of illness.
Regional paediatric infectious disease and public health specialists may be consulted for advice on seriously unwell children, specific infections, second-line investigations, interpretation of results, empirical therapy and infection control. They are usually contacted after consultation with local microbiologists and undertaking first-line investigations. They may recommend specific panels of serological/PCR tests based upon the travel history and presentation. Specialist laboratory services may be available through such regional centres or Public Health England
Differential diagnosis
The majority of febrile returning child travellers will have a mild self-limiting or easily treatable cosmopolitan infection. These are infections that are relatively common and can occur worldwide, such as respiratory or urinary tract infections (Case 1).8 ,15 ,16 Leptosporosis, mononucleosis and travellers’ diarrhoea are other important causes worldwide.8 ,18–23
Depending on the travel history, it is also vital to consider tropical and geographically localised infections including disease outbreaks since some may be life-threatening and highly contagious. Malaria is one of the commonest and most important causes of imported fever in children. After travel to sub-Saharan Africa, other important causes to consider include: schistosomiasis, amoebiasis, rickettsioses, meningococcal disease and VHF. After travel to Asia, important causes include: dengue, typhoid fever, chikungunya and emerging viral infections such as avian influenza. Brucellosis should be considered after travel to the Middle East and dengue and coccidioidomycosis after travel to South America and the Caribbean. Rocky Mountain spotted fever (RMSF), Q-fever and tick-borne encephalitis are examples of infections rare in the UK but endemic in North America, Australia and mainland Europe, respectively.8 ,18–23
Non-infectious causes of fever include Kawasaki disease, juvenile idiopathic arthritis, SLE, leukaemia and lymphoma. Some, such as haemophagocytic lymphohistiocytosis may be triggered by minor illnesses sustained during travel.
The clinician must decide which of these causes are more probable based upon the travel history, risk factors, clinical presentation, incubation periods and investigation results.
Therapy should be guided by local geographical patterns of antimicrobial resistance and culture results once available. For example, ceftriaxone or azithromycin is recommended for typhoid fever in child travellers to Asia due to widespread fluroquinolone resistance.37
Uncomplicated malaria is treated with oral antimalarials, and children with falciparum malaria should be admitted for at least 24 h observation.27 Severe malaria is treated with intravenous artesunate or quinine, and such children should be admitted to a paediatric intensive care or high-dependency unit.25 ,27 ,29
The management of infections, such as dengue fever and travellers’ diarrhoea, is usually supportive. However, severe dengue should be managed in intensive care and profuse diarrhoea can lead to rapid dehydration especially in younger children. Clinicians should have a lower threshold for commencing empirical antibiotics, such as azithromycin, for moderate and severe travellers’ diarrhoea including dysentery.33 ,34
VHF are endemic in parts of Africa, Asia, South America and Eastern Europe. Some are classified as Hazard Group 4 by virtue of their high mortality, diagnostic difficulty, absence of effective treatments and high contagiousness.38 Such VHF are extremely rare but may be considered in febrile children returning from an endemic region within 21 days particularly if they have bleeding, bruising or a negative malaria film.38 Confirmed cases are usually managed in a High Security Infectious Disease Unit.
Public Health England publishes a list of imported infections with a statutory requirement to notify the local Consultant in Communicable Disease Control. They may also recommend prophylaxis for close contacts and assist with contact tracing
Depending on the travel history, it is also vital to consider tropical and geographically localised infections including disease outbreaks since some may be life-threatening and highly contagious. Malaria is one of the commonest and most important causes of imported fever in children. After travel to sub-Saharan Africa, other important causes to consider include: schistosomiasis, amoebiasis, rickettsioses, meningococcal disease and VHF. After travel to Asia, important causes include: dengue, typhoid fever, chikungunya and emerging viral infections such as avian influenza. Brucellosis should be considered after travel to the Middle East and dengue and coccidioidomycosis after travel to South America and the Caribbean. Rocky Mountain spotted fever (RMSF), Q-fever and tick-borne encephalitis are examples of infections rare in the UK but endemic in North America, Australia and mainland Europe, respectively.8 ,18–23
Non-infectious causes of fever include Kawasaki disease, juvenile idiopathic arthritis, SLE, leukaemia and lymphoma. Some, such as haemophagocytic lymphohistiocytosis may be triggered by minor illnesses sustained during travel.
The clinician must decide which of these causes are more probable based upon the travel history, risk factors, clinical presentation, incubation periods and investigation results.
Malaria
In the UK each year, there are 1500–2000 cases of malaria with 10–20 deaths; 15–20% of cases occur in children.24–27 The majority are due to Plasmodium falciparum which tends to present within 2 months; other malaria species may present months or years after exposure. Malaria often presents with non-specific signs and symptoms including flu-like symptoms, malaise, nausea, vomiting, diarrhoea, abdominal pain, cough, jaundice, pallor and hepatosplenomegaly (Case 2). Headache, myalgia and rigors are less common in children.25 Young children are particularly susceptible to severe malaria including anaemia and cerebral malaria (box).25 ,27–29Box
Inability to sit, stand or feed
Respiratory distress or pulmonary oedema
Spontaneous bleeding
Jaundice with vital organ dysfunction
Circulatory shock
Severe anaemia (<7 g/dL)
Hypoglycaemia (<2.2 mmol/L)
Hyperparasitaemia (>2%/100 000/μL)
Metabolic acidosis (plasma pH < 7.3, bicarbonate <15 mmol/L, or lactate >5 mmol/L)
Disseminated intravascular coagulation
Renal/hepatic impairment, oliguiria or haemoglobinuria
Severe malaria29
Impaired consciousness or seizuresInability to sit, stand or feed
Respiratory distress or pulmonary oedema
Spontaneous bleeding
Jaundice with vital organ dysfunction
Circulatory shock
Severe anaemia (<7 g/dL)
Hypoglycaemia (<2.2 mmol/L)
Hyperparasitaemia (>2%/100 000/μL)
Metabolic acidosis (plasma pH < 7.3, bicarbonate <15 mmol/L, or lactate >5 mmol/L)
Disseminated intravascular coagulation
Renal/hepatic impairment, oliguiria or haemoglobinuria
Dengue and chikungunya
Dengue fever is a viral illness transmitted by the day-time biting Aedes aegypti mosquito in the tropics and subtropics. It is a relatively common and usually mild self-limiting infection in travellers returning especially from Asia and South America.8 In 2010 in the UK, there were 27 cases in children and teenagers.30 Chikungunya may occur after travel to Africa, Asia and the Indian Ocean islands. The symptoms of dengue are non-specific. In children, epistaxis, hepatomegaly and oliguria are more common.31 In older children and adults, headache, retro-orbital pain, arthralgia, petechiae and malaena are more common.31 Other symptoms may include diarrhoea, nausea, abdominal pain, cough and lymphadenopathy. Severe dengue and complications, such as encephalopathy, are rare in travellers. Children with a previous history of dengue infection are at increased risk of severe dengue. Dengue shock syndrome is more common than dengue haemorrhagic fever in children with severe dengue.31 Chikungunya has a similar presentation to dengue fever but typically with a more chronic polyarthralgia.Typhoid fever
Enteric fever is prevalent in conditions of poor sanitation worldwide and is particularly common in children VFRs in the Asian subcontinent. In sub-Saharan Africa, non-typhoidal salmonellae are more prevalent. Young children may present with a non-specific febrile illness. Older children with enteric fever may develop the classical features of headache, cough, diarrhoea, constipation, abdominal pain, transient truncal rose spots, hepatosplenomegaly and a relative bradycardia (Case 3).32Travellers’ diarrhoea
The majority of travellers’ diarrhoea is self-limiting. However, fever is more common in children and there is an increased risk of bacterial infection.33 ,34 Parasitic infections, such as giardiasis, and non-infectious causes, such as inflammatory bowel disease, should be considered especially in prolonged diarrhoea >14 days.33 ,34 Amoebiasis may present with dysentery and/or a liver abscess with hepatomegaly and abdominal pain. Systemic infections, such as malaria and typhoid fever, should also be considered.8Respiratory infections
Respiratory infections are a common cause of fever in travellers. Respiratory symptoms may be caused by common respiratory infections, such as influenza or streptococcus pneumoniae; atypical pneumonias; or non-respiratory tract infections, such as malaria and Loeffler’s syndrome.Tuberculosis
Tuberculosis typically affects the lungs, although disseminated and extrapulmonary disease is more common in young children. It should be suspected in returning child travellers presenting with a chronic cough (>3 weeks), night sweats, weight loss, lymphadenopathy or pyrexia of unknown origin, particularly in VFRs after prolonged travel to high-risk regions (tuberculosis incidence >40/100 000), or close contact with individuals with suspected/confirmed active pulmonary tuberculosis. Drug-resistant tuberculosis is becoming an increasing problem in certain parts of the world.Schistosomiasis
Acute schistosomiasis (Katayama’s fever) should be considered in a child with fever, urticarial rash, eosinophilia and a history of freshwater exposure in endemic regions of predominantly sub-Saharan Africa, as well as Southeast Asia, Latin America and the Caribbean. Diagnosis is challenging with initial serology, and stool/urine for ova frequently negative. Specific gastrointestinal and urological symptoms usually present later.Rickettsiae
Rickettsial diseases are transmitted worldwide by fleas, lice, ticks and mites, and are becoming increasingly recognised in travellers. Diagnosis is mainly clinical, with potential symptoms including headache, malaise, myalgia, rash (eschar, maculopapular, petechiae), lymphadenitis and photophobia. African tick bite fever should be considered after safari in sub-Saharan Africa. Mediterranean spotted fever (MSF) may occur after travel to countries adjacent to the Mediterranean Sea, Black Sea, sub-Saharan Africa or India. RMSF occurs in parts of the Americas including the USA. MSF and RMSF can be severe with multiple organ involvement if untreated.Treatment
The seriously ill child is managed according to APLS principles and often with empirical broad-spectrum antibiotics. National guidelines exist for the management of several imported infections including malaria and tuberculosis.25 ,29 ,35 Other resources, such as ‘The Blue Book’ provide guidance on the management of a variety of paediatric infections.36Therapy should be guided by local geographical patterns of antimicrobial resistance and culture results once available. For example, ceftriaxone or azithromycin is recommended for typhoid fever in child travellers to Asia due to widespread fluroquinolone resistance.37
Uncomplicated malaria is treated with oral antimalarials, and children with falciparum malaria should be admitted for at least 24 h observation.27 Severe malaria is treated with intravenous artesunate or quinine, and such children should be admitted to a paediatric intensive care or high-dependency unit.25 ,27 ,29
The management of infections, such as dengue fever and travellers’ diarrhoea, is usually supportive. However, severe dengue should be managed in intensive care and profuse diarrhoea can lead to rapid dehydration especially in younger children. Clinicians should have a lower threshold for commencing empirical antibiotics, such as azithromycin, for moderate and severe travellers’ diarrhoea including dysentery.33 ,34
Infection control and public health
Febrile returning child travellers should initially be managed in a side room with staff using universal precautions if there are respiratory or haemorrhagic symptoms. Specific suspected/confirmed infections may then require more or less intensive infection control measures. Laboratory personnel should be informed of certain suspected infections, such as typhoid fever.VHF are endemic in parts of Africa, Asia, South America and Eastern Europe. Some are classified as Hazard Group 4 by virtue of their high mortality, diagnostic difficulty, absence of effective treatments and high contagiousness.38 Such VHF are extremely rare but may be considered in febrile children returning from an endemic region within 21 days particularly if they have bleeding, bruising or a negative malaria film.38 Confirmed cases are usually managed in a High Security Infectious Disease Unit.
Public Health England publishes a list of imported infections with a statutory requirement to notify the local Consultant in Communicable Disease Control. They may also recommend prophylaxis for close contacts and assist with contact tracing