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Home , African tick bite fever, Lymphogranuloma venereum, Yaws

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THE TRAVELLER WITH FEVER THE RETURNING TRAVELLER WITH FEVER

As numbers of visitors returning from exotic destinations in less developed parts of the world increase, the challenges to the physician grow.

Travellers face a number of health risks during their journeys. The majority of incidents are related to trauma or to underly- ing co-morbid disease, most commonly cardiovascular dis- ease. Infectious diseases however are a significant problem and range from the potentially life-threatening, such as , to those that are more mundane, such as travellers’ diarrhoea. This article will focus on the traveller who returns with a suspected infectious disease and will discuss a diag- nostic approach, before describing important syndromes and their common causes.

HISTORY LUCILLE BLUMBERG JOHN FREAN Pyrexial illness is a presentation of most travel-associated MB BCh, MMed (Microbiol), MB BCh, MMed (Path), infectious diseases, but many common such as DTM&H, DOH, DCH DTM&H, MSc (Med Parasitol) influenza and also occur in the tropics or may be Specialist Microbiologist Specialist Microbiologist acquired en route to and from exotic regions. Patients may National Institute for National Institute for also have chronic or recurrent medical problems that are Communicable Diseases and Communicable Diseases and unrelated to their tropical exposure. In approaching a pyrexi- University of the University of the al patient, therefore, a general medical history should elicit Witwatersrand Witwatersrand Johannesburg Johannesburg the presence of underlying conditions, particularly those John Frean qualified at the associated with increased risk of infections such as diabetes, Lucille Blumberg is currently University of the malignancy, HIV , splenectomy, and pregnancy. head of the and Witwatersrand in 1980, and Outbreak Unit, and medical Specific questions about the current illness are listed below. currently holds a senior posi- consultant to the Viral The travel history, both recent and past, is of vital impor- tion in the National Institute Haemorrhagic Fever Unit. Dr for Communicable Diseases of tance. Duration of illness in relation to known incubation Blumberg has a background the National Health periods helps to include or eliminate certain infections. in clinical infectious diseases. Laboratory Service and the Areas visited and the nature of the travel may suggest likely Her special interest is in trav- University of the el-related infectious diseases, exposures, e.g. business travel in city hotels has a different Witwatersrand. His main in particular the prevention risk profile compared with river-rafting adventures. interests are parasitic and and management of malaria. zoonotic diseases. History — important questions

• Symptoms and sequence of symptoms • Travel departure and return dates • Purpose of travel (elicit specific details): business, leisure, missionary, military, expatriate • Onset of illness in relation to travel • Countries visited, including stopovers, and specific areas within the country • Season and climate • Type of travel: e.g. overland, air, sea, backpacking • Type of accommodation: e.g. camping, hotel • Pre-travel immunisations: what and when • Prophylaxis, including chemoprophylaxis, e.g. malaria: type and compliance with drugs

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• Exposures: see Table I Table I. Specific exposures and associated infections • Past illness: general plus specific ill- nesses such as A Type of exposure Associated infections • Co-morbid disease, • Immunosuppression: specific illness- Bites es or drug-induced, previous Mosquito Malaria, dengue, yellow fever, encephalitis, splenectomy filariasis • Specific symptoms: fever (onset of Borreliosis (, ), fever, fever pattern), headache, rig- rickettsioses (tick bite fever, , Rocky ors, photophobia, , Mountain ); Congo-Crimean haemor- , arthralgia, myalgia, pres- rhagic fever, , tularaemia, encephalitis, ence of rash or lesions (see below), , gastro- intestinal symptoms (diarrhoea, Fly African trypanosomiasis, , leishma- presence of blood, vomiting), jaun- niasis, , myiasis, loiasis dice, and haematuria. , tungiasis,

PHYSICAL EXAMINATION Triatomine bugs American trypanosomiasis (Chagas’ disease)

A thorough physical examination is Mammal Rabies, rat-bite fever, tularaemia, anthrax, Q fever, essential, and together with the histo- ry, will direct the choice of further radiological and laboratory investiga- Ingestion tions (Table II). A full blood count and Water (untreated) Hepatitis A/E, , Norwalk/caliciviruses, examination of blood smears is a Salmonella, Shigella, Giardia, poliomyelitis, nearly obligatory basic investigation. Cryptosporidium, Cyclospora, The physician should focus initially on those infections that carry the greatest Dairy (unpasteurised) Brucella, tuberculosis, Listeria morbidity and mortality, those that are Enteric (Salmonella, Shigella, E. coli, treatable and those that pose a public C. jejuni, etc.) health risk. Raw or undercooked food Helminths (Ascaris, Trichinella, Taenia – including UNDIFFERENTIATED FEVER (meat, fish, vegetables) cysticercosis, whipworm, Capillaria, Angiostrongylus), (amoebiasis, toxoplas- Diagnosis and management of malaria mosis) in travellers is urgent, and should be considered in anyone returning from a Freshwater skin , schistosomiasis, Acanthamoeba, or malaria area with symp- contact Naegleria toms of a flu-like illness, fever, rigors, Sand/dirt/mud skin Hookworm, cutaneous larva migrans, headache and/or myalgia, irrespec- contact visceral larva migrans, leptospirosis tive of the season or whether chemo- prophylaxis was taken. The risk of Sexual contact HIV, /C, , gonorrhoea, contracting malaria is highest in , herpes, papillomavirus and , followed by and Latin America. Most large cities in by inappropriate chemoprophylaxis or resistant Plasmodium falciparum is a South and Central America and poor compliance, and clinical illness problem globally. Artemisinin combi- are malaria-free but may be delayed in patients with non- nation therapy is considered highly this is not true of Africa (apart from falciparum malaria. A blood smear or effective, with quinine and South Africa, the Kenyan capital rapid detection test is usually as an alternative for malaria acquired Nairobi, Gaborone in Botswana, sufficient to confirm the diagnosis, but in Africa. Chloroquine and primaquine Windhoek in Namibia and Harare in a negative test does not exclude are effective for most strains of Zimbabwe). Plasmodium falciparum is malaria and repeat tests may be nec- Plasmodium vivax with the exception of the commonest species in Africa and essary. is frequent, some resistance in Oceania and overall the most serious, frequently even in uncomplicated cases. Choice . progressing rapidly to complicated dis- of treatment depends on severity of ease. Most travellers with malaria disease and the likely drug resistance characteristically pres- present 7 - 21 days after exposure but pattern of the parasite. Chloroquine- ents insidiously with fever, headache, incubation periods may be prolonged

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East African trypanosomiasis is gener- Table II. Differential diagnosis of physical findings for some ally an acute, often fulminating condi- febrile diseases tion with a substantial mortality. Physical finding Differential diagnosis Transmission to tourists has occurred recently in game reserves in Tanzania, Lymphadenopathy Plague, HIV, rickettsioses, , leishmania- Malawi and . The vectors are sis, dengue, , Lassa tsetse flies, which are aggressive and fever deliver an unmistakably painful bite, Hepatomegaly Malaria, leishmaniasis, amoebic liver , often through clothing. At the site of typhoid, hepatitis, leptospirosis the bite a trypanosomal may form a few days afterwards. Systemic Splenomegaly Malaria, leishmaniasis, trypanosomiasis, typhoid, disease is an acute febrile illness, not brucellosis, typhus, dengue unlike malaria. Disease may be rapid- ly complicated by myocarditis, coagu- Jaundice Hepatitis, malaria, leptospirosis, relapsing fevers, lation disorder including disseminated cholelithiasis, pancreatitis intravascular coagulation (DIC), and Petechiae/ecchymosis Meningococcaemia, yellow fever, dengue, rick- central nervous system invasion. ettsioses, viral haemorrhagic fevers Trypanosomes in the blood may be scanty and easily missed unless the Wheezing Löffler’s syndrome, Katayama fever, tropical pul- laboratory is warned of their possible monary eosinophilia presence. Specific treatment in the form of suramin or melarsoprol (in the Table III. Skin lesions associated with infections case of CNS invasion) is mandatory but is toxic and must be given under Skin lesion Differential diagnosis expert supervision.

Maculopapular Arboviruses, acute HIV, , syphilis, typhus, FEVER AND RASH bartonellosis, typhoid, rubeola, , , cercarial dermatitis, , arthropod bites Travel-related infectious diseases are commonly associated with skin lesions Petechiae/ecchymoses Rickettsiae, meningococcaemia, viral haemorrhag- or rashes. Important aids to diagnosis ic fevers, dengue, leptospirosis are the nature of the lesion, distribu- tion of the rash, appearance of the Tick bite fever, , anthrax, African try- skin lesion in relation to the course of panosomiasis, tularaemia, spider bites clinical illness, and the presence of Nodules Onchocerciasis, bartonellosis, myiasis other clinical (Table III). More than 150 arboviruses Ulcers Leishmaniasis, tropical ulcers, anthrax, tularaemia, affect humans. Arboviruses tend to be cutaneous diphtheria, , syphilis, , seasonal and regional in their distribu- tuberculosis, , lymphogranulo- tion so a history of travel to a specific ma venereum, arthropod bite geographical area often provides the clue to the specific causative Migratory Cutaneous larva migrans, larva currens, gnathosto- arbovirus. Many present with a char- miasis, loiasis, myiasis, paragonimiasis, acteristic clinical syndrome of fever, sparganosis rash and arthritis.

chills, and abdominal pain. There is Salmonella typhi on blood culture. In southern Africa, important arboviral frequently a paucity of clinical signs Isolation from stool or urine is support- infections include West Nile, Sindbis and fever may be the most prominent ive but not absolutely diagnostic as it and Chikungunya. Dengue is increas- clinical finding. An irritable cough, may merely indicate the carrier state. ingly seen in travellers returning from change in mental state, and A four-fold rise in agglutinating anti- endemic areas. Culicine mosquitoes splenomegaly may be noted. Rose bodies to the O capsular antigen is transmit Sindbis, West Nile and spots are uncommon. Characteristi- highly suggestive. Quinolones are Chikungunya . Fever, pol- cally there is leucopenia, with neu- highly effective. Alternative agents yarthropathy involving both small and trophilia and eosinopenia, thrombocy- include third-generation cephalospor- large joints, severe myalgia and rash topenia and a modest increase in ins, and ampicillin. are usual features. Arthritis may persist hepatic transaminases. The diagnosis resistance is a significant for several months to 2 years. is best confirmed by isolating problem in Southeast Asia. Malaise, conjunctivitis and pharyngitis

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Pyrexial illness is a presen- may be noted. Rash is prominent and tation of most travel-associ- in Sindbis is typically maculopapular, ated infectious diseases, with a characteristic halo surrounding each individual macule or (Fig. but many common infec- 1). Rash is variable in West Nile infec- tions such as influenza and tion, ranging from maculopapular to pneumonia also occur in discrete roseolar spots, diffuse small the tropics or may be spotted exanthem or even mottling of acquired en route to and the skin. Diffuse lymphadenopathy is common. Fig. 1. Sindbis rash, showing ‘halo’ from exotic regions. around the lesions.

In the northern hemisphere, West Nile mitted principally by daytime biting A full blood count and infections more commonly present as Aedes aegypti mosquitoes. Recently, examination of blood encephalitis. The rash of Chikungunya epidemics of dengue have occurred in is generally a fine diffuse macular or smears is a nearly obligato- Southeast Asia, notably in Thailand, papular rash that spreads centrifugal- ry basic investigation. and Vietnam, on the Indian ly, often to the palms and soles. subcontinent, and in Central and Dengue is caused by a flavivirus trans- . In Africa, dengue

Table IV. Causes of eosinophilia and fever in returning travellers

Disease or condition Substantiating evidence, caveats, Suggested investigations and clinical points

Acute schistosomiasis History of transient skin itching, tingling or Schistosomiasis , repeat in papular rash; dry cough common; a week if low/negative eosinophilia earliest sign, parasite ova only appear weeks or months later

Strongyloidiasis Transient urticarial rashes (larva currens); Stool (and sputum, if disseminated abdominal pain; nausea, diarrhoea, weight disease suspected) examination loss in more severe cases for larvae; serology not available in SA

Trichinosis History of eating raw or undercooked meat; Muscle needle biopsy; serology presents with nausea and vomiting, followed not available in SA by myalgia, and periorbital oedema; uncommon complications are myocarditis, meningoencephalitis

Gnathostomiasis History of eating raw/undercooked fish, Surgical removal of larvae (difficult); crabs, crayfish, birds, typically acquired in specific serological test available Far East, SE Asia but also recently in Africa; in Thailand only presents as larva migrans syndrome Albendazole (21 days) has proven successful

Löffler’s syndrome Transient parasitic , presents Chest X-ray shows transient with fever, cough, wheezing; most commonly infiltrates due to Ascaris lumbricoides larvae migrating through lung; less commonly, and strongyloidiasis

Toxocariasis Typically in children with history of pica Liver function tests (hyper-gamma- globulinaemia); Toxocara serology and contact with dogs; presents with fever, hepatomegaly, wheezing; sometimes cardiac and neurological dysfunction; ocular form can mimic retinoblastoma

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occurs in East and West Africa. Local associated with painful regional lym- al, protozoan infections do not pro- transmission in South Africa has not phadenopathy. The rash is typically duce eosinophilia; exceptions are been reported although occasionally maculopapular, and the distribution is Isospora belli and Dientamoeba frag- vectors have been imported in tyres on the trunk and limbs, classically ilis. Non-parasitic infectious diseases from endemic areas. The incubation involving the palms and soles (Fig. 4). causing eosinophilia include chronic period is 3 - 8 days, and presentation tuberculosis, resolving scarlet fever, is abrupt with headache, fever, chills, bronchopulmonary aspergillosis and myalgia, arthralgia, and retro-orbital histoplasmosis. There are many non- pain. On day 3 - 5, fever reduces and infectious causes of eosinophilia that a morbilliform rash appears on the may coincidentally be present in a trunk, spreading to the face and patient with fever (e.g. lymphomas, extremities. Characteristically, the rash leukaemias, other malignancies, drug tends to blanch (Fig. 2). Petechial allergies, toxins, dermatological, pul- haemorrhages may appear, but do not monary, and idiopathic conditions). necessarily indicate the Typhoid fever is classically associated of dengue haemorrhagic fever. Fig. 3. Eschar of tick bite fever. with an absence of peripheral blood Leucopenia and thrombocytopenia are eosinophils; systemic steroid therapy common findings. The diagnosis of also usually suppresses an eosinophilic arboviral infections is confirmed dur- reaction of any aetiology. ing the first week of illness by isolation from blood. Seroconversion LABORATORY may be demonstrated after the first INVESTIGATIONS week of illness. Management of arboviral disease is generally sympto- A full blood count gives valuable infor- matic. mation regarding aetiology as well as severity of disease. Leucocytosis is sug- Fig. 4. Rash of tick bite fever, involv- gestive of bacterial infection, leucope- ing palms. nia is frequent in malaria, typhoid and arboviral infections and thrombocy- In older patients, and in severe dis- topenia is invariable in malaria. ease, the rash may be haemorrhagic Eosinophilia is most likely to be due to with petechiae and even ecchymoses. a helminthic infection. Peripheral The disease is confirmed by the specif- blood smears for malaria are manda- ic serological test. A negative result in tory in febrile travellers from malaria the first week of illness is not uncom- risk areas. A liver function test is fre- mon, and repeat serology is indicated. quently very useful. The remaining Fig. 2. Dengue rash, showing blanch- The Weil-Felix test is neither sensitive investigations are guided by the sus- ing on pressure. nor specific for tick bite fever. Optimal pected diagnosis based on history and treatment is doxycycline, and a short travel. Cultures should ideally be sub- There are two forms of tick bite fever, course should even be considered in mitted prior to starting . the commonest rickettsial disease in young children and pregnant women. Interpretation of serological investiga- Africa. infection (bou- is much less effective. tions should take into account the sen- tonneuse fever) is largely a peri-urban There is limited experience with the sitivity and specificity of the test, and disease. infection new 4-fluorinated quinolones and they may need to be repeated to () is more com- . If treatment is delayed, demonstrate seroconversion or mon in rural areas, frequently in hikers tick bite fever may be complicated by increase in titre. and campers. The former tends to be multi-organ failure and DIC. more severe with a prominent rash, MANAGEMENT while the latter is generally milder, FEVER AND EOSINOPHILIA multiple may be present and The potentially most dangerous and rash is frequently absent. The incuba- Eosinophilia, defined as an absolute common causes of fever in returning tion period is 6 - 12 days. An initial eosinophil count of > 400/µl, is asso- travellers should be looked for first prodrome of severe headache, fever ciated with several infections, mainly and managed accordingly. Specific and frequently nightmares, is followed parasitic, that may present with a treatment is ideally given only once 3 - 5 days later by the rash. At the febrile illness (Table IV). the diagnosis is confirmed, influenced bite site the characteristic eschar (Fig. Schistosomiasis is the commonest however by the severity of the clinical 3) is generally noted, and usually cause in returning travellers. In gener- disease and the likelihood of a specif-

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ic disease. Drug-resistant organisms IN A NUTSHELL are a major problem globally and the likely sensitivity pattern of the specific organism acquired in a specific locale Thorough history of illness and travel movements is essential. must be taken into account. Ask about existing medical conditions.

Further reading Focus initially on diagnosing infections that are dangerous for patient and Blumberg L, Frean J. Dermatological manifesta- community. tions of tropical diseases. Dermatology Review 2004; 4: 5-14. Skin lesions are important clues to many travel-related infections. Blumberg L, Ogunbanjo GA, Durrheim DN. Malaria must always be considered in a traveller with fever and flu-like symp- Fever in adults – An approach to diagnosis and management. Family Practice 2000; 22: 23-26. toms. Isaacson M, Frean J. Diagnostic and manage- Tick bite fever is common in travellers in Africa, and the typical rash may be ment approaches in returning travellers. In: DuPont HL, Steffen R, eds. Textbook of Travel absent. Medicine and Health, 2nd ed. London: BC Decker Inc, 2001: 498-510. (Available from Fever, rash and arthritis is suggestive of arboviral infections. SAMA-HMPG. Price R1 115, members R1015.) Fever and eosinophilia is commonly due to acute schistosomiasis (Katayama National Department of Health. Guidelines for the Prevention of Malaria in South Africa Pretoria: fever). NDOH, 2003: 1043. Full blood count, blood smear examination, and liver function tests are obliga- National Department of Health. Guidelines for the Treatment of Malaria in South Africa Pretoria: tory initial investigations. NDOH, 2002: 1-18. Getting a diagnosis before treatment is ideal, but must be balanced against Spira AM. Assessment of travellers who return home ill. Lancet 2003; 361: 1459-1469. the need to treat severe illness. Wolfe MS. Advice on return from travel. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, vol 2. 5th ed. Philadelphia: Churchill Livingstone, 2000: 3252. (Available from SAMA-HMPG. Price R3270, members R2945.)

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