Behind The Medical Headlines

Fever in the Returning Traveller

• Dr CA Marwick, Infectious Diseases Unit, Ninewells Hospital and Medical School, Dundee, Scotland
• Dr D Nathwani, Infectious Diseases Unit, Ninewells Hospital and Medical School, Dundee, Scotland

Summary

Fifty million people travel to the developing world every year, many of whom develop a travel-related illness often involving fever caused by infection. In this article Dr Charis Marwick and Dr Dilip Nathwani provide an overview of the main regional causes of fever to aid diagnosis and treatment.

Declaration of interests: No conflict of interests declared

Introduction

With global travel increasing annually, there is an inevitable increase in imported infection. Of the 50 million travellers to the developing world each year, up to 5% will seek medical advice during their trip or on return, while 20–70% will report some illness associated with their travel.¹ Those visiting family or friends and adventure tourists are at greatest risk.¹ A systematic approach to the assessment of the febrile traveller with knowledge of the most common, region-specific pathogens will aid diagnosis and treatment.

Causes of fever

A large proportion of febrile returning travellers will have cosmopolitan infections such as pneumonia, viral respiratory tract infection and urinary tract infection. However, specific tropical infections must be considered with malaria and dengue being the most common.

In 2003, there were 996 cases of malaria in European travellers reported to TropNetEurop² (the European Network on Imported Infectious Disease surveillance system). Of these, 831 were P. falciparum infections (818 mono and 13 mixed infections), 133 were P. vivax and 32 were P. ovale.² Recently published data on 17,353 travellers from developed to developing countries have demonstrated important differences in morbidity depending on the country of destination³ (data from the multinational Geosentinel surveillance database.

The most common clinical presentation was a systemic febrile illness without localising symptoms or signs. Malaria was the most common diagnosis overall in these patients. However, in travellers from destinations other than sub-Saharan Africa and Central America, dengue was more prevalent. After malaria and dengue, infectious mononucleosis was the most common cause of fever, followed by rickettsial disease and then typhoid.

Acute diarrhoea was the second most common presentation. The most common identified causes were giardiasis, amoebiasis, campylobacter and shigella.

Destination-specific variations in the proportionate morbidity associated with different etiologic agents, in patients presenting with a systemic febrile illness or acute diarrhoea, are shown in Table 1.³ This may aid clinicians in narrowing down the likely aetiology of an illness. Similarly, a prospective study of 91 febrile travellers presenting to the Hospital of Tropical Medicine, London, demonstrated malaria, non-specific viral illness, dengue and dysentery as the most common diagnoses.⁴

Awareness of recent outbreaks of infection worldwide and the current regional susceptibility of malaria is necessary in assessing the ill traveller. Up-to-date information for non-healthcare professionals is available from the Scottish Centre for Infection & Environmental Health (SCIEH) and the World Health Organisation (WHO). Healthcare professionals involved in the advice and treatment of travellers should register with the SCIEH clinicians’ online resource and seek advice from regional infection units.

New emerging infections, such as H5N1 avian influenza, have been the focus of much media and public health interest. However, there have been no reported human cases of avian influenza in travellers, or in the UK, thus far. Southeast Asia remains the region with the highest number of human cases, but fatal cases have recently been reported in Turkey, Egypt and Iraq. Up-to-date information on avian influenza is available from the dedicated WHO website.

The travel history

An accurate and detailed travel history is mandatory and will often indicate the diagnosis. Specific attention should be paid to the travel destination(s), including the particular area within a country, duration of stay, date of return in relation to onset of symptoms, whether urban or rural areas were visited, purpose of travel (to indicate any occupational exposure), standard of accommodation, pre-travel vaccination and advice obtained, illness of any travel companions, type and adherence of malarial prophylaxis, history of sexual activity and any non-prescribed or illicit drug use.

It is important to be aware of the limitations of prophylactic medication. In particular, the most effective vaccination against typhoid is only 70% effective and does not prevent infection with S. paratyphi, a common cause of enteric fever in Asia and Eastern Europe.⁵ Malaria can still occur despite correct prophylaxis with strict adherence.

The timing of symptoms in relation to travel can exclude certain diagnoses and make others more likely. Febrile travellers presenting to the London School of Tropical Medicine attended within 14 days of return in 71% of cases while 11% presented more than six months after any travel to the Tropics.⁴ Malaria due to P. vivax or P. ovale may present months or years after travel due to the presence of dormant hypnozoite stages in its life cycle. Falciparum malaria presents within two months in 90% of cases but increasing use of mefloquine as prophylaxis can delay presentation to up to four months.⁵ The typical incubation periods of selected tropical infections is shown:⁶

• Short (<10 days)

  • Arboviral infections (including dengue fever)
  • Enteric bacterial infections
  • Typhus (louse borne, flea borne)
  • Plague
  • Paratyphoid
  • Haemorrhagic fevers

• Medium (10 -21 days)

  • Malaria
  • Typhoid fever
  • Scrub typhus, Q fever, spotted fever group
  • African trypanosomiasis
  • Brucellosis
  • Leptospirosis

• Long (>21 days)

  • Viral hepatitis
  • Malaria
  • Tuberculosis
  • HIV
  • Schistosomiasis (Katayama fever)
  • Amoebic liver abscess
  • Visceral leishmaniasis
  • Filariasis

Clinical examination

A thorough clinical examination is essential. This must involve all areas of the skin, including the genitals, to look for bites, rashes or other diagnostic skin lesions. The mouth and throat require detailed inspection. Particular attention should also be paid to the lymph nodes, liver and spleen. Typical clinical findings in selected tropical infections are listed in Table 2.⁵

Investigation

The single most important investigation in the febrile traveller is thick and thin blood films for malaria parasites. For the diagnosis of dengue, the most widely used test is the MAC-ELISA test, though paired tests, two weeks apart, may be needed to make a definitive diagnosis. Other first-line investigations include full blood count, urea and electrolytes, liver function tests, blood culture, urinalysis and chest X-ray. Further investigations will be guided by specific features in the history and examination or by the results of the initial investigations.

The diagnostic yield of blood films for malaria parasites depends on the experience of the operator, species of malaria, parasitaemia at the time of blood sampling and prior prophylaxis or treatment. Two further sets of blood films (12–24 hours later) must be examined in a patient in whom malaria is suspected and the first films are negative. Antigen detection kits are now used routinely to aid the diagnosis of malaria and species determination, but have not replaced blood films which remain the gold standard investigation. Thrombocytopenia is present in 50–80% of patients with malaria⁶ and, in conjunction with increased bilirubin, is highly suggestive in the appropriate clinical situation.

Eosinophilia is characteristic of acute schistosomiasis but also occurs in any helminth infection or drug reaction. Renal failure may occur in septic shock (of any aetiology), severe malaria, leptospirosis and the haemolytic uraemic syndrome associated with E. coli O157 infection. Liver function tests are usually grossly abnormal in acute viral hepatitis but usually more mildly deranged in malaria, Q fever, dengue fever, typhoid fever, HIV seroconversion and in any severe systemic infection. Blood cultures are helpful in diagnosing typhoid (in the first week), paratyphoid, salmonellosis, pneumococcal infection and bacteraemia of invasive urinary tract infection. Haematuria on dipstick examination is characteristic of schistosomiasis and should prompt microscopy of midday urine to look for ova, and ELISA tests for antibody detection, which indicates exposure rather than active infection. Urine should be sent for culture if symptoms or urinalysis indicate a urinary tract infection. Hot stool microscopy may identify ova or cysts in amoebiasis and giardiasis. Stool culture may be positive in enteric infection with salmonella, campylobacter, shigella, cryptosporidium and typhoid (in the second and subsequent weeks). Chest X-ray will aid the diagnosis of pneumonia, tuberculosis and liver abscess.

Management

The medical treatment of most imported infections is well-established and not subject to frequent updates. Two important exceptions, due to emerging drug resistance, are falciparum malaria and typhoid. Fluroquinolones are the drugs of choice for the treatment of typhoid, but reduced susceptibility and fully resistant strains are emerging in India and Vietnam. Lack of clinical response should raise this possibility and, where this occurs, treatment with a cephalosporin should be given.

The British Infection Society is developing a national algorithm for the assessment and management of acute malaria. The current draft is available via their website. Any patient with proven or suspected falciparum malaria should be admitted to hospital for diagnosis, drug treatment, monitoring for complications and supportive treatment as required. This should ideally be in a specialist infection unit. Treatment of non-falciparum malaria can be safely undertaken as an outpatient as long as the patient is well and the diagnosis is definite. If malaria parasites are seen but the species is uncertain, treatment is as for falciparum until proven otherwise.

Public Health notification of communicable diseases is an essential part of the management for epidemiological and economic purposes. The major imported infections are all notifiable conditions in the UK and should be reported even before a definitive diagnosis is made.

Prevention

The prevention of infection is the most important aspect of travel medicine. Simple measures such as basic hygiene, care to avoid undercooked food and infected drinking water, and the avoidance of bites, are essential. Expert advice with appropriate vaccinations and anti-malarial medication prior to travel has been shown to reduce travel-related morbidity but can never prevent all infection. Data from the Geosentinel survey indicate that over 50% of presenting ill travellers had received documented pre-travel advice³ (although adherence to this advice was not reported). In particular, accurate advice regarding malaria prophylaxis is crucial and must be based on information about current resistance patterns. Even if appropriate prophylaxis is provided, malaria is still the most important diagnosis to consider in the febrile traveller as poor compliance with preventive measures remains a key problem.

References

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2. Wichmann O, Muhlberger N, Jelinek T. TropNetEurop surveillance data: trends in imported malaria 2003. Eurosurveillance Weekly 2004; 8(26):126–37.
3. Freedman DO, Weld LH, Kozarsky PE et al. Spectrum of disease and relation to place of exposure among ill returned travellers. N Engl J Med 2006; 354(2):119–30.
4. Doherty JF, Grant AD, Bryceson AD. Fever as the presenting complaint of travellers returning from the tropics. QJM 1995; 88(4):277–81.
5. Nathwani D. How I manage the febrile returning traveller. Proc R Coll Physicians Edin 1998; 28:24–33.
6. Humar A, Keystone J. Evaluating fever in travellers returning from tropical countries. BMJ 1996; 312:953–6.