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Fever and rash
SYNDROMIC PRESENTATIONS
Fever and rash
What’s new?
John Yates C
Penelope Smith
C
Abstract The patient presenting with fever and a rash presents a diagnostic challenge. While this syndrome suggests an infectious aetiology, the differential diagnosis remains broad, and requires a thorough history and physical examination to distinguish potential non-infectious causes. Epidemiological evidence is important in the differential diagnoses. The commonest febrile illnesses presenting with rash in the returned traveller are arboviral infections (dengue and chikungunya), infectious mononucleosis caused by EpsteineBarr virus (EBV) or cytomegalovirus (CMV), and tick-borne diseases (rickettsioses).
Pattern of the illness e timing of the onset of illness related to travel provides an estimate of the incubation period of potential tropical infections. Presence of associated symptoms and the distribution of rash may provide important clues. Detailed travel history e including departure and return dates, urban or rural exposure, accommodation used and activities undertaken, with clear timings in relation to onset of illness. The travel history should also include previous tropical exposure. Exposure to vector-borne and zoonotic infections e exposure to specific vectors such as ticks, fleas, or mites, should be sought. Often ticks and mites are not seen whilst attached, but a history of walking in rural or wilderness areas indicates potential exposure. Possible exposure to zoonoses should be sought by direct questioning about animal contact but also through determining indirect exposure, for example, to fresh water for leptospirosis. Detailed sexual history e HIV seroconversion, secondary syphilis and disseminated gonococcal infection all commonly cause rash. Past medical history e for example, endocarditis risk factors and immunosuppression. Immunization history e childhood and travel immunizations. Drug history e including malarial prophylaxis, recent antibiotics, known allergies. Exposure to infectious contacts. Sun exposure.
Keywords chikungunya; dengue; fever; infectious mononucleosis; rash; rickettsiae; travel
Fever and rash is a relatively common presentation in travellers returning from the tropics, comprising around 4% of febrile ‘syndromes’ presenting to travel or tropical diseases clinics.1 The presence of a rash as part of a febrile illness, although rarely pathognomonic, focuses the differential diagnosis. It is important to remember that rashes are common and may be caused by another medical condition unrelated to travel, or a drug reaction to medications taken at the time of travel. A systematic approach is important, as a rash can be either a manifestation of a mild illness or an indicator of a potentially fatal contagious disease.
Diagnosis Initial assessment A preliminary assessment should focus on two broad considerations: Does this patient show signs of severe sepsis or organ dysfunction requiring urgent cardiorespiratory support and antibiotic therapy? Does the travel history indicate potential exposure to pathogens causing serious illness with a risk of nosocomial transmission, requiring immediate isolation and barrier precautions (e.g. viral haemorrhagic fevers (VHF))?
General examination Preliminary assessment should determine oxygenation, cardiovascular status and presence of cerebral impairment or meningism. Particular attention should be paid to: eyes e conjunctivitis, conjunctival petechiae, jaundice oropharyngeal mucosa e erythema, exudate, ulceration, vesicles, petechiae, Koplik’s spots, oral candida lymphadenopathy e localized, generalized hepatosplenomegaly genital examination e ulceration.
History Rash can be associated with tropical and cosmopolitan infections (Table 1). A detailed history is essential and should include:
John Yates MRCP MSc is a Consultant in Infectious Diseases and Acute Medicine at Mayday Hospital, Croydon, UK. Competing interests: none declared.
Examination of the skin Full exposure is very important. Distinctive signs, such as an eschar following a tick bite (Figure 1), can be limited to skin folds. Involvement of the palms and soles is a feature of particular infections, such as hand, foot and mouth disease (Coxsackie A16) and secondary syphilis. Rashes can be macular, papular, nodular, vesicular, bullous or pustular, evolving in different
Penelope Smith FRCP DTM&H MSc is a Consultant Physician in Acute Medicine and Infectious Diseases at the Royal Free Hospital, London, UK. Competing interests: none declared.
MEDICINE 42:2
Chikungunya is an arbovirus infection that has circulated in a recent epidemic originating in Reunion Island in the Indian Ocean since early 2005 with ongoing reports of spread to Europe and Australasia Due to exponential increases in global travel during recent years, clinicians must be alert to the possibility of exotic infections in the returned traveller
96
Ó 2014 Published by Elsevier Ltd.
SYNDROMIC PRESENTATIONS
Causes of rash and fever e tropical and cosmopolitan infections Organism/disease
Rash (% cases)
Dengue
M, MP, PP (50%)
Chikungunya
Distribution
Tropical, subtropical, worldwide M, MP (50%) Tropical, subtropical Africa and Asia M, MP, PP, V Worldwide MP, PP, V (46%) Sub-Saharan Africa MP, PP (90%) Mediterranean and sub-Saharan Africa, India MP, PP (90%) USA, Central and South America M, MP (35e90%) Asia, Pacific Islands
Rickettsia African tick typhus Mediterranean spotted fever Rocky Mountain spotted fever Scrub typhus e Orientia tsutsugamushi Typhoid fever e M (rose spots) Salmonella typhi/paratyphi (20%) Leptospirosis M, MP, PP (20%)
Wherever risk of faecal contamination of water Worldwide
Vector/exposure risk
Associated features
Aedes mosquito, urban and rural Aedes mosquito, urban and rural Ticks Ticks rural/wilderness Ticks, urban, suburban
Myalgia, haemorrhage, shock
Eschar common, headache Eschar common
Ticks, rural/wilderness
Eschar rare
Polyarthralgia
Larvae trombiculid mites Eschar common (chiggers), rural Faecaleoral, poor sanitation Prolonged fever, splenomegaly
Yellow fever
U (Katayama fever) PP
Lassa fever
MP, PP
Ebola/Marburg
MP, PP
South American haemorrhagic fevers West Nile virus
PP
Exposure to rat/rodent urine Conjunctivitis, myalgia (fresh water) Africa, Asia, South America, Freshwater snails Eosinophilia Caribbean Central and South America, Mosquito-borne urban/rural Jaundice Africa West Africa Rodent urine, rural Pharyngitis, retrosternal pain, encephalitis, haemorrhage West/Central Africa Unknown, ? monkeys/bats, Abdominal pain, D þ V, rural/wilderness haemorrhage South America
MP
Africa, USA
Measles Varicellaezoster virus EpsteineBarr virus
MP MP, V MP, PP
Worldwide Worldwide Worldwide
Cytomegalovirus
MP
Worldwide
Toxoplasmosis HIV
MP MP
Worldwide Worldwide
Rubella Staphylococcus aureus Streptococcus pyogenes Neisseria meningitidis Neisseria gonorrhoeae Syphilis, Treponema pallidum
MP PP, E E PP PP MP, PP, PU, V
Worldwide Worldwide Worldwide Worldwide Worldwide Worldwide
Schistosomiasis
Culex, Aedes mosquitoes, urban
Cats Sexual, IVDU, vertical transmission Human Human, IVDU Human Human Sexual Sexual
Encephalitis Cough, conjunctivitis, Koplik’s spots Coryza, pneumonitis Pharyngitis, lymphadenopathy, splenomegaly Pharyngitis, lymphadenopathy, splenomegaly Lymphadenopathy Pharyngitis, lymphadenopathy, splenomegaly Coryza, arthralgia Shock, heart murmur Pharyngitis, cellulitis, shock Shock, meningitis Septic arthritis Genital ulceration
D þ V, diarrhoea and vomiting; IVDU, intravenous drug use; M, macular; MP, maculopapular; PP, petechial/purpuric; E, erythrodermic; PU, pustular; U, urticarial; V, vesicular. The % values given for the frequency of rash in particular infections are derived from case series.
Table 1
Fever and rash in the returning traveller
stages of the illness. Generalized erythema is associated with bacteria producing erythrogenic toxins (Streptococcus pyogenes, Staphylococcus aureus) and drug reactions, and urticarial rashes are associated with parasitic infections. Combinations of the rash forms can occur, and a single infection, such as dengue, may cause various morphologies.
MEDICINE 42:2
The commonest febrile illnesses presenting with rash in the returned traveller are arboviral infections (dengue and chikungunya), infectious mononucleosis caused by EpsteineBarr virus (EBV) or cytomegalovirus (CMV), and tick-borne diseases (rickettsioses).2,3
97
Ó 2014 Published by Elsevier Ltd.
SYNDROMIC PRESENTATIONS
Figure 1 Eschar with generalized maculopapular rash of African tick typhus. Courtesy of Dr R. Behrens, Hospital for Tropical Diseases, London.
Figure 2 Dengue: blanching maculopapular rash, with islands of normal skin. Courtesy of Dr R. Behrens, Hospital for Tropical Diseases, London.
Sexually transmitted infections, especially HIV seroconversion and secondary syphilis, are important differential diagnoses, and Katayama syndrome (acute schistosomiasis), which can present with an urticarial rash 4e6 weeks after fresh water exposure in Africa, should also be considered. Although malaria is one of the commonest causes of febrile illness reported in travellers returning from tropical and subtropical regions, the presence of a rash is unusual.
Retrospective diagnosis can be made using serology. In patients with shock, early confirmation can be made by polymerase chain reaction (PCR), but positivity falls rapidly to less than 10% after 7 days of illness. Management: dengue fever is usually self-limiting. Management is symptomatic and non-steroidal anti-inflammatory drugs should be avoided because of the bleeding tendency. Monitoring for progression to DHF/DSS is important. A fall in platelet count below 100 109/litre is a predictor for progression and should precipitate admission for close clinical observation. Shock should be treated with fluid replacement and blood products.5
Dengue Epidemiology: dengue is a flavivirus distributed throughout tropical regions and transmitted by Aedes mosquitoes. The four serotypes cause 50e100 million cases of dengue fever each year, with significant morbidity and mortality associated with dengue haemorrhagic fever (DHF)/dengue shock syndrome (DSS). Rates of seroconversion are high in travellers to South East Asia and, in a study of fever and rash in travellers returning to France, dengue infection accounted for 26% of cases.3,4
Chikungunya Chikungunya virus is also transmitted by Aedes mosquitoes, with an incubation period of 4e7 days. Sporadic cases and epidemics occur in Africa and Australasia, and a recent outbreak in Papua New Guinea is estimated to have affected many thousands of individuals. Presentation is similar to dengue, with sudden onset of fever, chills, headache and myalgia, with macular or maculopapular rash.6 Chikungunya usually presents with small joint polyarthralgia, often disabling, and arthritis may persist for months.7 Shock does not occur and fatalities are rare. Management is symptomatic. Diagnosis is made by PCR or direct virus isolation in the acute phase of illness, and retrospectively by serology.
Presentation: after an incubation period of around 4e8 days, there is a spectrum of illness from a mild non-specific febrile illness to shock. Classic dengue fever is characterized by abrupt onset of fever with retro-orbital headache and marked musculoskeletal pain. Examination can reveal an inflamed pharynx, conjunctival injection, facial flushing and lymphadenopathy. Up to 80% of patients will develop a centrifugal, generalized macular or maculopapular rash (after 3e5 days of fever). The blanching rash can become confluent with sparing of islands of normal skin (Figure 2). DHF/DSS develop more frequently in individuals with previous alternate serotype infection, so immigrants from endemic areas who have returned from a visit there, or travellers who have made previous trips to endemic areas, are at higher risk. In DHF there is a bleeding tendency, which may manifest in the skin as petechiae, purpura or ecchymoses, thrombocytopenia and signs of plasma leakage, leading to shock.5
Infectious mononucleosis Infection due to EBV or CMV is important to consider in returned travellers. A macular or maculopapular rash occurs in 5e10% of cases on days 1e3 of the illness, and is located on the trunk and arms. The drug rash associated with ampicillin use early in this infection is well-recognized, with the characteristics of a widespread, erythematous, maculopapular eruption that can become confluent and desquamate.
Investigations: the initial diagnosis is usually clinical, and dengue fever is commonly associated with thrombocytopenia, leucopenia and raised serum transaminases. Indicators of plasma leakage and DHF are a rise in haematocrit of 20% (or fall of 20% after fluid replacement), pleural effusions or hypoproteinaemia. Low haemoglobin generally indicates haemorrhage.
MEDICINE 42:2
Rickettsioses and scrub typhus Zoonotic rickettsiae and the pathogen responsible for scrub typhus, Orientia (previously Rickettsia) tsutsugamushi, are transmitted to humans via lice, fleas, ticks and mites. Rickettsiae
98
Ó 2014 Published by Elsevier Ltd.
SYNDROMIC PRESENTATIONS
respiratory complications, renal failure, meningo-encephalitis and hepatitis, with a mortality of around 5% in untreated patients.
infect endothelial cells, inducing a vasculitis. They are an important differential in the diagnosis of fever and rash, as some have a significant mortality if not treated.8 The symptoms are very unpleasant but resolve rapidly with treatment.
Differential diagnoses not to be missed Infection with Staphylococcus aureus (especially endocarditis), Neisseria meningitidis and Gram-negative bacteria, particularly in immunosuppressed or asplenic patients, may be associated with a petechial or purpuric rash and septic shock. A generalized erythema with signs of shock should prompt consideration of infection with toxigenic strains of Streptococcus pyogenes and Staphylococcus aureus. In returned travellers a risk assessment should always be made for risk of ongoing transmission (VHFs, measles, typhoid). Non-infectious aetiologies, including drug eruptions, Still’s disease, vasculitides, Sweet’s syndrome and infiltrative processes including leukaemias should also be considered. A
Tick-borne spotted fever group The spotted fever group of rickettsiae causes illness with an average incubation period of 6e7 days. Patients present with fever, headache and myalgias, and rash (depending on the species). Distribution is patchy, dependent on the presence of the specific tick vector. Infection requires exposure to a specific tick vector, which contributes to the varying distribution of the rickettsioses. Inoculation often results in an eschar characterized by a black, necrotic centre with an erythematous halo. The commonest spotted fever presenting in travellers is African tick bite fever (ATBF), caused by Rickettsia africae, which is endemic in rural sub-Saharan Africa and the eastern Caribbean. In travellers from the UK it is most commonly found in those who have visited game parks in southern Africa. An eschar, often with local lymphadenopathy, is present in 95% of cases, and around 50% develop a maculopapular, vesicular or purpuric rash.9 Marked neck stiffness can occur. Laboratory findings may include elevated serum C-reactive protein, lymphopenia, abnormal liver function tests and thrombocytopenia. No case fatalities have been reported. First-line treatment is doxycycline 200 mg (single dose) followed by 100 mg twice daily for between 3 and 7 days. Alternatives include chloramphenicol, clarithromycin or azithromycin. Two other rickettsiae of the spotted fever group may cause severe disease. Rickettsia conorii, responsible for Mediterranean spotted fever, is found in a variety of geographical locations (Table 1). Around 70% of patients develop an eschar and the large majority of patients develop a maculopapular or purpuric rash (97%), Unlike ATBF, deaths occur in up to 5% of hospitalized patients, generally in those with co-morbidities. Multiorgan involvement is common, with renal impairment, hepatitis, meningo-encephalitis, and pneumonitis.
REFERENCES 1 Wilson ME, Weld LH, Boggild A, et al. Fever in returned travelers: results from the GeoSentinel surveillance network. Clin Infect Dis 2007; 44: 1560e8. 2 Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med 2006; 354: 119e30. 3 Hochedez P, Canestri A, Guihot A, Brichler S, Bricaire F, Caumes E. Management of travelers with fever and exanthema, notably dengue and chikungunya infections. Am J Trop Med Hyg 2008; 78: 710e3. 4 Wilder-Smith A, Schwartz E. Dengue in travelers. N Engl J Med 2005; 353: 924e32. 5 WHO. Dengue haemorrhagic fever diagnosis, treatment, prevention and control. WHO Publications. Also available at, www.who.int/csr/ resources/publications/dengue/Denguepublication/en; 1997 (accessed 23 September 2009). 6 Hochedez P, Jaureguiberry S, Debruyne M, et al. Chikungunya infection in travelers. Emerg Infect Dis 2006; 12: 1565e7. 7 Simon F, Parola P, Grandadam M, et al. Chikungunya infection: an emerging rheumatism among travelers returned from Indian Ocean islands. Report of 47 cases. Medicine (Baltimore) 2007; 86: 123e37. 8 Watt G, Parola P. Scrub typhus and tropical rickettsioses. Curr Opin Infect Dis 2003; 16: 429e36. 9 Raoult D, Fournier PE, Fenollar F, et al. Rickettsia africae, a tick-borne pathogen in travelers to sub-Saharan Africa. N Engl J Med 2001; 344: 1504e10.
Rocky Mountain spotted fever, caused by Rickettsia rickettsii, causes a similar illness and is prevalent in Central and South America. A visible eschar is rare. Around 90% of patients develop a maculopapular or purpuric rash. First-line antibiotic therapy for both these infections is with doxycycline 200 mg (single dose) followed by 100 mg twice daily for 7e14 days (at least 3 days after fever resolves), which should be started presumptively. Diagnosis of rickettsial spotted fevers is clinical, but can be confirmed by convalescent serology and fluorescence immunoassays. Scrub typhus Scrub typhus is caused by Orientia tsutsugamushi. Exposure occurs in rural areas of South East Asia, the Pacific islands and Australia. After an incubation period of 6e21 days, patients present with fever, headache and lymphadenopathy. Similar to the rickettsioses, eschar formation occurs at the site of inoculation (50% of travelrelated cases) and is frequently located in areas easily missed on examination, such as the scrotum. A centrifugal maculopapular rash occurs in 50% of patients. Treatment is with doxycycline 200 mg (single dose) followed by 100 mg twice daily, for between 3 and 14 days. Therapy is presumptive, as serology is reliably positive only in the convalescent stage. The disease can be severe with
MEDICINE 42:2
Practice points C
C
C
99
Although it is important to exclude malaria in patients returning from an endemic area with fever, the presence of a rash is unusual in malaria Accurate travel history and timing of exposure are important in allowing prompt diagnosis and early management of many travel-related infections Rickettsial infections should be considered in the differential diagnosis of fever and rash in the returned traveller because of significant mortality if left untreated
Ó 2014 Published by Elsevier Ltd.
Fever and rash
What’s new?
John Yates C
Penelope Smith
C
Abstract The patient presenting with fever and a rash presents a diagnostic challenge. While this syndrome suggests an infectious aetiology, the differential diagnosis remains broad, and requires a thorough history and physical examination to distinguish potential non-infectious causes. Epidemiological evidence is important in the differential diagnoses. The commonest febrile illnesses presenting with rash in the returned traveller are arboviral infections (dengue and chikungunya), infectious mononucleosis caused by EpsteineBarr virus (EBV) or cytomegalovirus (CMV), and tick-borne diseases (rickettsioses).
Pattern of the illness e timing of the onset of illness related to travel provides an estimate of the incubation period of potential tropical infections. Presence of associated symptoms and the distribution of rash may provide important clues. Detailed travel history e including departure and return dates, urban or rural exposure, accommodation used and activities undertaken, with clear timings in relation to onset of illness. The travel history should also include previous tropical exposure. Exposure to vector-borne and zoonotic infections e exposure to specific vectors such as ticks, fleas, or mites, should be sought. Often ticks and mites are not seen whilst attached, but a history of walking in rural or wilderness areas indicates potential exposure. Possible exposure to zoonoses should be sought by direct questioning about animal contact but also through determining indirect exposure, for example, to fresh water for leptospirosis. Detailed sexual history e HIV seroconversion, secondary syphilis and disseminated gonococcal infection all commonly cause rash. Past medical history e for example, endocarditis risk factors and immunosuppression. Immunization history e childhood and travel immunizations. Drug history e including malarial prophylaxis, recent antibiotics, known allergies. Exposure to infectious contacts. Sun exposure.
Keywords chikungunya; dengue; fever; infectious mononucleosis; rash; rickettsiae; travel
Fever and rash is a relatively common presentation in travellers returning from the tropics, comprising around 4% of febrile ‘syndromes’ presenting to travel or tropical diseases clinics.1 The presence of a rash as part of a febrile illness, although rarely pathognomonic, focuses the differential diagnosis. It is important to remember that rashes are common and may be caused by another medical condition unrelated to travel, or a drug reaction to medications taken at the time of travel. A systematic approach is important, as a rash can be either a manifestation of a mild illness or an indicator of a potentially fatal contagious disease.
Diagnosis Initial assessment A preliminary assessment should focus on two broad considerations: Does this patient show signs of severe sepsis or organ dysfunction requiring urgent cardiorespiratory support and antibiotic therapy? Does the travel history indicate potential exposure to pathogens causing serious illness with a risk of nosocomial transmission, requiring immediate isolation and barrier precautions (e.g. viral haemorrhagic fevers (VHF))?
General examination Preliminary assessment should determine oxygenation, cardiovascular status and presence of cerebral impairment or meningism. Particular attention should be paid to: eyes e conjunctivitis, conjunctival petechiae, jaundice oropharyngeal mucosa e erythema, exudate, ulceration, vesicles, petechiae, Koplik’s spots, oral candida lymphadenopathy e localized, generalized hepatosplenomegaly genital examination e ulceration.
History Rash can be associated with tropical and cosmopolitan infections (Table 1). A detailed history is essential and should include:
John Yates MRCP MSc is a Consultant in Infectious Diseases and Acute Medicine at Mayday Hospital, Croydon, UK. Competing interests: none declared.
Examination of the skin Full exposure is very important. Distinctive signs, such as an eschar following a tick bite (Figure 1), can be limited to skin folds. Involvement of the palms and soles is a feature of particular infections, such as hand, foot and mouth disease (Coxsackie A16) and secondary syphilis. Rashes can be macular, papular, nodular, vesicular, bullous or pustular, evolving in different
Penelope Smith FRCP DTM&H MSc is a Consultant Physician in Acute Medicine and Infectious Diseases at the Royal Free Hospital, London, UK. Competing interests: none declared.
MEDICINE 42:2
Chikungunya is an arbovirus infection that has circulated in a recent epidemic originating in Reunion Island in the Indian Ocean since early 2005 with ongoing reports of spread to Europe and Australasia Due to exponential increases in global travel during recent years, clinicians must be alert to the possibility of exotic infections in the returned traveller
96
Ó 2014 Published by Elsevier Ltd.
SYNDROMIC PRESENTATIONS
Causes of rash and fever e tropical and cosmopolitan infections Organism/disease
Rash (% cases)
Dengue
M, MP, PP (50%)
Chikungunya
Distribution
Tropical, subtropical, worldwide M, MP (50%) Tropical, subtropical Africa and Asia M, MP, PP, V Worldwide MP, PP, V (46%) Sub-Saharan Africa MP, PP (90%) Mediterranean and sub-Saharan Africa, India MP, PP (90%) USA, Central and South America M, MP (35e90%) Asia, Pacific Islands
Rickettsia African tick typhus Mediterranean spotted fever Rocky Mountain spotted fever Scrub typhus e Orientia tsutsugamushi Typhoid fever e M (rose spots) Salmonella typhi/paratyphi (20%) Leptospirosis M, MP, PP (20%)
Wherever risk of faecal contamination of water Worldwide
Vector/exposure risk
Associated features
Aedes mosquito, urban and rural Aedes mosquito, urban and rural Ticks Ticks rural/wilderness Ticks, urban, suburban
Myalgia, haemorrhage, shock
Eschar common, headache Eschar common
Ticks, rural/wilderness
Eschar rare
Polyarthralgia
Larvae trombiculid mites Eschar common (chiggers), rural Faecaleoral, poor sanitation Prolonged fever, splenomegaly
Yellow fever
U (Katayama fever) PP
Lassa fever
MP, PP
Ebola/Marburg
MP, PP
South American haemorrhagic fevers West Nile virus
PP
Exposure to rat/rodent urine Conjunctivitis, myalgia (fresh water) Africa, Asia, South America, Freshwater snails Eosinophilia Caribbean Central and South America, Mosquito-borne urban/rural Jaundice Africa West Africa Rodent urine, rural Pharyngitis, retrosternal pain, encephalitis, haemorrhage West/Central Africa Unknown, ? monkeys/bats, Abdominal pain, D þ V, rural/wilderness haemorrhage South America
MP
Africa, USA
Measles Varicellaezoster virus EpsteineBarr virus
MP MP, V MP, PP
Worldwide Worldwide Worldwide
Cytomegalovirus
MP
Worldwide
Toxoplasmosis HIV
MP MP
Worldwide Worldwide
Rubella Staphylococcus aureus Streptococcus pyogenes Neisseria meningitidis Neisseria gonorrhoeae Syphilis, Treponema pallidum
MP PP, E E PP PP MP, PP, PU, V
Worldwide Worldwide Worldwide Worldwide Worldwide Worldwide
Schistosomiasis
Culex, Aedes mosquitoes, urban
Cats Sexual, IVDU, vertical transmission Human Human, IVDU Human Human Sexual Sexual
Encephalitis Cough, conjunctivitis, Koplik’s spots Coryza, pneumonitis Pharyngitis, lymphadenopathy, splenomegaly Pharyngitis, lymphadenopathy, splenomegaly Lymphadenopathy Pharyngitis, lymphadenopathy, splenomegaly Coryza, arthralgia Shock, heart murmur Pharyngitis, cellulitis, shock Shock, meningitis Septic arthritis Genital ulceration
D þ V, diarrhoea and vomiting; IVDU, intravenous drug use; M, macular; MP, maculopapular; PP, petechial/purpuric; E, erythrodermic; PU, pustular; U, urticarial; V, vesicular. The % values given for the frequency of rash in particular infections are derived from case series.
Table 1
Fever and rash in the returning traveller
stages of the illness. Generalized erythema is associated with bacteria producing erythrogenic toxins (Streptococcus pyogenes, Staphylococcus aureus) and drug reactions, and urticarial rashes are associated with parasitic infections. Combinations of the rash forms can occur, and a single infection, such as dengue, may cause various morphologies.
MEDICINE 42:2
The commonest febrile illnesses presenting with rash in the returned traveller are arboviral infections (dengue and chikungunya), infectious mononucleosis caused by EpsteineBarr virus (EBV) or cytomegalovirus (CMV), and tick-borne diseases (rickettsioses).2,3
97
Ó 2014 Published by Elsevier Ltd.
SYNDROMIC PRESENTATIONS
Figure 1 Eschar with generalized maculopapular rash of African tick typhus. Courtesy of Dr R. Behrens, Hospital for Tropical Diseases, London.
Figure 2 Dengue: blanching maculopapular rash, with islands of normal skin. Courtesy of Dr R. Behrens, Hospital for Tropical Diseases, London.
Sexually transmitted infections, especially HIV seroconversion and secondary syphilis, are important differential diagnoses, and Katayama syndrome (acute schistosomiasis), which can present with an urticarial rash 4e6 weeks after fresh water exposure in Africa, should also be considered. Although malaria is one of the commonest causes of febrile illness reported in travellers returning from tropical and subtropical regions, the presence of a rash is unusual.
Retrospective diagnosis can be made using serology. In patients with shock, early confirmation can be made by polymerase chain reaction (PCR), but positivity falls rapidly to less than 10% after 7 days of illness. Management: dengue fever is usually self-limiting. Management is symptomatic and non-steroidal anti-inflammatory drugs should be avoided because of the bleeding tendency. Monitoring for progression to DHF/DSS is important. A fall in platelet count below 100 109/litre is a predictor for progression and should precipitate admission for close clinical observation. Shock should be treated with fluid replacement and blood products.5
Dengue Epidemiology: dengue is a flavivirus distributed throughout tropical regions and transmitted by Aedes mosquitoes. The four serotypes cause 50e100 million cases of dengue fever each year, with significant morbidity and mortality associated with dengue haemorrhagic fever (DHF)/dengue shock syndrome (DSS). Rates of seroconversion are high in travellers to South East Asia and, in a study of fever and rash in travellers returning to France, dengue infection accounted for 26% of cases.3,4
Chikungunya Chikungunya virus is also transmitted by Aedes mosquitoes, with an incubation period of 4e7 days. Sporadic cases and epidemics occur in Africa and Australasia, and a recent outbreak in Papua New Guinea is estimated to have affected many thousands of individuals. Presentation is similar to dengue, with sudden onset of fever, chills, headache and myalgia, with macular or maculopapular rash.6 Chikungunya usually presents with small joint polyarthralgia, often disabling, and arthritis may persist for months.7 Shock does not occur and fatalities are rare. Management is symptomatic. Diagnosis is made by PCR or direct virus isolation in the acute phase of illness, and retrospectively by serology.
Presentation: after an incubation period of around 4e8 days, there is a spectrum of illness from a mild non-specific febrile illness to shock. Classic dengue fever is characterized by abrupt onset of fever with retro-orbital headache and marked musculoskeletal pain. Examination can reveal an inflamed pharynx, conjunctival injection, facial flushing and lymphadenopathy. Up to 80% of patients will develop a centrifugal, generalized macular or maculopapular rash (after 3e5 days of fever). The blanching rash can become confluent with sparing of islands of normal skin (Figure 2). DHF/DSS develop more frequently in individuals with previous alternate serotype infection, so immigrants from endemic areas who have returned from a visit there, or travellers who have made previous trips to endemic areas, are at higher risk. In DHF there is a bleeding tendency, which may manifest in the skin as petechiae, purpura or ecchymoses, thrombocytopenia and signs of plasma leakage, leading to shock.5
Infectious mononucleosis Infection due to EBV or CMV is important to consider in returned travellers. A macular or maculopapular rash occurs in 5e10% of cases on days 1e3 of the illness, and is located on the trunk and arms. The drug rash associated with ampicillin use early in this infection is well-recognized, with the characteristics of a widespread, erythematous, maculopapular eruption that can become confluent and desquamate.
Investigations: the initial diagnosis is usually clinical, and dengue fever is commonly associated with thrombocytopenia, leucopenia and raised serum transaminases. Indicators of plasma leakage and DHF are a rise in haematocrit of 20% (or fall of 20% after fluid replacement), pleural effusions or hypoproteinaemia. Low haemoglobin generally indicates haemorrhage.
MEDICINE 42:2
Rickettsioses and scrub typhus Zoonotic rickettsiae and the pathogen responsible for scrub typhus, Orientia (previously Rickettsia) tsutsugamushi, are transmitted to humans via lice, fleas, ticks and mites. Rickettsiae
98
Ó 2014 Published by Elsevier Ltd.
SYNDROMIC PRESENTATIONS
respiratory complications, renal failure, meningo-encephalitis and hepatitis, with a mortality of around 5% in untreated patients.
infect endothelial cells, inducing a vasculitis. They are an important differential in the diagnosis of fever and rash, as some have a significant mortality if not treated.8 The symptoms are very unpleasant but resolve rapidly with treatment.
Differential diagnoses not to be missed Infection with Staphylococcus aureus (especially endocarditis), Neisseria meningitidis and Gram-negative bacteria, particularly in immunosuppressed or asplenic patients, may be associated with a petechial or purpuric rash and septic shock. A generalized erythema with signs of shock should prompt consideration of infection with toxigenic strains of Streptococcus pyogenes and Staphylococcus aureus. In returned travellers a risk assessment should always be made for risk of ongoing transmission (VHFs, measles, typhoid). Non-infectious aetiologies, including drug eruptions, Still’s disease, vasculitides, Sweet’s syndrome and infiltrative processes including leukaemias should also be considered. A
Tick-borne spotted fever group The spotted fever group of rickettsiae causes illness with an average incubation period of 6e7 days. Patients present with fever, headache and myalgias, and rash (depending on the species). Distribution is patchy, dependent on the presence of the specific tick vector. Infection requires exposure to a specific tick vector, which contributes to the varying distribution of the rickettsioses. Inoculation often results in an eschar characterized by a black, necrotic centre with an erythematous halo. The commonest spotted fever presenting in travellers is African tick bite fever (ATBF), caused by Rickettsia africae, which is endemic in rural sub-Saharan Africa and the eastern Caribbean. In travellers from the UK it is most commonly found in those who have visited game parks in southern Africa. An eschar, often with local lymphadenopathy, is present in 95% of cases, and around 50% develop a maculopapular, vesicular or purpuric rash.9 Marked neck stiffness can occur. Laboratory findings may include elevated serum C-reactive protein, lymphopenia, abnormal liver function tests and thrombocytopenia. No case fatalities have been reported. First-line treatment is doxycycline 200 mg (single dose) followed by 100 mg twice daily for between 3 and 7 days. Alternatives include chloramphenicol, clarithromycin or azithromycin. Two other rickettsiae of the spotted fever group may cause severe disease. Rickettsia conorii, responsible for Mediterranean spotted fever, is found in a variety of geographical locations (Table 1). Around 70% of patients develop an eschar and the large majority of patients develop a maculopapular or purpuric rash (97%), Unlike ATBF, deaths occur in up to 5% of hospitalized patients, generally in those with co-morbidities. Multiorgan involvement is common, with renal impairment, hepatitis, meningo-encephalitis, and pneumonitis.
REFERENCES 1 Wilson ME, Weld LH, Boggild A, et al. Fever in returned travelers: results from the GeoSentinel surveillance network. Clin Infect Dis 2007; 44: 1560e8. 2 Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med 2006; 354: 119e30. 3 Hochedez P, Canestri A, Guihot A, Brichler S, Bricaire F, Caumes E. Management of travelers with fever and exanthema, notably dengue and chikungunya infections. Am J Trop Med Hyg 2008; 78: 710e3. 4 Wilder-Smith A, Schwartz E. Dengue in travelers. N Engl J Med 2005; 353: 924e32. 5 WHO. Dengue haemorrhagic fever diagnosis, treatment, prevention and control. WHO Publications. Also available at, www.who.int/csr/ resources/publications/dengue/Denguepublication/en; 1997 (accessed 23 September 2009). 6 Hochedez P, Jaureguiberry S, Debruyne M, et al. Chikungunya infection in travelers. Emerg Infect Dis 2006; 12: 1565e7. 7 Simon F, Parola P, Grandadam M, et al. Chikungunya infection: an emerging rheumatism among travelers returned from Indian Ocean islands. Report of 47 cases. Medicine (Baltimore) 2007; 86: 123e37. 8 Watt G, Parola P. Scrub typhus and tropical rickettsioses. Curr Opin Infect Dis 2003; 16: 429e36. 9 Raoult D, Fournier PE, Fenollar F, et al. Rickettsia africae, a tick-borne pathogen in travelers to sub-Saharan Africa. N Engl J Med 2001; 344: 1504e10.
Rocky Mountain spotted fever, caused by Rickettsia rickettsii, causes a similar illness and is prevalent in Central and South America. A visible eschar is rare. Around 90% of patients develop a maculopapular or purpuric rash. First-line antibiotic therapy for both these infections is with doxycycline 200 mg (single dose) followed by 100 mg twice daily for 7e14 days (at least 3 days after fever resolves), which should be started presumptively. Diagnosis of rickettsial spotted fevers is clinical, but can be confirmed by convalescent serology and fluorescence immunoassays. Scrub typhus Scrub typhus is caused by Orientia tsutsugamushi. Exposure occurs in rural areas of South East Asia, the Pacific islands and Australia. After an incubation period of 6e21 days, patients present with fever, headache and lymphadenopathy. Similar to the rickettsioses, eschar formation occurs at the site of inoculation (50% of travelrelated cases) and is frequently located in areas easily missed on examination, such as the scrotum. A centrifugal maculopapular rash occurs in 50% of patients. Treatment is with doxycycline 200 mg (single dose) followed by 100 mg twice daily, for between 3 and 14 days. Therapy is presumptive, as serology is reliably positive only in the convalescent stage. The disease can be severe with
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Although it is important to exclude malaria in patients returning from an endemic area with fever, the presence of a rash is unusual in malaria Accurate travel history and timing of exposure are important in allowing prompt diagnosis and early management of many travel-related infections Rickettsial infections should be considered in the differential diagnosis of fever and rash in the returned traveller because of significant mortality if left untreated
Ó 2014 Published by Elsevier Ltd.