What’s new?

C Chikungunya is an arbovirus infection that has circulated in a

recent epidemic originating in Reunion Island in the Indian

SYNDROMIC PRESENTATIONS

Fever and rashJohn Yates

Penelope Smith

Ocean since early 2005 with ongoing reports of spread to

Europe and Australasia

C Due to exponential increases in global travel during recent

years, clinicians must be alert to the possibility of exotic in-

fections in the returned traveller

AbstractThe patient presenting with fever and a rash presents a diagnostic chal-

lenge. While this syndrome suggests an infectious aetiology, the differen-

tial 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 mononucle-

osis caused by EpsteineBarr virus (EBV) or cytomegalovirus (CMV), and

tick-borne diseases (rickettsioses).

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))?

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.

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 96

� Pattern of the illnesse timing of the onset of illness related to

travel provides an estimate of the incubation period of po-

tential 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 infectionse exposure

to specific vectors such as ticks, fleas, or mites, should be

sought. Often ticks andmites are not seenwhilst 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 fac-

tors and immunosuppression.

� Immunization historye childhood and travel immunizations.

� Drug history e including malarial prophylaxis, recent an-

tibiotics, known allergies.

� Exposure to infectious contacts.

� Sun exposure.

General examination

Preliminary assessment should determine oxygenation, cardio-

vascular status and presence of cerebral impairment or menin-

gism. 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.

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 partic-

ular 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

� 2014 Published by Elsevier Ltd.

Causes of rash and fever e tropical and cosmopolitan infections

Organism/disease Rash (% cases) Distribution Vector/exposure risk Associated features

Dengue M, MP, PP (50%) Tropical, subtropical,

worldwide

Aedes mosquito, urban

and rural

Myalgia, haemorrhage, shock

Chikungunya M, MP (50%) Tropical, subtropical

Africa and Asia

Aedes mosquito, urban

and rural

Polyarthralgia

Rickettsia M, MP, PP, V Worldwide Ticks

African tick typhus MP, PP, V (46%) Sub-Saharan Africa Ticks rural/wilderness Eschar common, headache

Mediterranean

spotted fever

MP, PP (90%) Mediterranean and

sub-Saharan Africa, India

Ticks, urban, suburban Eschar common

Rocky Mountain

spotted fever

MP, PP (90%) USA, Central and

South America

Ticks, rural/wilderness Eschar rare

Scrub typhus e

Orientia tsutsugamushi

M, MP (35e90%) Asia, Pacific Islands Larvae trombiculid mites

(chiggers), rural

Eschar common

Typhoid fever e

Salmonella typhi/paratyphi

M (rose spots)

(20%)

Wherever risk of faecal

contamination of water

Faecaleoral, poor sanitation Prolonged fever, splenomegaly

Leptospirosis M, MP, PP (20%) Worldwide Exposure to rat/rodent urine

(fresh water)

Conjunctivitis, myalgia

Schistosomiasis U (Katayama

fever)

Africa, Asia, South America,

Caribbean

Freshwater snails Eosinophilia

Yellow fever PP Central and South America,

Africa

Mosquito-borne urban/rural Jaundice

Lassa fever MP, PP West Africa Rodent urine, rural Pharyngitis, retrosternal pain,

encephalitis, haemorrhage

Ebola/Marburg MP, PP West/Central Africa Unknown, ? monkeys/bats,

rural/wilderness

Abdominal pain, D þ V,

haemorrhage

South American

haemorrhagic fevers

PP South America

West Nile virus MP Africa, USA Culex, Aedes mosquitoes,

urban

Encephalitis

Measles MP Worldwide Cough, conjunctivitis, Koplik’s spots

Varicellaezoster virus MP, V Worldwide Coryza, pneumonitis

EpsteineBarr virus MP, PP Worldwide Pharyngitis, lymphadenopathy,

splenomegaly

Cytomegalovirus MP Worldwide Pharyngitis, lymphadenopathy,

splenomegaly

Toxoplasmosis MP Worldwide Cats Lymphadenopathy

HIV MP Worldwide Sexual, IVDU, vertical

transmission

Pharyngitis, lymphadenopathy,

splenomegaly

Rubella MP Worldwide Human Coryza, arthralgia

Staphylococcus aureus PP, E Worldwide Human, IVDU Shock, heart murmur

Streptococcus pyogenes E Worldwide Human Pharyngitis, cellulitis, shock

Neisseria meningitidis PP Worldwide Human Shock, meningitis

Neisseria gonorrhoeae PP Worldwide Sexual Septic arthritis

Syphilis, Treponema

pallidum

MP, PP, PU, V Worldwide Sexual 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

SYNDROMIC PRESENTATIONS

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 97

Fever and rash in the returning traveller

The commonest febrile illnesses presentingwith rash in the returned

traveller are arboviral infections (dengue and chikungunya), infec-

tious mononucleosis caused by EpsteineBarr virus (EBV) or cyto-

megalovirus (CMV), and tick-borne diseases (rickettsioses).2,3

� 2014 Published by Elsevier Ltd.

Figure 1 Eschar with generalized maculopapular rash of African tick ty-

phus. 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.

SYNDROMIC PRESENTATIONS

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 Af-

rica, should also be considered. Althoughmalaria is one of the com-

monest causes of febrile illness reported in travellers returning from

tropical and subtropical regions, the presence of a rash is unusual.

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

Presentation: afteran incubationperiodof around4e8days, there is

a spectrumof illness fromamild non-specific febrile illness to shock.

Classic dengue fever is characterized by abrupt onset of fever with

retro-orbital headache and marked musculoskeletal pain. Exami-

nation can reveal an inflamed pharynx, conjunctival injection, facial

flushing and lymphadenopathy.Up to 80%of patientswill 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 developmore

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, throm-

bocytopenia and signs of plasma leakage, leading to shock.5

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 98

Retrospective diagnosis can be made using serology. In pa-

tients 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

Chikungunya

Chikungunya virus is also transmitted by Aedesmosquitoes, 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 in-

dividuals. Presentation is similar to dengue, with sudden onset of

fever, chills, headache and myalgia, with macular or mac-

ulopapular 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.

Infectious mononucleosis

Infection due to EBV or CMV is important to consider in returned

travellers. A macular or maculopapular rash occurs in 5e10% of

casesondays1e3of the illness, and is locatedon the trunkandarms.

The drug rash associatedwith ampicillin use early in this infection is

well-recognized, with the characteristics of a widespread, erythem-

atous, maculopapular eruption that can become confluent and

desquamate.

Rickettsioses and scrub typhus

Zoonotic rickettsiae and the pathogen responsible for scrub ty-

phus, Orientia (previously Rickettsia) tsutsugamushi, are trans-

mitted to humans via lice, fleas, ticks and mites. Rickettsiae

� 2014 Published by Elsevier Ltd.

SYNDROMIC PRESENTATIONS

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.

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 spe-

cies). 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 isAfrican

tick bite fever (ATBF), caused by Rickettsia africae, which is

endemic in rural sub-Saharan Africa and the eastern Caribbean. In

travellers from theUK it ismost commonly found in thosewhohave

visited game parks in southern Africa. An eschar, often with local

lymphadenopathy, is present in 95% of cases, and around 50%

develop amaculopapular, vesicular or purpuric rash.9Markedneck

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 200mg (single dose) followedby

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 hospi-

talized patients, generally in those with co-morbidities. Multi-

organ involvement is common, with renal impairment, hepatitis,

meningo-encephalitis, and pneumonitis.

Rocky Mountain spotted fever, caused by Rickettsia rickettsii,

causes a similar illness and is prevalent in Central and South

America.Avisible eschar is rare.Around90%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.

Practice points

Scrub typhus

C 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

C Accurate travel history and timing of exposure are important in

allowing prompt diagnosis and early management of many

travel-related infections

C Rickettsial infections should be considered in the differential

diagnosis of fever and rash in the returned traveller because of

significant mortality if left untreated

Scrub typhus is caused byOrientia 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 travel-

related 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 100mg 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 99

respiratory complications, renal failure, meningo-encephalitis and

hepatitis, with a mortality of around 5% in untreated patients.

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 dis-

ease, vasculitides, Sweet’s syndrome and infiltrative processes

including leukaemias should also be considered. A

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� 2014 Published by Elsevier Ltd.