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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In returning travelers, dermatoses are considered as one of the leading causes of health problems together with systemic febrile illness, such as dengue fever and rickettsial infections that may be revealed by febrile rash.4,5 Some studies have shown a broad spectrum of febrile illnesses and skin diseases in returning travelers, but no study had focused on febrile rash, although it is a common skin manifestation, being the presenting symptom in 4.1% of 269 returning travelers with skin diseases.6 In this setting, febrile exanthema is a cause for concern because some patients may require urgent treatment or be contagious and eventually require isolation.
The aim of this study was to evaluate the etiologies of febrile exanthema in returning travelers, together with the management of these patients. Additionally, the epidemiological, clinical, and biological characteristics of dengue and chikungunya infections were compared in these patients.
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MATERIALS AND METHODS |
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Routine laboratory tests included full blood-cell counts, liver enzymes, kidney function evaluation, and CRP, and these were performed for every patient. Specific serological tests were performed according to clinical presentation, area visited, vaccination coverage, and risk of exposure. Patients were serologically tested for dengue fever and chikungunya if they were returning from an endemic area and presented within 10 days after return. Diagnoses of dengue and chikungunya infection were confirmed by the presence of specific IgM (ELISA). Diagnosis of African tick bite fever (ATBF) was made either clinically if the patient presented within 10 days after return from an endemic area with fever, inoculation eschar, and a maculopapular or vesicular rash or relied on seroconversion for Rickettsia africae. Patients were tested serologically at 1 to 2 months interval for schistosomiasis if they presented with urticarial eruption after returning from an endemic area and reported exposure to infested fresh water. Seroconversion defined acute schistosomiasis. Every patient with no specific presentation was systematically tested for toxoplasmosis and primary EBV and CMV infections. Non-immunized patients were tested for measles and rubella. Patients were tested for primary HIV infection (viral load, antigenemia) if they reported at-risk exposure or in the absence of other etiology. Primary EBV, CMV, and HIV-1 infections, toxoplasmosis, measles, and rubella were defined by seroconversion for the corresponding agent or presence of IgM and/ or PCR according to the type of infections. Direct microscopic exam and bacterial culture of a skin swab were performed according to clinical presentation. Patients that remained with unproven diagnosis were considered as patients with a rash of undetermined origin. All patients were systematically seen again after 7–15 days, according to the disease. When patients could not come back, they were contacted by phone.
Differences between groups were tested for significance using the 
2 test and the Fisher’s exact test. Data were analyzed with SPSS software version 15.0 (SPSS, Chicago, IL).
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RESULTS |
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Considering the clinical manifestations, exanthema was macular in 39 cases (63%) maculopapular (MP) in 17 cases (27%), and MP with eschar in 6 cases (10%). Oral enanthema was observed in 8 cases (13%). There was no conjunctivitis or genital involvement. The median duration of fever was 5 days (range, 2–15) in the 31 patients for whom this information was available. Peripheral lymphadenopathies were present in 38 cases (61%), and asthenia and cephalalgia were reported in 45 (72%) and 31 cases (50%) each, respectively. There was no palpable splenomegaly nor hepatomegaly. Leucopenia was present in 29 cases (47%), lymphopenia in 41 cases (66%), neutropenia in 25 cases (40%), circulating lymphocytosis with presence of atypical lymphocytes in 19 cases (31%), thrombopenia in 30 cases (48%), anemia in 4 (6%), and an increase in ALAT in 45 cases (72%).
A specific etiology was found in 57 cases (92%) whereas in 5 the rash remained of undetermined origin (Table 1
). The 3 main etiologies were chikungunya (35%), dengue (26%), and ATBF (10%). However, diagnosis of ATBF was supported only by clinical presentation. Serological tests performed at presentation were negative, and the patients did not return for a second serology. Two parasitic diseases, primary toxoplasmosis and acute schistosomiasis, were diagnosed. One patient was diagnosed with a life-threatening adverse cutaneous drug reaction, i.e., hypersensitivity syndrome or drug rash with eosinophilia and systemic symptoms (DRESS) induced by nevirapine given as a post-sexual exposure prophylaxis. Travel to the Indian Ocean was significantly associated with diagnosis of chikungunya (P < 0.001). Travel to South Africa was significantly associated with diagnosis of ATBF (P < 0.001).
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). Leucopenia, neutropenia, and thrombopenia were significantly more frequent in dengue fever than in chikungunya (Table 3).
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DISCUSSION |
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Regarding the etiologies of fever and exanthema, our results contrast favorably with those of studies performed in other settings with a > 90% rate of diagnosis. In a study of 112 consecutive outpatients presenting with "atypical" exanthema (excluding "typical" presentations of measles, scarlet fever, rubella, erythema infectiosum, exanthema subitum, and chickenpox) at 2 Italian university dermatology departments, 32% of the cases remained undiagnosed.2 In a prospective study of 100 children presenting with acute erythematous rash and a febrile illness of short duration, 35% of the cases remained undiagnosed, infectious causative agents were identified in 65% of the patients, and viruses were involved in 72% (47) of these patients.3 Wherever the study takes place, viral infections are thus the leading causes of febrile exanthema.
Chikungunya was the leading cause of febrile exanthema in our travelers. This is not surprising considering the epidemic that occurred on the islands of the South West Indian Ocean during the years 2005 and 2006, especially on the island of La Reunion, a popular destination for French travelers.7–9 Chikungunya cases have been also recently reported in travelers returning from endemic areas to Europe, Canada, and the United States.10,11 Some of the patients included in this study gave us the opportunity to better describe the skin manifestations of imported chikungunya.7 Clinical manifestations are characterized by an abrupt onset of fever, polyarthralgia (involving mainly peripheral joints), asthenia, headache, myalgia, and a rash that seems to be very similar to that of dengue fever, being pruritic, macular, or maculopapular with sparing of small islands of normal skin.7
Despite the fact that chikungunya cases have been mainly reported in area where the 2 viruses co-exist, clinical and biological presentations of chikungunya and dengue infections have been compared in only 1 study to date, performed more than 40 years ago in Thailand.12 In our study, arthralgia was more frequently observed in chikungunya, whereas leucopenia, neutropenia, and thrombopenia were more frequently observed in dengue fever. However, the numbers of cases of chikungunya and dengue were small in our patients. Therefore, our results should be strengthened by larger studies. Among children in Thailand, chikungunya and dengue skin manifestations were difficult to differentiate, but the onset of symptoms was more abrupt, the febrile course shorter, and maculopapular rashes, conjunctival injection, and arthralgia were more common in chikungunya than in dengue cases. Shock and gastrointestinal hemorrhage occurred only in dengue patients.12
Regarding the subset of patients with rash of undetermined origin, other less frequent arboviral diseases presenting with fever, joint pain, and rash have not been evaluated here, although they could be involved.12 In this setting, physicians should be aware that some of the rashes of undetermined origin could be related to unusual arboviruses considering the extensive list of viruses potentially involved.13
Two of our patients were diagnosed with primary HIV infection. Travelers are particularly vulnerable to sexually transmitted diseases while abroad.14 In a cohort of Belgian expatriates studied between 1985 and 1987, risk factors for HIV seroconversion were as follows: sexual contact with local women (OR = 14.7, 2.81–76.9), sexual contact with prostitutes (OR = 10.8, 1.6–71.9), and injections by unqualified staff (OR = 13.5, 3.7–49.8).15
Although we did not diagnose viral hemorrhagic fevers (VHFs), such diseases should be systematically evaluated in this setting because fever and exanthema are part of the clinical manifestations for several of them, especially in Africa.16–18 For instance, Yellow fever should be suspected in any non-vaccinated travelers returning from areas of endemicity.17
The third etiology of fever and exanthema in our travelers was related to a rickettsial infection, ATBF. It has been considered as the most commonly encountered rickettsiosis in travel medicine and is endemic in large parts of rural sub-Saharan Africa and the eastern Caribbean.19 Our results confirm the high prevalence of ATBF in febrile travelers. Unsurprisingly all our travelers came back from South Africa, as largely reported. Presumptive therapy with doxycycline is recommended whenever a case of rickettsiosis is suspected, allowing for rapid recovery and prevention of complications.20 Our patients were systematically treated with doxycycline on clinical suspicion of ATBF at presentation. However, diagnosis of ATBF was not confirmed biologically. The serologies were negative because all were performed on admission, which was too early in the course of the disease, and PCR, though shown to be of high diagnosis value, was not been performed because of its high cost for the patient.20
Two patients required emergency management: 1 with an adverse drug reaction (DRESS) and 1 with a streptococcal-associated exanthema, similar to that seen in streptococcal toxic shock syndrome.21 This result illustrates that travelers can be exposed to life-threatening infections of cosmopolitan origin, as well as infections—such as VHFs—that are usually confined to restricted areas of the world.
As far as parasitic diseases are concerned, 1 of our patients returning from Mali was diagnosed with acute schistosomiasis. Urticarial rash with fever is a typical skin manifestation of acute schistosomiasis and is observed 2–6 weeks after exposure to infested fresh water.22,23 Among 14 nonimmune travelers who had bathed once in the Dogon region of Mali, acute schistosomiasis was accompanied by fever in 93% and acute urticaria in 57%.22 Another patient returning from French Guyana was diagnosed with acute toxoplasmosis. Although rarely observed, severe cases of acute disseminated toxoplasmosis have been reported among immunocompetent patients in French Guyana and who presented initially with fever accompanied by an altered general status with at least 1 visceral localization, mainly pulmonary involvement.24,25
Although seen only once in our study, hypersensitivity reaction to drugs must always be considered in diagnosis of fever and exanthema. They are a leading cause of febrile exanthema, being reported in 22% of the cases in an Italian study, and are usually considered as the second etiological group of febrile exanthema after viral infections.1 In travelers, cutaneous reactions among users of malaria prophylaxis have been reported.26 Our patient was a resident woman in Africa and the drug reaction was induced by nevirapine administered as a post-exposure treatment after a high-risk sexual exposure.
In conclusion, physicians treating travelers with fever and exanthema should screen their patients for exotic infections (e.g., arboviral infection, viral hemorrhagic fevers, rickettsial infections, schistosomiasis, leptospirosis) if they are returning from endemic areas and for more-cosmopolitan infections (e.g., HIV, EBV, CMV, rubella, toxoplasmosis, bacterial infection). In addition, an adverse drug reaction, which calls for immediate interruption of therapy, must be systematically ruled out by a targeted questionnaire.
Received October 12, 2007. Accepted for publication February 11, 2008.
* Address correspondence to Patrick Hochedez, Department of Infectious and Tropical Disease, Hôpital Pitié-Salpêtrière, Paris. E-mail: p.hochedez{at}free.fr 
Authors’ addresses: Patrick Hochedez, Ana Canestri, Amélie Guihot, François Bricaire, and Eric Caumes, Service de Maladies Infectieuses et Tropicales, Hôpital Pitié-Salpêtrière, 47–83 boulevard de l’Hôpital, 75013 Paris, France, Tel: 33-1-42-16-01-14, Fax: 33-1-42-16-01-65, E-mails: patrick.hochedez{at}free.fr, ana.canestris{at}psl.aphp.fr, amelie.guihot{at}psl.aphp.fr, francois.bricaire{at}psl.aphp.fr, and eric.caumes{at}psl.aphp.fr. Ségolène Brichler, Service de Virologie Hôpital Avicenne, Bobigny, France, Tel: 33-1-48-95-75-96, Fax: 33-1-48-95-59-11, E-mail: segolene.brichler{at}avc.aphp.fr.
Reprint requests: Eric Caumes, Service de Maladies Infectieuses et Tropicales, Hôpital Pitié-Salpêtrière, 47–83 boulevard de l’Hôpital, 75013 Paris, France, Tel: 33-1-42-16-01-14, Fax: 33-1-42-16-01-65, E-mail: eric.caumes{at}psl.aphp.fr.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
