schließen (X)

Case Study

Secondary dengue fever infection


Keywords | Summary | Correspondence | References




Dengue fever (DF) is the most common infection by arboviruses world wide. Endemic areas are seen in tropic and subtropic countries. Recently, more cases have been detected in Europe and mosquito vectors were identified in some Mediterranean regions. We report of a 21-year old German traveller returning from Indoneasia who presented with sudden onset fever, arthralgia and erythema with island of sparing. RT-PCR identified DF virus and serology disclosed IgG and IgM antibodies. Based on the medical history this DF infection was caused by type 4 virus. One year before, he had a primary infection with type 1 virus. The course in secondary infection often is more severe and the risk of complications such as haemorrhagic DF and DF shock syndrome is increased. Because of possible mucocutaneous symptoms dermatologists play an important role in diagnosis and infection control.


Uwe Wollina1and Jörn Lohmann2


1Department of Dermatology and Allergology and

2Centre for Travellers Medicine and Vaccination, Academic Teaching Hospital Dresden-Friedrichstadt, Friedrichstrasse 41, 01067 Dresden, Germany.



An estimated 100 million cases of dengue fever (DF) and 250,000 cases of dengue haemorrhagic fever (DHF) occurs annually worldwide [1]. The past 20 years have seen a dramatic geographic expansion of epidemic DF world wide. An increasing number of reports of DF and associated illness among travellers to DF virus–infected areas paralleled the changing epidemiology of DF in local populations [2].


DF is endemic to tropical and subtropical regions caused by Flaviviridiae. Four distinct types of this kind of viruses are known: DENF 1 to 4. Transmission of the virus is through insect bites of female mosquitoes, in particular Aedesmosquitoes [3]. In metropolitan France, DF is a mandatory notifiable disease sinceAedes albopictushas become established in Mediterranean France coats region in 2004, in Corsica in 2006, and 2009 in the centre of Marseille. DF vectors have settled in Europe [4].


DF is typically seen in older children and adults. It is characterized by sudden onset of fever with a biphasic course, headache, muscle and joint pain and gastrointestinal symptoms. Some dengue infected individuals develop the severe, life-threatening form of the disease, Dengue Hemorrhagic Fever/ Dengue Shock Syndrome (DHF/DSS) (Tab. 1). In Central Europe DF is seen in immigrants and travellers returning from the endemic regions [6].


Mucocutaneous symptoms are a hallmark of the disease, which is of importance in the differential diagnosis of sudden fever in travellers returning from abroad (Tab. 2; [7, 8]). With that knowledge, dermatologist can play an active role in early detection of possible DF infected patients. We wish to report a case of secondary DF with cutaneous manifestations from Saxony, Germany.



Case Report

A 21-year-old male German traveller presented with sudden onset of fever, malaise and rash. He returned from a business trip to rural Indonesia and the forest regions. He was in the same area one year ago. That time, he also had suffered from sudden onset fever with rash confirmed as DF virus type 1 infection.


This time the course of the disease was more severe. He presented with fever 38.7 degree Celcius followed by two fever-free days and then again fever > 38 degree Celsius with the development of head ache, arthralgia and rash. The rash also was different form the light cutaneous affection the patient remembered one year ago. He presented with a generalized confluent erythema with island of sparing like “white islands in a red sea”. Palms and soles were involved (Fig. 1a-c). There was a burning sensation with light itch but not excoriations due to scratching. Mucous membranes were not affected.


Laboratory investigations: Differential blood count, stool microbiology and routine lab normal. TB-spot, antibodies against hepatitis-C, HIV 1/2, cytomegaly virus, Chikunguny, and Orsriver  – all negative.


DF virus antibody haemagglutination assay: IgG positive, IgM negative. DF virus IgM enzyme immuno assay positive, IgM indirect immunofluorescence test (IIFT) 1:160, IgG IIFT 1:5120, DF virus antigen enzyme immuno assay positive. Reverse transcriptase-polymerase chain reaction for DF virus: type 1/4 positive.


Echocardiography, thoracic X-ray, and abdominal sonography – all normal.

Treatment and course: Because our first working hypothesis was a drug-related exanthema (DRESS syndrome) due to antipyretics we applied 100 mg prednisolone and 1 ml dimetinden i.v. once. The burning and itching sensations and arthralgia responded quickly. No other medication was necessary. Complete remission was achieved.



DF is seen in the Mediterranean area and North Africa, South Asia including China and India, and the Americas. DF is an emerging disease; it is increasing in geographical distribution and severity, despite being significantly underreported. Europe is also more and more affected, mainly by travellers.


The majority of DF infections of European travellers were acquired in South-East Asia [3]. In 2010 (until 14 April), five cases of DF including one case of DHF, have been reported from EuroTravNet sites in France and Sweden, in four travellers returning from the Comoros and one traveller returning from Zanzibar, Tanzania [4].


In order to protect themselves, travellers to areas where vector-borne diseases such as DF are present should be advised to adopt some protective measures to avoid mosquito bites. Moreover, physicians should be prepared to diagnose and manage imported cases of DF in travellers returning from endemic regions. Viraemic patients may spread the infection to regions where competent vectors are present, including the Mediterranean area and the south of Europe.The existence of four closely related dengue virus serotypes contributes to difficulties in diagnosis. In addition to fever, the most commonly reported symptoms of DF included malaise (96.7 %), headache (92.4 %), chills (90.2 %), myalgia (81.4 %), arthralgia (76.2 %), and hyporexia (75 %) (Tab. 1; [8]).

The mechanisms by which DF virus causes severe illness remain to be elucidated. Both viral and immune host factors seem to contribute to the level of the pathogenicity. Infection of dendritic cells initiates different responses in immature and mature dendritic cells with release of dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) or expression of Fc receptors. Activation of T-lymphocytes results in a very strong cytokine response responsible for vascular leakage in addition to activating effector cells. Antibodies and the virus itself are involved in release of complement and anaphylatoxins [9-12].

Fig. 1: Cutaneous manifestation of Dengue fever, secondary infection. (a) Erythema of the hand with island of sparing. (b) Palms involved. (c) Legs involved.

Immunity induced by natural infection is believed to provide serotype-specific lifelong protection. On the other hand, previous infection by a distinct serotype increases the risk for dengue hemorrhagic fever and dengue shock syndrome (DHF / DSS) [11-13]. We suspected a DF virus type 1 infection as primary infection in our patient and a recent virus type 4 infection.


Although the pathogenesis is not completely understood can we identify persons who are at risk for DHF? A matched case-control study in a dengue seropositive population in two Brazilian cities found significant associations DHF and white ethnicity, high income, high education, reported diabetes and reported allergy treated with steroids. Black individuals who reported being treated for hypertension had 13 times higher risk of DHF then black individuals reporting no hypertension [14]. Concerning clinical and laboratory signs, DHF is associated with age between 12 and 45 years, rash, vomiting, temperature >38 degrees C, leukocyte count <4500 / µL, and platelet count <90.000 / µL [15].

There seem to be several host genetic risk factors for DHF likeHLA, Fcgamma receptor, tumour necrosis factor alpha (TNFalpha), DC-SIGN genes, and JAK1 single-nucleotide polymorphisms [16].TNFalpha (-308) A allele and IL-10 (-1082 / -819 / -592) ACC / ATA haplotype were significantly associated with DHF. TNFalpha (-308) GG and tumor growth factor beta (TGFbeta) -1 (c25) GG genotypes were associated to protection [17].


Predictors for DF shock syndrome during the febrile stage are increase in hematocrit > 25 %, a platelet count < 40,000/microl, an activated partial thromboplastin time >44 seconds, a prothrombin time >14 seconds, a thrombin time >16 seconds or a von-Willebrand factor (VWF) antigen or VWF ristocetin co-factor > 210 %. The relative risk ranged from 4.8 to 10.9 [18].


Our patient returned from Indonesia. He obviously had a secondary infection with DF virus type 4. His primary infection was running a benign course with some days of sudden fever, head and muscle ache, and a limited rash. The secondary infection was more severe, as usual. We observed a generalized slightly itching confluent erythema with islands of sparing. Treatment of uncomplicated DF is symptomatic.


Address of Correspondence

Prof. Dr. Uwe Wollina
Department of Dermatology and Allergology
Academic Teaching Hospital Dresden-Friedrichstadt
Friedrichstrasse 41
D-01067 Dresden, Germany.


Dengue infections commonly occur among U.S. residents returning from travel to endemic areas as the Caribbean, South America, South Central Asia, and Southeast Asia. During 2006-2008, the highest proportion of laboratory-confirmed and probable cases with known travel histories were in persons who reported travel to the Dominican Republic (121; 20 %), Mexico (55; 9 %), and India (43; 7 %). The Center for Disease Control (CDC) therefore recommends that health-care providers should consider dengue in the differential diagnosis of patients with a history of travel to endemic areas within 14 days of fever onset [19]. It has been assumed that due to global climate change arboviral threats including DF will spread to Europe. The presence of vectors in some areas will support such expansion [20].


1. Gurugama P, Garg P, Perera J, Wijewickrama A, Seneviratne SL (2010) Dengue viral infections. Indian J Dermatol 55: 68-78.
2. Gubler DJ (1998) Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 11: 480-96.
3. Gautret P, Schlagenhauf P, Gaudart J, Castelli F, Brouqui P, et al. (2009) Multicenter EuroTravNet/GeoSentinel study of travel-related infectious disease in Europe. Emerg Infect Dis 15: 1783-90.
4. Gautret P, Simon F, Hervius Askling H, Bouchaud O, Leparc-Goffart I, et al. (2010) Dengue type 3 virus infections in European travellers returning from the Comoros and Zanzibar, February-April 2010. Euro Surveill 2010;15:pii=19541.
5. Goljan J, Myjak P, Nahorski W, Kubica-Biernat B, Felczak-Korzybska I, et al. (2010) Dengue antibodies in Polish travellers returning from the tropics. Evaluation of serological tests. Int Marit Health 61: 36-40.
6. Thomas EA, John M, Kanish B (2010) Mucocutaneous manifestations of dengue fever. Indian J Dermatol 55: 79-85.
7. Hafner C, Koellner K, Vogt T, Landthaler M, Szeimies R-M (2006) Hämorrhagisches Dengue-Fieber nach Malaysia-Aufenthalt. Hautarzt 57: 705-7.
8. Forshey BM, Guevara C, Laguna-Torres VA, Cespedes M, Vargas J, et al. (2010) Arboviral etiologies of acute febrile illnesses in Western South America, 2000-2007. PLoS Negl Trop Dis 4: e787.
9. Nielsen DG (2009) The relationship of interacting immunological components in dengue pathogenesis. Virol J 6: 211.
10. Malavige G, Fernando S, Fernando D, Seneviratne S (2004) Dengue viral infections. Postgrad Med J 80: 588–601.
11. Halstead S (1988) Pathogenesis of dengue: challenges to molecular biology. Science 239: 476–81.
12. Halstead S (2007) Dengue. Lancet 370: 1644–1652.
13. Endy T, Nisalak A, Chunsuttitwat S, Vaughn D, Green S, et al. (2004) Relationship of preexisting dengue virus (DV) neutralizing antibody levels to viremia and severity of disease in a prospective cohort study of DV infection in Thailand. J Infect Dis. 189: 990–1000.
14. Figueiredo MA, Rodrigues LC, Barreto ML, Lima JW, Costa MC, et al. (2010) Allergies and diabetes as risk factors for dengue hemorrhagic fever: results of a case control study. PLoS Negl Trop Dis 4: e699.
15. Diaz-Quijano FA, Villar-Centeno LA, Martinez-Vega RA (2010) Predictors of spontaneous bleeding in patients with acute febrile syndrome from a dengue endemic area. J Clin Virol 49: 11-5.
16. Silva LK, Blanton RE, Parrado AR, Melo PS, Morato VG, et al. (2010) Dengue hemorrhagic fever is associated with polymorphisms in JAK1. Eur J Hum Genet. in press.
17. Perez AB, Sierra B, Garcia G, Aguirre E, Babel N, et al. (2010) TNF-alpha, TGF-beta 1 and IL-10 gene polymorphisms: Implication in protection or susceptibility to Dengue Hemorrhagic Fever. Hum Immunol. in press.
18. Chuansumrit A, Puripokai C, Butthep P, Wongtiraporn W, Sasanakul W, et al. (2010) Laboratory predictors of dengue shock syndrome during the febrile stage. Southeast Asian J Trop Med Public Health 41: 326-32.
19. Centers for Disease Control and Prevention (CDC) (2010) Travel-associated Dengue surveillance - United States, 2006-2008. MMWR Morb Mortal Wkly Rep 18;59: 715-9.
20. Weaver SC, Reisen WK (2010) Present and future arboviral threats. Antiviral Res 85: 328-45.



Lost your password?