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.

Introduction

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.

Discussion

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.