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Clinical features and laboratory findings of dengue fever in German travellers: A single-centre, retrospective analysis
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Travel Medicine and Infectious Disease (2016) xx, 1e6
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevierhealth.com/journals/tmid
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Clinical features and laboratory findings of dengue fever in German travellers: A single-centre, retrospective analysis Pulad Tavakolipoor a, Jonas Schmidt-Chanasit b,c, Dieter Burchard Gerd a,d, Sabine Jordan a,* a Section Tropical Medicine, Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany b Bernhard Nocht Institute for Tropical Medicine, WHO Collaborating Centre for Arbovirus and Hemorrhagic Fever Reference and Research, Hamburg, Germany c German Centre for Infection Research (DZIF), partner site Hamburg-Luebeck-Borstel, Hamburg, Germany d Section Clinical Research and Epidemiology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
Received 7 December 2015; received in revised form 21 January 2016; accepted 22 January 2016
KEYWORDS Dengue; Travel-associated infection; Vector-borne disease; Arthropod-borne disease; Arboviral infection
Summary Background: Dengue fever (DF) is one of the most relevant human arboviral infections worldwide and has become a frequent cause of fever in the returning traveller. This retrospective study aimed to characterize epidemiological and clinical features and laboratory findings of dengue fever in German travellers. Methods: This descriptive study analyzed medical records of patients diagnosed with DF presenting at the Section of Tropical Medicine of the University Medical Centre HamburgEppendorf from 2007 to 2011. Data were collected and analyzed retrospectively. Results: In total, data of 119 DF patients (52 female, 67 male) were included in this study. The median age of the patients was 35 (range 15e75 years). DF was most frequently acquired in South-East Asia (n Z 65; 54.7%), and in particular in Thailand (n Z 23; 19.7%). A considerable percentage of DF infections (n Z 14; 11.8%) was imported from Africa. Patients predominantly presented with fever, headache, rash, myalgia and arthralgia but also with gastrointestinal symptoms, i.e. diarrhoea. Nine patients showed signs of minor haemorrhagic manifestations. Neurological complications occurred in 13 patients. Low platelet count, leukopenia and elevated liver enzymes were the most relevant laboratory findings. Twenty patients (17.8%) had to be hospitalized. Overall, the clinical course was mostly mild to moderate, 13 patients (10.9%) showed DF warnings signs, no fatalities occurred.
* Corresponding author. Section Tropical Medicine, Department of Medicine, Universitiy Medical Centre Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Tel.: þ49 40 7410 53910; fax: þ49 40 7410 58531. Q2 E-mail address: [email protected] (S. Jordan). http://dx.doi.org/10.1016/j.tmaid.2016.01.007 1477-8939/ª 2016 Published by Elsevier Ltd.
Please cite this article in press as: Tavakolipoor P, et al., Clinical features and laboratory findings of dengue fever in German travellers: A single-centre, retrospective analysis, Travel Medicine and Infectious Disease (2016), http://dx.doi.org/10.1016/j.tmaid.2016.01.007
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P. Tavakolipoor et al. Conclusions: DF presented as a mostly mild to moderate disease in this study cohort. Outpatient treatment was adequate for the majority of patients. Still, detailed knowledge of clinical symptoms and laboratory features is essential for appropriate triage. ª 2016 Published by Elsevier Ltd.
1. Introduction Around 3.5 billion people are living in dengue virus (DENV) countries with the major disease burden in South East Asia, South Asia and Latin America. There has been a 30-fold growth of the worldwide incidence of DENV in the last 50 years and DENV has become a great severe public health concern in many countries around the world [1e3]. DENV is not only relevant for DENV-endemic countries but has become a matter of significance for non-endemic areas i.e. Europe, Australia and Northern America. Dengue Fever (DF) is the most frequent arboviral infection among travellers and was shown to be the second most common reason for fever among returning travellers only second to malaria [4,5]. The main factors for the worldwide increase of the incidence of DF are rising international travel, urbanization, overpopulation and climate changes [6,7]. DF is an acute febrile illness caused by one of the four antigenically distinct DENV serotypes (DENV-1, DENV-2, DENV-3, DENV-4). The primary vector is the day biting and highly anthropophilic Aedes (Ae.) aegypti. Ae. aegypti mosquitos are effective vectors and their global distribution is matching the distribution of DENV [8,9]. The clinical presentation of DF ranges from asymptomatic infection or mild self-limiting febrile illness to a potentially fatal illness with haemorrhage or shock syndrome resulting in multiple organ failure, formerly classified as dengue haemorrhagic fever (DHF) and dengue shock syndrome [10]. Symptomatic patients typically present with one or more of the following symptoms: high fever, headache, retro-orbital pain, myalgia, arthralgia, rash or nausea/vomiting [11]. The clinical course of the infection can be divided into three phases: an initial febrile phase lasting 3e7 days, a 24e48 h lasting critical phase around defervescence and the recovery phase. In the critical phase, a small number of patients develop symptoms of plasma leakage, coagulation derangement and organ impairment. Severe dengue also includes patients with hepatitis, neurological disorders, myocarditis or severe bleeding without plasma leakage or shock. The febrile phase is often associated with leukopenia. An increase in haematocrit and rapid decrease of platelet count are associated with complications in the critical phase [10,12]. Severe cases of dengue fever with case fatality rates ranging from <1e5% are associated with secondary infections. Children living in endemic regions have the highest risk of acquiring these secondary infections [13]. The pathogenesis of dengue is likely to be a complex interplay of host immunity and genetic predisposition as well as viral virulence factors [14]. A revised WHO case classification was introduced in 2009, replacing the traditional dengue fever and dengue haemorrhagic fever/dengue shock
syndrome with dengue with and without warning signs and severe dengue. The revised guidelines aimed to facilitate early risk stratification and improve clinical management of patients with DF [15]. The increasing numbers of imported DF to Europe resulted in a rising number of autochthonous DF cases in several European countries where the potential vectors Ae. albopictus and Ae. aegypti are present. Since 2010 several cases have been reported from Croatia, Italy, Spain and France [16]. The so far largest outbreak of autochthonous DF in Europe occurred in Madeira, Portugal in October 2012 to February 2013 with more than 2000 local infections and with 81 cases imported to continental Europe. About 100 patients were hospitalized due to DF during the outbreak. No fatalities occurred [17,18]. Severe infections seem to be less common in travellers than in endemic populations but still there are reports of fatal cases [19e21]. Since there is an increasing number of returning travellers with DF, acquisition of detailed knowledge of symptoms of the disease, potential risk factors for severe disease and disease management is becoming important not only to infectious disease specialists in non-endemic countries but as well for general practitioners. Our study aimed to identify epidemiological and clinical characteristics as well as laboratory findings of a real life cohort of outpatients and hospitalized patients with acute DF in a tertiary care centre in Germany.
2. Material and methods For this retrospective single centre analysis, case records of patients presenting at the Section of Tropical Medicine at the University Hospital Hamburg-Eppendorf from January 2007 to April 2011 and were undergoing serological testing for DENV infection were revised. Potential cases were identified from laboratory records held at the Bernhard Nocht Institute for Tropical Medicine, which serves as a reference laboratory for tropical diseases in Germany and is the WHO Collaborating Centre for Arbovirus and Hemorrhagic Fever Reference and Research. The Section of Tropical Medicine serves as a tertiary care centre for infectious diseases in Hamburg and is a referral centre for imported tropical diseases in Germany. All patients gave written consent for the use of pseudonymized personal and medical data for research purposes.
2.1. Study subjects DENV IgM and IgG antibody tests and DENV real-time RT-PCR were performed as previously described [22]. In addition, the presence of DENV nonstructural protein-1 (NS1) antigen in serum samples was tested by ELISA (Bio-Rad Platelia
Please cite this article in press as: Tavakolipoor P, et al., Clinical features and laboratory findings of dengue fever in German travellers: A single-centre, retrospective analysis, Travel Medicine and Infectious Disease (2016), http://dx.doi.org/10.1016/j.tmaid.2016.01.007
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Clinical features and laboratory findings of dengue Dengue NS1 Ag) and rapid test (SD BIOLINE Dengue Duo NS1 Ag þ Ab Combo). Detection of DENV-specific-IgM antibodies, viral RNA or DENV NS1 antigen were considered as potential DF cases and matching medical records were revised. Patients with a recent history of travel to DENV endemic regions, signs of acute febrile illness and exclusion of concomitant infections were included in the analysis.
2.2. Clinical data Clinical data were taken from medical records and were retrospectively studied. Patient characteristics, travel history, presenting clinical features and laboratory indices were analyzed. Recorded data included following parameters: age, sex, travel destination, travel duration, reason for travel, clinical symptoms and signs, hemoglobin, white blood cell count, platelet count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatinine, C-reactive protein (CRP) and outpatient/inpatient treatment. A subgroup analysis was performed for hospitalized patients.
3. Results 3.1. Demographic findings In total, data of 119 patients diagnosed with DF were included in this retrospective study. The age of the patients ranged from 15 to 75 years with a median age of 35 years. Fifty-two patients (43.7%) were of female sex, 67 patients (56.3%) were male. 112 patients (94.1%) were of European origin, seven patients (5.9%) were of non-European origin. Four patients (3.4%) were of Asian origin, two patients (1.7%) of Latin American origin and one patient (0.8%) of African origin. One European and one non-European patient were permanently living in a DENV endemic region. Nineteen patients (16.0%) reported comorbidities (Table 1). No patient had a previous history of DF. Median travel duration was 21 days with a range of 7e365 days. Main reason for travel was tourism (n Z 90; 76.1%). The remaining patients stated business, volunteer work, education or visiting family and friends as reason for travel (Table 1). Infections were predominately imported from Southeast Asia (n Z 65; 54.7%) followed by South Asia (n Z 22; 17.9%), Latin America and the Caribbean (n Z 16; 13.4%) and Africa (n Z 14; 11.8%) with Thailand (n Z 23; 19.7%), India (n Z 16; 13.7%) and Indonesia (n Z 16 patients; 13.7%) most frequently stated as single travel destination (Table 2). In 18 cases (15.1%) the country of infection could not be defined due to multi destination travel.
3.2. Clinical findings All but three patients were febrile at the date of presentation (n Z 116; 97.5%). 59 patients (49.6%) presented with headache, 57 patients (47.9%) with rash and 50 patients (42.0%) with myalgia and arthralgia. Gastrointestinal symptoms were reported from 51 patients (42.9%), mainly diarrhoea (n Z 48; 40.3%). Other frequently reported symptoms were fatigue (n Z 27; 22.7%), anorexia
3 Table 1
Demographic data.
Sex male female Age Comorbidities Musculoskeletal disease Cardiovascular disease Endocrine disease Neurological disorder Gastrointestinal disorder Renal disease Skin disease Hematological disorder Duration of travel Reason for travel Tourism Business Visiting family and relatives Volunteer work Education Unknown Living in endemic country
Table 2
67 52 Median 35 19 4 3 4 2 2 1 2 1 Median 21
56.3% 43.7% Range 15e75 16.0% 3.4% 2.5% 3.4% 1.7% 1.7% 0.8% 1.7% 0.8% Range 7e365
90 10 1 6 2 7 2
76.1% 8.5% 0.8% 5.1% 1.7% 6.0% 1.7%
Travel destination.
Asia Southeast Asia Thailand Indonesia Indian subcontinent India The Americas Caribbean Central America South America Africa West Africa East Africa South Africa Oceania Unknown
65 23 16 22 16
54.6%
18.5%
2 3 11
1.7% 2.5% 9.2%
7 6 1 1 1
6.0% 5.1% 0.9% 0.9% 0.9%
(n Z 9; 7.6%), cough (n Z 8; 6.7%) and night sweat (n Z 7; 5.9%). Thirteen patients (10.9%) presented with neurological symptoms other than headache. Neurological symptoms presented were mostly mild such as vertigo and dizziness (n Z 7; 5.9%). One patient reported dysgeusia, another patient complaint of blurred vision. In four patients (3.4%) severe neurological complications occurred such as seizures in three patients and meningism in one patient. Nine patients (7.6%) showed minor bleeding manifestations such as petechiae (n Z 3), epistaxis (n Z 3), spontaneous hematoma (n Z 2), hypermenorrhea (n Z 1), gum bleeding (n Z 1) and hematochezia (n Z 1). Applying the in
Please cite this article in press as: Tavakolipoor P, et al., Clinical features and laboratory findings of dengue fever in German travellers: A single-centre, retrospective analysis, Travel Medicine and Infectious Disease (2016), http://dx.doi.org/10.1016/j.tmaid.2016.01.007
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2009 revised WHO classification of DF, epistaxis, gum bleeding and hematochezia are judged as warning signs.
3.3. Laboratory findings The laboratory findings are presented in Table 3. Thirty-one patients (26.1%) showed a leucocyte count less than 3.8 109/l with a lowest count of 1.8 109/l. Thrombocytopenia defined as a platelet count less than 150 109/l was detected in 39 patients (32.8%). Six patients (5.0%) presented a platelet count less than 50 109/l. Elevation of AST and ALT was seen in 39 patients (32.8%) and 41 patients (34.5%), respectively. Liver enzyme elevation was defined as serum activity of AST and ALT >50 U/l in men and >35 U/l in women. Most patients showed mild hepatitis with serum transaminases 200 U/l. 5 respectively 7 patients presented AST respectively ALT levels >200 U/l with levels up to 682 U/l for AST and 361 U/l for ALT. An elevation of lactate dehydrogenase (LDH) with levels >225 U/l was detected in 37 patients (31.1%) with a maximum level of 788 U/l. Mostly mild elevated levels of Creactive protein (CRP) were seen in 30 patients (25.2%). Four patients (3.4%) showed levels >50 mg/l with two patients (1.7%) showing levels >100 mg/l. Five patients (4.2%) presented mild impaired kidney function with creatinine levels >1.2 mg/dl. Routine coagulation tests such as prothrombin time, international normalized ratio and activated partial thromboplastin time did not show any abnormalities. The diagnosis of DENV infection was predominantly established by exclusive antibody testing (n Z 59; 49.6%) and combination of antibody and NS1 antigen testing (n Z 46; 38.7%). In 7 cases (5.9%) DENV RNA was detected by realtime RT-PCR.
3.4. Hospitalized patients Ninety nine (83.2%) patients were treated as outpatients, 20 (17.8%) patients were hospitalized. Frequency of clinical symptoms did not differ in outpatients and inpatients except for bleeding manifestations and neurological complications. In the group of inpatients three patients (15.0%) showed bleeding manifestations or neurological complications respectively. Bleeding manifestations remained mild and did not require specific treatment. Neurological complications presented as seizures of altered character in one patient with pre-existing seizure disorder. This patient required adjustment of neuroleptic treatment. The other
Table 3
two patients presented with meningism and dysgeusia without need for further medical procedures. Laboratory parameters differed in inpatients and outpatients with more patients presenting with leukopenia, thrombocytopenia and elevation of AST, ALT and LDH. Furthermore, nine patients (7.6%) showed a decline in their platelet count during the first days of admission with a concurrent rise in haematocrit to levels above baseline and therefore fulfilling criteria of dengue with warning signs. Four of these patients also developed a significant hepatitis with AST/ALT levels above tenfold normal ranges. Overall, clinical course was mostly uncomplicated. No patient fulfilled criteria of severe DF. There were no fatalities in the study group.
4. Discussion The significance of DF seems to be more relevant than ever before. Worldwide, DF is the most common human arboviral infection and it is endemic in more than 100 countries with approximately half of the world’s population living at risk of acquiring DENV infections [6,10]. The World Health Organization (WHO) classified DF as the ‘most important mosquito-borne viral disease in the world’. Caused by rising tourism in DENV endemic regions, DF has become a crucial differential diagnosis for fever in international travellers [2,3]. Clinical-based sentinel surveillance programs recorded a significant increase in reported DF cases [4,5,23]. The recent GeoSentinel analysis showed DF as the second most common cause for febrile disease in all returning travellers. In fact, in patients returning from Asia, the Caribbean or Latin America DF was the most common cause for febrile disease [4]. Furthermore, the re-emergence of autochthonous DF in several European countries and Japan demands profound knowledge of clinical course and diagnostics of dengue infection not only from infectious disease specialists but also from general practitioners [22]. Our study aimed to identify epidemiological and clinical characteristics and laboratory findings of patients with acute DF in a tertiary care centre in Germany. Data of 119 patients could be included into the study representing about 8% of all reported cases of DF in Germany during the study period. DENV infections have been reportable in Germany since 2001. During the study period, 1525 cases of DF were reported [27]. The study cohort consisted of a rather young group with a median age of 35 (IQR 26-46), the male to female ratio was 1.29:1. Only few patients (16%) reported comorbidities.
Laboratory findings of all patients with DF, inpatients with DF and outpatients with DF. All patients (n Z 119)
Leukopenia (<3.8 109/l) Thrombocytopenia (<150 109/l) ALT above normal range (m > 50 U/l; f > 35 U/l) AST above normal range (m > 50 U/l; f > 35 U/l) LDH above normal range (>225 U/l) CRP above normal range (>5 mg/l) Creatinine above normal range (>1.2 mg/dl)
31 39 41 39 37 30 5
Inpatients (n Z 20) 26.1% 32.8% 34.5% 32.8% 31.1% 25.2% 4.2%
11 14 10 13 11 8 0
Outpatients (n Z 99) 55% 70% 50% 65% 55% 40% 0%
20 25 31 26 26 22 5
20.2% 25.3% 31.3% 26.3% 26.3% 22.2% 5.1%
Please cite this article in press as: Tavakolipoor P, et al., Clinical features and laboratory findings of dengue fever in German travellers: A single-centre, retrospective analysis, Travel Medicine and Infectious Disease (2016), http://dx.doi.org/10.1016/j.tmaid.2016.01.007
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Clinical features and laboratory findings of dengue Consistent with other European studies on imported DF and German national surveillance data, the majority of cases (54.6%) were acquired in South-East Asia [5,24e26,28]. At least 23 patients were infected In Thailand. In six additional cases, Thailand was one of the potential countries where the infection was contracted. 18.5% and 13.4% of the cases were imported from South Asia and Latin America and the Caribbean respectively. Data are reflecting travel habits of German tourists with Thailand being one of the most popular long distance travel destinations of German travellers with about 550 000 German visitors yearly during the study period [29]. Infection rates themselves might be higher for less popular tourist destinations. India and Indonesia, for example, were determined as country of infection in 16 cases each, both noting considerable lower numbers of German visitors with about 240 000 respectively 150 000 visitors yearly [30,31]. Interestingly, with 11.8% a considerable percentage of patients acquired the infection in Sub-Saharan Africa. A recent study on hospitalized patients in Berlin and a study from Austria showed comparable rates of DF importations [25,32], but most studies on imported DF showed lower rates of imported cases from Africa [4,24,33]. DF might be underdiagnosed in travellers from Africa and should be considered as differential diagnosis in febrile patients, especially if malaria diagnostics turn out negative. As expected, the most frequent clinical symptoms included fever, headache, exanthema, myalgia/arthralgia and fatigue. More surprisingly, a high proportion of patients (42.9%) reported gastrointestinal symptoms mostly diarrhea. A recent study in Czech travellers reported similar figures [24] highlighting a further potential pitfall in DF diagnosis. Five patients reported signs of mucosal bleeding which is classified as a warning sign in the revised DF classification (Box 1) [15]. The patients themselves judged the bleeding signs as mild. On the other hand, thirteen patients (10.9%) presented with neurological symptoms such as seizures and meningism one would be tempted to rate as a potential warning sign. However, lethargy and restlessness are the only neurological symptoms on the list of warning signs. DF can manifest with a wide range of neurological complications such as encephalitis, myositis, myelitis, Guillain-Barre ´ syndrome (GBS) and mononeuropathies. The exact incidence of neurological complications is uncertain, ranging from 0.5% to 21% in different clinical settings [34,35]. Furthermore, former DENV infections are considered to predispose for development of GBS in sequential Flavivirus infections such as Zika virus infections [36]. One out of four patients presented with leukopenia, one third with thrombocytopenia with platelet counts as low as 19 109/l. Also one third of the patients showed elevated liver enzymes and an elevation of LDH. Even though an elevation of CRP was seen in 25.2% of patients, elevation was mostly mild with only four patients showing CRP levels >50 mg/l. Laboratory findings are consistent with published data [37,38]. Especially the normal levels or only mild elevation of the CRP level might be a useful tool in the differentiation between dengue fever versus malaria and enteric fever, since the CRP levels are usually markedly elevated in these two illnesses [37]. Twenty patients (17.8%) were hospitalized due to symptomatic DF. There were no defined criteria for hospital
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Textbox 1. Warning signs in DF according to the 2009 revised WHO dengue case classification [15].
Clinical warning signs
Laboratory warning signs
Abdominal pain or tenderness Persistent vomiting Clinical fluid accumulation Mucosal bleeding Lethargy, restlessness Liver enlargement >2 cm Increase in HCT concurrent with rapid decrease in platelet count
admission. Patients were hospitalized at the clinicians’ discretion. Frequency of clinical symptoms did not differ in outpatients and inpatients except for bleeding manifestations and neurological complications. Three patients (15%) exhibited clinical warning signs, i.e. mucosal bleeding. Inpatients presented significantly more often with laboratory abnormalities. Seventy percent of the hospitalized patients showed low platelets counts at the time of their admission. Additionally, leukopenia and elevation of liver enzymes and LDH were seen in over the half of the patients (Table 3). Laboratory parameters of these patients were closely monitored during the hospital stay. We could demonstrate a further decline of platelet count and concurrent rise of liver enzymes in several patients, which is consistent with data from Japan where the development of thrombocytopenia and increase of liver enzyme levels was shown during the period of defervescence [39]. Furthermore, nine of the twenty hospitalized patients (45%) showed a rapid decrease of platelets and concurrent increase of the haematocrit during the first days after hospital admission. This laboratory constellation is part of the 2009 defined Dengue warning signs (Box 1) [15]. The discrepancy of the high frequency of warning signs and the relatively benign clinical course of DF in inpatients presumably lies in hospitalization itself, allowing close monitoring and adequate fluid resuscitation. Altogether, our data emphasize the need for close monitoring of laboratory findings in addition to the clinical symptoms in the course of DF. Especially patients with primarily mild symptoms treated as outpatients should be informed about potential clinical warning signs as well as the need for close outpatient monitoring during the course of the infection.
5. Conclusion In conclusion, DF presented as a mostly mild to moderate disease in returning travellers at a large German specialized outpatient centre. Outpatient treatment was adequate for the majority of patients. Still, about one-fifth of the patients had to be hospitalized. A profound knowledge of the clinical symptoms and laboratory features is essential for appropriate management of the patients. Close monitoring of clinical symptoms and laboratory
Please cite this article in press as: Tavakolipoor P, et al., Clinical features and laboratory findings of dengue fever in German travellers: A single-centre, retrospective analysis, Travel Medicine and Infectious Disease (2016), http://dx.doi.org/10.1016/j.tmaid.2016.01.007
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6 findings in the course of DF has to be warranted for both outpatients as well as inpatients. The 2009 revised WHO case classification [15] proves to be a helpful tool for patient triage.
Conflicts of interest The authors declare that there are no conflicts of interest.
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P. Tavakolipoor et al. [20] Huhtamo E, Vuorinen S, Uzcategui NY, Vapalahti O, Haapasalo H, Lumio J. Fatal dengue virus infection in a Finnish traveler. J Clin Virol 2006;37(4):323e6. [21] Jensenius M, Berild D, Ormaasen V, Maehlen J, Lindegren G, Falk KI. Fatal subarachnoidal haemorrhage in a Norwegian traveller with dengue virus infection. Scand J Infect Dis 2007; 39(3):272e4. [22] Schmidt-Chanasit J, Emmerich P, Tappe D, Gunther S, Schmidt S, Wolff D, et al. Autochthonous dengue virus infection in Japan imported into Germany, September 2013. Euro Surveill 2014;19(3). [23] Jelinek T. Trends in the epidemiology of dengue fever and their relevance for importation to Europe. Euro Surveill 2009; 14(25). [24] Trojanek M, Maixner J, Sojkova N, Kyncl J, Rohacova H, Maresova V, et al. Dengue fever in Czech travellers: a 10-year retrospective study in a tertiary care centre. Travel Med Q3 Infect Dis 2015;15:00106e114. Jun 25. pii: S1477-8939. [25] Hoffmeister B, Suttorp N, Zoller T. The revised dengue fever classification in German travelers: clinical manifestations and indicators for severe disease. Infection 2015;43(1):21e8. [26] Rocklov J, Lohr W, Hjertqvist M, Wilder-Smith A. Attack rates of dengue fever in Swedish travellers. Scand J Infect Dis 2014; 46(6):412e7. [27] Robert Koch Institute (RKI). SurvStat@RKI. [accessed 19.1.2016]. German. Available from: http://www3.rki.de/ SurvStat. [28] Frank C, Faber M, Hellenbrand W, Wilking H, Stark K. Important vector-borne infectious diseases among humans in Germany. Bundesgesundheitsblatt Gesundheitsforsch Gesundheitsschutz May 2014;57(5):557e67. [29] Department of tourism, Thailand. Visitor statistics. [accessed 19.1.2016]. Available from:: http://www.tourism.go.th/ home/listcontent/11/221/276. [30] Statistics Indonesia. Number of Foreign visitor Arrivals to Indonesia by Country of Residence, 2002e2014 [accessed 19.1.2016]. Available from:: http://www.bps.go.id/ linkTabelStatis/view/id/1388. [31] Ministry of tourism, India. India tourism statistics at a Glance 2014. [accessed 19.1.2016]. Available from:: http://tourism. nic.in/writereaddata/CMSPagePicture/file/marketresearch/ statisticalsurveys/India%20Tourism%20Statistics%20at%20a% 20Glance%202014.pdf. [32] Laferl H, Szell M, Bischof E, Wenisch C. Imported dengue fever in Austria 1990e2005. Travel Med Infect Dis 2006;4(6):319e23. [33] Gautret P, Cramer JP, Field V, Caumes E, Jensenius M, Gkrania-Klotsas E, et al. Infectious diseases among travellers and migrants in Europe, EuroTravNet 2010. Euro Surveill 2012; 17(26). [34] Carod-Artal FJ, Wichmann O, Farrar J, Gascon J. Neurological complications of dengue virus infection. Lancet Neurol 2013; 12(9):906e19. [35] Verma R, Sahu R, Holla V. Neurological manifestations of dengue infection: a review. J Neurol Sci 2014;346(1e2): 26e34. [36] Oehler E, Watrin L, Larre P, Leparc-Goffart I, Lastere S, Valour F, et al. Zika virus infection complicated by GuillainBarre syndromeecase report. December 2013. Euro Surveill French Polynesia 2014;19(9). [37] Cooper EC, Ratnam I, Mohebbi M, Leder K. Laboratory features of common causes of fever in returned travelers. J Travel Med 2014;21(4):235e9. [38] Wichmann O, Stark K, Shu P-Y, Niedrig M, Frank C, Huang J-H, et al. Clinical features and pitfalls in the laboratory diagnosis of dengue in travellers. BMC Infect Dis 2006;6:120. [39] Itoda I, Masuda G, Suganuma A, Imamura A, Ajisawa A, Yamada K-I, et al. Clinical features of 62 imported cases of dengue fever in Japan. Am J Trop Med Hyg 2006;75(3):470e4.
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Travel Medicine and Infectious Disease (2016) xx, 1e6
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Clinical features and laboratory findings of dengue fever in German travellers: A single-centre, retrospective analysis Pulad Tavakolipoor a, Jonas Schmidt-Chanasit b,c, Dieter Burchard Gerd a,d, Sabine Jordan a,* a Section Tropical Medicine, Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany b Bernhard Nocht Institute for Tropical Medicine, WHO Collaborating Centre for Arbovirus and Hemorrhagic Fever Reference and Research, Hamburg, Germany c German Centre for Infection Research (DZIF), partner site Hamburg-Luebeck-Borstel, Hamburg, Germany d Section Clinical Research and Epidemiology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
Received 7 December 2015; received in revised form 21 January 2016; accepted 22 January 2016
KEYWORDS Dengue; Travel-associated infection; Vector-borne disease; Arthropod-borne disease; Arboviral infection
Summary Background: Dengue fever (DF) is one of the most relevant human arboviral infections worldwide and has become a frequent cause of fever in the returning traveller. This retrospective study aimed to characterize epidemiological and clinical features and laboratory findings of dengue fever in German travellers. Methods: This descriptive study analyzed medical records of patients diagnosed with DF presenting at the Section of Tropical Medicine of the University Medical Centre HamburgEppendorf from 2007 to 2011. Data were collected and analyzed retrospectively. Results: In total, data of 119 DF patients (52 female, 67 male) were included in this study. The median age of the patients was 35 (range 15e75 years). DF was most frequently acquired in South-East Asia (n Z 65; 54.7%), and in particular in Thailand (n Z 23; 19.7%). A considerable percentage of DF infections (n Z 14; 11.8%) was imported from Africa. Patients predominantly presented with fever, headache, rash, myalgia and arthralgia but also with gastrointestinal symptoms, i.e. diarrhoea. Nine patients showed signs of minor haemorrhagic manifestations. Neurological complications occurred in 13 patients. Low platelet count, leukopenia and elevated liver enzymes were the most relevant laboratory findings. Twenty patients (17.8%) had to be hospitalized. Overall, the clinical course was mostly mild to moderate, 13 patients (10.9%) showed DF warnings signs, no fatalities occurred.
* Corresponding author. Section Tropical Medicine, Department of Medicine, Universitiy Medical Centre Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Tel.: þ49 40 7410 53910; fax: þ49 40 7410 58531. Q2 E-mail address: [email protected] (S. Jordan). http://dx.doi.org/10.1016/j.tmaid.2016.01.007 1477-8939/ª 2016 Published by Elsevier Ltd.
Please cite this article in press as: Tavakolipoor P, et al., Clinical features and laboratory findings of dengue fever in German travellers: A single-centre, retrospective analysis, Travel Medicine and Infectious Disease (2016), http://dx.doi.org/10.1016/j.tmaid.2016.01.007
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P. Tavakolipoor et al. Conclusions: DF presented as a mostly mild to moderate disease in this study cohort. Outpatient treatment was adequate for the majority of patients. Still, detailed knowledge of clinical symptoms and laboratory features is essential for appropriate triage. ª 2016 Published by Elsevier Ltd.
1. Introduction Around 3.5 billion people are living in dengue virus (DENV) countries with the major disease burden in South East Asia, South Asia and Latin America. There has been a 30-fold growth of the worldwide incidence of DENV in the last 50 years and DENV has become a great severe public health concern in many countries around the world [1e3]. DENV is not only relevant for DENV-endemic countries but has become a matter of significance for non-endemic areas i.e. Europe, Australia and Northern America. Dengue Fever (DF) is the most frequent arboviral infection among travellers and was shown to be the second most common reason for fever among returning travellers only second to malaria [4,5]. The main factors for the worldwide increase of the incidence of DF are rising international travel, urbanization, overpopulation and climate changes [6,7]. DF is an acute febrile illness caused by one of the four antigenically distinct DENV serotypes (DENV-1, DENV-2, DENV-3, DENV-4). The primary vector is the day biting and highly anthropophilic Aedes (Ae.) aegypti. Ae. aegypti mosquitos are effective vectors and their global distribution is matching the distribution of DENV [8,9]. The clinical presentation of DF ranges from asymptomatic infection or mild self-limiting febrile illness to a potentially fatal illness with haemorrhage or shock syndrome resulting in multiple organ failure, formerly classified as dengue haemorrhagic fever (DHF) and dengue shock syndrome [10]. Symptomatic patients typically present with one or more of the following symptoms: high fever, headache, retro-orbital pain, myalgia, arthralgia, rash or nausea/vomiting [11]. The clinical course of the infection can be divided into three phases: an initial febrile phase lasting 3e7 days, a 24e48 h lasting critical phase around defervescence and the recovery phase. In the critical phase, a small number of patients develop symptoms of plasma leakage, coagulation derangement and organ impairment. Severe dengue also includes patients with hepatitis, neurological disorders, myocarditis or severe bleeding without plasma leakage or shock. The febrile phase is often associated with leukopenia. An increase in haematocrit and rapid decrease of platelet count are associated with complications in the critical phase [10,12]. Severe cases of dengue fever with case fatality rates ranging from <1e5% are associated with secondary infections. Children living in endemic regions have the highest risk of acquiring these secondary infections [13]. The pathogenesis of dengue is likely to be a complex interplay of host immunity and genetic predisposition as well as viral virulence factors [14]. A revised WHO case classification was introduced in 2009, replacing the traditional dengue fever and dengue haemorrhagic fever/dengue shock
syndrome with dengue with and without warning signs and severe dengue. The revised guidelines aimed to facilitate early risk stratification and improve clinical management of patients with DF [15]. The increasing numbers of imported DF to Europe resulted in a rising number of autochthonous DF cases in several European countries where the potential vectors Ae. albopictus and Ae. aegypti are present. Since 2010 several cases have been reported from Croatia, Italy, Spain and France [16]. The so far largest outbreak of autochthonous DF in Europe occurred in Madeira, Portugal in October 2012 to February 2013 with more than 2000 local infections and with 81 cases imported to continental Europe. About 100 patients were hospitalized due to DF during the outbreak. No fatalities occurred [17,18]. Severe infections seem to be less common in travellers than in endemic populations but still there are reports of fatal cases [19e21]. Since there is an increasing number of returning travellers with DF, acquisition of detailed knowledge of symptoms of the disease, potential risk factors for severe disease and disease management is becoming important not only to infectious disease specialists in non-endemic countries but as well for general practitioners. Our study aimed to identify epidemiological and clinical characteristics as well as laboratory findings of a real life cohort of outpatients and hospitalized patients with acute DF in a tertiary care centre in Germany.
2. Material and methods For this retrospective single centre analysis, case records of patients presenting at the Section of Tropical Medicine at the University Hospital Hamburg-Eppendorf from January 2007 to April 2011 and were undergoing serological testing for DENV infection were revised. Potential cases were identified from laboratory records held at the Bernhard Nocht Institute for Tropical Medicine, which serves as a reference laboratory for tropical diseases in Germany and is the WHO Collaborating Centre for Arbovirus and Hemorrhagic Fever Reference and Research. The Section of Tropical Medicine serves as a tertiary care centre for infectious diseases in Hamburg and is a referral centre for imported tropical diseases in Germany. All patients gave written consent for the use of pseudonymized personal and medical data for research purposes.
2.1. Study subjects DENV IgM and IgG antibody tests and DENV real-time RT-PCR were performed as previously described [22]. In addition, the presence of DENV nonstructural protein-1 (NS1) antigen in serum samples was tested by ELISA (Bio-Rad Platelia
Please cite this article in press as: Tavakolipoor P, et al., Clinical features and laboratory findings of dengue fever in German travellers: A single-centre, retrospective analysis, Travel Medicine and Infectious Disease (2016), http://dx.doi.org/10.1016/j.tmaid.2016.01.007
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Clinical features and laboratory findings of dengue Dengue NS1 Ag) and rapid test (SD BIOLINE Dengue Duo NS1 Ag þ Ab Combo). Detection of DENV-specific-IgM antibodies, viral RNA or DENV NS1 antigen were considered as potential DF cases and matching medical records were revised. Patients with a recent history of travel to DENV endemic regions, signs of acute febrile illness and exclusion of concomitant infections were included in the analysis.
2.2. Clinical data Clinical data were taken from medical records and were retrospectively studied. Patient characteristics, travel history, presenting clinical features and laboratory indices were analyzed. Recorded data included following parameters: age, sex, travel destination, travel duration, reason for travel, clinical symptoms and signs, hemoglobin, white blood cell count, platelet count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatinine, C-reactive protein (CRP) and outpatient/inpatient treatment. A subgroup analysis was performed for hospitalized patients.
3. Results 3.1. Demographic findings In total, data of 119 patients diagnosed with DF were included in this retrospective study. The age of the patients ranged from 15 to 75 years with a median age of 35 years. Fifty-two patients (43.7%) were of female sex, 67 patients (56.3%) were male. 112 patients (94.1%) were of European origin, seven patients (5.9%) were of non-European origin. Four patients (3.4%) were of Asian origin, two patients (1.7%) of Latin American origin and one patient (0.8%) of African origin. One European and one non-European patient were permanently living in a DENV endemic region. Nineteen patients (16.0%) reported comorbidities (Table 1). No patient had a previous history of DF. Median travel duration was 21 days with a range of 7e365 days. Main reason for travel was tourism (n Z 90; 76.1%). The remaining patients stated business, volunteer work, education or visiting family and friends as reason for travel (Table 1). Infections were predominately imported from Southeast Asia (n Z 65; 54.7%) followed by South Asia (n Z 22; 17.9%), Latin America and the Caribbean (n Z 16; 13.4%) and Africa (n Z 14; 11.8%) with Thailand (n Z 23; 19.7%), India (n Z 16; 13.7%) and Indonesia (n Z 16 patients; 13.7%) most frequently stated as single travel destination (Table 2). In 18 cases (15.1%) the country of infection could not be defined due to multi destination travel.
3.2. Clinical findings All but three patients were febrile at the date of presentation (n Z 116; 97.5%). 59 patients (49.6%) presented with headache, 57 patients (47.9%) with rash and 50 patients (42.0%) with myalgia and arthralgia. Gastrointestinal symptoms were reported from 51 patients (42.9%), mainly diarrhoea (n Z 48; 40.3%). Other frequently reported symptoms were fatigue (n Z 27; 22.7%), anorexia
3 Table 1
Demographic data.
Sex male female Age Comorbidities Musculoskeletal disease Cardiovascular disease Endocrine disease Neurological disorder Gastrointestinal disorder Renal disease Skin disease Hematological disorder Duration of travel Reason for travel Tourism Business Visiting family and relatives Volunteer work Education Unknown Living in endemic country
Table 2
67 52 Median 35 19 4 3 4 2 2 1 2 1 Median 21
56.3% 43.7% Range 15e75 16.0% 3.4% 2.5% 3.4% 1.7% 1.7% 0.8% 1.7% 0.8% Range 7e365
90 10 1 6 2 7 2
76.1% 8.5% 0.8% 5.1% 1.7% 6.0% 1.7%
Travel destination.
Asia Southeast Asia Thailand Indonesia Indian subcontinent India The Americas Caribbean Central America South America Africa West Africa East Africa South Africa Oceania Unknown
65 23 16 22 16
54.6%
18.5%
2 3 11
1.7% 2.5% 9.2%
7 6 1 1 1
6.0% 5.1% 0.9% 0.9% 0.9%
(n Z 9; 7.6%), cough (n Z 8; 6.7%) and night sweat (n Z 7; 5.9%). Thirteen patients (10.9%) presented with neurological symptoms other than headache. Neurological symptoms presented were mostly mild such as vertigo and dizziness (n Z 7; 5.9%). One patient reported dysgeusia, another patient complaint of blurred vision. In four patients (3.4%) severe neurological complications occurred such as seizures in three patients and meningism in one patient. Nine patients (7.6%) showed minor bleeding manifestations such as petechiae (n Z 3), epistaxis (n Z 3), spontaneous hematoma (n Z 2), hypermenorrhea (n Z 1), gum bleeding (n Z 1) and hematochezia (n Z 1). Applying the in
Please cite this article in press as: Tavakolipoor P, et al., Clinical features and laboratory findings of dengue fever in German travellers: A single-centre, retrospective analysis, Travel Medicine and Infectious Disease (2016), http://dx.doi.org/10.1016/j.tmaid.2016.01.007
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2009 revised WHO classification of DF, epistaxis, gum bleeding and hematochezia are judged as warning signs.
3.3. Laboratory findings The laboratory findings are presented in Table 3. Thirty-one patients (26.1%) showed a leucocyte count less than 3.8 109/l with a lowest count of 1.8 109/l. Thrombocytopenia defined as a platelet count less than 150 109/l was detected in 39 patients (32.8%). Six patients (5.0%) presented a platelet count less than 50 109/l. Elevation of AST and ALT was seen in 39 patients (32.8%) and 41 patients (34.5%), respectively. Liver enzyme elevation was defined as serum activity of AST and ALT >50 U/l in men and >35 U/l in women. Most patients showed mild hepatitis with serum transaminases 200 U/l. 5 respectively 7 patients presented AST respectively ALT levels >200 U/l with levels up to 682 U/l for AST and 361 U/l for ALT. An elevation of lactate dehydrogenase (LDH) with levels >225 U/l was detected in 37 patients (31.1%) with a maximum level of 788 U/l. Mostly mild elevated levels of Creactive protein (CRP) were seen in 30 patients (25.2%). Four patients (3.4%) showed levels >50 mg/l with two patients (1.7%) showing levels >100 mg/l. Five patients (4.2%) presented mild impaired kidney function with creatinine levels >1.2 mg/dl. Routine coagulation tests such as prothrombin time, international normalized ratio and activated partial thromboplastin time did not show any abnormalities. The diagnosis of DENV infection was predominantly established by exclusive antibody testing (n Z 59; 49.6%) and combination of antibody and NS1 antigen testing (n Z 46; 38.7%). In 7 cases (5.9%) DENV RNA was detected by realtime RT-PCR.
3.4. Hospitalized patients Ninety nine (83.2%) patients were treated as outpatients, 20 (17.8%) patients were hospitalized. Frequency of clinical symptoms did not differ in outpatients and inpatients except for bleeding manifestations and neurological complications. In the group of inpatients three patients (15.0%) showed bleeding manifestations or neurological complications respectively. Bleeding manifestations remained mild and did not require specific treatment. Neurological complications presented as seizures of altered character in one patient with pre-existing seizure disorder. This patient required adjustment of neuroleptic treatment. The other
Table 3
two patients presented with meningism and dysgeusia without need for further medical procedures. Laboratory parameters differed in inpatients and outpatients with more patients presenting with leukopenia, thrombocytopenia and elevation of AST, ALT and LDH. Furthermore, nine patients (7.6%) showed a decline in their platelet count during the first days of admission with a concurrent rise in haematocrit to levels above baseline and therefore fulfilling criteria of dengue with warning signs. Four of these patients also developed a significant hepatitis with AST/ALT levels above tenfold normal ranges. Overall, clinical course was mostly uncomplicated. No patient fulfilled criteria of severe DF. There were no fatalities in the study group.
4. Discussion The significance of DF seems to be more relevant than ever before. Worldwide, DF is the most common human arboviral infection and it is endemic in more than 100 countries with approximately half of the world’s population living at risk of acquiring DENV infections [6,10]. The World Health Organization (WHO) classified DF as the ‘most important mosquito-borne viral disease in the world’. Caused by rising tourism in DENV endemic regions, DF has become a crucial differential diagnosis for fever in international travellers [2,3]. Clinical-based sentinel surveillance programs recorded a significant increase in reported DF cases [4,5,23]. The recent GeoSentinel analysis showed DF as the second most common cause for febrile disease in all returning travellers. In fact, in patients returning from Asia, the Caribbean or Latin America DF was the most common cause for febrile disease [4]. Furthermore, the re-emergence of autochthonous DF in several European countries and Japan demands profound knowledge of clinical course and diagnostics of dengue infection not only from infectious disease specialists but also from general practitioners [22]. Our study aimed to identify epidemiological and clinical characteristics and laboratory findings of patients with acute DF in a tertiary care centre in Germany. Data of 119 patients could be included into the study representing about 8% of all reported cases of DF in Germany during the study period. DENV infections have been reportable in Germany since 2001. During the study period, 1525 cases of DF were reported [27]. The study cohort consisted of a rather young group with a median age of 35 (IQR 26-46), the male to female ratio was 1.29:1. Only few patients (16%) reported comorbidities.
Laboratory findings of all patients with DF, inpatients with DF and outpatients with DF. All patients (n Z 119)
Leukopenia (<3.8 109/l) Thrombocytopenia (<150 109/l) ALT above normal range (m > 50 U/l; f > 35 U/l) AST above normal range (m > 50 U/l; f > 35 U/l) LDH above normal range (>225 U/l) CRP above normal range (>5 mg/l) Creatinine above normal range (>1.2 mg/dl)
31 39 41 39 37 30 5
Inpatients (n Z 20) 26.1% 32.8% 34.5% 32.8% 31.1% 25.2% 4.2%
11 14 10 13 11 8 0
Outpatients (n Z 99) 55% 70% 50% 65% 55% 40% 0%
20 25 31 26 26 22 5
20.2% 25.3% 31.3% 26.3% 26.3% 22.2% 5.1%
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Clinical features and laboratory findings of dengue Consistent with other European studies on imported DF and German national surveillance data, the majority of cases (54.6%) were acquired in South-East Asia [5,24e26,28]. At least 23 patients were infected In Thailand. In six additional cases, Thailand was one of the potential countries where the infection was contracted. 18.5% and 13.4% of the cases were imported from South Asia and Latin America and the Caribbean respectively. Data are reflecting travel habits of German tourists with Thailand being one of the most popular long distance travel destinations of German travellers with about 550 000 German visitors yearly during the study period [29]. Infection rates themselves might be higher for less popular tourist destinations. India and Indonesia, for example, were determined as country of infection in 16 cases each, both noting considerable lower numbers of German visitors with about 240 000 respectively 150 000 visitors yearly [30,31]. Interestingly, with 11.8% a considerable percentage of patients acquired the infection in Sub-Saharan Africa. A recent study on hospitalized patients in Berlin and a study from Austria showed comparable rates of DF importations [25,32], but most studies on imported DF showed lower rates of imported cases from Africa [4,24,33]. DF might be underdiagnosed in travellers from Africa and should be considered as differential diagnosis in febrile patients, especially if malaria diagnostics turn out negative. As expected, the most frequent clinical symptoms included fever, headache, exanthema, myalgia/arthralgia and fatigue. More surprisingly, a high proportion of patients (42.9%) reported gastrointestinal symptoms mostly diarrhea. A recent study in Czech travellers reported similar figures [24] highlighting a further potential pitfall in DF diagnosis. Five patients reported signs of mucosal bleeding which is classified as a warning sign in the revised DF classification (Box 1) [15]. The patients themselves judged the bleeding signs as mild. On the other hand, thirteen patients (10.9%) presented with neurological symptoms such as seizures and meningism one would be tempted to rate as a potential warning sign. However, lethargy and restlessness are the only neurological symptoms on the list of warning signs. DF can manifest with a wide range of neurological complications such as encephalitis, myositis, myelitis, Guillain-Barre ´ syndrome (GBS) and mononeuropathies. The exact incidence of neurological complications is uncertain, ranging from 0.5% to 21% in different clinical settings [34,35]. Furthermore, former DENV infections are considered to predispose for development of GBS in sequential Flavivirus infections such as Zika virus infections [36]. One out of four patients presented with leukopenia, one third with thrombocytopenia with platelet counts as low as 19 109/l. Also one third of the patients showed elevated liver enzymes and an elevation of LDH. Even though an elevation of CRP was seen in 25.2% of patients, elevation was mostly mild with only four patients showing CRP levels >50 mg/l. Laboratory findings are consistent with published data [37,38]. Especially the normal levels or only mild elevation of the CRP level might be a useful tool in the differentiation between dengue fever versus malaria and enteric fever, since the CRP levels are usually markedly elevated in these two illnesses [37]. Twenty patients (17.8%) were hospitalized due to symptomatic DF. There were no defined criteria for hospital
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Textbox 1. Warning signs in DF according to the 2009 revised WHO dengue case classification [15].
Clinical warning signs
Laboratory warning signs
Abdominal pain or tenderness Persistent vomiting Clinical fluid accumulation Mucosal bleeding Lethargy, restlessness Liver enlargement >2 cm Increase in HCT concurrent with rapid decrease in platelet count
admission. Patients were hospitalized at the clinicians’ discretion. Frequency of clinical symptoms did not differ in outpatients and inpatients except for bleeding manifestations and neurological complications. Three patients (15%) exhibited clinical warning signs, i.e. mucosal bleeding. Inpatients presented significantly more often with laboratory abnormalities. Seventy percent of the hospitalized patients showed low platelets counts at the time of their admission. Additionally, leukopenia and elevation of liver enzymes and LDH were seen in over the half of the patients (Table 3). Laboratory parameters of these patients were closely monitored during the hospital stay. We could demonstrate a further decline of platelet count and concurrent rise of liver enzymes in several patients, which is consistent with data from Japan where the development of thrombocytopenia and increase of liver enzyme levels was shown during the period of defervescence [39]. Furthermore, nine of the twenty hospitalized patients (45%) showed a rapid decrease of platelets and concurrent increase of the haematocrit during the first days after hospital admission. This laboratory constellation is part of the 2009 defined Dengue warning signs (Box 1) [15]. The discrepancy of the high frequency of warning signs and the relatively benign clinical course of DF in inpatients presumably lies in hospitalization itself, allowing close monitoring and adequate fluid resuscitation. Altogether, our data emphasize the need for close monitoring of laboratory findings in addition to the clinical symptoms in the course of DF. Especially patients with primarily mild symptoms treated as outpatients should be informed about potential clinical warning signs as well as the need for close outpatient monitoring during the course of the infection.
5. Conclusion In conclusion, DF presented as a mostly mild to moderate disease in returning travellers at a large German specialized outpatient centre. Outpatient treatment was adequate for the majority of patients. Still, about one-fifth of the patients had to be hospitalized. A profound knowledge of the clinical symptoms and laboratory features is essential for appropriate management of the patients. Close monitoring of clinical symptoms and laboratory
Please cite this article in press as: Tavakolipoor P, et al., Clinical features and laboratory findings of dengue fever in German travellers: A single-centre, retrospective analysis, Travel Medicine and Infectious Disease (2016), http://dx.doi.org/10.1016/j.tmaid.2016.01.007
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6 findings in the course of DF has to be warranted for both outpatients as well as inpatients. The 2009 revised WHO case classification [15] proves to be a helpful tool for patient triage.
Conflicts of interest The authors declare that there are no conflicts of interest.
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Please cite this article in press as: Tavakolipoor P, et al., Clinical features and laboratory findings of dengue fever in German travellers: A single-centre, retrospective analysis, Travel Medicine and Infectious Disease (2016), http://dx.doi.org/10.1016/j.tmaid.2016.01.007
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