Article: Dr. Wiemer

Dengue Fever: Clinic, Epidemiology and Prevention

Endemic Areas and Infections of Travellers according to GeoSentinel

1. Clinic, Epidemiology and Prevention

Endemic Areas and Infections of Travellers according to GeoSentinel

Globally, an estimated 50 million people become infected with dengue virus in approximately 100 countries. The reason for this is the increasing spread of vectors, above all Aedes albopictus, in the tropics and subtropics, as well as in the Mediterranean area today. 1

The proportional morbidity of dengue fever among all returning travellers is between 1.4%2 and 3.3%3. In the last 10 years this has significantly increased among returning travellers with fever from 1% 3 to 16% 4.

The incidence of dengue virus infections among travellers returning from endemic areas ranges from 10.2 to 30 per 1,000 people, depending on the destination and duration of travel. (5)

The surveillance networks TropNet and Geosentinel have also observed with relative consistency over the last 20 years that most of the dengue infections are imported from Southeast Asia. (Table 2: Proportion of dengue virus infections between 1999 and 2014 according to regions )

Today, therefore, dengue virus infections among travellers returning from Southeast Asia and the Pacific region who have fever represent the most important differential diagnosis, while malaria now plays a very subordinate role in the meantime.

Clinical Picture and Complications

A dengue virus infection can cause mild influenza-like symptoms or lead to serious complications such as haemorrhages or a severe shock syndrome. Everyday clinical practice shows that all syndromes flow seamlessly into one another and the severity cannot always be clearly defined on the basis of the case definitions. 

In the resource-poor regions of the world it is often only possible to arrive at a diagnosis on the basis of the clinical picture. How difficult it can be here to determine the correct points of focus is reflected by the multiple adjustments made to the case definitions of the WHO since 1975 (Table 3: Overview of WHO case definitions). The new classification of 2009 now appears to be able to determine the severity of the disease with a high level of sensitivity in the clinical setting of the highly endemic areas. 6. Nevertheless, the latest version from 2009 has also received some criticism. One criticism was that the distinction into only two categories was imprecise and prone to errors due to the selected parameters.7Furthermore, the usefulness with respect to specificity and sensitivity outside of highly endemic areas was considered to be low 3. 

One condition continues to remain associated with the diagnosis of a dengue virus infection, i.e. appropriate exposure, as a traveller, an inhabitant of an endemic area or a current outbreak. 

As a rule, a dengue virus infection is accompanied by fever and associated general symptoms, with an unmistakable feeling of being ill, headaches and aching limbs, as well as fatigue. The result of the tourniquet test is positive.[1]

Whether there are actually asymptomatic courses of the disease is unclear, since simple serological antibody detection is non-specific due to cross-reactivity with other flaviviruses. 1

The incubation period is approximately 4 – 10 days; as in the case of many viral diseases, the course consists of three phases. ("All infectious diseases are kinetic, consisting of the invasion of the microorganism (afferent phase) followed by the host response (efferent phase), including disease and elimination of the organism.8

In the first phase, which can last between 2 and 7 days, the patient has an unmistakable feeling of being ill, fever up to 40°C and severe headaches and muscle and joint pain. A maculopapular skin rash, mild signs of bleeding (petechiae, bleeding from points where the skin has been punctured) and vomiting may also occur. Clinical laboratory tests reveal mild leucopenia and thrombopenia and moderately elevated transaminases. After this phase, a large portion of the patients recover. 

In the second phase, children and young adults in particular may develop dengue shock syndrome, which has recently also being called "dengue vascular permeability syndrome" (DVPS) by 8. As a result, the main focus is on the pathomechanism of the progressive loss of fluid in the so-called "third space". It has also been ascertained by 9 that capillary leak syndrome represents the greatest danger to the patient. Haemorrhaging is a secondary aspect of this phenomenon, although as a rule there is no actual tendency to bleeding as a result of a change to coagulation associated with the dengue virus infection.10

DVPS occurs suddenly and is identified by the increase in haematocrit, hypoproteinaemia and the occurrence of pleural effusions or ascites. If a manifest shock with hypotension develops without appropriate therapy, this can result in organ failure and death. When bleeding occurs, this is predominantly from the mucous membranes or into the skin in adults1. Significant gastrointestinal haemorrhaging is frequently the result of pre-existing ulcers or gastritis. In children, bleeding has mostly been seen only as a consequence of inappropriate, delayed or the failure to initiate shock therapy.7 Encephalopathies and – in very rare cases – myocarditis and hepatitis without the presence of a capillary leak have also been observed. The leak closes itself within 24 – 36 h. 8

The third phase comprises convalescence, which can certainly take a considerable time, and during which bradycardia, ventricular extrasystoles and itching are frequently observed. 

Epidemiological data on dengue virus infection, as well as information on the clinical course and potential complications, is based on the data from the surveillance systems of the countries in which this disease occurs. In the Southeast Asian states such as Thailand, Cambodia or Vietnam, it can be assumed that not all cases are recorded and that there is a certain observation bias, as the reporting systems in Thailand, for example, only record hospitalised or confirmed cases, or in Cambodia only cases involving children under the age of 15 11. It appears that in these countries the dengue virus infection is a "childhood disease" in which most cases occur in the age group between 5 and 24 years 12. It follows from this that most of the data on the course of the disease stem from the observation of children 7. 

Travellers appear to have a range of symptoms with a different point of focus, i.e. predominantly fever (86%-100%), muscle pain (42.2%-79%), headaches (59.2%-68%) and skin rash (29.2%-74%), accompanied by significant thrombopenia (< 100000/mm3 52.6%–72%), leukopenia (80%-89.5%) and elevated liver values (ALT, 47%-70%). On the other hand, nausea, vomiting, abdominal pain and diarrhoea tend to be uncommon 5 13. 

Initial and Subsequent Infections and their Influence on Suitability for Tropical Deployments

Approximately 6% of all symptomatic dengue virus infections in the endemic areas are said to lead to complications 14. Which factors contribute to the fact that patients develop DVPS is the subject of intensive research. The associated investigations are mainly based on the observation of children with a second infection and infants of mothers with dengue antibodies in the highly endemic areas. The hospitalisation rate due to DVPS in the case of second infections was low in studies from the 1960s15–18 (2-4%).

One of the most popular hypotheses concerning the development of DVPS in the case of a second infection is so-called "antibody enhancement". The weakly neutralising antibodies formed during the first infection bind to the virus with the new serotype and thereby enable the infection of cells which bear the FcyR receptor, such as monocytes and macrophages, resulting in a significant increase in the replication rate of the virus. In turn, however, it has not yet been determined how this phenomenon leads to the occurrence of DVPS.

It has recently been possible to show experimentally that the non-structural protein of the dengue virus (NS1) is a Toll-like receptor 4 antagonist and therefore triggers the secretion of cytokines which lead to the secondary capillary leak. It was also found that NS1 directly damages the endothelial cells. It is assumed that "antibody enhancement" (see above) also stimulates the production of NS1 and in this way results in DVPS 8. 

These hypotheses are the subject of controversial discussions 19 although other factors such as age, genetic factors, the virus subtype 20, immune status and diet appear to play a role (summary in 21

Due to the heterogeneity of the possible risk factors for a complicated course of the disease (see above), there is as yet no agreement on which factors represent a danger to travellers. 5

There are individual case reports of fatal outcomes among returning travellers 22. Complication rates are stated as being between 0.9% and 3% 5. The cause of this is not least the use of different case definitions (see above).

In a small study, DVPS was seen in equal proportions in first and second infections23 and among healthy individuals who had been infected experimentally with dengue virus 24

The results in a retrospective study of 219 travellers with dengue virus infection were similarly ambiguous. On the one hand, the presence of antibodies after an initial infection was significantly associated with spontaneous bleeding and a serious clinical course; on the other hand, 50% of the patients with these symptoms had an initial infection25.

From this it follows that no recommendations have so far been issued by professional associations specialising in tropical medicine or specialists in occupational medicine on restricting further journeys to dengue virus epidemic areas for individuals who have already been infected with the dengue virus. 

[1] Tourniquet test (Rumpel-Leede test): A blood pressure cuff is placed around the patient's upper arm and inflated to a pressure between the diastolic and systolic pressure (90 mm Hg). The test is positive if more than 10 petechiae are detectable after 10 min. 

Dr. Wiemer

Date: 11/07/2017