Question 7. PHYSIOPATHOLOGICAL MECHANISMS OF SEVERE FORMS OF DENGUE

1Can research into the physiopathological mechanisms of the severe forms of dengue improve management of the disease?

2Michel Strobel and André Cabié addresses this question in the article La recherche sur les mécanismes physiopathologiques des formes sévères de la dengue peut-elle améliorer la prise en charge de la maladie?

3The clinical expression of dengue fever is acute, polymorphic and nonspecific. The symptoms (fever, aches, prostration) are disruptive, but in about 99 % of cases perfectly benign.

4However, in some cases the disease develops into a severe form, which may or may not be hemorrhagic but which is fatal in a high proportion of cases. Severe forms have made their appearance during epidemics in the FDAs in recent years.

5Until now, no-one has identified factors for assessing the risk of an “ordinary” dengue case developing into a severe form, or predicting the frequency and lethality of severe dengue cases during an epidemic.

6So far, no drug to stop the progress of the illness and no satisfactory presumptive signs have been identified. Only by observing the clinical picture with great vigilance from the onset of fever can one be ready to treat the symptoms of the severe form as soon as they appear.

7The benign nature of the initial symptoms can militate against early action and attentiveness: patients may not consult a doctor or may opt for self-medication; if they consult, they may not keep as close a watch on their symptoms as the doctor advises.

8As regards the possibilities for managing the severe forms of the disease, there are four preliminary questions to consider:

• What are the clinical manifestations of dengue, its variants and their specific features?
• What are the severe forms of the illness?
• How can they be recognized and predicted?
• What medical management do they receive at present in the FDAs?

Clinical manifestations of dengue, variants and specific features

9From the clinical manifestations, several forms of dengue can be distinguished:

10Brief, undifferentiated fever lasting one to four days with no other symptoms. This seems to be common in children. This form is of low specificity and is rarely diagnosed except during epidemics, for example when there are several cases in the same family. This results in considerable underestimation of the number of dengue cases.

11Common or classic dengue lasts seven days, with high fever, severe headache, backache and joint pains, extreme asthenia or prostration, and skin rashes in 30 to 50 % of cases.

12Common dengue with very minor, local hemorrhaging is still a benign form, but difficult to distinguish from a stage in the evolution to hemorrhagic dengue.

13Dengue hemorrhagic fever (DHF) as defined by the WHO: extensive, abundant hemorrhaging, particular of the digestive tract though any part of the body may be concerned. A biological indication of this form is that the upward curve of the platelet count intersects with the downward hematocrit curve. Mortality rates vary between 1 % and 10 %.

14Dengue shock syndrome (DSS), with or without bleeding, is also strictly defined by the WHO. It is more severe, with 10 % to 40 % mortality in adults.

15Various severe forms of dengue that do not meet WHO criteria for DHF or DSS. Information is lacking, but cases are reported increasingly often, in the FDAs and elsewhere. They include severe thrombopenia, agranulocytosis, encephalitis, severe or even fulminating hepatitis, myocardia and burst spleen.

Definition of severe forms of dengue

16These include DHF and DSS (the only forms recognized by the WHO), and other non-hemorrhagic but potentially lethal forms. Because these other forms are not classed as notifiable diseases, their incidence is not known, and they may be as frequent as DHF. They account for a certain number of deaths, mainly adult deaths, that are not included in the figures for deaths from DHF and DSS.

Recognition and prediction of severe forms

17The severe forms are not easy to recognize; the criteria are essentially clinical symptoms. In the first stages there is nothing to distinguish the severe forms from common dengue. Symptoms worsen suddenly between the third and fifth days of illness. Simple but non-specific biological indicators can help: full blood count, platelet count, hematocrit, protidemia, transaminase, CPK, creatinine.

18It is even harder to predict the degree of severity in a patient: there are no satisfactory clinical criteria and few validated biological criteria. Individual factors such as age, family antecedents, genetic factors, etc., should be considered. Factors frequently put forward to explain severity are earlier contact with the virus and the virulence of the strain. Doctors need to know whether a patient has suffered an earlier attack, in which case particular care must be taken.

19At the community level, for a given geographical area, experience shows that although the magnitude of an epidemic can be fairly reliably predicted from the local history of epidemics, it is hazardous to predict clinical severity, morbidity or mortality rates. The severity of an epidemic does not depend entirely on the sequence of earlier epidemics.

20For example, Martinique and Guadeloupe were hit by an outbreak of DEN3 in 2000-2001. This serotype had not been in circulation in the region for twenty years. One might suppose that resistance was therefore very low and that a widespread epidemic was to be expected. As was indeed the case. On the other hand, since serotypes 1, 2 and 4 had all caused epidemics during the 1990s, the preconditions for a major incidence of DHF seemed to be present. But there was no major incidence of DHF. So a sequence of heterologous infections does not seem to be a sufficient condition for severe forms to occur. Other factors must be involved, such as the virulence of the strain and vector competence.

Treatment and medical management

21Ambulatory treatment is sufficient for common dengue. However, symptoms should be monitored; this is essential from day three to day six, the period when development to a severe form may occur.

22Cases with signs of a severe form must be hospitalized immediately. Suspicion of severe dengue must be clearly stated without fear of exaggeration, because in hospital the case must be monitored in a ward near an intensive care unit.

23Applying the criteria for hospitalization is a matter of medical judgement; this again points up the need to raise doctors' awareness.

24In the absence of any specific treatment for dengue, paracetamol and abundant oral rehydration are recommended for the classic form. Aspirin is counter-indicated because of the risk of hemorrhage.

25DHF and DSS require treatment of symptoms in an emergency ward for shock (re-establishing hemodynamic equilibrium) and for impairment of hepatic, cardiac or cerebral functions etc.

26Treatment of these severe forms is directly based on recently-acquired knowledge of the physiopathological mechanisms of shock and hemorrhage, and has already helped to reduce the number of deaths from dengue.

27This is significant progress, and implies that research into the physiopathological mechanisms of severe forms of dengue should be continued.

28The recurrent nature of dengue epidemics, increasing incidence of atypical cases of severe dengue, the difficulty of diagnosing the disease, the virtual impossibility so far of predicting the development of benign dengue into a severe form, and the continuing absence of a specific medical treatment – all these factors argue for intensifying the drive to educate the population about dengue, its prevention, and what to do in the event of fever, especially during dengue epidemics.

29For the same reasons, doctors in private practice could usefully be offered annual training sessions on the medical management of dengue. Hospital doctors, especially in emergency wards, should have suitable training in diagnosis and medical management of the ordinary and severe forms of dengue. And it seems essential that all those working in dengue prevention and control in the FDAs should receive effective help and supervision for epidemiological assessment.