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Research needs related to dengue case management in the health system

1 Oct 2007

Source: WHO/TDR


Lucy Lum 1 , Nguyen Thanh Hung 2 , Siripen Kalayanarooj 3 , Eric Martinez 4 , Jeremy Farrar 5 , Eva Harris 6 , Ivo Castelo Branco Coelho 7 , Nidia Rizzo 8 , Martin Weber 9 , Olaf Horstick 10 , Susanne Carai 9

1Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
2Department of Dengue Hemorrhagic Fever, Children's Hospital N1, Ho Chi Minh City, Viet Nam
3Queen Sirikit National Institute of Child Health, Rajavithi Road, Bangkok, Thailand
4Instituto de Medicina Tropical ‘Pedro Kouri’, Autopista Novia del Mediodia, Havana, Cuba
5Centre for Tropical Diseases, University of Oxford, Ho Chi Minh City, Viet Nam
6Division of Infectious Diseases, School of Public Health, University of California, Berkeley, California, USA
7Nùcleo de Medicina Tropical, Universidade Federal do Ceara, Rua Carolina Sucupira, 770/202, Aldeota, Fortaleza, CE, CEP 60140-120, Brazil
8Centers for Disease Control, Regional Office for Central America and Panama, Center for Health Studies, Universidad del Valle, Guatemala City, Guatemala
9Department of Child and Adolescent Health and Development, World Health Organization, Geneva, Switzerland
10UNICEF-UNDP-World Bank-WHO Special Programme for Research and Training in Tropical Diseases, Geneva, Switzerland

Working paper for the Scientific Working Group on Dengue Research, convened by the Special Programme for Research and Training in Tropical Diseases, Geneva, 1–5 October 2006

Full text source: Scientific Working Group, Report on Dengue, 1–5 October 2006, Geneva, Switzerland, Copyright © World Health Organization on behalf of the Special Programme for Research and Training in Tropical Diseases, 2007,


The objectives of this paper are to summarize the current state of dengue management, and to identify areas of clinical management needing further improvement and research, in order to improve the clinical outcome of dengue.

The mechanisms of pathogenesis in severe dengue are complex and remain incompletely understood, but it is clear that the critical abnormality that differentiates severe dengue from its mild form is the presence of increased vascular permeability. This phenomenon begins during the febrile phase, but at a time when the viral load and body temperature are declining. This period, known as defervescence, is defined by an axillary temperature of less than 38 °C, and usually occurs between day 3 and day 5 of fever. An early sign of increased vascular permeability is haemoconcentration but, with continued plasma leakage, pleural effusion, ascites and depletion of the intravascular volume leading to hypovolemic shock become apparent. It is at the time of defervescence that the disease manifests its severity, unlike other viral illnesses for which a clinical improvement is to be expected with a decline in body temperature. Treatment that is focused on the early recognition of plasma leakage and shock, and replacement of intravascular fluids and restoration of haemodynamic stability is associated with a good clinical outcome [25,2]. In contrast, when the early state of shock is not diagnosed and the consequent delay in administration of intravenous fluid therapy leads to prolonged shock, multi-organ dysfunction and significant haemorrhage set in to complicate the clinical picture [4,14]. Thus, in order to reduce mortality and morbidity caused by dengue, the goals of dengue management should be:

  • To recognize dengue infection at an early stage;

  • To detect the early onset of plasma leakage in these patients; and

  • To appropriately manage dehydration and hypovolemia.

Recognizing infection at an early stage

There are no currently accepted guidelines for the recognition of early dengue infection. Kalayanarooj et al. [11] have demonstrated that when children were recruited having had a fever for less than 72 hours, those with dengue infection were more likely to have marked gastrointestinal symptoms of nausea, vomiting and anorexia, a positive tourniquet test and leukopenia than those with non-dengue viral illnesses. Additionally, children with raised levels of liver enzymes were more likely to have severe dengue than those whose levels of liver enzymes were normal at recruitment. The mean age of the children in this study was 6–8 years.

How applicable are these clinical features in distinguishing dengue from non-dengue infection in a wider population including adults, who are increasingly bearing the burden of illness? Current laboratory confirmation of dengue is largely by dengue IgM serology. In most patients with dengue, IgM serology begins to become positive at the time of defervescence, and hence is not helpful in identifying an early infection.

Research priorities:

  • To acquire a better understanding of the clinical and laboratory features of the early stage of infection with dengue in both children and adults.

  • To determine the early indicators of severe disease.

  • To validate the early warning signs and symptoms (for clinician and caregivers).

  • To identify criteria for hospital admission.

  • To identify high-risk populations—infants, patients with obesity, bronchial asthma, underlying diseases, adults with comorbid conditions.

  • To identify early viral markers of dengue infection that can be applied in the field [12].

  • To characterize the spectrum of dengue infections and unusual manifestations, such as myocarditis, encephalitis [15,17,21].

Outpatient management of patients with dengue

Once a clinician suspects or is able to confirm that his patient is infected with dengue, what is the best way to provide the care that will determine a good outcome?

Early dengue

An international study on the economic burden of dengue has shown that about 80% of patients with dengue in Cambodia, Malaysia and Thailand make the first visit to a medical doctor within the first 2 days of fever (LCS Lum, personal communication). This early contact could be provoked by generalized body pains or marked gastrointestinal symptoms that may cause dehydration.

Research questions:

  • To validate the early warning signs and symptoms of severe disease. What is the best system for caring for outpatients with dengue? A patient could be given a follow-up card that has information including the diagnosis of suspected dengue, serial full-blood-count results (to include, at least, haematocrit [erythrocyte volume fraction]) and indicators for admission, at the first medical contact. This card would be shown to the doctor providing the subsequent care, thus providing some degree of continuity. Would this practice reduce the incidence of patients being turned away from admission, resulting in late presentation of shock?

  • Would this follow-up card system result in a more effective triage system at the emergency department?

    Physicians at the emergency department who may not be familiar with the disease presentation might be alerted to the possibility of a severe disease and thus initiate prompt referral and treatment.

    Harris and colleagues [6] have demonstrated that ingestion of fluids such as water, fruit juices and lemonade in the 24 hours before being seen by a clinician is protective against hospitalization. What is the best fluid that could be tolerated by patients with marked gastrointestinal symptoms? A possible candidate is the reduced-osmolarity oral rehydration solution (sodium, 75 mEq/l; chloride, 65 mEq/l; potassium, 20 mEq/l; citrate, 290 mg/l; glucose or rice powder as carbohydrate) recently recommended by WHO and the United Nations Children's Fund (UNICEF) [1]. This formulation has been demonstrated to be associated with an extremely low incidence of symptomatic hyponatremia in patients with dehydrating diarrhoeal diseases, irrespective of their age and the cause of diarrhoea.

  • Would this reduced-osmolarity oral rehydration solution be tolerated by ambulatory or inpatient dengue patients? Would it prevent dehydration and hyponatremia?

  • Would the reduced-osmolarity oral rehydration solution reduce the severity of shock and avoid hyponatremia and metabolic acidosis?

Patients in the critical phase of dengue

Patients with severe dengue do present for the first time in a busy emergency department and are attended by a junior physician who may not be familiar with the disease [20]. In the context of the Integrated Management of Childhood Illness, most countries in south-east Asia have adopted guidelines to recognize severe dengue in first-level health facilities [26].

Patients may be triaged based on certain parameters, such as temperature, heart rate and blood pressure. Patients in whom blood pressure is thought to be normal and the temperature normal or below normal, as would be the case in dengue shock syndrome, would receive the lowest priority in a triage based on presence or absence of fever. Furthermore, in patients in a state of shock, blood pressure measurements using the automated oscillometric method, in which the systolic and diastolic pressures and pulse rate are displayed digitally, have been found to be higher than measurements with the conventional sphygmomanometer. A literature search suggests that this technology has been validated in children and adults with haemodynamic stability [5,16]. There has been no study to compare blood pressure readings taken with the oscillometric method and those taken using the conventional sphygmomanometer in patients in different states of haemodynamic instability.

Research questions:

  • To compare the automated oscillometric blood pressure method with the conventional sphygmomanometer in patients with severe dengue in various states of haemodynamic instability.

  • To compare capillary refill time, quality of pulse, cold extremities and other signs of shock with blood pressure and pulse pressure as early signs of shock, to monitor progress and fluid therapy.

  • What are the clinical features of shock in children and adults?

  • Will early oral fluid therapy while waiting in the outpatient department reduce severity of shock?

  • Will intravenous fluid therapy prevent dengue shock and when should it be started?

  • Will the prescription of 0.9% saline solution at a dose of 5 to 10 ml/kg body weight given intravenously during 1 hour to all patients with a history of more than 3 days of fever and any one of the following signs—repeated vomiting, severe abdominal pain, lethargy (regardless of the intravascular status)—reduce the severity of subsequent shock, i.e. reduce the need for subsequent fluid replacement?

  • How useful is ultrasound examination of the chest and abdominal cavity in detecting subclinical plasma leakage? To validate this against clinical signs of significant plasma leakage. Gall bladder wall-thickening and or fluid peri-gall bladder wall as measured by ultrasound [22–23].

  • Additional laboratory markers, such as cholesterol, albumin, aspartate amino transferase, and alanine aminotransferase, could be useful for differentiating dengue and severe dengue and for guiding management, e.g. where baseline haematocrit [erythrocyte volume fraction] is not known, or cases of bleeding where erythrocyte volume fraction may not be elevated, a low albumin level may alert the physician to possibility of dengue. Would any of the markers apart from haematocrit alert the physician to the possibility of increased capillary permeability and hence prompt the early initiation of fluid therapy?

Treatment of severe dengue that is entirely orientated towards prompt assessment and replacement of fluid needs is live-saving. Comprehensive guidelines for dengue case management published by the WHO Regional Office for South-East Asia have shown that early volume replacement of lost plasma with isotonic salt solution can modify the severity of disease and prevent shock.

Indications for intravenous fluid therapy for dengue haemorrhagic fever grade I and II are developed in Viet Nam for one or more of the following signs/symptoms:

  • Repeated vomiting;

  • Acute, severe abdominal pain; rapid liver enlargement;

  • Haematemesis, melaena, frank gingival bleeding, severe epistaxis;

  • Lethargy;

  • Rapid pulse;

  • High degree of haemoconcentration, rapidly rising haematocrit.

Among thousands of patients treated each year in Viet Nam, around one quarter of the patients with dengue haemorrhagic fever grade I and II need intravenous fluid therapy during 24–48 hours in the critical phase of the illness. Early volume replacement of lost plasma by intravenous fluid therapy in these patients can modify the severity of disease.

Haemorrhagic manifestations in severe dengue are to be expected but are usually minor. Severe and clinically significant haemorrhages are however, unusual, despite the severe thrombocytopenia and prolonged coagulation profile. In severe dengue, significant haemorrhage is a complication of the disease rather than an integral to it and usually accompanies prolonged shock. However, there have been several reports of severe bleeding in patients who did not have or had minimal evidence of plasma leakage [3,7,18–19,24]. The latter phenomenon has a high morbidity and mortality and pathophysiology is still poorly understood.

There are no studies on the management of severe bleeding in severe dengue. The administration of prophylactic transfusions of platelets or blood products is still widely practiced. Although there is evidence that these practices are not useful in the prevention of significant haemorrhage [13], demonstrating their harmfulness to the patient with dengue might further deter the use of prophylactic transfusions of platelets and fresh frozen plasma. How useful is platelet transfusion in a patient with severe dengue and significant haemorrhage?

Research questions:

  • Are platelet transfusions harmful for patients with non-bleeding severe dengue?

  • How useful is platelet transfusion in a patient with severe dengue and significant haemorrhage?

  • What is the optimal method of management of bleeding in a patient with severe dengue—fresh whole blood or packed cells, with or without platelets, etc?

  • How can significant but occult haemorrhage be detected? Is there a formula that suggests that significant haemorrhage has occurred?

  • Is hormonal therapy useful in reducing the severity of per-vaginal bleeding in menstruating patients with dengue?

  • To identify the cause of death in dengue—e.g. delayed recognition of dengue, fluid overload.

Severe dengue in adults

Previously an almost exclusively childhood disease, severe dengue is now increasingly being observed in adults, especially young adults, in countries with intermediate economies, such as Malaysia, Singapore and some parts of Thailand. While childhood dengue is well described, severe dengue in adults is a relatively unexplored area, and nowhere is the challenge greater for physicians than in adults during pregnancy or with comorbid conditions such as diabetes mellitus, hypertension, and asthma.

Training in case management of dengue and severe dengue

Successful management of severe dengue demands the highest clinical acumen from the physician. Reorganizing the delivery of care to patients with dengue may enhance the acquisition of knowledge and skills. Teams dedicated to the case management of dengue have been successfully formed in countries such as Thailand [9], Viet Nam and, more recently, Malaysia. If reorganizing delivery of care to patients can have a positive impact on the outcome (e.g. reducing length of stay, reducing use of blood products, more uniform care, economic burden, morbidity and mortality), perhaps hospital management will be motivated to support the establishment of such a team.

Dr Suchitra Nimmannitya and Dr Siripen Kalayanarooj (Queen Sirikit National Institute of Child Health, Children's Hospital, Department of Medical Services, Ministry of Public Health, Bangkok, Thailand) have conducted an effective training programme on case management for medical staff in Thailand and other countries for many years.

In Viet Nam; the National Control Program for dengue has developed and organized a training programme on the standard case management of dengue and severe dengue for medical staff, including physicians, nurses, medical students, and health workers at all levels of the health-care system. The programme also focuses on health education on dengue for mothers/caregivers. Training of trainers has been organized and on-site intervention teams have been set up in provincial and referral hospitals. A dengue-management team has been set up in each hospital. Staff of the teams can consult together regarding the management of severe cases. They can also discuss directly with experienced teams in regional and central hospitals via a hotline connecting all health-care facilities by telephone, fax and e-mail, which has been set up in order to exchange information and experience on the case management of severe dengue. These measures have a good impact on reducing the fatality of severe dengue in southern Viet Nam [8] Such programmes should be extended to countries where case fatality for severe dengue is high.

Evaluation of impact of training (translational research)

Evaluating the impact of training will require research into cost-effectiveness, better-trained nurses, capacity building, how best to deliver health care via the system, organization of health care, implementation research in the context of a health-care system. How can the medical knowledge acquired in Malaysia, Nicaragua, Thailand, and Viet Nam be transferred to other countries with less experience in dengue management?


In summary, research priorities in clinical dengue research include studies on optimization of clinical management in the outpatient system, clinical and laboratory indicators of early dengue infection, plasma leakage and shock, as well as a safe method of managing severe bleeding, dengue in pregnancy and patients with comorbidity. The impact of existing and future training programmes should be evaluated.

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