Communities of practice
Research needs related to dengue case management in the health system
1 Oct 2007
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
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, http://www.who.int/tdr/publications/publications/swg_dengue_2.htm
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:
Recognizing infection at an early stage
There are no currently accepted guidelines for the recognition of early dengue infection. Kalayanarooj et al.  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.
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?
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.
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 . 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 .
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.
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:
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 , 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?
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 , 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  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.
5. Gurdial SM, Balraj SH, James MW, Comparison of the automated non-invasive oscillometric blood pressure monitor (BpTRU) with the auscultatory mercury sphygmomanometer in a paediatric population. Blood Press Monit 9: 39-45.
12. Libraty DH, etal High circulating levels of dengue virus non-structural protein NSI early in dengue illness correlate with the development of dengue hemorrhagic fever. J Infect Dis 186: 1165-1168.
26. WHO, Department of Child and Adolescent Health and Development, (2005) Dengue, dengue hemorrhagic fever and dengue shock syndrome in the context of the Integrated Management of Childhood Illness Geneva:World Health Organization .
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