The Clinical Epidemiology of Hospitalized Dengue Cases in Malaysia
The Clinical Epidemiology of Hospitalized Dengue Cases in Malaysia
Dengue infection has been identified as the fastest spreading mosquito-borne viral disease by
 World Health Organization (WHO), which affects more than 2.5 billion people living in the
 subtropical and tropical regions. Malaysia is hyper-endemic with all four dengue virus
 serotypes circulating and responsible for the escalating number of cases over the years. As
 of 28 February 2015, there are 62 deaths secondary to dengue infection being reported in
 Malaysia; and the total number of dengue cases reported in the same period was 23,966 which
 is 46% higher than the same reporting period of 2014. Although dengue virus has been
 identified for so many years and plenty of research work has been carried out, it was proven
 that there are still many aspects that we are not too sure about the disease. Therefore, this
 multi-center, observational cohort study is designed to investigate the clinical course of
 hospitalized dengue infection in Malaysia. The study population of this study consists of
 male or female patients with dengue to be randomly sampled from hospitals in Malaysia. This
 study will be conducted in 2 stages whereby the 1st stage will only focus on the basic social
 and clinical data to describe the clinical course of dengue as general and the 2nd stage will
 collect the more detailed clinical and management data to describe the detailed clinical
 course, management and prognosis of dengue. All hospital participation in this study is
 voluntary, and approval will be obtained from National Institute of Health (NIH) and Medical
 Research Ethics Committee (MREC) prior to any recruitment.
Dengue infection have resurged and disseminated globally since late 1970s after successful
 eradication programs of the dengue vector Aedes mosquitoes in Latin America in the 1940s. It
 has been identified as the fastest spreading mosquito-borne viral disease by World Health
 Organization (WHO), which affects more than 2.5 billion people living in the subtropical and
 tropical regions. Approximately 75% of the current global dengue disease burden comes from
 the population residing at Southeast Asia and Western Pacific regions, which subsequently
 lead to the formation of the Asia Pacific Dengue Strategic Plan (2008-2015) and the recent
 Global Strategy for Prevention and Control (2012-2020) to reduce the dengue burden.

 Malaysia is hyper-endemic with all four dengue virus serotypes circulating and responsible
 for the escalating number of cases over the years. The number of reported dengue cases in
 Malaysia has increased fourfold from 44.3 per 100,000 population in 1999 to 181 per 100,000
 in 2007; with increased in dengue deaths in the adult populations since 2002. Worst still, as
 of 28 February 2015, there are 62 deaths secondary to dengue infection being reported in
 Malaysia; and the total number of dengue cases reported in the same period was 23,966 which
 is 46% higher than the same reporting period of 2014.

 The WHO has revised the dengue classification in 2009, which were shown to be more sensitive
 than the WHO 1997 classification system in predicting severity of dengue. According to this
 WHO 2009 classification, dengue infection is now categorized into dengue, dengue with warning
 signs, and severe dengue. The proposed warning signs include abdominal pain or tenderness,
 persistent vomiting, clinical fluid accumulation, mucosal bleed, lethargy or restlessness,
 liver enlargement > 2cm, increase in hematocrit concurrent with rapid decrease in platelet
 count. Severe dengue is then defined as dengue infection with severe plasma leakage with
 shock, severe bleeding or severe organ involvement.

 Although a large number of patients may recover from this self-limiting disease, a small
 proportion may progress to develop severe dengue manifestations, which requires admission to
 intensive care unit (ICU) for closer monitoring and intervention. However, the progression to
 severe clinical manifestations is usually unpredictable. Early identification of signs that
 can predict severe dengue may save lives by facilitating early initiation of interventions
 and frequent monitoring. Dengue epidemics in Malaysia lead to a strong demand for hospital
 beds and manpower, and inflicting large public and private hospitalization costs. Hence, it
 is crucial to determine a predictive tools which can help to triage patients into those that
 are least and most likely to develop complications in order for a better allocation of
 limited healthcare resources.

 A few studies have been done to validate the utility of the proposed warning signs by WHO
 2009 dengue classification, but the results vary and none of these studies are conducted in
 our local setting. Although dengue virus has been identified for so many years and plenty of
 research work has been carried out, it was proven that there are still many aspects that we
 are not too sure about the disease. It got more confused with the sudden surge of dengue
 cases and dengue mortality cases since last year. Therefore, this study aims to look into the
 clinical course of the hospitalized dengue cases in Malaysia. It will then allow us to zoom
 in to the specific area for more future research work.

 General Objective:

 To study the clinical course of hospitalized dengue cases in Malaysia in from year 2009 till
 2015.

 Specific Objectives are to:

 1. Describe the characteristics of patients hospitalized for dengue

 2. Describe the clinical presentation of patients hospitalized for dengue

 3. Verify the diagnosis of reported dengue cases

 4. Describe the spectrum of disease severity among patients hospitalized for dengue

 5. Describe the management of patients hospitalized for dengue including ICU care

 6. Describe the prognosis of patients hospitalized for dengue

 7. Estimate the resource utilization and cost of care of patients hospitalized for dengue

 8. Estimate the mortality outcome of patients hospitalized for dengue

 This will be a multi-center, observational cohort study designed to investigate the clinical
 course of patients hospitalized for dengue infection in Malaysia. This study will be
 conducted in 2 stages for the duration of 6 months. Data will be retrieved retrospectively in
 both stages.

 In Stage 1, a sample of dengue cases who visited general practitioner or who were
 hospitalized in from year 2009 until 2015 will be sampled using PIK and Health insurance
 claims database as sampling frame. Each hospital will be given a list of the dengue cases and
 the local coordinator from respective hospital Clinical Research Centre (CRC) will trace the
 medical records of all these dengue cases. Once the case notes of all the dengue cases are
 traced, two trained research assistants will travel to the hospital to extract the basic
 clinical data on social demographics, presentation and discharge status by using case report
 form A. All the data collected in phase 1 will be categorized as basic clinical set.

 In Stage 2, a subset of the basic clinical set will be sampled conveniently. Only the cases
 that were tested positive by dengue non-structural protein 1 (NS1), immunoglobulin-M (IgM) or
 high-titre immunoglobulin-G (IgG) will be included in the Stage 2 study. A more detailed
 clinical subset data will be collected by research assistants at site. All co-morbidity,
 serial clinical and laboratory data, in-hospital course and treatment data and Intensive Care
 Unit (ICU) admission data will be extracted from medical records with case report form B. All
 variables/data in the case report form is defined in Appendix I. All data collected in Stage
 1 and 2 will then be compiled and analyzed with software Stata Version 10.0.

 WHO 2009 classification will be adopted in this study. According to the WHO 2009 criteria,
 probable dengue is defined as fever and two of the following: nausea or vomiting, rash, aches
 and pain, leucopenia, and any warning signs. Warning signs are abdominal pain or tenderness,
 persistent vomiting, clinical fluid accumulation, mucosal bleed, lethargy or restlessness,
 hepatomegaly and hematocrit changes ≥20% concurrent with platelet <50,000 on the same day.
 Severe dengue is present if any of the following criteria fulfilled:

 I) Plasma leakage evidenced by hematocrit change of ≥20%, pleural effusion or ascites, or
 hypoproteinemia, leading to:

 -  Dengue shock syndrome (tachycardia, cold and clammy extremities, capillary refill time
 greater than 3 seconds, weak or undetectable pulse, narrow pulse pressure ≤20 mmHg, or
 systolic blood pressure <90 millimetre mercury (mmHg) or unrecordable blood pressure);
 or

 -  Fluid accumulation with respiratory distress (respiratory rate ≥30/minute, oxygen
 saturation ≤92% on room air, or mechanical ventilation) II) Severe bleeding manifesting
 as gastrointestinal bleeding or menorrhagia, or requirement for transfusion of packed
 red blood cells or whole blood.

 III) Severe organ involvement as follows:

 -  Serum alanine or aspartate transaminase ≥1000 units/L;

 -  Impaired consciousness;

 -  Acute renal impairment defined as serum creatinine > two times upper limit of normal;

 -  Myocarditis or encephalopathy/encephalitis
Inclusion Criteria:

 -  Stage 1:

 -  Discharge diagnosis with International Classification of Disease (ICD) code A90 -
 A99

 -  Availability of minimal dataset (name, IC, age, sex, diagnosis, date admit, date
 discharge, discharge status)

 -  Stage 2:

 -  Laboratory confirmed dengue (Non-structural 1 antigen, dengue IgM, high-titre
 dengue IgG, and dengue polymerase chain reaction (PCR) positive)

 Exclusion Criteria:

 -  Nil