Introduction

Dengue infection is caused by one of four dengue virus serotypes and transmitted by the Aedes mosquito. Over 2.5 billion people in tropical and subtropical regions worldwide are at risk of the disease. With no effective vaccine or antiviral treatment, close observation and judicious fluid therapy remain crucial [1]. The fatality rate due to dengue shock syndrome (DSS), the most severe form of dengue disease may be reduced to as low as <0.2% with careful management [2]. Understanding the risk factors for progression to severe dengue and death is essential in determining triage and management algorithms.

Risk factors for fatality in patients with dengue infection have been identified in studies in the Americas [3-8], Africa [9], Australia [10], Pacific islands [11], South Asia [12,13] and Southeast Asia [14-17]. In addition to endemic countries, fatal imported cases have been reported in Norway and Germany [18,19]. Significant risk factors associated with fatality reported were hematemesis and melena [3], tachycardia on admission [20], profound thrombocytopenia and leucocytosis [15]. Juneja et al reported that APACHE II may predict higher risk for death among dengue patients admitted to intensive care unit (ICU)[12]. In Cuba, dengue hemorrhagic fever (DHF) and DSS fatality and hospitalization rates were the highest among young infants and the elderly[6].

Singapore is hyperendemic for dengue , with all four serotypes circulating [21]. Deaths from dengue have required government notification since 1977 [20,22,23]. The case fatality rate of dengue in Singapore is among the lowest in the world. We previously reported the findings from our multi-center adult dengue death cohort study across the years 2004-2008 in Singapore in which dengue infection was confirmed by the presence of dengue virus RNA by polymerase chain reaction (PCR) or non-structural protein 1 (NS1) antigen in serum [24]. Our dengue death cohort revealed fatality occurred most commonly among older patients with co-morbidities.

This case-control study was intended to: (1) compare demographic, clinical and laboratory features of fatal and non-fatal adult dengue patients, (2) compare warning signs and dengue severity classifications among fatal and non-fatal dengue patients, and (3) identify predictors of dengue fatality on hospital admission.

Methods

Results

Discussion and Conclusion

Our previous series of fatal cases reported shock as the commonest cause of death followed by organ impairment (71.4% with acute renal impairment, 57.1% with impaired consciousness and 53.6% with severe hepatitis) [24]. A case-control study from Singapore reported tachycardia on admission as independently associated with death [20]. Another case-control study from Brazil reported patients with hypotension and shock to be at greater risk of progression to death (p<0.05) [8]. A Puerto Rican case series suggested that presentation with shock should alert doctors of the risk of severe dengue [5]. In our study, fatal cases had a significantly higher pulse rate on admission to hospital compared with controls. High hematocrit was reported as an independent predictor of fatality in a study from Brazil [31]. This was not the case in our study as we found similar hematocrit levels between cases and controls.

We performed a multivariate analysis by including symptoms, signs and laboratory parameters on admission which were significant in univariate analysis. We found that a unit increase in leucocyte count led to a significantly higher risk of fatality (adjusted odds ratio 2.94). Leucocytosis was identified as a warning sign of severe dengue in a study from Taiwan [15].Studies from India and Taiwan reported that this phenomenon may be associated with secondary bacterial infection [15,32]. However, only 4 (14.3%) of fatal cases had documented bacteremia in our study. Myalgia is known to be associated with dengue fever, however, its significance in disease severity is not well established. Lee et al from Taiwan reported in 2012 that although fatal cases had myalgia more frequently, statistical significance was not reached[15]. A study on 31 adult dengue patients with muscle involvement showed muscle dysfunction in dengue is benign, transient and self-limiting [33]. In our study, significantly fewer fatal cases had muscle pain, thus its presence is unlikely to be a risk factor for fatality. Less seriously ill patients who complained of myalgia might have been admitted to the hospital and contributed to lower odds towards fatality. This highlights the importance of objective clinical examinations and laboratory investigations in assessing and predicting disease severity.

Interestingly, patients who fulfilled criteria for critical illness with a PBS >4 points on hospital admission were found to be significantly associated with fatality in univariate analysis in our cohort. This score based on mental status, vital signs, requirement for mechanical ventilation, and recent cardiac arrest was initially derived to assess the severity of acute illness at the time of positive blood culture [28]. The score has shown to be useful in predicting fatality in septic shock. Its correlation with APACHE II score has been established [34] which was shown to predict death in dengue cases admitted to ICU in a study from India [12].

A study from Mexico using national surveillance data reported risk factors associated with fatality were hematemesis (relative risk [RR] 2.6) and melena (RR 2.2) [3]. Another study from Brazil reported gastrointestinal bleeding was associated with higher risk of death [8]. In our study, fatal cases had similar hemorrhagic manifestations as controls.

Our study on adult fatal dengue identified by multi-organ impairment as an important cause [24]. This is consistent with a report by Simmons et al [1]. However in our current case-control study, aspartate transaminase (AST) and alanine transaminase (ALT) were not useful in predicting fatal outcomes. This reflects the inability of AST and ALT to discriminate DHF or severe dengue cases reported in a retrospective study from Singapore [35]. Serum bilirubin levels of fatal cases were significantly higher in cases highlighting a need for further research on liver involvement in dengue fatality. Fatal cases had elevated levels of serum urea and creatinine at presentation similar to the reports from Taiwan but they were not independently associated with fatality [36,37].

In our study, severe dengue as defined in WHO 2009 criteria at hospital presentation was found to be associated with eventual fatality. Although cases had a higher proportion of DHF and DSS at presentation, it could not differentiate progression to death from controls. This supported previous reports on the lack of sensitivity of the WHO 1997 dengue severity criteria in adequately differentiating clinically severe from non-severe cases [5,20]. Interestingly, we observed a higher proportion of patients with warning signs at presentation in cases versus controls, but the presence of warning signs was not discriminatory.

One of the strengths of our study was that all dengue infections were confirmed by PCR or NS1. In contrast, previous reports on fatal dengue often relied on serology only. Most of these studies did not focus on fatality among adults or were limited to specific time periods. Our data came from five major public hospitals in Singapore across the years 2004 to 2008. In the years 2004-2008, 42,653 dengue cases were reported from Singapore [38]. In our cohort, the highest numbers of fatalities were nine and eight in the year 2005 and 2007 respectively, when Singapore had large dengue outbreaks. The predominant strains were serotype 1 in 2005 and serotype 2 in 2007 [39]. Our study lacks data on primary or secondary infection status. There was no serotype data for individual patients. None of the cases had autopsies performed. Finally, this study does not attempt to compare dengue management protocols at the different hospitals. Our relatively small number of fatal cases also limited the implementation of multivariate modelling to include more covariates that are statistically significant in the univariate analysis. However, our findings based on readily available clinical parameters could be useful in guiding clinicians in dengue case management.

In conclusion, the case fatality rate of dengue in Singapore is low. Fatal cases were significantly associated with existence of medical co-morbidities. Presentation with severe dengue as defined by the 2009 WHO guideline showed association with fatality, but not presentation with DHF/DSS. Absence of myalgia and leucocytosis at presentation to hospital were independently associated with fatality in our study.

Supporting Information

Acknowledgments

Authors thanks Dr Vernon Lee and Dr Hao Ying for invaluable advice in study design and statistical methods respectively.