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Table of Contents
RESEARCH ARTICLE
Year : 2021  |  Volume : 58  |  Issue : 4  |  Page : 329-334

Predictors of severe dengue amongst children as per the revised WHO classification


Department of Pediatrics, ABVIMS and Dr. RML Hospital, Delhi, India

Date of Submission12-May-2020
Date of Acceptance08-Oct-2021
Date of Web Publication25-Mar-2022

Correspondence Address:
Dr. Devki Nandan
Division of Pediatric Pulmonology and Intensive Care, ABVIMS & Dr. Ram Manohar Lohia Hospital, Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-9062.318312

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  Abstract 

Background & objectives: World Health Organization (WHO) revised its guidelines for classification and management of dengue in 2009. This revised system was found out to have good sensitivity and negative predictive value but poor specificity as well as positive predictive value.
Methods: This retrospective study was carried out in a tertiary care hospital of Delhi, India to assess factors predicting the occurrence of severe dengue in children as per the revised classification. A total of 647 suspected dengue cases were admitted in the hospital in the year 2015. Detailed clinical and epidemiological data of 170 patients who were confirmed as dengue either by NS1 antigen test or by serology (Ig M positive) were recorded and statistically analyzed. Results: The number of laboratory-confirmed cases was 170 and included thirty (17.65%) dengue fever (DF), 106 (62.35%) dengue with warning signs (DWS) and 34 (20.0%) severe dengue (SD) patients. Regression analysis revealed that presence of vomiting, altered sensorium, shock, peri-orbital edema, hepatomegaly, splenomegaly, severe anemia, thrombocytopenia, elevated urea and creatinine, decreased total protein and globulin were significantly associated with occurrence of severe disease.
Interpretation & conclusion: The addition of clinical features (peri-orbital edema and splenomegaly); and laboratory findings (elevated urea and creatinine, decreased serum protein and globulin) might help improve the sensitivity and specificity of the revised WHO dengue classification in predicting severe dengue.

Keywords: Children; Dengue; Predictors; Severe; WHO 2009


How to cite this article:
Arora SK, Nandan D, Sharma A, Benerjee P, Singh DP. Predictors of severe dengue amongst children as per the revised WHO classification. J Vector Borne Dis 2021;58:329-34

How to cite this URL:
Arora SK, Nandan D, Sharma A, Benerjee P, Singh DP. Predictors of severe dengue amongst children as per the revised WHO classification. J Vector Borne Dis [serial online] 2021 [cited 2022 May 21];58:329-34. Available from: https://www.jvbd.org/text.asp?2021/58/4/329/318312




  Introduction Top


The worldwide incidence of dengue fever has been rising for the past few decades, especially in the tropical countries like India[1]. Dengue fever is endemic in Delhi and rest of northern India. Delhi has experienced several outbreaks of dengue fever in the last two decades[2]. The epidemiological, clinical and lab profile of this illness has also been changing with each epidemic.

As per 1997 World Health Organization (WHO) classification, dengue disease used to be classified on the basis of presence or absence of shock and/or hemorrhagic manifestations. This classification was considered to be rigid as considerable overlap between the disease manifestations was often been observed that in turn affected the management and triage of patients[3],[4]. In 2009, WHO revised its criteria for classifying dengue disease severity as dengue without warning signs (DF), dengue with warning signs (DWS), and severe dengue (SD)[5]. The revised classification was seen to be having good sensitivity and negative predictive value; easy for carrying out triage and case management; and convenient for surveillance and epidemiological purposes[3],[4]. But it is also debated to be having poor specificity and positive predictive value. After this revision, very few studies have been done to find out the factors predicting the occurrence of severe dengue disease in children following the revised classification.

The present study was carried out in the pediatrics department of a tertiary care hospital of Delhi with the following objectives: (a) to compare the epidemiological, clinical and lab profiles of the confirmed dengue cases amongst the different categories of disease severity as per 2009 WHO classification; and (b) to find out the predictors of occurrence of severe disease in the patients.


  Material & Methods Top


This retrospective study was carried out in a tertiary care hospital of Delhi from September to December 2017. The authors retrospectively analyzed the records of 647 pediatric patients up to 16 years of age who were admitted in the hospital from July 2015 to December 2015 with acute febrile illness. One hundred and seventy (out of total 647) patients were diagnosed to be suffering from dengue infection (based on positive NS1 antigen test or serology IgM). Detailed clinical and epidemiological data of these 170 patients were recorded and statistically analyzed. The epidemiological parameters recorded were name, age, sex and residential area. The clinical details that were recorded included presenting symptoms, examination findings at the day of admission, presence/absence of shock at presentation, total fever duration and duration of stay. Patients’ final diagnoses (at the time of discharge) were recorded as dengue fever without warning signs (DF), dengue with warning sign (DWS) or severe dengue (SD) as per WHO criteria (3). The lab parameters analyzed were the investigations one at the time of admission i.e., hemoglobin, total leucocyte count, platelet count, electrolytes, renal and liver function tests and dengue serology (Ig M). NS1 Antigen report was also recorded wherever available.

The data were statistically analyzed by IBM SPSS statistics software for windows, version 23. Normally distributed continuous variables were compared using the unpaired t test, whereas the Mann-Whitney U test was used for those variables that were not normally distributed. Categorical variables were analyzed using either the chi square test or Fisher’s exact test. Univariate and multivariate ordinal regression analysis was performed to assess correlation of demographic characteristics, clinical features and to assess risk factors for severe disease. Odds ratios (ORs) with 95% confidence intervals (CIs), and all reported P values are two-tailed.

Ethical statement

Clearance was obtained from the Institutional Ethical Committee.


  Results Top


A total of 647 cases aged between 0–16 years admitted to the pediatric ward of the hospital were suspected to have dengue fever and were investigated for it during this period. The incidence of lab confirmed dengue was 26.27% (170/647) amongst all the children suspected to be having dengue clinically. This included 65 females and 105 males. Out of these 170 cases were confirmed to be suffering from dengue either by NS1 antigen (101 or 59.41%), dengue Ig M serology (84 or 49.41%) or both (17 or 10%). The average age of confirmed cases was 9.24 ± 3.61 years (range = 2 months–16 years). Four cases of severe dengue expired and the overall mortality rate was 0.023% (4/170) amongst the lab confirmed cases. Three of the expired cases had both NS1 Ag and serology positive whereas one was diagnosed on the basis of NS1 Ag positivity alone.

Thirty (17.65%) patients were classified as dengue fever (DF), 106 (62.35%) were classified as dengue with warning signs (DWS) and 34 (20.0%) were categorized as severe dengue (SD). [Table 1] depicts the comparison of the means (for quantitative variables) and proportions (for qualitative variables) of different demographic, clinical, and laboratory characteristics of patients in the three disease categories. The clinical features that differed significantly among the three groups were: abdominal pain (p < 0.001); vomiting (p = 0.01); altered sensorium (p < 0.001); shock (p < 0.001); peri-orbital edema (p = 0.01); hepatomegaly (p < 0.001); splenomegaly (p < 0.001); and duration of hospitalization (p < 0.001). The laboratory parameters that differed significantly among the three groups were: total leucocytes count (p = 0.02); blood urea (p < 0.001); serum creatinine (p = 0.04); total serum protein (p = 0.01); and globulin (p = 0.01).
Table 1: Comparison of demographic, clinical and laboratory parameters in the three disease categories.

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Univariate ordinal regression analysis [Table 2] was performed to find out the parameters that significantly predicted the disease severity as per WHO 2009 classification. The results showed that presence of vomiting (p = 0.002), altered sensorium (p = 0.01), shock (p < 0.001), peri-orbital edema (p = 0.004), hepatomegaly (p = 0.04), splenomegaly (p = 0.03), severe anemia i.e. Hb < 7 g/ dL (p = 0.01), thrombocytopenia i.e. platelet count < 5 x 109 / L (p = 0.02), elevated blood urea > 40 mg/dL (p = 0.003), elevated serum creatinine > 1.0 mg/dL (p = 0.04), serum total protein < 6.0 g/dL (p = 0.03) and low serum globulin < 2.0 g/dL (p = 0.01) were associated with more severe disease. Multivariate ordinal regression was done with parameters having p < 0.05 to adjust for confounding factors which suggested that the presence of vomiting (p = 0.01) was the only factor that predicted the occurrence of severe dengue.
Table 2: Univariate and multivariate ordinal regression of parameters for predicting severity of dengue

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  Discussion Top


The 1997 WHO classification system of dengue as dengue fever, dengue hemorrhagic fever and dengue shock syndrome was perceived to be difficult to use, less sensitive to pick up severe disease, not useful for triage of cases and hence used to misguide the management[6]. This classification was revised in 2009 with the aim to improve the timely identification and management of severe dengue cases. The new system relies on a set of symptoms, signs and some basic laboratory investigations for disease classification and earlier identification of severe dengue. It is found to have good sensitivity for detection of severe dengue and is easier to apply[7]. A study published in 2014 from Brazil demonstrated that the revised classification system had better sensitivity (86.8% vs. 62.3%) and negative predictive value (NPV) (91% vs. 83.2%) over the previous classification[8]. But for the detection of severe forms of dengue, the previous classification system performed better in terms of specificity (93.4% vs. 73.0%) and positive predictive value (PPV) (82.6% vs. 61.6%). The revised system is also debated to be too broad and many researchers have suggested to make the definitions of warning signs more specific[3],[9].

In the present study we compared the occurrence of symptoms, signs and lab investigations at initial presentation amongst the three disease severity groups DF/ DWS/ SD i.e., the final diagnosis at the time of discharge. The initial presenting features that differed significantly amongst the three groups were abdominal pain, vomiting, altered sensorium, shock, hepatomegaly, and total leucocyte count. These are already a part of WHO 2009 dengue disease severity classification. The additional parameters that differed significantly in the three groups were presence of peri-orbital edema and splenomegaly amongst clinical criteria; and levels of blood urea, serum creatinine, total serum protein and globulin amongst lab criteria. Addition of these parameters to the revised WHO classification might further help improve its sensitivity, specificity, NPV and PPV.

The clinical features that individually turned out to be the predictors of occurrence of severe disease in this study were presence of vomiting, altered sensorium, shock, periorbital edema, hepatomegaly, and splenomegaly. The revised classification utilizes presence of clinical fluid accumulation as one of the warning signs. But presence of peri-orbital edema in particular, and splenomegaly during the initial stage might be regarded as an additional warning sign or risk factor for the occurrence of severe disease.

Amongst the laboratory derangements, the present classification system utilizes only rising haematocrit and falling platelet counts as warning signs to predict severe dengue. This study observed that presence of severe anemia (Hb <7 g/dL) and thrombocytopenia (platelet count <5 x 109 / L) at the time of hospitalization were significant predictors of occurrence of severe disease. The revised guidelines for diagnosing severe dengue on the basis of presence of severe organ dysfunction do not define any laboratory criteria/ cut off. The present study observed that presence of elevated blood urea (>40 mg/dL), elevated serum creatinine (>1.0 mg/dL), low serum total protein (<6.0 g/dL) and low serum globulin (<2.0 g/dL) served as significant predictors of occurrence of severe dengue. Utilizing these parameters might help in predicting severe dengue at the time of initial presentation in a resourceful setting.

Very few pediatric studies have been carried out to assess the predictors of severe dengue since the 2009 revision of WHO guidelines. In one such study carried out amongst adult patients, it was observed that presence of previous co-morbidities, vomiting, diarrhea, pleural effusion, low systolic blood pressure, high haematocrit, low albumin and high urea were found as significant risk factors for severe dengue[10]. Thein et al.[11] carried out a study amongst adult patients to assess the performance of the 7 warning signs of the revised guidelines to predict the occurrence of dengue hemorrhagic fever and severe dengue. They observed that though persistent vomiting, hepatomegaly, haematocrit rise and rapid platelet drop, and clinical fluid accumulation, as well as any 3 or 4 WS were highly specific but no single warning sign was very sensitive in predicting occurrence of severe disease.

Hence, to conclude, addition of clinical features (periorbital edema and splenomegaly); and laboratory findings (elevated blood urea and serum creatinine, decreased serum total protein and globulin) might help improve the sensitivity and specificity of the revised WHO dengue classification particularly in reference to children. The possible shortcomings of the present study were: (1) its retrospective design; and (2) IgG was not tested in the included cohort of patients. This being a single center retrospective study, the authors suggest that similar large scale prospective, multicentric studies must be planned to improve our knowledge for earlier prediction of severe dengue in children. This will aid in improving clinical case management as well as outcome of children suffering from dengue.

Conflict of Interest: None



 
  References Top

1.
WHO. Global strategy for dengue prevention and control, 2012-2020. Geneva: World Health Organisation; 2012.  Back to cited text no. 1
    
2.
Telle O, Vaguet A, Yadav NK. The spread of dengue in an endemic urban milieu - The case of Delhi, India. PLoS One 2016; 11(1): e0146539.  Back to cited text no. 2
    
3.
Hadinegoro SRS. The revised WHO dengue case classification: does the system need to be modified? Paediatr Int Child Health 2012; 52(s1): 33-38.  Back to cited text no. 3
    
4.
Horstick O, Martinez E, Guzman MG, Martin JL, Ranzinger SR.WHO dengue case classification 2009 and its usefulness in practice: an expert consensus in the Americas. Pathog Glob Health 2015; 109(1): 19-25.  Back to cited text no. 4
    
5.
Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control: New Edition. Geneva: World Health Organization; 2009. Available from: http://www.who.int/tdr/publications/documents/dengue-diagnosis.pdf. (Accessed on January 01, 2020)  Back to cited text no. 5
    
6.
Horstick O, Jaenisch T, Martinez E, et al. Comparing the usefulness of the 1997 and 2009 WHO dengue case classification: a systematic literature review. Am J Trop Med Hyg 2014; 91(3): 621-634.  Back to cited text no. 6
    
7.
Prasad D, Kumar C, Jain A, Kumar R. Accuracy and applicability of the revised WHO classification (2009) of dengue in children seen at a tertiary healthcare facility in northern India. Infection 2013; 41(4): 775-782.  Back to cited text no. 7
    
8.
Macedo GA, Gonin MLC, Pone SM, Cruz OG, Nobre FF, Brasil P. Sensitivity and specificity of the World Health Organization dengue classification schemes for severe dengue assessment in children in Rio de Janeiro. Ooi EE, ed. PLoS ONE 2014; 9(4): e96314.  Back to cited text no. 8
    
9.
Barniol J, Gaczkowski R, Barbato EV, et al. Usefulness and applicability of the revised dengue case classification by disease: multi-centre study in 18 countries. BMC Infect Dis 2011; 11: 106.  Back to cited text no. 9
    
10.
Tamibmaniam J, Hussin N, Cheah WK, Ng KS, Muninathan P. Proposal of a Clinical Decision Tree Algorithm Using Factors Associated with Severe Dengue Infection. PLoS One 2016; 11(8): e0161696.  Back to cited text no. 10
    
11.
Thein TL, Gan VC, Lye DC, Yung CF, Leo YS. Utilities and limitations of the World Health Organization 2009 warning signs for adult dengue severity. PLoS Negl Trop Dis 2013; 7(1): e2023.  Back to cited text no. 11
    



 
 
    Tables

  [Table 1], [Table 2]



 

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