The Value of Warning Signs From the WHO 2009 Dengue Classification in Detecting Severe Dengue in Children

Background: World Health Organization proposed 7 warning signs to identify the risk of severe dengue in 2009. This study aimed to evaluate the value of these warning signs in detecting severe dengue in children. Material and Methods: A cross-sectional study was conducted utilizing data of children with clinical dengue infection obtained from medical records between January 2009 and December 2018 in Jakarta. Children with confirmed dengue were analyzed and stratified into 3 age groups: infants less than 1 year old, children 1–14 years and adolescents 15–18 years of age. Positive predictive value, negative predictive value (NPV), sensitivity and specificity of each warning sign present or absent on admission in detecting severe dengue were computed. Results: Six hundred ninety-nine children with clinical dengue infection were enrolled, among whom 614 (87.8%) had confirmed dengue infection, either by antigen or antibody serological tests. Severe dengue occurred in 211/614 (34.4%) cases. In infants, important warning signs on admission to detect or exclude severe dengue were liver enlargement (NPV 80.8%) and clinical fluid accumulation (NPV 75%). In children and adolescents, warning sign with highest NPV (in children 76.6% and in adolescents 91.9%) was increase in hematocrit concurrent with a rapid decrease in platelet count. Other warning signs with high NPV values in children were abdominal pain (72%), vomiting (70%), clinical fluid accumulation (69.3%), and in adolescents’ abdominal pain (80.7%), vomiting (75.7%), clinical fluid accumulation (82.7%). NPVs increase with more than 1 warning sign in all age groups. Conclusion: In infants, liver enlargement or clinical fluid accumulation are important warning signs for severe dengue, when both are absent, severe dengue is unlikely. In older children and adolescents, an increase in hematocrit with the concurrent rapid decrease in platelet count is most discriminative; followed by the absence of abdominal pain, vomiting or fluid accumulation are unlikely severe dengue.

(Pediatr Infect Dis J 2024;43:630-634) D engue virus infection has a wide spectrum, with manifes- tations ranging from very mild to severe, sometimes lethal forms.Severe dengue can lead to intravascular leakage and, without adequate supportive therapy, multiple organ failure and even death. 1he World Health Organization (WHO) reported that about 3.9 billion people living in 128 countries are at risk of contracting dengue.Annually, an estimated 50-100 million cases of dengue infection occur worldwide, and the number of deaths increased from 16,957 in 1990 to 40,467 in 2017. 2,3This makes dengue an important public health problem globally. 4According to the 1997 WHO Dengue Classification (WHO-1997), symptomatic dengue virus infections are grouped into 3 categories: undifferentiated fever, dengue fever and dengue hemorrhagic fever (DHF).The DHF cases are further classified into 4 severity grades, with grades III and IV being defined as dengue shock syndrome (DSS). 5Changes in the epidemiology of dengue led to criticism on the usefulness and applicability of this classification in clinical care and in 2009 the WHO issued a new guideline that classifies clinical dengue as: (1) dengue without warning signs, (2) dengue with warning signs and (3) severe dengue (WHO-2009). 6he new guideline includes warning signs (WSs) that help early identification of (imminent) DSS, severe bleeding manifestations or severe organ impairment. 7Delay in diagnosis, referral to healthcare and fluid management during the critical phase in dengue disease progression can lead to higher mortality in severe dengue cases, and therefore early detection of disease progression is crucial.The WSs included in the guideline were selected to support healthcare professionals in resource-limited healthcare settings in the clinical assessment of dengue-infected patients. 8][11] Timely recognition or ruling of severe dengue among children with dengue is notoriously difficult.Studies on the performance of WSs to predict severe dengue in pediatric care are rare, while WSs might also differ between infants and older children.The diagnostic value of WSs in different age groups thus needs to be explored in larger groups of dengue dengue-infected cases, of whom some develop severe dengue.Evidence on the value of WS should be given attention to prevent complications and mortality.The International Classification of Disease (ICD) 10th revision currently employs WHO-1997, but WHO has revised it in ICD 11, incorporating the diagnosis of dengue based on WHO-2009 criteria.This revision came into effect on January 1, 2022 (source: https://www.who.int/news-room/detail/18-06-2018-who-releasesnew-international-classification-of-diseases-(icd-11).
In Indonesia, children with severe dengue need referral to a secondary or tertiary care hospital center and hence adequate discrimination of children with severe versus nonsevere dengue in primary healthcare facilities is essential.The aim of this study was to evaluate the diagnostic value of WHO-2009 WSs on admission to the hospital in detecting severe pediatric dengue, with patients

Laboratory Confirmed Dengue Infection
Serological confirmation tests of nonstructural 1 (NS1) dengue antigen, or IgM, IgG dengue antibody were performed from acute blood samples.Dengue viral infection was confirmed by positive NS1 detection using Dengue NS1 Ag Strip (Panbio).Primary dengue infection was defined when only IgM was positive, secondary dengue infection was defined when both IgM and IgG were positive and indeterminate dengue (prior dengue infection) was defined when IgG was positive but IgM was negative.Nondengue was defined when both IgG and IgM were negative.For dengue serology, the presence of dengue IgM and IgG in acutephase serum was assessed using a rapid immunochromatographic test (Panbio Dengue Duo Cassette).

Outcome Definition
Patients were classified as having nonsevere or severe dengue according to WHO-2009 case definitions.Severe dengue includes: (1) severe plasma leakage with shock (DSS) or presence of hypotension, tachycardia and signs of poor capillary perfusion with or without narrow pulse pressure; (2) severe bleeding, including bleeding from the gastrointestinal tract with or without the need for transfusions of blood products or (3) severe organ impairment defined as elevated levels of aspartate transaminase or alanine transaminase of 1000 IU/L or higher, central nervous system impaired consciousness or heart and other organ involvement. 7An independent trained physician classified the clinical dengue cases to classify patient outcomes as nonsevere dengue or severe dengue.

Definition of WSs on Admission
The WSs considered included: abdominal pain, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy, liver enlargement and laboratory results showing an increase in hematocrit concurrent with a rapid decrease in platelet count.Abdominal pain was defined as abdominal tenderness and continuous (ie, not intermittent) pain.Persistent vomiting was defined as more than 3 episodes of vomiting within 12 hours.Fluid accumulation was defined as pleural effusion visible on a chest radiograph or ultrasound and ascites detected by abdominal ultrasound.Mucosal bleeding was defined as bleeding gums or conjunctiva, epistaxis, vaginal bleeding, hemoptysis or hematuria.Lethargy was defined as an alteration of consciousness with a Glasgow score of less than 15.Hepatomegaly was defined based on the liver edge palpation of more than 2 cm below the right costal margin.Increased hematocrit concurrent with a rapid decrease in platelet count (high hematocrit/low platelets) was defined as any increase in hematocrit from baseline at admission in the febrile phase, with a concurrent rapid decrease in platelet count of at least 10,000 cells/mm 3 in 24 hours or with a drop of platelet count below 100,000 cells/mm. 3,12The Presence or absence of each warning sign on admission was enumerated per patient.

Statistical analysis
All laboratory-confirmed cases of dengue infection were included in the analysis.Patients were stratified into 3 age groups, namely infants (less than 1 year old), children (1-14 years old) and adolescents (15-18 years old).Clinical WSs were compared between patients with and without severe dengue using χ 2 tests or Fisher exact tests where appropriate.We assessed the value of each warning sign to discriminate between severe and nonsevere dengue using the following diagnostic test criteria: positive predictive value, negative predictive value (NPV), sensitivity and specificity, stratified by age group.Next, we computed the diagnostic test criteria for combinations of WSs.Data were analyzed by using SPSS version 22 (IBM, Chicago) and MedCalc's diagnostic test evaluation calculator (https://www.medcalc.org/calc/diagnostic_test. php).

RESULTS
A total of 699 medical records were reviewed for children with clinical dengue admitted to Cipto Mangunkusumo Hospital during the study period.Of these, 614 (87.8%) cases with confirmed dengue infection were included in the study ( The most common manifestation of severe dengue was severe plasma leakage in all age groups (Fig. 1).Severe bleeding and severe organ involvement occurred more frequently in infants compared to other age groups.Some patients had more than 1 manifestation of severe dengue, as depicted in Figure 2. Severe organ impairment in infants manifested as impaired consciousness, in 8 © 2024 The Author(s).Published by Wolters Kluwer Health, Inc Karyanti et al of 16 infant cases with severe dengue, whereas in children 1-14 years of age, it was mostly increased transaminase levels (>1000 IU/L, 7 cases) and cardiac involvement (2 cases).In adolescents, severe organ impairment manifested as increased transaminase levels in 2 cases, and as impaired consciousness in 2 cases.All 6 deaths occurred in the age group 1-14 years: 2 cases were 3 years, 2 were 5 years and 1 case each were 7 and 11 years of age.
In infants, liver enlargement was most discriminative with an NPV of 80.8 %, followed by clinical fluid accumulation (NPV: 75%).In older children, all WSs, except for mucosal bleeding and lethargy.Restlessness was significantly more common among patients with severe dengue.NPV was highest for an increase in hematocrit concurrent with a rapid decrease in platelet count (76.1 %).Other WSs with good NPVs in children 1-14 years were abdominal pain, persistent vomiting and clinical fluid accumulation.In adolescents, results on the discriminative value of individual WS were largely in line with results for 1-14-year-olds.
In infants, the combination of the 2 most discriminative WSs (liver enlargement and clinical fluid accumulation), had a NPV of 88%.In adolescents, several combinations of WS each had comparable discriminative power (Table, Supplemental Digital Content 2, http://links.lww.com/INF/F495),including abdominal pain and increase in hematocrit concurrent with rapid decrease in platelet count (NPV: 100%), increase in hematocrit concurrent with rapid decrease in platelet count and clinical fluid accumulation (NPV: 100%).When the number of WSs increases, the discriminatory ability, notably NPV and specificity, improves, especially in infants (

DISCUSSION
This study showed that in infants, the most discriminative warning sign for severe dengue is liver enlargement with positive predictive value of 68.8% and NPV of 80.8 %, followed by clinical fluid accumulation with NPV of 75%.In older age groups, an increase in hematocrit concurrent with a rapid decrease in platelet count was most discriminative WS with NPV (76.1% and 91.9% in children 1-14 years and adolescents, respectively).Other WSs with high NPVs in children 1-14 years and adolescents were abdominal pain, persistent vomiting and clinical fluid accumulation.In the absence of one of these 3 WSs in older children, it leads to unlikelyto-severe dengue.
The prevalence of severe dengue in our pediatric cohort was about 34.4%, which was higher compared to another study from Medan, Indonesia, where the severe dengue prevalence was 25% among children less than 18 years old, 13 but lower than the estimate from another study among pediatric patients, by Pothapregada et al. 14 in India, where severe dengue occurred in 40.6%.The high prevalence obtained in the present study is probably due to the fact that the subjects came from a national tertiary referral hospital, predominantly attracting severe pediatric dengue cases.][17] Clinical awareness and assessment of the WSs as proposed in the WHO-2009 guidelines 7 is crucial to monitor the critical phase in dengue-infected patients.When specific warning signs with a high NPV are absent, this can be used to guide clinical decision-making on watchful waiting versus referral,  as the post-test probability of severe dengue is substantially reduced in these subjects.While the specificity of the WS can also be a helpful measure, its impact on post-test probability may be low if the particular WS is uncommon in both diseased and undiseased (ie, the absence of the WS does not rule out disease).The NPV is, therefore, the most useful test characteristic to use in this context of clinical decision-making.
In infants WSs based on clinical assessment such as mucosal bleeding and lethargy each have an NPV of 63.2%, whereas when we combine 2 WSs of lethargy and liver enlargement, the NPV to 76.5%.WSs based on laboratory results of increased hematocrit and decreased platelet count, and those based on radiology examination to detect clinical fluid accumulation, have high NPVs, but these WSs can only be detected in healthcare facilities equipped with laboratory or radiology facilities.While new diagnostic tools such as NS1 serotype-specific IgG measured by ELISA or PCR-based techniques with rapid results to detect dengue virus are being developed to assist the assessment of disease severity, medical management still heavily relies on clinical judgment as the time from onset of WSs to severe illness in most dengue cases is typically less than 1 day and patients may progress toward hypovolemic shock and even death if adequate fluid therapy is not administered immediately. 18In addition, access to more advanced diagnostic testing and imaging may be limited in many primary healthcare settings, further stressing the importance of the clinical WSs in early patient assessment to reduce morbidity and mortality in children. 19he fact that the dengue cases in this study were from a tertiary hospital is a potential limitation as circumstances and prevalence in primary or secondary healthcare settings may differ, with consequences for the applicability of our conclusions.The strength of this study was that the patients were obtained from a 10-year period with complete datasets of clinical manifestations, laboratory and radiology findings monitored daily until discharge and focus on pediatrics with age stratification.

CONCLUSIONS
In infants, important WSs to detect severe dengue are liver enlargement and clinical fluid accumulation; when both these WSs are absent in infants, severe dengue is unlikely.In older children, the presence of any of the WSs-an increase in hematocrit concurrent with a rapid decrease in platelet count, abdominal pain, vomiting or fluid accumulation-is likely severe dengue.

TABLE 1 .
Characteristics of Children with Confirmed Dengue Infection Admitted Between January 2009 and December 2018 (n = 614)

2 .
Warning Signs on Admission Among 614 Confirmed Dengue Patients Stratified by Age and by Severe or Nonsevere Dengue HCT, hematocrit; NPV, negative predictive value; PPV, positive predictive value; Sn, sensitivity; Sp, specificity.