Predicting the risk of mortality in children with dengue-induced hepatitis admitted to the paediatric intensive care unit

Table 1 Baseline clinical and laboratory characteristics of study participants on pediatric intensive care unit admission and associated outcomes at discharge (n = 459), n (%)

Characteristics	No. participants	Statistics
Age (years)	457	7.7 (4.3-10.1)
Female patients	459	193 (42)
Underlying diseases	459	38 (8.3)
Day of occurrence of dengue shock since onset of fever (days)	451	5 (4-5)
Grading of DSS	459
Compensated DSS		402 (87.6)
Decompensated DSS		57 (12.4)
Severe bleeding	456	76 (16.7)
Respiratory rate (breaths/minute)	405	26 (24-30)
Systolic shock index (bpm/mmHg)	390	1.33 (1.15-1.6)
Diastolic shock index (bpm/mmHg)	390	1.83 (1.5-2.25)
Vasoactive-inotropic score > 30	459	45 (9.8)
White blood cell count, (× 109/L)	456	5.35 (3.76-7.8)
Peak hematocrit	446	47 (44-51)
Nadir hematocrit	446	38 (33-41)
Platelet cell count, (× 109/L)	457	32.6 (20-48)
Aspartate aminotransferase (IU/L)	459	751 (465-1416)
Alanine aminotransferase (IU/L)	459	344 (221-638)
International normalized ratio	406	1.40 (1.18-1.96)
Prothrombin time (second)	404	18 (15-27)
Activated partial thromboplastin time (second)	405	52 (43-69)
Peak serum bilirubin level (mg/dL)	119	1.9 (1.04-5.3)
Peak serum ammonia level (µmol/L)	64	117 (80-197)
Blood creatinine (µmol/L)	447	54 (44-63)
Troponin I (ng/mL)	164	0.036 (0.01-0.22)
Blood lactate (mmol/L)	293	2.9 (2.0-4.5)
Length of pediatric intensive care unit stay (days)	459	3 (2-5)
Length of hospital stay (days)	459	5 (4-10)
Fatal outcome	459	42 (9.2)

Summary statistics are presented as median (interquartile range) for continuous variables and frequency (%) for categorical variables. DSS: Dengue shock syndrome.

Table 2 Area under the receiver operating characteristic curve for biomarkers and cut-offs for in-hospital mortality of children experiencing severe dengue-associated hepatitis

Parameters	Area under the curve of mortality (95%CI)	P value	Optimal cutoff points of the parameters	Sensitivity	Specificity		Accuracy	Youden index
INR peak during first 24 hours of PICU admission	0.907 (0.858-0.956)	< 0.001	INR peak ≥ 2.11 during first 24 hours of admission	0.902	0.855		0.859	0.757
Peak of total serum bilirubin during 72 hours of PICU admission (mg/dL)	0.790 (0.704-0.875)	< 0.001	Peak of total serum bilirubin during the first 72 hours of PICU admission ≥ 1.7 (mg/dL)	0.941	0.565	0.672		0.506

INR: International normalized ratio peak; PICU: Pediatric intensive care unit.

Table 3 Clinical predictors of in-hospital mortality in pediatric intensive care unit-admitted children with severe dengue-associated hepatitis from univariable and multivariable logistic analyses

Factors	Non-survivors (n = 42)	Survivors (n = 417)	Unadjusted OR (95%CI), Pa	Adjusted OR (95%CI), Pb
Age (years)	7 (4.2-10)	7.8 (4.4-10.2)	0.98 (0.9-1.06), P = 0.55	-
Gender
Female	16 (38)	177 (42)	1.2 (0.62-2.3), P = 0.58	-
Male	26 (62)	240 (58)
Grading of DSS
Compensated DSS	29 (69)	373 (89)	3.8 (1.84-7.85), P < 0.001	-
Decompensated DSS	13 (31)	44 (11)
Severe bleeding
No	11 (26)	372 (89)	23.1 (10.9-49.1), P < 0.001	-
Yes	31 (74)	45 (11)
Levels of consciousness (on the Alert, Verbal, Pain, Unresponsive scale)
Alert and verbal response	15 (36)	387 (93)	23.2 (11.1-48.2), P < 0.001	4.43 (1.12-17.5), P = 0.03
Pain and unresponse	27 (64)	30 (7)
High vasoactive inotropic score (> 30)
No	7 (17)	407 (98)	204 (73-568), P < 0.001	39.2 (9.2-167), P < 0.001
Yes	35 (83)	10 (2)
Peak hematocrit (%)	46 (40-51)	47 (44-51)	0.95 (0.9-0.99), P = 0.024	-
Low platelet counts, (< 20 x 109/L)
No	25 (60)	319 (76)	2.21 (1.15-4.27), P = 0.018	-
Yes	17 (40)	98 (24)
Severe transaminitis
No	9 (21)	260 (62)	6.07 (2.83-13.0), P < 0.001	-
Yes	33 (79)	157 (38)
Serum sodium, (mmol/L)	128 (124-133)	128 (125-131)	1.0 (0.95-1.07), P = 0.74	-
Highest level of blood lactate (mmol/L)	10.3 (7.2-13.4)	2.4 (1.8-4.2)	1.67 (1.47-1.89), P < 0.001	1.61 (1.34-1.94), P < 0.001
Serum creatinine (µmol/L)	73 (58-123)	53 (44-61)	1.03 (1.02-1.04), P < 0.001	-

Summary statistics are median (interquartile) for continuous data and frequency (%) for categorical data. P^a and P^b withdrawn from complete-case analysis univariable and multivariable logistic analyses, respectively. DSS: Dengue shock syndrome; OR: Odds ratio.

Table 4 Multivariable logistic models for predicting 28-day in-hospital mortality among dengue shock syndrome children with clinical predictors and biomarkers

Prognostic factors	Model 1		Model 2		Model 3
	OR (95%CI), Pa		OR (95%CI),Pb		OR (95%CI), Pc
Pain and unresponsive levels on the Alert, Verbal, Pain, Unresponsive scale	13.86 (3.71-51.8)	< 0.001	14.36 (4.12-50.1)	< 0.001	13.96 (3.73-52.2)	< 0.001
High vasoactive inotropic score (> 30)	18.1 (4.99-65.4)	< 0.001	17.4 (5.06-60.2)	< 0.001	18.0 (4.98-65.3)	< 0.001
Highest level of blood lactate (mmol/L)	1.5 (1.27-1.78)	< 0.001	1.62 (1.37-1.91)	< 0.001	1.5 (1.27-1.78)	< 0.001
International normalized ratio levels, ≥ 2.11	11.3 (2.62-48.3)	0.001	_	_	9.1 (1.72-47.9)	< 0.01
Peak serum bilirubin level, ≥ 1.7 mg/dL	_	_	4.72 (1.12-19.8)	0.03	1.5 (0.29-7.81)	0.62

P^a, P^b, and P^c withdrawn from multivariable logistic analyses with multiple imputation data. Model 1: Clinical predictors and international normalized ratio (INR); Model 2: Clinical predictors and total serum bilirubin; Model 3: Clinical predictors, INR, and total serum bilirubin. OR: Odds ratio.

Table 5 Performance of prognostic models with internal validation

Prognostic models	C-statistic	Calibration slope	Brier score
Model 1	0.974 (0.967)	1 (0.892)	0.021 (0.023)
Model 2	0.966 (0.960)	1 (0.906)	0.023 (0.027)
Model 3	0.975 (0.968)	1 (0.884)	0.020 (0.023)

Statistics are summarized for training (test) sets performed with bootstrap and internal validation. Model 1: Clinically developed model and international normalized ratio (INR); Model 2: Clinically developed model and total serum bilirubin; Model 3: Clinically developed model, INR, and total serum bilirubin.