Infant Dengue a 10-Year Experience from a Tertiary Center in South India

ABSTRACT.

Dengue remains a major problem in the tropics. Several Asian countries have reported an increasing trend in the proportion of infants with dengue fever. However, most studies are limited to case reports or small case series from isolated outbreaks. We planned this study to look at clinico-laboratory profile, outcome, and predictors of severity in a large cohort of infants over a decade. Electronic medical records of infants admitted at a tertiary center of South India, with laboratory confirmed dengue infection between 2009 and 2019 were reviewed. Diagnosis was based on detection of NS-1 antigen and/or immunoglobulin M antibody against DENV(dengue virus) or positive DENV RNA polymerase chain reaction in infants presenting with acute febrile illness and clinical features consistent with dengue. Of 395 children with dengue admitted during study period, 99 (25%) were infants. A cyclical incidence pattern was noted, with higher cases in alternate years. Fever (99%) was most common, followed by gastrointestinal symptoms (vomiting, diarrhea—28%) and upper respiratory symptoms (cough, coryza—22%). Fifty-three infants had severe dengue, and 39 had shock. Fourteen children had multiorgan dysfunction syndrome, and 13 died. Infants with severe dengue were older than those with nonsevere disease, had lower serum albumin and greater frequency of severe thrombocytopenia, and had coagulopathy. On multivariable analysis, low serum albumin predicted development of severe dengue [P = 0.003, odds ratio 12.4 (95% confidence interval: 2.42–63.7)]. Dengue in infants may be challenging to recognize because of its undifferentiated presentation, with gastrointestinal and upper respiratory symptoms that are similar to other viral illness. Severe dengue is common in this sample, and lower serum albumin at presentation was predictive of severe disease.

INTRODUCTION

Dengue is an acute systemic viral infection that remains a major public health concern in the tropical and subtropical countries around the world. The WHO estimates that nearly 50% of the world population lives in countries where dengue is endemic.¹ India, a dengue-endemic country, has one of the largest case burdens. In 2016, the national vectorborne disease control program reported 100,000 laboratory-confirmed cases of dengue.² Dengue affects persons of all age groups, although the highest incidence is reported in children aged 5 to 15 years.³ There have been increasing reports from Asian countries of young infants being diagnosed with dengue virus (DENV) infection; however, most studies are limited to case reports and small case series.^4–8

DENV infection can present with symptoms ranging from undifferentiated fever to multiorgan dysfunction with shock and/or hemorrhage. One would expect that infants in dengue-endemic countries should be protected from clinical disease by virtue of transfer of maternal antibodies. However, because of antibody-dependent enhancement, infants born to mothers with past dengue infection are at risk of more severe disease when infected with a different DENV strain. Little is known about the symptoms of dengue in infants. A few published reports from India exist describing the clinical characteristics of infants with dengue infection,^5–7 but most of these describe cases of infant dengue that occurred during an outbreak. On this premise, we planned a retrospective study to look at the epidemiology, incidence rates, clinical features, disease severity, laboratory characteristics, and outcome of dengue infection in infants over a period of 10 years.

MATERIALS AND METHODS

We retrospectively reviewed the electronic medical records of children younger than 1 year (infants) admitted to a unit in the Department of Pediatrics at Christian Medical College, Vellore, India, with laboratory-confirmed dengue infection between 2009 and 2019. Diagnosis was based on detection of NS-1 antigen and/or immunoglobulin (Ig)M antibody against dengue virus by ELISA or positive dengue virus RNA polymerase chain reaction in infants presenting with acute febrile illness and clinical features consistent with dengue fever. The study was approved by institutional review board and the ethics committee.

Demographic, clinical, and laboratory data were collected on a predesigned case record form. Clinical variables include presenting symptoms and their duration and physical examination findings. If liver was palpable more than 2 cm below the right costal margin, it was termed as hepatomegaly, and any palpable spleen was classified as splenomegaly. Laboratory features included hemoglobin, platelet, and white blood cell count and renal and liver function tests. Platelet count of <50,000/cu mm was categorized as severe thrombocytopenia.⁹ Complications such as shock, acute respiratory distress syndrome and acute kidney injury were defined according to standard guidelines.^10,11 Severity of dengue was defined as per WHO guidelines.¹² The outcome included length of hospital stay and mortality.

The data were analyzed using SPSS for windows (version 22.0, Chicago, IL) and Microsoft Excel. Descriptive statistics were used for representation of data (frequency, mean, and SD). Data not following normal distribution were represented as median and interquartile range (IQR). Infants were grouped based on severe and nonsevere dengue. Groups were compared using chi-square or Fisher’s exact test for categorical variables and Student’s t-test for continuous variables. Mann-Whitney U-test was used for not normally distributed continuous variables. Multivariable logistic regression analysis was carried out to identify the predictors of shock. A P value < 0.05 was considered significant.

RESULTS

A total of 395 children with laboratory confirmed dengue infection were admitted during the study period from 2009 to 2019. Of these patients, 99 were infants (i.e., less than 1 year of age).

The mean (SD) age of this cohort was 7 (2.7) months. Male to female ratio was 1.3:1. Year-wise distribution of cases showed highest number of cases during the calendar years 2015 and 2019 (Figure 1). The months of November followed by October and September recorded the highest numbers of cases, suggesting a seasonal trend (Figure 2). History of fever was present in almost all cases (n = 98). Median (IQR) duration of fever was 4 (4–5) days. Poor feeding with lethargy (n = 41, 41.4%) was the second most common symptom. Gastrointestinal (GI) manifestations (e.g., vomiting and diarrhea; n = 28, 28.3%) and respiratory symptoms (e.g.,. cough and coryza; n = 22, 22.2%) were each seen in approximately a quarter of patients (Table 1). Glasgow Coma Scale score < 15 was present in 18 (18%) infants. On examination, a rash was present in 16 infants, frequently within the first few (1–5) days of fever onset. The rash was commonly maculopapular and distributed over the entire body. Liver was enlarged in nearly two-thirds of patients (n = 58, 59%), and spleen was palpable in approximately one-fifth of patients (n = 18, 18%). Ascites was present in 19 (19%) infants, and pleural effusion was detected in 30 (30%) patients. Fourteen (14%) patients had bleeding manifestations (petechiae in six, endotracheal tube bleeds in six, hematemesis in two, prolonged bleeding from the venepuncture site and bleeding from the umbilicus in one each). Laboratory features of infants are described in Table 2. Almost half of the admitted infants had severe dengue (n = 53, 53.5%). Nearly a third (n = 39, 39.4%) had shock; of these patients, 92% required vasopressors and/or inotropes. Multiorgan dysfunction syndrome (MODS) was present in 14 infants. Twenty-three infants (24%) required admission into the intensive care unit. Nearly one-third (n = 28, 28.3%) of the cases required respiratory support, of which 70% (n = 20) required invasive ventilation. Thirteen infants died. Of these, nine had progressive MODS, whereas in four, acute pulmonary hemorrhage was the preterminal event. Older age, severe thrombocytopenia, coagulopathy, and lower serum albumin levels were associated with development of severe dengue. On multivariable analysis, presence of lower serum albumin was the only predictor for the development of severe dengue.

Figure 1.

Year-wise distribution of cases. This figure appears in color at www.ajtmh.org.

Figure 2.

Month-wise distribution of cases. This figure appears in color at www.ajtmh.org.

Table 1.

Baseline and clinical characteristics, care received and treatment outcomes.

Characteristics	N = 99
Age in (months)	7 (5–10)
Males	56 (57)
Birth weight (kg)	3 (2.7–3.3)
Weight at admission (kg)	7.5 (6.3–8.3)
Clinical features
History of fever	98 (99)
Duration of fever (days)	4 (4–5)
Cough	22 (22.2)
Tachypnoeic at admission	13 (13.1)
Poor feeding and lethargy	41 (41.4)
Seizures	18 (18.2)
Vomiting	17 (17.2)
Rash	16 (16.2)
Abdominal distension	15 (15.2)
Diarrhea	11 (11.2)
Petechiae	6 (6.2)
Hepatomegaly	58 (59)
Pleural effusion	30 (30.3)
Ascites	19 (19.2)
Splenomegaly	18 (18.2)
Shock	39 (39.4)
Supportive care
Any respiratory support	28 (28.3)
Invasive ventilation	20 (20)
Vasoactive/inotrope drug therapy	33 (33.3)
Antibiotics	89 (90)
Packed red blood cell transfusion	22 (23)
Platelets concentrate transfusion	20 (20)
Fresh-frozen plasma transfusion	28 (29)
Clinical outcomes
Multiorgan dysfunction	14 (14)
PICU admission	23 (24)
Length of PICU stay (days)	4 (2.5–7)
Length of hospital stay (days)	4 (3–7)
Death	13 (13)

PICU = pediatric intensive care unit. Values are expressed as median (interquartile range) or numbers (%).

Table 2.

Laboratory parameters

Laboratory parameters	N
NS1 antigen positive	76	73 (74)
Dengue IgM positive	98	84 (85)
Dengue IgG positive	99	8 (8.2)
PT (seconds)	77	14 (12–17)
PTT (seconds)	76	58 (44–73)
Coagulopathy (abnormal PT and/or PTT)	77	70 (71)
Haemoglobin g/dL	98	11.5 (10.3–12.5)
Platelet count cells/mm3	99	26000 (15,000–43,000)
Severe thrombocytopenia (< 50,000 cells/mm3)	99	80 (81)
Total WBC cells/mm3	98	9300 (6,600–12,150)
Serum albumin g/dL	43	3 (2.5–3.4)
Alanine transaminase IU/L	95	88 (41–261)
Aspartate transaminase IU/L	44	563 (182–2,189)

Ig = immunoglobulin; PT = prothrombin time; PTT = partial thromboplastin time; WBC = white blood cell count. Values are expressed as median (interquartile range) or numbers (%).

DISCUSSION

In our study, infants comprised nearly 25% of laboratory-confirmed cases of symptomatic dengue infection hospitalized in the 10-year period of the study. Of these, approximately one-third had shock, and nearly half were admitted with severe dengue.

DENV infection can be asymptomatic or cause only mild illness in most cases. A prospective community-based study estimates asymptomatic infection accounts for nearly 80% of laboratory proven cases.¹³ Even in those with symptomatic infection, the proportion of cases with severe disease is low, constituting only 8% to 11%. However, in the infant age group, the proportion of symptomatic disease and the number of cases with severe infections are reportedly higher.⁴ Maternal DENV infection plays an important role in the pathogenesis of disease in infants.¹⁴ In the first 2 to 4 months of life, maternal antidengue IgG antibodies are present in high titers in infants with levels directly proportional to the maternal antibody titers.¹⁵ A high titer of maternally derived antibody would protect infants against dengue infection. After 2 to 4 of months of age, when the maternal IgG begins to decay to subneutralizing levels,⁴ these infants are at risk of antibody-dependent enhancement of dengue virus, resulting in more severe disease manifestations, including dengue hemorrhagic fever and dengue shock syndrome.¹⁶ The rate of antibody decay is variable and depends on the ethnicity, maternal age, and the DENV serotype that infected the mother.^17–20 The risk of severe disease peaks between the ages of 7 and 9 months of age.^21,22 This is similar to our study where the median (IQR) age at presentation was 7 (5–10) months, and infants with severe disease were older.

Fever was present in most, but we found that gastrointestinal (GI) symptoms of vomiting and diarrhea and respiratory symptoms of cough and coryza were common at presentation. Upper respiratory symptoms at presentation in cases of infant dengue have been reported in other studies.^23,24 Older children frequently presented with fever and vomiting, whereas diarrhea and cough are unusual. Rash has been reported to be more common (up to 50%) among infants, but in our cohort, rash was noted only in 16 infants (16.2%).^5,25 It was maculopapular, noted within 1 to 5 days of fever onset, and had no specific area of distribution. Appearance of rash early in the course before admission and darker skin color obscuring detection could be the reasons for its low frequency in our cohort. Our findings show that dengue in infants can present like any other undifferentiated viral fever with respiratory and GI symptoms; hence, one must have a higher index of suspicion, especially in a low-middle income setting where respiratory and GI infections are prevalent. In a population-based prospective study conducted in Vellore, over 1-year period (2017–2018), among children (6 months to 14 years of age), the highest number of cases of dengue fever were recorded in October.²⁶ In our study population, the cases of infant dengue showed an increase from July to December, peaking in October and November. July to December are the monsoon and post-monsoon seasons in the southern part of India, with September and October receiving the maximum rainfall.²⁷ Temperature, humidity, and rainfall are known to affect mosquito breeding and dengue transmissibility.²⁸ Studies reported increased dengue incidence rates 2 months after the rainy season.²⁶ In the 10-year period, we observed maximum cases in 2015 (25cases), 2017 (14 cases), and 2019 (21 cases). Epidemiologic studies showed that major outbreaks occur in 2- to 3-year cycles once dengue becomes well established in a region.²⁹ This probably explains our finding of higher admission rates for infant dengue cases at 2-year interval (Figure 1).

Low platelet count in dengue is a universal finding. Although minor bleeding is seen, severe bleeding is uncommon unless the course is complicated with severe shock and multiorgan failure. In our study too, severe thrombocytopenia (81%) and coagulopathy (71%) were prominent features, but bleeding manifestations were noted in only 14 infants. Bleeding ranged from mild with minor petechiae to life-threatening pulmonary hemorrhage occurring in those with shock and organ dysfunction. The underlying mechanism of bleeding in dengue is complex and is usually an interplay among thrombopathy, vasculopathy, and coagulopathy.³⁰ There is some evidence that antibodies against DENV might cross-react with platelets, coagulation factors, and vascular endothelium, resulting in bleeding.^31–33 Hemoconcentration was less prominent in our study, probably because of the underlying nutritional anemia prevalent among the children in our country,³⁴ which masks the effect of plasma leakage on hematocrit. Dengue shock was seen in approximately one-third (n = 36, 36%) of infants. All were treated with bolus fluids, and most (n = 33, 92%) required vasoactive and/or ionotropic support. Studies done among children have shown that the frequency of shock in cases of dengue varied between 30% and 50%.^35,36 This variation is probably due to differing incidence across age groups, the inpatient setting, and the definitions used to identify shock. Severe dengue, as defined by the WHO criteria of 2009, was present is almost half (53.5%) of the infants admitted to our unit. On univariate analysis, older age, presence of severely low platelet count, coagulopathy, and low serum albumin levels were significantly associated with development of severe disease in infants. However, on multivariable analysis, presence of low serum albumin levels at admission was the only factor significantly associated with severe dengue in infants (Table 3). Hypoalbuminemia in dengue is due to plasma leakage through the leaky vascular endothelium. Increased vascular permeability is not only a characteristic feature of severe dengue but is also the most important pathogenic mechanism resulting in severe form of this disease.³⁰ Hence, a severe hypoalbuminemia could be surrogate for severe disease, particularly in young infants.

Table 3.

Comparison between cases with severe and nonsevere dengue

Variable	Severe dengue (n = 53)	Nonsevere dengue (n = 46)	Univariate analysis P value	Multivariable analysis P value	Multivariable analysis OR (95% CI)
Age (months)	7.6 (2.5)	6.5 (2.7)	0.03*	0.68	0.9 (0.54–1.5)
Male	26	30	0.15†	0.57	0.54 (0.07–4.5)
Presence of rash	7	9	0.42†
Fever duration (days)	4 (4–5.5)	4 (3–5)	0.31‡
Hepatomegaly	34	24	0.22†	0.79	0.73 (0.07–7.3)
Splenomegaly	13	5	0.12†
Severe thrombocytopenia (< 50,000 cells/mm3)	47	33	0.04†	0.7	0.51 (0.02–14.4)
Hemoglobin (g/dL)	11.5 (1.6)	11.6 (1.6)	0.83*
Coagulopathy	45	25	0.03†	1.00
Serum albumin (g/dL)	2.7 (0.6)	3.7 (0.7)	0.004*	0.003	12.4 (2.42–63.7)
NS1 positive	40	33	0.82†	0.29	0.3 (0.03–2.9)

CI = confidence interval.

^*Independent sample Student’s t-test.

^†Chi-square test.

^‡Mann-Whitney U-test.

Our study has some important strengths. This is one of the largest studies on infant dengue describing clinical characteristics and outcome over a decade. We analyzed the predictors for shock in a sizeable sample. The retrospective method of data collection was the major drawback of this study. Also, because our hospital is a tertiary care center, selection bias of including subjects toward the severe end of disease spectrum is unavoidable.

CONCLUSIONS

Infants with dengue present a special challenge in disease recognition because of the undifferentiated presentation, with GI and upper respiratory symptoms similar to other viral illnesses. Lower serum albumin values at presentation may be predictive of severe disease with shock.