• View in gallery

    Nearly overlapping peaks of SARS-CoV-2 cases in the region where the study was conducted and children with dengue presenting to the study site. This figure appears in color at www.ajtmh.org.

  • 1.

    Wolff D, Nee S, Hickey NS, Marschollek M, 2020. Risk factors for COVID-19 severity and fatality: a structured literature review. Infection 49: 1528.

    • Search Google Scholar
    • Export Citation
  • 2.

    Castagnoli R, Votto M, Licari A, Brambilla I, Bruno R, Perlini S, Rovida F, Baldanti F, Marseglia GL, 2020. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review. JAMA Pediatr 174: 882.

    • Search Google Scholar
    • Export Citation
  • 3.

    Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P, 2020. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet 395: 16071608.

    • Search Google Scholar
    • Export Citation
  • 4.

    Consiglio CR et al., 2020. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell 183: 968981.e7.

  • 5.

    Lee PY et al., 2020. Distinct clinical and immunological features of SARS-CoV-2-induced multisystem inflammatory syndrome in children. J Clin Invest 130: 59425950.

    • Search Google Scholar
    • Export Citation
  • 6.

    Gruber CN et al., 2020. Mapping systemic inflammation and antibody responses in Multisystem Inflammatory Syndrome in Children (MIS-C). Cell 183: 982995.e14.

    • Search Google Scholar
    • Export Citation
  • 7.

    Chen Y et al., 2020. Active or latent tuberculosis increases susceptibility to COVID-19 and disease severity. medRxiv 2020.03.10.20033795.

  • 8.

    Gupta N, Srivastava S, Jain A, Chaturvedi UC, 2012. Dengue in India. Indian J Med Res 136: 373390.

  • 9.

    Dash N, Rose W, Nallasamy K, 2020. India’s lockdown exit: are we prepared to lock horns with COVID-19 and dengue in the rainy season? Pediatr Res 89:10471048.

    • Search Google Scholar
    • Export Citation
  • 10.

    Din M, Asghar M, Ali M, 2021. COVID-19 and dengue coepidemics: a double trouble for overburdened health systems in developing countries. J Med Virol 93: 601602.

    • Search Google Scholar
    • Export Citation
  • 11.

    Miah MdA , Husna A, 2021. Coinfection, coepidemics of COVID-19, and dengue in dengue-endemic countries: a serious health concern. J Med Virol 93: 161162

    • Search Google Scholar
    • Export Citation
  • 12.

    Tiwari L, Shekhar S, Bansal A, Kumar P, 2020. COVID-19 with dengue shock syndrome in a child: coinfection or cross-reactivity? BMJ Case Rep CP 13: e239315.

    • Search Google Scholar
    • Export Citation
  • 13.

    Masyeni S, Santoso MS, Widyaningsih PD, Asmara DW, Nainu F, Harapan H, Sasmono RT, 2021. Serological cross-reaction and coinfection of dengue and COVID-19 in Asia: experience from Indonesia. Int J Infect Dis 102: 152154.

    • Search Google Scholar
    • Export Citation
  • 14.

    Guabiraba R, Ryffel B, 2014. Dengue virus infection: current concepts in immune mechanisms and lessons from murine models. Immunology 141: 143156.

    • Search Google Scholar
    • Export Citation
  • 15.

    Goldstein B, Giroir B, Randolph A, International Consensus Conference on Pediatric Sepsis , 2005. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med J Soc Crit Care Med World Fed Pediatr Intensive Crit Care Soc 6: 28.

    • Search Google Scholar
    • Export Citation
  • 16.

    Magalhaes T, Chalegre KDM, Braga C, Foy BD, 2020. The endless challenges of arboviral diseases in Brazil. Trop Med Infect Dis 5:75.

  • 17.

    Nolen LD, Seeman S, Bruden D, Klejka J, Desnoyers C, Tiesinga J, Singleton R, 2020. Impact of social distancing and travel restrictions on non–coronavirus disease 2019 (non–COVID-19) respiratory hospital admissions in young children in rural Alaska. Clin Infect Dis 72: 21962198.

    • Search Google Scholar
    • Export Citation
  • 18.

    Kuitunen I, Artama M, Mäkelä L, Backman K, Heiskanen-Kosma T, Renko M, 2020. Effect of social distancing due to the COVID-19 pandemic on the incidence of viral respiratory tract infections in children in Finland during early 2020. Pediatr Infect Dis J 39: e423e427.

    • Search Google Scholar
    • Export Citation
  • 19.

    Angoulvant F et al., 2021. Coronavirus disease 2019 pandemic: impact caused by school closure and national lockdown on pediatric visits and admissions for viral and nonviral infections—a time series analysis. Clin Infect Dis 72: 319322

  • 20.

    Sakamoto H, Ishikane M, Ueda P, 2020. Seasonal influenza activity during the SARS-CoV-2 outbreak in Japan. JAMA 323: 19691971.

  • 21.

    Phadke R, Mohan A, Çavdaroğlu S, Dapke K, Costa AC dos S, Riaz MMA, Hashim HT, Essar MY, Ahmad S, 2021. Dengue amidst COVID-19 in India: the mystery of plummeting cases. J Med Virol 93: 41204121.

    • Search Google Scholar
    • Export Citation
  • 22.

    Williams V, Menon N, Bhatia P, Biswal M, Sreedharanunni S, Rawat A, Jayashree M, Nallasamy K, 2020. Serum ferritin predicts neither organ dysfunction nor mortality in pediatric sepsis due to tropical infections. Front Pediatr 8: 607673.

    • Search Google Scholar
    • Export Citation
  • 23.

    Teotônio IMSN, de Carvalho JL, Castro LC, Nitz N, Hagström L, Rios GG, de Fátima Rodrigues de Oliveira M, Dallago BSL, Hecht M, 2021. Clinical and biochemical parameters of COVID-19 patients with prior or active dengue fever. Acta Trop 214: 105782.

    • Search Google Scholar
    • Export Citation
  • 24.

    Yan G et al., 2020. Covert COVID-19 and false-positive dengue serology in Singapore. Lancet Infect Dis 20: 536.

  • 25.

    Joubert A, Andry F, Bertolotti A, Accot F, Koumar Y, Legrand F, Poubeau P, Manaquin R, Gérardin P, Levin C, 2021. Distinguishing non severe cases of dengue from COVID-19 in the context of co-epidemics: a cohort study in a SARS-CoV-2 testing center on Reunion Island. PLoS Negl Trop Dis 15: e0008879.

    • Search Google Scholar
    • Export Citation
  • 26.

    Nicolelis MAL, Raimundo RLG, Peixoto PS, de Andreazzi CS, 2020. How super-spreader cities, highways, hospital bed availability, and dengue fever influenced the COVID-19 epidemic in Brazil. medRxiv 2020.09.19.20197749.

    • Search Google Scholar
    • Export Citation
  • 27.

    Nath H, Mallick A, Roy S, Sukla S, Biswas S, 2021. Computational modelling supports that dengue virus envelope antibodies can bind to SARS-CoV-2 receptor binding sites: is pre-exposure to dengue virus protective against COVID-19 severity? Comput Struct Biotechnol J 19: 459466.

    • Search Google Scholar
    • Export Citation
  • 28.

    Lustig Y, 2020. Potential antigenic cross-reactivity between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and dengue viruses. Clin Infect Dis (Corrected Proof, Ahead of print).

 
 
 
 

 

 
 

 

 

 

 

 

 

Impact of Recent SARS-CoV-2 Infection on the Course and Severity of Dengue in Children: A Prospective Observational Study from North India

View More View Less
  • 1 Pediatric Intensive Care and Pulmonology Units, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India;
  • | 2 Pediatric Emergency and Intensive Care Units, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India;
  • | 3 Department of Immunopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India;
  • | 4 Department of Virology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

ABSTRACT.

In 2020, a considerable overlap occurred between the COVID-19 pandemic and seasonal dengue transmission in India. This study aimed to evaluate the effects of acute or recent infection with SARS-CoV-2 on the course and outcomes of dengue fever in children. We prospectively enrolled 44 children with a clinical and laboratory diagnosis of dengue fever. Assessment of acute and recent SARS-CoV-2 infection was done using reverse transcription–polymerase chain reaction and IgG antibody through ELISA. Children were grouped based on evidence of SARS-CoV-2 exposure and clinical severity, and outcomes were compared. The median age of the study cohort was 96 months (interquartile range [IQR]: 69–129 months). Fever (98%), vomiting (78%), abdominal pain (68%), hepatomegaly (68%), and edema (32%) were the common features. About two-thirds (N = 30) had severe dengue; 20 (45%) had dengue shock. Liver dysfunction (58%) and acute kidney injury (25%) were other major organ dysfunctions. Nineteen (43%) children stayed in the pediatric intensive care unit for a median duration of 5 days (IQR: 2–11 days). None had acute SARS-CoV2 infection; however, IgG against SARS-CoV-2 was detected in 15 (34%) cases. Children with recent exposure to SARS-CoV-2 showed a trend toward a lower incidence of acute kidney injury, fewer organ dysfunctions, and a lower frequency of invasive ventilation. Four children (9%) died; none of the deaths were in the SARS-CoV-2–exposed group. The present study exposes preliminary evidence that dengue fever might follow a less severe course in children with recent exposure to SARS-CoV-2 infection. However, it is pertinent to understand the antigenic similarity and cross-protective antibody response between the two viruses and their clinical relevance.

INTRODUCTION

In 2020, SARS-CoV-2 virus spread rapidly across the globe, resulting in unprecedented health care burden and mortality. Infection in adults is characterized by primarily respiratory system involvement with a wide range of severity.1 Children were less severely affected.2 However, the relief was short lived as a new multisystem inflammatory syndrome (MIS-C) emerged, almost exclusively in children, a few weeks after exposure to the virus. This was characterized by an exaggerated immune response presenting with fever, rash, conjunctival injection, gastrointestinal symptoms, shock, and multi-organ dysfunction.3 Although there were some clinical similarities with Kawasaki disease, it was soon identified as a distinct pathological entity with a different immune-pathological phenotype.4 As more research is being carried out, the immunological effects of SARS-CoV-2 infection are emerging. Lymphopenia, alterations in lymphoid cell subsets, and the upregulation of inflammatory cytokines and autoantibodies have been reported in clinical studies.5,6 Altered immunity induced by SARS-CoV-2 has the potential to alter the immune response to other infections. The association between SARS-CoV-2 exposure and other infections at this point is largely unknown. Some preliminary studies reported an increased severity of SARS-CoV-2 infection in patients with pulmonary tuberculosis;7 however, limited literature is available regarding its association with dengue.

Dengue fever is an arboviral illness prevalent in southeast Asia during the post-monsoon season. In north India, this season extends from August to November. Dengue is a significant contributor to the outpatient visits and pediatric inpatient admissions during this period.8 The peaks of SARS-CoV-2 infections and dengue fever overlapped during the pandemic year of 2020, and health systems were stretched to their limits.911 Several countries reported individual case reports of coinfection of SARS-CoV-2 and dengue with variable outcomes and concerns over cross-reactivity between the two antibodies.12,13 From current understanding, the stormy immune response seen with severe dengue may be caused either by dysregulated T-cell response or an exaggerated humoral response due to past infection.14 The latter is commonly known as antibody-dependent enhancement. Whether current or recent infection with SARS-CoV-2 is responsible in altering the course of dengue fever is an unanswered but pertinent question. We prospectively enrolled children hospitalized with dengue fever and tested them for active and recent SARS-CoV-2 infection to determine its effect on the clinical course and severity of dengue.

MATERIALS AND METHODS

This was a prospective observational study conducted at the Pediatric Emergency and Intensive Care Units of a tertiary care teaching hospital in north India between August and December 2020. The protocol was approved by the Institute Ethics Committee (No.INT/IEC/2020/SPL-1523). All consecutive children aged 12 years or younger admitted with clinical illness compatible with dengue were screened for eligibility using a predesigned screening proforma. Those with laboratory-confirmed dengue (detection of NS1 antigen by ELISA and/or IgM anti-dengue antibodies by μ capture ELISA) were enrolled in the study. Children with pre-existing immunodeficiency, inflammatory disorder, or malignancy or those under immunosuppressive therapy were excluded from the study. All enrolled children underwent tests for evidence of acute or recent SARS-CoV-2 infection using Indian Council of Medical Research recommended reverse transcription–polymerase chain reaction assay for SARS-CoV-2 RNA detection or IgG antibodies against SARS-CoV-2 by semiquantitative micro-ELISA (EUROIMMUN kit, Medizinische Labordiagnostika AG 23560 Luebeck, Germany), respectively. The baseline demographic and clinical data were recorded during enrolment. Illness severity was measured using the Pediatric Sequential Organ Failure Assessment (p-SOFA) score and incidence of multiorgan dysfunction syndrome (MODS), defined as per the International Pediatric Sepsis Consensus conference definition.15 The worst MODS score, defined as the maximum number of concurrent organ dysfunctions at any time during admission, was recorded. Laboratory parameters at admission, including hemoglobin, platelet count, white blood cell count, serum albumin, liver function tests, and renal function tests, were recorded. Interleukin 6 was measured through cytometric bead array (BD Biosciences, Franklin Lakes, NJ). Details of supportive care, such as mechanical ventilation, vasoactive drug therapy, and hospital outcome, including length of hospital stay, pediatric intensive care unit (PICU) stay, and mortality, were noted.

Statistical analysis.

Data entry was done in Microsoft excel 2020 (Microsoft, Redmond, WA), and statistical analysis was performed on SPSS software version 22 (SPSS Statistics for Windows, Version 21.0; IBM, Armonk, NY). Categorical variables were described as percentages. Continuous variables were described as mean and standard deviation or median and interquartile range. Proportions were compared between groups using χ2 test or Fisher’s exact test, whichever was applicable. Numerical variables were compared between two groups by Student’s t-test or Mann-Whitney U test, depending upon normality of distribution. A P value < 0.05 was considered significant.

RESULTS

A total of 50 children with clinical illness compatible with dengue were screened, and five were excluded due to confirmation of an alternate diagnosis. One child was excluded from analysis due to sample processing error. Of 44 patients enrolled, 14 tested positive for NS1 antigen, 22 were positive for IgM anti-dengue antibodies, and 8 tested positive for both. The median age of the study population was 96 months (IQR: 60–129 months). Twenty-seven (61%) were boys. The clinical features with severity and outcome are depicted in Table 1. Fever (98%) was the most common presenting feature, followed by vomiting (78%) and abdominal pain (68%). Hepatomegaly (68%) and edema (32%) were the common examination findings. Most patients had profound thrombocytopenia, elevated transaminases, and hypoalbuminemia. The laboratory features are summarized in Table 2. The cohort had a high proportion of severe dengue (N = 30; 68%), where two-thirds of them (N = 20; 45%) presented with features of shock. Nineteen (43.2%) children required admission to the PICU for a median period of 5 days (IQR: 2–11 days). Organ supportive therapies included invasive ventilation (22.7%) and renal replacement therapy (10%). None of the children was positive for SARS CoV2 RNA by reverse transcription–polymerase chain reaction during hospital admission, whereas IgG antibodies against SARS-CoV-2 were detected in 15 (34%) children, suggesting recent exposure to SARS-CoV-2, although none had symptomatic infection or history of contact with a known case of SARS-CoV-2 infection in the recent past. Age and laboratory markers, including proinflammatory cytokines (IL-6), were comparable between children with and without IgG antibodies against SARS-CoV-2. Interestingly, children with recent SARS-CoV-2 exposure developed fewer organ dysfunctions (acute kidney injury, central nervous system dysfunction) and could be managed with a lower frequency of invasive ventilation. This trend is reflected in the composite organ dysfunction scores (Pediatric Sequential Organ Failure Assessment and MODS scores); however, none of these differences was statistically significant (Table 3). Death was recorded in 4 (9%) children, but no deaths were recorded in those possessing IgG antibodies against SARS-CoV-2.

Table 1

Demographic and clinical characteristics of the study population (N = 44)

CharacteristicsFrequency/Values
Age in months96 (69–129)
Boys27 (61)
Clinical features
 Fever43 (98)
 Vomiting32 (78)
 Abdominal pain30 (68)
 Hepatomegaly30 (68)
 Myalgia17 (39)
 Rapid breathing15 (34)
 Edema14 (32)
 Rash10 (23)
Severity
 Dengue with warning signs14 (32)
 Severe Dengue30 (68)
 Dengue shock syndrome20 (45)
 Compensated shock13 (29.5)
 Hypotensive shock7 (15.9)
 Need for inotrope/vasoactive drug therapy17 (38.6)
Duration of inotrope/vasoactive drug therapy in hours60 (24–115)
Encephalopathy9 (20.9)
Liver dysfunction25 (58.1)
Acute kidney injury11 (25)
KDIGO
 Stage 15 (11.3)
 Stage 22 (4.5)
 Stage 34 (9)
Renal replacement therapy4 (9.1)
Invasive ventilation10 (22.7)
p-SOFA score at admission5 (3–7)
Worst p-SOFA score5 (3–7)
PICU admission19 (43)
Length of PICU stay in days5 (2–11)
Length of hospital stay in days4 (3–6)
Deaths4 (9.1)

IQR = interquartile range; KDIGO = Kidney Disease: Improving Global Outcomes; PICU = pediatric intensive care unit; p-SOFA = Pediatric Sequential Organ Function Assessment. Values expressed are in numbers (%) or median (interquartile range).

Table 2

Laboratory parameters in study patients

ParametersPositive (%)/values
Dengue diagnosis
 NS1 antigen14 (32)
 IgM antibody22 (50)
 Both NS1 and IgM8 (18)
SARS-CoV-2 infection
 RT-PCR0
 IgG antibody15 (34)
Hemoglobin at admission (g/dL)12 (10.7–14)
Total leukocyte count at admission (×109 cells/L)8.45 (4.87–11.65)
Platelet count at admission (×109 cells/L)26 (16–47)
Lowest platelet count (×109 cells/L)21 (12–43)
Aspartate transaminase (IU/L)607 (161.5–1,470)
Alanine transaminase (IU/L)235.5 (66–616.75)
Albumin (g/dL)2.5 (2.03–3.13)
IL-6 (pg/mL)20.7 (11.1–67.4)

RT-PCR = reverse transcription polymerase chain reaction. Values expressed are in numbers (%) or median (interquartile range).

Table 3

Comparison between SARS-CoV-2 exposed and unexposed groups

SARS-CoV-2 exposed (N = 15)SARS-CoV-2 unexposed (N = 29)P value
Age in months84 (48–120)96 (66–132)0.40
Hemoglobin at admission (g/dL)12.6 (11.1–14.2)12 (10.4–13.8)0.54
Total leukocyte count at admission (×109 cells/L)8.7 (3.9–11.83)8.2 (4.9–11.6)0.91
Platelet count at admission (×109 cells/L)29 (2–46)24 (13–5)0.34
Lowest platelet count (×109 cells/L)25 (19–46)19 (1–40.5)0.15
Aspartate transaminase (IU/L)472.5 (72.5–1,930)607 (165–1,431)0.64
Alanine transaminase (IU/L)178.5 (50.75–907.75)281.5 (68–580.25)0.78
Albumin (g/dL)2.5 (2–3.28)2.5 (2–2.8)0.57
Interleukin-6 (pg/mL)20.7 (10.2–67.4)22.3 (11.4–84.2)0.77
Severe dengue10 (67)22 (76)0.52
Shock8 (53)12 (41)0.45
Encephalopathy1 (6.7)8 (28.6)0.13
Liver dysfunction7 (46)18 (64)0.26
Acute kidney injury1 (6.7)10 (34)0.06
 Stage 10 (0)5 (17.9)
 Stage 21 (6.7)1 (3.6)
 Stage 30 (0)4 (14.3)
Renal replacement therapy1 (6.7)3 (10.3)1.00
Invasive ventilation1 (6.7)9 (31)0.13
p-SOFA score at admission3 (3–6)5.5 (3–8.5)0.25
Worst p-SOFA score4 (3–7)6 (3–10.5)0.15
Organ dysfunctions at admission1 (1–3)2 (1–4)0.08
Worst MODS score2 (1–3)3 (1–4.5)0.07
Length of PICU stay, days4.5 (2–9.75)5 (2.5–11)0.75
Length of hospital stay, days4 (2–6)4 (3–8.5)0.68
Deaths04 (13.7)0.28

MODS = multiorgan dysfunction syndrome; p-SOFA = Pediatric Sequential Organ Function Assessment. Values are expressed in numbers (%) or median (interquartile range).

DISCUSSION

In this prospective observational study, it was observed that one-third of all hospitalized children with dengue during the 2020 outbreak had recent exposure to SARS-CoV-2 infection. The clinical outcomes, including mortality, length of PICU, and length of hospital stay, were not different between children with and without SARS-CoV-2 exposure. There was, however, a trend toward a lower frequency of acute kidney injury and in the number of organ dysfunctions in children with recent exposure to SARS-CoV-2. A considerable overlap between the COVID-19 pandemic and seasonal dengue outbreak was noted during 2020 in India. The peak cases of COVID-19 in the Chandigarh region were reported between August 15 and October 15, 2020, coinciding with dengue transmission (Figure 1). This is in concurrence with reports from Brazil and other regions where both viruses peaked simultaneously, causing co-epidemics.16 Several studies from different parts of the world have reported a decline in the incidence of respiratory viral infections during 2020, possibly due to widely following COVID-appropriate behavior, including the use of masks, limiting outdoor activities, and closure of schools.1720 In fact, a similar reduction was observed in feco-orally transmitted infections.19 Dengue, however, is a mosquito-borne arboviral disease with a seasonal incidence. Asian tiger mosquitoes, Aedes albopictus and Aedes aegypti, are the principal vectors of its transmission. The effects of the ongoing COVID-19 pandemic and alterations in social structure on dengue are not very clear. The National Vector Borne Disease Control Program of India reported a sharp decline of 75% (39,419 versus 157,315) in dengue incidence during 2020 as compared with 2019. The possible reasons for this reduction could be lower transmission of the vector, less exposure due to COVID-19 lockdown, and, potentially, a disparity in the reported data possibly due to underdiagnosis or underreporting because of increased attention to the COVID-19 pandemic.21 In an earlier study conducted in 2019 at our center, 41 children with dengue were enrolled, a figure comparable to the current study.22

Figure 1.
Figure 1.

Nearly overlapping peaks of SARS-CoV-2 cases in the region where the study was conducted and children with dengue presenting to the study site. This figure appears in color at www.ajtmh.org.

Citation: The American Journal of Tropical Medicine and Hygiene 105, 3; 10.4269/ajtmh.21-0586

The clinical presentation of dengue in this study was very similar to previous cohorts. The majority of patients presented with fever and one or more warning signs. At the outset, it may be difficult to differentiate between dengue and COVID-19, particularly MIS-C, in children due to overlapping clinical and laboratory features. Fever, headache, myalgia, abdominal pain, and vomiting are some of the shared clinical features in dengue and MIS-C. Leukopenia, thrombocytopenia, and elevated transaminases are common laboratory abnormalities. In addition, a false‐positive serology for dengue has been noted in patients with confirmed COVID‐19.23,24 In a study in adults, Joubert et al25 have observed that nonsevere dengue cases were more symptomatic than mild to moderate COVID-19. Body aches, headache, and retro-orbital pain were the presentations in dengue, whereas anosmia and delayed presentation (> 3 days post onset) were suggestive of COVID-19. No literature is available to establish whether SARS-CoV-2 exposure alters the clinical presentation or course of dengue. In our experience, the clustering of cases during the post-monsoon season, the presence of third spacing, hemoconcentration, and profound thrombocytopenia were some of the distinguishing features noted in dengue.

We noted a trend toward a higher incidence of acute kidney injury and a greater number of organ dysfunctions in children not exposed to SARS-CoV-2; however, due to the small sample size, we were not able to draw meaningful conclusions. Researchers from Brazil reported that the intensity of SARS-CoV-2 epidemic, in terms of number, severity, and rapidity of spread of infections, was lower in areas where a high prevalence of dengue fever was reported in the previous season.26 The biological plausibility of this hypothesis has been elucidated by molecular docking studies, which showed that antibodies to dengue virus bound to antigens on the SARS-CoV-2 virus.27 This indicates the existence of antigen mimicry between the two viruses and a possibility of cross-reactivity between the antibodies.28 Some authors expressed uncertainty over the possible course of dengue fever in patients with past exposure to SARS-CoV-2. The dilemma was whether the cross-reactive antibodies would provide partial protection against severe dengue infection or lead to increased severity due to the well-known phenomenon of antibody-dependent enhancement seen in dengue.27 We hypothesize that the presence of antibodies to SARS-CoV-2 might decrease the severity of dengue. Larger multicentric clinical studies or population data from dengue endemic regions might help in understanding the existence of the cross-reactive, cross-protective association between these two single-stranded, positively coiled +SS RNA viruses.

The strength of the present study lies in its novel attempt to assess the effect of recent SARS-CoV-2 exposure on dengue infection in children. Both these viruses are of significant public health concerns in the region. However, the study has a limitation of small sample size.

The present study exposes preliminary evidence that dengue fever might follow a less severe course in children with recent exposure to SARS-CoV-2 infection. However, it is pertinent to understand the antigenic similarity and cross-protective antibody response between the two viruses and their clinical relevance.

ACKNOWLEDGMENTS

We acknowledge the support offered by regional Viral Research and Diagnostic Laboratory (VRDL), Department of virology, PGIMER and National Vector Borne Disease Control Programme (NVBDCP), Government of India in laboratory testing for dengue NS1antigen and IgM antibodies. The American Society of Tropical Medicine and Hygiene has waived the Open Access fee for this article due to the ongoing COVID-19 pandemic and has assisted with publication expenses.

References

  • 1.

    Wolff D, Nee S, Hickey NS, Marschollek M, 2020. Risk factors for COVID-19 severity and fatality: a structured literature review. Infection 49: 1528.

    • Search Google Scholar
    • Export Citation
  • 2.

    Castagnoli R, Votto M, Licari A, Brambilla I, Bruno R, Perlini S, Rovida F, Baldanti F, Marseglia GL, 2020. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review. JAMA Pediatr 174: 882.

    • Search Google Scholar
    • Export Citation
  • 3.

    Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P, 2020. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet 395: 16071608.

    • Search Google Scholar
    • Export Citation
  • 4.

    Consiglio CR et al., 2020. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell 183: 968981.e7.

  • 5.

    Lee PY et al., 2020. Distinct clinical and immunological features of SARS-CoV-2-induced multisystem inflammatory syndrome in children. J Clin Invest 130: 59425950.

    • Search Google Scholar
    • Export Citation
  • 6.

    Gruber CN et al., 2020. Mapping systemic inflammation and antibody responses in Multisystem Inflammatory Syndrome in Children (MIS-C). Cell 183: 982995.e14.

    • Search Google Scholar
    • Export Citation
  • 7.

    Chen Y et al., 2020. Active or latent tuberculosis increases susceptibility to COVID-19 and disease severity. medRxiv 2020.03.10.20033795.

  • 8.

    Gupta N, Srivastava S, Jain A, Chaturvedi UC, 2012. Dengue in India. Indian J Med Res 136: 373390.

  • 9.

    Dash N, Rose W, Nallasamy K, 2020. India’s lockdown exit: are we prepared to lock horns with COVID-19 and dengue in the rainy season? Pediatr Res 89:10471048.

    • Search Google Scholar
    • Export Citation
  • 10.

    Din M, Asghar M, Ali M, 2021. COVID-19 and dengue coepidemics: a double trouble for overburdened health systems in developing countries. J Med Virol 93: 601602.

    • Search Google Scholar
    • Export Citation
  • 11.

    Miah MdA , Husna A, 2021. Coinfection, coepidemics of COVID-19, and dengue in dengue-endemic countries: a serious health concern. J Med Virol 93: 161162

    • Search Google Scholar
    • Export Citation
  • 12.

    Tiwari L, Shekhar S, Bansal A, Kumar P, 2020. COVID-19 with dengue shock syndrome in a child: coinfection or cross-reactivity? BMJ Case Rep CP 13: e239315.

    • Search Google Scholar
    • Export Citation
  • 13.

    Masyeni S, Santoso MS, Widyaningsih PD, Asmara DW, Nainu F, Harapan H, Sasmono RT, 2021. Serological cross-reaction and coinfection of dengue and COVID-19 in Asia: experience from Indonesia. Int J Infect Dis 102: 152154.

    • Search Google Scholar
    • Export Citation
  • 14.

    Guabiraba R, Ryffel B, 2014. Dengue virus infection: current concepts in immune mechanisms and lessons from murine models. Immunology 141: 143156.

    • Search Google Scholar
    • Export Citation
  • 15.

    Goldstein B, Giroir B, Randolph A, International Consensus Conference on Pediatric Sepsis , 2005. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med J Soc Crit Care Med World Fed Pediatr Intensive Crit Care Soc 6: 28.

    • Search Google Scholar
    • Export Citation
  • 16.

    Magalhaes T, Chalegre KDM, Braga C, Foy BD, 2020. The endless challenges of arboviral diseases in Brazil. Trop Med Infect Dis 5:75.

  • 17.

    Nolen LD, Seeman S, Bruden D, Klejka J, Desnoyers C, Tiesinga J, Singleton R, 2020. Impact of social distancing and travel restrictions on non–coronavirus disease 2019 (non–COVID-19) respiratory hospital admissions in young children in rural Alaska. Clin Infect Dis 72: 21962198.

    • Search Google Scholar
    • Export Citation
  • 18.

    Kuitunen I, Artama M, Mäkelä L, Backman K, Heiskanen-Kosma T, Renko M, 2020. Effect of social distancing due to the COVID-19 pandemic on the incidence of viral respiratory tract infections in children in Finland during early 2020. Pediatr Infect Dis J 39: e423e427.

    • Search Google Scholar
    • Export Citation
  • 19.

    Angoulvant F et al., 2021. Coronavirus disease 2019 pandemic: impact caused by school closure and national lockdown on pediatric visits and admissions for viral and nonviral infections—a time series analysis. Clin Infect Dis 72: 319322

  • 20.

    Sakamoto H, Ishikane M, Ueda P, 2020. Seasonal influenza activity during the SARS-CoV-2 outbreak in Japan. JAMA 323: 19691971.

  • 21.

    Phadke R, Mohan A, Çavdaroğlu S, Dapke K, Costa AC dos S, Riaz MMA, Hashim HT, Essar MY, Ahmad S, 2021. Dengue amidst COVID-19 in India: the mystery of plummeting cases. J Med Virol 93: 41204121.

    • Search Google Scholar
    • Export Citation
  • 22.

    Williams V, Menon N, Bhatia P, Biswal M, Sreedharanunni S, Rawat A, Jayashree M, Nallasamy K, 2020. Serum ferritin predicts neither organ dysfunction nor mortality in pediatric sepsis due to tropical infections. Front Pediatr 8: 607673.

    • Search Google Scholar
    • Export Citation
  • 23.

    Teotônio IMSN, de Carvalho JL, Castro LC, Nitz N, Hagström L, Rios GG, de Fátima Rodrigues de Oliveira M, Dallago BSL, Hecht M, 2021. Clinical and biochemical parameters of COVID-19 patients with prior or active dengue fever. Acta Trop 214: 105782.

    • Search Google Scholar
    • Export Citation
  • 24.

    Yan G et al., 2020. Covert COVID-19 and false-positive dengue serology in Singapore. Lancet Infect Dis 20: 536.

  • 25.

    Joubert A, Andry F, Bertolotti A, Accot F, Koumar Y, Legrand F, Poubeau P, Manaquin R, Gérardin P, Levin C, 2021. Distinguishing non severe cases of dengue from COVID-19 in the context of co-epidemics: a cohort study in a SARS-CoV-2 testing center on Reunion Island. PLoS Negl Trop Dis 15: e0008879.

    • Search Google Scholar
    • Export Citation
  • 26.

    Nicolelis MAL, Raimundo RLG, Peixoto PS, de Andreazzi CS, 2020. How super-spreader cities, highways, hospital bed availability, and dengue fever influenced the COVID-19 epidemic in Brazil. medRxiv 2020.09.19.20197749.

    • Search Google Scholar
    • Export Citation
  • 27.

    Nath H, Mallick A, Roy S, Sukla S, Biswas S, 2021. Computational modelling supports that dengue virus envelope antibodies can bind to SARS-CoV-2 receptor binding sites: is pre-exposure to dengue virus protective against COVID-19 severity? Comput Struct Biotechnol J 19: 459466.

    • Search Google Scholar
    • Export Citation
  • 28.

    Lustig Y, 2020. Potential antigenic cross-reactivity between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and dengue viruses. Clin Infect Dis (Corrected Proof, Ahead of print).

Author Notes

Address correspondence to Karthi Nallasamy, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. E-mail: ny.karthi@gmail.com

†These authors contributed equally to this work.

Authors’ addresses: Namita Ravikumar, Pediatric Intensive Care and Pulmonology Units, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India, E-mail: namitu.ravi@gmail.com. Manjinder Singh Randhawa, Karthi Nallasamy, Suresh Kumar Angurana, and Muralidharan Jayashree, Division of Pediatric Critical Care, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India, E-mails: randhawams192@gmail.com, ny.karthi@gmail.com, sureshangurana@gmail.com, and mjshree@hotmail.com. Mahendra Kumar, Department of Immunopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India, E-mail: drbindmahendra@gmail.com. Gursimran Kaur Mohi and Radha Kanta Ratho, Department of Virology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India, E-mails: gkmohi@gmail.com and rathopgi@yahoo.com.

Save