Abstract
Background :
Outcome data of children with heart disease who acquired COVID-19 infection are limited.
Aims :
We sought to analyze outcome data and identify risk factors associated with mortality in children with heart disease and grown-ups with congenital heart disease (GUCH) who had a laboratory-confirmed COVID-19 infection.
Settings and Design :
This is a retrospective, multicentric, observational study.
Materials and Methods :
The study included children with heart disease and GUCH population, who presented with either symptomatic or asymptomatic COVID-19 infection to any of the participating centers. COVID-19-negative patients admitted to these centers constituted the control group.
Results :
From 24 pediatric cardiac centers across India, we included 94 patients with a median age of 12.5 (interquartile range 3–96) months and 49 (52.1%) patients were males. Majority (83 patients, 88.3%) were children. One-third of the patients (n = 31, 33.0%) had acyanotic congenital heart disease, and 41.5% (n = 39) were cyanotic, with > 80% of the patients being unoperated. Only 30 (31.9%) patients were symptomatic for COVID-19 infection, while the rest were incidentally detected positive on screening. A total of 13 patients died (case fatality rate: 13.8%). The in-hospital mortality rate among hospitalized patients was significantly higher among COVID-19-positive cases (13 of 48; 27.1%) as compared to COVID-negative admissions (9.2%) during the study period (P < 0.001). On multivariate analysis, the independent predictors of mortality among COVID-19-positive cases were severity of illness at admission (odds ratio [OR]: 535.7, 95% confidence interval [CI]: 6.9–41,605, P = 0.005) and lower socioeconomic class (OR: 29.5, 95% CI: 1.1–814.7, P = 0.046).
Conclusions :
Children with heart disease are at a higher risk of death when they acquire COVID-19 infection. Systematic preventive measures and management strategies are needed for improving the outcomes.
Keywords: Congenital heart disease, grown-ups with congenital heart disease, low- and middle-income countries and SARS-CoV-2 infection, outcome, surgery
INTRODUCTION
Children constitute between 2% and 14% of all COVID-19 cases worldwide.[1,2] Children in general are at a lower risk of serious illness and mortality due to COVID-19 as compared to adults.[3,4] However, children with comorbidities may be at a higher risk of serious illness and death.[5] Children with heart disease are perceived to be at a higher risk of serious complications from SARS-CoV-2 infection due to various reasons.[6] However, data about the outcomes of children with preexisting heart disease acquiring a COVID-19 infection are limited. The published large series either focused entirely[7,8] or mostly[9,10] on grown-ups with congenital heart disease (GUCH) population. The reports in children are limited to less than ten patients.[11] All these series, mostly from the developed nations, reported complication and mortality rates comparable to the general population.[8] Majority of the patients in these reports were already operated for congenital heart disease (CHD). On the other hand, majority of the patients with an CHD contracting a COVID-19 infection in low-and middle-income countries (LMICs) are unoperated for heart disease.[11,12]
Like most other countries in the world, India faced the raging pandemic from March 2020. Anticipating high number of COVID-19 cases, India adopted a strict nationwide lockdown in the beginning of the first wave of the COVID-19 pandemic. While the lockdown helped in slowing down the pandemic, it posed unforeseen challenges in access to limited pediatric cardiac centers, which are mostly concentrated in the metros. Late presentation and out-of-pocket expenses[13,14] are unique problems encountered in Indian health care, and these challenges were exaggerated during the pandemic times. In addition, unfavorable demographics and socioeconomic status of most of these children in LMICs made timely detection and management of heart disease challenging in the pandemic times. These factors might impact the outcomes of children with heart disease. Therefore, the Pediatric Cardiac Society of India (PCSI) conducted this multicentric retrospective study to evaluate the outcomes of children with heart disease and GUCH population, who acquired COVID-19 during the first wave of the COVID-19 pandemic in India.
MATERIALS AND METHODS
In this multicentric, retrospective, observational study, data from 24 Indian pediatric cardiac centers between April 1, 2020, and August 31, 2020, were collected. The detailed methodology is published elsewhere.[15] We included all consecutive children (<18 years) or GUCH patients seen in the outpatient departments or hospitalized in the participating pediatric cardiac facilities across India. Children with any form of heart disease including CHD, acquired heart diseases such as rheumatic heart disease, and previously diagnosed myocardial diseases were included in the study. Children presenting with multisystem inflammatory syndrome associated with COVID-19 in the absence of preexisting heart disease were excluded from the study. All the included patients had a positive naso- and oro-pharyngeal swab for SARS-CoV-2 nucleic acid using reverse-transcriptase quantitative-polymerase chain reaction (RT-PCR) assay or cartridge-based nucleic acid amplification test (CBNAAT) in the preceding 28 days. Tests may have been performed either due to symptoms suggestive of COVID-19 infection or for screening prior to admission or intervention. COVID-19-negative patients with CHDs seen in the outpatient department or admitted to the participating centers during the same period constituted the control group. Ethical approval or a no-objection certificate was obtained at each of the participating institutions. The study was registered in the Clinical Trials Registry-India (CTRI) database (CTRI registration number CTRI/2020/10/028251).
We invited all the major pediatric cardiac centers of the country for participation in the study. Out of the 24 centers participating in the primary study,[15] only 13 centers reported encountering COVID-19 patients fulfilling the inclusion and exclusion criteria of the study. The site investigator was responsible for data collection using the study pro forma [Supplementary Appendix 1].
Demographic and clinical details and laboratory parameters of COVID-19-positive patients were collected [Supplementary Appendix 1]. COVID-19 status and approximate socioeconomic class (modified Kuppuswamy scale)[16] of the family were recorded. Presence or absence, and duration of symptoms suggestive of COVID-19, and presenting symptoms were noted. The severity of illness at presentation was classified into severe and nonsevere illness based on the presence of cyanotic spells, refractory heart failure, persistent shock, or requirement for ventilatory support. Due to the retrospective nature of the study, we could not discern the relative contribution of cardiac illness and respiratory involvement due to COVID-19 in causing a severe illness at presentation. However, the treating physician was required to identify the contribution of COVID-19 in the causation of death as definite, possible, or incidental. We classified the types of heart diseases into obstructive, acyanotic, and cyanotic CHD and acquired heart disease in children. Data regarding need for surgery, whether surgery was done in the index hospitalization, postoperative mortality, and in-hospital mortality were noted. The outcome data were recorded as death or hospital discharge.
We collected the hospital statistics including the number of outpatient visits, hospitalizations, surgeries performed, and mortality in COVID-19-negative patients from all these 13 centers over the same time period in 2020. The Risk Adjustment for Congenital Heart Surgery (RACHS-1) scoring[17] was used to stratify the complexity of all the surgeries performed in both COVID-19-positive and COVID-19-negative patients.
Statistical analysis
Categorical variables were presented as frequency and percentages, and continuous variables were presented as mean ± standard deviation, or median (Q25–Q75) as appropriate. Comparisons of various characteristics between COVID-positive and COVID-negative patients were done using the Chi-square test. All the categorical and continuous predictors were compared with in-hospital mortality using the Chi-square test/Fisher's exact test and Wilcoxon rank sum test, respectively. A univariate followed by a step-wise logistic regression analysis was used to find out the independent predictors of mortality with entry and removal probability of 0.05 and 0.25, respectively. The results were presented as odds ratio (OR) and 95% confidence interval (CI). Stata 16.0 (StataCorp LLC, TX, USA) was used for all statistical analyses. P <0.05 was considered significant.
RESULTS
Data of 94 patients (49 males; 52.1%) with COVID-19 infection seen at the 13 participating pediatric cardiac centers across India were analyzed. The study population included 10 neonates (10.6%), 37 infants (39.4%), 36 children aged between 1 and 18 years (38.3%), and 11 GUCH (11.7%) patients (range 18–62 years), and the median age was 13 months (range 3 days to 62 years). Two large centers contributed more than 15 COVID-19-positive cases each. Ninety-two patients had RT-PCR positivity, and two patients had CBNAAT positivity. The demographic characteristics at presentation are summarized in Table 1. One-third (n = 31, 33%) of the patients had acyanotic CHD, and 41.5% (n = 39) were cyanotic. The details of cardiac lesions are summarized in Supplementary Table 1. Out of the 94 patients, only 18 (19.1%) patients had undergone a previous percutaneous or surgical intervention. Syndromes associated with CHD were identified in seven children (7.4%).
Table 1.
Baseline characteristics of coronavirus disease-2019-positive patients in the study
| Characteristics | Observed values (n=94) Mean±SD or n (%) |
|---|---|
| Median age (IQR) (months) | 12.5 (3-96) |
| Mean age - children* (months) (n=83) | 40.0±59.1 |
| Mean age - GUCH (years) (n=11) | 33.5±14.3 |
| Males | 49 (52.1) |
| Details of heart disease | |
| CHD | |
| Cyanotic | 39 (41.4) |
| Acyanotic | 31 (33.0) |
| Obstructive | 12 (12.8) |
| Acquired heart disease in children | 12 (12.8) |
| Socioeconomic status | |
| Lower | 22 (23.4) |
| Lower-middle | 23 (24.5) |
| Middle | 40 (42.5) |
| Upper | 9 (9.6) |
| Malnourished on initial assessment | 27 (28.7) |
| Duration of symptoms prior to admission (days) | 4.0±6.2 |
| Severity of illness at admission | |
| Severe | 12 (12.8) |
| Not severe | 82 (87.2) |
| Mean SpO2 (%) | 89.1±9.4 |
| Prior ACE inhibitors/ARB | 11 (11.7) |
*<18-years-old including neonates and infants. SD: Standard deviation, IQR: Interquartile range, GUCH: Grown-ups with congenital heart disease, ACE: Angiotensin-converting enzyme, ARB: Angiotensin receptor blocker, SpO2: Oxygen saturation, CHD: Congenital heart disease
Supplementary Table 1.
Diagnosis of individual lesions among coronavirus disease-2019-positive patients (n=94)
| Type of heart disease | n (%) |
|---|---|
| CHD | |
| Cyanotic CHD | 39 (41.5) |
| Tetralogy of Fallot | 16 |
| Transposition of great arteries | 5 |
| VSD pulmonary atresia | 5 |
| TAPVC | 3 |
| Others | 10 |
| Acyanotic CHD | 31 (33.0) |
| VSD | 13 |
| Atrial septal defect | 8 |
| Patent ductus arteriosus | 6 |
| Others | 4 |
| Obstructive CHD | 12 (12.8) |
| Coarctation of aorta | 5 |
| Aortic stenosis | 3 |
| Pulmonary stenosis | 3 |
| Congenital mitral stenosis | 1 |
| Acquired heart disease in children | 12 (12.8) |
| Infective endocarditis* | 3 |
| Idiopathic pulmonary hypertension | 2 |
| Dilated cardiomyopathy | 2 |
| Rheumatic heart disease | 2 |
| Others | 3 |
*All three had underlying heart disease but were primarily admitted for infective endocarditis. CHD: Congenital heart disease, VSD: Ventricular septal defect, TAPVC: Total anomalous pulmonary venous connection
Out of the 11 GUCH patients (6 females) included in the study, 5 were symptomatic for COVID-19 with fever. Two patients had serious illness due to acute respiratory distress syndrome (ARDS) related to COVID-19, and both the patients required noninvasive ventilation. Rest of the GUCH patients had mild illness. No deaths were observed in the GUCH population with COVID-19 infection. Two unoperated adult patients with atrial septal defect underwent surgery 1–3 months after recovery from COVID-19 infection.
Only 30 patients (31.9%) were symptomatic for COVID-19 at the time of testing, and the remaining patients had incidental positive reports, performed as part of preprocedural screening. Symptoms suggestive of COVID-19 included fever in 25 patients, tachypnea unexplained by heart disease in 14 children, and new-onset cyanosis in 5 patients, who did not have a cyanotic CHD. Nearly half of the patients (n = 48; 51.1%) needed hospitalization following a positive COVID test and the rest were managed at home, a decision based on clinical assessment by the treating team, and prevailing hospital policies. The hospital course and major in-hospital complications are summarized in Table 2. Thrombotic complications were noted in three patients and included a left ventricular clot in a child with dilated cardiomyopathy, prosthetic heart valve thrombosis of mitral valve in a child with rheumatic heart disease, and ischemic stroke in an infant following closure of ventricular septal defect. One patient received dialysis and one patient required tracheostomy. Of the 13 patients requiring intubation and ventilation at admission, 9 died. Patients who survived invasive ventilation included one patient each requiring emergency aortic valve balloon dilatation, surgery for coarctation of aorta, management of atrial tachyarrhythmia, and surgical closure of ventricular septal defect.
Table 2.
Characteristics of hospitalized coronavirus disease-2019-positive patients in the study
| Characteristics | Observed values (n=48) Mean±SD or n (%) |
|---|---|
| Complications during hospital stay* | |
| ARDS | 7 (14.5) |
| Pneumothorax | 1 (2.1) |
| Arrhythmia | 2 (4.2) |
| Myopericarditis | 1 (2.1) |
| Superadded infections | 7 (14.5) |
| Elevated liver enzymes | 4 (8.3) |
| Hypoglycemia | 3 (6.2) |
| Acute kidney injury | 3 (6.2) |
| Seizure | 2 (4.2) |
| Investigations** | |
| Hemoglobin (g/dL) | 13.0±3.2 |
| Neutrophil: lymphocyte ratio | 1.5±1.3 |
| Platelet count (lakh/mm3) | 2.6±1.1 |
| C-reactive protein (mg/dL) | 6.0±3.5 |
| Serum creatinine (mg/dL) | 0.5±0.5 |
| Need for medications related to COVID-19* | |
| Corticosteroids | 12 (25) |
| Remdesivir | 6 (12.5) |
| Heparin | 14 (29.2) |
| Inotrope/ventilation requirement* | |
| Need for invasive ventilation | 13 (27.1) |
| Need for noninvasive ventilation | 6 (12.5) |
| Shock | 11 (22.9) |
| Heart failure | 12 (25) |
| Procedures during index hospitalization* | |
| Emergency interventions | 3 (6.2) |
| Emergency surgery | 2 (4.2) |
| Surgery after recovery from COVID-19 | 17 (35.4) |
| Death* | 13 (27.1) |
*Percentage of number of hospitalized patients, **Performed in limited number of patients. ARDS: Acute respiratory distress syndrome, COVID-19: Coronavirus disease-2019, SD: Standard deviation
Two neonates (one each underwent patenting ductus arteriosus [PDA] ligation; coarctation of aorta repair) underwent emergency surgery, and 3 children (one each underwent emergency balloon dilation of coarctation; pulmonary valve balloon dilation [PVBD]; aortic valve balloon dilation) underwent an emergent interventional procedure using strict personal protective equipment protocols. The patient who underwent PDA ligation already had ARDS and systemic inflammatory response syndrome, which did not improve even after PDA ligation. The patient who underwent PVBD expired a few days after the procedure due to ARDS and shock. Three children were detected to be COVID-19 positive upon retesting following a COVID-19-like respiratory illness in the postoperative period. In rest of the children who underwent a cardiac surgery during the index hospitalization, the surgery was done after 10–28 days of recovery from COVID-19 infection. Apart from this, surgical or interventional management was required in another 51 patients but had to be deferred as most hospitals followed an “emergency cases-only” policy during the pandemic.
As compared to the COVID-19-negative group, COVID-19-positive patients had lesser proportion of neonates and GUCH patients [Table 2]. A higher proportion of COVID-19-positive patients required hospitalization and preoperative ventilation. However, the proportion of patients undergoing a cardiac surgery or emergency procedures was lower among hospitalized COVID-19-positive patients. RACHS-1 score distribution suggested increased complexity of surgeries performed in COVID-19-positive patients, but the difference was statistically insignificant, possibly due to small numbers.
A total of 13 deaths (13.8%) occurred in the COVID-19-positive cases including 3 among 19 patients operated for heart disease during index hospitalization. The overall mortality of the cohort as well as the in-hospital mortality was significantly higher in the COVID-19 positive-group as compared to all COVID-19-negative patients in the corresponding study period [Table 3]. Majority of the excess deaths occurred in unoperated patients, and the postoperative mortality among the groups was comparable [Table 3]. The individual details of the deceased patients are presented in Table 4. In nine deaths (69.2%), the treating physician attributed COVID-19 infection as a definite causative factor for mortality.
Table 3.
Comparison of coronavirus disease-2019-positive versus coronavirus disease-2019-negative patients hospitalized during the study period
| COVID-19 positive, n (%) | COVID-19 negative, n (%) | P | |
|---|---|---|---|
| Total number of outpatient visits | 94 | 9182 | - |
| Age distribution among outpatient patients | |||
| Neonate | 10 (10.6) | 1991 (21.7) | 0.03 |
| Infants/children | 73 (77.7) | 6390 (69.6) | |
| GUCH | 11 (11.7) | 801 (8.7) | |
| Number of children admitted | 48 (51.1) | 1187 (12.9) | <0.001 |
| Overall mortality | 13 (13.8) n=48 | 109 (1.2) n=1187 | <0.001 |
| Among hospitalized patients Total number | |||
| Need for preoperative ventilation | 13 (27.1) | 123 (10.4) | <0.001 |
| Proportion of admitted children undergoing surgery | 19 (39.6) | 686 (57.8) | 0.01 |
| Need for emergency surgery | 2 (4.2) | 245 (20.6) | 0.003 |
| RACHS category of surgeries performed | n=19 | n=686 | |
| Category 1 | 4 (21.1) | 134 (19.5) | 0.05 |
| Category 2 | 5 (26.3) | 344 (50.1) | |
| Category 3 | 9 (47.4) | 147 (21.4) | |
| Category 4 | 0 | 5 (0.7) | |
| Others | 1 (5.2) | 56 (8.2) | |
| In-hospital mortality | 13 (27.1) | 109 (9.2) | <0.001 |
| Preprocedural mortality | 9 (18.8) | 24 (2.0) | <0.001 |
| Postoperative mortality | 3/19 (15.8) | 85/686 (12.4) | 0.72 |
GUCH: Grown-ups with congenital heart disease, RACHS: Risk Adjustment for Congenital Heart Surgery
Table 4.
Individual details of the deceased patients with coronavirus disease-2019
| Age (months) | Gender | Diagnosis | SpO2 (%) | Details | COVID as a cause of mortality |
|---|---|---|---|---|---|
| 0.3 | Male | Transposition of great arteries, intact ventricular septum, patent ductus arteriosus | 80 | COVID-19 negativity at admission. Postarterial switch operation - deterioration of respiratory status 2 days after extubation, reintubated and died due to pulmonary hemorrhage | Definite |
| 1 | Female | Large patent ductus arteriosus | 88 | Surgical ligation done for failed medical therapy | Definite |
| 2 | Male | Obstructed total anomalous pulmonary venous connection | 74 | COVID-19 negativity at admission. Following an emergency surgery, acute respiratory distress syndrome-like picture; COVID-19-positive on retest | Definite |
| 3 | Male | S/P infracardiac total anomalous pulmonary venous return repair, Restenosis of pulmonary vein confluence to left atrium | 90 | Had severe pulmonary hypertension and right ventricular dysfunction. Was planned for early surgery after recovery from COVID-19 | No |
| 6 | Male | Tricuspid atresia, pulmonary atresia, generous patent ductus arteriosus | 72 | Patient died prior to scheduled surgery | Definite |
| 9 | Male | Severe pulmonary stenosis, moderate right ventricle dysfunction | 82 | Underwent emergency pulmonary valve balloon dilation in cath lab | Definite |
| 20 | Male | Tetralogy of Fallot, cyanotic spell | 50 | Died due to severe cyanotic spell, awaiting an emergency surgery | Possible |
| 63 | Male | Dilated cardiomyopathy in acute decompensated heart failure, left ventricle clot | 85 | Patient expired soon after visiting hospital emergency | Definite |
| 86 | Male | S/P mitral valve replacement, severe respiratory distress | 80 | Acute diarrhea for 2 days, severe dehydration, prosthetic heart valve thrombosis | Definite |
| 2 | Female | Large perimembranous ventricular septal defect | 90 | Patient was on mechanical ventilator in view of respiratory tract infection | Definite |
| 12 | Male | Tetralogy of Fallot | 80 | Patient was treated in a local hospital for COVID-19, and died early after transfer | Definite |
| 1 | Male | Situs inversus, dextrocardia, atrioventricular canal defect, and pulmonary hypertension | 84 | Patient died immediately after discharge against medical advice | No |
| 144 | Female | Bicuspid aortic valve, Aortic valve replacement for infective endocarditis | 97 | Patient died due to sequelae of infective endocarditis | No |
COVID-19: Coronavirus disease-2019, SpO2: Oxygen saturation
On univariate analysis, lower socioeconomic class, presence of cyanosis, tachypnea, shock, ARDS, need for intubation, and severe illness at admission predicted mortality among COVID-19-positive patients with CHD [Table 5]. The type of CHD and surgery during index hospitalization, however, did not predict mortality. On multivariate analysis, the independent predictors of mortality were severity of illness at admission (OR: 535.7, 95% CI: 6.9–41,605, P = 0.005), and lower socioeconomic class (OR: 29.5, 95% CI: 1.1–814.7, P = 0.046).
Table 5.
Univariate differences between dead and survivors among patients hospitalized with coronavirus disease-2019 and congenital heart disease
| Characteristics | Mean±SD or n (%) | P | |
|---|---|---|---|
|
| |||
| Death (n=13) | Survived (n=81) | ||
| Mean age (months) | 26.8±44.2 | 90.9±149.5 | 0.07 |
| Gender | |||
| Male | 10 (20.4) | 39 (79.6) | 0.07 |
| Female | 3 (6.7) | 42 (93.3) | |
| Socioeconomic class | |||
| Upper and middle | 3 (6.1) | 46 (93.9) | 0.04 |
| Lower middle and lower | 10 (22.2) | 35 (77.8) | |
| Type of CHD | |||
| Obstructive lesions | 1 (8.3) | 11 (91.7) | 0.30 |
| Acyanotic CHD | 2 (6.5) | 29 (93.6) | |
| Cyanotic CHD | 7 (17.9) | 32 (82.1) | |
| Acquired heart disease | 3 (25.0) | 9 (75.0) | |
| Pulmonary hypertension | 8 (15.4) | 44 (84.6) | 0.77 |
| Fever | 5 (20.0) | 20 (80.0) | 0.32 |
| Cyanosis | 10 (25.0) | 30 (75.0) | 0.01 |
| Tachypnea | 10 (38.5) | 16 (61.5) | <0.001 |
| Shock at presentation | 7 (63.6) | 4 (36.4) | <0.001 |
| Need for intubation | 9 (69.2) | 4 (30.8) | <0.001 |
| ARDS | 6 (85.7) | 1 (14.3) | <0.001 |
| SpO2 (%) | 80.9±11.5 | 90.4±8.4 | <0.001 |
| Severity of illness | |||
| Not severe | 4 (5.1) | 78 (94.9) | <0.001 |
| Severe | 9 (72.7) | 3 (27.3) | |
| Hemoglobin (g/dL) | 12.5±2.2 | 13.2±3.4 | 0.65 |
| Neutrophil/lymphocyte ratio | 2.8±1.4 | 1.1±1.0 | 0.001 |
| Platelets (lakhs/mm3) | 2.5±1.4 | 2.6±1.0 | 0.41 |
| Serum creatinine | 1.1±1.0 | 0.4±0.3 | 0.10 |
| Surgery during index hospitalization | 3 (15.8) | 16 (84.2) | 0.72 |
CHD: Congenital heart disease, ARDS: Acute respiratory distress syndrome, SD: Standard deviation, SpO2: Oxygen saturation
DISCUSSION
This multicentric retrospective study conducted under the aegis of the PCSI is one of the largest series of children with heart disease who acquired COVID-19 infection. Children with CHD represent a high-risk vulnerable group for any viral infection including COVID-19 infection. However, outcome studies are limited in children with heart disease and COVID-19 infection. The significant finding of our study is the higher case fatality rate observed among a predominantly young unoperated children with serious CHD and COVID-19 infection. The study represents real-time, cross-sectional practice across India.
A recently published large primary care data base study involving more than 200,000 children and adolescents estimated a hospitalization rate of 0.3%–1.3% with negligible fatality rate when they acquired a COVID-19 infection.[4] Even among children admitted to the pediatric intensive care units, the mortality is reported as low as 4%.[18] However, children with heart disease are a high-risk group and could have adverse outcomes following a COVID-19 disease. Early case series of children with COVID-19 hospitalized in general pediatric wards, and a few small case series consisting of children with CHD, suggested a high mortality rate when they had a COVID-19 infection.[19] In the initial phase of illness, the CDC in the USA reported that CHD was one of the frequent underlying medical conditions (18%) among patients <21 years, who died due to COVID-19.[20]
A few focused studies reported the outcomes of patients with CHD who acquired a SARS-CoV-2 infection, but all of them included predominantly operated GUCH population. The case fatality rate in a nationwide survey from Italy (n = 76; only 4 children) and a single-center series from New York (n = 53; only 10 children) was 0% and 6%, respectively.[9,10] A multicentric registry of 105 GUCH patients from 25 European centers, reported a case fatality rate of 4.8%.[7] However, a large worldwide multicentric study involving 1044 GUCH patients reported a case fatality rate of 2.8% only.[8] The authors suggested that structural CHD did not portend an increased risk of mortality due to COVID-19 infection as compared to the general population. However, these studies did not include patients who were operated during COVID-19 infection.[8,9,10]
The case fatality rate in our study population consisting of unoperated young children with serious heart disease was high (13.8%) as compared to the previously quoted studies involving a predominant GUCH population.[7,8,9,10] Most of the excess mortality was preprocedural. Severity of illness at admission was an independent predictor of mortality. Eventhough the postoperative mortality was comparable between the COVID-19-positive and COVID-19-negative patients, all the 13 hospitals reported a higher postoperative mortality in 2020 as compared to that of 2019.[15] A small study from Iran (n = 9), which had a comparable patient population, reported a mortality of 22.2%.[11] Another interesting question was to ascertain the proportion of patients who died due to COVID-19 rather than with COVID-19, and this was difficult to assess in a retrospective study. Treating doctors opined that in 9 out of 13 deaths, COVID-19 could have been a definite causative factor.
The spectrum of SARS-CoV-2 infection in children is similar to that of the adult population and varies from an asymptomatic to a severe illness needing mechanical ventilation. COVID-19 risk estimation in patients with CHD is limited to GUCH population. The risk markers of death/severe disease varied between studies, and included male sex,[8] cyanosis,[7,8] pulmonary hypertension,[8] hospitalization for heart failure,[8] obesity,[8] presence of comorbidities,[7,8] and advanced physiological state.[10] Expectedly, physiological factors were more predictive than anatomical factors in these studies. In our study, the mean SpO2 was predictive of mortality on univariate analysis; however, the presence of pulmonary hypertension was not predictive. This could be related to the higher proportion of neonates and infants in our cohort with a treatable cause of pulmonary hypertension, unlike a GUCH population with residual pulmonary hypertension in other studies. Lower socioeconomic class is associated with a higher mortality in our study. Such a gradient in outcomes with socioeconomic class has been reported in COVID-19 and many conditions already, and the reasons are multifactorial.[21,22]
Pneumonia is the most common noncardiac cause of death in children with CHD, who are known to have poorer outcomes with influenza and other common respiratory viral and bacterial infections.[23,24] In addition, COVID-19 pneumonia in a child with CHD may lead to progressive hypoxia, worsening V/Q mismatch, embolic events, worsening pulmonary hypertension, and hypercapnic vasoconstriction. The combined effect is likely to be more pronounced in children with cyanotic CHD, leading to worsening of tissue oxygenation and perfusion. Endothelial dysfunction is widely prevalent in various forms of CHD, and endothelitis associated with COVID-19 could further aggravate it.[25,26,27] Vascular inflammation in the lung parenchyma and pulmonary vascular bed may contribute to adverse outcomes, especially if these children need to undergo early cardiac surgery using cardiopulmonary bypass. Extensive lung damage following cardiac surgery without an obvious cardiac cause was observed in four children who had undergone a cardiac surgery. Thus, the optimal timing of open-heart surgery following recovery from COVID-19 infection is a matter of debate, and it may be prudent to postpone it for 2 months if the clinical condition allows.[28,29,30,31]
COVID-19 could also lead to direct cardiac injury and dysfunction, and manifest as elevated troponins, myocarditis, heart failure, and arrhythmias.[19,32] In our series, only two children had arrhythmia and one patient had myo-pericarditis. However, troponin was not serially measured in most of these children. Coagulopathy and thrombotic manifestations are commonly reported in COVID-19 infection,[33] which was observed in three of our patients. In fact, coagulopathy could have played a causal role in death among two of them.
Limitations
This retrospective multicentric study has inherent limitations. Further, selection bias due to inclusion of more serious patients presenting to the hospital during the epidemic might influence the results. Hence, the case fatality rate in the population might be lower than reported. Because we collected data about the GUCH population in patients and control as per protocol, we cannot separate the effects in children alone, but we believe, this would not influence the implications or theme of our results.
The study has important implications. Most of the guidelines, risk classification, and consensus statements for COVID-19-positive children with CHD are not based on data.[34,35,36,37,38] This is the first report of sizable unoperated children with CHD and COVID-19. This study and similar data from LMICs are important as they have a higher burden of unoperated CHD and exposure to COVID-19. Children with CHD in developing countries, especially those with unoperated serious CHD, should be prioritized for vaccine allocation once approved for use in this age group. Efforts must focus on effective screening, early diagnosis, and timely management of serious CHD during the successive waves of the pandemic.
CONCLUSIONS
Children with heart disease presenting to tertiary care pediatric centers are at a higher risk of mortality related to COVID-19 infection. Mortality is higher in children belonging to lower socioeconomic class and those with severe illness at presentation. Systematic preventive measures and management strategies are needed for improving the outcomes in children with heart disease and grown-ups with congenital heart disease.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
The authors acknowledge the critical inputs and support provided during study design and review by Dr. Rajesh Sharma, Chief Pediatric Surgeon, Indraprastha Apollo Hospital, New Delhi. The authors also acknowledge the inputs provided by Late Dr. Biswajit Bandopadhyay, Chief Pediatric Cardiologist at Narayana Hrudalaya Rabindranath Tagore International Institute of Cardiac Sciences, Kolkata, West Bengal, for the critical inputs and support provided during study design.
SUPPLEMENTARY APPENDIX
Supplementary Appendix 1
Study Pro forma: PCSI COVID study
Part 2: Details of CHD cases confirmed/suspected to have COVID
(Separate part 2 to be filled for each patient)
Site ID Participant ID
A. Presentation/admission
| Clinical inclusion criteria |
| Age : |
| Gender: M F |
| COVID 19 status : Suspect Confirm |
| If Confirm, Method of diagnosis: PCR Ag assay |
| Ab Rapid |
| First COVID detection date |
| Indication for testing : Screen before planned admission/Screened before consultation/symptomatic |
| Caregiver's relation |
| Caregiver's status |
A. Other Demographics
Family member COVID positive: Father/Mothers/sibling/Others
Approximate social status Upper/Middle/Lower middle/Lower
B. Preexisting cardiac diagnosis:
C. Age at first cardiac diagnosis
D. Any other co-morbidities (If Syndromic, Indicate here)
E. Malnutrition: Yes/No
F. Onset and admission
Date of admission
First symptom onset (days before admission)
How many days after symptom COVID was tested?
Presenting symptoms
G. Clinical features on admission
Fever Yes/No
SPO2
Tachypnea yes/No
Requirement of respiratory support Yes/No
BP
CFT
Height Weight
Clinically in shock Yes/No
H. Pre admission medications: (Tick whichever applicable)
Diuretics
Digoxin
ACE Inhibitors/ARBs
Beta-blockers
Ibuprofen
Other NSAIDs
Antiarrhythmics
I. Hospital course
Initially admitted in: Daycare/Ward/ICU
Patient‘s most severe state: Mild symptoms/Severe symptoms/Critical
c. Broad categories of treatment used
-
Non-invasive ventilation? (Any) ‘YES ‘NO ‘Unknown
If YES, total duration: _________days ‘Unknown
Invasive ventilation? (Any) ‘YES ‘NO ‘Unknown If YES, total duration: _________days ‘Unknown
Prone Positioning? ‘YES ‘NO ‘Unknown If YES, total duration: _________days ‘Unknown
Inhaled Nitric Oxide? ‘YES ‘NO ‘Unknown
Tracheostomy inserted? ‘YES ‘NO ‘Unknown
Extracorporeal support (ECMO)? ‘YES ‘NO ‘Unknown If YES, total duration: _________days ‘Unknown
Renal replacement therapy (RRT) or dialysis? ‘YES ‘NO ‘Unknown
Inotropes/vasopressors? ‘YES ‘NO ‘Unknown If YES, total duration: _________days ‘Unknown
ICU or High Dependency Unit admission? ‘YES ‘NO ‘Unknown If YES, total duration: _________days ‘Unknown
J. Medications while in the hospital
a. Antivirals ‘YES ‘NO ‘Unk
i. If yes Which drug Duration
b. Chloroquine/hydroxychloroquine ‘YES ‘NO ‘Unk
i. If yes, Duration
c. Antibiotics ‘YES ‘NO ‘Unk
i. If yes, which drug Duration
d. Corticosteroids ‘YES ‘NO ‘Unk
-
i. If yes, Which drug Oral/IV
Duration
-
e. Heparin ‘YES ‘NO ‘Unk
Duration
K. Complications
| Viral pneumonia/pneumonitis | ′YES ′NO ′Unk | Stroke/Cerebrovascular accident | ′YES ′NO ′Unk | |
|---|---|---|---|---|
| Bacterial pneumonia | ′YES ′NO ′Unk | Meningitis/Encephalitis | ′YES ′NO ′Unk | |
| Acute Respiratory Distress Syndrome | ′YES ′NO ′Unk | Bacteremia | ′YES ′NO ′Unk | |
| If Yes : Severity Mild/Moderate/Severe | ||||
| Pneumothorax | ′YES ′NO ′Unk | Pulmonary embolism | ′YES ′NO ′Unk | |
| Pleural effusion | ′YES ′NO ′Unk | Anemia | ′YES ′NO ′Unk | |
| Cryptogenic organizing pneumonia (COP) | ′YES ′NO ′Unk | Rhabdomyolysis/Myositis | ′YES ′NO ′Unk | |
| Bronchiolitis | ′YES ′NO ′Unk | Acute renal injury/Acute renal failure | ′YES ′NO ′Unk | |
| Cardiac arrest | ′YES ′NO ′Unk | Gastrointestinal haemorrhage | ′YES ′NO ′Unk | |
| Myocardial infarction | ′YES ′NO ′Unk | Pancreatitis | ′YES ′NO ′Unk | |
| Cardiac ischaemia | ′YES ′NO ′Unk | Liver dysfunction | ′YES ′NO ′Unk | |
| Cardiac arrhythmia | ′YES ′NO ′Unk | Hyperglycemia | ′YES ′NO ′Unk | |
| Myocarditis/Pericarditis | ′YES ′NO ′Unk | Hypoglycemia | ′YES ′NO ′Unk | |
| Endocarditis | ′YES ′NO ′Unk | Other | ||
| Cardiomyopathy | ′YES ′NO ′Unk | If YES specify: | ||
| Congestive heart failure | ′YES ′NO ′Unk | |||
| Seizure | ||||
A. Laboratory details
| Parameter | Value | Not done | Parameter | Value | Not done |
|---|---|---|---|---|---|
| Hemoglobin | Urea | ||||
| WBC count (x109/L) | Create | ||||
| DLC | P L M E | Lactate | |||
| Platelets | Na/K | ||||
| PT (seconds) | PCT | ||||
| APTT (S) | CRP | ||||
| INR | LDH | ||||
| AST/ALT | CKMB | ||||
| Bil Total | Trop I | ||||
| Blood Sugar Mg/dl | D Dimer | ||||
| S ferritin | IL-^ levels |
N. In-Hospital outcome
Death/survived
Date of death/discharge
Whether cardiac surgery done during index hospitalization? Yes/No
-
Condition needed an elective surgery Yes/No
- Surgery done later
- Awaiting surgery
Remarks
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