key: cord-0940510-kgcxgrnf
authors: Sachdeva, Sakshi; Ramakrishnan, Sivasubramanian; Choubey, Mrigank; Koneti, Nageswara Rao; Mani, Kalaivani; Bakhru, Shweta; Gupta, Saurabh Kumar; Gangopadhyay, Debasree; Kasturi, Soumya; Mishra, Jayashree; Nayak, Hemant Kumar; Sivakumar, Kothandam; Bobhate, Prashant; Awasthy, Neeraj; Das, Debasis; Chakrabarti, Manisha; Muthukumaran, Chinnaswamy Sivaprakasam; Saileela, Rajan; Dhulipudi, Bhargavi; Chaudhary, Shiv Kumar; Jayranganath, Mahimarangaiah; Saxena, Anita; Iyer, Krishna Subramony; Kumar, Raman Krishna; Kothari, Shyam S; Kulkarni, Snehal; Rao, Suresh G
title: Outcome of COVID-19-positive children with heart disease and grown-ups with congenital heart disease: A multicentric study from India
date: 2021-08-26
journal: Ann Pediatr Cardiol
DOI: 10.4103/apc.apc_134_21
sha: d90e1a440abd9bb00225997aefcd3eca9135bcd1
doc_id: 940510
cord_uid: kgcxgrnf

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.

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.

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 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. [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.

Categorical variables were presented as frequency and percentages, and continuous variables were presented as mean ± standard deviation, or median (Q 25 -Q 75 ) 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. 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.

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 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.

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).

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 SpO 2 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.

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.

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.

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The authors acknowledge the critical inputs and support provided during study design and review by Dr. Rajesh Sharma, Chief Pediatric Surgeon, Indraprastha Apollo