key: cord-0895269-tvt200g1
authors: Leftin Dobkin, Shoshana C.; Collaco, Joseph M.; McGrath‐Morrow, Sharon A.
title: Protracted respiratory findings in children post‐SARS‐CoV‐2 infection
date: 2021-09-17
journal: Pediatr Pulmonol
DOI: 10.1002/ppul.25671
sha: eeaf4aca89cd6df589354b0fbeea99e9d96e7d64
doc_id: 895269
cord_uid: tvt200g1

INTRODUCTION: Although prolonged respiratory symptoms following severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection have been described in adults, data are emerging that children also experience long‐term sequelae of coronavirus disease 2019 (COVID‐19). The respiratory sequelae of COVID‐19 in children remain poorly characterized. In this study we describe health data and respiratory findings in pediatric patients presenting with persistent respiratory symptoms following COVID‐19. METHODS: This study included patients referred to Pulmonary Clinic at the Children's Hospital of Philadelphia between December 2020 and April 2021 (n = 29). Inclusion criteria included a history of SARS‐CoV‐2 RNA positivity or confirmed close household contact and suggestive symptoms. A retrospective chart review was performed and demographic, clinical, imaging, and functional test data were collected. RESULTS: The mean age at presentation to clinic was 13.1 years (range: 4–19 years). Patients had persistent respiratory symptoms ranging from 1.3 to 6.7 months postacute infection. Persistent dyspnea and/or exertional dyspnea were present in nearly all (96.6%) patients at the time of clinic presentation. Other reported chronic symptoms included cough (51.7%) and exercise intolerance (48.3%). Fatigue was reported in 13.8% of subjects. Many subjects were overweight or obese (62.1%) and 11 subjects (37.9%) had a prior history of asthma. Spirometry and plethysmography were normal in most patients. The six‐minute walk test (6MWT) revealed exercise intolerance and significant tachycardia in two‐thirds of the nine children tested. CONCLUSION: Exertional dyspnea, cough and exercise intolerance were the most common respiratory symptoms in children with postacute COVID‐19 respiratory symptoms seen in an outpatient pulmonary clinic. Spirometry (and plethysmography when available), however, was mostly normal, and exertional intolerance was frequently demonstrated using the 6MWT.

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began spreading through the United States in early 2020, and there have been over 40 million cases in the United States as of September 2021, of which 4.8 million have been reported in children (14. 8% of all cases). An overall rate of 6374 cases of SARS-CoV-2 infection per 100,000 children has been reported in the population. 1,2 Although severe illness due to SARS-CoV-2 infection is rare among children, 3 there is emerging data that children can also experience persistent symptoms known as post-acute COVID-19 syndrome. 4 Although the definition is evolving, most studies define long COVID as the persistence of symptoms or development of sequelae beyond 3 or 4 weeks from the onset of acute symptoms of COVID-19. 4 Evidence on long term outcomes in children is still limited to small studies with a range of prevalence. A recent cross sectional study out of Italy of 129 children found that 42.6% had at least one persistent symptom more than 60 days after infection, including children with history of asymptomatic or mild acute COVID-19, and 27.1% had at least one symptom 120 days or more after diagnosis. 5 Another study from Australia suggested that in children aged 0-19 years (median 3 years) with a history of predominantly mild COVID-19, 8% had persistent symptoms after 3-6 months. 6 A study

from Switzerland comparing children who tested positive for SARS-CoV-2 to a population-based seronegative control group found a prevalence of 4% with persistent symptoms beyond 12 weeks. 7 In adult studies, persistent symptoms have been described in 76% of patients 6 months after diagnosis. 8 Previous studies have reported that even among young adults aged 18-34 years with no chronic medical conditions, approximately one in five had not returned to their usual state of health 14-21 days after acute infection. 9 Adult studies have described pulmonary manifestations of long COVID ranging from dyspnea to pulmonary fibrosis among COVID-19 survivors. Dyspnea is the most commonly reported persistent symptom in adult patients with a prevalence of 42%-66% at follow-up after 60-100 days. On pulmonary function testing, a reduction in diffusion capacity is the most frequently reported impairment, and the degree of reduction is directly related to the severity of acute illness. 4 The respiratory sequelae of COVID-19 in pediatric patients, however, remain poorly characterized. The aim of this study was to describe baseline health data and respiratory findings in a cohort of pediatric patients experiencing prolonged symptoms following acute COVID-19 infection. 

Over a 5-month period, 29 pediatric subjects presented to CHOP Pulmonary Clinic for evaluation of persistent symptoms 6 weeks or more after SARS-CoV-2 infection (Table 1) . Of subjects seen for COVID-related complaints, 14% had previously been followed in CHOP Pulmonary Clinic for other concerns before their acute SARS-CoV-2 infection. The mean age at presentation was 13.1 ± 3.9 years (range: 4-19 years). Females (58.6%) and non-whites (55.2%) made up the majority of the patients seen. Many subjects were either overweight (24.1%; body mass index

[BMI] between 85th and 95th percentile) or obese (37.9%; BMI >95th percentile). Baseline atopy, defined as presence of asthma, eczema, and/ or allergic rhinitis, was present in 65.5% of subjects. Of the eleven subjects with asthma, 55% had mild asthma, 36% had moderate asthma, and 9% had severe asthma. Eight subjects with asthma were previously prescribed a daily inhaled corticosteroid. Most subjects (96.4%) reported engagement in regular physical activity before acute COVID-19.

All subjects had positive SARS-CoV-2 PCR testing or confirmed close household contacts with positive SARS-CoV-2 testing and suggestive clinical symptoms at the time of initial illness. The most common reported acute COVID-19 symptoms were fever (69%), cough (55.2%), dyspnea (48.3%), ageusia/anosmia (41.4%) and myalgia (37.9%) ( 

Subjects presented to clinic a mean of 3.2 ± 1.5 months after a SARS-CoV-2 positive PCR or confirmed close contact and suggestive clinical symptoms (range: 1.3-6.7 months) ( Table 3) . Persistent dyspnea and/or exertional dyspnea were present in nearly all (96.6%) of the patients at the time of clinic presentation. Other commonly reported chronic symptoms were cough (51.7%) and exercise intolerance (48.3%). Fatigue was reported in four subjects (13.8%). One subject had an ongoing supplemental oxygen requirement. Oxyhemoglobin saturations ranged from 97% to 100%. Lung auscultation findings were normal in 27 subjects. Two subjects (6.9%) had abnormal auscultatory findings including decreased breath sounds and intermittent wheezing. Spirometry was performed in 28 patients. Mean percent predicted spirometry results included an FEV 1 of 107 ± 12%, an FVC of 110 ± 16%, an FEV 1 /FVC of 86 ± 8%, and an FEF 25%-75% of 100 ± 23%. Obstructive ventilatory defects were present in three subjects. There were no patients with restrictive ventilatory defects. Improvement following bronchodilator administration was observed in 38.1% of the 21 subjects who underwent post-bronchodilator testing. Broncho-responsiveness occurred in eight patients, four of whom had known underlying asthma and four of whom did not.

Plethysmography was performed in 14 subjects and diffusion capacity testing was performed in 15 subjects. Average percent predicted plethysmography results include a TLC of 108 ± 17%, a VC of 120 ± 14%, an FRC of 99 ± 20%, and a RV of 81 ± 48%. An elevated RV/TLC above 30% was observed in four patients ranging from 32% to 89%, suggestive of air trapping. Average percent predicted DLCO was 95 ± 17% and DLCO/VA was 96 ± 14%. Exercise intolerance on a 6MWT was observed in six out of nine patients (66.7%). Notably, these patients were found to have significant tachycardia for age (HR range: 120-213 bpm). Of the eight patients who had chest radiographs performed at the time of follow-up, only one was abnormal (12.5%). All of the 15 patients who had follow-up cardiac evaluations had normal EKG and/or echocardiographic findings (Table 3) .

This is a descriptive study of patients referred to a tertiary care pediatric pulmonary clinic for chronic respiratory symptoms 1-7 months after a diagnosis of SARS-CoV-2 infection. Most patients seen for protracted respiratory symptoms following SARS-CoV-2 occurred in children as young as 4 years old.

In our study, patients reported persistent exertional dyspnea, cough and exercise intolerance, however, spirometry, plethysmography, and diffusion studies were primarily normal in those children who underwent pulmonary function testing as were pulse-oximetry and imaging. The 6MWT, however, revealed exercise intolerance and significant tachycardia in two-thirds of the nine children who were tested. This finding suggests that the 6MWT may be a low-cost and simple way to evaluate children after COVID-19 and provide a quantitative result that can be trended over time to assess improvement or progression of disability.

The most frequent protracted symptoms reported by our patients included dyspnea and exertional dyspnea, exercise intolerance and cough.

This differs from existing studies of children with long COVID in which the most frequently reported symptoms among seropositive children include fatigue, increased need for sleep, insomnia, mild postviral cough, nasal congestion, muscle and joint pains, and difficulty concentrating. [5] [6] [7] Our findings were similar to one of the first case reports of children with long-term effects after COVID-19 featuring five children, all of whom experienced dyspnea and three of whom experienced low exercise tolerance. 13 In comparable studies of adults who did not require hospitalization during acute COVID-19, the most common complaints were dyspnea and fatigue. 14, 15 In contrast, in our pediatric study population, fatigue was only reported by four patients (13.8%). Similar to our study in which we found that exertional dyspnea was presented in almost all patients, Townsend et al. 16 reported that 62% of adult survivors of COVID-19 reported persistent dyspnea and exertional limitation 75 days after their acute illness. Interestingly, persistent dyspnea and exertional limitation were not associated with initial disease severity in their study.

We found an increased prevalence of atopy and obesity in our study population that presented with prolonged post-SARS-CoV-2 infection respiratory symptoms. According to the CDC, the most | 3685 recent national asthma data from 2019 suggests an asthma prevalence of 7% in children under 18 years. 17 The asthma prevalence in our study population was 37.9%, which is nearly five times higher than the general population, and two-thirds were atopic.

This may suggest that asthma and atopy are risk factors for developing long COVID respiratory symptoms in children and will require larger studies to confirm this association. Obesity, defined as a BMI above the 95th percentile, may also be linked to persistent symptoms after COVID-19. Our study population has a higher rate of child obesity of 37.9% compared to the local population rate of 20.3% 18 ; however, this again may reflect study sample bias.

These findings echo those in a recent prospective cohort study out of Russia evaluating risk factors for long COVID in previously hospitalized children, which found that predictors of persistent A final major limitation of our study is that we did not have complete data on the patients. Additionally, although the same clinical data was collected by the physicians seeing these patients, a standardized questionnaire was not used, and as such one patient is missing baseline stamina and respiratory support information. This highlights the importance of increased objective testing and surveillance for respiratory sequelae in children post-COVID-19. Children in our study also did not undergo third level tests which may have revealed evidence of pulmonary damage as an explanation for persistent respiratory symptoms. In a case report by Buonsenso et al., 22 

State-Level Data Report. 2021. Accessed

Coronavirus infections in children including COVID-19: an Overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children

Post-acute COVID-19 syndrome

Preliminary evidence on long COVID in children

Post-acute COVID-19 outcomes in children with mild and asymptomatic disease

Long-term symptoms after SARS-CoV-2 infection in children and adolescents

6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network -United States

Reference ranges for spirometry across all ages: a new approach

Standardisation of spirometry

Guidelines for the six-minute walk test

Case report and systematic review suggest that children may experience similar long-term effects to adults after clinical COVID-19

Persistent symptoms in patients after acute COVID-19

Sequelae in adults at 6 months after COVID-19 infection

Persistent poor health after COVID-19 is not associated with respiratory complications or initial disease severity

Prevalence, disparities, and trends in obesity and severe obesity among students in the school district of

Risk factors for long covid in previously hospitalised children using the ISARIC Global follow-up protocol: a prospective cohort study

Returning to physical activity after covid-19

Are vaccines safe in patients with Long COVID? A prospective observational study. medRxiv

Evidence of lung perfusion defects and ongoing inflammation in an adolescent with post-acute sequelae of SARS-CoV-2 infection. The Lancet Child & Adolescent Health

Immune profile of children with post-acute sequelae of SARS-CoV-2 infection (Long Covid). medRxiv. Forthcoming 2021. How to cite this article: Leftin Dobkin SC, Collaco JM, McGrath-Morrow SA. Protracted respiratory findings in children post-SARS-CoV-2 infection

The authors wish to thank the patients and their families who participated in this study. The study was funded by The Children's