Abstract
Importance
During the COVID-19 [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] pandemic, reports emerged of croup secondary to SARS-CoV-2 in the pediatric population. Children with croup and concurrent SARS-CoV-2 infection seemed to require a greater number of doses of dexamethasone and nebulized epinephrine and were more likely to need hospitalization and intensive care unit (ICU) admission compared to pre-SARS-CoV-2 croup.
Objective
This study aimed to compare the outcomes of children presenting with SARS-CoV-2-associated croup and those with conventional croup.
Design
Observational, retrospective review.
Setting
Tertiary care pediatric hospital.
Participants
Children (age <18 years) presenting with croup between January 2019 and February 2022.
Exposure
SARS-CoV-2
Main outcome measure
Number of doses of dexamethasone and nebulized epinephrine, need for hospital admission, ICU admission, assisted ventilation, and length of stay.
Results
Two thousand and three hundred ninety-eight children [68.2% male, median (interquartile range) age 25 months (15-42 months)] were included. Twenty-seven patients (1.1%) tested positive for SARS-CoV-2, 467 (19.5%) tested negative for SARS-CoV-2, and 1904 (79.4%) were not tested for SARS-CoV-2. Dexamethasone was given to 27 (100%) SARS-CoV-2-positive and 457 (98%) SARS-CoV-2-negative patients at an average of 1.4 (±1.2) and 1.1 (±1.0) doses, respectively. SARS-CoV-2-positive patients were more likely to require nebulized epinephrine (41%) compared to SARS-CoV-2-negative (12%, OR: 4.2; 95% CI 1.8-9.6, P < .001) patients, and were more often admitted (30%) to hospital than SARS-CoV-2-negative (3.4%) patients (OR: 12; 95% CI 4.4-37.7, P < .001). ICU admission was required for 3 SARS-CoV-2-negative patients, but none of the SARS-CoV-2-positive patients. Length of stay was similar across groups.
Conclusion
Patients with croup and SARS-CoV-2 infection were found to have an increased need for nebulized epinephrine and an increased frequency of admission to the hospital. However, there was no increased need for ICU admission or longer length of stay in the hospital.
Level of Evidence
III.
Introduction
Croup, also known as laryngotracheitis, is the most common cause of upper airway obstruction in young children. 1 Croup is clinically diagnosed based on the classic features of bark-like cough, hoarseness, and, in more severe cases, inspiratory stridor. 2 These symptoms are believed to result from laryngotracheal inflammation and subglottic narrowing, with viral infection being the leading cause.1,3 Although croup is a self-limiting illness, hospitalization and intubation are required in 6% and 1.4% of cases, respectively.4,5 Steroids have been shown to reduce the frequency and duration of hospitalization and intubation and are considered the mainstay of management.6 -8 Nebulized epinephrine helps to decrease subglottic inflammation and is reserved for the management of severe croup, which is characterized by prominent stridor, frequent bark-like cough, marked chest wall indrawing, or lethargy.9,10
Croup is commonly caused by parainfluenza and respiratory syncytial viruses. During the COVID-19 [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] pandemic, reports emerged of croup secondary to SARS-CoV-2 in the pediatric population.11,12 Termed “SARS-CoV-2 croup,” children with croup and concurrent SARS-CoV-2 infection seemed to require a greater number of doses of dexamethasone and nebulized epinephrine, and were more likely to need hospitalization, intensive care unit (ICU) admission, and ventilatory support, compared to pre-SARS-CoV-2 croup.11,13 -17 However, preexisting studies investigating croup secondary to SARS-CoV-2 infection were small case series or involved large databases, which were limited by variability in treatment paradigms and a lack of direct comparison of clinical outcomes with conventional croup. We therefore performed a retrospective review aimed at characterizing the clinical course of a large cohort of patients who presented with croup to a single pediatric tertiary care hospital and compared outcomes of those with and without SARS-CoV-2 infection.
Materials and Methods
Study Design and Patient Population
Approval was obtained by the Research Ethics Board at the Hospital for Sick Children (SickKids), Toronto, Canada (REB #1000079287). A retrospective review was conducted of all patients aged ≤18 years with an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) 18 diagnosis of croup who presented to the emergency department at SickKids between January 2019 and February 2022. This time interval captured a cohort of patients diagnosed with croup prior to March 2020, when cases began to increase in Toronto and routine SARS-CoV-2 testing was implemented at SickKids. Croup was diagnosed based on clinical symptoms of bark-like cough, hoarseness, or inspiratory stridor. Objective findings of subglottic narrowing on x-ray or flexible nasolaryngoscopy were supportive but not necessary for diagnosis. Patients were excluded if they had incomplete records with respect to diagnosis and treatment, and/or had a preexisting tracheostomy.
Management Approach
Croup is managed at our institution in accordance with the Canadian Paediatric Society guidelines. 19 Children who presented to the emergency department with symptoms of croup were generally treated with dexamethasone (0.6 mg/kg of bodyweight) given orally as a single dose. Intramuscular or intravenous dexamethasone was administered for children who did not tolerate the oral route, such as those with significant respiratory distress or persistent vomiting. Nebulized 1:1000 L-epinephrine was reserved for moderate to severe croup, defined by the presence of stridor, chest wall indrawing, agitation, or lethargy. Children who had minimal improvement with dexamethasone and nebulized epinephrine, characterized by ongoing stridor at rest, respiratory distress, agitation, or lethargy, were admitted to the hospital for further observation and management.
Respiratory Virus Identification
Routine SARS-CoV-2 testing was implemented at our institution in March 2020 following regional public health alerts. This marked the start of systematic screening for all symptomatic patients. Patients seen before this date were not subjected to institutional testing unless tested externally. All patients with croup who presented to the emergency department on or after this date were offered SARS-CoV-2 testing with polymerase chain reaction (PCR) or rapid antigen test (RAT). Specimens for SARS-CoV-2 PCR or RAT testing were obtained from nasopharyngeal, saliva, or oropharyngeal sources. Patients were considered SARS-CoV-2-positive if SARS-CoV-2 PCR or RAT showed detectable virus and were considered SARS-CoV-2-negative if SARS-CoV-2 PCR or RAT returned with no detectable virus.
Outcome Measurements and Data Collection
Baseline demographic information was recorded. Number of doses of dexamethasone, number of doses of nebulized epinephrine, need for hospital admission, need for ICU admission, need for assisted ventilation (defined as either intubation or non-invasive ventilation), and length of stay were recorded.
Statistical Analysis
Baseline patient characteristics were calculated using numbers (%) for binary and categorical variables and median [interquartile range (IQR)] for continuous variables. These were compared statistically using Fisher’s exact test for binary variables, chi-squared test for categorical variables, and Mann-Whitney test for continuous variables. Statistical analyses were primarily descriptive, with comparisons made between COVID-19-positive and COVID-19-negative groups using appropriate univariate tests. Due to the retrospective nature of the study and the relatively small number of COVID-19-positive cases, a formal power calculation was not conducted, and the study was not powered to detect small differences across groups. Furthermore, age was the only variable consistently documented and clinically relevant across the cohort, and thus was the sole variable adjusted for in the analyses. All data were analyzed using R version 3.6.1 (R Foundation for Statistical Computing). 20
Results
Baseline Patient Characteristics
A total of 2398 patients [68.2% male, median (IQR) age 25 months (15-42)] with croup met the inclusion criteria. Of this cohort, 1438 presented between January 2019 and March 2020 with croup, and 960 presented between March 2020 and February 2022 with croup. Of the 960 patients presenting between March 2020 and February 2022, 492 (51.2%) consented to COVID testing, and 468 (48.8%) declined COVID testing. Twenty-seven patients (1.1%) tested positive for SARS-CoV-2, 467 patients (19.5%) tested negative for SARS-CoV-2, and 1904 patients (79.4%) were not tested for SARS-CoV-2. SARS-CoV-2-positive patients were younger at presentation [median (IQR) age 18 months (10-30 months)] compared to SARS-CoV-2-negative [median age (IQR) 27 months (17-43 months); P < .01] patients. Two (7.4%) SARS-CoV-2-positive patients had a history of prior croup compared to 69 (14.7%) of SARS-CoV-2-negative patients, although the difference was not significant. Fifteen patients tested positive for viral infections other than COVID-19. Ten of these patients were not tested for COVID-19, and 5 were negative for COVID-19. Other infections included the following: enterovirus/rhinovirus (n = 4), human metapneumovirus (n = 2), parainfluenza (n = 2), influenza A (n = 2), respiratory syncytial virus (n = 1), bocavirus (n = 1), coronavirus NL63 (n = 1), Epstein-Barr virus (EBV) (n = 1). One patient had parainfluenza virus 3, bocavirus, and rhinovirus. No other significant demographic differences were found across groups. Patient demographics are shown in Table 1.
Demographics.
Abbreviation: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
P values were calculated using Fisher’s exact test for binary variables, chi-squared test for categorical variables, and the Mann-Whitney test for continuous variables.
Two children tested positive for SARS-CoV-2 at external institutions prior to transfer; results were documented upon arrival.
Outcomes
Dexamethasone was given to 27 (100%) SARS-CoV-2-positive and 457 (98%) SARS-CoV-2-negative patients at an average of 1.4 (±1.2) and 1.1 (±0.97) doses, respectively. The difference in doses of dexamethasone administered was not significantly different across groups. Nebulized epinephrine was given to 11 (41%) SARS-CoV-2-positive and 56 (12%) SARS-CoV-2-negative patients at 1.4 (±2.50) and 0.3 (±1.26) doses, respectively. Multivariate regression analysis demonstrated that SARS-CoV-2-positive patients were more likely to need epinephrine as compared to SARS-CoV-2-negative (OR: 4.2; 95% CI 1.8, 9.6, P < .001) patients. SARS-CoV-2-positive patients also required more doses of epinephrine compared to SARS-CoV-2-negative patients (IRR: 3.3; 95% CI 1.0, 15.7, P = 0.07). Treatment details can be found in Table 2.
Outcome Characteristics.
Abbreviations: BiPAP, bilevel positive airway pressure; ICU, intensive care unit; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
P values were calculated using Fisher’s exact test for binary variables, chi-squared test for categorical variables, and the Mann-Whitney test for continuous variables.
SARS-CoV-2-positive patients were more often admitted (n = 8; 30%) to the hospital than SARS-CoV-2-negative (n = 16; 3.4%) patients (OR: 12, 95% CI 4.4-37.7, P < .001). Length of stay was similar across SARS-CoV-2-positive and SARS-CoV-2-negative patients at 2.12 (±1.73) and 2.88 (±2.12) days, respectively. ICU admissions were calculated for patients who required hospital admission (n = 86). No SARS-CoV-2-positive patients required ICU admission compared to 3 (19%) SARS-CoV-2-negative patients. None of the SARS-CoV-2-positive patients required assistive ventilation, while 2 (n = 2/467, 0.4%) SARS-CoV-2-negative patients required assistive ventilation. Due to small numbers, regression analyses were not calculated for ICU admissions and assistive ventilation-related outcomes.
Discussion
Previous reports on SARS-CoV-2-associated-croup in the form of case reports, small case series, and large databases have lacked comparison with a group of children without SARS-CoV-2.11,13 -16,21 We therefore performed a large retrospective review at a single tertiary care center to further evaluate the clinical characteristics and outcomes of children presenting with croup during the SARS-CoV-2 pandemic and compared outcomes with those presenting with conventional croup.
The present study found that almost all patients with croup received dexamethasone, and there was no significant difference in the number of doses of dexamethasone given in SARS-CoV-2-positive (1.4 doses) versus SARS-CoV-2-negative (1.1 doses) patients. Dexamethasone is a long-acting corticosteroid with a half-life of 36 to 72 hours. In the croup setting, symptoms generally begin improving within 2 to 3 hours after administration of a single oral dose of dexamethasone and persist for over 24 hours. Given the long duration of action, symptoms of croup may have improved with other treatments before the next dose of dexamethasone was required. Previous reports on SARS-CoV-2-croup, however, have found an increased requirement for dexamethasone.11,13 -15,22 These differences may be due to the lack of clinical guidelines outlining the frequency, timing, or symptoms required for continued treatment of croup with dexamethasone. 23 This may result in varied practice patterns among clinicians or institutions in terms of dosing regimens in this population. Alternatively, our sample size may not have been large enough to power a statistically significant finding.
SARS-CoV-2-positive patients were 3 times more likely to require nebulized epinephrine compared with SARS-CoV-2-negative patients. This is similar to previous reports on SARS-CoV-2 croup that found an increased requirement for epinephrine.11,13 -15,22 SARS-CoV-2-positive patients in our study required ~1.4 doses of nebulized epinephrine, which is comparable with other studies looking at SARS-CoV-2-croup, which found a median of 2 doses. 14 Increased nebulized epinephrine requirements are related to croup severity, since nebulized epinephrine is typically reserved for management of moderate to severe croup. Corticosteroids have been well-established for reducing the need for frequent administration of nebulized epinephrine in moderate to severe croup pre-SARS-CoV-2.24,25 Our findings suggest that SARS-CoV-2-associated croup may lead to a more severe inflammatory response, which could require increased use of both epinephrine and corticosteroids. This is consistent with clinical experience and other studies that have observed the need for more intensive treatment in these cases. The higher hospitalization rates noted in our study further support the idea that SARS-CoV-2-related croup may present more severely, necessitating a more aggressive management approach. This highlights the importance of considering the heightened inflammatory response when treating children with SARS-CoV-2-associated croup. The incidence of hospitalization for croup was greater among SARS-CoV-2-positive children (n = 8; 30%) compared to SARS-CoV-2-negative (n = 16; 3.4%) children. Similarly, a recent propensity score-matched study found that SARS-CoV-2-related croup had a 2-fold increase in hospital admission. 21 This rate is much higher than the pre-SARS-CoV-2 literature, whereby ~6% of children with croup required hospital admission. These results suggest that SARS-CoV-2-associated croup may be more aggressive than pre-SARS-CoV-2 croup.26 -28 Our institution’s 30% admission rate for SARS-CoV-2-positive children with croup is higher than studies published since the onset of the SARS-CoV-2-pandemic which reported up to a 12% hospitalization rate in pediatric patients. Patients in our study may have had a greater severity of croup, or our institution may have had a lower threshold for admission.13,14 Once admitted, we found a similar average length of stay of 2.1 and 2.9 days across SARS-CoV-2-positive and SARS-CoV-2-negative groups, respectively. This is in keeping with studies published since the onset of the SARS-CoV-2 pandemic, reporting a median length of stay between 1 and 2 days.13,14 The comparable length of hospital admission across both groups, despite SARS-CoV-2-positive patients being more likely to require epinephrine, may be due to a difference in medical comorbidities across groups. Notably, the SARS-CoV-2-positive group requiring admission was relatively healthy, with only 1 patient (12.5%) having a prior diagnosis of asthma. In contrast, of admitted SARS-CoV-2-negative patients, 6 (37.5%) had comorbidities, including extreme prematurity (ie, gestational age <28 weeks; n = 3), hypotonia (n = 2), asthma (n = 2), and prior intubation (n = 1). These comorbidities may have prompted a more conservative management approach with prolonged monitoring in the hospital.
There were no ICU admissions or requirements for assistive ventilation among SARS-CoV-2-positive patients. Interestingly, 3 SARS-CoV-2-negative patients required ICU admission, 2 of whom required intubation. The past medical history of these 2 patients was notable for extreme prematurity (n = 1) and prior intubation (n = 1). These findings suggest that while SARS-CoV-2 croup initially has a severe presentation compared to conventional croup, the majority of patients respond well to a short admission and repeated doses of nebulized epinephrine, with ICU admission generally not required. Increased requirements for ICU admission and assistive ventilation have been reported for children with croup in the SARS-CoV-2 era compared to the rate described pre-SARS-CoV-2, which was 1%. 26 A larger number of patients with ICU admission may be required to better tease this out.
Our study contributes to the growing body of literature characterizing croup associated with SARS-CoV-2, a clinical entity that appears to differ in some respects from classic viral croup. Recent studies have explored this issue with differing conclusions. Scribner et al reported that pediatric croup cases linked to the Omicron variant were significantly more severe than non-COVID croup cases, with markedly higher hospitalization (22.7% vs 3.9%) and ICU admission rates (5.7% vs 1.5%), 29 suggesting a more aggressive disease phenotype. However, Colom-Balaña et al challenged these findings, reporting no significant differences in clinical features, treatments, or admission rates during the Omicron wave compared to pre-pandemic croup. 30 Further, Lee et al examined presentations of COVID-19-associated croup and highlighted variability in disease characteristics and outcomes across care settings. 31 These contrasting findings may reflect differences in healthcare systems, viral co-infections, or study methodologies, and underscore the importance of larger, multicenter investigations to better understand the clinical behavior and optimal management of SARS-CoV-2-associated croup.
Limitations
Limitations of this study are its retrospective, single-center design, which limits the extent of data available for analysis and the generalizability of results. Furthermore, this study was conducted at a tertiary referral center, and our patients may represent a population with increased disease severity. Patients in our cohort may have been treated at other institutions prior to receiving care at our institution, which may impact the severity of their symptoms and, thus, the treatment required. In addition, hospital practice changes during the pandemic, such as restrictions on aerosol-generating procedures, may have influenced decisions to administer nebulized epinephrine. 32 Since SARS-CoV-2 was a relatively new entity, health care providers may have been more likely to admit children due to uncertainty about the course of illness.
Another limitation is the lack of specific reporting on the use of high flow nasal cannula (HFNC) for oxygen support. While HFNC is commonly used in the management of severe croup, our retrospective data did not consistently capture the modality or timing of oxygen delivery in sufficient detail to allow reliable analysis. In addition, many patients received multiple forms of oxygen therapy during their clinical course, further complicating retrospective classification. Similarly, although we documented the duration of supplemental oxygen use in days, more granular data—such as the degree of oxygen desaturations—were not available for all patients, as continuous pulse oximetry was not uniformly applied. These limitations reflect the constraints of retrospective data collection and highlight the need for prospective studies to better characterize these aspects of care.
A limitation of our study is that we did not account for the impact of school closures and isolation during the pandemic on croup epidemiology. Delayed Emergency Department visits and parental reluctance to seek care for less severe symptoms may have influenced the timing and severity of cases. Additionally, comparing data from 2019 may not fully reflect the true impact of COVID-19 on croup patterns. A comparison with data from 2021 to 2022 would provide a more accurate picture of croup epidemiology during the later stages of the pandemic.
Only patients who consented to SARS-CoV-2 PCR or RAT testing and tested positive were considered SARS-CoV-2-positive. It is possible that children who presented prior to institution-wide implementation of symptomatic SARS-CoV-2 testing were not included in the SARS-CoV-2-positive group. Moreover, comprehensive viral testing was not uniformly performed on all patients, and therefore, we cannot exclude the possibility of viral co-infection, which may have increased the severity of croup. Lastly, each variant of SARS-CoV-2 may present differently, and therefore, further analysis of symptoms due to each variant is required. Nevertheless, this study is among a handful of studies to include a control group when comparing outcomes of croup treatment in the pre- and post-SARS-CoV-2 pandemic era and provides a greater insight into the clinical outcomes of patients with SARS-CoV-2 infection and croup.
Conclusion
Patients with croup and coexisting SARS-CoV-2 infection were found to have an increased need for nebulized epinephrine and an increased frequency of admission to hospital. However, there was no increased need for ICU admission or longer hospital stay, despite the limitation of a small number of positive SARS-CoV-2 croup cases. These results suggest that SARS-CoV-2-associated croup may present more aggressively than conventional croup, but with proper management, the outcomes are still favorable.
Footnotes
Acknowledgements
This paper was presented as an oral presentation at the 2023 American Society of Pediatric Otolaryngology Meeting in Boston, MA, USA.
Data Availability Statement
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Considerations
The Research Ethics Board at the Hospital for Sick Children approved this study.
