Codetections of Other Respiratory Viruses Among Children Hospitalized With COVID-19

This cross-sectional study included children <18 years of age identified through the Coronavirus Disease 2019-Associated Hospitalization Surveillance Network (COVID-NET) from March 1, 2020, to February 28, 2022. COVID-NET, a population-based surveillance system, includes data on laboratory-confirmed COVID-19-associated hospitalizations among residents of 99 counties in 14 states (California, Colorado, Connecticut, Georgia, Iowa, Maryland [data only through December 4, 2021], Michigan, Minnesota, New Mexico, New York, Ohio, Oregon, Tennessee, and Utah) comprising approximately 10% of the US population. COVID-NET cases are defined as any patient residing in the predefined catchment area with a positive viral SARS-CoV-2 test (polymerase chain reaction [PCR] or antigen testing, excluding at-home tests) during, or in the 14 days before, hospitalization. Using a standardized case report form, trained surveillance officers collect clinical data: history of underlying medical conditions, COVID-19 vaccination status, clinical presentation, diagnostic testing (including other respiratory virus testing done [via PCR] in the 14 days before, and first 7 days of hospital admission), and clinical course including discharge diagnoses, treatment, and outcomes.¹⁴  Data were abstracted for all children <18 years old identified through COVID-NET from March 2020 to November 2021. Because of high volume of pediatric hospitalizations between December 2021 and February 2022, some sites collected clinical data on a random representative sample of pediatric cases. Sampling was conducted using random numbers and sampling weights were created to account for selection probability, as previously described.¹⁵ 

This analysis included hospitalized children who: (1) met the case definition for COVID-NET surveillance, (2) had a completed case report form, and (3) were admitted primarily for a febrile or respiratory illness or presumed COVID-19 between March 1, 2020 and February 28, 2022, as indicated in the chief complaint or history of present illness. Those with another primary reason for admission, including obstetrics or labor and delivery admission, planned inpatient surgery or procedures, psychiatric admission needing acute medical care, trauma, other, and unknown, were excluded. Two physicians reviewed other reasons for admission and chief complaints to determine whether they were not likely COVID-19-related, eg, skin and soft tissue infections. Children diagnosed at discharge with multisystem inflammatory syndrome (MIS-C) were excluded from the analysis.

This activity was reviewed by the Centers for Disease Control and Prevention (CDC) and conducted consistent with applicable federal law and CDC policy (see eg, 45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. §241(d); 5 U.S.C. §552a; 44 U.S.C. §3501 et seq.). When required, participating sites obtained approval from respective state and local institutional review boards.

First, the unweighted frequency and weighted proportion of children with non-SARS-CoV-2 viral testing and those who had viral codetections (defined as having positive viral testing for SARS-CoV-2 and at least 1 other respiratory virus) are described and compared by pathogen tested, age group, and time-period. We use the term “codetection” instead of “coinfection” as coinfection implies that a child is actively infected with both SARS-CoV-2 and another virus; however, this cannot be presumed based on positive testing. COVID-NET surveillance identified and recorded standard of care respiratory virus testing results for RSV, rhinovirus or enterovirus (in general, current PCR testing cannot discriminate between these 2 viruses),¹⁶  influenza A and B, adenovirus, human metapneumovirus, parainfluenza, and endemic human coronaviruses. Admission periods are characterized by national SARS-CoV-2 variant predominance (if a variant accounted for >50% of sequenced isolates) and include pre-Delta-predominant (March 1, 2020– June 26, 2021), Delta-predominant (June 27, 2021–December 18, 2021), and Omicron-predominant (December 19, 2021–February 28, 2022) periods.

Second, demographic and clinical features of children with and without non-SARS-CoV-2 respiratory viral testing are described and compared. Additionally, among those children with any non-SARS-CoV-2 viral testing, those with complete and partial additional testing were compared. “Complete additional viral testing” is defined as having testing for all the following pathogens: RSV, rhinovirus or enterovirus, influenza A and B, adenovirus, human metapneumovirus, parainfluenza (at least 1 of the 4 subtypes), and endemic human coronavirus (229E, HKU1, NL63, OC43, or no subtype specified).

Third, demographic characteristics, clinical features, and outcomes of children with and without codetections among those who had any non-SARS-CoV-2 viral testing are described and compared. Children with only SARS-CoV-2 testing were excluded to decrease potential bias because of differential testing practices based on clinical or other confounders. Frequencies presented are unweighted and prevalence or proportions are weighted to account for sampling and nonresponse. χ² tests were used to compare proportions (including 95% confidence intervals [CI]) and Wilcoxon rank sum tests used for medians using α = .05.

The association between viral codetections and severe respiratory illness among hospitalized children is described using multivariable logistic regression models with generalized estimating equations to account for clustering within sites and stratified by age: 0 to 23 months, 2 to 4 years, and 5 to 17 years. Severe respiratory illness is defined as being admitted to the ICU and requiring either continuous (CPAP) or bilevel positive airway pressure (BiPAP) or invasive mechanical ventilation (IMV). Only children with complete additional viral testing were included in the regression analysis to limit potential misclassification (ie, undiagnosed codetections) and potential confounding by indication - more severely ill children may be more likely to receive complete viral testing compared with children who received no or partial viral testing.

For each age group, 1 model described the multivariable association between any respiratory viral codetection and severe respiratory illness, and a second model described multivariable associations between RSV codetection, rhinovirus or enterovirus codetection, and codetection with a respiratory virus other than RSV or rhinovirus or enterovirus (all combined in the same model) and severe respiratory illness. Rhinovirus or enterovirus codetections were assessed specifically because of their high frequency and uncertain clinical relevance. Covariates included sex, race and ethnicity, history of any underlying condition, and time period of admission for all age groups; being <6 months old and premature at birth for the 0 to 23 month age group; and COVID-19 vaccination status, being 5 to 11 years old, and presence of obesity (based on history reported, International Classification of Diseases 10th Revision codes, and BMI at time of hospitalization) for the 5 to 17 year age group.

A sensitivity analysis was done to assess the effect of replacing the covariate for having any underlying condition with a covariate including only underlying conditions that have been shown to be associated with severe COVID-19 illness in children. Based on Woodruff et al,¹⁷  among those <2 years old, prematurity, chronic lung disease, neurologic disorders, cardiovascular disease, and airway abnormalities were significantly associated with severe illness. Among those ≥2 years old, obesity, diabetes mellitus, and feeding tube dependence were significantly associated with severe illness.

Adjusted odds ratios (aORs) including 95% CI are presented for multivariable associations. Analyses were done using SAS (version 9.4; SAS Institute).

From March 1, 2020 to February 28, 2022, 6487 children <18 years of age were hospitalized with SARS-CoV-2 infection and had a complete case report form. Of those with a complete form, 4658 (74%) were likely admitted for a febrile or respiratory illness or presumed COVID-19, of which 286 (6%) were diagnosed with MIS-C at discharge and excluded from the analysis. Among the remaining 4372 children, 2659 (62%) had testing for at least 1 respiratory virus other than SARS-CoV-2, of which 1670 (62%) had complete additional viral testing (Fig 1). Proportions of children who had RSV or influenza testing increased from pre-Delta to Delta- and Omicron-predominant periods (from ∼40%–50% to 60%–70% to 75%–80%, respectively), as well as those tested for rhinovirus or enterovirus and other viruses (from ∼35% in pre-Delta to 45% in Delta- and Omicron-predominant periods, Fig 2).

Compared with children with only SARS-CoV-2 testing, those with any non-SARS-CoV-2 testing were significantly more likely to be <5 years of age or of non-Hispanic white race; present with upper or lower respiratory symptoms or tachypnea; have respiratory-related discharge diagnoses; require ICU admission, high flow nasal cannula (HFNC), CPAP, or BiPAP; and receive systemic steroids, remdesivir, or intravenous immune globulin (IVIG, Supplemental Table 4). Compared with children with partial additional testing, children with complete additional testing were significantly more likely to be non-Hispanic Black, have an underlying medical condition, be diagnosed with acute respiratory failure, receive remdesivir, require CPAP or BiPAP or IMV, and be admitted to the ICU (Supplemental Table 5).

Among the 2659 children with non-SARS-CoV-2 viral testing, 537 (21%) had codetections (Table 1). Percent positivity among all children tested for viruses other than SARS-CoV-2 was 7% (172 of 2460) for RSV, 1% (20 of 2639) for influenza, 15% (261 of 1733) for rhinovirus or enterovirus, and 10% (167 of 1762) for other viruses (Fig 1). By age group, percent positivity ranged from <1% (among those 12– 17 years of age) to 11% (<6 month and 6–23-months) for RSV and from 5% (12–17 years) to 24% (6–23 months) and 28% (2–4 years) for rhinovirus or enterovirus. Percent positivity for influenza was <1% in all age groups (Supplemental Table 6).

The proportion of all children hospitalized who had RSV codetections increased from <1% before Delta predominance to 13% and 7% during Delta and Omicron predominance, respectively. Those with rhinovirus or enterovirus codetections fluctuated from 13% (pre-Delta) to 19% (Delta), and to 12% (Omicron). Influenza codetections remained infrequent throughout all time periods. During Delta predominance, the proportion of those with RSV codetections increased to 17%, 26%, and 20% among those <6 months, 6 to 23 months and 2 to 4 years of age, respectively (Fig 2).

Among hospitalized children with non-SARS-CoV-2 viral testing, compared with those who only had SARS-CoV-2 infection, those with codetections were more likely to be 12 to 23 months (20% vs 9%) or 2 to 4 years of age (22% vs 12%, P < .001) and less likely to have any underlying medical condition (51% vs 58%, P = .003, Table 1). Those with codetections were more likely to present with upper respiratory symptoms (71% vs 52%, P < .001), shortness of breath (54% vs 38%, P < .001), or hypoxemia (21% vs 13%, P < .001). They were more likely to have a discharge diagnosis of acute respiratory failure (44% vs 25%, P < .001), asthma exacerbation (18% vs 8%, P < .001), bronchiolitis (24% vs 3%, P < .001), or bronchitis (25% vs 9%, P < .001), and more likely to receive systemic steroids (47% vs 37%, P < .001), require HFNC (21% vs 9%, P < .001) or CPAP or BiPAP (10% vs 6%, P < .001), and be admitted to the ICU (38% vs 27%, P < .001). Length of stay was not statistically different (1.9 vs 1.8 days, P = .73, Table 2).

Among children <5 years old with complete additional viral testing, having any viral codetection (<2 years: adjusted odds ratio [aOR] 2.1 [95% confidence interval or CI 1.5–3.0]; 2–4 years: aOR 1.9 [95% CI 1.2–3.1]) or rhinovirus or enterovirus codetection (<2: aOR 2.4 [95% CI 1.6–3.7]; 2–4: aOR 2.4 [95% CI 1.2–4.6]) was significantly associated with severe respiratory illness. Having an RSV codetection was significantly associated with severe illness only among children <2 years old (aOR 1.9 [95% CI 1.3–2.9]). Having a viral codetection was not significantly associated with severe illness among children ≥5 years old (Table 3). The sensitivity analysis with the alternative underlying condition covariate yielded similar results (Supplemental Table 7).

Using comprehensive data from a US surveillance network of more than 4300 children hospitalized with laboratory-confirmed SARS-CoV-2 infection and admitted primarily for febrile or respiratory illness or presumed COVID-19, this study found that respiratory virus codetections were rare in the first year of the pandemic, RSV and rhinovirus or enterovirus codetections increased during the Delta-predominant period and influenza codetections were infrequent throughout the first 2 years of the pandemic. This study also suggests that viral codetections can play a clinically important role. Among children <5 years of age who had complete additional viral testing, those with any viral codetection or rhinovirus or enterovirus codetection had approximately twice the odds of severe respiratory illness compared with those with negative viral testing. Children <2 years of age with RSV codetection specifically also had twice the odds of severe illness.

The COVID-19 pandemic had a profound effect on seasonal circulation of non-SARS-CoV-2 respiratory viruses.³  During the pre-Delta period, even though testing for other viruses frequently occurred among children hospitalized with COVID-19, virtually no codetections of SARS-CoV-2 with RSV, influenza and other viruses usually associated with fall and winter pediatric hospitalizations were identified. However, the frequency of RSV codetections increased in the Delta-predominant period starting in the summer of 2021, along with increasing circulation of SARS-CoV-2 and other respiratory pathogens.^4,5  In contrast, rhinovirus or enterovirus codetections were noted throughout the pandemic period. This aligns with evidence that rhinovirus or enterovirus circulation did not decrease as much as other respiratory viruses and resurged earlier in the pandemic than other viruses, whereas influenza circulation remained low and codetections among children rarely occurred through the first 2 years of the pandemic.^18–20 

The higher frequency of viral codetections among children ages <5 years old is consistent with prepandemic data on viral codetections among hospitalized children. Previously published data suggested that among children hospitalized with community acquired pneumonia, those <5 years old were more likely than older children to have codetections, the majority of which were RSV and human rhinovirus.²¹  Our study did not find a difference in codetections by race and ethnicity but did demonstrate increased odds of non-SARS-CoV-2 testing among non-Hispanic white children. Children with codetections were also more likely to have respiratory-related diagnoses and complications and more likely to receive systemic steroids than those with COVID-19 alone. Although systemic steroids are recommended for children hospitalized with COVID-19 who require high-flow oxygen or greater respiratory support,²²  they are often not recommended for uncomplicated respiratory illness caused by other respiratory viruses, such as RSV-associated bronchiolitis.²³  Increased use of steroids among those with codetections, compared with those with only SARS-CoV-2 infection, may be related to increased overall disease severity or differential clinical presentation in children with codetections.

Among hospitalized children tested for multiple viral pathogens, children <5 years of age with any viral codetection or rhinovirus or enterovirus codetections had approximately twice the odds of severe illness than those hospitalized who tested negative for other viruses. Rhinovirus can be detected in asymptomatic children and usually causes mild upper respiratory symptoms.^16,24,However, it can cause severe illness resulting from asthma exacerbations and lower respiratory tract illness including pneumonia and bronchiolitis.^25,26,27,28  One study demonstrated that rhinovirus or enterovirus codetection is associated with SARS-CoV-2 persistence (ie, evidence of SARS-CoV-2 nasopharyngeal RNA for >2 weeks after initial diagnosis),²⁹  but data are limited and the impact of rhinovirus codetections on severity of COVID-19 illness remains poorly understood.

Hospitalized children <2 years of age with RSV codetections had approximately twice the odds of severe respiratory illness compared with those without RSV. RSV is one of the most common causes of severe respiratory illness in children, particularly those <5 years of age.^25,26,30,31  Given the relatively low incidence of RSV infections throughout much of the pandemic,¹⁹  little has been published on the epidemiology or impact of RSV and SARS-CoV-2 codetections. One study noted that among children <5 years hospitalized with COVID-19 in 6 children’s hospitals during July to August 2021, approximately 22% had RSV codetections,¹³  similar to our findings during the Delta-predominant period. Determining whether SARS-CoV-2 or RSV is the primary driver of illness in children hospitalized with both viruses is not possible, but coinfection with both viruses may increase the risk of severe illness. Further, cocirculation of both pathogens may have strained pediatric hospitals during periods of high incidence, increasing the burden, and possibly the severity, of respiratory-related admissions.³² 

Our findings have clinical and public health implications. Identifying hospitalized children with COVID-19 who have viral codetections and are possibly at risk for more severe illness can inform infection control recommendations, including cohorting, guide timing of interventions and escalation of care, and help predict clinical course (given that SARS-CoV-2 and other viral diseases can differ in their course^16,23,33 ). Furthermore, our findings demonstrate the impact of reemerging non-SARS-CoV-2 pathogens on pediatric hospitalizations; continued surveillance of circulation of SARS-CoV-2 and other viruses can help predict future increases in hospital utilization. Lastly, better understanding the prevalence and impact of children hospitalized with multiple viral infections can help prioritize resources and guide diagnostic, antiviral therapeutic, and vaccine development.

These findings and their interpretation have several limitations. First, COVID-NET represents a surveillance network accounting for 10% of the US population and findings may not be generalizable to the general US population. Second, this analysis aimed to include only children who were admitted for a febrile or respiratory illness or presumed COVID-19, but misclassification may have occurred as the primary reason for admission was not always clear. Third, testing for SARS-CoV-2 and other respiratory viruses was clinician or facility-dependent, data on testing for other viral pathogens was only collected during the first 7 days of hospital admission, and some viral testing results may not have been available in the electronic medical record; these factors may have led to an underestimation of COVID-19 cases and viral codetections. Testing practices may have biased the results since children tested for non-SARS-CoV-2 viruses differed from those who were not tested and children with complete additional testing differed from those with incomplete additional testing; children who had more severe illness or other clinical characteristics may have been more likely to be tested or undergo more complete testing and subsequently diagnosed with a codetection. The multivariable analysis was restricted to only children who had complete additional viral testing performed, but residual biases may remain. Fourth, it was not possible to know the relative timing of infection by multiple pathogens or whether a viral detection, either of SARS-CoV-2 or another virus, was the cause of the illness episode.

Using detailed clinical data from more than 4300 pediatric hospitalizations drawn from a large population-based surveillance system over the first 2 years of the COVID-19 pandemic, this study demonstrates that starting in the summer of 2021, codetections with non-SARS-CoV-2 respiratory viral pathogens increased among children hospitalized with febrile or respiratory illness in the setting of SARS-CoV-2 infection. However, frequency of codetections varied, rarely occurring early in the pandemic and increasing substantially during the Delta- and Omicron-predominant periods (June 2021–February 2022). Codetections with viral pathogens, including RSV and rhinovirus or enterovirus, may contribute to increased severity of illness among children hospitalized with COVID-19, particularly in children <5 years old. Young children who are hospitalized for COVID-19 may benefit from additional viral respiratory pathogen testing, especially when circulation of other pathogens is high. Identification of codetections can help inform clinical and public health practice.

We thank the COVID-NET sites, specifically: Ashley Coates, MPH, Jeremy Roland, MPH, Monica J. Napoles, MPH, Joelle Nadle, MPH (California Emerging Infections Program Oakland, CA); Isaac Armistead MD, MPH, Sarah McLafferty, MPH, Millen Tsegaye, MHA, Jordan Surgnier, MPH, Madelyn Lensing, MPH (Colorado Department of Public Health and Environment, Denver, CO); Ann Basting, BS, Tessa Carter, MPH, Maria Correa, MPH, Daewi Kim, MBS, Carol Lyons, MPH, Amber Maslar, MPA, Hazhia Sorosindi, BS (Connecticut Emerging Infections Program, Yale School of Public Health, New Haven, CT); Emily Fawcett, MPH, Katelyn Ward, MPH, Jana Manning, MPH, Sabrina Hendrick, MPH, Chandler Surell, MPH (Georgia Emerging Infections Program, Georgia Department of Public Health Atlanta, GA; Division of Infectious Diseases, School of Medicine, Emory University, Atlanta, GA; Atlanta Veterans Affairs Medical Center, Atlanta, GA); Shannon Johnson, MPH, Justin Henderson, MPH, Libby Reeg, MPH, Alexander Kohrman, MPH, Lauren Leegwater, MPH, Chloe Brown, MPH, Sierra Peguies-Khan, MPH, Alyanna Melicor, MPH, Sanchitha Meda, MPH (Michigan Department of Health and Human Services, Lansing, MI); Erica Mumm, MPH, Erica Bye, MPH, Kathryn Como-Sabetti, MPH (Minnesota Department of Health Saint Paul, MN); Jennifer E. Akpo, MPH, Celina E. Chavez, BSN, RN, Murtada Khalifa, MBBS, Alesia Reed, PHN, Yassir Talha, MBBS (CDC Foundation, Santa Fe, NM); Cory Cline, MPH, Adrienne Domen, MPH, Melissa Judson, MPH, Sunshine Martinez, CBCS, CMAA, Florent Nkouaga MS, MA, Kelly Plymesser, RN, Jasmyn Sanchez, Daniel M. Sosin, MD, MPH, (New Mexico Department of Health Santa Fe, NM); Kathy M. Angeles, MPH, Molly Bleecker, MA, Nancy Eisenberg, MPH, Emily B. Hancock, MS, Sarah A. Khanlian, MPH, Sarah Lathrop, DVM, PhD, Francesca Pacheco, MPH, Dominic Rudin, BS, Sarah Shrum Davis MA, MPH (University of New Mexico Health Sciences Center, Albuquerque, NM); Nancy L. Spina, MPH, Kerianne C. Engesser, MPH, Adam J. Rowe, BA (New York State Department of Health, Albany, New York); Sophrena Bushey, MPH, Virginia Cafferky, BS, Christina B. Felsen, MPH, Maria Gaitán, BS, Thomas Peer, MPH (University of Rochester School of Medicine and Dentistry Rochester, NY); Julie Freshwater, MPH, PhD, Ann Salvator, MS, Denise Ingabire-Smith, MPH, CLS (ASCP), Rebekah Sutter, BSN, RN, MPH, Nancy E. Moran, DVM, MPH (Ohio Department of Health, Columbus, OH); Sam Hawkins, MPH (Public Health Division, Oregon Health Authority, Portland OR); Tiffanie Markus, PhD, Karen Leib, RN, Katie Dyer, Terri McMinn, Danielle Ndi, MPH, Anise Elie, RN, Kathy Billings, Manideepthi Pemmaraju, MPH, Bentley Akoko, MPH, Victoria Umutoni, MPH (Vanderbilt University Medical Center, Nashville, TN); Amanda Carter, BS, Andrea Price, LPN, Andrew Haraghey, BS, Ashley Swain, CHES, Laine McCullough, MPH, Mary Hill, MPH, Melanie Crossland, MPH, and Ryan Chatelain, MPH (Salt Lake County Health Dept, Salt Lake City, UT).

aOR

adjusted odds ratio

BiPAP

bilevel positive airway pressure

CI

confidence interval

COVID-19

coronavirus disease 2019

COVID-NET

Coronavirus Disease 2019-Associated Hospitalization Surveillance Network

CPAP

continuous positive airway pressure

HFNC

high-flow nasal cannula

IMV

invasive mechanical ventilation

IVIG

intravenous immune globulin

MIS-C

multisystem inflammatory syndrome in children

PCR

polymerase chain reaction

RSV

respiratory syncytial virus

SARS-CoV-2

severe acute respiratory syndrome coronavirus-2