OBJECTIVES

Coronavirus disease 2019 (COVID-19) treatment guidelines rapidly evolved during the pandemic. The December 2020 Infectious Diseases Society of America (IDSA) guideline, endorsed by the Pediatric Infectious Diseases Society, recommended steroids for critical disease, and suggested steroids and remdesivir for severe disease. We evaluated how medications for children hospitalized with COVID-19 changed after guideline publication.

METHODS

We performed a multicenter, retrospective cohort study of children aged 30 days to <18 years hospitalized with acute COVID-19 at 42 tertiary care US children’s hospitals April 2020 to December 2021. We compared medication use before and after the December 2020 IDSA guideline (pre- and postguideline) stratified by COVID-19 disease severity (mild–moderate, severe, critical) with interrupted time series.

RESULTS

Among 18 364 patients who met selection criteria, 80.3% were discharged in the postguideline period. Remdesivir and steroid use increased postguideline relative to the preguideline period, although the trend slowed. Postguideline, among patients with severe disease, 75.4% received steroids and 55.2% remdesivir, and in those with critical disease, 82.4% received steroids and 41.4% remdesivir. Compared with preguideline, enoxaparin use increased overall but decreased among patients with critical disease. Postguideline, tocilizumab use increased and hydroxychloroquine, azithromycin, anakinra, and antibiotic use decreased. Antibiotic use remained high in severe (51.7%) and critical disease (81%).

CONCLUSIONS

Although utilization of COVID-19 medications changed after December 2020 IDSA guidelines, there was a decline in uptake and incomplete adherence for children with severe and critical disease. Efforts should enhance reliable delivery of guideline-directed therapies to children hospitalized with COVID-19 and assess their effectiveness.

What’s Known on the Subject:

The impact of the coronavirus disease 2019 (COVID-19) pandemic on children has been substantial. Guidelines for the management of COVID-19 in hospitalized children changed rapidly as new evidence emerged. The December 2020 Infectious Disease Society of America guidelines consolidated key treatment recommendations.

What This Study Adds:

This study describes the patterns of medication utilization for children hospitalized with COVID-19 during 2020 and 2021, as well as adherence to the December 2020 Infectious Disease Society of America treatment guidelines. We note guideline adoption successes and areas for improvement.

Coronavirus disease 2019 (COVID-19) forced clinicians, researchers, and public health experts to confront a novel pathogen with limited information. As the pandemic evolved, health systems rapidly developed policies and treatment guidelines to align with emerging evidence. The impact of the pandemic on US children has been substantial; as of April 11, 2022, children accounted for 19% of all US COVID-19 cases, >41 000 hospitalizations, and almost 1500 deaths.1,2  Furthermore, as variants emerged, such as Δ and ο, prevalence and hospitalizations increased among children with COVID-19.1,2 

Management of acute COVID-19 in children was particularly challenging because the pediatric population was largely excluded from clinical trials and management recommendations were often based on expert consensus or extrapolated from adult data.3  Therapies studied during the pandemic included investigational agents such as remdesivir and repurposed medications (eg, hydroxychloroquine, ivermectin).4  Furthermore, prophylactic anticoagulation to prevent thrombotic complications and antibiotics because of concern for secondary bacterial infections were commonly used.5,6 

National best practice guidelines evolved rapidly as new data emerged. By the end of March 2020, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for chloroquine and hydroxychloroquine, and in May 2020, remdesivir received an EUA for treatment of hospitalized patients with severe COVID-19.7,8  However, by June 2020, the EUA for chloroquine and hydroxychloroquine was revoked.9  In August 2020, the Infectious Diseases Society of America (IDSA) and Pediatric Infectious Diseases Society (PIDS), recommendations focused on glucocorticoid and remdesivir use with some variation in recommendation strength by severity of illness.10,11 

By December 2020, coinciding with a winter surge in COVID-19, revised IDSA guidelines (endorsed by PIDS) were published online.12  The guidelines focused on acute COVID-19 treatment recommended glucocorticoids for hospitalized critically ill patients, although noting that remdesivir appeared less beneficial in these patients (eg, mechanical ventilation or extracorporeal membrane oxygenation [ECMO]).12  Steroids and remdesivir were suggested for patients with severe disease (eg, pulse oxygen saturation ≤94% on room air).12 

In the context of shifting recommendations, the extent to which therapies recommended and not recommended by the December 2020 national guidelines were used for hospitalized children with COVID-19 remains largely unknown. In this study, we describe how treatment of children with acute COVID-19 at US children’s hospitals evolved and the extent to which clinicians followed published national COVID-19 treatment guidelines from December 2020 onward.

We performed a multicenter, retrospective cohort study of children hospitalized with COVID-19 at 42 tertiary children’s hospitals in the United States who are part of the Children’s Hospital Association (Lenexa, KS) and contribute clinical and resource utilization data to the Pediatric Health Information System (PHIS). This billing and utilization database includes International Classification of Diseases, 10th Revision (ICD-10) codes for diagnoses and Current Procedural Terminology codes for procedures, as well as demographics, and is subject to quality and reliability checks.13,14  The Institutional Review Board at the Children’s Hospital of Philadelphia determined the study did not meet criteria for human subjects research.

We identified the index hospitalization for children aged 30 days to <18 years discharged from April 1, 2020 to December 30, 2021. We included children with a primary COVID-19 diagnosis (ICD-10 code U.071) or a secondary COVID-19 diagnosis when their primary diagnosis was a complication known to occur concurrently with acute COVID-19 (Supplemental Table 4).14,15  The intent of these inclusion criteria was to capture patients with symptomatic COVID-19 as the primary reason for admission, as opposed to patients who screened positive on admission but were hospitalized for unrelated conditions. COVID-19 ICD-10 code U.071 was established April 1, 2020, rapidly adopted, and has high predictive value in identifying hospitalized patients with a positive polymerase chain reaction result.14,16,17  We excluded neonates who never left the hospital and children aged <30 days to be consistent with previous studies that suggested this population is frequently admitted for other non–COVID-19 conditions.14  We excluded hospitalizations for multisystem inflammatory syndrome in children (MIS-C) or Kawasaki disease because our objective was to describe treatment of acute COVID-19 (Supplemental Table 5). MIS-C is a post-COVID-19 complication requiring different treatment.

Medications for COVID-19 were included in the analysis if they had an FDA EUA and/or were listed in IDSA COVID-19 treatment guidelines.4,7,8,12  Systemic corticosteroids included dexamethasone, methylprednisolone, prednisolone, and prednisone. Hydroxychloroquine was included because use in this population was more likely intended for COVID-19 therapy than antimalarial treatment. We also examined medications used to prevent thrombotic complications (enoxaparin) and treat potential secondary bacterial infections (antibiotics) because these were commonly used in this cohort. Antibiotics were identified using the National Healthcare Safety Network list of all pediatric antibacterial agents for systemic administration.18  Azithromycin was evaluated separately from other antibiotics because it was a proposed COVID-19 treatment. Famotidine was not included because of difficulty in determining whether it was intended to treat COVID-19.

COVID-19 disease severity was classified in mutually exclusive categories including mild–moderate, severe (noncritical), and critical disease (eg, ECMO, shock, mechanical ventilation) to mirror IDSA guidelines and previous COVID-19 and respiratory disease-related research (Table 1).4,12,14,19 

TABLE 1

COVID-19 Disease Severity Classification and Recommended Medications

Critical DiseaseSevere (Noncritical) DiseaseMild–Moderate Disease
Classification of disease severity for study population 
ICU and at least 1 of the following:
• Invasive mechanical ventilation
• Sepsis
• Shock (use of vasopressors)
• ECMO
Or death 
ICU without any of the following:
• Invasive mechanical ventilation
• Sepsis
• Shock (use of vasopressors)
• ECMO
Or respiratory failurea 
Admission (inpatient/observation) not meeting criteria for critical or severe disease 
IDSA guideline recommendations for select COVID-19 medications as of December 202012  
• Recommend steroids
• Remdesivir less beneficial in patients on mechanical ventilation or ECMO
• Hydroxychloroquine not recommended
• Hydroxychloroquine plus azithromycin not
recommended
• Tocilizumab not recommended
• Anakinra (no guidelines)
• Ivermectin (no guidelines) 
• Suggests steroids
• Suggests remdesivir
• Hydroxychloroquine not recommended
• Hydroxychloroquine plus azithromycin not
recommended
• Tocilizumab not recommended
• Anakinra (no guidelines)
• Ivermectin (no guidelines) 
No therapies recommended 
Critical DiseaseSevere (Noncritical) DiseaseMild–Moderate Disease
Classification of disease severity for study population 
ICU and at least 1 of the following:
• Invasive mechanical ventilation
• Sepsis
• Shock (use of vasopressors)
• ECMO
Or death 
ICU without any of the following:
• Invasive mechanical ventilation
• Sepsis
• Shock (use of vasopressors)
• ECMO
Or respiratory failurea 
Admission (inpatient/observation) not meeting criteria for critical or severe disease 
IDSA guideline recommendations for select COVID-19 medications as of December 202012  
• Recommend steroids
• Remdesivir less beneficial in patients on mechanical ventilation or ECMO
• Hydroxychloroquine not recommended
• Hydroxychloroquine plus azithromycin not
recommended
• Tocilizumab not recommended
• Anakinra (no guidelines)
• Ivermectin (no guidelines) 
• Suggests steroids
• Suggests remdesivir
• Hydroxychloroquine not recommended
• Hydroxychloroquine plus azithromycin not
recommended
• Tocilizumab not recommended
• Anakinra (no guidelines)
• Ivermectin (no guidelines) 
No therapies recommended 
a

Given lack of patient-level data on oxygen saturation or receipt of oxygen therapy, ICD-10 codes for respiratory failure (Supplemental Table 4) were used as a surrogate measure of hypoxia requiring supplemental oxygen (pulse oxygen saturation ≤94%) to categorize non-ICU patients as severe disease per IDSA guidelines (n = 48 patients).12 

Pre- and postguideline periods were defined as April 2020 to November 2020 and December 2020 to December 2021, respectively, coinciding with the online publication of the IDSA guidelines endorsed by PIDS on December 2, 2020.12  Although various guidelines were published and modified throughout the pandemic, by December 2020, there was general consensus around recommendations for the treatment of pediatric patients. Because our goal was to assess guideline adherence, we purposefully chose the date that IDSA guidelines were published.

The distribution of patients overall and for each period was summarized by frequencies and percentages for categorical variables and median and interquartile range for continuous variables. Categories included age, sex, race and ethnicity, payer, COVID-19 disease severity, and medication received. Patient characteristics and medications used were compared between pre- and postguidelines periods using χ2 tests and Wilcoxon Rank–Sum tests as appropriate. The proportion of patients receiving steroids, remdesivir, hydroxychloroquine, azithromycin, tocilizumab, anakinra, enoxaparin, ivermectin, and antibiotics were compared between pre- and postguideline periods including stratification by COVID-19 illness severity. Monthly discharges by disease severity category were assessed over the study period, as well as monthly use of hydroxychloroquine and ivermectin. Interrupted time series were used to analyze monthly pre- and postguideline use of guideline-recommended COVID-19 therapies (steroids and remdesivir), and enoxaparin, stratified by COVID-19 disease severity. SAS version 9.4 (SAS Institute, Inc) was used for all analyses. A P value threshold of <.05 was considered statistically significant.

There were 18 364 patients included in the study, of whom 80.3% were discharged from their index hospitalization in the postguideline period (Table 2). There was a higher percentage of Hispanic patients in the preguideline period versus the postguideline period (42.6% vs 26.2%, P < .001), and the opposite was observed for non-Hispanic White patients (24.6% vs 39.5%, P < .001). COVID-19 hospitalizations for each disease severity category fluctuated with COVID-19 incidence over time (Fig 1). The majority (64.2%) of the 134 patients with an ICD-10 code for respiratory failure were cared for in the ICU, and this proportion was similar pre- and postguideline. Only 48 non-ICU patients had an ICD-10 code for respiratory failure and were classified as severe disease.

FIGURE 1

Volume of inpatient discharges over time for children hospitalized with COVID-19 stratified by disease severity. The dotted line represents the number of children hospitalized with mild–moderate COVID-19; dashed line, children with severe (noncritical) disease; solid line, children with critical disease.

FIGURE 1

Volume of inpatient discharges over time for children hospitalized with COVID-19 stratified by disease severity. The dotted line represents the number of children hospitalized with mild–moderate COVID-19; dashed line, children with severe (noncritical) disease; solid line, children with critical disease.

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TABLE 2

Comparison of Demographics, COVID-19 Disease Severity, and Medications across Pre/Postguideline Periods of COVID-19 Pandemic

PreguidelinePostguideline
All InpatientsApril 2020– November 2020December 2020– December 2021P
N 18 364 3618 (19.7) 14 746 (80.3)  
Age 
 Median (IQR) 6 (0–14) 6 (0–14) 6 (0–14) .056 
 0–4 y, n (%) 8414 (45.8) 1698 (46.9) 6716 (45.5) .004 
 5–11 y, n (%) 3744 (20.4) 666 (18.4) 3078 (20.9) 
 12–17 y, n (%) 6206 (33.8) 1254 (34.7) 4952 (33.6)  
Sex, n (%) 
 Female 8517 (46.4) 1682 (46.5) 6835 (46.4) .881 
 Male 9847 (53.6) 1936 (53.5) 7911 (53.6) 
Race and ethnicity, n (%) 
 Non-Hispanic White 6716 (36.6) 889 (24.6) 5827 (39.5) <.001 
 Non-Hispanic Black 4551 (24.8) 856 (23.7) 3695 (25.1) 
 Hispanic 5406 (29.4) 1543 (42.6) 3863 (26.2) 
 Asian American 451 (2.5) 88 (2.4) 363 (2.5) 
 Other 1240 (6.8) 242 (6.7) 998 (6.8) 
Payer, n (%) 
 Private 5343 (29.1) 807 (22.3) 4536 (30.8) <.001 
 Government 12 101 (65.9) 2673 (73.9) 9428 (63.9) 
 Other 920 (5) 138 (3.8) 782 (5.3) 
Disease severity, n (%) 
 Mild–moderate 13 496 (73.5) 2606 (72.0) 10 890 (73.9) <.001 
 Severe (noncritical) 2269 (12.4) 386 (10.7) 1883 (12.8) 
 Critical 2599 (14.2) 626 (17.3) 1973 (13.4) 
Medications, n (%) 
 Steroids 7769 (42.3) 1125 (31.1) 6644 (45.1) <.001 
 Remdesivir 3750 (20.4) 226 (6.2) 3524 (23.9) <.001 
 Hydroxychloroquine 61 (0.3) 37 (1.0) 24 (0.2) <.001 
 Azithromycin 1131 (6.2) 257 (7.1) 874 (5.9) .008 
 Tocilizumab 204 (1.1) 19 (0.5) 185 (1.3) <.001 
 Anakinra 391 (2.1) 123 (3.4) 268 (1.8) <.001 
 Enoxaparin 4620 (25.2) 845 (23.4) 3775 (25.6) .005 
 Ivermectin 4 (0) 0 (0) 4 (0) .322 
 Antibioticsa 8492 (46.2) 1930 (53.3) 6562 (44.5) <.001 
PreguidelinePostguideline
All InpatientsApril 2020– November 2020December 2020– December 2021P
N 18 364 3618 (19.7) 14 746 (80.3)  
Age 
 Median (IQR) 6 (0–14) 6 (0–14) 6 (0–14) .056 
 0–4 y, n (%) 8414 (45.8) 1698 (46.9) 6716 (45.5) .004 
 5–11 y, n (%) 3744 (20.4) 666 (18.4) 3078 (20.9) 
 12–17 y, n (%) 6206 (33.8) 1254 (34.7) 4952 (33.6)  
Sex, n (%) 
 Female 8517 (46.4) 1682 (46.5) 6835 (46.4) .881 
 Male 9847 (53.6) 1936 (53.5) 7911 (53.6) 
Race and ethnicity, n (%) 
 Non-Hispanic White 6716 (36.6) 889 (24.6) 5827 (39.5) <.001 
 Non-Hispanic Black 4551 (24.8) 856 (23.7) 3695 (25.1) 
 Hispanic 5406 (29.4) 1543 (42.6) 3863 (26.2) 
 Asian American 451 (2.5) 88 (2.4) 363 (2.5) 
 Other 1240 (6.8) 242 (6.7) 998 (6.8) 
Payer, n (%) 
 Private 5343 (29.1) 807 (22.3) 4536 (30.8) <.001 
 Government 12 101 (65.9) 2673 (73.9) 9428 (63.9) 
 Other 920 (5) 138 (3.8) 782 (5.3) 
Disease severity, n (%) 
 Mild–moderate 13 496 (73.5) 2606 (72.0) 10 890 (73.9) <.001 
 Severe (noncritical) 2269 (12.4) 386 (10.7) 1883 (12.8) 
 Critical 2599 (14.2) 626 (17.3) 1973 (13.4) 
Medications, n (%) 
 Steroids 7769 (42.3) 1125 (31.1) 6644 (45.1) <.001 
 Remdesivir 3750 (20.4) 226 (6.2) 3524 (23.9) <.001 
 Hydroxychloroquine 61 (0.3) 37 (1.0) 24 (0.2) <.001 
 Azithromycin 1131 (6.2) 257 (7.1) 874 (5.9) .008 
 Tocilizumab 204 (1.1) 19 (0.5) 185 (1.3) <.001 
 Anakinra 391 (2.1) 123 (3.4) 268 (1.8) <.001 
 Enoxaparin 4620 (25.2) 845 (23.4) 3775 (25.6) .005 
 Ivermectin 4 (0) 0 (0) 4 (0) .322 
 Antibioticsa 8492 (46.2) 1930 (53.3) 6562 (44.5) <.001 

IQR, interquartile range.

a

Excluding azithromycin. Disease severity: mild–moderate, did not require ICU or have respiratory failure ICD-10 code; severe (noncritical), respiratory failure ICD-10 code or in ICU but without invasive mechanical ventilation, ECMO, shock, or sepsis; critical, in ICU with invasive mechanical ventilation, ECMO, shock, sepsis, or died during admission.

The most common medications in the preguideline period included antibiotics (53.3%), steroids (31.1%), enoxaparin (23.4%), azithromycin (7.1%), and remdesivir (6.2%). Remdesivir and steroids significantly increased after the guidelines were published but remained used in a minority of hospitalized children. Hydroxychloroquine, azithromycin, anakinra, and antibiotics significantly decreased postguideline. Ivermectin use was low postguideline. There was a small but statistically significant increase in enoxaparin and tocilizumab postguideline (Table 2).

Because the guideline recommendations are based on COVID-19 illness severity (eg, steroids and remdesivir), Table 3 and Fig 2 can be used to illustrate adherence to treatment guidelines. Although the percentage of patients receiving steroids and remdesivir significantly increased within each disease severity category from the pre- to the postguideline period (Table 3), the trend analysis suggests the slope was significantly lower postguideline for mild–moderate and critical disease (Fig 2, Supplemental Table 6). Overall, 75.4% of severe disease and 82.4% of critical disease patients received steroids in the postguideline period, when steroid treatment was suggested or recommended, respectively (Tables 1 and 3).12  In the postguideline period, patients with severe disease received remdesivir more frequently (55.2%) than those with critical disease (41.4%), consistent with the recommendation for use in patients with severe disease who are not on mechanical ventilation or ECMO.12  Remdesivir use both pre- and postguideline was higher in children aged ≥12 years.

TABLE 3

Medications by COVID-19 Disease Severity and Pre/Postguideline Periods

Mild–ModerateSevere (Noncritical)Critical
PreguidelinePostguidelinePPreguidelinePostguidelinePPreguidelinePostguidelineP
N 2606 10 890  386 1883  626 1973  
Steroids 474 (18.2%) 3599 (33.0%) <.001 182 (47.2%) 1419 (75.4%) <.001 469 (74.9%) 1626 (82.4%) <.001 
Remdesivir 62 (2.4%) 1669 (15.3%) <.001 68 (17.6%) 1039 (55.2%) <.001 96 (15.3%) 816 (41.4%) <.001 
 Age <12 12 (0.7%) 663 (8.7%) <.001 23 (11.5%) 380 (39.5%) <.001 38 (10.9%) 420 (35.1%) <.001 
 Age ≥12 50 (6.3%) 1006 (30.9%) <.001 45 (24.2%) 659 (71.6%) <.001 58 (20.9%) 396 (51.1%) <.001 
Hydroxychloroquine 10 (0.4%) 19 (0.2%) .038 10 (2.6%) 1 (0.1%) <.001 17 (2.7%) 4 (0.2%) <.001 
Azithromycin 146 (5.6%) 509 (4.7%) .048 57 (14.8%) 182 (9.7%) .003 54 (8.6%) 183 (9.3%) .623 
Tocilizumab 0 (0) 32 (0.3%) .006 3 (0.8%) 67 (3.6%) .004 16 (2.6%) 86 (4.4%) .043 
Anakinra 19 (0.7%) 30 (0.3%) .001 12 (3.1%) 33 (1.8%) .082 92 (14.7%) 205 (10.4%) .003 
Enoxaparin 307 (11.8%) 1700 (15.6%) <.001 167 (43.3%) 1020 (54.2%) <.001 371 (59.3%) 1055 (53.5%) .011 
Ivermectin 0 (0%) 0 (0%) — 0 (0%) 0 (0%) — 0 (0%) 4 (0.2%) .260 
Antibioticsa 1149 (44.1%) 3989 (36.6%) <.001 237 (61.4%) 974 (51.7%) .001 544 (86.9%) 1599 (81.0%) .001 
Mild–ModerateSevere (Noncritical)Critical
PreguidelinePostguidelinePPreguidelinePostguidelinePPreguidelinePostguidelineP
N 2606 10 890  386 1883  626 1973  
Steroids 474 (18.2%) 3599 (33.0%) <.001 182 (47.2%) 1419 (75.4%) <.001 469 (74.9%) 1626 (82.4%) <.001 
Remdesivir 62 (2.4%) 1669 (15.3%) <.001 68 (17.6%) 1039 (55.2%) <.001 96 (15.3%) 816 (41.4%) <.001 
 Age <12 12 (0.7%) 663 (8.7%) <.001 23 (11.5%) 380 (39.5%) <.001 38 (10.9%) 420 (35.1%) <.001 
 Age ≥12 50 (6.3%) 1006 (30.9%) <.001 45 (24.2%) 659 (71.6%) <.001 58 (20.9%) 396 (51.1%) <.001 
Hydroxychloroquine 10 (0.4%) 19 (0.2%) .038 10 (2.6%) 1 (0.1%) <.001 17 (2.7%) 4 (0.2%) <.001 
Azithromycin 146 (5.6%) 509 (4.7%) .048 57 (14.8%) 182 (9.7%) .003 54 (8.6%) 183 (9.3%) .623 
Tocilizumab 0 (0) 32 (0.3%) .006 3 (0.8%) 67 (3.6%) .004 16 (2.6%) 86 (4.4%) .043 
Anakinra 19 (0.7%) 30 (0.3%) .001 12 (3.1%) 33 (1.8%) .082 92 (14.7%) 205 (10.4%) .003 
Enoxaparin 307 (11.8%) 1700 (15.6%) <.001 167 (43.3%) 1020 (54.2%) <.001 371 (59.3%) 1055 (53.5%) .011 
Ivermectin 0 (0%) 0 (0%) — 0 (0%) 0 (0%) — 0 (0%) 4 (0.2%) .260 
Antibioticsa 1149 (44.1%) 3989 (36.6%) <.001 237 (61.4%) 974 (51.7%) .001 544 (86.9%) 1599 (81.0%) .001 
a

Excluding azithromycin. Disease severity: mild–moderate, did not require ICU or have respiratory failure ICD-10 code; severe (noncritical), respiratory failure ICD-10 code or in ICU but without invasive mechanical ventilation, ECMO, shock, or sepsis; critical, in ICU with invasive mechanical ventilation, ECMO, shock, sepsis, or died during admission.

—, not applicable.

FIGURE 2

Trends in medication use over time for children hospitalized with COVID-19 stratified by disease severity. Vertical line indicates IDSA Guideline, Version 3.5.1, online publication December 2, 2020. Solid orange line represents the trend of medication use preguideline; dashed orange line, the postguideline trend; blue line, the projected trend postguideline if no change occurred with guideline publication; p value, the change in slope pre- to postguideline.

FIGURE 2

Trends in medication use over time for children hospitalized with COVID-19 stratified by disease severity. Vertical line indicates IDSA Guideline, Version 3.5.1, online publication December 2, 2020. Solid orange line represents the trend of medication use preguideline; dashed orange line, the postguideline trend; blue line, the projected trend postguideline if no change occurred with guideline publication; p value, the change in slope pre- to postguideline.

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Across pre- to postguideline periods, hydroxychloroquine significantly decreased across all disease severity categories, with a noticeably abrupt decline correlating with EUA revocation June 2020 (Table 3, Supplemental Fig 3).9  Azithromycin use significantly decreased in patients with mild–moderate and severe disease (Table 3). In the postguideline period, percentage of enoxaparin use significantly increased among mild–moderate and severe disease and decreased among critical disease (Table 3). The interrupted time series analysis suggests these trends began in the preguideline period for mild–moderate and critical disease but use in severe disease was declining preguideline and then significantly increased postguideline (Fig 2, Supplemental Table 6). Antibiotic use significantly declined across all disease severity categories postguideline, although remained high in critical disease (81%) and severe disease (51.7%) (Table 3).

In our retrospective cohort study of children with COVID-19 discharged from children’s hospitals, we found increased use of steroids and remdesivir and decreased use of hydroxychloroquine and azithromycin during the postguideline period. Although changes in percentage utilization pre- versus postguideline appear consistent with IDSA guidelines, uptake in steroid and remdesivir use generally declined postguideline and adherence to recommendations was incomplete. Although guideline adherence for no use of hydroxychloroquine was close to 100%, steroids were used only in 82.4% of critically ill patients despite a strong recommendation.

Throughout the pandemic, clinicians and researchers rapidly developed and revised guidelines leading to changes in therapies for COVID-19 within children’s hospitals. Publications and webinars by various organizations led to early adaptation of therapies from adult experience. As experience grew, several guidelines, some pediatric-specific, were published. Although we found compliance with COVID-19 guidelines was not 100%, the speed of uptake compared with other non–COVID-19 guidelines was extremely high.20  It is frequently stated that it takes about 17 years for research evidence to reach clinical practice.21  Media attention, clinician webinars, use of social media, and gravity of COVID-19 illness might have contributed to rapid implementation and higher level of guideline compliance.

Recommended therapies such as remdesivir and steroids increased throughout the pandemic, although use was not universal in severe and critical illness. Steroids represent a commonly available and familiar medication and were consistently suggested or recommended for children with severe and critical disease, respectively. Postguideline, only steroid use in severe disease continued to increase after the preguideline trend. The trend in steroid use for mild disease decreased consistent with guideline recommendations. However, the postguideline trend in steroid use for patients with critical disease became static despite recommendations, leading to incomplete adoption. Despite their availability, adherence to this guideline-recommended therapy remains around 80% for children with critical disease and less for children with severe noncritical disease. However, both rates exceed the use of remdesivir in severe noncritical patients (55.2%), a population in which remdesivir is suggested throughout guideline revisions.

Trends in remdesivir use decreased postguideline for all disease categories. This was consistent with the recommendation for no therapy in patients with mild–moderate disease and decreased benefit for patients with critical disease on mechanical ventilation or ECMO, but less consistent with suggested use in severe illness. Barriers to remdesivir use in the severely ill population may include perceived lack of efficacy on meaningful outcomes (eg, recovery versus mortality) or FDA approval in October 2020 only for hospitalized patients aged ≥12 years and weighing ≥40 kg, whereas use for younger children weighing ≥3.5 kg remained under an EUA during the study period.7  In our study, children aged ≥12 years had higher percentages of remdesivir use compared with younger children, although use significantly increased for both age groups pre- to postguideline.

Finally, the postguideline use of steroids (33%) or remdesivir (15.3%) for mild–moderate illness warrants further exploration, given the suggestion against use in this population. The use of tocilizumab and anakinra was not common, reflecting the lack of clear recommendations for anakinra and recommendation against routine use of tocilizumab in the December 2020 IDSA Guidelines (Table 1). The recommendation against tocilizumab was revised in February 2021 to a suggestion for use in patients with progressive severe or critical disease with elevated markers of systemic inflammation, in addition to standard of care (ie, steroids), and further mention of anakinra was dropped.12,22  Although it is difficult to assess guideline adherence, we note that use of both these medications was higher in critically ill patients.

Early studies suggested high incidence of thrombosis in children and adults with potential benefits to anticoagulation.2325  International Society of Thrombosis and Hemostasis interim guidelines recommended D-dimer screening and anticoagulation in adults with COVID-19, which correlated to decreased mortality.5,26  Although there were no pediatric-specific guidelines, many children’s hospitals routinely used anticoagulation in hospitalized patients on the basis of adult studies.27  Subsequently, International Society of Thrombosis and Hemostasis pediatric consensus guidelines and COVID-19 PICU guidelines advocated for anticoagulation in children with COVID-19 with an elevated D-dimer (5 times above normal) or other coagulopathy risk factors.27,28  Early in the pandemic, observational studies reported heparin use in 18.1% and enoxaparin use in 14.8% of hospitalized children with COVID-19.29  Another single-center study found 65% of PICU patients and 16% of all hospitalized children with COVID-19 received anticoagulation during the early period of the pandemic.30  However, a systematic review of the literature published through January of 2021 concluded that thrombotic and thromboembolic events are rare in children with COVID-19 or MIS-C.31  In December 2020, updated National Institutes of Health guidelines stated that, for hospitalized children with COVID-19, indications for venous thromboembolism prophylaxis should be the same as those for children without COVID-19.32  In our current study, 59.3% of children with critical illness received enoxaparin preguideline and its use significantly decreased to 53.5% postguideline; however, the overall change in trend was not significant, possibly because of the rise in use during fall 2021. Enoxaparin use in mild–moderate and severely ill patients increased significantly pre- to postguideline, with a significant positive upward trend postguideline in severe patients. Overall, it appears that anticoagulation is still common in children with COVID-19 despite current recommendations, acknowledging the difficulty in deimplementing low-value care.33 

The interest in hydroxychloroquine for COVID-19 treatment emerged early in the pandemic with publication of an open-label nonrandomized study.34  After this publication, the FDA issued a letter on March 28, 2020, granting EUA of chloroquine and hydroxychloroquine for patients with COVID-19.8  The use of hydroxychloroquine fell appropriately to <1% after EUA revocation.9  Azithromycin use for COVID-19 therapy in combination with hydroxychloroquine also declined after IDSA and National Institutes of Health COVID-19 Treatment Guideline publication.35,36  Finally, ivermectin was not mentioned in December 2020 and use outside a clinical trial was not recommended in the 2021 IDSA guidelines.22,37  The results of initial clinical trials were reported in late 2020, and meta-analyses published soon afterward, suggesting benefits were later retracted.38  The infrequent use of ivermectin in our study was heartening, suggesting that guidelines continued to be followed in pediatric patients despite media attention.

The decrease in antibiotic use over time across disease severity categories may indicate more confidence among clinicians as time progressed with the management of COVID-19 as a viral illness, both in the spectrum of illness and radiographic appearance of COVID-19 pneumonia. In our study, we could not determine whether there was presumed or confirmed secondary bacterial infection that warranted antibiotics or if antibiotics were used initially in critically ill patients because of a concern for sepsis. However, we note that antibiotics were commonly used in this cohort of children hospitalized for COVID-19.

There are several limitations that may influence study interpretation. Guideline implementation during a pandemic may not be representative of other situations because of rapid guideline development with limited data over time. Furthermore, the PHIS database predominantly includes tertiary and quaternary care children’s hospitals, where guideline uptake may differ from community hospitals or smaller centers. Additionally, our primary analysis estimated guideline adherence as a percentage for each study period, but this pre- and postdesign may not account for within-period trends, which are visually displayed for key medications in our figures. Patients may have been misclassified by utilizing ICD-10 diagnosis codes as a proxy for disease severity. For example, it is possible children who were asymptomatic or required supplemental oxygen in a noncritical setting without the ICD-10 code for respiratory failure were miscategorized as mild–moderate disease. Additionally, PHIS is a billing database and lacks patient-level clinical data such as duration of symptoms, oxygen saturation, or receipt of oxygen therapy and laboratory test results. Data on timing of disease onset was not available for our study but may have affected choice of therapy because remdesivir is thought to be more effective in the early phase of symptomatic disease.39  Furthermore, we were not able to determine therapy-specific indications for non–COVID-19 treatments, such as steroids for asthma. Finally, the PHIS database does not reliably include experimental medications for some uncommonly used therapies (eg, convalescent plasma) and these were not included in our study. Despite these limitations, our study reports important trends in adherence to national treatment guidelines in children hospitalized with COVID-19 and identifies potential targets for care improvement.

COVID-19 medications for hospitalized children evolved throughout the pandemic as clinicians confronted a novel pathogen with limited therapeutic data in children. Despite these challenges, guidelines rapidly emerged, and clinicians increasingly adhered to them. However, approximately 1 in 5 critically ill patients did not receive steroid treatment in our postguideline period despite a strong recommendation. As the COVID-19 pandemic continues to impact the world and increasingly our pediatric patients, consideration should be given to approaches aimed at more reliable delivery of guideline-directed therapy to children, to best use our collective knowledge to improve outcomes.

Drs Burns and Teufel conceptualized and designed the study, interpreted the data, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Thurm and Hall substantially contributed to study design, analyzed the data, and critically reviewed the manuscript; Drs Antoon, Grijalva, Hersh, Hester, Korn, Reyes, Shah, and Totapally conceptualized and designed the study, interpreted the data, and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: Dr Grijalva was supported in part by National Institutes of Health–National Institute of Allergy and Infectious Diseases (K24 AI148459). No other funding was secured for this study. The National Institutes of Health had no role in the design and conduct of the study.

CONFLICT OF INTEREST DISCLAIMER: Dr Totapally is participating in the “Overcoming COVID-19: Influenza and other emerging respiratory pathogens surveillance registry” study funded by the Centers for Disease Control and Prevention at Nicklaus Children's Hospital; however, he received no compensation for this activity. Dr Grijalva reports consultancy fees from Pfizer, Merck, and Sanofi-Pasteur, and grants from Campbell Alliance/Syneos Health, the Centers for Disease Control and Prevention, National Institutes of Health, the Food and Drug Administration, Agency for Health Research and Quality, and Sanofi, outside the submitted work. The remaining authors have indicated they have no conflicts relevant to this article to disclose.

COVID-19

coronavirus disease 2019

ECMO

extracorporeal membrane oxygenation

EUA

emergency use authorization

FDA

Food and Drug Administration

ICD-10

International Classification of Diseases, 10th Revision

IDSA

Infectious Disease Society of America

ICU

Intensive Care Unit

MIS-C

multisystem inflammatory syndrome in children

PHIS

Pediatric Health Information System

PIDS

Pediatric Infectious Diseases Society

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Supplementary data