Factors prompting clinicians to request viral testing in children are unclear. We assessed patterns prompting clinicians to perform viral testing in children discharged from an emergency department (ED) or hospitalized with an acute respiratory infection (ARI).
Using active ARI surveillance data collected from November 2017 through February 2020, children aged between 30 days and 17 years with fever or respiratory symptoms who had a research respiratory specimen tested were included. Children’s presentation patterns from their initial evaluation at each health care setting were analyzed using principal components (PCs) analysis. PC-specific models using logistic regression with robust sandwich estimators were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between PCs and provider-ordered viral testing. PCs were assigned respiratory virus/viruses names a priori based on the patterns represented.
In total, 4107 children were enrolled and tested, with 2616 (64%) discharged from the ED and 1491 (36%) hospitalized. In the ED, children with a coviral presentation pattern had a 1.44-fold (95% CI, 1.24–1.68) increased odds of receiving a provider-ordered viral test than children showing clinical symptoms less representative of coviral-like infection. Whereas children in the ED and hospitalized with rhinovirus-like symptoms had 71% (OR, 0.29; 95% CI, 0.24–0.34) and 39% (OR, 0.61; 95% CI, 0.49–0.76) decreased odds, respectively, of receiving a provider-ordered viral test during their medical encounter.
Viral tests are frequently ordered by clinicians, but presentation patterns vary by setting and influence the initiation of testing. Additional assessments of factors affecting provider decisions to use viral testing in pediatric ARI management are needed to maximize patient benefits of testing.
Outside the neonatal period, acute respiratory infections (ARIs) are the leading cause of childhood morbidity and mortality worldwide.1 In the United States, ARIs account for 41% and 40% of annual infectious disease-related emergency department (ED) visits and hospitalizations, respectively.2 ARIs are most often caused by respiratory viruses, such as respiratory syncytial virus (RSV), rhinovirus, and influenza, but can also be caused by bacteria.3–5 Given the overlapping clinical presentations of viral and bacterial ARIs, clinicians frequently order viral diagnostic tests to assess viral and bacterial etiologies.4,5 Viral diagnostic testing includes rapid antigen (influenza and RSV) and, more recently, nucleic acid amplification tests (NAAT). Differentiating between viral and bacterial ARIs may help clinicians target their treatment choices (eg, antiviral agents, antibiotics, symptomatic management only). In addition, distinguishing ARIs of viral or bacterial origin can reduce antibiotic use and duration when an ARI of viral origin is suspected and confirmed.
Despite the potential advantages of distinguishing ARIs of viral or bacterial origin, national guidelines discourage routine viral diagnostic testing for bronchiolitis6 and advise against relying on rapid antigen testing for diagnosing influenza if there is a high clinical suspicion.7 The primary reason against testing to determine the pathogen causing bronchiolitis or influenza is because in most cases, the clinical management would not be altered.6,7 In spite of this recommendation, a study that included 42 US children’s hospitals noted that viral testing was performed in 45% of children hospitalized with bronchiolitis, and testing practices varied across institutions.8 Before the COVID-19 pandemic, pediatric hospitals tended to use molecular testing, whereas EDs primarily focused on rapid influenza antigen testing.3,8 Studies examining patient and clinical factors influencing provider-ordered viral testing across settings are limited. Understanding factors prompting viral testing practices across health care settings may help develop more specific testing guidelines or components for diagnostic stewardship programs. Our aim was to assess patient and clinical characteristics (presentation patterns) that prompt clinicians to obtain respiratory viral testing on children presenting to an ED or hospitalized with an ARI.
Methods
Study Design
We conducted a secondary analysis using data collected from an ongoing ARI surveillance as part of the Centers for Disease Control and Prevention–funded New Vaccine Surveillance Network9,10 in Nashville, Tennessee, between November 2, 2017, and February 28, 2020. Year-round recruitment at a single southern children’s hospital occurred 4 days/week in the ED and 7 days/week in the inpatient setting. Children who were enrolled in the ED and subsequently admitted to the hospital were classified as an inpatient. Institutional review boards at our institution and the Centers for Disease Control and Prevention reviewed and approved this study (see 45 C.F.R. part 46; 21 C.F.R. part 56).11
Study Population
Eligible children were younger than age 18 years, resided within the catchment/surveillance area (ie, Davidson, Williamson, Cheatham, Dickson, Rutherford, Montgomery, Roberson, and Sumner counties), and presented to an ED or were hospitalized within 48 hours of enrollment with 1 or more of the following symptoms within 14 days of onset: fever, cough, earache, nasal congestion, runny nose, sore throat, posttussive vomiting, wheezing, shortness of breath/rapid or shallow breathing, myalgia, apnea, apparent-life threatening event, or brief resolved unexplained event (eg, unresponsive; Supplemental Fig 3).9,10 A child was ineligible if any of the following criteria were met: chemotherapy-associated fever and neutropenia (absolute neutrophil count <500/µL), newborns never discharged since birth, transferred from another hospital >48 hours after initial admission, recently hospitalized (≤5 days), or previously enrolled in the study within the past 14 days.9,10
In addition, we excluded infants age <30 days because of the increased risk of serious bacterial infections compared with other groups6,12 (eg, group B Streptococcus) and unique clinical management/practices. Children with multiple ARI visits were considered susceptible to a new ARI infection (either viral or bacterial) if each visit was ≥90 days from the previous visit.
Interviews and Medical Chart Abstractions
After informed consent, trained research personnel interviewed the child’s parent/guardian to collect demographic information (age, sex, race, and ethnicity), clinical symptoms, and medical history using a standardized case report form. Race and ethnicity were included as social construct variables to understand potential health care disparities driven by interpersonal and systemic racism and bias. Physical examination findings, vital signs at the time of presentation, and provider-ordered viral testing (ie, rapid antigen and NAAT) were abstracted from medical charts. Final clinical disposition was determined by the highest level of care provided to the child during the visit (ie, children enrolled in the ED and later hospitalized were considered an inpatient). During the study period, providers at our institution did not have any diagnostic stewardship programs or testing cost information guiding their decisions and were able to order the following viral tests: rapid influenza antigen, rapid RSV antigen, and NAAT testing. Demographic, interview, medical record, and laboratory results were maintained in a secure REDCap (Research Electronic Data Capture, Vanderbilt University, Nashville, TN) database.13
Provider-Ordered Viral Tests
Our main outcome was a provider-ordered viral test, which included at least 1 of the following: rapid influenza antigen, rapid RSV antigen, and/or NAAT (ie, BioFire FilmArray Respiratory Panel); dichotomized into tested versus not tested.
Principal Components Analysis
A principal components analysis (PCA; a dimensionality-reduction method) was used to derive different presentation patterns (ie, principal components—the set of intercorrelated variables that embody the greatest amount of variance [information]) using the following variables: age (years), illness duration (days), maximum temperature (none, moderate [≥100.4 °F to <102.0 °F], or severe [≥102.0 °F]), pulmonary symptoms (cough, nasal congestion, rhinorrhea, self-reported wheezing, and shortness of breath; yes or no), number of nonpulmonary symptoms (fatigue, earache, myalgia, diarrhea, vomiting, sore throat), respiratory rate (breaths/minute), heart rate (beats/minute), oxygen saturation on room air (%), wheezing (yes or no), retractions (yes or no), time of year (respiratory season [October–April] or nonrespiratory season), any underlying medical condition (yes or no), underlying respiratory condition (yes or no), underlying asthma/reactive airway disease (yes or no), underlying cardiovascular condition (yes or no), underlying neurologic condition (yes or no), underlying oncologic/immunosuppressive condition (yes or no), prematurity (yes or no), public insurance (yes or no), private insurance (yes or no), none/self-pay insurance (yes or no), and previous antibiotic use in past 14 days (yes or no). Continuous variables were standardized to have a mean of 0 and SD equal to 1.
Presentation patterns were derived for children in each health care setting (ie, ED and hospital). The principal components derived from the PCA analysis were rotated to maximize the variance explained by each pattern. Scree plots were generated to summarize the total number of principal components (PCs) with the greatest amount of variance explained. The strongest PCs whose eigenvalues (ie, the coefficients that provide us with summary statistics that depict the amount of variance carried from each PC) were greater than 1 were chosen to represent the independent presentation patterns. Final PCs were dichotomized at the median using cut-points among children who did not receive a provider-ordered test (n = 1322). Our pediatricians (N.H. and S.K.) assigned respiratory virus/coviral names to each PC based on their clinical suspicion from the presentation patterns represented. Coviral refers to a presentation pattern of a child with more than 1 respiratory virus.
Validation of Clinical Diagnostic PC Patterns
PCs were validated using test results from our research specimens. Research specimens (eg, nasal, oropharyngeal, tracheal aspirates) were collected from all enrolled children and placed in viral transport medium by study personnel. All research specimens were transported to our research laboratory and stored at 4 °C until processed, within 48 hours. Testing was performed using quantitative reverse transcription-polymerase chain reaction assays for the following viruses: adenovirus, human metapneumovirus, influenza (A, B, and C), parainfluenza (types 1–4), RSV, rhinovirus, and endemic coronaviruses (OC43, 229E, NL63, and HKU1). Research specimen collection and molecular testing were performed in accordance with the New Vaccine Surveillance Network study protocol.9,10
Statistical Analysis
Sociodemographic and clinical characteristics of children by setting were summarized using frequency for categorical variables and mean (SD) for continuous variables. We performed multiple imputation for 266 children with ≥1 missing covariates (missingness: 1 covariate [n = 258] children; 2 covariates [n = 6]; 3 covariates [n = 2]), using predictive mean matching with 10 imputation samples.14 Our final analytic sample size consisted of 4107 children.
PC-specific models were built using unconditional logistic regression with robust sandwich estimators (to account for repeat visits) to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between different clinical presentation patterns and provider-ordered viral testing. All analyses were performed in R (version 3.6.1).
Results
From November 2017 to February 2020, 4271 (57%) of 7482 eligible children were enrolled, among whom 4212 (99%) had a research specimen tested. A total of 151 enrollments were excluded based on a previous enrollment occurring within <90 days. Our final cohort included 4107 children, of which 2616 (64%) were from the ED and 1491 (36%) were hospitalized (Fig 1). A total of 455 children from our final cohort had multiple ARI visits ≥90 days apart, with some children incurring multiple visits in both health care settings (n = 12).
Consort diagram of children (age >30 days–17 years) enrolled in an emergency department or hospitalized with acute respiratory illness, November 2017–February 2020. ARI, acute respiratory illness. a Declination reasons: refused (n = 1673), discharged before approaching for enrollment (n = 343), no parent/legal guardian present when approached for enrollment (n = 288), no reason provided (n = 141), child’s provider refused (n = 38), missed (n = 42), parent/legal guardian didn’t speak English or Spanish (n = 605), parent/legal guardian spoke Spanish, but translator was not available (n = 75), parent/legal guardian requested child be withdrawn from study (n = 6). b Total enrolled include children with multiple ARI visits ≤14 days apart. c 390 children had 2 ARI visits ≥90 days apart and 65 children ≥3 ARI visits ≥90 days apart. d 241 children with 2 ARI visits ≥90 days apart and 34 children had ≥3 ARI visits ≥90 days apart were discharged from the emergency department. e 149 children with 2 ARI visits ≥90 days apart and 31 children with 3 ARI visits ≥90 days apart were hospitalized.
Consort diagram of children (age >30 days–17 years) enrolled in an emergency department or hospitalized with acute respiratory illness, November 2017–February 2020. ARI, acute respiratory illness. a Declination reasons: refused (n = 1673), discharged before approaching for enrollment (n = 343), no parent/legal guardian present when approached for enrollment (n = 288), no reason provided (n = 141), child’s provider refused (n = 38), missed (n = 42), parent/legal guardian didn’t speak English or Spanish (n = 605), parent/legal guardian spoke Spanish, but translator was not available (n = 75), parent/legal guardian requested child be withdrawn from study (n = 6). b Total enrolled include children with multiple ARI visits ≤14 days apart. c 390 children had 2 ARI visits ≥90 days apart and 65 children ≥3 ARI visits ≥90 days apart. d 241 children with 2 ARI visits ≥90 days apart and 34 children had ≥3 ARI visits ≥90 days apart were discharged from the emergency department. e 149 children with 2 ARI visits ≥90 days apart and 31 children with 3 ARI visits ≥90 days apart were hospitalized.
Provider-Ordered Viral Testing by Setting
Emergency Department
Enrolled children were a median age of 3 years, predominately Black, non-Hispanic, and 31% had at least 1 underlying medical condition (Table 1). Cough, nasal congestion/runny nose, and fever were the most frequently reported symptoms. A provider-ordered viral test occurred in 49% (1294/2616) of children with an ARI-related ED visit, 97% of whom received 1 test (1255/1294; 87% rapid influenza; 1% rapid RSV; 13% NAAT), 3% received 2 tests (38/1294; 100% rapid influenza; 42% rapid RSV; 58% NAAT), and <1% had 3 tests (1/1294). In total, 64% of children had at least 1 virus detected from their research specimen, with influenza being most common (Table 1).
Sociodemographic and Clinical Characteristics of Children (Aged >30 Days–17 Years) Enrolled in Emergency Departments and Hospitalized With Acute Respiratory Illness, November 2017–February 2020
Characteristic(s) . | Emergency Department N = 2616 . | Inpatient N = 1491 . |
---|---|---|
Age, y, mean (SD) | 4.6 (4.4) | 3.4 (4.1) |
Age, y, median (IQR) | 3.0 (1.1, 7.0) | 1.6 (0.5, 4.9) |
0 to <2 y, no. (%) | 1028 (39.3) | 832 (55.8) |
2 to <5 y, no. (%) | 662 (25.3) | 293 (19.7) |
≥5 to <18 y, no. (%) | 926 (35.4) | 366 (24.5) |
Sex, male, no. (%) | 1405 (53.7) | 873 (58.6) |
Race/ethnicity, no. (%) | ||
White, non-Hispanic | 353 (13.5) | 676 (45.4) |
Black, non-Hispanic | 1115 (42.6) | 355 (23.8) |
Other non-Hispanic | 182 (7.0) | 135 (9.1) |
Hispanic | 940 (35.9) | 310 (20.8) |
Unknown | 26 (1.0) | 15 (1.0) |
Insurance type, no. (%) | ||
Public | 2093 (80.0) | 968 (64.9) |
Private | 219 (8.4) | 395 (26.5) |
Both | 13 (0.5) | 27 (1.8) |
None/self-pay | 262 (10.0) | 80 (5.4) |
Unknown | 29 (1.1) | 21 (1.4) |
Social exposures, no. (%) | ||
Daycare/school attendancea | 1419b (54.3) | 677 (45.4) |
Smoke exposure | 687b (26.3) | 392c (26.3) |
E-cigarette exposure | 95b (3.6) | 114d (7.6) |
Underlying medical conditions, no. (%) | ||
≥1 Underlying medical condition | 869 (33.2) | 765 (51.3) |
Respiratory | 471 (18.0) | 406 (27.2) |
Asthma/RAD, only | 433 (16.6) | 292 (19.6) |
Cardiovascular | 52 (2.0) | 127 (8.5) |
Neurologic/neuromuscular | 120 (4.6) | 220 (14.8) |
Oncologic/immunosuppressive | 318 (12.2) | 267 (17.9) |
Renal | 4 (0.2) | 15 (1.0) |
Gastrointestinal/hepatic | 64 (2.4) | 156 (10.5) |
Endocrine | 9 (0.3) | 38 (2.5) |
Other | 76 (2.9) | 88 (5.9) |
Prematurity, <37 wk,e no. (%) | 109 (4.2) | 144 (9.7) |
Time of illness,f no. (%) | ||
Respiratory season | 2002 (76.5) | 1148 (77.0) |
Antibiotic consumption ≤14 d before visit/hospitalization, no. (%) | 158 (6.0) | 257 (17.2) |
Clinical symptoms at enrollment, no. (%) | ||
Fever, >100.2 °F | 1997 (76.3) | 1069 (71.7) |
Maximum temperature, °F, mean (SD) | 101.3g (2.1) | 101.3h (2.2) |
Cough | 2146 (82.0) | 1267 (85.0) |
Nasal congestion/runny nose | 2100 (80.3) | 1182 (79.3) |
Lethargy | 1643 (62.8) | 1124 (75.4) |
Earache | 663 (25.3) | 202 (13.5) |
Sore throat | 1107 (42.3) | 377 (25.3) |
Myalgia | 608 (23.2) | 224 (15.0) |
Wheezing | 1115 (42.6) | 943 (63.2) |
Shortness of breath | 1219 (46.6) | 1139 (76.4) |
Illness duration, days, mean (SD) | 2.8i (2.3) | 3.3j (2.6) |
Vital signs at presentation, mean (SD) | ||
Heart rate, beats/min | 135.6k (28.5) | 150.3 (27.2) |
Respiratory rate, beats/min | 28.5l (9.2) | 38.5m (13.7) |
Oxygen saturation, capillary | 98.4n (1.9) | 95.5 (5.3) |
Physical assessment, no. (%) | ||
Wheezing | 278 (10.6) | 539 (36.2) |
Retractions | 232 (8.9) | 767 (51.4) |
Research laboratory results, no. (%) | ||
Virus, positive | 1689 (64.6) | 917 (61.5) |
Adenovirus | 101 (6.0) | 26 (2.8) |
Influenza | 464 (27.5) | 101 (11.0) |
RSV | 252 (14.9) | 288 (31.4) |
Rhinovirus | 247 (14.6) | 184 (20.1) |
Parainfluenza (types 1–4) | 172 (10.2) | 77 (8.4) |
Human metapneumovirus | 84 (5.0) | 62 (6.8) |
Coronaviruses (OC43, 229E, NL63, HKU1) | 106 (6.3) | 41 (4.5) |
≥2 respiratory viruses | 263 (15.6) | 138 (15.0) |
Characteristic(s) . | Emergency Department N = 2616 . | Inpatient N = 1491 . |
---|---|---|
Age, y, mean (SD) | 4.6 (4.4) | 3.4 (4.1) |
Age, y, median (IQR) | 3.0 (1.1, 7.0) | 1.6 (0.5, 4.9) |
0 to <2 y, no. (%) | 1028 (39.3) | 832 (55.8) |
2 to <5 y, no. (%) | 662 (25.3) | 293 (19.7) |
≥5 to <18 y, no. (%) | 926 (35.4) | 366 (24.5) |
Sex, male, no. (%) | 1405 (53.7) | 873 (58.6) |
Race/ethnicity, no. (%) | ||
White, non-Hispanic | 353 (13.5) | 676 (45.4) |
Black, non-Hispanic | 1115 (42.6) | 355 (23.8) |
Other non-Hispanic | 182 (7.0) | 135 (9.1) |
Hispanic | 940 (35.9) | 310 (20.8) |
Unknown | 26 (1.0) | 15 (1.0) |
Insurance type, no. (%) | ||
Public | 2093 (80.0) | 968 (64.9) |
Private | 219 (8.4) | 395 (26.5) |
Both | 13 (0.5) | 27 (1.8) |
None/self-pay | 262 (10.0) | 80 (5.4) |
Unknown | 29 (1.1) | 21 (1.4) |
Social exposures, no. (%) | ||
Daycare/school attendancea | 1419b (54.3) | 677 (45.4) |
Smoke exposure | 687b (26.3) | 392c (26.3) |
E-cigarette exposure | 95b (3.6) | 114d (7.6) |
Underlying medical conditions, no. (%) | ||
≥1 Underlying medical condition | 869 (33.2) | 765 (51.3) |
Respiratory | 471 (18.0) | 406 (27.2) |
Asthma/RAD, only | 433 (16.6) | 292 (19.6) |
Cardiovascular | 52 (2.0) | 127 (8.5) |
Neurologic/neuromuscular | 120 (4.6) | 220 (14.8) |
Oncologic/immunosuppressive | 318 (12.2) | 267 (17.9) |
Renal | 4 (0.2) | 15 (1.0) |
Gastrointestinal/hepatic | 64 (2.4) | 156 (10.5) |
Endocrine | 9 (0.3) | 38 (2.5) |
Other | 76 (2.9) | 88 (5.9) |
Prematurity, <37 wk,e no. (%) | 109 (4.2) | 144 (9.7) |
Time of illness,f no. (%) | ||
Respiratory season | 2002 (76.5) | 1148 (77.0) |
Antibiotic consumption ≤14 d before visit/hospitalization, no. (%) | 158 (6.0) | 257 (17.2) |
Clinical symptoms at enrollment, no. (%) | ||
Fever, >100.2 °F | 1997 (76.3) | 1069 (71.7) |
Maximum temperature, °F, mean (SD) | 101.3g (2.1) | 101.3h (2.2) |
Cough | 2146 (82.0) | 1267 (85.0) |
Nasal congestion/runny nose | 2100 (80.3) | 1182 (79.3) |
Lethargy | 1643 (62.8) | 1124 (75.4) |
Earache | 663 (25.3) | 202 (13.5) |
Sore throat | 1107 (42.3) | 377 (25.3) |
Myalgia | 608 (23.2) | 224 (15.0) |
Wheezing | 1115 (42.6) | 943 (63.2) |
Shortness of breath | 1219 (46.6) | 1139 (76.4) |
Illness duration, days, mean (SD) | 2.8i (2.3) | 3.3j (2.6) |
Vital signs at presentation, mean (SD) | ||
Heart rate, beats/min | 135.6k (28.5) | 150.3 (27.2) |
Respiratory rate, beats/min | 28.5l (9.2) | 38.5m (13.7) |
Oxygen saturation, capillary | 98.4n (1.9) | 95.5 (5.3) |
Physical assessment, no. (%) | ||
Wheezing | 278 (10.6) | 539 (36.2) |
Retractions | 232 (8.9) | 767 (51.4) |
Research laboratory results, no. (%) | ||
Virus, positive | 1689 (64.6) | 917 (61.5) |
Adenovirus | 101 (6.0) | 26 (2.8) |
Influenza | 464 (27.5) | 101 (11.0) |
RSV | 252 (14.9) | 288 (31.4) |
Rhinovirus | 247 (14.6) | 184 (20.1) |
Parainfluenza (types 1–4) | 172 (10.2) | 77 (8.4) |
Human metapneumovirus | 84 (5.0) | 62 (6.8) |
Coronaviruses (OC43, 229E, NL63, HKU1) | 106 (6.3) | 41 (4.5) |
≥2 respiratory viruses | 263 (15.6) | 138 (15.0) |
RAD, reactive airway disease; RSV, respiratory syncytial virus.
Reported attending daycare/school ≥4 times/wk.
n = 2615.
n = 1489.
n = 1488.
History of prematurity was reported for children aged <2 y.
Respiratory season, October–April.
n = 2511.
n = 1465.
n = 2615.
n = 1489.
n = 2603.
n = 2602.
n = 1490.
n = 2605.
Inpatient
Among 1491 hospitalized children, the median age was 1.6 years, 46% were white, non-Hispanic; 47% of hospitalized children had at least 1 underlying medical condition and the mean length of stay was 3 days. Twenty percent were admitted to the ICU. Cough, nasal congestion/runny nose, and shortness of breath were the 3 most common symptoms reported; on physical examination, 51% and 36% had retractions and wheezing, respectively (Table 1). A provider-ordered test occurred in 64% (955/1491) of the children with an ARI-related hospitalization, with 82% receiving 1 test (784/955; 22% rapid influenza, 3% rapid RSV, 75% NAAT), 15% had 2 tests (143/955; 95% rapid influenza; 46% rapid RSV; 59% NAAT), and 3% had 3 tests (28/955). Overall, 61% of children had at least 1 virus detected from their research specimen, with RSV (31%) and rhinovirus (20%) most commonly detected.
PC Patterns by Setting
Emergency Department
A total of 4 PCs accounting for 63% of cumulative variance were identified in the ED (Table 2, Supplemental Fig 4). PC1ED described 26% of variance and had a pattern mimicking RSV bronchiolitis: younger children with a higher temperature, more likely to have respiratory symptoms, short illness duration, lower oxygen saturation, no underlying medical conditions, and not regularly attending daycare. PC2ED had a pattern resembling rhinovirus-like presentation: children older than those in PC1ED, less likely to have fever present, more likely to present with respiratory symptoms, have wheezing and retractions present on physical examination, and no underlying medical conditions. PCs 3ED-4ED accounted for 12% and 11% of variance, respectively, and both patterns comprised older children. PC3ED represented coviral-like (eg, influenza, rhinovirus) infections with a pattern of a short illness duration, high temperature, more likely to present with respiratory symptoms, low respiratory rate, and low oxygen saturation. PC4ED closely followed an influenza-like presentation with a pattern of longer illness duration, respiratory symptoms present, high respiratory rate and low oxygen saturation, and underlying medical conditions dominated by respiratory disorders. Univariable summary statistics for PCs can be found in Supplemental Table 4.
Principal Components of Children (Aged >30 Days–17 Years) Enrolled in Emergency Departments and Hospitalized With Acute Respiratory Illness, November 2017–February 2020
Covariate(s) . | Emergency Department (n = 2616) . | Inpatient (n = 1491) . | |||||
---|---|---|---|---|---|---|---|
PC1ED RSV-like pattern . | PC2ED Rhinovirus-like pattern . | PC3ED Coviral-like pattern . | PC4ED Influenza-like pattern . | PC1IP Influenza-like pattern . | PC2IP Rhinovirus-like pattern . | PC3IP RSV-like pattern . | |
Age, y | −0.56 | −0.05 | 0.16 | 0.15 | 0.54 | 0.24 | 0.14 |
Antibiotic consumption ≤14 d before visit/hospitalization | 0.00 | −0.02 | −0.03 | 0.01 | 0.05 | −0.07 | 0.04 |
Illness duration, d | −0.04 | 0.03 | −0.89 | 0.21 | 0.06 | −0.30 | 0.41 |
Temperature | 0.18 | −0.72 | 0.14 | −0.02 | 0.15 | −0.63 | 0.06 |
Fever | 0.06 | −0.25 | 0.03 | 0.00 | 0.04 | −0.24 | 0.02 |
Respiratory symptoms | 0.00 | 0.01 | −0.04 | 0.03 | −0.02 | 0.02 | 0.05 |
Nonrespiratory symptoms | −0.17 | −0.57 | −0.26 | 0.22 | 0.22 | −0.42 | 0.30 |
Respiratory rate | 0.51 | 0.20 | −0.11 | 0.11 | −0.52 | 0.06 | 0.22 |
Heart rate at presentation | 0.55 | −0.16 | 0.06 | −0.03 | −0.51 | −0.21 | 0.02 |
Oxygen saturation at presentation | −0.13 | −0.07 | −0.23 | −0.91 | 0.09 | −0.26 | −0.77 |
Wheezing on physical examination | 0.02 | 0.08 | 0.02 | 0.08 | −0.04 | 0.14 | 0.12 |
Retractions on physical examination | 0.05 | 0.06 | 0.00 | 0.07 | −0.14 | 0.10 | 0.16 |
Respiratory season | −0.01 | −0.02 | −0.04 | 0.01 | −0.02 | −0.01 | 0.05 |
Underlying medical conditions | −0.06 | 0.05 | 0.05 | 0.11 | 0.11 | 0.15 | 0.07 |
Respiratory | −0.07 | 0.04 | 0.06 | 0.10 | 0.10 | 0.15 | 0.09 |
Asthma/RAD, only | −0.07 | 0.04 | 0.05 | 0.09 | 0.09 | 0.12 | 0.06 |
Cardiovascular | 0.00 | 0.00 | 0.01 | 0.02 | 0.01 | 0.03 | 0.04 |
Neurologic/neuromuscular | −0.01 | 0.00 | 0.01 | 0.02 | 0.06 | 0.05 | 0.02 |
Oncologic/immunosuppressive | −0.03 | 0.02 | 0.02 | 0.04 | 0.08 | 0.06 | 0.00 |
Prematurity, <37 wk | 0.01 | 0.01 | 0.00 | 0.01 | −0.02 | 0.02 | 0.00 |
Public insurance | 0.01 | 0.01 | −0.02 | −0.02 | −0.03 | 0.02 | 0.00 |
Private insurance | 0.00 | 0.00 | 0.01 | 0.02 | 0.04 | −0.01 | 0.01 |
Self-pay insurance | 0.01 | 0.00 | 0.00 | −0.00 | 0.00 | 0.00 | −0.01 |
Sex | 0.03 | 0.01 | 0.00 | 0.01 | 0.00 | 0.01 | −0.04 |
Daycare | −0.19 | −0.01 | 0.07 | 0.05 | 0.16 | 0.03 | 0.08 |
Proportion of variance explained (%) | 26.02 | 14.19 | 11.53 | 11.11 | 22.35 | 15.08 | 11.34 |
Eigenvalue(s) | 2.39 | 1.31 | 1.06 | 1.02 | 2.25 | 1.52 | 1.14 |
Covariate(s) . | Emergency Department (n = 2616) . | Inpatient (n = 1491) . | |||||
---|---|---|---|---|---|---|---|
PC1ED RSV-like pattern . | PC2ED Rhinovirus-like pattern . | PC3ED Coviral-like pattern . | PC4ED Influenza-like pattern . | PC1IP Influenza-like pattern . | PC2IP Rhinovirus-like pattern . | PC3IP RSV-like pattern . | |
Age, y | −0.56 | −0.05 | 0.16 | 0.15 | 0.54 | 0.24 | 0.14 |
Antibiotic consumption ≤14 d before visit/hospitalization | 0.00 | −0.02 | −0.03 | 0.01 | 0.05 | −0.07 | 0.04 |
Illness duration, d | −0.04 | 0.03 | −0.89 | 0.21 | 0.06 | −0.30 | 0.41 |
Temperature | 0.18 | −0.72 | 0.14 | −0.02 | 0.15 | −0.63 | 0.06 |
Fever | 0.06 | −0.25 | 0.03 | 0.00 | 0.04 | −0.24 | 0.02 |
Respiratory symptoms | 0.00 | 0.01 | −0.04 | 0.03 | −0.02 | 0.02 | 0.05 |
Nonrespiratory symptoms | −0.17 | −0.57 | −0.26 | 0.22 | 0.22 | −0.42 | 0.30 |
Respiratory rate | 0.51 | 0.20 | −0.11 | 0.11 | −0.52 | 0.06 | 0.22 |
Heart rate at presentation | 0.55 | −0.16 | 0.06 | −0.03 | −0.51 | −0.21 | 0.02 |
Oxygen saturation at presentation | −0.13 | −0.07 | −0.23 | −0.91 | 0.09 | −0.26 | −0.77 |
Wheezing on physical examination | 0.02 | 0.08 | 0.02 | 0.08 | −0.04 | 0.14 | 0.12 |
Retractions on physical examination | 0.05 | 0.06 | 0.00 | 0.07 | −0.14 | 0.10 | 0.16 |
Respiratory season | −0.01 | −0.02 | −0.04 | 0.01 | −0.02 | −0.01 | 0.05 |
Underlying medical conditions | −0.06 | 0.05 | 0.05 | 0.11 | 0.11 | 0.15 | 0.07 |
Respiratory | −0.07 | 0.04 | 0.06 | 0.10 | 0.10 | 0.15 | 0.09 |
Asthma/RAD, only | −0.07 | 0.04 | 0.05 | 0.09 | 0.09 | 0.12 | 0.06 |
Cardiovascular | 0.00 | 0.00 | 0.01 | 0.02 | 0.01 | 0.03 | 0.04 |
Neurologic/neuromuscular | −0.01 | 0.00 | 0.01 | 0.02 | 0.06 | 0.05 | 0.02 |
Oncologic/immunosuppressive | −0.03 | 0.02 | 0.02 | 0.04 | 0.08 | 0.06 | 0.00 |
Prematurity, <37 wk | 0.01 | 0.01 | 0.00 | 0.01 | −0.02 | 0.02 | 0.00 |
Public insurance | 0.01 | 0.01 | −0.02 | −0.02 | −0.03 | 0.02 | 0.00 |
Private insurance | 0.00 | 0.00 | 0.01 | 0.02 | 0.04 | −0.01 | 0.01 |
Self-pay insurance | 0.01 | 0.00 | 0.00 | −0.00 | 0.00 | 0.00 | −0.01 |
Sex | 0.03 | 0.01 | 0.00 | 0.01 | 0.00 | 0.01 | −0.04 |
Daycare | −0.19 | −0.01 | 0.07 | 0.05 | 0.16 | 0.03 | 0.08 |
Proportion of variance explained (%) | 26.02 | 14.19 | 11.53 | 11.11 | 22.35 | 15.08 | 11.34 |
Eigenvalue(s) | 2.39 | 1.31 | 1.06 | 1.02 | 2.25 | 1.52 | 1.14 |
Eigenvalues are the coefficients that provide summary statistics that depict the amount of variance carried from each PC. Principal components analysis is the dimensionality-reduction method that acts to transform set of intercorrelated variables into fewer components (ie, combinations of variables that embody the greatest amount of variance [information]). ED, emergency department; IP, inpatient; PC, principal components.
Children who were more likely to represent the coviral-like presentation pattern (≥median, PC3ED) had 44% (OR, 1.44; 95% CI, 1.24–1.68) increased odds of receiving a provider-ordered viral test during their visit than those children showing clinical symptoms less representative of coviral-like infection (<median, PC3ED; Table 3). In contrast, children with symptoms representing the rhinovirus-like pattern (≥median, PC2ED) had 71% (OR, 0.29; 95% CI, 0.24–0.34) decreased odds of receiving a provider-ordered viral test compared with those with symptoms less representative of the rhinovirus-like pattern (<median, PC2ED). No associations were observed for the patterns of PC1ED (RSV-like) and PC4ED (influenza-like) with provider-ordered testing.
Association of Principal Components and Clinical Provider-Ordered Viral Testing,a by Health Care Setting, November 2017–February 2020
Pattern(s) . | PC Value . | No. With Provider-Ordered Testing . | No. Without Provider-Ordered Testing . | Odds Ratio . | 95% CI . | P . |
---|---|---|---|---|---|---|
Emergency Department (n = 2616)b | ||||||
RSV-like pattern | ||||||
PC1ED, <median | <0.17 | 650 | 661 | Ref | Ref | Ref |
PC1ED, ≥median | ≥0.17 | 644 | 661 | 0.99 | 0.85–1.15 | .906 |
Rhinovirus-like pattern | ||||||
PC2ED, <median | <0.41 | 1004 | 661 | Ref | Ref | Ref |
PC2ED, ≥median | ≥0.41 | 290 | 661 | 0.29 | 0.24–0.34 | <.001 |
Coviral-like pattern | ||||||
PC3ED, <median | <0.04 | 530 | 661 | Ref | Ref | Ref |
PC3ED, ≥median | ≥0.04 | 764 | 661 | 1.44 | 1.24–1.68 | <.001 |
Influenza-like pattern | ||||||
PC4ED, <median | <–0.18 | 627 | 661 | Ref | Ref | Ref |
PC4ED, ≥median | ≥–0.18 | 667 | 661 | 1.06 | 0.91–1.24 | .429 |
Inpatient (n = 1491)c | ||||||
Influenza-like pattern | ||||||
PC1IP, <median | <–0.08 | 525 | 268 | Ref | Ref | Ref |
PC1IP, ≥median | ≥–0.08 | 430 | 268 | 0.82 | 0.66–1.01 | .065 |
Rhinovirus-like pattern | ||||||
PC2IP, <median | <0.24 | 592 | 268 | Ref | Ref | Ref |
PC2IP, ≥median | ≥0.24 | 363 | 268 | 0.61 | 0.49–0.76 | <.001 |
RSV-like pattern | ||||||
PC3IP, <median | <0.08 | 481 | 268 | Ref | Ref | Ref |
PC3IP, ≥median | ≥0.08 | 474 | 268 | 0.99 | 0.80–1.22 | .892 |
Pattern(s) . | PC Value . | No. With Provider-Ordered Testing . | No. Without Provider-Ordered Testing . | Odds Ratio . | 95% CI . | P . |
---|---|---|---|---|---|---|
Emergency Department (n = 2616)b | ||||||
RSV-like pattern | ||||||
PC1ED, <median | <0.17 | 650 | 661 | Ref | Ref | Ref |
PC1ED, ≥median | ≥0.17 | 644 | 661 | 0.99 | 0.85–1.15 | .906 |
Rhinovirus-like pattern | ||||||
PC2ED, <median | <0.41 | 1004 | 661 | Ref | Ref | Ref |
PC2ED, ≥median | ≥0.41 | 290 | 661 | 0.29 | 0.24–0.34 | <.001 |
Coviral-like pattern | ||||||
PC3ED, <median | <0.04 | 530 | 661 | Ref | Ref | Ref |
PC3ED, ≥median | ≥0.04 | 764 | 661 | 1.44 | 1.24–1.68 | <.001 |
Influenza-like pattern | ||||||
PC4ED, <median | <–0.18 | 627 | 661 | Ref | Ref | Ref |
PC4ED, ≥median | ≥–0.18 | 667 | 661 | 1.06 | 0.91–1.24 | .429 |
Inpatient (n = 1491)c | ||||||
Influenza-like pattern | ||||||
PC1IP, <median | <–0.08 | 525 | 268 | Ref | Ref | Ref |
PC1IP, ≥median | ≥–0.08 | 430 | 268 | 0.82 | 0.66–1.01 | .065 |
Rhinovirus-like pattern | ||||||
PC2IP, <median | <0.24 | 592 | 268 | Ref | Ref | Ref |
PC2IP, ≥median | ≥0.24 | 363 | 268 | 0.61 | 0.49–0.76 | <.001 |
RSV-like pattern | ||||||
PC3IP, <median | <0.08 | 481 | 268 | Ref | Ref | Ref |
PC3IP, ≥median | ≥0.08 | 474 | 268 | 0.99 | 0.80–1.22 | .892 |
CI, confidence interval; ED, emergency department; IP, inpatient; PC, principal components; RSV, respiratory syncytial virus; RT-qPCR, reverse transcriptase polymerase chain reaction.
Includes rapid influenza, rapid RSV, and RT-qPCR.
Total no. of tests performed = 1294/2616 (rapid influenza = 1126; RT-qPCR = 157; rapid RSV = 11).
Total no. of tests performed = 955/1491 (rapid influenza = 339; RT-qPCR = 593; rapid RSV = 23).
Inpatient
A total of 3 PCs accounting for 49% cumulative proportion of variance were identified among hospitalized children (Table 2, Supplemental Fig 4, and Supplemental Table 4). PC1IP explained 22% of observed ordering variation and resembled influenza-like illness. These children were older (school-aged) and characterized by short illness duration, high temperature, increased frequency of nonrespiratory symptoms (eg, myalgia, vomiting, diarrhea), low respiratory and heart rates, and underlying conditions. PC2IP described 15% variance and consisted of children with rhinovirus-like illness. These patients were younger than those in the PC1IP group (influenza-like) and presented with a short illness duration, no fever, greater likelihood of respiratory symptoms, low heart rate, low oxygen saturation, wheezing on physical examination, and underlying conditions dominated by respiratory disorders (ie, asthma/reactive airway disease). PC3IP mimicked RSV-like illness and captured young children presenting with a high respiratory rate, low oxygen saturation, and wheezing and retractions on physical examination.
Among hospitalized children, children with symptoms representing the rhinovirus-like pattern (≥median, PC2IP) had 39% (OR, 0.61; 95% CI, 0.49–0.76) decreased odds of receiving a provider-ordered viral test during their stay than those with dissimilar symptoms (≤median, PC2IP; Table 3). An association was not observed for the patterns of PCs 1 (influenza-like) and 2 (rhinovirus-like) with provider-ordered testing.
Validation of PCA Patterns With Research Specimens by Setting
Emergency Department
Among children who were tested, the frequency of viral detection from a research specimen was highest in PCsED 1 and 4 (68% and 67%, respectively; Fig 2). RSV (20%) and ≥2 respiratory viruses (20% [RSV/coronavirus codetection = 9%;17/182]) were the most often detected in PC1ED (RSV-like), whereas influenza was most common in PC3ED (30%; coviral-like) and PC4ED (30%; influenza-like). In PC2ED (rhinovirus-like), rhinovirus (25%) and RSV (19%) were the 2 most frequent viruses detected.
Validation of principal components respiratory virus distribution using research specimen results, by health care setting, November 2017–February 2020.
Validation of principal components respiratory virus distribution using research specimen results, by health care setting, November 2017–February 2020.
Inpatient
Among children who had a provider-ordered viral test, positivity was highest in PC3IP (RSV-like), with RSV accounting for 36% of all virus-positive detections (Fig 2). In PC2IP (rhinovirus-like), rhinovirus (30%) and RSV (29%) were the 2 most commonly detected viruses, whereas in PC1IP (influenza-like), rhinovirus and influenza were identified in 22% and 21% of virus-positive specimens, respectively.
Discussion
In our prospective study of 4107 ARI-related ED visits and hospitalizations in Nashville, TN, we demonstrate provider-ordered viral testing practices vary across health care settings. In the ED, nearly one-half of children with an ARI-related illness were administered a provider-ordered viral test, with rapid influenza accounting for 87% of all tests performed. In comparison, two-thirds of hospitalized children underwent viral testing with more than 60% receiving a molecular test. Coviral-like presentation patterns were more likely to receive provider-ordered testing in the ED, whereas rhinovirus-like patterns were less likely to receive testing in either setting. Thus, presentation patterns among children with ARI vary by health care setting and influence decisions to initiate viral testing.
In the ED, we found that the coviral-like presentation pattern was associated with provider-ordered viral test. Rapid influenza tests accounted for more than three-quarters of all tests administered, whereas 66% of virus-positive research specimens in the coviral-like pattern were non-influenza viruses. The abundance of rapid influenza tests may be attributed to the decision of initiating prompt antiviral therapy, which was only available for influenza before the SARS-CoV-2 pandemic. Furthermore, these findings suggest that non–influenza-like presentation patterns, such as RSV (common cause bronchiolitis), were not targeted with appropriate diagnostic testing. The limited use of RSV testing adheres to the American Academy of Pediatrics clinical practice guidelines for bronchiolitis, which recommends clinicians diagnose children based on history and physical examination and advises against routine viral testing.6 In the pediatric guidelines for community-acquired pneumonia (common viral ARI condition), rapid influenza testing is strongly recommended as a first step to reduce additional diagnostic testing, initiate antiviral therapy, and minimize unnecessary antibiotic therapy.15 From a diagnostic standpoint, the clinical patterns and associated viral testing practices we identified in the ED appear to be well aligned with the common ARI condition(s) guidelines. However, the confluence of clinical factors, laboratory findings, and institutional practices that shape management of children discharged from the ED with a non-influenza ARI and a negative influenza rapid test deserves systematic analysis.
The proportion of provider-ordered viral tests for hospitalized children were nearly 20% more compared with the ED, with the majority performed using NAAT. This difference might be attributed to time allowance for testing results in the inpatient setting, potential antiviral use, the need to rule out serious bacterial infections, insurance reimbursement, or decision-making about further laboratory evaluation, such as blood tests, cerebrospinal fluid assessment, or radiography.4,16
Despite the availability of NAAT to our ED clinicians, this resource was sparingly used, perhaps a reflection of the influence of a positive result on the clinical management plan. A meta-analysis assessing the use of rapid viral tests in the ED revealed null effects of viral testing on provider decisions about clinical management.3 In a retrospective study using the National Hospital Ambulatory Medical Care Survey, rapid influenza testing in US EDs decreased the use of antibiotics and ancillary testing.17 Most studies assessing rapid viral testing and its impact on clinical management in the ED are methodologically aimed at influenza,3 and findings have not been uniformly replicated in hospitalized patients.5 Discordant results across settings could be due to variability in patient acuity, provider practices, or the prevalence of viral testing performed. Studies evaluating pathogen-appropriate testing and influence of results on patient management and outcomes are needed to define the true clinical impact of testing on pediatric ARI.
In our study, rhinovirus was detected in nearly a quarter of children with a research specimen (23%, including codetections). Despite being common in both the ED and inpatient settings, children with rhinovirus-like patterns were less likely to receive a provider-ordered test. Rhinovirus is often associated with asthma exacerbations, bronchiolitis, and community-acquired pneumonia in children, particularly among those with underlying respiratory conditions (ie, asthma/reactive airway disease).18–20 Limited use of viral testing in both the ED and inpatient settings for rhinovirus-like presentation pattern might be ascribable to clinical management guidelines, as previously mentioned, or specific clinical presentations observed in children with rhinovirus ARIs.19 Of note, in a prospective multicenter study assessing differences among children younger than age 2 years hospitalized with bronchiolitis caused by RSV and rhinovirus, patients with rhinovirus ARI presented similarly to older children with asthma.21 Differences in clinical presentation may underlie variations in patient management, including viral testing, highlighting opportunities for improvement initiatives and standardization of care across settings.
A major strength of our study is systematic, active, prospective enrollment and molecular viral testing conducted over consecutive years among children with ARI in both the ED and inpatient settings. However, certain limitations apply. First, our study only included children enrolled before March 2020 and does not reflect practices during the COVID-19 pandemic. Second, we used principal components, a data-driven approach, to understand the presentation patterns influencing provider-ordered viral testing. Third, our findings represent a single center and may not be generalizable to other states or regions.2 Fourth, we were unable to assess clinician years of experience in either setting, which may affect viral testing practices. Finally, our study focused on testing practices for viral ARIs and did not assess clinical testing for bacterial ARIs.
Variability in provider-ordered viral testing was observed across presentation patterns and testing options by health care setting. Rapid influenza testing was the most common test performed in the ED, whereas utilization of NAATs was more common in the inpatient setting. The diversity of testing practices and clinical presentations we identified across the ED and inpatient setting may assist in the development of setting specific diagnostic stewardship programs and highlights the need for broadening viral testing in the ED. Future research should target identification of individual drivers of pediatric viral testing practices and policies and impact of those decisions on ARI management and outcomes.
Acknowledgments
HALASA/CHAPPELL Research Investigators: Rebekkah Varjabedian, Jessica Villarreal, Marcia Blair, Lauren J. Ezell, Samarian J. Hargrave, Jennifer L. Luther, Bryan P. M. Peterson, Laura L. Short, Margaret E. Whitsett.
We thank our research personnel and the families who participated in this study.
Contributed equally as co-senior authors.
A complete list of study group members appears in the Acknowledgments.
Dr Rankin conceptualized and designed the study, performed data analysis, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Stewart, Herazo Romero, McHenry, Yanis, and Guevara Pulido coordinated and supervised data collection and critically reviewed and revised the manuscript for important intellectual content; Dr Slaughter, Ms Deppen, Dr Chappell, and Ms Katz conceptualized and provided intellectual content to the study methods and reviewed and revised the manuscript; Ms Stahl and Ms Stopczynski reviewed data analyses and reviewed and revised the manuscript; Dr Halasa conceptualized and designed the study, data collection instruments, supervised data collection, and critically reviewed and revised the manuscript; Dr Khankari conceptualized and designed the study, conceptualized and supervised study methods, 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: This work was supported by the US Centers for Disease Control and Prevention (cooperative agreement CDC-RFA-IP16-004) and National Center for Advancing Translational Sciences (grant UL1TR000445). Drs Rankin and Deppen are supported by the National Institutes of Health (awards TL1TR002244, D.A.R.; U01CA152662, S.D.).
CONFLICT OF INTEREST DISCLOSURES: Dr Halasa receives grant support from Sanofi, Quidel, and speaker compensation from an education grant supported by Genentech. The other authors have indicated they have no potential conflicts of interest to disclose. The National Center for Advancing Translational Sciences nor the National Institutes of Health had a role in the design or conduct of the study.
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