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Research Articles

Association of Respiratory Picornaviruses With High Acuity and Severe Illness in a Pediatric Health Care System

Katherine E. Fleming-Dutra, Harold K. Simon, James D. Fortenberry, Robert Jerris, Jaime Radecke and Daniel A. Hirsh
Hospital Pediatrics August 2015, 5 (8) 432-438; DOI: https://doi.org/10.1542/hpeds.2014-0111
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Abstract

OBJECTIVES: We aimed to determine the illness severity associated with respiratory picornaviruses (rhinovirus/enterovirus).

METHODS: Electronic medical records of pediatric emergency department (PED) visits were reviewed. The percent positive of respiratory pathogens, tested by using viral polymerase chain reaction panel, was determined for the July 2012 to June 2013 period. Logistic regression was used to determine the association of picornaviruses, respiratory syncytial virus (RSV), and influenza with ICU admission during the 2012−2013 academic year. Medical records of visits leading to ICU admission with picornaviruses were reviewed.

RESULTS: During 2012−2013, picornaviruses were more commonly identified (22.6%) among admitted patients than influenza (6.4%) or RSV (15.1%). Picornaviruses and RSV were associated with ICU admission (picornaviruses: adjusted odds ratio [aOR], 1.99 [95% confidence interval (CI): 1.68−2.36]; RSV: aOR, 1.49 [95% CI: 1.20−1.85]) while influenza was not (aOR, 0.93 [95% CI: 0.66−1.29]). Of visits resulting in ICU admission, 79% were from patients with previous high-risk medical conditions, of which asthma or a history of wheezing was the most common (43%).

CONCLUSIONS: Picornaviruses can be associated with severe disease in children, especially those with underlying medical conditions. During times of high picornavirus activity, hospitals should target infection control measures to limit the spread of picornaviruses and protect the vulnerable patients. Future research into targeted therapies for picornaviruses and vaccines is needed.

During the summer and fall of 2012, a large, pediatric quaternary health care system in metropolitan Atlanta experienced a situation of unexpected, near-record high volumes and acuity across the entire system; it was recognized in real-time because it caused capacity constraints. Volumes mirrored the peak of the 2009 influenza A (H1N1) pandemic; however, influenza activity remained low. Unlike during the 2009 pandemic, during which volumes were high but acuity was low,1 acuity appeared to be high during the 2012 high-volume period. Interestingly, picornaviruses were the most commonly identified respiratory viral pathogen during this period.

Respiratory viral pathogen testing at this health care system routinely included picornaviruses (rhinovirus/enterovirus) starting in July 2012. Rhinoviruses and enteroviruses are both common causes of respiratory illnesses in children.2–5 Rhinovirus has been previously associated with severe disease and outbreaks in pediatric populations,6,7 and recently enterovirus D68 has caused an outbreak of severe respiratory illness in children.8 However, rhinovirus can also be found in asymptomatic control children.9–12 Thus, high levels of positive rhinovirus test results may or may not be related to high levels of disease. The objective of the present study was to determine the severity of illness associated with respiratory picornavirus infection during the July 2012 to June 2013 period.

Methods

Electronic medical records of a large, pediatric quaternary care health care system in metropolitan Atlanta were retrospectively reviewed. The system has 3 hospitals, 532 beds, and 860 849 patient visits annually. Data from the system’s 2 major quaternary care hospitals were included because these sites are referral hospitals, and they have ICUs and fully electronic medical records whereas the third hospital has neither. These 2 hospitals are both in suburban settings, and 1 has an academic affiliation and the majority of the training programs.13 We first compared visits to the pediatric emergency department (PED), admissions and ICU admissions at the system’s 2 major hospitals from July 1 through June 30 of the following year (the academic year) for 2012−2013, 2010−2011, and 2009−2010 (the latter of which included the 2009 influenza A [H1N1] pandemic). We used the academic year (ie, July through June of the following year) to capture an entire year’s worth of data with only 1 influenza and respiratory syncytial virus (RSV) season. During this time, the number of ICU beds at the study institution remained stable, and institutional policy changed to allow high-flow nasal cannula outside of the ICU beginning in 2010; otherwise, policies affecting ICU admission thresholds remained unchanged.

Because picornavirus testing was only conducted starting in 2012, we examined picornavirus activity from July 1, 2012, through June 30, 2013 (the 2012−2013 academic year). First, the percent positive of respiratory pathogens for 2012−2013 was determined. Standard practice at the study institution is to screen admitted patients with respiratory symptoms for viral respiratory pathogens, but the test is ordered at the clinician’s discretion. Testing is performed by using a viral respiratory pathogen polymerase chain reaction (PCR) panel collected from a nasopharyngeal aspirate specimen with the FilmArray Assay (BioFire Diagnostics, Salt Lake City, UT), which was approved by the US Food and Drug Administration, and by using previously described methods.14 The assay includes tests for: influenza; RSV; rhinovirus/enterovirus; parainfluenza types 1, 2, 3, and 4; coronavirus; adenovirus; and human metapneumovirus. Picornaviruses (rhinovirus/enterovirus) were added to this panel in July 2012. The FilmArray Assay does not differentiate between rhinovirus and enterovirus, and results are reported to clinicians as rhinovirus/enterovirus.

To determine the severity of illness associated with picornaviruses during 2012–2013, we next used logistic regression analysis to determine the adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) of ICU admissions for admitted patients who were tested for respiratory pathogens. ICU admission was defined as admission to the pediatric or cardiac ICU, excluding NICU admission. Data from the entire academic year were included to compare picornavirus infection with influenza and RSV infection, 2 viruses traditionally believed to cause more severe disease. Patients with coinfections of multiple respiratory pathogens were excluded from the model to focus on the effect of picornaviruses, as has been done in previous studies.4,10,11,15 For the model, age was dichotomized into <18 or ≥18 months, corresponding to the internal, institutional treatment pathway cutoff for bronchiolitis versus reactive airway disease/asthma in children with wheezing. Within the study institution, most children with wheezing who are aged <18 months are treated for bronchiolitis, which could affect the threshold for ICU admission.

Finally, we performed a descriptive analysis of patient visits initiating in the PED from July 1, 2012, through June 30, 2013, with severe picornavirus infection as identified by requiring ICU admission during their hospitalization with a positive laboratory test result for picornaviruses. The admission history and physical and discharge summaries of the electronic medical records for these visits were abstracted by 1 author (J.R.). Ten percent of abstracted charts were reviewed unblinded by another author (K.E.F.D.); agreement was 95.9% between the abstractors (κ statistic: 0.85, P < .001). Medical history was classified as high risk if it corresponded to a condition that predisposed the patient to complications from influenza, as defined by the Advisory Committee on Immunizations Practices.11,16 These conditions included: prematurity, asthma or a history of wheezing (including reactive airway disease or bronchiolitis), other lung disease, heart disease, seizure disorders, other neurologic disorders, sickle cell anemia, other blood disorders, diabetes mellitus, other endocrine disorders, kidney disease, liver disease, immunosuppression or immunocompromised status, aspirin therapy, and metabolic disease.16 All Patient Refined Diagnostic Related Groups (APR-DRGs; 3M Corporation, Salt Lake City, UT)17 were used to classify diagnoses for these ICU admissions. APR-DRGs are used by Medicaid to classify patients according to reason for admission, and an APR-DRG is assigned to all admitted patients on inpatient status. We examined the number of ICU admissions with a positive test result for picornaviruses who had an acute respiratory illness–related APR-DRG during the 2012−2013 academic year, including: infections of the upper respiratory tract; bronchiolitis and RSV pneumonia; other pneumonia; pulmonary edema and respiratory failure; respiratory system diagnoses with ventilator support for >96 hours; major respiratory infections and inflammations; asthma; other respiratory diagnoses except signs, symptoms, and minor diagnoses; and respiratory signs, symptoms, and minor diagnoses. Finally, we examined the need for respiratory support, defined as any supplemental oxygen, high-flow nasal cannula or continuous positive airway pressure, and/or mechanical ventilation via an endotracheal or tracheostomy tube. To focus on severe, acute picornavirus infection, patients who were determined to have picornaviruses detected from a specimen collected >2 days into their hospital admission were excluded from the descriptive analysis.

Statistical significance was determined by using the Pearson χ2 test or an independent samples median test. Statistical significance was considered at an α level <.05. SPSS versions 20 and 21 (IBM SPSS Statistics, IBM Corporation, Armonk, NY) and Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA) were used for statistical analysis. The present study was approved by the institutional review boards of Children’s Healthcare of Atlanta and Emory University, and a waiver of informed consent was obtained for this retrospective study.

Results

During 2012−2013, a total of 158 737 visits to the PED occurred at the system’s 2 hospitals, compared with 141 155 visits during 2011−2012, a total of 142 605 during 2010−2011, and a total of 148 228 during 2009−2010, which included the influenza A (H1N1) pandemic. Total PED visits, admissions, and ICU admissions according to month and academic year are shown in Fig 1. Although the peak of visits during 2012−2013 occurred in December, visit numbers during July through October were higher than in the 2 previous academic years, although not as high as during the 2009 influenza A (H1N1) pandemic. In addition, number of all admissions and ICU admissions remained higher throughout all of 2012−2013 compared with previous academic years, including the 2009 influenza A (H1N1) pandemic.

FIGURE 1
FIGURE 1

Number of (A) PED visits, (B) hospital admissions from the PED, and (C) ICU admissions according to month and academic year. Of note, the 2009–2010 academic year included the influenza A (H1N1) pandemic.

During 2012−2013, a total of 5685 patient visits leading to admission had an associated respiratory pathogen viral PCR panel. During 2012−2013, picornaviruses were more commonly identified (n = 1284 [22.6%]) among admitted patients than influenza (n = 362 [6.4%]), RSV (n = 861 [15.1%]), or other respiratory viruses (n = 789 [13.9%]). The percent positive for picornaviruses, RSV, influenza and other respiratory viruses according to month during 2012−2013 is shown in Fig 2. Picornaviruses were the most commonly identified respiratory viral pathogens from July through November 2012. In December, influenza and RSV were increasingly identified among viral respiratory specimens. In February, picornaviruses again became the most commonly identified respiratory viral pathogen and remained so throughout the rest of 2012−2013.

FIGURE 2
FIGURE 2

Percent positive respiratory viral testing by month for the 2012–2013 academic year. Other respiratory viruses included: parainfluenza types 1, 2, 3, and 4; coronavirus; adenovirus; and human metapneumovirus.

Of the 5685 admitted patients tested for respiratory pathogens during 2012−2013, a total of 1284 (22.6%) were positive for picornaviruses. Of these, 253 (19.7%) were positive for picornaviruses and at least 1 other respiratory virus; RSV was the most common coinfection (n = 116 [45.8%]). Other viruses that were coidentified with picornaviruses were human metapneumovirus (n = 36 [14.2%]), parainfluenza type 3 (n = 35 [13.8%]), adenovirus (n = 30 [11.9%]), coronavirus (n = 24 [9.5%]), influenza (n = 17 [6.7%]), parainfluenza type 4 (n = 8 [3.2%]), parainfluenza type 2 (n = 4 [1.6%]), and parainfluenza type 1 (n = 2 [0.8%]). Furthermore, of the 253 visits with picornaviruses and at least 1 additional virus, 17 (6.7%) were positive for 2 additional respiratory viruses, and 1 (0.4%) was positive for 3 additional viruses (influenza and parainfluenza types 3 and 4).

The logistic regression model included 5,354 patient visits admitted during 2012−2013 who were tested for a respiratory virus; to focus on the severity of picornaviruses alone, we excluded 331 visits during which multiple respiratory viruses were identified. Picornavirus infection was independently associated with ICU admission (aOR: 1.99 [95% CI: 1.68−2.36]) when adjusted for influenza infection, RSV infection, age, race, and gender (Table 1). RSV infection was also independently associated with ICU admission (aOR: 1.49 [95% CI: 1.20−1.85]), whereas influenza was not (aOR: 0.93 [95% CI: 0.66−1.29]).

View this table:
TABLE 1

ICU Admissions (aOR With CIs) for Admitted Patients Who Were Tested for Respiratory Pathogens During the 2012–2013 Academic Year

Three hundred patient visits resulted in an ICU admission with picornaviruses detected. Fifteen visits were excluded because picornaviruses were detected from specimens collected >2 days after admission to the hospital (median: 10 days [range: 3−120 days]). Of the remaining 285 visits, the median number of days to specimen collection was zero. Seventy-five percent had an acute respiratory illness–related APR-DRG (Table 2). Seventy-nine percent of visits resulting in ICU admissions were from patients with previous high-risk medical conditions, of which asthma or history of wheezing was the most common (43%). In addition, 94% of visits to the ICU resulted in supplemental oxygen use (61% required either high-flow nasal cannula or continuous positive airway pressure). Sixty-one patients (21%) required mechanical ventilation, of whom 11 (3.9%) had a tracheostomy tube and/or home ventilator.

View this table:
TABLE 2

Characteristics of Patient Visits (N = 285) With a Positive Picornavirus Test Result From a Specimen Collected Within 2 Days of Admission Resulting in an ICU Admission From July 1, 2012, Through June 30, 2013

Discussion

Admitted patients during the 2012−2013 academic year with picornaviruses were more likely to be admitted to the ICU than those with influenza and as likely to be admitted to the ICU as those with RSV, 2 viruses traditionally considered to be associated with more severe disease. The majority of children admitted to the ICU with picornaviruses had underlying medical conditions, most commonly asthma or a history of wheezing. Our results indicate that picornaviruses were associated with severe disease in children at our institution in 2012−2013, especially in those with underlying medical conditions, even before the 2014 enterovirus D68 outbreak.

Rhinoviruses are 1 of the most commonly identified respiratory viruses in children.3,9,12 They are known to cause respiratory diseases in children, including bronchiolitis, croup, and upper respiratory tract infections,4 and have also been associated with asthma exacerbations and wheezing episodes in older children.2,3,18,19 Recently, enterovirus D68 has been associated with severe respiratory illness in children.8 In our study, picornaviruses were associated with severe illness in children 2 years before the current outbreak of enterovirus D68, and our study may represent the severity of picornaviruses seen in more typical years. In addition, we detected picornaviruses throughout the academic year, with the highest percent positive of respiratory viral testing occurring in the fall and late spring. Previous studies have shown that rhinovirus is commonly identified year-round.4,9–11,15,20–22 Seasonality is difficult to establish because rhinovirus peaks have occurred in the summer, spring, and fall.4,5,9,12,15,20–22

Rhinoviruses have also been found in 2.25% to 33% of asymptomatic children.9–12 One study in Alaskan native children <3 years old found similar rates of rhinovirus detection in case subjects and in control subjects.9 However, 3 studies found that rhinoviruses were more commonly detected in older children with respiratory disease than in control subjects (aged 2−16 years,18 1−4 years,10 and 2−5 years11) but not in younger children with respiratory disease compared with control subjects. Other studies found higher rates of rhinovirus in case subjects than in control subjects in all those studied, including children aged ≤5 years,12 children aged <2 years,21 and children aged ≥2 years.19

Rhinovirus is detectable by using PCR from nasopharyngeal specimens for up to 4 to 5 weeks after onset of symptoms during an infection and 1 week before infection.23 Thus, although some of the picornavirus detections in the present study could have been due to asymptomatic or resolving infections, it is likely that many of the picornavirus detections, particularly in children aged >1 to 2 years, were associated with the disease requiring PED visits and hospitalizations. In our study, children with picornaviruses had higher odds of being admitted to the ICU than those with influenza during 2012−2013 and similar odds of ICU admission as those with RSV, indicating that picornaviruses can be associated with severe disease in children. Previous studies have indicated that the rhinovirus infections may be associated with clinical disease in children that is similar in presentation and severity to RSV10,21 and other viruses22 and as likely or more likely to be associated with ICU admission as other respiratory viruses.11,24

Another finding in our study was that most children with picornaviruses in the ICU had underlying medical conditions which put them at high risk for complications from respiratory viral illnesses. Two-thirds of these children had lung disease, with asthma or a history of wheezing in 43%. These findings are consistent with previous studies in which hospitalized children with underlying medical conditions had associated rhinovirus infections3,11,15,22,24 and in which rhinovirus was associated with wheezing episodes.2,3,18,19 The present study as well as earlier research indicate that picornaviruses likely cause the most severe disease in at-risk children with underlying medical conditions.

Furthermore, 5% of the ICU cases with picornaviruses in the present study had a respiratory specimen collected >2 days after admission (median: 10 days after admission), which suggests possible nosocomial transmission. However, we are unable to determine in these cases if respiratory symptoms started after admission, if there was a delay in specimen collection, or if there was prolonged shedding of picornaviruses. However, another study found that 22% of rhinovirus infections among hospitalized children were nosocomial, with illness starting at least 2 days after admission.15 Rhinoviruses and enteroviruses seem to be a common cause of outbreaks, including severe occurrences.8,25 These studies support the use of infection control practices targeted at stopping the spread of picornaviruses in health care facilities.

In our study, at least 1 additional respiratory virus was detected in 20% of patients with picornaviruses, similar to previous studies in which codetection of other respiratory viruses with rhinovirus was common.10,11,15,26 RSV was the most common coinfection. However, even when visits of patients with multiple viral infections were excluded from our logistic regression model, picornavirus detection was independently associated with ICU admission. Although we could not exclude the possibility that picornaviruses were associated with severe disease in the setting of either bacterial illnesses or pathogens for which we did not test, our results taken in context with previous studies3,10,11,18 indicate that picornaviruses alone may be associated with severe disease in children.

Our study has some additional limitations. First, no testing for picornaviruses occurred before the 2012−2013 academic year, which limited our ability to compare data with previous years and to determine if the high levels of picornaviruses during 2012−2013 were expected. In addition, testing for picornaviruses was only conducted among symptomatic patients, not among asymptomatic control subjects. In addition, viral testing was performed at the clinician’s discretion in our institution and usually is performed only on admitted patients with respiratory symptoms, which could lead to bias toward sicker patients. Also, our facilities are quaternary care facilities, which could bias our study toward more severe cases. Furthermore, viral testing at our facility targeted both rhinovirus and enterovirus, making it difficult to distinguish between the contributions of each virus, although both rhinovirus and enterovirus cause respiratory illness.2,8 The analysis is limited by the fact that we were unable to sequence the viruses, nor were we able to distinguish between rhinovirus and enterovirus (or among species of rhinoviruses and enteroviruses). However, most clinical providers will not be able to differentiate between rhinovirus and enterovirus. Thus, our study reflects the severity of illness associated with picornaviruses, as detectable on a commercially available assay used in hospitals and as the results would be reported to clinicians.

Conclusions

Picornaviruses, even before the current enterovirus D68 outbreak, were associated with severe disease in children. During the 2012−2013 academic year, children with picornaviruses were as likely as those with RSV and more likely than those with influenza to be admitted to the ICU. Most patients with picornaviruses admitted to the ICU had high-risk, underlying medical conditions, the most common of which was a history of asthma or wheezing. Thus, during times of volume surge when respiratory pathogens contribute to illness, hospitals should consider picornaviruses as a potential contributing pathogen. Clinicians should be aware that picornaviruses can be associated with severe disease, even in years with more typical picornavirus activity. Future research into targeted therapies for picornaviruses and vaccines is needed. In times of high picornavirus activity, hospitals should target infection control measures against picornaviruses to protect our vulnerable patients.

Footnotes

  • Dr Fleming-Dutra designed the study, carried out the analyses, drafted the initial manuscript, and approved the final manuscript as submitted. Dr Simon assisted with design of the study, interpretation of analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr Fortenberry assisted with design of the study, interpretation of analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr Jerris assisted with design of the study, interpretation of analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted. Ms Radecke assisted with design of data collection tools, abstracted medical records, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr Hirsh conceptualized and designed the study, carried out the analyses, and reviewed and revised the manuscript, and approved the final manuscript as submitted.

  • FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

  • FUNDING: No external funding.

  • POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Association of Respiratory Picornaviruses With High Acuity and Severe Illness in a Pediatric Health Care System
Katherine E. Fleming-Dutra, Harold K. Simon, James D. Fortenberry, Robert Jerris, Jaime Radecke, Daniel A. Hirsh
Hospital Pediatrics Aug 2015, 5 (8) 432-438; DOI: 10.1542/hpeds.2014-0111
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