|Year : 2018 | Volume
| Issue : 4 | Page : 230-236
|Clinical characteristics and outcomes of human rhinovirus positivity in hospitalized children
Pui-Ying Iroh Tam1, Lei Zhang2, Zohara Cohen2
1 Division of Pediatric Infectious Diseases, University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA; Paediatric and Child Health Research Group, Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi
2 Biostatistical Design and Analysis Center, Clinical and Translational Science Institute, University of Minnesota, Minneapolis, MN, USA
|Date of Submission||05-Sep-2017|
|Date of Acceptance||21-May-2018|
|Date of Web Publication||10-Oct-2018|
Dr. Pui-Ying Iroh Tam
Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre
| Abstract|| |
BACKGROUND: The clinical relevance of positive human rhinovirus (HRV) in hospitalized patients is unclear. Our objective was to describe the clinical characteristics and outcomes of HRV positivity in a heterogeneous population of hospitalized children, compared to those positive for another respiratory virus and those where no respiratory virus was detected.
METHODS: A retrospective case–control study of children hospitalized between January 2014 to April 2015 who had a respiratory viral specimen collected. Clinical and laboratory data were collected, and baseline characteristics and clinical variables were compared.
RESULTS: During the study period, there were 671 specimens obtained from 577 patients that were processed for the respiratory viral polymerase chain reaction assay, of which 198 were positive for HRV, 167 positive for another respiratory virus, and 306 where no respiratory virus was detected. A history of asthma was significantly associated with HRV-positive patients (odds ratio [OR] 3.71; P < 0.001). On multivariate analysis, HRV-positive patients had a higher requirement for mechanical ventilation (OR 1.44), lower rates of readmission (OR 0.53), and lower mortality (OR 0.35) compared to patients with no respiratory virus isolated; however, none were statistically significant. HRV-positive patients did have a significantly shorter length of stay (LOS) compared with patients with no respiratory virus isolated (difference–0.35; P = 0.001). Similar outcomes were seen in patients positive for other respiratory viruses.
CONCLUSIONS: HRV-positive hospitalized pediatric patients with a heterogeneous set of clinical diagnoses had higher association with asthma compared to patients who had another, or no, respiratory virus isolated. HRV-positive patients had shorter LOS compared to patients who had no respiratory viruses isolated. These findings suggest that HRV positivity in hospitalized pediatric patients may not lead to adverse clinical outcomes, although asthma is a risk factor regardless of clinical comorbidities and diagnoses. Further research is warranted to understand the predisposition of asthma to HRV positivity.
Keywords: Children, comorbidity, diagnostics, hospitalization, respiratory virus, severity
|How to cite this article:|
Tam PYI, Zhang L, Cohen Z. Clinical characteristics and outcomes of human rhinovirus positivity in hospitalized children. Ann Thorac Med 2018;13:230-6
Human rhinovirus (HRV) is a cause of the common cold and has been implicated in acute lower respiratory tract infections,,,,, as well as asthma exacerbations.,,,, Although HRV has been associated with acute life-threatening events in infants and acute respiratory hospitalizations in children,,,,,,, it has also been detected in up to 44% of asymptomatic cases,,,,, making interpretation, and clinical relevance, of a positive HRV result in children unclear.
Few studies have looked at the relevance of HRV positivity on clinical outcomes in hospitalized children, nor accounted for a broad spectrum of clinical comorbidities and diagnoses. The objective of our study was to examine HRV positivity in hospitalized children with heterogeneous clinical comorbidities and diagnoses, and to compare characteristics, clinical management and outcomes with other hospitalized children who received respiratory viral testing during the same period.
| Methods|| |
We conducted a retrospective case–control study from January 2014 to April 2015 of patients within the Fairview Health System network of Minnesota. This health system includes four community hospitals with a pediatric unit, and the University of Minnesota Masonic Children's Hospital, a 96-bed academic tertiary care children's hospital.
Our inclusion criteria consisted of children up to 18 years of age who had a respiratory viral polymerase chain reaction (PCR) specimen obtained during hospitalization. Patients who were discharged from the emergency department were excluded. If a patient had multiple positive respiratory viral specimens during a hospital encounter, only the first positive result was selected. Readmissions within a 2-month interval were excluded and readmissions ≥2 months intervals were treated as independent events.
Clinical diagnoses and comorbidities (asthma, cystic fibrosis, other pulmonary disorders, cardiac, renal, hematologic, neurologic, and metabolic disorder) were based on the International Classification of Diseases, Ninth Revision codes and laboratory results obtained closest to the time of the respiratory viral test, hospital length of stay (LOS), 14-day readmission, and mortality were extracted from the medical record. Criteria for hospitalization, respiratory viral testing, and discharge was based on clinical judgment of the physician and based on presenting symptoms and signs, underlying comorbidities, suspected or confirmed clinical diagnoses, and laboratory results. As respiratory viral testing was performed at the discretion of the provider and is not part of routine care, each patient had a clinical indication to warrant testing. This study was approved by the Institutional Review Board of the University of Minnesota.
The respiratory viral PCR test has been previously described. The assay (GenMark's eSensor Respiratory Viral Panel, GenMarkDx, Carlsbad, CA) incorporates a multiplex reverse transcription-PCR amplification followed by suspension array detection. The respiratory viruses tested include adenovirus Groups B, C, and E; influenza A virus (including subtype determination); influenza B virus; human metapneumovirus; parainfluenza virus types 1, 2, and 3; respiratory syncytial virus types A and B; and HRV. The test was carried out at the Infectious Diseases Diagnostic Laboratory for the entire Fairview Health System, commencing on January 8, 2014. It was performed daily, Monday to Friday, with results typically available in 24 h.
Patients were sorted into three groups based on whether their respiratory viral PCR detected HRV with or without another respiratory virus, some other respiratory virus, or no respiratory virus. Primary outcome measures were requirement for mechanical ventilation, LOS, 14-day readmission, and mortality. Descriptive statistics were shown as frequencies and percentages, or as a mean/median (range), as appropriate. Natural log transformation was applied for data with skewed distribution. P value is calculated from two-sample t-test or Wilcoxon signed-rank test for continuous variables and Chi-square test for categorical variables. On univariate analysis after applying Bonferroni's adjustment for multiple comparisons, P ≤ 0.05/3 = ≤0.016 was considered statistically significant. Multivariate analysis using ANOVA was performed controlling for age at admission, sex, race, medical unit, and number of comorbidities. P value was adjusted for multiple comparisons by Tukey's method and P ≤ 0.05 was considered statistically significant. During summer-fall of 2014, there was an epidemic of Enterovirus D68 which cross-reacted with HRV on the respiratory viral PCR assay. To account for this potential confounder, we performed a separate analysis excluding all data during this period (August 2014–January 2015). All data management was performed using Microsoft Excel 2011 v. 14.5.6 and statistical analyses were performed using SAS v. 9.3 (SAS Institute, Cary, NC). Graphs were plotted in R (http://www.r-project.org).
| Results|| |
Over the 16-month period, there were a total of 671 respiratory viral PCR specimens obtained from separate hospital encounters of 577 patients. Of these, 198 specimens were positive for HRV only, 167 were positive for another respiratory virus with or without HRV, and 307 had no respiratory virus detected [Table 1]. Respiratory viruses detected included HRV (55.7%), respiratory syncytial virus (21.8%), Human metapneumovirus (11.3%), adenovirus (9.0%), parainfluenza type 3 (6.5%), influenza A (4.0%), influenza B (2.8%), parainfluenza type 2 (1.7%), and parainfluenza type 1 (0.9%).
|Table 1: Characteristics of the three respiratory virus test study populations|
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The mean age for patients who tested positive for HRV was 3.23 years, compared to 3.06 for patients positive for other respiratory viruses. Patients where no respiratory virus was detected were significantly older at 6.09 years (P < 0.001). In addition, patients with no respiratory virus detected had more comorbid conditions (mean 3.1) compared to those who were positive for HRV (mean 2.5) or another respiratory virus (mean 2.3; P < 0.001). The only comorbidity that was significantly associated with HRV was a history of asthma (38.9% compared to 22.8% positive for another respiratory virus and 19.6% with no virus; P < 0.001).
Respiratory viral coinfection was noted in 32 specimens. Patients with HRV coinfection were noted more frequently compared to patients coinfected with other respiratory viruses (16.2% compared to 10.2%), but this was not a statistically significant difference (P = 0.10). The most common coinfecting respiratory viruses were respiratory syncytial virus (38%) followed by adenovirus (31%), parainfluenza type 3 (22%), and Human metapneumovirus (13%). Detection of HRV was noted most commonly among young children under 2 years of age and was generally more prominent in the summer-fall months [Figure 1], although our study period coincided with the epidemic of Enterovirus D68 during this season which had high cross-reactivity with HRV in the respiratory viral PCR assay.
|Figure 1: Monthly distribution of human rhinovirus positivity in hospitalized patients, by age group|
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On univariate analysis, HRV-positive patients were more likely to have a history of asthma compared with patients with no respiratory virus isolated (odds ratio [OR] 3.71, P < 0.001) [Figure 2] and remained significant even when compared to patients positive with another respiratory virus (OR 2.62; P < 0.001). Leukocytosis and thrombocytosis were most common in HRV-positive patients (21.1% and 7.1%, respectively), whereas leukopenia and thrombocytopenia were most common in patients with no virus detected (5.5% and 25.5%, respectively), and these differences were statistically significant (P = 0.001 and P < 0.001, respectively). For clinical outcomes, patients who had no respiratory virus detected had a longer mean hospital log LOS at 1.93 compared to 1.50 for HRV patients and 1.47 for those with other respiratory viruses (P < 0.001). Mortality was also highest in patients who had no respiratory virus detected (7.8%) compared to HRV patients (2.0%) and patients with other respiratory viruses (1.2%; P < 0.001). Oseltamivir use was, not surprisingly, highest in patients who had other respiratory viruses detected (13.2%) compared to HRV patients (2.5%) and patients with no respiratory virus detected (2.3%; P = 0.001). Vancomycin use was highest in patients with no respiratory virus detected (39.2%) compared to HRV-positive patients (23.2%) and patients positive for another respiratory virus (19.8%; P < 0.001).
|Figure 2: Odds ratio of characteristics in human rhinovirus-positive versus human rhinovirus-negative patients|
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On multivariate analysis [Table 2], after controlling for age, sex, race, medical unit, and number of comorbidities, HRV-positive patients had a higher requirement for mechanical ventilation (OR 1.44), lower rates of readmission (OR 0.53), and lower mortality (OR 0.35) compared to patients with no respiratory virus isolated [Table 2]; however, none of these results were statistically significant. HRV-positive patients did have a significantly shorter LOS compared with patients with no respiratory virus isolated (difference − 0.35; P = 0.001). By comparison, patients with another respiratory virus isolated also had a significantly shorter LOS (difference − 0.28; P = 0.008) compared to patients with no respiratory virus isolated. This cohort, similar to HRV-positive patients, had a higher requirement for mechanical ventilation (OR 1.54), lower rates of readmission (OR 0.33), and lower mortality (OR 0.43) compared to patients with no respiratory virus isolated, although these differences again were not statistically significant.
|Table 2: Multivariate analysis evaluating clinical characteristics, management and outcomes of human rhinovirus-positive patients compared to those positive and negative for other respiratory viruses|
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| Discussion|| |
This study evaluated almost 200 hospital encounters of pediatric patients who were HRV-positive and demonstrated that this population, compared to hospitalized patients who had another, or no, respiratory viruses detected, was significantly more likely to have a history of asthma. Compared to patients with no respiratory virus detected, HRV-positivity was significantly associated with shorter LOS. Patients' positive for other respiratory viruses had similar outcomes to HRV-positive hospitalized patients.
The strong correlation between HRV positivity and asthma has been well described.,,,, However, previous studies have not evaluated HRV positivity among hospitalized patients with a broad spectrum of clinical comorbidities and diagnoses. Our study results are notable in that asthma appears to be a risk factor for HRV positivity regardless of the clinical diagnosis. Research on this topic indicates that airway epithelial cells, which are the primary site of infection and replication of HRV, play a key role in this process, that HRV provokes symptoms through virus-specific cytopathic effects, rather than through direct cytotoxic effects, and that interleukin-8, a chemoattractant and activator of neutrophils, is a major determinant of clinical outcomes of HRV infection. However, the fundamental mechanism that underlies these associations is still largely unknown.
These findings support other studies that showed no significant difference between HRV and other respiratory viruses and severity of disease. A prospective study of HRV in hospitalized children, which also enrolled asymptomatic controls, detected HRV in 15% of patients with respiratory illness but also in 13% of asymptomatic controls. Clinical presentations and outcomes were similar among HRV species, and this study also noted that patients were less likely to have a LOS longer than 3 days compared to those with other viruses, although the median duration of stay was not different. In adults, a prospective study demonstrated that while HRV was associated with a substantial number of emergency department visits and hospitalizations for acute respiratory illness, they were less likely to be hospitalized than to be seen in the outpatient setting.
The lack of adverse outcomes among HRV-positive patients in our study may have been due to the prolonged positivity of HRV in nasal secretions, which has been documented to last up to 7 weeks, as well as the high rates of asymptomatic carriage.,,,,, A community surveillance study of respiratory viruses found that HRV was associated with symptoms in only 56% of episodes where it was detected and 93% of participants had HRV detected in at least one weekly sample within the study period. Hence, our study population may have consisted of a large proportion of HRV-positive patients with asymptomatic carriage and those who had recovered from a respiratory illness, even though we excluded patients readmitted within a 2 months interval.
The epidemic of Enterovirus D68 during summer-fall of 2014 could be a potential confounder, as this virus cross-reacts with HRV on the respiratory viral PCR assay. One would expect worse clinical outcomes in HRV-positive patients, although Enterovirus D68 has similar characteristics to HRV infections,, it is also associated with more severe disease. However, this was not supported by our statistical analysis. When we performed a separate analysis excluding all data during this period (August 2014–January 2015), we did not find substantially difference results: both HRV-positive patients and patients positive for another respiratory virus still had a significantly shorter LOS compared to patients with no respiratory virus detected (1.42 and 1.37, respectively, compared to 1.67 in log scale).
Our study has several limitations. This was a multicenter study which included one tertiary children's hospital and several community hospitals. Hence, while we consider this a strength, the findings may not be generalizable to other settings. Our study is limited in that molecular detection of nasopharyngeal samples does not precisely correlate with lower respiratory tract involvement, and PCR results may not reflect a causative pathogen directly attributable to the patient's hospitalization. Our laboratory PCR did not differentiate between HRV species and hence it is unknown whether HRV A and B were predominantly represented in our patient population, nor whether HRV C was more common in patients who had more severe disease, as has been previously reported.,,,, Another limitation is that since HRV is frequently a part of coinfection, it is therefore difficult to definitively attribute findings to HRV or the other coinfecting respiratory virus. Furthermore, as the multiplex PCR panel detects a finite number of respiratory viruses, we may have missed other clinically relevant viruses including human bocavirus and coronavirus. While we adjusted for age in our multivariate analysis, we did not stratify our analysis by age group. Hence, we may have missed age-related associations.
| Conclusions|| |
This study provides data that hospitalized pediatric patients with a heterogeneous set of clinical comorbidities and diagnoses and who are HRV positive did not have adverse clinical outcomes compared to patients who had no respiratory viruses isolated. These patients had similar clinical outcomes to patients who had another respiratory virus isolated. This study also supports earlier evidence that HRV positivity is strongly associated with asthma and asthma appears to be a risk factor regardless of the clinical diagnosis. Further research is warranted to understand the predisposition of asthma to HRV positivity, to guide clinician interpretation of a positive test in a hospitalized patient.
We would like to thank Emily Melcher and Sonya Grillo for the data collection. We thank the Infectious Diseases Diagnostic Laboratory at University of Minnesota Medical Center, Fairview, for processing isolates. We thank Patricia Ferrieri for reviewing manuscript drafts. This work was presented in abstract form at the Pediatric Academic Societies meeting in Baltimore in March–April 2016.
Financial support and sponsorship
Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Iwane MK, Prill MM, Lu X, Miller EK, Edwards KM, Hall CB, et al.
Human rhinovirus species associated with hospitalizations for acute respiratory illness in young US children. J Infect Dis 2011;204:1702-10.
Jartti T, Aakula M, Mansbach JM, Piedra PA, Bergroth E, Koponen P, et al.
Hospital length-of-stay is associated with rhinovirus etiology of bronchiolitis. Pediatr Infect Dis J 2014;33:829-34.
Mansbach JM, Piedra PA, Teach SJ, Sullivan AF, Forgey T, Clark S, et al.
Prospective multicenter study of viral etiology and hospital length of stay in children with severe bronchiolitis. Arch Pediatr Adolesc Med 2012;166:700-6.
Miller EK, Edwards KM, Weinberg GA, Iwane MK, Griffin MR, Hall CB, et al.
A novel group of rhinoviruses is associated with asthma hospitalizations. J Allergy Clin Immunol 2009;123:98-1040.
Miller EK, Lu X, Erdman DD, Poehling KA, Zhu Y, Griffin MR, et al.
Rhinovirus-associated hospitalizations in young children. J Infect Dis 2007;195:773-81.
Piotrowska Z, Vázquez M, Shapiro ED, Weibel C, Ferguson D, Landry ML, et al.
Rhinoviruses are a major cause of wheezing and hospitalization in children less than 2 years of age. Pediatr Infect Dis J 2009;28:25-9.
Ferreira A, Williams Z, Donninger H, van Schalkwyk EM, Bardin PG. Rhinovirus is associated with severe asthma exacerbations and raised nasal interleukin-12. Respiration 2002;69:136-42.
Jartti T, Lehtinen P, Vuorinen T, Osterback R, van den Hoogen B, Osterhaus AD, et al.
Respiratory picornaviruses and respiratory syncytial virus as causative agents of acute expiratory wheezing in children. Emerg Infect Dis 2004;10:1095-101.
Louie JK, Roy-Burman A, Guardia-Labar L, Boston EJ, Kiang D, Padilla T, et al.
Rhinovirus associated with severe lower respiratory tract infections in children. Pediatr Infect Dis J 2009;28:337-9.
Papadopoulos NG, Bates PJ, Bardin PG, Papi A, Leir SH, Fraenkel DJ, et al.
Rhinoviruses infect the lower airways. J Infect Dis 2000;181:1875-84.
Papadopoulos NG, Papi A, Psarras S, Johnston SL. Mechanisms of rhinovirus-induced asthma. Paediatr Respir Rev 2004;5:255-60.
Calvo C, Garcia ML, Pozo F, Reyes N, Pérez-Breña P, Casas I, et al.
Role of rhinovirus C in apparently life-threatening events in infants, Spain. Emerg Infect Dis 2009;15:1506-8.
Calvo C, García-García ML, Blanco C, Pozo F, Flecha IC, Pérez-Breña P, et al.
Role of rhinovirus in hospitalized infants with respiratory tract infections in Spain. Pediatr Infect Dis J 2007;26:904-8.
Byington CL, Ampofo K, Stockmann C, Adler FR, Herbener A, Miller T, et al.
Community surveillance of respiratory viruses among families in the utah better identification of germs-longitudinal viral epidemiology (BIG-loVE) study. Clin Infect Dis 2015;61:1217-24.
Fry AM, Lu X, Olsen SJ, Chittaganpitch M, Sawatwong P, Chantra S, et al.
Human rhinovirus infections in rural Thailand: Epidemiological evidence for rhinovirus as both pathogen and bystander. PLoS One 2011;6:e17780.
Jartti T, Lehtinen P, Vuorinen T, Koskenvuo M, Ruuskanen O. Persistence of rhinovirus and enterovirus RNA after acute respiratory illness in children. J Med Virol 2004;72:695-9.
Peltola V, Waris M, Osterback R, Susi P, Ruuskanen O, Hyypiä T, et al.
Rhinovirus transmission within families with children: Incidence of symptomatic and asymptomatic infections. J Infect Dis 2008;197:382-9.
Singleton RJ, Bulkow LR, Miernyk K, DeByle C, Pruitt L, Hummel KB, et al.
Viral respiratory infections in hospitalized and community control children in Alaska. J Med Virol 2010;82:1282-90.
Pierce VM, Hodinka RL. Comparison of the genMark diagnostics eSensor respiratory viral panel to real-time PCR for detection of respiratory viruses in children. J Clin Microbiol 2012;50:3458-65.
McAllister SC, Schleiss MR, Arbefeville S, Steiner ME, Hanson RS, Pollock C, et al.
Epidemic 2014 enterovirus D68 cross-reacts with human rhinovirus on a respiratory molecular diagnostic platform. PLoS One 2015;10:e0118529.
Bizzintino J, Lee WM, Laing IA, Vang F, Pappas T, Zhang G, et al.
Association between human rhinovirus C and severity of acute asthma in children. Eur Respir J 2011;37:1037-42.
Khetsuriani N, Lu X, Teague WG, Kazerouni N, Anderson LJ, Erdman DD, et al.
Novel human rhinoviruses and exacerbation of asthma in children. Emerg Infect Dis 2008;14:1793-6.
Miller M, Tam AB, Cho JY, Doherty TA, Pham A, Khorram N, et al.
ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6. Proc Natl Acad Sci U S A 2012;109:16648-53.
Arruda E, Boyle TR, Winther B, Pevear DC, Gwaltney JM Jr., Hayden FG, et al.
Localization of human rhinovirus replication in the upper respiratory tract by in situ
hybridization. J Infect Dis 1995;171:1329-33.
Slater L, Bartlett NW, Haas JJ, Zhu J, Message SD, Walton RP, et al.
Co-ordinated role of TLR3, RIG-I and MDA5 in the innate response to rhinovirus in bronchial epithelium. PLoS Pathog 2010;6:e1001178.
Miller EK, Linder J, Kraft D, Johnson M, Lu P, Saville BR, et al.
Hospitalizations and outpatient visits for rhinovirus-associated acute respiratory illness in adults. J Allergy Clin Immunol 2016;137:734-430.
Calvo C, Cuevas MT, Pozo F, García-García ML, Molinero M, Calderón A, et al.
Respiratory infections by enterovirus D68 in outpatients and inpatients Spanish children. Pediatr Infect Dis J 2016;35:45-9.
Orvedahl A, Padhye A, Barton K, O'Bryan K, Baty J, Gruchala N, et al.
Clinical characterization of children presenting to the hospital with enterovirus D68 infection during the 2014 outbreak in St. Louis. Pediatr Infect Dis J 2016;35:481-7.
Midgley CM, Watson JT, Nix WA, Curns AT, Rogers SL, Brown BA, et al.
Severe respiratory illness associated with a nationwide outbreak of enterovirus D68 in the USA (2014): A descriptive epidemiological investigation. Lancet Respir Med 2015;3:879-87.
Han TH, Chung JY, Hwang ES, Koo JW. Detection of human rhinovirus C in children with acute lower respiratory tract infections in South Korea. Arch Virol 2009;154:987-91.
Linsuwanon P, Payungporn S, Samransamruajkit R, Posuwan N, Makkoch J, Theanboonlers A, et al.
High prevalence of human rhinovirus C infection in thai children with acute lower respiratory tract disease. J Infect 2009;59:115-21.
Piralla A, Rovida F, Campanini G, Rognoni V, Marchi A, Locatelli F, et al.
Clinical severity and molecular typing of human rhinovirus C strains during a fall outbreak affecting hospitalized patients. J Clin Virol 2009;45:311-7.
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