Original Studies
Back-to-School Upper Respiratory Infection in Preschool and Primary School-Age Children in Israel Michal Perry Markovich, DVM,* Aharona Glatman-Freedman, MD, MPH,*†‡ Michal Bromberg, MD, MPH,* Arie Augarten, MD,§¶ Hanna Sefty, MSc,* Zalman Kaufman, MSc,* Hilda Sherbany, BSc,‖ Liora Regev, MSc,‖ Gabriel Chodick, PhD, MPH,**†† Ella Mendelson, PhD,‖†† Tamy Shohat, MD, MPH,*†† Michal Mandelboim, PhD,‖ and The Israel Pediatric Upper Respiratory Infection Network (IPURIN) Background: Increased upper respiratory infection (URI) among children at the beginning of school year is well known to parents and pediatricians. However, this phenomenon is not well documented or characterized. Methods: Computerized datasets from a large health maintenance organization in Israel were used to calculate the weekly rates of URI among children 3–14 years old for the years 2007–2012. In addition, nasopharyngeal swabs were collected in 2010–2012 from children with URI symptoms and controls during school opening time. Swabs were tested by real-time polymerase chain reaction for the presence of respiratory viruses. Results: Time-series analysis demonstrated a peak of URI in September each year. The peaks reached their height 2 weeks after school opening and returned to baseline within 4–7 weeks. The main 3 viruses detected both in URI patients and in healthy controls during the first weeks of school opening were rhinovirus, adenovirus and enterovirus. The detection rate of any respiratory virus, and of rhinovirus in particular, was significantly higher among cases than among controls (54% vs. 16%, P < 0.001 for any virus, and 35% vs. 6.0%, P < 0.01 for rhinovirus). When adjusting for age and sex cases had 5.8 times more viral detection when compared with controls. Upper respiratory symptoms were significantly more prevalent among the virus-positive cases when compared with negative ones. Conclusions: Back-to-school illness consisting of URI has a distinct epidemiological pattern demonstrating a rapid rise peaking within 2 weeks of school opening and is associated predominantly with rhinovirus. Key Words: upper respiratory infection, school, surveillance (Pediatr Infect Dis J 2015;34:476–481)
Accepted for publication October 31, 2014. From the *Israel Center for Disease Control, Israel Ministry of Health, TelHashomer, Israel; †Department of Pediatrics, and ‡Department of Family and Community Medicine, New York Medical College, Valhalla, New York; §Department of Pediatric Emergency Medicine, Safra Children’s Hospital, Chaim Sheba Medical Center, Tel Hashomer, Israel; ¶Department of Pediatrics, Sackler Faculty of Medicine, Tel-Aviv University, TelAviv, Israel; ‖Central Virology Laboratory, Chaim Sheba Medical Center, Israel Ministry of Health, Tel-Hashomer, Israel; **Maccabi Healthcare Services, Israel; and ††Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Israel. The Members of the Israel Pediatric Upper Respiratory Infection Network (IPURIN) are listed in the Appendix. M.P.M. and A.G-.F. contributed comparably to this work. M.B., M.M., M.P.M., T.S., Z.K., E.M. and A.A. designed the study. M.P.M., M.B., G.C., M.M., H.Se., H.Sh. and L.R. collected, analyzed and synthesized the data. M.P.M., Z.K., A.G-.F., T.S., M.M., M.B. and E.M. interpreted the data. M.P.M., A.G-.F. and M.M. wrote the manuscript. All authors reviewed and revised the first and final drafts of this manuscript. The authors have no conflicts of interest or funding to disclose. Address for correspondence: Michal Perry Markovich, DVM, Israel Center for Disease Control, Tel-Hashomer 5265601, Israel. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3405-0476 DOI: 10.1097/INF.0000000000000627
476 | www.pidj.com
I
ncreased appearance of upper respiratory infection (URI) among children at the beginning of school year is well known to parents and pediatricians. However, this phenomenon is not well documented. Recently, increased number of acute care visits because of respiratory illness at the start of the school year was reported.1 The routine surveillance of URI in the community, performed by the Israel Center for Disease Control, has demonstrated an increase in the rate of URI, reoccurring each September. This pattern of illness was observed primarily in preschool and primary school children. Although respiratory illness during the winter is associated mainly with respiratory syncytial virus (RSV) and influenza virus infections2–4 and summer respiratory illness is usually associated with parainfluenza infection,3 the etiology of URI at the beginning of the school year is not well known. The aim of this study was to characterize the pattern of the yearly URI that occurs in association with the opening of the school year and to identify the viruses that are associated with this illness.
MATERIALS AND METHODS Surveillance of URI URI surveillance is carried out routinely at the Israel Center for Disease Control. Data of outpatient visits are received daily from all outpatient clinics of “Maccabi Healthcare Services”, a two million member Health Maintenance Organization (HMO) operating in Israel, of which approximately 430,000 are 3–14 years old. The daily computerized datasets of URI (ICD9 codes 460–465, 475, 478.9) were aggregated into weekly data from the first week of 2007 to the 52nd week of 2012. Weekly rates of URI among patients 3–14 years old were calculated as the number of outpatient visits per 10,000 enrolled members in this age group. Repeated visits within 14 days were omitted. The results were plotted on a time-series graph.
Clinics Participating in the Study To identify the viruses involved in causing URI during the early fall, a convenience sample of general pediatric outpatient clinics (4 clinics for the years 2010 and 2011 and 8 clinics for 2012) was selected to participate in this study, from among the sentinel clinics that participate in influenza surveillance in Israel each year. The Orthopedic and Endocrine outpatient clinics of the Safra Children’s Hospital, at the Sheba Medical Center in Israel, also participated in the study as the site to recruit non-URI participants. All participating clinics were located in the center of Israel.
Study Participants Cases were children ages 3–14 years attending the pediatric sentinel clinics and presenting with URI symptoms. Controls were children of the same age group without URI symptoms for the preceding 7 days, attending the Orthopedic and Endocrine clinics at the Safra Children’s Hospital, Sheba Medical Center in Israel. URI patients with acute asthma exacerbation were excluded from the study. Controls with acute asthma exacerbation or malignancies were also excluded from
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
the study. Sample collection started 2 days from school opening date and included the entire month of September. In 2010 only cases were studied, and in 2011 and 2012 both cases and controls were studied.
Sample and Data Collection Nasopharyngeal swab samples were obtained from symptomatic children who presented with fever (>37.8°C) along with at least one of the following symptoms: sneezing, nasal congestion, coryza, cough, sore/dry throat or hoarseness (cases). To be included in the study, time from symptoms onset to nasopharyngeal swabbing of cases should not have exceed 3 days. Samples were collected only on working days. If samples were collected from more than one symptomatic family member, only one that was randomly selected was included in the study. A short questionnaire was filled out by the patients’ physicians (for cases) or by a designated nurse (for controls). The questionnaire included demographic data as well as medical information about the current illness (for cases) and any febrile illness during the past month (for controls). Follow-up of cases or controls after sample collection was not performed as part of this study.
Laboratory Analysis Viral genome was extracted from nasopharyngeal samples using NucliSENS easyMAG (BioMerieux, France). The presence of respiratory viruses was determined by TaqMan Chemistry using the ABI 7500 instrument. The detection of RNA viruses was performed using a panel of real-time reverse transcription-polymerase chain reaction (rRT-PCR) assays as previously described: Influenza A and B,5 influenza A(H1N1)pdm09,6,7 RSV,8 human metapneumovirus,9 enterovirus,10 rhinovirus11 and parainfluenza 312 viruses. For detection of adenovirus (DNA virus), RT-PCR was performed, as previously described.13 For the RNA rRT-PCR assays, the Ambion Ag-Path master mix (Life Technologies, Carlsbad, CA) was used, whereas for the DNA assays, ABgene Absolute Blue (Thermo, UK) was used. Both were used according to the manufacturer’s instructions.
Statistical Analysis For the generation of time-series, the daily computerized datasets of URI form Maccabi Health Services were aggregated into weekly
Back-to-School URI
data. Weekly rates of URI among patients 3–14 years old were calculated as the number of outpatient visits per 10,000 enrolled members. Demographic characteristics of cases and controls were compared using t test or χ2 test. Comparisons between viral detection rate by age and sex in cases and controls were done using the χ2 test. Logistic regression model was used to control for confounders. A 2-tailed P value of
Back-to-School Upper Respiratory Infection in Preschool and Primary School-Age Children in Israel Michal Perry Markovich, DVM,* Aharona Glatman-Freedman, MD, MPH,*†‡ Michal Bromberg, MD, MPH,* Arie Augarten, MD,§¶ Hanna Sefty, MSc,* Zalman Kaufman, MSc,* Hilda Sherbany, BSc,‖ Liora Regev, MSc,‖ Gabriel Chodick, PhD, MPH,**†† Ella Mendelson, PhD,‖†† Tamy Shohat, MD, MPH,*†† Michal Mandelboim, PhD,‖ and The Israel Pediatric Upper Respiratory Infection Network (IPURIN) Background: Increased upper respiratory infection (URI) among children at the beginning of school year is well known to parents and pediatricians. However, this phenomenon is not well documented or characterized. Methods: Computerized datasets from a large health maintenance organization in Israel were used to calculate the weekly rates of URI among children 3–14 years old for the years 2007–2012. In addition, nasopharyngeal swabs were collected in 2010–2012 from children with URI symptoms and controls during school opening time. Swabs were tested by real-time polymerase chain reaction for the presence of respiratory viruses. Results: Time-series analysis demonstrated a peak of URI in September each year. The peaks reached their height 2 weeks after school opening and returned to baseline within 4–7 weeks. The main 3 viruses detected both in URI patients and in healthy controls during the first weeks of school opening were rhinovirus, adenovirus and enterovirus. The detection rate of any respiratory virus, and of rhinovirus in particular, was significantly higher among cases than among controls (54% vs. 16%, P < 0.001 for any virus, and 35% vs. 6.0%, P < 0.01 for rhinovirus). When adjusting for age and sex cases had 5.8 times more viral detection when compared with controls. Upper respiratory symptoms were significantly more prevalent among the virus-positive cases when compared with negative ones. Conclusions: Back-to-school illness consisting of URI has a distinct epidemiological pattern demonstrating a rapid rise peaking within 2 weeks of school opening and is associated predominantly with rhinovirus. Key Words: upper respiratory infection, school, surveillance (Pediatr Infect Dis J 2015;34:476–481)
Accepted for publication October 31, 2014. From the *Israel Center for Disease Control, Israel Ministry of Health, TelHashomer, Israel; †Department of Pediatrics, and ‡Department of Family and Community Medicine, New York Medical College, Valhalla, New York; §Department of Pediatric Emergency Medicine, Safra Children’s Hospital, Chaim Sheba Medical Center, Tel Hashomer, Israel; ¶Department of Pediatrics, Sackler Faculty of Medicine, Tel-Aviv University, TelAviv, Israel; ‖Central Virology Laboratory, Chaim Sheba Medical Center, Israel Ministry of Health, Tel-Hashomer, Israel; **Maccabi Healthcare Services, Israel; and ††Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Israel. The Members of the Israel Pediatric Upper Respiratory Infection Network (IPURIN) are listed in the Appendix. M.P.M. and A.G-.F. contributed comparably to this work. M.B., M.M., M.P.M., T.S., Z.K., E.M. and A.A. designed the study. M.P.M., M.B., G.C., M.M., H.Se., H.Sh. and L.R. collected, analyzed and synthesized the data. M.P.M., Z.K., A.G-.F., T.S., M.M., M.B. and E.M. interpreted the data. M.P.M., A.G-.F. and M.M. wrote the manuscript. All authors reviewed and revised the first and final drafts of this manuscript. The authors have no conflicts of interest or funding to disclose. Address for correspondence: Michal Perry Markovich, DVM, Israel Center for Disease Control, Tel-Hashomer 5265601, Israel. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3405-0476 DOI: 10.1097/INF.0000000000000627
476 | www.pidj.com
I
ncreased appearance of upper respiratory infection (URI) among children at the beginning of school year is well known to parents and pediatricians. However, this phenomenon is not well documented. Recently, increased number of acute care visits because of respiratory illness at the start of the school year was reported.1 The routine surveillance of URI in the community, performed by the Israel Center for Disease Control, has demonstrated an increase in the rate of URI, reoccurring each September. This pattern of illness was observed primarily in preschool and primary school children. Although respiratory illness during the winter is associated mainly with respiratory syncytial virus (RSV) and influenza virus infections2–4 and summer respiratory illness is usually associated with parainfluenza infection,3 the etiology of URI at the beginning of the school year is not well known. The aim of this study was to characterize the pattern of the yearly URI that occurs in association with the opening of the school year and to identify the viruses that are associated with this illness.
MATERIALS AND METHODS Surveillance of URI URI surveillance is carried out routinely at the Israel Center for Disease Control. Data of outpatient visits are received daily from all outpatient clinics of “Maccabi Healthcare Services”, a two million member Health Maintenance Organization (HMO) operating in Israel, of which approximately 430,000 are 3–14 years old. The daily computerized datasets of URI (ICD9 codes 460–465, 475, 478.9) were aggregated into weekly data from the first week of 2007 to the 52nd week of 2012. Weekly rates of URI among patients 3–14 years old were calculated as the number of outpatient visits per 10,000 enrolled members in this age group. Repeated visits within 14 days were omitted. The results were plotted on a time-series graph.
Clinics Participating in the Study To identify the viruses involved in causing URI during the early fall, a convenience sample of general pediatric outpatient clinics (4 clinics for the years 2010 and 2011 and 8 clinics for 2012) was selected to participate in this study, from among the sentinel clinics that participate in influenza surveillance in Israel each year. The Orthopedic and Endocrine outpatient clinics of the Safra Children’s Hospital, at the Sheba Medical Center in Israel, also participated in the study as the site to recruit non-URI participants. All participating clinics were located in the center of Israel.
Study Participants Cases were children ages 3–14 years attending the pediatric sentinel clinics and presenting with URI symptoms. Controls were children of the same age group without URI symptoms for the preceding 7 days, attending the Orthopedic and Endocrine clinics at the Safra Children’s Hospital, Sheba Medical Center in Israel. URI patients with acute asthma exacerbation were excluded from the study. Controls with acute asthma exacerbation or malignancies were also excluded from
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
the study. Sample collection started 2 days from school opening date and included the entire month of September. In 2010 only cases were studied, and in 2011 and 2012 both cases and controls were studied.
Sample and Data Collection Nasopharyngeal swab samples were obtained from symptomatic children who presented with fever (>37.8°C) along with at least one of the following symptoms: sneezing, nasal congestion, coryza, cough, sore/dry throat or hoarseness (cases). To be included in the study, time from symptoms onset to nasopharyngeal swabbing of cases should not have exceed 3 days. Samples were collected only on working days. If samples were collected from more than one symptomatic family member, only one that was randomly selected was included in the study. A short questionnaire was filled out by the patients’ physicians (for cases) or by a designated nurse (for controls). The questionnaire included demographic data as well as medical information about the current illness (for cases) and any febrile illness during the past month (for controls). Follow-up of cases or controls after sample collection was not performed as part of this study.
Laboratory Analysis Viral genome was extracted from nasopharyngeal samples using NucliSENS easyMAG (BioMerieux, France). The presence of respiratory viruses was determined by TaqMan Chemistry using the ABI 7500 instrument. The detection of RNA viruses was performed using a panel of real-time reverse transcription-polymerase chain reaction (rRT-PCR) assays as previously described: Influenza A and B,5 influenza A(H1N1)pdm09,6,7 RSV,8 human metapneumovirus,9 enterovirus,10 rhinovirus11 and parainfluenza 312 viruses. For detection of adenovirus (DNA virus), RT-PCR was performed, as previously described.13 For the RNA rRT-PCR assays, the Ambion Ag-Path master mix (Life Technologies, Carlsbad, CA) was used, whereas for the DNA assays, ABgene Absolute Blue (Thermo, UK) was used. Both were used according to the manufacturer’s instructions.
Statistical Analysis For the generation of time-series, the daily computerized datasets of URI form Maccabi Health Services were aggregated into weekly
Back-to-School URI
data. Weekly rates of URI among patients 3–14 years old were calculated as the number of outpatient visits per 10,000 enrolled members. Demographic characteristics of cases and controls were compared using t test or χ2 test. Comparisons between viral detection rate by age and sex in cases and controls were done using the χ2 test. Logistic regression model was used to control for confounders. A 2-tailed P value of
