The Influenza Incidence Surveillance Project (IISP) provides a unique opportunity to assess the age-specific burden of PIVs in outpatient practice across multiple years and a broad geographic range in the United States. Since 2010, the IISP has monitored the year-round incidence of influenza-like illness (ILI) and associated incidence of respiratory viruses, including PIVs 1–4, in a network of outpatient clinics across 13 US states and jurisdictions. Using IISP data from 2010 to 2014, we describe the seasonality and age-specific burden of PIVs in the IISP, which will help to improve understanding of these viruses in the outpatient setting and support efforts for the prevention and treatment of PIV-associated illness.
MATERIALS AND METHODS
Influenza Incidence Surveillance Project and Parainfluenza Virus Surveillance
Detailed methodology for the IISP has been published previously.9,10 Briefly, surveillance was conducted year-round, with surveillance years defined from August to July. We included data from 12 state and local health departments (sites) from August 2010 to July 2013 and from 5 sites from August 2013 to July 2014 as follows: Florida, Los Angeles County, Minnesota (MN) and Wisconsin (WI) from 2010 to 2014; Iowa, New Jersey, New York City, North Dakota, Oregon, Philadelphia and Virginia from 2010 to 2013; Utah (UT) from 2010 to 2011; and Texas from 2011 to 2014. The IISP conducted nonresearch, public health surveillance.
Participating public health departments, or sites, recruited ≈5 small to moderate sized outpatient healthcare providers (HCPs) with enumerated patient populations to report weekly age-specific counts of ILI and all-cause patient visits. Among patients aged ≥2 years, ILI was defined as fever with cough or sore throat; among patients aged <2 years, fever with ≥1 of the following respiratory symptoms: cough, sore throat, nasal congestion or rhinorrhea. Respiratory specimens (nasal, nasopharyngeal or oropharyngeal) were collected from the first 10 ILI patients each week along with demographic and clinical data; the sampling of up to 10 ILI patients each week ensured that a large proportion of all ILI patients would be sampled, given the small clinic size of HCPs.
Specimens were tested using molecular-based respiratory virus panels chosen by the participating laboratories: Los Angeles County, New Jersey, New York City, North Dakota, Texas and Virginia used Luminex xTAG respiratory virus panel (Luminex Diagnostics, Toronto, Canada); Florida, Iowa, MN, Oregon and Philadelphia used the virus-specific reverse transcriptase–polymerase chain reaction assay developed by Centers for Disease Control and Prevention11; UT and WI used ResPlex II v2.0 (Qiagen, Venlo, The Netherlands). PIVs 1–3 were included in the respiratory virus panels at all health departments; PIV4 was included in the testing panel in MN, UT and WI. Information regarding proficiency testing was published previously.10
Analysis was limited to children aged <18 years who met the ILI case definition, presented for care within 7 days of illness onset and were tested for PIV. Parainfluenza virus 4 detections were insufficient for analyses beyond overall proportions.
To identify PIV seasons, we calculated the weekly percent contribution or the percent of the entire surveillance year’s PIV positives that were detected each week. Onset of a season was defined as the first of 3 consecutive weeks with ≥2% of the specimens contributing to the total yearly detections; the conclusion of a season was defined as the last of 3 consecutive weeks with ≥2% contribution. At least 4 consecutive weeks of ≥2% contribution were required to be determined as a season.
The proportion of ILI patients who tested positive for each PIV type each week, or the weekly percent positive, was multiplied by the weekly count of ILI patients to extrapolate the number of PIV-associated ILI visits. Incidence estimates were then calculated per 100,000 children, using the weekly patient population size as the denominator. Incidence estimates for individual weeks were summed by surveillance year to generate the cumulative incidence for each year and age group. Bootstrapping methods were used to calculate 95% confidence intervals of PIV rates.9,10.
Differences in seasonality between PIV types were demonstrated by plotting the 3-week moving average of the extrapolated detection totals for each week for the 4 surveillance years; the 3-week moving average was centered on the week reported and was used to better visualize the seasonal trends of each PIV.
To evaluate the frequency of symptoms included in the ILI case definition (fever, cough and sore throat) across the parainfluenza virus types, we used a subset of IISP data collected among sites that systematically conducted surveillance for more broadly defined acute respiratory illness (ARI). Patients with ARI were defined as having at least 2 respiratory symptoms, including fever, cough, sore throat, nasal congestion and rhinorrhea. These patients were inclusive of ILI, and sites followed the same methodology as previously described for ILI surveillance. Data from the following sites participating in ARI surveillance was included: MN and WI from 2010 to 2014; Iowa from 2010 to 2013; New Jersey and New York City from 2010 to 2012; and Florida, Los Angeles County, North Dakota, UT and Virginia from 2010 to 2011. All other symptoms were evaluated using data from ILI surveillance conducted by all sites in all years.
Demographic characteristics and symptoms were compared between PIV-positive and PIV-negative cases and across PIV types using the χ2 test for association. A P value of <0.05 was considered statistically significant. Relative risk and 95% CIs for PIV detections by age group were calculated using the 5–17-year age group as the reference. Analyses were conducted using SAS Version 9.3 (SAS Institute Inc., Cary, NC).
From August 2010 to July 2014, a total of 114 HCPs participated in IISP, ranging from 30–74 per year. Participating HCPs were primary care clinics (90%), urgent care (9%) and student health (1%) facilities. The clinics were split between rural (27%), suburban (32%) and urban (41%) locations, and 57% of the HCPs were identified as private organizations. The distribution of ages in the surveillance population was similar to the US population; 25% of the population was pediatric compared with 24% in the United States, with the following age distribution: 2% <12 months (US 1%), 2% 12–24 months (US 1%), 4% 2–4 years (US 4%) and 16% 5–17 years (US 17%).
PIVs Within the IISP Population
Among 560,941 pediatric outpatient visits, 19,277 (3.4%) were reported as ILI. Specimens were collected from 7716 (40%) children and tested for PIV 1–3; the distribution of PIV 1–3 detections by type are shown in Table 1. Among 2552 (33%) children tested for all 4 PIV types, 229 (9.0%) tested positive for at least one PIV, including 62 (2.4%) PIV1, 57 (2.2%) PIV2, 98 (3.8%) PIV3 and 12 (0.5%) PIV4. The distribution of virus types among all detections was 27% PIV1, 25% PIV2, 43% PIV3 and 5% PIV4. At least one additional respiratory virus was detected in 19% of 619 children positive for PIV 1–3: most commonly, rhinovirus/enterovirus (49%), adenovirus (23%), coronavirus (18%) and influenza (11%). Parainfluenza virus co-detections were identified in 5 children (0.8%), including 1 PIV1/PIV2, 1 PIV3/PIV4, 1 PIV2/PIV3 and 2 PIV1/PIV3. Across all years, 63% of ILI patients negative for PIV 1–3 tested positive for at least one respiratory virus (data not shown).
Parainfluenza Virus Seasonality
During the 4 surveillance years, PIV1 and PIV2 were most frequently detected in the fall and winter (Fig. 1). The PIV1 season generally lasted from October to January, with onset occurring between August 28 and October 29 and offset between January 1 and March 17; the PIV2 season began between 16 September and 23 October, but demonstrated a wide offset range between November 27 and March 13 (Fig. 2). Detection of PIV1 was significantly increased in odd-numbered years compared with even-numbered years (relative risk 6.1, 95% CI: 4.4–8.6), with a peak percent positive of 29% in elevated seasons. Conversely, PIV2 detections were significantly higher in even-numbered years as compared with odd years (odds ratio 2.4, 95% CI: 1.6–3.6) with a peak between 14% and 22% positive. PIV3 demonstrated an annual spring with an onset between February 3 and April 13 and offset between April 21 and July 22 (Fig. 1), and peak percent positive between 17% and 33%. The percent of ILI patients with PIV3 detected was significantly lower in odd-numbered years compared with even-numbered years, when circulation of PIV1 was elevated (P < 0.05). During the 2012–2013 surveillance year, 2 time periods met PIV3 season criteria, including 14 weeks from September to December 2012 and 12 weeks from February to April 2013; detections occurring during January and February did not meet season criteria (Fig. 2). Circulation patterns of PIV1, 2 and 3 were evaluated by geographic region and found to be consistent across the United States.
Burden of PIVs by Surveillance Year
The incidence of parainfluenza virus-associated ILI visits varied significantly by surveillance year and virus type (see Table, Supplemental Digital Content 1, http://links.lww.com/INF/C419, which provides incidence of parainfluenza virus-associated ILI by surveillance year and age group). In 2010–2011, PIV3 predominated (110 per 100,000 children), while PIV1 predominated in 2011–2012 (89 per 100,000 children). The 2012–2013 surveillance year was characterized by dual-predominance of PIV2 and PIV3 (88 and 131 per 100,000 children, respectively), and in 2013–2014, PIV3 predominated (100 per 100,000 children). A particularly high burden of PIV was observed in 2012–2013, indicated by an incidence of PIV-associated visits of 251 per 100,000 children and age-specific incidence ranging from 367 to 1307 per 100,000 children.
Burden of PIVs by Age
Children with any PIV detection were significantly younger than PIV-negative children (median age 4.7 vs. 6.3 years, respectively; P < 0.05). Sixty-three percent of PIV 1–3 detections were in children aged <5 years, and age varied significantly between each of the PIV types. Parainfluenza virus 3 affected significantly younger children than PIV1 or PIV2 (median age = 3.3 years; P < 0.05), while PIV2 affected older children than the other PIV types (median age = 7.1 years; P < 0.05; Table 1).
Figure 3 demonstrates the variation in cumulative incidence of PIV types by age group and surveillance year. The burden of PIV3 tended to be highest among children aged 1 to <2 years in all years (range by season 222–868 per 100,000 children). During biennial years of elevated circulation, the incidence of PIV1- associated and PIV2-associated visits was greatest in children aged 2 to 4 years (388 and 273 per 100,000 children for PIV1 in 2011–2012 and 2013–2014; 193 and 412 per 100,000 children for PIV2 in 2010–2011 and 2012–2013). In general, PIV3 affected children aged <2 years more frequently than PIV1 or PIV2 with the exception of 2011–2012 when PIV1 overwhelmingly predominated (Fig. 3 and Table, Supplemental Digital Content 1, http://links.lww.com/INF/C419).
Comparative Symptomatology of PIVs
Among children presenting with more broadly defined ARI, 79% (282/355) of PIV-positive children met ILI case criteria, which did not vary significantly by PIV type or age group (see Table, Supplemental Digital Content 2, http://links.lww.com/INF/C420, which provides symptomatology of PIV-associated ILI and ARI). Children with ARI and any PIV detection were more likely to have cough (91%) and fever (80%) compared with PIV-negative ARI children (P < 0.05). PIV2 was detected more frequently among children with sore throat (71%) than were PIV1 (55%) or PIV3 (35%; P < 0.05). Among children presenting with ILI, myalgia and chills were reported significantly more frequently among PIV-negative ILI patients as compared with PIV-positive ILI patients (P < 0.05). Children with ILI and PIV3 were 1.7 times as likely to report rhinorrhea compared with those with PIV1 or PIV2 (95% CI: 1.4–2.0).
PIVs represented a substantial burden of respiratory illnesses among children in IISP, accounting for 9% of all ILI-related pediatric outpatient visits overall and up to 33% of visits at season peak. Consistent annual spring PIV3 and biennial fall PIV1 and PIV2 epidemics were observed across 4 years, yielding an ILI visit incidence range by season of 130–251 visits per 100,000 children. The incidence of PIV-associated visits was highest among children aged <5 years, and we also observed substantial variation by age for PIV types.
The IISP is a well-established respiratory virus surveillance network; however, this analysis was nevertheless subject to limitations. The IISP reflects ILI in the outpatient setting; thus, our analysis does not capture PIV patients with non-ILI presentation. However, we found that among a limited number of sites conducting surveillance including all ARI patients, 79% of the PIV-positive patients reported ILI symptoms within the 7 days before the clinical visit. As a more sensitive case definition, we expect that surveillance of ARI patients would have produced greater numbers of PIV cases than ILI surveillance; however because of decreased specificity, the percent positivity of PIV among ARI patients would be lower than among ILI patients. Surveillance for PIVs was reduced in the 2013–2014 surveillance year from 12 to 5 participating health departments, leading to decreased PIV detections for that year; although PIV data from 2013 to 2014 was consistent with previous surveillance years, the analysis may have been subject to bias related to decreased specimen collection and testing. Finally, although all sites used sensitive and specific reverse transcriptase–polymerase chain reaction assays for PIV detection, small differences between the assays may have resulted in minor differences in PIV detection.
We acknowledge the invaluable contributions of the many epidemiologists, laboratorians and health care providers involved in IISP, who have provided their expertise and continued dedication to the Influenza Incidence Surveillance Project.
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Keywords:Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
parainfluenza virus; population-based; surveillance; epidemiology; children