Seasonality and clinical impact of human parainfluenza viruses

Background Widespread availability of rapid diagnostic testing for respiratory viruses allows more in‐depth studies of human parainfluenza viruses (HPIV). Objectives This study aimed to assess seasonality of HPIV types 1‐4, clinical outcomes by HPIV type, and risk factors for illness severity. Patients/Methods This retrospective study was performed from January 2013 to December 2015 in children and adults with HPIV, detected by multiplex reverse transcription polymerase chain reaction, participating in a community surveillance study of acute respiratory infections (ARIs) in New York City and patients admitted to a tertiary care center in the same neighborhood. Seasonality trends by HPIV type were compared between the community and hospital groups. The associations between HPIV type, demographics, clinical characteristics, and illness severity were assessed. Results HPIV was detected in 69 (4%) of 1753 community surveillance participants (median age 9.2 years) and 680 hospitalized patients (median age 6.8 years). Seasonality for HPIV types 1‐3 agreed with previously described patterns; HPIV‐4 occurred annually in late summer and fall. In the community cohort, 22 (32%) participants sought medical care, 9 (13%) reported antibiotic use, and 20 (29%) reported ≥1 day of missed work or school. Among hospitalized patients, 24% had ≥4 chronic conditions. Multivariable ordinal logistic regression demonstrated that increased severity of illness was significantly associated with HPIV‐4 and chronic cardiovascular and respiratory conditions in children and with age ≥65 years and chronic respiratory conditions in adults. Conclusions HPIV‐4 presented late summer and early fall annually and was associated with increased severity of illness in hospitalized children.


| INTRODUC TI ON
Human parainfluenza viruses (HPIV) types 1-4 are common respiratory pathogens that cause both upper and lower respiratory tract illnesses, especially in young children. 1 HPIV-1 and HPIV-2 are more common in children and more often associated with croup. 1 HPIV-3 is more frequently associated with bronchiolitis, bronchitis, and pneumonia. HPIV-4, while least well-characterized, has been described as associated with both mild illness in children and lower respiratory tract disease. 2 HPIV types have varying seasonality, prevalence, and clinical manifestations. In the United States, HPIV-1 usually occurs in the fall of odd numbered years, HPIV-2 occurs every fall, and HPIV-3 occurs in spring and summer. 1, 3 The seasonality of HPIV-4 has not been as well defined, often due to its low prevalence. 4 A recent study conducted in Colorado found a year-round prevalence of HPIV-4 with peaks in the fall of odd numbered years. 5 However, estimates of HPIV-4 prevalence are increasing, potentially due to improved and increased diagnostic testing, but few recent studies have assessed this. 6,7 Widespread availability of multiplex reverse transcription polymerase chain reaction (RT-PCR) assays allows for more in-depth studies of the epidemiology and impact of HPIV types. The population of this study included both a community-based cohort and hospitalized children and adults with laboratory-detected HPIV. The inclusion of the community cohort allowed for a broader evaluation of the impact of HPIV than has been previously assessed. The study's objectives were to (a) assess the seasonality of HPIV types 1-4, (b) determine clinical outcomes by HPIV type, and (c) identify risk factors for increased severity of illness.

| Study design, site, and subjects
A retrospective study of participants in a community surveillance cohort and hospitalized patients with HPIV types 1-4 detected from January 1, 2013 to December 31, 2015 was performed. The community cohort was derived from the Mobile Surveillance for Acute Respiratory Infections (ARIs) and Influenza-like Illness (ILI) in the Community (MoSAIC) study, a 5-year community-based surveillance ordinal logistic regression demonstrated that increased severity of illness was significantly associated with HPIV-4 and chronic cardiovascular and respiratory conditions in children and with age ≥65 years and chronic respiratory conditions in adults.
Conclusions: HPIV-4 presented late summer and early fall annually and was associated with increased severity of illness in hospitalized children.

K E Y W O R D S
epidemiology, parainfluenza, respiratory, seasonality, viruses F I G U R E 1 Flowcharts depicting the overall number of respiratory viral panel (RVP) tests ordered which yielded the final number of human parainfluenza virus (HPIV) types in the community cohort (1A) and in hospitalized patients (1B) study in New York City (NYC) that includes 250 households annually. 8,9 Households were identified by contacting a random sample of participants who had taken part in a large population-based survey of an urban, primarily immigrant Latino community. For this   study, eligible households had 3 or more members with at least 1   member under 18 years of age, were Spanish-or English-speaking, and had a cellular telephone with text messaging. 8 Text messages were sent twice weekly inquiring about possible respiratory illness among household members. Nasal swabs were collected from ill participants by research staff if at least two of the following were reported to be present: fever/feverishness, runny nose/congestion, sore throat, cough, and/or myalgia. For infants, either runny nose or congestion prompted collection of a swab.
Hospitalized adults and children with laboratory-detected HPIV admitted to a university-affiliated medical center in NYC located in the same neighborhood as the community cohort were included. Testing was requested by treating clinicians, and as per the standard of care, is generally recommended for all hospitalizations to evaluate acute respiratory symptoms and guide transmission precautions. Patients hospitalized within 2 calendar-days of HPIV detection were included.
Those with HPIV detected >2 days before admission, >2 days after admission and those with a second positive test for the same HPIV type within 4 weeks of the first positive test were excluded.

| Diagnostic testing
Nasopharyngeal swabs for both the community cohort and the hospitalized patients were tested for respiratory pathogens using multiplex RT-PCR (BioFire Diagnostics, Inc. Salt Lake City, Utah) which has been reported to have 91%-100% sensitivity and 98%-100%  10,11 Swabs from the community were tested in a research laboratory at Columbia University Medical Center (CUMC). Swabs from hospitalized patients were tested in the clinical microbiology laboratory at NewYork-Presbyterian Hospital at CUMC. Blood, urine, and respiratory tract cultures for bacteria were sent by treating clinicians as per the standard of care for suspected infections and also processed by the clinical microbiology laboratory.

| Data collection
For the community cohort, days of missed school or work; medical care in primary care clinics, urgent care, or emergency departments; hospitalizations; and use of antibiotics were collected by follow-up calls at least 15 days after the resolution of respiratory illness.
For hospitalized patients, demographic and clinical characteristics were obtained from electronic medical records (EMR).
Primary ICD-9 diagnoses were categorized as respiratory or nonrespiratory. Patients' primary and secondary diagnoses were categorized into groups of chronic conditions previously described as risk factors for severe respiratory disease in adults and children with respiratory viruses. [12][13][14] Conditions were excluded if they could not be classified within a chronic condition category, had <15 occurrences across all patients, or have not been associated with severe respiratory disease, for example bipolar disorder. Manual chart review of readmitted patients was performed to determine whether readmissions within 4 weeks were due to respiratory illness.
Hospital course and healthcare utilization data were obtained from the EMR including radiographs within 2 days of HPIV detection; all antibiotics within 2 days prior to or 7 days after HPIV detection; ICU admission and 30-day mortality. Respiratory support including use of continuous positive airway pressure (CPAP), mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) was determined by billed procedure codes. Use of bilevel positive airway pressure (BiPAP) or oxygen supplementation was not assessed, as accurate usage data were unavailable in structured electronic sources.
TA B L E 1 Comparison of demographic characteristics, symptoms, and outcomes of participants in a community cohort, by human parainfluenza viruses (HPIV) type

| Analysis
To assess seasonality, epidemiologic curves that modeled the detection of each HPIV type in the community cohort versus hospitalized patients were created. Demographic and clinical characteristics of the two groups were analyzed as proportions, means, and/or medians; associations between HPIV type and clinical course were examined using chi-square, Fisher's exact, and ANOVA tests, as appropriate.
TA B L E 2 Comparison of demographic and clinical characteristics of hospitalized patients with different human parainfluenza viruses (HPIV)

| Subjects
In the community cohort, 1805 swabs were obtained, of which 69 (4%) of 1753 participants were positive for at least one HPIV type ( Figure 1A). The 69 HPIV-positive swabs were from 59 households;

| Hospital course and co-infections
The mean length of hospitalization was 5.3 (SD ± 8.4) days and varied by HPIV type (   were associated with higher odds of increased severity of illness.

| Severity of illness in hospitalized patients
Among the 290 adults, 12 (4%) had severe, 41 (14%) had moderate, and 237 (82%) had mild illness (Table 5). In the final adjusted model for adults, age ≥65 years and respiratory conditions were associated with higher odds of increased severity of illness.

| D ISCUSS I ON
We had a unique opportunity to compare the epidemiology and clinical impact of HPIV types among individuals in a communitybased surveillance study and among hospitalized patients during the same time and in the same geographic area. The seasonality of HPIV types 1-3 was consistent with published trends, 1,3 but we found that HPIV-4 occurred annually in late summer and fall, suggestive of a local epidemiologic trend that has not been previously described. We found that HPIV-3 was most common among hospitalized patients (52%) while HPIV-4 was most common in the community cohort (36% We modified a previously validated severity of illness score to further explore the predictors of illness severity. In children, increased severity of illness was associated with respiratory conditions, cardiovascular conditions and HPIV-4 while in adults, increased severity of illness was associated with age ≥65 years and cardiovascular conditions. The association of comorbid conditions and severe illness in those with HPIV is consistent with other respiratory viruses, most notably RSV and influenza, which both can exacerbate underlying cardiac and pulmonary conditions. [12][13][14]21,22 This may also explain why 21% of hospitalized patients had a nonrespiratory primary diagnosis.
The rate of co-detection was similar across HPIV strains and as others have shown, viral co-detections did not impact severity of disease. 23 However, due to limited sample size, we could not assess the impact of specific co-infections. While only 17% of HPIV-positive patients had a positive bacterial culture, 73% received at least one dose of an antibiotic between 2 days before and 7 days after HPIV detection. Thus, most antibiotic usage represented empiric therapy, suggesting an opportunity for antibiotic stewardship.
This study had limitations. The community cohort was 100% Hispanic/Latino, reducing the study's generalizability, and small, limiting our ability to find differences in severity of illness or symptomatology associated with HPIV types. Our hospital is a referral center and cares for many patients with underlying conditions. Furthermore, its referral status could impact accurate interpretation of "local" epidemiology as only 32% of the hospitalized patients lived in the same zip codes as the MoSAIC study participants (M. Stockwell, personal communication).
Testing of hospitalized patients relied on clinicians' judgement.
We did not review radiographic findings or capture BiPAP use which may have biased assessment of severity of illness. The severity of illness score was developed for children and not previously tested in adults. Use of administrative data restricted our ability to assess patients' symptomatology. Although most patients had a respiratory diagnosis, we may have misclassified HPIV infections that actually represented prolonged HPIV shedding from previous illnesses. We did not classify positive bacterial cultures as consistent with infection vs. colonization vs. contamination.

| CON CLUS IONS
In this study, each HPIV type demonstrated seasonality, but each was similar in the community and among hospitalized patients.
We found that HPIV-4 had distinct epidemiology, not previously described, and was associated with increased severity of illness in hospitalized children. As demonstrated for other respiratory viruses, older age and underlying conditions, particularly respiratory and cardiac conditions, were associated with increased severity of illness. Additional studies exploring HPIV incidence and severity in both children and adults could help reinforce the need for vaccine development.

ACK N OWLED G EM ENT
The authors thank Alexandra Hill-Ricciuti for analytic assistance.