key: cord-1013822-5u9wd7ks
authors: Emanuels, Anne; Heimonen, Jessica; O’Hanlon, Jessica; Kim, Ashley E; Wilcox, Naomi; McCulloch, Denise J; Brandstetter, Elisabeth; Wolf, Caitlin R; Logue, Jennifer K; Han, Peter D; Pfau, Brian; Newman, Kira L; Hughes, James P; Jackson, Michael L; Uyeki, Timothy M; Boeckh, Michael; Starita, Lea M; Nickerson, Deborah A; Bedford, Trevor; Englund, Janet A; Chu, Helen Y
title: Remote Household Observation for Non-influenza Respiratory Viral Illness
date: 2020-11-17
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa1719
sha: f1e219496505cfe37ec209fddd57ae9218556a86
doc_id: 1013822
cord_uid: 5u9wd7ks

BACKGROUND: Non-influenza respiratory viruses are responsible for a substantial burden of disease in the United States. Household transmission is thought to contribute significantly to subsequent transmission through the broader community. In the context of the COVID-19 pandemic, contactless surveillance methods are of particular importance. METHODS: From November 2019 to April 2020, 303 households in the Seattle area were remotely monitored in a prospective longitudinal study for symptoms of respiratory viral illness. Enrolled participants reported weekly symptoms and submitted respiratory samples by mail in the event of an acute respiratory illness (ARI). Specimens were tested for fourteen viruses, including SARS-CoV-2, using RT-PCR. Participants completed all study procedures at home without physical contact with research staff. RESULTS: In total, 1171 unique participants in 303 households were monitored for ARI. Of participating households, 128 (42%) included a child aged <5 years and 202 (67%) included a child aged 5-12 years. Of the 678 swabs collected during the surveillance period, 237 (35%) tested positive for one or more non-influenza respiratory viruses. Rhinovirus, common human coronaviruses, and respiratory syncytial virus were the most common. Four cases of SARS-CoV-2 were detected in three households. CONCLUSIONS: This study highlights the circulation of respiratory viruses within households during the winter months during the emergence of the SARS-CoV-2 pandemic. Contactless methods of recruitment, enrollment and sample collection were utilized throughout this study, and demonstrate the feasibility of home-based, remote monitoring for respiratory infections.

A c c e p t e d M a n u s c r i p t 3

Respiratory viruses cause notable rates of morbidity and mortality in the United States, especially among young children, the elderly, or the immunocompromised. 1 Respiratory syncytial virus (RSV), parainfluenza viruses (PIV), human metapneumovirus (hMPV), human rhinovirus (hRV), human coronavirus (hCoV), and adenovirus (AdV) often co-circulate with influenza viruses in the winter months and can cause acute respiratory illness (ARI) and lower respiratory tract infections (LRTI). [1] [2] [3] Globally, LRTIs are estimated to cause 2.3 million deaths annually. 3 In the United States, an estimated 500 million non-influenza viral respiratory infections occur annually. 1 However, most ARI surveillance is based on reports of outpatient visits, emergency department visits, or hospitalizations, which may underestimate disease incidence. [4] [5] [6] Prospective household cohort studies are useful to study incidence of illness in the community across a range of age groups and identify chains of transmission between household contacts. 7, 10 Households are an important setting for the spread of respiratory viruses between individuals and may play a role in community transmission. [7] [8] [9] [10] [11] Household study platforms can be expanded to study SARS-CoV-2 spread, based on preliminary data showing viral transmission among household contacts . 12, 13 Contactless surveillance methods are of particular interest in context of the COVID-19 pandemic.

Using online contactless recruitment, enrollment, and surveillance, we conducted a longitudinal prospective cohort study of ARI in households of three or more individuals with at least one child from November 2019 to April 2020. The aims are to describe household-level risk factors for respiratory viral infections, estimate incidence of primary and secondary infections for non-influenza viral pathogens in households, and examine the association A c c e p t e d M a n u s c r i p t 4 between upper respiratory virus levels in primary cases and incidence of secondary infections in household contacts.

A prospective longitudinal cohort study of children and their households was implemented in the Seattle metropolitan area from November 2019 to April 2020 as a part of the Seattle Flu Study. 14 Households were recruited at the beginning of the school year and remotely monitored weekly from November 14, 2019, until April 1, 2020, for symptoms of respiratory illness. Recruitment took place at elementary and middle schools beginning in September, and households continued to participate after the school district's closure on March 11, 2020. Participating schools advertised the study to families through social media, newsletters, posters on campus, and after-school events. Eligible households consisted of three or more individuals sleeping in the home for ≥4 days per week, with at least one adult English-speaker and one child aged three months through 17 years. Individuals in enrolled households were permitted to opt-out of participation if the remaining household members met eligibility criteria. Interested households completed an online screening questionnaire before informed consent took place over the phone between at least one adult household member and a research team member.

Other adults and children in the household were then prompted to review and complete their documentation of consent through a web-based platform. Children aged 7-17 years provided electronic assent alongside a parent or guardian's consent.

This study was approved by the University of Washington Institutional Review Board.

Upon completion of the informed consent process, households answered demographic questions in an online questionnaire before receiving mid-turbinate nasal swabs (Copan A c c e p t e d M a n u s c r i p t 5 Diagnostics, Murietta, CA), collection tubes with universal transport media (BD, Franklin Lakes, NJ), instructions, and returned shipping materials in the mail. One adult was designated as the household reporter and contacted weekly by text message and/or email to complete a symptom log each week on behalf of all household participants. Additions to households during the study were identified through monthly questionnaires and were invited to enroll and participate in the study. The study procedures did not require any physical contact between participants and researchers.

The study population included a subset of households enrolled in an interventional study focused on home-based diagnosis and treatment of influenza; detailed methods for the intervention study are registered with ClinicalTrials.gov (Trial no. NCT04141930). This analysis includes observational data on the non-influenza respiratory viruses detected in all households.

Data on influenza viruses in households will be reported separately.

After consent and enrollment, each participant was asked to collect a mid-turbinate nasal swab in the event of an acute respiratory illness (ARI) reported in the weekly symptom log as early as possible and within 72 hours of illness onset. Samples collected beyond 72 hours after illness onset were excluded from analysis. For children aged <13 years, a parent or guardian was advised to assist with swab collection and shipping. Home-collected nasal swabs were mailed at ambient-temperature to the Northwest Genomics Center at the University of Washington via USPS following standard IATA shipping procedures, with a median shipping time of two days. If a participant experienced ARI, defined as either a) acute cough, or b) two or more concurrent symptoms (see Appendix A for a complete list of qualifying symptoms) with symptom onset within 72 hours, or 48 hours in the interventional subset, the household reporter A c c e p t e d M a n u s c r i p t 6 was prompted to fill out a clinical illness questionnaire. One week following specimen collection, participants were sent a follow-up questionnaire to collect information about illness progression and its effects on healthcare seeking behavior, school/work attendance, and travel. If a participant experienced multiple illness episodes during the study period, these procedures were repeated. Reminders to complete questionnaires and collect swabs when prompted were delivered by automated messages and by personalized emails and phone calls from the study team. Study data were collected remotely via online questionnaires and entered and managed 

To assess household-level risk factors for respiratory viral infection, demographic characteristics of participating households were compared using Chi-Squared tests or two-sided t-tests assuming independent variances between those with and without at least one positive test result for a respiratory viral infection. P-values of <0.05 were considered statistically significant. We restricted this analysis to households submitting at least one weekly symptom A c c e p t e d M a n u s c r i p t 7 log prior to April 1, 2020. Participants were required to experience at least seven days without symptoms before being eligible to record another illness episode and submit another specimen.

A primary case was defined as an ARI episode with a respiratory virus detected preceded by 14 days without the same virus identified in the household. Cases that occurred in one household with the same day of symptom onset were defined as co-primary. Pathogens analyzed included RSV subtypes A and B, PIV types 1-4, hMPV, hRV, coronavirus (hCoV -HKU1, NL63, 229E and OC43), AdV, human bocavirus (hBoV), and SARS-CoV-2. SARS-CoV-2 testing was added February 25, 2020, including testing of samples collected after January 1, 2020. The person-time at risk was defined as the total number of surveillance weeks multiplied by the number of people in the household. Surveillance was defined as the period between each household's first symptom log and either April 1st or date of their final symptom log. A secondary case was defined as identification of a virus preceded by an illness in a household member with the same virus within 14 days. Person-time at risk for each secondary case was defined as the fourteen days following illness onset for the primary case. Incidence rates were calculated with Poisson models, with an offset of log days at risk. Confidence intervals were based on a robust variance adjusted for clustering by household.

Upper respiratory viral levels were evaluated using C rt values from RT-PCR testing. Viral levels were compared between primary cases with and without an associated secondary case. (Figure 3 ).

The highest primary incidence rates in this cohort were found with hRV (21.7 primary cases per 100 person-years) and hCoV (19.6 primary cases per 100 person-years; Table 3 ). This design permitted detection of symptomatic respiratory viral infection without direct contact between participants and researchers. Online enrollment, symptom monitoring via email or text messaging, home-collected swabs, and electronic illness questionnaires allowed this study to be conducted with minimal inconvenience and risk of exposure to participating households. Households could receive weekly symptom log reminders via email or text messages, which previous research has shown to be an effective mechanism for rapid, homebased detection of ARI. 9 Social distancing has become a necessary component of further research on SARS-CoV-2 transmission, and this remote study design provides a safe mechanism for investigation.

A c c e p t e d M a n u s c r i p t

The presence of children under 5 years old was a predictor of non-influenza virus detection in a household. 18, 19 Over half of households with at least one confirmed infection had a child aged <5 years, compared to only 26% of those without a non-influenza viral infection (p < 0.001). However, the presence of a child aged 13-17 years old was negatively correlated with infection, with 33% of households without viral infection containing a child in this age range compared to 14% of households with at least one infection. Families with adolescent children may be less likely to also include a younger child. A higher proportion of households with an infection than those without infection included adults aged 18-49 years, while more households with adults aged 50-64 years had no cases of viral infection. This may be due to younger adults being more likely to have children under 5 years of age.

A majority of recorded illness episodes were not medically attended, confirming another cohort study where only 17% of influenza cases were medically attended. 20 Non-influenza viruses were responsible for 34% of illness samples, and only 12% of these cases were medically attended. hRV and hCoV cases alone accounted for a majority of positive swabs.

These findings align with other prospective cohort studies in children and adults, where hRV and hCoV were detected at greater frequency in the community than in hospital-based ARI studies. [21] [22] [23] Additionally, these results show a majority of coinfection cases and AdV cases occurring in children younger than five years, a majority of PIV cases in children 5-17 years, and the remaining organisms predominating in adults 18-64 years old, although sample sizes are small after stratifying by virus type and age group. Overall, children under 5 years had the highest percent positivity rate (70%). These findings are comparable to previous household studies conducted in the United States. 10, 24 The relative thresholds (C rt values) of primary cases did not differ significantly between the primary cases that were and were not associated with a secondary infection. Possible explanations for this finding include that C rt values may not be a direct quantitative measure of A c c e p t e d M a n u s c r i p t 12 viral load. Additionally, due to the 72-hour window of eligibility to collect swabs and variation in home-swab collection among individuals, specimen collections likely varied among samples included in this analysis. Finally, given the broad time frame under which a case may be considered a secondary case, it is possible that some secondary cases became infected from sources outside of the household.

There are several limitations to this study. First, participants were instructed to selfcollect a nasal swab in the event of an acute respiratory illness. While this approach allows for more complete capture of respiratory pathogens with limited inconvenience to participants, it allows for some uncertainty in validity of the reported symptoms, as well as uncertainty due to potential inconsistency of at-home specimen collection. Additionally, this approach did not capture asymptomatic cases during the surveillance period and may have resulted in an underestimation of the incidence of the viruses analyzed. The rarity of smokers and high rates of influenza immunization, the exclusion of non-English speakers, the low enrollment of individuals older than 65 years, and the number of households with an annual income greater than $150,000 indicate that this study population may not be representative of the Seattle area. 25, 26 Another limitation is absence of clinical data for some cases of illness. Households occasionally mailed a swab to the laboratory without filling out the corresponding illness questionnaire (n=74). While these events were infrequent, they unfortunately included all four of the SARS-CoV-2 cases detected in this population, so our ability to describe these cases is limited. In our statistical analysis, we included weeks between first and last symptom log for each household within the study period to be time at risk. This includes time in which no symptom logs were submitted, potentially lowering the primary incidence rates. Finally, the study includes time before and after the COVID-19 pandemic, and illness reporting and careseeking behavior likely changed over the study period. A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 3 Figure 3 

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