key: cord-0269722-u6l8ox4z authors: Heimonen, J. T.; McCulloch, D. J.; O'Hanlon, J.; Kim, A. E.; Emanuels, A.; Wilcox, N.; Brandstetter, E.; Stewart, M.; McCune, D.; Fry, S.; Parsons, S.; Hughes, J. P.; Jackson, M. L.; Uyeki, T. M.; Boeckh, M.; Starita, L. M.; Bedford, T.; Englund, J. A.; Chu, H. Y. title: A Remote Household-Based Approach to Influenza Self-Testing and Antiviral Treatment date: 2021-02-03 journal: nan DOI: 10.1101/2021.02.01.21250973 sha: 7c4143891e27ff4b29c54cde7e8bdc83bed64577 doc_id: 269722 cord_uid: u6l8ox4z Background: Households represent important settings for transmission of influenza and other respiratory viruses. Current influenza diagnosis and treatment relies upon patient visits to healthcare facilities, which may lead to under-diagnosis and treatment delays. This study aimed to assess the feasibility of an at-home approach to influenza diagnosis and treatment via home testing, telehealth care, and rapid antiviral home delivery. Methods: We conducted a pilot interventional study of remote influenza diagnosis and treatment in Seattle-area households with children during the 2019-2020 influenza season using pre-positioned nasal swabs and home influenza tests. Home monitoring for respiratory symptoms occurred weekly; if symptoms were reported within 48 hours of onset, participants collected mid-nasal swabs and used a rapid home-based influenza immunoassay. An additional home-collected swab was returned to a laboratory for confirmatory influenza RT-PCR testing. Baloxavir antiviral treatment was prescribed and delivered to symptomatic and age-eligible participants, following a telehealth encounter. Results: 124 households comprising 481 individuals self-monitored for respiratory symptoms, with 58 home tests administered. 12 home tests were positive for influenza, of which 8 were true positives confirmed by RT-PCR. The sensitivity and specificity of the home influenza test was 72.7% and 96.2%, respectively. There were 8 home deliveries of baloxavir, with 7 (87.5%) occurring within 3 hours of prescription, and all within 48 hours of symptom onset. Conclusions: We demonstrate the feasibility of self-testing combined with rapid home delivery of influenza antiviral treatment. This approach may be an important control strategy for influenza epidemics and pandemics. In the United States, influenza is typically diagnosed during an in-person healthcare visit and if antiviral treatment is prescribed, a subsequent visit to a pharmacy is required. This multi-step process may lead to delays in receipt of antivirals and potentially exposes other individuals in clinics and pharmacies to influenza. Since antiviral therapy is most effective when started within 48 hours of symptom onset, reducing delays to treatment initiation may improve outcomes in treated persons. [1] [2] [3] Baloxavir is an oral FDA-approved antiviral for early treatment of uncomplicated influenza in individuals aged 12 years and older. The long half-life of baloxavir allows a single treatment dose in contrast to five twice-daily doses of oseltamivir. Moreover, baloxavir treatment is associated with shorter duration of influenza virus detection compared with oseltamivir or placebo. 4 Households, particularly those with young children, play a key role in seasonal influenza epidemics because the frequency and intensity of contacts among household members are greater than in the broader community. 5 Prior studies have shown that young children are important contributors to the introduction and transmission of influenza in households. 6, 7 Therefore, households represent an important setting to study influenza intervention strategies. Home-based influenza testing and rapid treatment with home-delivered antivirals have not been evaluated in clinical trials. Home diagnosis of respiratory infections via self-testing or telemedicine services has the potential for widespread use, particularly during a pandemic where periods of social distancing and restricted movement occur. Similarly, home-based initiation of antiviral therapy may decrease time from symptom onset to initiation of therapy and could improve outcomes compared with current management practices. Advances in telemedicine services (telehealth), rapid delivery services, and the ongoing development of home-based influenza assays may make this a feasible strategy to employ. Here we report the results of a pilot study examining the feasibility of a test-and-treat method for influenza in All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 3, 2021. ; https://doi.org/10.1101/2021.02.01.21250973 doi: medRxiv preprint households with children, including the use of home influenza testing, telehealth, and rapid antiviral delivery. We conducted a prospective interventional study to assess the feasibility of a home-based approach to diagnosis and treatment of influenza in households with children. This study was conducted in the Seattle metropolitan area as part of the Seattle Flu Study. 8 The recruitment process and eligibility criteria were previously described. 9 Briefly, households of ≥ 3 individuals sleeping in the home for ≥ 4 days per week, with at least one child aged three months to 17 years, and containing ≥ 2 baloxavir age-eligible individuals, were eligible to participate. Recruitment was conducted via web-based advertisements and social media. Households were consented, and all data were captured using a remote, electronic platform in Project REDCap (Research Electronic Data Capture). 10 All informed consent conferences took place via phone, with written consent by household members. At enrollment, one household member was designated the lead contact and provided demographic and baseline health information about all household members. All enrolled households were asked to complete a weekly survey regarding the presence or absence of acute respiratory infection (ARI) symptoms. ARI was defined as new or worsening acute cough and stored at 4°C prior to testing. Samples were extracted (Magnapure 96, Roche, Basel, CH) and tested for respiratory pathogens, including influenza virus types and influenza A subtypes, by TaqMan RT-PCR (Thermofisher, Waltham, MA) on a QuantStudio 12 (Applied Biosystems, Foster City, CA) ( Table 2A) . Positive and negative controls were included in each extraction and RT-PCR run. All samples were tested for Rnase P, a human cellular marker, and Rnase P relative cycle threshold (Crt) values were used to evaluate sample quality. Analyses were restricted to enrolled households that completed at least one symptom log prior to February 7, 2020. The illness results presented here are confined to specimens that were collected and received in the laboratory by February 7, 2020. Participant-level demographic information is reported by RT-PCR-confirmed influenza status. Chronic respiratory disease was defined as a history of asthma or reactive airway disease, COPD or emphysema, or chronic bronchitis. Other chronic diseases such as diabetes, heart failure, or cancer were defined as non-respiratory chronic disease. Participant-reported home influenza test usability, hypothetical behavioral changes when ill with and without the use of the home influenza test, as well as the sensitivity, specificity, and Cohen's kappa coefficient (κ) were calculated; concordance measures compared the influenza home test with the TaqMan assay, where the TaqMan assay represented the gold standard. A p-value <0.05 was considered statistically significant. All analyses were conducted using SAS software version 9.4. 7 conditions ( Table 1) . Most individuals were insured, and 79.4% reported receiving the seasonal influenza vaccine. The study population predominately consisted of white individuals aged 18 to 49 years (44.7%) or 5 to 17 years (37.4%). Among participants experiencing respiratory symptoms, 58 influenza home tests were used during the test-and-treat phase of the study, yielding 12 positive results. Home influenza test results were compared with RT-PCR results from the confirmatory nasal swabs ( Table 2) . Measures of agreement of the home influenza test were similar for influenza A and influenza B, though measures of agreement were higher for influenza A than influenza B: 75.0% sensitivity and 100% specificity for influenza A, 71.4% sensitivity and 92.2% specificity for influenza B. Likewise, Cohen's kappa was higher for influenza A (κ = 0.848) compared with influenza B (κ = 0.566). Notably, the majority of false positives were influenza B, while the percent of false negatives were similar for influenza A (25%) and influenza B (28.5%). The overall sensitivity of the home influenza test was 72.7% and the specificity was 96.2%, suggesting home test performance was concordant with RT-PCR (κ = 0.633). Among 47 participants who used the home influenza test and completed the follow-up questionnaire, 93.6% reported that experiencing respiratory symptoms and a positive result would lead to minimizing contact with others while 89.4% reported that experiencing respiratory symptoms and a positive result would lead to missing work or school ( Table 3 ). In contrast, 78.7% reported they would minimize contact with others if experiencing respiratory symptoms but no home test result or diagnosis was available, while 59.6% reported they would miss work or school if experiencing respiratory symptoms but no home test result or diagnosis was available. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. There were 58 nasal swabs collected concurrently with the home influenza test at the time of illness. These were returned to the laboratory for RT-PCR, and yielded 11 (19.0%) influenzapositive cases from 11 individuals (7 influenza B and 4 influenza A) ( Figure 1B) . Among influenza cases, 4 were baloxavir-ineligible due to age or medical history and 7 were eligible, but 3 of these 7 baloxavir-eligible influenza cases were not treated. Two of these 3 (66.7%) individuals had false negative results by home influenza test compared with RT-PCR, and 1 (33.3%) opted not to pursue telehealth care. Likewise, 4 influenza-negative individuals received antiviral baloxavir treatment; all of these individuals had false positive home test results compared with RT-PCR. Overall, there were 4 RT-PCR-confirmed influenza-positive and 4 RT-PCR-confirmed influenza-negative individuals who received baloxavir. To our knowledge, this is the first report of a remote, household-based approach to influenza diagnosis and treatment in which no face-to-face contact with a healthcare provider or pharmacist was required. In this pilot study, participants successfully self-monitored for the onset of respiratory symptoms, self-conducted a rapid home influenza test, remotely discussed their illness with a healthcare provider, and received prompt delivery of a prescribed antiviral medication when indicated. Participants were adherent to study procedures, with 124 (82.6%) of households participating in weekly respiratory surveillance and 58 successfully completing home influenza All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 3, 2021. ; https://doi.org/10.1101/2021.02.01.21250973 doi: medRxiv preprint tests. The vast majority of participants reported that the home influenza test and app were easy to use and that the results were easy to understand. The results of rapid home influenza testing were largely concordant with RT-PCR. Concordance was higher for influenza A than influenza B. Notably, the test-and-treat strategy encompassed only a part of the 2019-2020 influenza season. In particular, cases of influenza B predominantly occurred prior to influenza A cases, which is unusual but consistent with other results published for the 2019-2020 influenza season. 14 Thus, the measures of concordance for influenza B may be skewed due to the timeline of when the test-and-treat strategy started. Home influenza test results may have assisted telehealth providers in making an accurate influenza diagnosis. Previous studies have demonstrated that influenza diagnosis based on a provider review of symptoms has low sensitivity; 15,16 adding a sensitive home-based test has the potential to significantly improve influenza diagnostic accuracy. A small number of influenza-positive participants received baloxavir, yet our results suggest a home-delivery approach is feasible, particularly because all 8 individuals received drug within 48 hours of symptom onset, and 87.5% of home-deliveries arrived within 3 hours from the time of prescription. Four influenza-negative individuals received baloxavir therapy, although no adverse effects were observed and no major differences were seen among baloxavir treated and untreated groups. Our remote approach to home testing and treatment of influenza may be an important future control strategy, particularly during a severe epidemic or pandemic, 17 and even with noninfluenza viruses, such as SARS-CoV-2. Current reports suggest a version of this strategy may be operational for the 2020-2021 influenza season. 18 The potential public health importance of a home-based test and treat strategy is supported by the large percentage of participants who reported that a positive influenza test result would influence their behavior, such as limiting contact with others or not attending work or school while sick, compared with the reported lack of behavioral change from experiencing respiratory symptoms without any test result or All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 3, 2021. ; https://doi.org/10.1101/2021.02.01.21250973 doi: medRxiv preprint diagnosis. Moreover, the majority of our participants received baloxavir antiviral treatment within 30 hours of symptom onset. While baloxavir confers the greatest clinical benefit when initiated within 24 hours 4 , our findings suggest that rapid antiviral-home delivery is feasible and that a remote approach to influenza diagnosis and treatment can decrease the time from symptom onset to initiation of antiviral therapy. There are several limitations to this study. First, the results of this pilot study encompassed only part of one influenza season, and thus did not capture the peak of local influenza A virus transmission, leading to a small sample size for that pathogen. Data were based on selfcollection and self-report, which may be subjective particularly for variables such as symptoms or illness duration. Furthermore, despite good compliance with study procedures, there were a few instances of participants collecting nasal swabs without providing clinical information. Additionally, these results were derived from a largely homogeneous volunteer study population of highly educated, middle to upper-class, white households, and may limit the generalizability of the results. The results presented here are also limited by the antiviral therapy being prescribed to a small number of households in a regulated, well-resourced study environment. Further studies are needed to assess the feasibility of this home-based influenza test and rapid home antiviral delivery strategy in larger or more remote populations. The moderate sensitivity of the rapid home influenza test coupled with successful antiviral home-delivery suggest that the implementation of intervention or control strategies in households with children could be feasible and may be particularly useful when circumstances dictate restricted movement or social distancing. Further studies on this topic would help understand the usefulness of these strategies in more remote or diverse populations. While the strategy for early diagnosis and treatment of influenza was studied, it has the potential to be applied to other respiratory viruses that cause epidemics and pandemics as home-based diagnostic and treatment options become available. The Seattle Flu Study is funded by Gates Ventures. The funder was not involved in the design of the study, does not have any ownership over the management and conduct of the study, the data, or the rights to publish. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. T a b l e 1 . P a r t i c i p a n t d e m o g r a p h i c s c h a r a c t e r i s t i c s f r o m e n r o l l e d h o u s e h o l d s b y R T -P C R c o n f i r m e d i n f l u e n z a s t a t u s b a s e d o n i n f l u e n z a c a s e s d e t e c t e d d u r i n g t h e T e s t -a n d -T r e All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. T a b l e 2 . H o m e i n f l u e n z a t e s t r e s u l t s i n c o m p a r i s o n t o R T -P C R -c o n f i r m e d i n f l u e n z a t e s t r e s u l t s P a r t A . 2 x 2 T a b l e o f E l l u m e T e s t c o m p a r e d t o T a q M a n A s s a y f o r I n f l u e n z a A R T -P C R -c o n f i r m e All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. T a b l e 3 . H o m e i n f l u e n z a t e s t u s a b i l i t y f i n d i n g s f r o m p a r t i c i p a n t s t h a t u s e d a h o m e i n f l u e n z r t i c i p a n t t e l e h e a l t h u s a g e a n d h o m e a n t i v i r a l d e l i v e r y r e s u l t s f r o m D e c e m b e r 2 3 , 2 0 1 9 t o F e b r u a r y 7 , 2 0 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. S u p p l e m e n t a l T a b l e s T a b l e A 1 . L i s t o f s y m p t o m s u s e d t o d e t e r m i n e f o r e l i g i b i l i t y f o r n a s a l s w a b c o l l e c t i o n . A c u t e c o u g (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. T a b l e A 2 . P a t h o g e n s f o r w h i c h r e s p i r a t o r y s p e c i m e n s a r e t e s t e d u s i n g a T a q M a n R T -P C R . V i r u s e s B a c t e r i a I n f l u e n z a A / H 1 N 1 S t r e p t o c o c c u s p n e u m o n i a All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 3, 2021. ; https://doi.org/10.1101/2021.02.01.21250973 doi: medRxiv preprint Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial Remote Household Observation for Noninfluenza Respiratory Viral Illnesses in Research electronic data capture (REDCap)-a metadata-driven metholody and workflow process for providing translational research informatics support Early Detection of Covid-19 through a Citywide Pandemic Surveillance Platform Evidence for limited early spread of COVID-19 within the United States COVID-19 in a long-term care facility We gratefully acknowledge the Seattle Flu Study team for their work on this project, as well as the University of Washington Montlake Investigational Drug Service and Inpatient pharmacies for serving as our 24/7 study pharmacy. Thank you to the 98point6 team of providers that helped make this project functional. We would like to thank the participating households for the time they spent conducting our study procedures. REDCap at ITHS is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1 TR002319.