Title: Mapping patterns of viral load emission in exhaled breath over the course of acute respiratory virus infections
Funder: Department of Health and Social Care

Abstract: Background Respiratory viruses such as Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and influenza cause significant morbidity and mortality. The gold standard of diagnosis is nasopharyngeal sampling (NPS). However, many patients can be positive for SARS-CoV-2 by NPS for prolonged periods without being infectious.The NIHR have identified understanding the risk of transmissibility of SARS-CoV-2 and its viability airborne as a research priority. The Barer group (Leicester) has pioneered the use of sampling pathogens in exhaled breath using modified face-masks containing polyvinylalcohol sampling strips (face-mask sampling, FMS). I am first author in a study that is the first in the world to detect and quantify exhaled SARS-CoV-2 using FMS. In this study, we found that viral loads on FMS were highest during early symptom onset and that there was weak, but significant correlation between concomitant FMS and NPS samples. The proposed fellowship was developed with the involvement of 10 patient and public involvement (PPI) representatives who will remain throughout the PhD. Ultimately, the fellowship will determine whether FMS can be used as a tool to rapidly quantify the infectiousness of individuals with respiratory viruses and potential earliar diagnosis. Research questions 1: What is the longitudinal pattern of viral load on FMS during the first two weeks of acute illness for respiratory viruses? 2. How do viral loads on FMS compare with NPS? Methods The project is divided into three work packages. Work package (WP) 1 involves a systematic review and diagnostic test meta-analysis assessing the sensitivity and specificity of existing methods that detect pathogens in exhaled breath, compared to their gold standards (generally, NPS for viruses and sputum for bacteria). WP2 will use five serial face-mask and nasopharyngeal samples from patients infected with the most common respiratory viruses in Leicester (likely SARS-CoV-2 but may also includ influenza if SARS-CoV-2 cases drop) to determine the natural history of emission and its relationship to symptomology and PCR/lateral flow tests on NPS. WP3 will use mathematical modelling to map the viral kinetics from FMS and NPS over the course of acute disease, taking into account data collected from work package 2. Timelines for delivery WP1 will be performed within the first 6 months of starting the PhD. WP 2 and 3 will be performed in parallel to fully map viral load during acute illness, without causing significant participant inconvenience from providing too many samples.Impact and dissemination This work is of public health interest and has the potential to open up new approaches to the understanding and control of respiratory virus infections. Should FMS help to determine the infectiousness of a patient, there would be immediate benefit to the NHS - such as early de-escalation of isolation precautions for infected patients, and early identification of infectious patients at the workplace before symptom onset, and mass testing at big events and travelling abroad. The PPI group will guide dissemination to patients, and results will be presented at national and international conferences to simulate interest and enthusiasm for collaboration into larger, definitive transmission studies.

Lay abstract: Background Respiratory virus infections can cause significant problems for infected patients, the economy and the NHS. The most profound example of this is the COVID-19 pandemic, but seasonal flu and other viruses also exist. In older frail patients, such infections can be fatal.The diagnosis of respiratory virus infections is by a swab in the back of the throat and nose (nasopharyngeal swab). However, this can be very uncomfortable - and although it can help a doctor diagnose whether someone has a respiratory virus infection, it doesn't necessarily tell us whether that person is contagious to others. This is likely because most people who get exposed to an infected person are not exposed to the virus in their throat, but by the virus that they breathe out. In fact, many patients who are positive for SARS-CoV-2 on the nasopharyngeal swab are not contagious to others if they are already several days into their illness. Study aims I have supported the development of a method to sample virus that is breathed out by infected patients, by using harmless strips that are placed on the inside of routinely used duckbilled-shaped facemasks. These strips are able to quantify the amount of virus that someone breathes out over time. We have recently shown that this mask based sampling system is able to detect SARS-CoV-2 virus in infected patients. The aim of this PhD fellowship is see whether the amount of virus detected time on the facemask is different to that detected by the nasopharyngeal swab. Ultimately, the mask could be a more accurate marker of individual contagiousness than the nasopharyngeal swab. If this is the case, it could be of immediate public health benefit, allowing infectious patients to be isolated before they are symptomatic; allowing non-contagious patients to be discharged to a nursing home in a timely fashion without worry of transmission to other residents; as well as allowing non-contagious persons to go to work or travel abroad. Methods There are three work packages (WP) of this fellowship: Work package 1: To systematically review existing methods of sampling the breath for bacteria and viruses Work package 2: To sample 100 study participants and one member of each of their households using the masks with the special strips inside and the nasopharyngeal swabs. Each study participant will provide five masks and swab samples over two weeks. The design of this study will form the basis for future bigger studies and will see if there are any problems with patients wearing the masks; how many patients can we get at different stages of infection; if patients can be followed up successfully; what measures might work well for future, larger studies.Study participants will also fill out a symptom diary, grading their symptoms on a daily basis and a brief questionnaire detailing their basic demographic details (age, sex, ethnicity etc). Work package 3: Use mathematical modelling methods to try and map out quantities of virus throughout the first two weeks of illness based on WP2 data. Patient and public involvement (PPI) PPI has been in place since the study was conceived and will continue throughout the project. I sought the opinion of ten PPI representatives, all of whom thought the work was important and will form a project group that will meet bi-annually to discuss study results. Dissemination of findings Results will be shared with participants and the public through the involvement of PPI representatives; presented at academic conferences and published in high impact journals.

Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION