Breakout Group: Best Methods for Studying Droplet Spray Transmission November 4, 2010 and November 5, 2010 – Atlanta, GA “Understanding the Modes of Influenza Transmission” Workshop

What are the key questions/ gaps remaining in understanding the contribution of droplet transmission to the spread of influenza among humans?

Droplet Transmission Breakout Group: Remaining Key Questions/Gaps  There are no data discriminating relative contribution of spray compared to other potential modes of transmission  Use of masks versus respirators cannot distinguish between these modes because The conjunctiva are exposed which may or may not be a route of infection Masks differ widely by their ability to filter some smaller particles  People touch their faces many times in an hour and so difficult to exclude indirect contact transmission in non-experimental model  The experimental models that mimic human generation of influenza droplets and aerosols may not be valid in  Methods that generation propulsion of fluids/aerosols may Alter viability of virus Not be designed to capture particils of all size, especially large sizes Use an artificial matrix or have missing cofactors that alter viability and/or infectivity of the viruses or the particle size distribution  Size distribution of particles in natural infection not well characterized  Needs to be determined for different states (e.g. tidal breathing, talking, coughing, singing)  More information is needed to understand person to person variability in particle size distribution

Droplet Transmission Breakout Group: Remaining Key Questions/Gaps  Need to characterize deposition of droplet spray on different sites of infection, and infectious dose by site of deposition  What sites of deposition of droplets (eyes, nose, etc) will most likely results in infection (efficiency of infection by site of deposition)  During droplet spray, what proportion of droplets is distributed at different sites of the body that might lead to human infection  These data could be applied to a model such as that developed by Nicas, et al.  Better understanding of correlation between viral copies as measured by rt-PCR compared to live virus and how this relates to potential infectivity  Better understanding of the virus dose needed by route of infection  Human experimental models did not look at more than one route of transmission in the same experiment  Relatively low secondary attack rate and Ro for influenza inconsistent with report of very small inoculum requirement reported for aerosol transmission in studies such as Alford, et al  Variability in viral shedding among individuals and pre-existing cross- reactive immunity within households/populations difficult to assess and control for in population-based studies

What are the best study designs and their pros/cons? What study designs would be best for understanding the contribution of droplet transmission to the other transmission routes?

Droplet Transmission Breakout Group: Best Study Design and Pros/Cons  Considerations for studying the relative contribution of droplet spray  Because spray implies a ballistic event, issues of temperature and humidity in the environment should be less of an issue However, humidity and temperature effects on the host may also affect susceptibility by this route as for other transmission routes  Study may be less complicated compared to aerosol or contact since the virus from droplets is expected to be outside of the infected person for much less than a second before it reaches the new host  Studies to assess the distribution of influenza virus from droplet spray  Persons infected with influenza (preferentially persons naturally infected ) would Cough, sneeze and/or speak toward an artificial target (e.g. mannequin, splash plates, growth media) o Assess distribution of amount of virus hitting mannequin targets that may lead to infection (e.g. lips, conjunctiva, mouth, nasal mucosa)  This would allow for better understanding of the distribution of large droplets onto a target  Human experimental studies that would eliminate different modes of transmission  Assess risk of human to human transmission using methods to eliminate droplet spray, e.g. Face shield protecting eyes, nose and mouth on potential recipient which prevents only spray, but not aerosol Using UV light in the room when exposure occurs ( to eliminate aerosol mode) Using a gentle crosswind between the infected and exposed persons to eliminate aerosol route o The wind speed would be important to tune to particle size and different wind speeds could be used to select different particle size ranges

Droplet Transmission Breakout Group: Best Study Design and Pros/Cons  Community studies of influenza  Use face shields instead of masks for intervention group and compare to a control group  Prospective design would help to eliminate delay in initiating intervention E.g. this is has been a difficulty with community studies that enrolled an index case after influenza diagnosis and then sought to establish different control measures among house hold members, may of whom were already exposed to influenza from the index case prior to enrollment  Comparison of the relative efficiency of transmission by deposition on different parts of face  One of the gaps in knowledge is where influenza viruses may deposit on the face and what proportion of viruses expelled from an infected person land on a mucosal surface where infection may then result  Concern expressed was that artificially made sprays or sprays onto a mannequin may not provide good comparison to natural infection  Prospective surveillance for and identification of influenza-infected hospitalized patients and conduct follow-up of exposed persons to identify secondary cases and the types of exposures they had to the index cases  Would require intensive monitoring of staff and their activities, use of PPE, amount of time spent with the index patient, particularly face-to-face time that may have allowed for droplet spray  Conduct full genome sequencing of viruses from index case to any contacts that become infected to determine if viruses likely from the same source or from another exposure  Observational studies of healthcare workers to determine the amount of time they are face to face with a patient and may be likely exposed to droplet sprays through patient coughing, talking or sneezing

Pros and Cons of Different Methods  Series of studies to estimate probability of exposure to droplets and types of exposures needed to cause infection  Cost high especially for human experimental infection studies  Ethical concerns for human inoculation/exposure studies  Variability in results due to differences between viruses, host variability, pre-existing immunity among exposed persons, and routes of infection  Variability in models and samplers used in terms of  Ability to capture different sizes of particles  Ability to detect live virus  Sample sizes for human studies would be high  Generalizability of findings  Compliance with interventions and control for multiple exposures in community studies