Evaluating Modes of Influenza Transmission Observational Study of Community Acquired Influenza (EMIT)

Evaluating Modes of Influenza Transmission Work Package 1: Observational Study of Community Acquired Influenza

The recent swine origin influenza pandemic (2009), new emergence of swine origin H3N2v, and delayed availability of vaccine for these agents highlight the need to test and optimize public health intervention strategies to reduce transmission of influenza. We will use a new technology for biological particle collection (U.S. Provisional Patent Application No. 61/162,395, McDevitt et al., Aerosol Sci Technol 2013) to make fundamental observations on infectious respiratory droplets in a study of up to 200 naturally occurring seasonal influenza cases. We will collect respiratory droplets shed by participants while breathing normally, talking, and spontaneously coughing. We will characterize the size distribution of droplets containing infectious virus. We will use these basic data to examine the roles of large and small respiratory droplets and examine how the interaction of host factors and virus type impact the shedding of infectious respiratory droplets. Subjects will be recruited through a web based respiratory illness surveillance system, health clinics and advertisement in the campus community. Sitting in the collection booth will not create additional discomfort or risk for volunteers already suffering from influenza infection. We will recruit up to 1000 persons with symptoms of acute respiratory illness for screening with collection of nasopharyngeal swabs and questionnaire. From among those screened, we will recruit 250 to give exhaled breath samples, and ask 50 people with influenza to return for follow up exhaled breath samples on up to two subsequent days. We hypothesize that (1) fine aerosols (<5 microns in aerodynamic diameter) will contain more viral copies than coarse aerosol particles (>= 5 microns) (2) fine aerosols will contain culturable virus indicating that the fine aerosols are infectious, (3) aerosol shedding will correlate with virus load measured by swabs, (4) presence of active cough during sampling will be associated with increased aerosol shedding, (5) clinical symptoms and signs, including fever can be used to predict viral aerosol shedding.

Study Overview

• Status: Completed
• Conditions: Influenza Virus Infection Transmission in Humans
• Intervention / Treatment: Other: Observational Study of influenza aerosol shedding -- No Intervention

Detailed Description

This study is a follow-on to earlier projects funded by the US Centers for Disease Control and Prevention (CDC) and the National Institute for Allergy and Infectious Diseases (NIAID) that developed the sampler and studied the impact of surgical masks on reducing viral aerosol release by persons infected with influenza virus. The funding organizations have no direct control over the study design, execution, or reporting and no access to identifiable human data. The CDC IRB has determined that the CDC is not engaged in human subjects research in this cooperative agreement.

Hypotheses:

• Fine particle aerosols will contain greater numbers of viral copies than will coarse aerosol particles.
• Clinical symptoms and signs, including fever can be used to predict viral aerosol shedding
• Fine aerosols will contain culturable virus indicating that the fine aerosols are infectious
• Aerosol shedding will correlate with virus load measured by nasopharyngeal and throat swabs
• Presence of active cough during sampling will be associated with increased aerosol shedding with a stronger correlation to be found with coarse than fine particle virus aerosols

• Study Type: Observational
• Enrollment (Actual): 178

Contacts and Locations

Study Locations

• United States
  • Maryland
    • College Park, Maryland, United States, 20742
      • University of Maryland School of Public Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Students, faculty, and staff at the University of Maryland College Park and residents of the surrounding communities

Description

Inclusion Criteria:

• Presence of symptomatic respiratory infection or other evidence of respiratory infection:

  • During the influenza season, subjects will be enrolled if they have

    • influenza-like illness (symptoms of fever and either cough or sore throat) and either
    • a positive point of care rapid test for influenza infection or
    • objectively documented fever in the setting of a documented local influenza outbreak (presence of rapid test or PCR confirmed cases).
    • Onset within the previous 48 hours
  • Prior to onset of influenza season and if we have not achieved enrollment of our target population by the end of flu season, we will enroll subjects with cough, coryza (stuffy runny nose, sore throat, sneezing), and malaise (fatigue) characteristic of the 'common cold' often resulting from Human Rhinovirus, RSV, parainfluenza, and to some extent influenza virus.

Exclusion Criteria:

-

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Community acquired respiratory infection; Measurement of exhaled breath aerosol	Other: Observational Study of influenza aerosol shedding -- No Intervention; No intervention -- observational study only

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Viral Copy Number in 30-minute Exhaled Breath Sample	Total viral RNA copies detected in breath aerosol exhaled during a 30-minute sample collection. Participants sit for 30 minutes with face inside the cone/funnel of the Gesundheit-II (G-II) human bioaerosol collector (https://doi.org/10.1080/02786826.2012.762973) collecting air at 130 L/min. Particles in air are concentrated into a small volume of buffer. The copies per mL of buffer is measured by PCR and corrected to the total amount collected per 30-min sample. See publication in the Proceedings of the National Academy of Sciences (https://doi.org/10.1073/pnas.1716561115) and PLoS Pathogens (https://doi.org/10.1371/journal.ppat.1003205) for more details.	Daily measurements on days 1 through 3 post onset of symptoms (each person contributed 1 to a max of 3 samples). Reported values are the geometric mean over all samples and persons.
Total Fine Aerosol Infectious Influenza Virus in 30-minute Exhaled Breath Sample	Fluorescent Focus Assay detection of infectious influenza virus in Fine Particle (≤5 µm) aerosol reported as fluorescent focus units (FFU) per 30-minute breath sample. Aerosol samples were collected at 130 L/min for 30 minutes by an aerosol sampler that concentrated the aerosol in a small volume of liquid. The FFU/ml were multiplied by the volume of liquid in the final concentrate sample to obtain the total infectious particles per 30-minute sample. This outcome was peer reviewed and published in the Proceedings of the National Academy of Sciences.	Daily measurements on days 1 through 3 post onset of symptoms (each person contributed 1 to a max of 3 samples). Reported values are the geometric mean over all samples and persons.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of exhaled particle counts and viral copy numbers	Hypothesis: exhaled particle numbers counted with an optical particle counter (Exhalair, Pulmatrix, Inc, Lexington, MA) during tidal breathing will correlate with exhaled viral copy numbers, especially in the fine particle fraction	At enrollment and over 2 days follow-up
Impact of multiple infection	Hypothesis: co-infection with other respiratory agents will increase aerosol production	At enrollment and over 2 days of follow-up

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of Exhaled Virus in Community Acquired and Experimental Infection	We compared influenza A viral aerosol shedding from volunteers nasally inoculated with A/Wisconsin/2005 (H3N2) and college community adults naturally infected with influenza A/H3N2 (2012-2013), selected for influenza-like illness with objectively measured fever or a positive Quidel QuickVue A&B test. Propensity scores were used to control for differences in symptom presentation observed between experimentally and naturally infected groups.	Maximal shedding during days 1-3 post onset of symptoms (natural infections) or days 1-4 post inoculation (nasally inoculated volunteers)

Collaborators and Investigators

• Sponsor: University of Maryland, College Park
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Centers for Disease Control and Prevention
• Investigators: Principal Investigator: Donald K Milton, MD, DrPH, University of Maryland

Publications and helpful links

General Publications

• Fabian P, McDevitt JJ, DeHaan WH, Fung RO, Cowling BJ, Chan KH, Leung GM, Milton DK. Influenza virus in human exhaled breath: an observational study. PLoS One. 2008 Jul 16;3(7):e2691. doi: 10.1371/journal.pone.0002691.
• Milton DK, Fabian MP, Cowling BJ, Grantham ML, McDevitt JJ. Influenza virus aerosols in human exhaled breath: particle size, culturability, and effect of surgical masks. PLoS Pathog. 2013 Mar;9(3):e1003205. doi: 10.1371/journal.ppat.1003205. Epub 2013 Mar 7.
• McDevitt JJ, Koutrakis P, Ferguson ST, Wolfson JM, Fabian MP, Martins M, Pantelic J, Milton DK. Development and Performance Evaluation of an Exhaled-Breath Bioaerosol Collector for Influenza Virus. Aerosol Sci Technol. 2013 Jan 1;47(4):444-451. doi: 10.1080/02786826.2012.762973. Epub 2013 Jan 25.
• Yan J, Grantham M, Pantelic J, Bueno de Mesquita PJ, Albert B, Liu F, Ehrman S, Milton DK; EMIT Consortium. Infectious virus in exhaled breath of symptomatic seasonal influenza cases from a college community. Proc Natl Acad Sci U S A. 2018 Jan 30;115(5):1081-1086. doi: 10.1073/pnas.1716561115. Epub 2018 Jan 18.

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: January 14, 2013
• First Submitted That Met QC Criteria: January 15, 2013
• First Posted (Estimated): January 16, 2013

Study Record Updates

• Last Update Posted (Actual): April 25, 2025
• Last Update Submitted That Met QC Criteria: April 8, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: influenza virus; aerosol transmission; contact transmission; large droplet transmission; airborne infection
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Influenza, Human
• Other Study ID Numbers: 017086-001; 1U01IP000497 (U.S. NIH Grant/Contract); 3U01CI000446 (U.S. NIH Grant/Contract); RC1AI086900 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The study data for natural infections are available upon request. All analysis scripts and readme files required to reproduce analyses are available at https://gitlab.com/jacob bueno /natur al_vs_ artif icial_infection
• IPD Sharing Time Frame: open access indefinately
• IPD Sharing Access Criteria: Open
• IPD Sharing Supporting Information Type: SAP; ANALYTIC_CODE