Influenza Virus Infection Transmission in Humans
Conditions
Keywords
influenza virus, aerosol transmission, contact transmission, large droplet transmission, airborne infection
Brief summary
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.
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
Interventions
OTHERObservational Study of influenza aerosol shedding -- No Intervention
No intervention -- observational study only
Sponsors
Centers for Disease Control and Prevention
National Institute of Allergy and Infectious Diseases (NIAID)
University of Maryland, College Park
Study design
Observational model
CASE_ONLY
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
10 Years to No maximum
Healthy volunteers
No
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
\-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Viral Copy Number in 30-minute Exhaled Breath Sample | 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 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. |
| Total Fine Aerosol Infectious Influenza Virus in 30-minute Exhaled Breath Sample | 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. | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Exhaled Virus in Community Acquired and Experimental Infection | Maximal shedding during days 1-3 post onset of symptoms (natural infections) or days 1-4 post inoculation (nasally inoculated volunteers) | 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. |
Countries
United States
Participant flow
Recruitment details
Self reported ILI and influenza diagnosed by campus health center
Pre-assignment details
must have fever measured by campus medical provider or by research clinic with a sore throat or cough, or a positive rapid antigen test for influenza A or B and must be within 3 days of onset of symptoms
Participants by arm
| Arm | Count |
|---|---|
| Community Acquired Influenza Virus Infection Volunteers with positive rapid antigen test or objectively measured fever with complaint of cough or sore throat during the influenza season. | 178 |
| Total | 178 |
Baseline characteristics
| Characteristic | Community Acquired Influenza Virus Infection |
|---|---|
| Age, Continuous | 21 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 177 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 32 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants |
| Race (NIH/OMB) More than one race | 24 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 109 Participants |
| Region of Enrollment United States | 178 participants |
| Sex: Female, Male Female | 87 Participants |
| Sex: Female, Male Male | 91 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 178 |
| other Total, other adverse events | 0 / 178 |
| serious Total, serious adverse events | 0 / 178 |
Outcome results
Primary
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.
Time frame: 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.
Population: Participants with complete data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Community Acquired Respiratory Infection | Total Fine Aerosol Infectious Influenza Virus in 30-minute Exhaled Breath Sample | 41 Total FFU/30-minute sample | Standard Deviation 30 |
Primary
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.
Time frame: 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.
Population: All cases meeting enrollment criteria
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Community Acquired Respiratory Infection | Viral Copy Number in 30-minute Exhaled Breath Sample | Fine aerosol RNA copy number, Total copies per 30-minute breath sample | 38,000 Fine aerosol RNA copy number | Standard Deviation 13 |
| Community Acquired Respiratory Infection | Viral Copy Number in 30-minute Exhaled Breath Sample | Coarse aerosol RNA copy number, Total per 30-minute breath sample | 12,000 Fine aerosol RNA copy number | Standard Deviation 14 |
Other Pre-specified
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.
Time frame: Maximal shedding during days 1-3 post onset of symptoms (natural infections) or days 1-4 post inoculation (nasally inoculated volunteers)
Population: Adults naturally infected with influenza A H3N2
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Community Acquired Respiratory Infection | Comparison of Exhaled Virus in Community Acquired and Experimental Infection | 39000 Fine aerosol RNA copies/ 30-min sample | Standard Deviation 15.12 |
| Volunteers Nasally Inoculated With A/Wisconsin/2005 (H3N2) | Comparison of Exhaled Virus in Community Acquired and Experimental Infection | 5100 Fine aerosol RNA copies/ 30-min sample | Standard Deviation 4.72 |
Post Hoc
Correlation of Exhaled Particle Counts and Viral Copy Numbers
A convenience subsample were tested for exhaled particle counts using an optical particle counter during research clinic visits as a postdoctoral exploratory investigation. No formal analysis was completed.
Time frame: 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.
Population: Convenience subsample
Post Hoc
Impact of Co-infection With Viral or Bacterial Pathogens on Fine Aerosol Shedding
Exploratory analysis of impact of other respiratory present in nasopharyngeal swabs on extent of aerosol shedding.
Time frame: Within 3 days of onset of influenza like illness
Population: Postdoc left lab without completing write up of analysis due to lack of finding a correlation. Notes and data from 12 years ago are no longer easily accessible.