Acute Respiratory Infections

Seasonal outbreaks of acute respiratory infections (ARI) are a leading cause of morbidity in the Military Health System (MHS), particularly among military trainees and deployed service members. With approximately 400,000 medical encounters and 1,000 hospitalizations per year, ARIs not only affect the health of military personnel, but also greatly impact operational readiness through missed training and lost duty days.

Research Area Description 

Increased virulence of known respiratory pathogens, limited effectiveness of vaccines, diagnostic difficulties, and heightened potential for transmission from crowded, stressful living conditions are all factors contributing to the high prevalence of ARIs in service members. The goal of the ARI Research Area is to substantially reduce the burden of ARIs in military populations by generating evidence needed to inform the development of effective control strategies designed to limit the impact of ARIs on health, performance, and mission readiness.

Led by CAPT Timothy Burgess, the multi-site, longitudinal ARI Consortium Natural History Study (ARIC NHS) was initiated in 2009 to collect data on the etiology, epidemiology, and immunology of influenza-like illness (ILI) and severe ARI in the military and provide surveillance reports to the Armed Forces Health Surveillance Division, Global Emerging Infections Surveillance program and Naval Health Research Center. In 2019, data collection for ARIC NHS was suspended so personnel and resources could be dedicated to a new large-scale initiative, the Pragmatic Assessment of Influenza Vaccine Effectiveness in the DoD (PAIVED) clinical trial.
 
The PAIVED clinical trial (led by CAPT Burgess) is a two-year study designed to determine whether there are clinically meaningful differences in the effectiveness and immunogenicity between eggderived, cell-culture-derived, and recombinant licensed influenza vaccines. Enrollment began in October 2018 at five military hospitals. During the first influenza season of the study, >1,600 participants were enrolled with 200 of these subjects also enrolling in the immunogenicity substudy. Due to a low influenza attack rate (1%), the number of enrollment sites was expanded, and the target study size was increased to 15,000 subjects. Enrollment in the second year of the study began in October 2019.
 
As a result of concerns regarding limited vaccine effectiveness in service members, the impact of repeated immunization on influenza acquisition and severity in the MHS is being assessed in the Impact of Influenza Vaccine Experience on Effectiveness protocol, sponsored by the National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases. Presently, abstraction of electronic medical records is nearing completion and data analysis is expected to be completed in mid-2020.
 
Another protocol is the Flu Breath Study, led by Lt Col Brian White, in collaboration with Menssana Research Inc., to assess the use of exhaled volatile organic compounds in influenza diagnosis. Enrollment was completed with breath samples collected from 250 military trainees experiencing an outpatient ILI. Data analysis is expected to be completed in 2020.
 
The Study to Address Threats of ARI in Congregate Military Populations (ATARI), led by Dr. Christian Coles, is focused on the assessment of ILI transmission, etiology, and epidemiology among U.S. Army recruits at Fort Benning, GA. Analysis of spatial
and temporal patterns of transmission is underway, as well as the genomic sequencing of a sample of coronaviruses and parainfluenza viruses collected from the trainees.
 
In 2020, enrollment in PAIVED and analysis of the data will continue to be a major focus of the ARI Research Area. Furthermore, a follow-up longitudinal study to ATARI to describe patterns of ILI acquisition and transmission in large trainee populations is being
developed. Analyses to expand surveillance of ARIs in the deployed setting, including shipboard and ground force populations, are also planned.

 

Key Studies

IDCRP-045: The Acute Respiratory Infection Consortium – A multi-center military consortium for clinical research into the natural history, host response, and potential therapy of acute respiratory infection in military members and their families (ARIC NHS) The Acute Respiratory Infection Consortium (ARIC), established in 2009, is now actively engaged in the analysis of clinical and laboratory data from the ARIC Natural History Study. Numerous manuscripts are in development, with the major objectives to describe the epidemiology and clinical characteristics of influenza-like illness, to evaluate the sensitivity and specificity of new multiplex diagnostic panels, and to assess the impact of antiviral treatment, as well as vaccination, on the clinical course and outcome of influenza infection. The team is in the final stage of development of a standardized symptom severity scale for influenza. Finally, the ARI research area continues its participation in a NIAID-sponsored, multi-center randomized controlled trial of hyperimmune plasma for the treatment of severe influenza.

IDCRP-045-01: Severity symptom grading scale for influenza infection (Flu-PRO) IDCRP-046: Pilot study for collection of anti-influenza A H1N1 (Swine flu) hyper-immune plasma IDCRP-058: Clinical characteristics of novel H1N1 influenza infection in US-based military treatment facilities: A one-year retrospective review IDCRP-062: A randomized, open-label, phase 2, multicenter safety and exploratory efficacy study of investigational anti-influenza A immune plasma for the treatment of influenza

IDCRP-070: Self-administered nasal influenza vaccine: immunogenicity and feasibility of group administration

IDCRP-081: Evaluation of Psychometric Testing Properties of Severity Symptom Grading Scale of Influenza Infection: Flu-Pro Stage III

Military Impact

In 2019, the DoD Infectious Disease Threat Prioritization Panel ranked influenza as the second-highest infectious disease threat to U.S. Armed Forces. Since inception, findings from ARI
Research  Area studies have advanced the understanding of the changing distribution, risk factors, and control of ARI in the MHS. Hospital-based surveillance efforts provide valuable data on ARI epidemiology, clinical severity, and disease burden for high-priority pathogens that may directly impact operational readiness. Furthermore, although there is widespread coverage of the influenza vaccine in the MHS, overall vaccine effectiveness varies from 19% in service members to 51% in DoD beneficiaries. Findings from  PAVED  and the  Influenza  Vaccine  Experience studies may provide insight to account for the disparities in vaccine effectiveness in military personnel and beneficiaries and support the next generation of influenza vaccinations and vaccine policies in the MHS. Furthermore, ARIs are a frequent occurrence in  congregate military populations,  such as trainees.  Findings from  ATARI  and anonymous surveys related to transmission patterns and health care seeking behavior may inform educational interventions to reduce the risk of ARI transmission.

Highlights / Key Findings

  • One out of every 6 non-recruit participants enrolled in PAIVED during the 2018/19 influenza season experienced a confirmed ILI with coronavirus (15%), rhinovirus (10%), and respiratory syncytial virus (8%) being most common. Symptoms lasted 6-8 days in duration with approximately 3-4 days of reduced activity.
  • Among recruits at the Marine Corps Recruit Depot San Diego enrolled in PAIVED during the 2018/19 influenza season, 23% reported an ILI with influenza A(H3) being the most common. Approximately 82% of the ILIs were during the first 3 weeks of training, resulting in a total of 168 days of reduced training and 47 days of missed training.
  • Findings from an anonymous survey of >2,400 trainees found that only 40% of trainees who experienced an ILI sought health care, indicating that ILIs are more common during training than what is indicated in medical records. Recruits who are male and over 30 years of age were less likely to seek health care for ILIs.

Partners and Collaborators

IDCRP collaborates with the National Institute of Allergy and Infectious Diseases (NIAID), Walter Reed Army Institute of Research (WRAIR), Naval Medical Research Center (NMRC), the Armed Forces Health Surveillance Branch (AFHSB) Global Emerging Infections Surveillance and Response System (GEIS) and partner military treatment facilities inside and outside the continental United States.

Publications 2017

Fairchok M, Schofield C, Chen WJ, et al. Inverse Correlation between 25-OH Vitamin D levels and severity of viral respiratory illness in infants. Journal of Infectious Disease and Epidemiology. 2017; 2(1): 1-7

Beigel JH, Tebas P, Elie-Turenne MC, et al. Immune Plasma for the Treatment of Severe Influenza: An Open-label, Multicentre, Phase 2 Randomised Study. Lancet Respiratory Medicine. 2017;5(6):500-511.

Presentations 2017 

ID Week 2016, October 26-30, New Orleans, LA:

  1. Poster # 238: Chen WJ, Arnold J, Fairchok MP, et al. Comparative Evaluation of Diatherex TEM-PCR and Biofire Film Arrau in the Detection of Viral and Bacterial Respiratory Infection.
  2. Poster # 1271: Deiss R, Chen WJ, Coles, et al. Differences in Self-Reported Severity of Symptoms Between Women and Men Experiencing Influenza-like Illness.  
  3. Poster #1273: Fairchok MP, Chen WJ, Schofield C, et al. Antibiotic Prescription Related to Influenza-like Infection.
  4. Poster #2202:  Flores MS, Sun P, Fairchok MP, et al. Cytokine Analysis and Correlation to Viral Loads in a Other-wise Healthy Population with Influenza Infection.

ISPOR 2017, May 20-24, Boston, MA

Poster PIN51: Powers J, Bacci E, Leidy NK, et al. Evaluation of the Performance Properties of the Influenza Patient-Reported Outcomes Instrument (FluPRO) in Patients with Influenza-like Illness (ILI).

MHSRS 2017, August 27-30, Kissimee, FL:

Oral Presentation: Coles CL, Chen WJ, Milzman JO,  et al. Study to Address Threats of Acute Respiratory Infections among Congregate Military Populations (ATARI).

ID Week 2017, October 4-8, 2017, San Diego, CA

  1. Poster #647:  Lewnard J, Chen WJ, Milzman JO, et al. Transmission dynamics of respiratory viruses in a congregated military population: prospective cohort study.
  2. Poster #661:  Chen WJ, Milzman JO, Danahar P, et al. Burden of Influenza-like Illness among military personnel receiving advanced training at Ft. Sam Houston, TX.
  3. Poster #1027: Coles C, Chen WJ, Milzman JO, et al. Study to Address Threats of Acute Respiratory Infections among Congregate Military Populations (ATARI).
  4. Poster #1048: Fairchok M, Chen WJ, Mor D,  et al. Clinical Characteristics of Parainfluenza Virus Infection among Healthy Subjects with Influenza-like Illness.
  5. Poster #1460: Lee R, Won S, Hansen C, et al. Are Higher Vitamin D Levels Associated with Improved Influenza Vaccine Immunogenicity and Fewer Healthcare Encounters for Respiratory Infections among Young Adults?
  6. Poster #1996: Schofield C, Chen WJ, Fairchok M, et al. Epidemiologic Risk, Influenza Subtype, Clinical Severity and Viral Shedding as a Function of Baseline Influenza A Viral Load.
  7. Poster #2001: Maves R, Chen WJ, Fairchock, et al. Etiology and Clinical Characteristics of Influenza-like Illness in Healthy Adults by Hospitalization Status.

Publications 2015

Chen WJ, Arnold JC, Fairchok MP, et al. Epidemiologic, clinical, and virologic characteristics of human rhinovirus infection among otherwise healthy children and adults: Rhinovirus among adults and children. Journal of Clinical Virology. 2015;64(3):74-82.

Fairchok MP, Chen WJ, Arnold JC, et al. Neuraminidase inhibitor therapy in a military population. Journal of Clinical Virology. 2015;67:17-22.

Reference

Sanchez JL, Cooper MJ, Myers CA, Cummings JF, Vest KG, Russell KL, Sanchez JL, Hiser MJ, Gaydos CA. 17 June 2015. Respiratory infections in the U.S. military: recent experience and control. Clin Microbiol Rev. 

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