Acute Respiratory Infections

Seasonal outbreaks of acute respiratory infections (ARI) represent a considerable threat to both the health of military personnel and operational readiness during deployment. Among active-duty service members, 30% of infectious disease hospitalizations are the result of ARIs, highlighting the burden of these infections on the Military Health System (MHS).

Research Area Description 

Acute respiratory infections (ARI) remain a Military Health System research priority with seasonal outbreaks posing a substantial threat to operational unit readiness as ARIs contribute approximately 30% of infectious disease hospitalizations among active-duty service members.

As a result of living in close quarters during training and deployment, along with stressful working conditions in disease endemic regions, military personnel are at increased risk for ARIs. Timely data are needed to accurately describe and monitor the ARI burden in the U.S. military, improve clinical management of influenza-like illness (ILI), and develop and evaluate the impact of ARI control measures.

Led by Dr. Chris Coles and CAPT Timothy Burgess, the cornerstone of the research area is the multi-site, longitudinal ARI Consortium Natural History Study (ARIC NHS), which collects data on the etiology, epidemiology, and immunology of ILI and severe ARI (SARI) in the military. Since initiation of the study in 2009, ARIC NHS has enrolled over 1,910 and 175 cases of ILI and SARI, respectively. Monthly surveillance reports on enrollment, along with ARI etiology and burden data, were provided to the Armed Forces Health Surveillance Branch (AFHSB) Global Emerging Infections Surveillance (GEIS) program and Naval Health Research Center.

Despite wide influenza vaccine coverage in the MHS, effectiveness has been sub-optimal (~19% in Armed Forces personnel and ~51% in military beneficiaries); however, reasons for the disparities are unknown. As a result, a new protocol, the Pragmatic Assessment of Influenza Vaccine Effectiveness in the DoD (PAIVED), was developed to assess if differences in vaccine formulations accounted for the variation in effectiveness. The two-year study led by CAPT Burgess began enrolling subjects at five military hospitals in October. Another novel protocol, the Impact of Influenza Vaccine Experience on Effectiveness, will examine the effect of repeated immunizations on influenza acquisition and severity in DoD populations.

Led by Dr. Coles, the Study to Address Threats of ARI in Congregate Military Populations (ATARI) focuses on the assessment of ILI transmission, etiology, and epidemiology among U.S. Army recruits at Fort Benning (GA). In the early weeks of training, symptomatic ILI was associated with coronavirus, rhinovirus, enterovirus, and influenza. Based on self-reporting, 33% of the enrolled trainees had an ILI episode with the majority not seeking healthcare. These findings demonstrate that attack rates based on clinic attendance largely underestimates the ILI burden.

Enrollment at five ARIC NHS sites (led by CDR Janine Danko) as part of the collaborative, multi-site National Institutes of Allergy and Infectious Diseases (NIAID)-sponsored FluPlasma 2 trial designed to examine the efficacy of hyperimmune anti-influenza plasma for treatment of severe influenza closed in 2018 and data analysis is underway. In the coming year, the IDCRP will continue to partner with GEIS to conduct ILI surveillance in the high-risk trainee population at Fort Sam Houston (TX), as well as contribute samples to the GEIS Bioinformatics Consortium for advanced etiology characterization.

In 2019, the ARI Research Area will build on its collaborative network, along with investigator expertise and experience in conducting interventional studies, with particular emphasis on influenza vaccine effectiveness. Furthermore, opportunities to examine ILI in deployed settings, such as shipboard populations, will be investigated.

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

The goal of the ARI Research Area is to support the development of effective ARI control strategies for the U.S. military to limit the impact of ARI on the health, performance, and mission-readiness of active-duty personnel. Since 2009, our findings have advanced understanding of the changing distribution and determinants of ARI in this population, as well as its control. This is achieved through continued military hospital-based ARI surveillance to provide epidemiology, clinical severity, and burden of disease estimates in relevant groups; surveillance for viral respiratory pathogens with pandemic potential and “routine” respiratory pathogens that might impact operational readiness; characterization of temporal and regional changes in circulating influenza virus subtypes and genotype strains; contributing healthcare utilization and operational burden data to allow comparison of the cost-effectiveness of different control measures designed to enhance force health protection; and providing performance data on detection tools needed to assess impact on routine surveillance for pathogen-specific respiratory infections.

Highlights / Key Findings

  • The Pragmatic Assessment of Influenza Vaccine Effectiveness in the DoD (PAIVED) is a novel protocol that is designed to determine whether there are clinically meaningful differences in the effectiveness and immunogenicity between egg-derived, cell-culture-derived, and recombinant licensed influenza vaccines.
  • Influenza contributed the greatest burden to SARI cases (detected in 43% of patients), while rhinovirus/ enterovirus had the highest proportion in ILI cases (17% of patients) followed by influenza (12% of patients).
  • In an ARIC NHS study, 12% of 902 subjects were positive for coronavirus with HCoV-OC43 contributing the greatest proportion. Except for greater gastrointestinal symptoms with HCoV-HKU1 species, there were no species-specific differences in clinical characteristics.
  • Assessment of the standardized FLU-PRO questionnaire by hospitalized and non-hospitalized patients with ILI found the scores to be reliable, reproducible, and responsive to change in patients testing negative for influenza, suggesting that it can be used in studies of confirmed influenza and ILI.

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. 

IDCRP is committed to reducing the impact of infectious diseases in the military population through collaborative clinical research
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