Antivirals Recommended in Settings with High Transmission Risk
By Annette M. Boyle
WASHINGTON— While influenza vaccine is the first line of defense against an infectious disease that can dramatically affect troop readiness, it is far from 100% effective. That is why military medicine increasingly looks to a second line of defense: antivirals.
With the effectiveness of flu vaccine even lower among older patients, the VA also looks to neuraminidase inhibitors (NAIs) for an added layer of defense to shorten duration of illness and to prevent complications.
The DoD announced in August that all military personnel will receive an annual influenza vaccination, with a goal of greater than 90% of personnel immunized by Dec. 15. The Army expects to use 1.6 million doses of the injectable vaccine, accounting for more than half of the total number of doses ordered by the DoD annually.
If a severe influenza epidemic develops, a vaccine shortage occurs, or distribution is delayed, the DoD has a Plan B that prioritizes “air crews, ships’ crews, and personnel involved in combat or assigned to alert status,” individuals critical to continuity of operations or government, and high-risk beneficiaries.
The back-up plan reflects the challenge that influenza can pose to readiness. “Influenza is one of the few infections able to stop military operations, even when its symptoms are rarely severe, due to the ability of respiratory infections to rapidly move through crowded groups of soldiers,” according to a review of the flu’s impact on armed forces in the Journal of Military and Veterans’ Health (JMVH). 1
Despite high vaccination rates, significant numbers of military personnel contract influenza each year. An article published recently in the Journal of Infectious Disease and Treatment, noted that, during the latest five-year period (2007-2012) for which there is published data by the Armed Forces Health Surveillance Branch (AFHSC) in Silver Spring, MD, influenza was found to be responsible for as many as 7,000 to 25,000 cases per week in the MHS, of which 40% to 65% involved military personnel.2
“Even though a large proportion of U.S. military personnel are immunized with current influenza vaccines, influenza viruses continue to affect them,” according to study authors. They noted that infections may occur despite immunization because of the need for annual immunizations, that vaccines may be poorly matched to circulating subtypes, frequent travel by military personnel to areas of the world with different influenza subtypes, and a vaccine efficacy rate of 60% to 80% for inactivated vaccines and much lower for live attenuated formulas.
Based on effectiveness recommendations by the national Centers for Disease Control and Prevention (CDC), the Army will not be offering live attenuated influenza vaccine this flu season. CDC’s Advisory Committee on Immunization Practices (ACIP) recently voted that live attenuated influenza vaccine (LAIV), delivered as a nasal spray, should not be used this year. That decision was based on data showing poor or relatively lower effectiveness of LAIV from 2013 through 2016.
Who’s at risk?
The groups most at risk have remained the same since the influenza pandemic of 1918-1919 killed 32,000 U.S. warfighters. Those “new to the military were particularly at risk of lethal outcome and the greatest number of deaths occurred in recruit camps,” noted the JMVH authors. This group is at increased risk for the seasonal influenza, too, “as they are immunologically inexperienced and are suddenly crowded together with persons from many different areas under stressful conditions,” the authors add.
To minimize the risk of infection, all new recruits receive influenza vaccinations, but if an outbreak occurs, other methods often are needed to protect the unit and their mission. “Antivirals can be used in institutional settings when there are increased numbers of influenza cases,” according to the Army Medical Command Public Health Directorate. That “might be basic training or AIT [advanced infantry training].”
The CDC recommends three influenza antiviral medications approved by the U.S. Food and Drug Administration (FDA) for use in the United States during the influenza season: oral oseltamivir, marketed asTamiflu; inhaled zanamivir, marketed as Relenza, and intravenous peramivir, marketed as Rapivab. Those NAIs have activity against both influenza A and B viruses by interfering with the release of progeny influenza virus from infected host cells.
Another class of antiviral, the M2 inhibitors, which includes amantadine and rimantadine, target the ion channel protein in the viral envelope. Because both H3N2 and H1N1 viruses have developed widespread resistance to the M2 inhibitors, they are not currently recommended for use.
The Army wrote 9,801 scripts for antivirals in FY2015, according to the Defense Health Agency.
The use of antivirals by the Army could depend on the number infected and other factors. “Typically if increased cases were to occur in one of these settings, clinical care staff and Preventive Medicine staff at the local military treatment facility would work together to decide if mass treatment was necessary and who would be included in the treatment,” an Army Medical Command spokesperson told U.S. Medicine.
The DoD’s priority groups of air crews, ships’ crews and combat personnel also face increased risk of influenza, and the disease can have an outsized impact on their mission readiness. The flu can quickly ground air crews if key members or large numbers become ill. The JMVH authors noted that it is not unusual for 10% or more of Air Force personnel to be off duty for 48 hours or more as a result of contracting the flu.
Even on the ground, influenza affects airmen. In the summer of 2009, the U.S. Air Force Academy experienced an influenza outbreak with 134 cases confirmed by nasal-wash specimens and 33 suspected cases of novel H1N1. While no deaths or hospitalizations were associated with the outbreak, the mean duration of illness exceeded five days, and some cadets subsequently received diagnoses of bronchitis or pneumonia.3
To control the outbreak, the academy isolated infected cadets in a separate dorm area within 24 hours of identification of the first suspected cases. Patients remained separated until they were a week from symptom onset and symptom free for 24 hours. The academy quickly rolled out a public health campaign to minimize further spread of the disease, distributed hand sanitizer and initiated regular screenings. The cadets were prescribed antivirals if their symptoms had started within 72 hours. Antiviral therapy was also offered to healthcare personnel caring for the cadets; no healthcare workers contracted the flu. The outbreak resolved within 18 days of its identification.
Tight quarters on ships and submarines also increase the risk of outbreaks in the Navy, sometimes forcing a return to port. In 2014, 25 of 102 crew members on the USS Ardent sought medical care because of influenza-like illness (ILI) over a three-day period, according to a study in the Center for Disease Control and Prevention’s Morbidity and Mortality Weekly Report.4
In that case, rapid influenza testing indicated 16 cases of influenza A and nine negative results, and further testing indicated the outbreak was 99% identical to strains circulating during the 2013-14 influenza season and antigenically similar to the H3N2 component of the 2013-14 influenza vaccine. Yet, at the time of the outbreak, 99% of the crew had received an influenza vaccine.
“Shipboard personnel are at especially high risk because of constant close quarter exposure to a large number of crew members,” according to the MMWR article. “Virtually all areas onboard ships are shared, and movement frequently requires touching handrails, door knobs, and other objects that can be contaminated with nasal secretions. In addition, ventilation systems can circulate infectious pathogens throughout a ship.”
To limit the impact of the disease, antivirals were prescribed to each crew member who reported that symptoms had developed within the last 48 hours, regardless of their vaccination history or rapid influenza testing results. Affected crew members were sent home for 48 hours, individuals with symptoms were urged to seek medical evaluation, the ship was thoroughly cleaned and personnel were regularly reminded of hand hygiene and to cover their mouths when they coughed. Individuals with influenza symptoms wore N95 filtering facepiece respirators while shipboard for five days after symptom onset. The control measures proved effective: no new cases occurred more than six days after the first crew member fell ill.
Medical staff at the Air Force Academy and on the USS Ardent implemented several steps identified as effective in military settings in a review of respiratory infections and responses in the U.S. military. According to reports, those included the implementation of early isolation of patients, active case identification, early antiviral treatment, chemoprophylaxis of medical staff, the use of hand sanitizers, and face masks for ill patients. Antiviral “ring chemoprophylaxis” of co-workers and unit members also had “clearly documented efficacy.”5
For patients at VA hospitals and long-term care facilities, influenza poses a substantially greater risk than among otherwise healthy servicemembers. Many VA patients are elderly and have multiple comorbidities that increase mortality associated with flu infection—and their illnesses may mask the early stages of an outbreak.
In one case, a VA dementia care unit with 105 patients experienced unexplained sharply increased mortality, with 21 deaths in a one-month period. An investigation found that 45 patients, 42.8% of residents, met the clinical definition for influenza-like illness, and all the autopsies conducted confirmed death from bronchopneumonia or aspiration pneumonia. Authors of a case study of the incident concluded that “the presentation of influenza-like illness can be subtle in onset, underappreciated in this population, and not recognized until excess mortality, which affects the most frail, is noted.”6
The CDC notes that “use of antiviral drugs for treatment and chemoprophylaxis of influenza is a key component of influenza outbreak control in institutions that house patients at higher risk for influenza complications.”
And, the earlier, the better: “Early initiation of antiviral treatment—as close to illness onset as possible—is most clinically beneficial in reducing the risk of critical illness and death in hospitalized influenza patients, as has been shown in observational studies,” said Ian Branam, health communication specialist at the CDC’s National Center for Immunization and Respiratory Diseases.
To avoid high mortality rates among vulnerable veteran populations, the VA diligently promotes uptake of annual seasonal influenza vaccination among its veteran patients, said Gary Roselle, MD, director of VHA’s National Infectious Diseases Service.
If a veteran becomes ill with influenza infections, Roselle told U.S. Medicine that the VA follows CDC guidelines that recommend antiviral treatment for those at higher risk of complications including:
- adults aged 65 years and older;
- persons with certain chronic medical conditions;
- persons with immunosuppression, including that caused by medications or by HIV infection;
- women who are pregnant or postpartum (within two weeks after delivery);
- American Indians/Alaska Natives;
- persons who are morbidly obese (i.e., BMI is 40 or greater); and
- residents of nursing homes and other chronic-care facilities.
In addition to the use of antivirals in residential care facilities and hospitals, the VA wrote 23,389 prescriptions for influenza antivirals for outpatient veterans, Roselle noted.
“Timely use of influenza antiviral medication may reduce symptoms as well as reduce the time a person is sick by a day or two or even reduce the need for hospitalization,” Roselle said.
Branam urged early treatment as well, particularly for those at high risk. “CDC recommends that the neuraminidase inhibitor influenza antiviral drugs be used for early treatment of people who are very sick with influenza or of people who are sick who are at high risk of serious influenza-associated complications.”
- Hodge J, Shanks D. The ability of seasonal and pandemic influenza to disrupt military operations. JMVH. 2011;19(4):13-18.
- Sanchez JL, Cooper MJ. Influenza in the US Military: An Overview. J Infec Dis Treat. 2016, 2:1.
- Witkop CT, Duffy MR, Macias EA, Gibbons TF, Escobar JD, Burwell KN, Knight KK. Novel Influenza A (H1N1) outbreak at the U.S. Air Force Academy: epidemiology and viral shedding duration. Am J Prev Med. 2010 Feb;38(2):121-6.
- Aquino TL, Brice GT, Hayes S, Myers CA, McDowell J, White B, Garten R, Johnston D. Influenza Outbreak in a Vaccinated Population – USS Ardent, February 2014. Morb Mortal Wkly Rep. 2014 Oct 24;63(42):947-9.
- Sanchez JL, Cooper MJ, Myers CA, Cummings JF, Vest KG, Russell KL, Sanchez Jl, Hiser MJ, Gaydos CA. Respiratory infections in the U.S. Military: Recent Experience and Control. Clin Microbiol Rev. 2015 July;28(3):743-800.
- Brandeis GH, Berlowitz DR, Coughlin N. Mortality associated with an influenza outbreak on a dementia care unit. Alzheimer Dis Assoc Disord. 1998 Sep;12(3):140-5.
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