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This comprehensive review outlines the impact of military-relevant respiratory infections, with special attention to recruit training environments, influenza pandemics in 1918 to 1919 and 2009 to 2010, and peacetime operations and conflicts in the past 25 years. Outbreaks and epidemiologic investigations of viral and bacterial infections among high-risk groups are presented, including i experience by recruits at training centers, ii impact on advanced trainees in special settings, iii morbidity sustained by shipboard personnel at sea, and iv experience of deployed personnel. Utilizing a pathogen-by-pathogen approach, we examine i epidemiology, ii impact in terms of morbidity and operational readiness, iii clinical presentation and outbreak potential, iv diagnostic modalities, v treatment approaches, and vi vaccine and other control measures. We also outline military-specific initiatives in i surveillance, ii vaccine development and policy, iii novel influenza and coronavirus diagnostic test development and surveillance methods, iv influenza virus transmission and severity prediction modeling efforts, and v evaluation and implementation of nonvaccine, nonpharmacologic interventions. INTRODUCTION Infectious diseases have been of great significance to the U. These respiratory infections also constitute a common cause of morbidity among adults in the United States ,. Acute respiratory diseases ARDs are also the leading cause of outpatient illness, with significant impact in terms of disability-adjusted life years, accounting for 115. The Military Trainee Environment and Increased Risks Related to Training ARDs have been particularly problematic in recruit and other military training environments, where close and crowded living conditions , physical and psychological stresses , environmental challenges , and demanding physical training lead to more intense exposure as well as a state of relative immune compromise. Higher ARD rates are routinely seen among recruits than among older, more experienced military personnel. The earliest comprehensive ARD studies took place in the 1940s and were conducted by the Commission on Acute Respiratory Diseases in World War II WWII. These studies led to groundbreaking findings documenting distinct seasonality and epidemiological patterns of disease transmission at basic combat training BCT locations. Winter epidemics were clearly documented for recruits at Fort Bragg, NC, and at Fort Dix, NJ, during the mid- to late 1940s; these investigations also defined a higher-risk period during the initial 4 to 6 weeks of training ,. Navy investigators clearly documented trainee-related ARD outbreaks in winter at the Great Lakes Naval Training Center in Illinois. A principal finding of naval recruit studies in the 1950s and 1960s was the observed direct correlation of pneumonia and ARD rates with greater degrees of crowding ,. ARD continue to have a substantial impact among military recruits and newly mobilized troops. In the past 2 decades, U. Navy , , and Armed Forces Health Surveillance Center AFHSC , investigators have been able to quantify the military burden of ARD. The incidence of hospitalizations for respiratory disease among recruits exceeds that among comparable civilian adults in the United States by at least 3- to 4-fold, accounting for 25% to 30% of infectious disease-related hospitalizations. Severe ARD is seen mostly in recruit and advanced individual training phases early in a military career. Nontrainee and Deployed Military Environment Respiratory infections are also of significance among active-duty, nonrecruit personnel, where they were estimated to account for 300,000 to 400,000 medical encounters affecting 200,000 to 600,000 service members each year during the influenza seasons in the years 2012 through 2014 , ,. Influenza continues to have a large medical impact, accounting for a total of 10,708 to 13,423 bed-days and 89,953 to 95,241 lost-duty days during the October-through-May periods in 2011 to 2012 and 2012 to 2013, respectively our unpublished data, 13 March 2014. Exposure to novel respiratory pathogens may occur during deployments in areas where these diseases are endemic. During military deployments in the Persian Gulf War and Balkan peacetime engagements in the 1990s, such infections accounted for 14% of all medical encounters, being exceeded only by noncombat orthopedic injuries. Military personnel performance was affected in 14% and 34% of respiratory illness cases in 2003 to 2004 and 2005 to 2006, respectively ,. Host-Related and Environmental Risk Factors Overexertion, sleep deprivation, psychological stress, as well as environmental factors such as exposure to dust, smoke, and air contaminants; extremes of temperature e. Physiologic and immunologic changes are produced in individuals subjected to physically and psychologically stressful conditions which are characteristic of military training and which may result in altered immunologic function, increasing susceptibility to infection ,. Other important factors, such as the nature of the military mission e. Conflicting data have been reported regarding the roles of age and gender. In one study, a greater risk of respiratory illness was seen for older personnel 2% higher for each year of age and females 44% higher deployed to Iraq and Afghanistan. In another study during the Persian Gulf War , no such associations were found. Respiratory infection rates tend to be higher among troops billeted in tightly constructed air-conditioned buildings ,. Empirical evidence of transmission of human adenovirus in enclosed settings, such as schools and military training camps, seems to indicate that close proximity of personnel e. Clinical Presentations and Seasonality Some key clinical features and epidemiological characteristics of respiratory pathogens to consider in military settings are outlined in ,. Clinical symptoms resulting from infection by different pathogens may overlap, so a specific etiologic diagnosis based on clinical grounds only is often inaccurate. Knowledge of seasonality patterns may be helpful in distinguishing among these pathogens. For example, in temperate climates, influenza virus, adenovirus, RSV, and HCoV predominate in the winter, whereas rhinovirus may be seen year-round, with higher rates of circulation in the fall, winter, and spring ,. In tropical regions, respiratory infections with all these pathogens tend to be more frequent during wet and cold weather. When an infected person coughs or sneezes, most of these pathogens are readily spread person-to-person to susceptible individuals located within 1 to 2 m of the infected individual. The timing of pathogen shedding plays an important role as a determinant of transmissibility. For severe acute respiratory syndrome coronavirus SARS-CoV , shedding usually begins at the time of symptom onset, whereas for most other viruses, it begins 24 to 48 h prior to illness and lasts 5 to 7 days in adults and longer 7 to 10 days in young children ,. Bacterial pathogens can be shed in saliva and droplet nuclei for periods of weeks to months, depending on the stage of disease, patient infectiousness, and the presence or absence of effective treatment of carriage e. Background historical information and epidemiology. Soon thereafter, Hilleman and Werner, working at the Walter Reed Army Institute of Research WRAIR , identified cytopathic effects in HeLa and human tracheal cell cultures of throat washing samples from ill recruits at Fort Leonard Wood, MO. After two additional years of collaborative scientific work by these investigators with Enders et al. Adenoviruses caused significant morbidity among military recruits prior to the advent of Ad4 and Ad7 vaccination in the early 1970s. Moreover, it was estimated that three-fourths of ARD cases were due to adenoviral infection, especially during the late fall through early spring, with unit-specific attack rate AR estimates being as high as 50% to 80%. For further historical details and relevant studies, the reader is referred to an excellent review by Russell. Humoral, antibody-mediated immunity plays a key role in adenovirus epidemiology. A lack of preexisting, type-specific immunity against Ad4 and Ad7 has been documented to represent the most significant factor in predisposing recruits to infection and disease. Low levels of preexisting immunity among incoming recruits were noted in the mid- to late 1970s and subsequently in the mid-1990s by other Army investigators , , where it was estimated that 76% to 88% of incoming recruits were nonimmune to Ad4 or Ad7 upon arrival in training. The role of gender has not been well defined to date. In the Fort Jackson study noted above, higher rates of hospitalization and infection among male recruits were noted, with relative risks of admission and infection that were 1. Outbreak potential during nonvaccination periods. A summary of the most notable adenovirus-related outbreaks, studies, and deaths in military populations undergoing training during the past 2 decades is presented in , ,, ,,. In summary, thousands of cases and nine deaths were documented by U. Outbreaks took place during periods of nonavailability of Ad4 and Ad7 oral vaccine after its sole manufacturer Wyeth Labs ceased production in 1994. Relative shortages ensued until mid-1999, when all supplies were exhausted, and adenovirus-associated febrile respiratory illnesses FRIs returned to recruit training centers. It was not until late October 2011, when production resumed and recruit vaccination was restarted, that dramatic and sustained reductions in FRI and adenovirus isolation rates were achieved ,. Notable adenovirus-associated outbreaks, studies, and deaths in military-related populations from 1995 to 2012 a Adenovirus-associated FRI outbreaks have also affected other non-U. These reports of foreign militaries illustrate well the continued worldwide threat to the military. Is Ad14 an emerging threat to the military? Ad14 was first identified as the predominant infection among Dutch military recruits in Ossendrecht, the Netherlands, in 1955. Fifty-one years later, an Ad14 variant emerged in the United States, most often associated with sporadic cases in civilian communities and clusters of cases among military trainees. The most notable military Ad14 outbreak took place in the spring of 2007 at the U. Air Force recruit training center in Lackland, TX, where a cluster of trainees with severe FRI was identified ,. Many trainees were hospitalized, and several were in intensive care. Sporadic Ad14 cases were identified at other U. Ad14 subsequently went on to affect recruits in all eight training centers during the years 2006 through 2009. Thus, Ad14 has been shown to represent an emerging threat to the military in that it seems to cause more severe disease, although the reasons for this propensity are not well understood and deserve more comprehensive study ,. Military and associated public health authorities were concerned that implementation of Ad4 and Ad7 vaccination might create an environment where Ad14 would become a major source of respiratory disease among recruits. Clinical spectrum of illness. The incubation period for naturally acquired adenovirus disease of the respiratory tract is 4 to 8 days median, 6 days but may be up to 2 weeks ,. Viral shedding begins shortly before the onset of symptoms within 1 to 2 days and continues for up to a week after symptom resolution. Adenovirus-associated respiratory disease in the military setting has most often been associated with types 3, 4, 7, 14, and 21 and usually presents with an acute onset of moderate to severe nonsuppurative pharyngitis, fever similar to ILI , and conjunctivitis, which may be prominent and may serve as a useful diagnostic finding compared to other pathogens ,. Until the reintroduction of vaccination in October 2011, adenoviruses were a common cause of viral pneumonia among military recruits, occurring in as many as 5% to 10% of adenovirus-associated FRI cases, especially in association with certain types, such as Ad14 ,. The characteristics of adenovirus-associated pneumonia are similar to those due to other pathogens, thus making it difficult to establish a diagnosis using clinical or radiographic findings alone. Diagnosis of adenovirus infection may be achieved by virus isolation or by direct detection of viral antigens or nucleic acids from appropriate specimens of respiratory secretions, conjunctival swabs, stool, and urine, depending on the clinical syndrome. An enzyme-linked immunosorbent assay ELISA or an immunofluorescence assay IFA can be used to directly detect viral antigen in clinical specimens. The time required to detect adenoviruses in cell culture can be shortened to 1 to 2 days by employing shell vial centrifugation culture SVCC systems followed by fluorescent-antibody staining. Although virus isolation by culture remains the gold standard, the rapid turnaround time and high-throughput nature of detection by nucleic acid amplification tests NAATs have led to their increased use in clinical laboratories. Several commercial PCR-based assays detect adenovirus from purified extracts of respiratory samples ,. Adenoviruses can also be rapidly detected by several relatively new NAATs that are multiplexed to detect several viruses at the same time ,. These assays include i a multiplex PCR whose resulting products are labeled by a primer extension step and then hybridized to detection microbeads that can be specifically sorted based on their internal dye content ; ii a multiplex PCR whose resulting products are converted to a single-stranded form and hybridized to both a capture probe and signal probes, which allows electrochemical detection ; and iii an automated nested multiplex PCR system including sample purification, which uses melting-curve analysis for detection of target sequences and provides results within 1 h ,. None of the commercially available single-target PCRs or broad-spectrum multiplex PCRs provide genotyping data on the adenoviruses detected due to the number and diversity of types causing respiratory disease. Tests applied in accordance with an algorithm for molecular typing of isolates exist and may also be useful in detecting evidence of coinfections and novel intermediate adenovirus strains; this algorithm is of particular relevance in investigations of outbreaks and clusters of unusually severe adenovirus-associated disease. This method relies upon hexon sequencing and a gel-based PCR method for fiber determination of genotype. Serologic diagnosis is primarily of epidemiological relevance, and type-specific neutralizing antibody titer determinations have been helpful in investigating outbreaks among military personnel. There are no U. Food and Drug Administration FDA -approved antiviral treatments for adenovirus infection. Intravenous ganciclovir and cidofovir have been used in the treatment of seriously ill immunocompromised patients; however, both drugs have been associated with significant renal toxicity or neutropenia ,. Brincidofovir, a lipid-linked derivative of cidofovir, has also been used in the treatment of disseminated infections among immunocompromised patients ,. Intravenous ribavirin or ribavirin combined with immunoglobulin has been used in specific cases; unfortunately, failures with these drugs are common ,. Resumption of this program at military training centers took place in late October 2011 after a 12-year hiatus. Adenovirus Type 4 and Type 7 Vaccine, Live, Oral 1 dose , is administered to enlisted recruits 17 to 50 years of age. This vaccine can be administered simultaneously or at any interval before or after other vaccines, including live vaccines. There are specific contraindications, including individuals known to have sustained severe allergic reactions to any components of the vaccine, pregnant females, nursing mothers, or females considering pregnancy within 6 weeks of receiving the vaccine. Additional details of this vaccination program and its large impact on the U. Influenza pandemics of major importance to the military. During the 1918-1919 pandemic, an estimated 25% of the American Expeditionary Forces became ill. The case fatality rate CFR was estimated to be 5% range, 1. Moreover, an estimated 8. At Camp Funston, KS, for example, at one point during the peak of the first wave in February 1918, it was noted that as many as 50 to 150 patients were being hospitalized daily. During the 2009 pandemic, the U. Hospitalization rates were also 3 to 4 times higher than those for the two preceding years, with rates being as high as 60 to 100 per 100,000 person-years our unpublished data, 28 October 2014. A summary of the most notable reports on pH1N1-related deaths, outbreaks, and clusters in military-related populations during the period of April 2009 through December 2010 is presented in , , ,. Notable influenza deaths, outbreaks, and clusters in military-related populations due to pH1N1 virus from 2009 to 2010 a In general, there is great variability in terms of the ARs experienced; however, pH1N1 was noted to affect several risk groups, including i shipboard personnel 8% to 39% , ii recruits in initial entry training 7% to 70% , iii military high school-equivalent students 12% to 15% , iv military service academy students 11% , v advanced engineer military trainees 3% to 19% , and vi military personnel deploying to Southwest Asia SWA 5% to 10%. Outbreaks involved recruit training centers as well as installations where personnel were being processed for deployment to SWA , including large outbreaks at Fort Riley, KS; Fort Hood, TX; Fort Lewis, WA; and Fort Bliss, TX, with subsequent spread to U. Intervention control measures were evaluated in the course of these pH1N1-related outbreak investigations. These measures included i the use of mass antiviral oseltamivir chemoprophylaxis in a ship crew, shown by U. Navy investigators to limit pH1N1 spread ; ii implementation of early isolation, active case finding, early oseltamivir treatment, and chemoprophylaxis of medical staff, which was shown to limit large-scale spread to military members and the civilian populace in New York City ; iii evaluation of patient isolation and restriction measures in shipboard personnel, with limitation of influenza spread , ; iv early fever screening i. Seasonal influenza in the U. Seasonal influenza virus strains are also responsible for clusters of illness in the United States and remote areas where military personnel operate but are not usually associated with a high degree of morbidity. During the latest 5-year period 2007 to 2012 for which there are reported data from the AFHSC, influenza was found to be responsible for as many as 7,000 to 25,000 cases per week in the MHS, of which 3,000 to 16,000 40% to 65% involved military personnel. Although pH1N1 viruses have continued to circulate worldwide , drifted H3N2 viruses have begun to predominate, causing an increase in the number of laboratory-confirmed influenza-associated hospitalizations among both U. It appears that influenza-associated respiratory illnesses are also common among dependents of military personnel e. The influenza-related mortality rate among military personnel has been very low, with only nine influenza-associated deaths being documented during the past 16 years 1998 to 2014 , three of which occurred during the 2009-2010 pandemic period ; R. This relatively low mortality level most likely represents a true reflection of the low virulence of influenza virus during this period, as real-time, systematic reporting of military deaths is in place. Unfortunately, even though autopsies were performed on these cases, the data were often limited to the physician-determined cause of death, without additional pathogen laboratory workup or tissue analyses to better assess the underlying contributing factors or the role of other coinfections. There is no adequate dependent-based mortality registry to estimate the mortality impact for this group. Human infections with other avian-derived influenza viruses AIVs such as H5N1 have been reported since 1997 and are of concern to the military. As of May 2015, a total of 840 laboratory-confirmed human cases and 447 deaths have been reported to the WHO from 16 countries. Sporadic infections or small family clusters have been detected, especially among individuals living in the same household or those exposed to infected household poultry or contaminated environments ,. Fortunately, H5N1 does not appear to transmit easily among humans, and the risk of community-level spread remains low ,. To date, there have been no reported H5N1 infections in the U. Attendance at animal fairs where close contact between swine and young children takes place and at which there is a lack of personal hygiene interventions e. These viruses have the capacity for easier spread from pigs to people than other swine-origin viruses, and limited transmission between humans has also been documented on three separate occasions ,. H3N2v viruses are considered to be of human concern, with potential for epidemic spread among highly susceptible, younger age groups. Enhanced vigilance among swine-exposed populations, increased sanitation, and simple personal hygiene measures are believed to play an important role in the containment of these viruses. As of May 2015, there have been no reported cases among U. The risk to military personnel is deemed to be low U. On 31 March 2013, the first three human infections with H7N9 virus were reported to the WHO by Chinese authorities. These viruses, which have become enzootic in China , , have spread efficiently among live-poultry market LPM workers, close household contacts, and health care providers HCPs in China and Hong Kong , and constitute a significant threat to the military. These novel triple-reassortant viruses cause severe disease in humans. They are closely related to low-pathogenic H9N2 avian viruses, which became endemic among poultry in the Far East, causing widespread outbreaks in 2010 through 2013 ,. H7N9 viruses appear to be more readily transmissible from animals to humans than H5N1 viruses, although human-to-human transmission continues to be limited , ,. As of May 2015, H7N9 viruses had caused a total of 657 laboratory-confirmed human cases, including 261 deaths among civilians who had been exposed mostly in LPMs , ,,. A case-control study conducted in April through June 2013 in eight provinces in China documented specific risk factors for H7N9 infection such as poultry contact in LPMs but not raising poultry at home, consuming poultry, or exposure in other settings such as farms or lakes with waterfowl. HW was found to be protective against infection. This epidemic continues to be spread from LPMs in China, and the risk of H7N9 infection to personnel in markets across Asia appears to be very high. Three waves of H7N9 virus activity have been seen: the first in February through May 2013; the second starting in October 2013 and tapering off in April 2014; and a third between November 2014 and April 2015 , , ,; our unpublished data, 6 May 2015. Preliminary studies in mice indicate that infection with these H7N9 viruses is associated with increased lethality , similar to that seen with 1918 H1N1 virus infection. To date, there have been no reported cases of H7N9 infection in the U. Additional AIVs continue to emerge or reemerge in East and Southeast Asia ,. These influenza virus subtypes do not currently appear to transmit easily among people; thus, their risk of community-level spread or threat to the military remains low ,. At least three H10N8- and three H5N6-associated cases of severe pneumonia, each of which was fatal, were identified in China between November 2013 and February 2015. Additionally, one ILI case due to H6N1 was reported in China, and three ILI cases due to H9N2 were reported in China and Egypt. Human infection with the latter four subtypes probably represents spillover from LPMs or backyard poultry farms, which act as gene sources facilitating reassortment of AIV gene segments. Elsewhere, two asymptomatic H1N2 infections in swine farmers in Sweden were reported in April 2014; no further swine-to-human or human-to-human transmission has been documented in this instance. Lastly, but of great concern in the United States, 18 human infections 1 death due to influenza A H1N1 v viruses have been detected since December 2005 , ,. Thus, these novel subtypes may continue to spread, and additional surveillance of high-risk populations is needed to reveal the extent of their circulation , ,,. No cases due to these additional AIVs have been identified in the U. Clinical spectrum of illness. Seasonal influenza viruses H1N1, H3N2, and B subtypes have a very short incubation period median, 2 days; range, 1 to 4 days , which may be longer up to 8 to 9 days for infections caused by other AIVs ,. Shedding begins 24 to 48 h prior to symptom onset, peaks within 48 to 72 h after onset, and can continue for up to a week after symptom resolution, especially among nonimmune individuals. Hospitalized adults may shed infectious virus for up to a week or longer after illness onset. Viremia rarely occurs in uncomplicated influenza, except in cases of H5N1-infected patients, for whom detection of viral RNA in blood is associated with a worsened prognosis. Most adults with symptomatic influenza virus infection have uncomplicated illness, with sudden onset of fever, cough, headaches, and malaise, which resolve over 3 to 5 days, although cough and fatigue may persist longer; some adults with pH1N1 virus infection may also have diarrhea. Although most persons with influenza virus infection do not develop critical illness, those who are pregnant , or obese , are at a greater risk of respiratory complications and mortality. Deterioration in clinical status occurs rather rapidly, 4 to 5 days after symptom onset, with development of acute respiratory distress syndrome ARDS characterized by hypoxemia, shock, and multiorgan dysfunction , , an illness which is the result of an intense inflammatory host response to the virus. Influenza infections may also be complicated by secondary bacterial pneumonia, especially with Staphylococcus aureus including methicillin-resistant S. Influenza virus can be readily isolated in tissue culture rhesus monkey kidney cells, Madin-Darby canine kidney cells, cynomolgus monkey kidney cells, and Vero cells of nasal aspirates or nasopharyngeal NP swabs ,. As with adenoviruses, the time required to detect influenza viruses in cell culture can be shortened to 1 to 2 days by employing SVCC systems followed by fluorescent-antibody staining. Rapid diagnosis can also be facilitated by commercially available RIDTs. These tests are antigen detection tests that detect influenza virus nucleoprotein antigen. They can provide results at bedside within 15 min or less ; thus, results are available in a clinically relevant time frame to inform clinical decisions. Unfortunately, RIDT sensitivities have varied widely 10% to 80% compared to viral culture or reverse transcriptase PCR RT-PCR and are dependent largely on the type of sample as well as on the patient's age and phase of illness. RIDT sensitivity is lower in adults and elderly patients than in young children, whose nasal secretions may contain larger quantities of virus ,. RIDT sensitivity is also likely to be higher early in the course of illness within 48 to 72 h of onset , when viral shedding is maximal. Thus, care should be exercised when utilizing RIDTs later in the course of illness, as sensitivity can be low as viral shedding decreases. Two recent FDA-cleared assay systems that rely on instrument optics to determine an objective result, as opposed to a subjective read by the operator, may improve the sensitivity and specificity of RIDTs. Sample processing automation, combined with user-friendly platforms for NAATs and information management systems, facilitates high-throughput molecular diagnostics for the detection of viral nucleic acids, including those of influenza A virus, from a variety of respiratory tract samples. Molecular assays can be used in conjunction with other diagnostic assays, and with clinical and epidemiological information, to assist in patient management and treatment. A molecular-based testing platform, termed the Joint Biological Agent Identification and Diagnostic System JBAIDS , was developed by the U. Subsequently, its use was expanded to the rapid diagnosis of influenza A and B viruses in field operational settings. Additionally, in 2013 to 2014, U. Navy scientists at the Naval Health Research Center NHRC , in collaboration with the Swiss Armed Forces Spiez Laboratory, Spiez, Switzerland and the University of Hong Kong, evaluated an H7N9 influenza virus detection rapid test. By using clinical samples spiked with viral material, this point-of-care test was found to have a positive predictive accuracy of 95% and a negative predictive accuracy of 100%; however, true H7N9 clinical samples were unavailable for testing, and studies required for emergency use authorization by the FDA have been limited. Subsequently, this assay received FDA authorization for emergency use on 25 April 2014. This rapid detection test is intended for use by the U. Government USG laboratories outside the United States, for testing of American citizens living in and traveling abroad to China and other affected areas and who may be potentially exposed to H7N9 virus. Joint Biological Agent Identification and Diagnostic System. This ruggedized, deployable, and portable system for the field environment was first developed by the U. New FDA-cleared multiplex PCR tests that also allow the simultaneous detection of influenza virus as well as other respiratory agents, either as single viruses or as copathogens, have been made available ,, ,, ,. Among adult patients with ARI in one study using this type of testing in the United States in 2012 to 2013, 5% to 8% were found to sustain viral coinfections, including influenza virus, HCoVs, RSV, and HRV. One influenza virus typing kit based on the RT-PCR electrospray ionization mass spectrometry PCR-ESI-MS platform allows the detection of 16 hemagglutinin HA and 9 neuraminidase NA subtypes as well as detection of drift of specific genes over time ,. Because of its ability to detect recombination, drifting, or shifting events, PCR-ESI-MS typing analysis can be useful in detecting newly emerging influenza virus strains. However, this test is currently performed as a service only by AthoGen Carlsbad, CA. As with adenoviruses, serologic assays for influenza A and B viruses exist but are not routinely used for clinical diagnosis. However, these assays have important roles in outbreak response and epidemiological studies and can be used to help characterize the behavior of new influenza virus strains, such as the pH1N1, H3N2v, and H7N9 strains that have recently emerged , ,. Treatment and chemoprophylaxis modalities. The ion channel protein present within the viral envelope denominated the M2 protein is the target of the M2 inhibitors. In comparison, the NIs target viral neuraminidase, which acts on surface glycoproteins of the virus. The M2 inhibitors are active, in vitro and in vivo, against all strains of influenza A virus; however, they are not active against influenza B viruses, and antiviral resistance has increased since the emergence of the pH1N1 strain in 2009. Therefore, M2 inhibitors are not presently recommended for use in the United States. The NIs represent the main drug class for the treatment of influenza infection, notwithstanding a recently reported Cochrane review questioning their efficacy. In placebo-controlled randomized clinical trials RCTs , oseltamivir was found to be effective in reducing the duration of influenza symptoms by 21% from 123 h down to 98 h and the risk of hospitalization by 65% 0. In addition to recommending the use of influenza virus vaccine for preventing influenza, the CDC and the FDA recommend the use of NIs for the treatment of influenza infection ,. NIs have also been found to be effective in reducing mortality rates for patients hospitalized with pH1N1 virus infection, including, but not limited to, pregnant women ,. Oseltamivir may be less effective in patients infected with subtype B than in those infected with subtype A viruses ,. Early treatment after symptom onset e. An oseltamivir dosage of 75 mg twice daily should be given for at least 5 days in uncomplicated cases. An increased duration of up to 10 days, or a higher dose e. The FDA recently approved peramivir, a third NI treatment option, which is administered intravenously as a single 600-mg dose, for the treatment of uncomplicated influenza infection in adults. For severely ill patients with influenza who have strongly suspected or documented oseltamivir resistance or malabsorption, gastric stasis, or gastrointestinal bleeding, intravenous zanamivir, an investigational drug, can be considered; it is available through enrollment in a clinical trial ClinicalTrials registration no. Severely ill patients can also potentially benefit from combination therapies involving NIs and other antiviral therapeutic agents, although further controlled clinical trial data are needed to judge their efficacy. In patients with severe disease such as pneumonia or ARDS , empirical broad-spectrum antimicrobial therapy should be initiated to cover bacterial coinfections, with appropriate de-escalation of antimicrobials when lower respiratory tract bacterial cultures return with definitive results. Several additional non-NI classes of drugs under development hold special promise to enhance influenza treatment options. The first drug, nitazoxanide NTX , a first-in-class thiazolide anti-infective which is licensed in the United States for treatment of diarrhea caused by Cryptosporidium parvum and Giardia lamblia and which has been widely used in Latin America for treatment of intestinal parasitic infections, has been found to inhibit the replication of influenza viruses in cell culture. NTX has been found to be synergistic with NIs and to inhibit influenza viruses that are NI resistant ,. Treatment with NTX orally 600 mg twice daily for 5 days has been shown to reduce the duration of influenza-associated symptoms in subjects with acute uncomplicated influenza virus infection and may represent another alternative in the near future. The second drug, favipiravir T-705 , a viral polymerase inhibitor approved in Japan for the treatment of novel or reemerging influenza virus infections, has been shown to be effective orally. The third candidate drug, fludase DAS181 , a fusion agent which destroys sialic acid-containing cellular receptors for viral hemagglutinin, has been formulated as an inhalant, which can last for 2 or more days. This drug has been tested in a phase 2 RCT and was found to reduce viral replication, although its use has not been associated with improved clinical outcomes. The fourth and latest drug in advanced development, VX-787, another viral polymerase inhibitor, was recently shown to reduce viral shedding as well as attain reductions in the severity and duration of influenza-like symptoms in influenza-infected patients in a 2013 phase 2a study. Additional research efforts for the development and testing of anti-influenza drugs are available in the literature ,. In addition, in a recent meta-analysis of 32 studies of hospitalized patients with influenza, the use of convalescent plasma or serum was seen to be associated with lower mortality rates than those for untreated patients historical controls infected with 1918 H1N1, pH1N1, or H5N1 virus. However, RCTs to adequately judge their efficacy are lacking. Chemoprophylaxis has also been shown to be beneficial, if given for at least 7 days postexposure. Systematic reviews have found that NIs, but not M2 agents, provide some degree of protection as chemoprophylactic agents. Oseltamivir at a dose of 75 mg daily and zanamivir at a dose of 10 mg daily have been demonstrated to be efficacious as both seasonal 70% to 90% efficacy and postexposure 67% to 89% efficacy chemoprophylaxis against influenza virus in households. However, they have not been shown to prevent community-wide transmission of influenza virus ,. Inhaled laninamivir has also been shown to reduce secondary illness rates among household contacts 78% efficacy in a RCT and may represent a third option for chemoprophylaxis. At this time, neither the CDC nor U. However, the potential for the use of NI chemoprophylaxis can and should be considered by public health officials under the following circumstances: i during circulation of a highly virulent strain, ii for high-risk patients during outbreaks in confined facilities or homes, iii for unvaccinated HCPs, iv in a perceived or real compromise of a military mission, or v during an overwhelming epidemic. Vaccination in the U. The goal is to exceed 90% immunization of all military personnel by mid-December of each year; however, delays in receipt of vaccine and other logistic and access issues are taken into consideration, and all organizations are encouraged to continue efforts to immunize throughout the influenza season. Compliance among military HCPs for 2012 to 2013 and for 2013 to 2014 has been excellent, with vaccination rates exceeding 95% each year. In comparison, compliance rates among civilian HCPs in the United States have not exceeded 75%. For many years, the CDC recommended influenza immunization only for the aged and infirm, while the U. Finally, because of the important need for protection of military personnel, U. Even though a large proportion of U. First, humoral immunity is transitory, requiring annual immunizations. This is most likely explained by distinct patterns of B-cell activation and priming resulting in lower cross-protection against heterovariant and heterosubtypic influenza virus strains. Second, subtypes contained in annual vaccine formulations often do not match prevailing circulating subtypes; thus, vaccine-derived immunity is nonefficacious in many cases. Third, even under the best of circumstances, the rate of vaccine efficacy among healthy adults is no higher than 60% to 80% for inactivated vaccines and is much lower for live attenuated formulations, leaving many vaccinees susceptible to infection , ,. Finally, military personnel often travel or are deployed to areas of the world where prevailing influenza viruses differ from the subtypes included in U. Continued assessment of influenza vaccine efficacy and effectiveness in the U. Background historical information and epidemiology. RSV has a worldwide distribution and is associated with annual outbreaks of infection in late fall, winter, or spring. Unfortunately, immunity against either group A or group B strains is not long lasting, and reinfections in children and adults are common, even with the same strain. RSV was first identified as a potential military-relevant pathogen in 1959 among recruits at Fort Ord, CA. Shortly thereafter, military investigators at Camp Lejeune, NC, were able to document serologic evidence of infection and reinfection among Marine Corps recruits in 1961. The first large-scale study by Dutch military investigators in 1967 to 1968 identified RSV as a relatively uncommon cause of pneumonia among Dutch military recruits, responsible for 3% of radiographically proven cases of pneumonia. RSV infection was second only to adenovirus 21% as a cause of such illnesses. In NHRC-led surveillance of recruits during October 2011 through March 2013, RSV was found to be a significant pathogen, accounting for upwards of 6% to 8% of FRIs in the winter, and was often detected in association with other respiratory viruses. RSV was also documented to cause 10% to 14% of FRIs among Army recruits at Fort Benning, GA, and 14% of FRIs among Royal Navy recruits in the United Kingdom ,. RSV infection is also common among patients with ILI at U. MTFs 3% to 4% USAFSAM, unpublished data, 30 March 2015. In troops deployed to Iraq and Afghanistan 2004 to 2007 , asymptomatic infections were common, affecting 46% of those not previously immune. RSV has the potential to spread rapidly through a military unit; high ARs may occur under conditions of overcrowding or deficient personal sanitation ,. Aerosol and fomite transmissions are common, especially in nosocomial settings, where sustained outbreaks have been documented. This possibility is supported by civilian-based studies in household contacts of index cases, where rates of secondary transmission to older siblings and adults have been documented to be as high as 33% to 50%. Epidemiological studies of RSV in military settings are needed in order to assess this pathogen's transmissibility and military impact. Clinical spectrum of illness. Viral shedding may be longer lasting in children 1 to 3 weeks than in adults usually no longer than 1 week. Other presentations, such as acute bronchitis, ILI, pneumonia, and exacerbations of asthma and chronic bronchitis, have also been described in adults with RSV infection. In children, but not adults, bronchiolitis has been associated with a family history of asthma as well as with secondhand exposure to cigarette smoke. It is unknown if these predisposing factors have any relevance in the military. RSV can be diagnosed by observation of cytopathic effects in HEp-2, HeLa, or A549 cell cultures as early as 2 to 7 days following specimen inoculation. As with influenza viruses and adenoviruses, the time required to detect RSV in cell culture can be shortened to 1 to 2 days by employing SVCC systems followed by fluorescent-antibody staining. Rapid antigen detection tests RADTs have been developed; however, the sensitivity of such tests is greatly dependent on the quality of the specimen, with NP aspirates being superior to NP brushing or swab specimens. As with RIDTs, these RSV antigen detection tests are also more sensitive in children than in adults, given the higher level of RSV shedding in children. Microarray- and nanochip-based assays for RSV detection have been marketed in the United States as part of larger panels for respiratory pathogen detection ,. RSV is also one of the viruses easily detected in respiratory specimens by several FDA-approved multiplex PCR assays , , , , ,. RSV is often included in smaller multiplex PCR tests that also detect influenza virus A and B subtypes , , , , and an FDA-cleared duplex real-time PCR assay also exists. Treatment and chemoprophylaxis modalities. Aerosolized ribavirin is the only FDA-approved antiviral treatment for RSV ,. It has been found to have high levels of in vitro activity against RSV, reduce viral shedding, and shorten the course of illness in some studies. However, it is recommended only for patients at high risk for serious disease. Ribavirin is difficult to administer, and its effectiveness in adult stem cell transplant patients has been questionable. It is uncertain if this treatment would be of benefit in otherwise healthy adults or in military populations. A promising drug under development is a fusion inhibitor, GS-5806, which blocks RSV replication by inhibiting F-mediated fusion of RSV RNA. It was shown to modulate RSV infection e. This drug appears to be safe, with only mild transient elevations in serum aminotransferase levels and reversible decreases in neutrophil counts. Additional treatment approaches, such as inhaled nanobodies, aerosolized peptides, nucleoside analogues, and RNA interference molecules, need to be explored in RCTs and are discussed elsewhere ,. Subsequently, a safer, humanized anti-F glycoprotein monoclonal antibody formulation, palivizumab, was developed commercially and approved by the FDA in 2009. Used as a prophylactic medication, palivizumab requires monthly administration and has been shown to reduce morbidity as well as RSV-associated hospitalization rates by as much as 45% to 55% in controlled trials ,. There are no licensed vaccines for RSV. The main problem has been the lack of a strong and robust protective immune response following formalin-inactivated vaccine administration. In addition, enhanced pulmonary disease due to immune complex activation with formalin-inactivated RSV vaccines has been described; in a large trial in the late 1960s, a number of subjects required hospitalization, and two deaths occurred. Given that this initial trial of an inactivated RSV vaccine gave disappointing results, a number of vaccine candidates have subsequently been developed. Background historical information and epidemiology. Human coronaviruses HCoVs , first isolated in the 1930s, include a broad range of enveloped RNA viruses which can be classified into two main groups, groups I and II. Group I includes strains 229E and NL63, and group II includes strains OC43 and HKU1. In addition, novel coronavirus strains, such as SARS-CoV and Middle East respiratory syndrome coronavirus MERS-CoV , are also members of group II; however, their antigenic and virulence characteristics separate them clearly from the more common HCoVs causing upper respiratory tract illnesses. SARS-CoV was first identified in China in November 2002 and spread first to Hong Kong; then to countries in Southeast Asia, Europe, North America; and finally throughout the world. This outbreak stimulated such a rapid and intense public health response that, by July 2003, transmission had ceased, without reappearance in the past 12 years. HCoVs are transmitted by means of respiratory aerosols and by the fecal-oral route, targeting primarily mucosal surfaces of the respiratory and gastrointestinal tracts and causing illnesses of various severities. Their potential for person-to-person transmission is very high, and viral shedding starts at symptom onset and can last for up to 10 days in the case of SARS-CoV. Thus, strict isolation precautions are needed in order to control their spread, especially within health care facilities. HCoVs are considered to be a threat to the U. There are two well-documented reports that illustrate the relevance of HCoVs in the recruit training setting ,. In the most recent one, involving U. In the second report, involving Marine Corps recruits in Parris Island, SC, in the early 1970s, strain OC43 was identified in one winter, with 1% to 2% of such recruits sustaining infections and some of them being hospitalized for characteristic ARD. HCoV infections are an uncommon cause of ILI among patients seen at U. HCoV outbreaks among deployed military populations have not been well documented to date; however, further studies are warranted to better assess their impact on the military. MERS-CoV, an emerging pathogen with pandemic potential. A total of 25 countries have been affected worldwide , , ,. All primary cases were exposed in the Middle East; however, in South Korea in May—June 2015, for the first time, an imported case has resulted in secondary transmission to other patients and family members. The majority of the infected HCPs presented with no or minor symptoms; many of these HCPs were asymptomatic contacts identified through screening of close contacts of confirmed cases ,. Additional cases have also been reported among other patients receiving treatment for conditions unrelated to MERS-CoV and among people visiting MERS-CoV-infected patients. In the initial hospital-based cluster in Jordan in April 2012 , a total of six HCPs were subsequently found to be infected by serology, and the infection rate among potentially exposed hospital personnel was found to be 10% 6 of 57 exposed. More recently, in 2014 to 2015, four clusters involving health care settings were reported in the Kingdom of Saudi Arabia KSA 2 hospitals and 255 cases , the United Arab Emirates UAE 1 hospital and 37 cases , and the United States 1 hospital and 2 cases ,. Fortunately, MERS-CoV strains have not undergone further adaptation to enhance sustained human-to-human transmission, other than in health care settings. As of this writing, at least 33 patient clusters involving close contacts have been identified, predominantly in the Arabian Peninsula our unpublished data, 28 May 2015. The low reproduction number R 0 estimates have been as low as 0. No MERS-CoV infections have been identified in the U. Clinical spectrum of illness. Mild to moderate upper respiratory symptoms may be variable in duration, lasting anywhere between 3 and 18 days. Otitis media, asthma exacerbations, and pneumonia can also be seen in young healthy adults but are less common , ,. Lower respiratory tract illnesses occur more frequently in older adults, in those with cardiopulmonary disease, or in immunocompromised patients ,. SARS-CoV and MERS-CoV represent a phylogenetically distinct, more virulent family of coronaviruses. SARS-CoV-associated disease usually presents with fever, headache, malaise, and myalgias, followed by nonproductive cough and dyspnea. Rhinorrhea and pharyngitis are notably absent. A quarter of infected people also have diarrhea ,. Another quarter of cases, mostly older adults or those with comorbidities, develop ARDS, with mortality rates reaching upwards of 12% ,. Chest radiographs demonstrate bilateral lower lobe and peripheral airspace opacities. Chest computed tomography can show ground-glass densities, consolidation, or a combination of the two patterns ,. Laboratory examination often reveals lymphopenia as well as elevated serum creatine kinase, lactic dehydrogenase, and aspartate aminotransferase levels , , ,. While still a relatively newly described pathogen, MERS-CoV, much like SARS-CoV, may cause acute severe respiratory illness consisting of fever, cough, dyspnea, and pneumonia and progression to ARDS, multiorgan failure, and death. MERS-CoV-infected patients often develop severe respiratory symptoms due to pneumonia, and some suffer from diarrheal symptoms ,. The estimated CFR is roughly 37% to 40%, although earlier in the epidemic in late 2013, the CFR was estimated to be as high as 51% to 65% , , ,. HCoVs originally were not thought to be connected to severe human illnesses; however, the emergence of SARS-CoV and later MERS-CoV during the past decade has changed the approach that clinicians take toward their treatment and control. Diagnostic modalities and control. Viral culture, antigen detection, molecular methods, and antibody tests can be used to identify HCoVs. Only specialized reference laboratories, such as those at the CDC, are able to apply all these methods. Routine clinical diagnosis is performed by molecular methods, specifically rRT-PCR, which is favored for diagnosis. Secretions from the upper e. Obtaining specimens from multiple sources and later during infection increases the yield , ,. Tests that combine several specific primers and probes have reportedly shown good performance. Although at least two multiplex PCR assays can be used for PCR-based diagnosis of HCoV strains HKU1, NL63, 229E, and OC43 , , only the nested multiplex PCR system has been cleared by the FDA. As the microbead-based method is likely to be used to detect other respiratory pathogens, this assay can find use under alternate accreditation schemes, such as those of the College of American Pathologists and the Commission on Office Laboratory Accreditation. Additionally, immunofluorescence assays IFAs are available for the detection of all HCoVs. Various serologic assays are available for antibody detection of coronavirus infections, including complement fixation, hemagglutination inhibition, neutralization, IFAs, and ELISAs. Although they are less frequently used for clinical diagnosis, serologic assays play a very important part in diagnosis during outbreak investigations and epidemiological studies. IgM antibody can be detected acutely for 3 to 4 weeks. IgG antibody appears as soon as 10 days after symptom onset and can be detected in all patients by 4 weeks. The CDC has provided interim guidance for health professionals on which types of patients and contacts should be evaluated for MERS-CoV infection ; military-specific guidance has been provided by the AFHSC. All HCoVs can be detected by the PCR-ESI-MS test platform mentioned in the influenza diagnostics section above. In one civilian-based study, HCoVs represented the third most common viral pathogen detected among patients with respiratory symptoms, being exceeded only by influenza virus and RSV. It should be noted that since MERS-CoV patients may shed virus for periods as long as 30 days or more, extended PCR testing may be necessary for patients and contacts infected with this pathogen. Standard, contact, and airborne precautions are recommended for the management of hospitalized patients with known or suspected MERS-CoV infection. Although these recommendations focus on the hospital setting, the recommendations for personal protective equipment PPE , source control e. In addition, the WHO has provided i updated recommendations on the control of infection among at-risk groups , ii updated recommendations on the control of international spread , and iii travel advice on MERS-CoV for pilgrimages to the Middle East. Treatment modalities and vaccines. There are no FDA-approved drugs for the treatment of any of the HCoVs. During the SARS-CoV-associated epidemic of 2002 to 2003, oral and intravenous ribavirin with and without corticosteroids were used; however, ribavirin was subsequently found to show little antiviral activity in vitro. Clinical studies suggest some benefit of corticosteroids and interferon alpha, and in vitro studies have demonstrated some activity with the protease inhibitor combination of lopinavir and ritonavir. However, no study to date has demonstrated conclusive evidence that any of these treatments has had any benefit for SARS-CoV-infected patients. In contrast to the experience with SARS-CoV, recent treatment of patients with severe MERS-CoV infections in the KSA with oral ribavirin and interferon alpha has been shown to improve short-term 14-day and 28-day survival, with survival rates of 70% and 30%, compared to 29% and 17%, respectively, for those who did not receive such therapy. Controlled studies of these and other therapies, such as lopinavir, mycophenolate, cyclosporine A, and chloroquine, in randomized trials of MERS-CoV-infected patients need to be conducted in order to further assess their efficacy. Additionally, the use of convalescent plasma or highly neutralizing antibody preparations appears to be safe, represents a promising intervention that warrants careful clinical study, and may offer additional therapeutic options in the near future , ,. National Institutes of Health NIH and industry partners are supporting the development and testing of drugs to treat MERS-CoV infection , including small-molecule inhibitors, monoclonal antibodies, and NTX, an approved antiparasitic drug already shown to be efficacious for influenza see above. The WHO has also provided guidance on the clinical management of MERS-CoV-infected patients. Vaccine development approaches are also being sought by the NIH, including DNA-based vaccines, recombinant proteins such as virus-like particles, peptides, inactivated and live attenuated vaccines, and virus vectors. Background historical information and epidemiology. First described by investigators in the Netherlands in 2001, hMPV was originally isolated from nasopharyngeal secretions of children with upper respiratory tract infections. Parainfluenza virus type 1 PIV-1 to PIV-4 and rhinoviruses, first isolated in the 1950s, represent the most common etiologic agents of the common cold, having been implicated in as many as 30% to 50% of such cases ,. Serologic studies appear to indicate that exposure to hMPV is universal by the age of 5 years and that these viruses have been circulating for at least 50 years. In temperate climates, circulation of hMPV is detected mostly during late winter and early spring months, frequently overlapping the circulation of influenza virus and other seasonal respiratory pathogens. In comparison, PIV-3 tends to occur year-round, whereas other PIV types cause annual epidemics in the fall ,. Human rhinovirus HRV infections can occur throughout the year; however, they are most predominant in the fall, winter, and spring ,. Human metapneumovirus represents the third most common cause of serious lower respiratory tract disease in children, behind RSV and influenza virus. It can also be a relatively frequent cause of pneumonia in adults. Important hMPV-associated outbreaks have taken place in the United States in 2012 among older adults in skilled-nursing facilities in West Virginia and Idaho; at two such facilities, 57 cases were identified, 25 56% of whom had radiologically confirmed pneumonia and 6 11% of whom died. Outbreaks of hMPV and PIV have not been well documented among military populations to date. In comparison, recent respiratory illness surveillance of recruits and U. Among patients with ILI seen at U. Finally, in routine surveillance of FRI cases among Singaporean military personnel May 2009 through October 2012 , infection rates of 1. As shown by the data presented above, these three pathogens are being increasingly recognized as significant causes of respiratory illnesses among military personnel. As with other respiratory viruses, person-to-person transmission is common with these three pathogens , , ,. Therefore, these pathogens have been included in this review as military-relevant pathogens, given their propensity for transmission in closed, crowded environments as well as additional factors such as their endemicity in the general population, the lack of effective long-term immunity in humans, and their capacity for reinfection over the course of a lifetime. Clinical spectrum of illness. The incubation period for hMPV is between 3 and 5 days, although little is known about this pathogen , ,. In healthy adults, these viruses cause upper respiratory tract infection commonly presenting as ILI or as a syndrome consistent with the common cold. Symptoms include fever, chills, cough, and rhinorrhea. Conjunctivitis, pharyngitis, laryngitis, and pneumonia are less frequently observed. Among recruits, HRV infections have been associated with lower respiratory tract symptoms of shortness of breath and diagnoses of pneumonia ,. In young, otherwise healthy adults, these three pathogens usually cause mild self-limited illnesses , ,. Among hMPV-infected patients, however, lower respiratory tract symptoms, including dyspnea and wheezing, can appear with older age, resembling the symptomatology seen in younger RSV-infected patients. For patients infected with hMPV, chronic obstructive pulmonary disease exacerbations have also been noted to occur. In the case of hMPV and PIVs, individuals who are immunosuppressed or with cardiopulmonary comorbidities are at a greater risk for community-acquired pneumonia CAP and hospitalization , , ,. Transmission with these three pathogens likely occurs as a result of direct or indirect contact with infected secretions spread by fomites or via large-particle aerosols, similar to transmission with other respiratory viruses. In addition to the recommended standard and droplet precautions, as for influenza virus control, the infection control measures for these should include contact precautions to prevent transmission by contact with infected secretions and fomites. Identification of these three pathogens is performed by amplification in viral culture , , , , using IFA-based direct detection , PCR detection by NAATs , , , and, albeit rarely, antibody detection. Viral culture of hMPV requires special conditions and up to 21 days to note a cytopathic effect. It also requires confirmation of hMPV infection by using an IFA with hMPV-specific antibodies or RT-PCR of the cell supernatant ,. An IFA using virus-specific monoclonal antibodies is available but is deemed to be less sensitive than RT-PCR. Thus, molecular methods are favored for the detection of hMPV. Several genes, including those for the F, N, M, and L proteins, have conserved regions that can be used for amplification using RT-PCR. Infection is confirmed by amplification of two different gene products. As hMPV is commonly detected in conjunction with other common respiratory pathogens , the above-mentioned multiplex PCR assays that detect several pathogens in nasal or respiratory secretions are commonly used in the clinical setting , , ,. An FDA-cleared duplex assay specific for hMPV and RSV is also commercially available. PIVs can be readily detected by viral culture in primary rhesus or cynomolgus monkey kidney cells and a monkey kidney line, LLC-MK2, within 3 to 7 days. HRVs can be isolated in human diploid embryonic lung cells e. As with influenza viruses, adenoviruses, and RSV, SVCC systems followed by fluorescent-antibody staining can also rapidly detect PIVs and HRVs within 1 to 2 days. Detection of PIV and HRV nucleic acids is done mainly in the context of the broad multiplex PCRs mentioned above ,. Both bead-based and electrochemical-based methods can specifically detect PIV-1 to -3, while the nested multiplex PCR system can detect PIV-1 to -4. A stand-alone PCR assay that can detect and distinguish PIV-1 to -3 is commercially available for use on many standard laboratory platforms. The complicated HRV phylogeny often makes it difficult to design PCR assays that can capture the breadth of the rhinovirus species without cross-reacting with other viruses from the Enterovirus genus. No specific tests for any HRV genome type exist as yet, although a recently issued emergency use authorization by the FDA will allow enterovirus D68 diagnostics to be rapidly developed. Identification of the exact HRV serogroup requires follow-up nucleotide sequencing. Although not used for routine clinical diagnosis, serologic assays are available for these three pathogens in research settings for use in seroepidemiological studies requiring acute- and convalescent-phase sera with at least a 4-fold rise in antibody titers , , ,. There are no FDA-approved drugs for the treatment of hMPV-, PIV-, or rhinovirus-associated respiratory illnesses , ,. There have been no RCTs evaluating the efficacy of ribavirin or other antiviral therapies for these three pathogens. Ribavirin has been found to be effective against other paramyxoviruses in vitro and in vivo such as RSV and could potentially be used to treat hMPV infection. One study also suggested that ribavirin with intravenous immunoglobulin IVIG has antiviral activity against hMPV in vitro. This combination has been used for the treatment of severe hMPV infections in immunocompromised patients. The use of ribavirin as an aerosolized or intravenous preparation for treatment of PIV infection after heart and stem cell transplantation has been reported in anecdotal cases; however, controlled studies are lacking. Fludase DAS181 may be effective for the treatment of immunocompromised patients with severe PIV-related lung disease, with reductions in viral load being associated with clinical improvement ,. Human monoclonal antibody therapy with palivizumab and other formulations has been attempted in hMPV-infected animal models; however, there are no adequate data to support their use as an adjunct to supportive therapy among humans. Animal studies have also shown promise in terms of the use of hMPV-specific fusion inhibitors, which are currently in development. Even more constrained, and despite considerable effort, there are currently no commercially available therapeutic interventions with proven efficacy for the treatment of HRV infections. Interferon beta has been found to reduce asthma-related symptoms in one study of Japanese children with virus-associated exacerbations; its efficacy in adults is unknown, however. Vapendavir, an antiviral used in picornavirus-infected patients, has been found to reduce viral loads in HRV-infected patients and may represent a future treatment option. There are no licensed vaccines for hMPV, PIVs, or HRVs. Approaches to such vaccine development have included i live attenuated vaccines, ii subunit vaccine constructs, and iii virus-like particle vaccines. The development of inactivated vaccines has been abandoned after the use of a formalin-inactivated hMPV vaccine led to an increase in lung disease in animal models and hypersensitivity responses similar to those seen among children given formalin-inactivated RSV vaccine. An excellent review of hMPV vaccines in development by Principi and Esposito provides further details on this topic. In contrast, inactivated vaccines for PIV-1 to -3 have not been associated with side effects similar to those of hMPV vaccines, and such approaches, as well as subunit and live attenuated vaccine approaches, have continued to be pursued. Background historical information and epidemiology. In the past 2 decades, major pneumococcal outbreaks have continued to occur among unvaccinated military personnel, including i Marine Corps trainees at Camp Pendleton, CA, in 1990 and 2000, with hundreds of cases ; ii U. Army Ranger students at Fort Benning, GA, in 1990 and 1998 to 1999, with increased rates due to cessation of benzathine penicillin G BPG chemoprophylaxis , ; iii U. Navy shipboard personnel off the coast of Italy in 1991 our unpublished data, 28 May 2015 ; iv Russian military trainees in the 1990s, with CAP rates as high as 5% to 20% , ; v Israeli Defense Forces and Indian Army recruits in 2005 , ; vi Finnish military recruits in 2006 ; vii several U. Army recruit training units during the period of 2000 to 2008, with hundreds of pneumonia cases U. Army recruits at Fort Leonard Wood, MO, with 2 meningitis deaths and an additional 72 pneumonia cases. These outbreaks highlight the relevance of this pathogen, particularly among recruits undergoing intense physical and psychological training. Pneumococcus and influenza: what is the connection? Of relevance to the military is the interaction between the pneumococcus and influenza viruses, as these are important interactions in terms of enhancement of their infectivity and pathogenicity. Detailed examination of the interaction between these two pathogens suggested several possible mechanisms ,. Second, higher pneumococcal NP carriage rates are seen during winter months due to increased crowding, reduced ventilation, and the facilitating effect of other upper respiratory tract viral infections. Third, clear increases in pneumococcal pneumonia rates were seen among military populations during previous pandemics , especially in 1918, when influenza infection was documented to increase the risk of infection with other bacterial pathogens such as S. Fourth, reported studies of CAP and pneumococcal pneumonia hospitalizations in the United States documented that concurrent influenza infection increases the risk of pneumonia in patients of all ages. Sixth, in ferret animal models, pneumococcal infection of already influenza virus-infected animals has been shown to result in more severe disease than infection with either pathogen alone. Finally, recent studies of the live attenuated influenza vaccine LAIV have shown 2- to 5-fold increases in the mean duration of NP carriage as well as densities of S. Clinical spectrum of illness. The incubation period for pneumococcus-associated respiratory illness is usually 1 to 3 days, although infection is thought to be preceded by asymptomatic colonization of the upper respiratory tract. As suggested by its name, S. Infections range in severity from mild lower respiratory illness to severe overwhelming sepsis with a high mortality rate. Pneumococcal pneumonia generally presents acutely with rigors and productive cough with rusty sputum. Chest pain, nausea, vomiting, diarrhea, and confusion may also occur. It can infrequently be associated with fulminant diarrhea, known as croupous colitis. Diagnosing pneumococcal pneumonia has its challenges, as there is not one diagnostic test that is completely sensitive or specific. Diagnosis is routinely performed by sputum culture, although the yield is variable and depends on whether antimicrobials have already been administered, how the specimen is obtained, and the criteria by which it is evaluated ,. The Infectious Diseases Society of America IDSA recommends sputum Gram's stain and culture for those patients with CAP and any one of the following: i failed outpatient therapy, ii intensive care unit admission, iii cavitary infiltrates upon imaging, iv pleural effusion, v history of alcohol abuse or severe obstructive or structural lung disease, or vi a positive Legionella or pneumococcal urinary antigen test result. Blood cultures should always be part of the workup for these patients. The pneumococcal urinary antigen test constitutes a rapid bedside diagnostic antigen detection card test and represents a convenient way to diagnose or rule out S. Its sensitivity and specificity have been estimated to be 70% and 96%, respectively, among hospitalized patients. Several promising research assays have been developed for the PCR amplification of pneumococci from respiratory specimens, but none are yet FDA cleared ,. A challenge for the use of these assays on respiratory specimens is interpretation of their results, given that PCR assays done on respiratory specimens do not distinguish between pneumococcal carriage e. Quantitative PCR can provide better accuracy with the use of the lytA gene target, raising the sensitivity to 94% and the specificity to 96%. Diagnostic imaging for pneumococcal pneumonia may reveal a variety of findings that are nonspecific. Chest radiographs may reveal one or more of the following: i lobar opacities, ii patchy bronchopneumonia, or iii an interstitial pattern. It is rare to find cavitation or necrotizing pneumonia, unless another organism is implicated ,. Early initiation of empirical antimicrobial therapy improves patient outcomes ,. Final antimicrobial therapy should depend on the patient's condition and the antimicrobial sensitivity profile of the isolate. For penicillin-sensitive isolates, penicillin G or amoxicillin is preferred. There are three different MIC breakpoints for penicillin and S. For individuals with a penicillin allergy, and in order to avoid cross-allergy with first-generation cephalosporins , a macrolide, a second- or third-generation cephalosporin, clindamycin, doxycycline, or a fluoroquinolone can be used. For penicillin-resistant isolates, the drug should be chosen based on antimicrobial susceptibility testing results. A cephalosporin or fluoroquinolone is a likely choice. Alternatives include vancomycin, linezolid, or high-dose amoxicillin. Use of the rapid urinary antigen test mentioned above allows narrowing of therapy to amoxicillin in test-positive young military personnel with nonsevere CAP and can be used as an adjunct for patient evaluation prior to more definitive antimicrobial susceptibility testing results ,. In cases of influenza virus coinfection, it appears that the increased susceptibility to bacterial invasive disease and pneumococcal pneumonia is especially pronounced within the first 7 days of influenza virus infection. In cases of influenza virus and bacterial coinfections, it may be wise to initiate combination therapy with NIs and clindamycin plus azithromycin ,. Management of bacteremic S. In observational studies, critically ill patients with bacteremic S. Although there are few evidence-based data regarding the duration of treatment, antimicrobials are generally prescribed for 5 to 7 days for mild disease, or for 3 to 5 days after the patient has defervesced for severe disease. Combination therapy for severe bacteremic pneumonia is usually limited to 3 to 5 days or until antimicrobial susceptibility testing results are available, followed by monotherapy to finish a 10- to 14-day course. For critically ill patients, combination therapy can be continued until a clinical response is attained. Pneumococcal disease prevention in the military. Military pneumococcal pneumonia outbreaks have been halted by using mass antimicrobial chemoprophylaxis , , mass pneumococcal vaccination , , , or a combination of both ,,. The administration of antimicrobials is important, since the response to the pneumococcal vaccine takes at least 7 to 10 days to be effective, while in such outbreaks, an immediate response is needed. The provision of long-acting drugs, such as BPG or a macrolide such as azithromycin or erythromycin, is also well justified in order to eradicate NP pneumococcal carriage and achieve a prolonged reduction of spread of the implicated S. Unfortunately, pneumococcal vaccines have not shown consistent effectiveness in reducing NP carriage rates and subsequent spread to susceptible personnel. Moreover, in a large RCT of the 23-valent pneumococcal vaccine among U. Influenza vaccination has been shown to reduce secondary bacterial infections, including pneumococcal infections and pneumonia, and should be routinely administered to personnel at high risk ,. Finally, smoking has been found to increase pneumococcal NP carriage and illness rates and should be strongly discouraged. Pneumococcal vaccination of military recruits or other trainees at high risk of infection such as U. Army Ranger students as well as all smokers may be advisable and is consistent with U. Background historical information and military impact. Group A streptococcus respiratory infections have had a long history of impact on the U. In more recent times, streptococcus-related respiratory disease has continued have an impact on the military. A summary of the most notable streptococcus-associated respiratory illness outbreaks and reports in U. No fewer than 17 separate outbreaks involving thousands of cases were recognized by U. Since 2011, no streptococcal respiratory disease outbreaks have been documented in the U. Jordan, personal communication, 6 February 2015. Major streptococcus-associated illness outbreaks and reports in U. Risk factors associated with group A streptococcus infection have included i participation in recruit training, ii increased crowding in unit billeting areas, iii lack of antimicrobial chemoprophylaxis, iv close contact with an S. Of these risk factors, organism shedding by asymptomatic NP streptococcus carriers is the key factor that begins and prolongs outbreaks in the military setting. This one issue was recognized as the single control point in an outbreak among Marine Corps recruits in 1989, where prolongation of the outbreak was attributed to shedding by untreated carriers. Because of the complexity in diagnosis of infection and the important role that streptococcal carriers play, chemoprophylaxis and treatment of all members of the high-risk population are important. Clinical spectrum of illness. In adults, it can follow a primary viral infection, such as infection with varicella virus, which induces a relative state of immunodeficiency. Streptococcus pyogenes can cause uncomplicated respiratory and skin infections, severe invasive infections, and postinfectious autoimmune illnesses. This review focuses on uncomplicated group A streptococcal pharyngitis and tonsillitis. Cases appear to predominate during the winter, probably due to increased crowding and close proximity of recruits. Physical examination of the posterior pharynx may reveal erythema, edema, lymphoid hyperplasia, tonsillar enlargement, and exudates. Generally, the fever resolves first, within 4 to 5 days, followed by resolution of the other symptoms within 1 to 2 weeks. Scarlet fever may accompany streptococcal pharyngitis and presents as a blanching erythematous rash involving the trunk, limbs, face, and neck. Less commonly, group A streptococcal pharyngitis may be followed by suppurative complications as a result of direct extension or systemic streptococcal spread and toxin-mediated tissue damage. These suppurative complications include peritonsillar or retropharyngeal abscesses, suppurative lymphadenitis, mastoiditis, sinusitis, otitis media, meningitis, brain abscesses, venous sinus thrombosis, pneumonia, and necrotizing fasciitis ,. Pneumonia due to group A streptococcus has also been known to follow influenza virus infection , , including rapidly fatal hemorrhagic pneumonia. These severe complications are usually associated with mucoid strains harboring a specific emm gene, which encodes the cell surface M virulence protein and which forms the basis for typing of S. Hematogenous spread may result in suppurative arthritis, endocarditis, meningitis, brain abscess, osteomyelitis, or liver abscess. Postinfectious autoimmune syndromes following streptococcal pharyngitis can present as acute rheumatic fever or acute glomerulonephritis and are not discussed here. Adults with acute pharyngitis often present with clinical features suggestive of a viral etiology. In the absence of these features rhinorrhea, cough, oral ulcers, or hoarseness , the IDSA recommends diagnosing group A streptococcal pharyngitis by using a throat swab. RADTs are highly specific, more cost-effective, and less labor-intensive and have a quicker turnaround time, so they are more frequently used in the clinical setting. Streptococcal culture may be clinically useful when RADT results are negative and the clinician has a high index of suspicion, especially for children and adolescents but not necessarily for adults ,. As with many situations, molecular assays are increasingly being used to clinically detect streptococcal infections in affected patients. The increased sensitivity of molecular assays compared to that of culture is in part due to their ability to detect nonviable material that may still be present in the affected area. One method cleared by the FDA is the loop-mediated isothermal amplification LAMP test. This test is advantageous in terms of ease of use and time to result; however, identification is made by measuring pyrophosphate precipitation, a by-product of polymerase activity. Thus, LAMP does not distinguish which target was amplified, only that amplification took place. This system moves the patient sample through a series of physically separated sections of a tube to perform each step of sample extraction and amplification. Both of these systems can provide backup for suspicious cases that are negative by RADTs and provide answers quicker than traditional culture. Methods for determining antistreptococcal antibody titers are available but are not clinically useful for acute diagnosis, as they are often reflective of prior infections. Diagnosis of invasive group A streptococcal infection is based on clinical manifestations as well as Gram's stain and culture results. Additional tests, such as imaging studies computerized tomography and magnetic resonance imaging , may serve to guide diagnosis and treatment, which should be started as soon as possible, with empirical antimicrobial therapy, immediate surgical intervention for affected tissue sites, drainage of body fluids, and follow-up cultures. Treatment with oral penicillin or amoxicillin for 10 days is the first-line therapy for group A streptococcal pharyngitis. For patients with a penicillin allergy, there are three alternatives: i a first-generation cephalosporin for 10 days , ii clindamycin for 10 days , or iii a macrolide such as clarithromycin for 10 days or azithromycin for 5 days. Treatment with benzathine penicillin G BPG is not recommended at this time, as it is reserved for use as a chemoprophylaxis drug see below. Symptoms can be managed with acetaminophen or a nonsteroidal anti-inflammatory drug. Treatment of suppurative or invasive complications requires intravenous antimicrobials, preferably penicillin and clindamycin. However, the choice of treatment should be dependent upon whether other organisms, such as anaerobes, are present. Treatment should also include surgical debridement of infected tissue when necessary and supportive care. Treatment with antimicrobials is generally continued for 7 to 10 days or longer once source control is accomplished. IVIG has been used in combination with clindamycin; however, there is a lack of efficacy data on its use, and it is not routinely recommended at this time. Finally, hyperbaric oxygen therapy has been found to be beneficial, especially in cases of severe disease such as necrotizing fasciitis where surgical and antimicrobial therapy has failed ,. Streptococcal disease prevention in the military. Clearly, ongoing surveillance for streptococcus-associated disease is of the utmost relevance to the military, especially at recruit training centers. This effort has been continued for almost 50 years and has served as a valuable resource in understanding the epidemiology of streptococcus-related respiratory disease ,. Monitoring of streptococcus-related illnesses among recruits has served as the basis for evaluation of the impact and effectiveness of chemoprophylaxis and treatment measures on outbreak control. Additional details are provided in military guidance documents ,. With the advent of penicillin, long-term sequelae such as acute rheumatic fever have been controlled to the point that no more than 5 to 10 cases are reported among military personnel on an annual basis our unpublished data, 26 January 2015. Seminal studies performed at Fort Warren, WY presently named Warren Air Force Base , in the early 1950s set the treatment standards still in use today , and led to an Armed Forces Epidemiological Board initial recommendation to the Surgeons General in 1959 for the use of BPG. Modifications to these recommendations were subsequently provided by this board to the U. Navy and Marine Corps in 1983, and these recommendations have been maintained to the present, supporting year-round and seasonal chemoprophylaxis programs. Although questioned by some, published outbreak investigations and reports seem to indicate that BPG has been effective in controlling group A streptococcal carriage rates and streptococcus-associated respiratory illness and severe sequelae in the military , ,. In the recruit setting, the use of BPG for early treatment as well as in mass or tandem chemoprophylaxis schemes has been shown to control streptococcus-related illnesses. In accordance with U. Options for penicillin-allergic trainees include erythromycin and azithromycin. Due to its fewer side effects and its more acceptable dosing regimen, azithromycin 500 mg taken orally once a week for 4 weeks is the preferred chemoprophylaxis option. Chemoprophylaxis with BPG is presently used routinely at seven of nine recruit training centers. Navy and Air Force presently administer BPG to basic trainees upon arrival, and the Army does the same, with the exception of recruits at Fort Jackson, SC, where its use is reserved for outbreak control. In the Marine Corps, BPG chemoprophylaxis is in place at training centers in San Diego, CA, and Parris Island, SC. However, in San Diego, three doses are spread across the training cycle 4 weeks apart , whereas in South Carolina, a single dose is provided, with the use of two doses 4 weeks apart only in the October-through-April time frame. Of note, BPG is not routinely administered by the U. Coast Guard at their recruit training center or by any of the other military commands, where it is recommended only as a method to interrupt outbreaks. Due to the small number of truly penicillin-allergic trainees and concerns over the selection of antimicrobial-resistant strains, some training sites forego chemoprophylaxis without apparent outbreaks of group A streptococcal disease. However, with cessation of BPG chemoprophylaxis, there is a risk of reemergence of invasive streptococcal illnesses among recruits as well as a real possibility of creating a bacterial reservoir by not providing alternative chemoprophylaxis to penicillin-allergic trainees. BPG chemoprophylaxis for Streptococcus pyogenes in recruit training camps a At all recruit training centers, streptococcal infection is monitored in conjunction with ARD activity and is reported as the Streptococcal-Acute Respiratory Disease Surveillance Index SASI ,. Weekly tracking of this SASI indicator of streptococcal disease activity serves to identify populations at risk, provides a basis for prompt intervention with BPG, and measures the impact of other outbreak control measures. Background historical information and epidemiology. In the 1970s, prospective studies of U. Navy recruits found infection rates as high as 57% , and in the late 1980s, U. Further studies among recruits in the 1960s through the 1990s identified M. In one outbreak in 2004, M. Chlamydophila pneumoniae has been identified relatively recently as a significant cause of respiratory disease morbidity in the military. Outbreaks among Finnish and Turkish recruits have been documented , , and this pathogen has also caused significant problems in personnel aboard ships at sea. A recent outbreak in 2007 affected 179 17% members of a U. Navy crew of 1,074 persons, including 69 ARD cases and 50 radiographically confirmed pneumonia cases. Nonrecruit trainees have also been found to be at high risk: a large outbreak affecting U. Another significant cluster of cases at Fort Leonard Wood, MO, was recently reported, involving at least 70 advanced trainees presenting with radiographically confirmed pneumonia during the January-through-May 2014 time frame, of which at least 44 cases were confirmed by PCR ; A. Hawksworth, personal communication, 19 June 2014. More recently, in 2013 to 2014, among U. Air Force Academy cadets at Colorado Springs, CO, 11 73. Navy investigators, led by Gray in 1989, reported that 8 3. Subsequently, in 1998 at the U. Naval Academy in Annapolis, MD, in an 11-month follow-up study of 1,243 midshipmen, 41 3. Other important pathogens found in that study included M. In ongoing surveillance by U. Navy investigators in the past 15 years, C. Hawksworth, personal communication, 19 June 2014. In another report, AFHSC investigators found infection rates as high as 4% to 7% among personnel deployed to Afghanistan in 2004 to 2007; M. Clearly, military recruits, advanced trainees, shipboard personnel, and personnel on deployment who train and live in crowded quarters are at particularly high risk for infection with these two pathogens. Clinical spectrum of illness. In military populations, M. After a 6- to 32-day incubation period , it presents with onset of fever, malaise, headache, and nonproductive cough that gradually worsens and becomes debilitating. Breath sounds may be normal, or minimal rales may be heard. Skin, cardiac, central nervous system, and renal involvement are not commonly seen in military populations but have been observed elsewhere. The incubation period can be quite variable, from as short as 10 to as long as 30 days. In young, otherwise healthy adults, atypical pneumonia due to C. Both organisms require special processing and media and prolonged culture time in specialized media or tissue culture. Culture results can be confirmed by immunofluorescence staining. The cold agglutinin assay was previously used for Mycoplasma but is neither very sensitive 50% to 70% nor specific. Research-based molecular PCR testing of oropharyngeal or NP swabs has been the mainstay of diagnosis for C. Serologic tests for M. Macrolides azithromycin, erythromycin, and clarithromycin constitute the first-line therapy for the treatment of both Mycoplasma- and Chlamydophila-associated pneumonias. Fluoroquinolones moxifloxacin and levofloxacin or doxycycline are acceptable alternatives. The recommended duration of treatment is 7 to 14 days. A longer duration or increased dosage may be required for extrapulmonary involvement of Mycoplasma. Historical background, recent resurgence, and military impact. This vaccination program led to a major decrease in incidence compared with that in the prevaccine era. Concomitant with the advent of acellular pertussis vaccination in the United States, and the associated waning of vaccine-derived immunity, a resurgence among older children, adolescents, and adults has been noted in the past 2 decades ,. An increase in the incidence of pertussis among U. This is best exemplified by a large outbreak in Germany during the period of April through June 2005. In that outbreak, a total of 75 cases were identified, 39 52% of which involved children aged 5 to 14 years and another 25 33% of which occurred among adolescents and young adults. For all individuals, complete age-appropriate immunization with a pertussis-containing vaccine was documented. Additionally, during the period of January 2005 through June 2012, clear increases in the incidences of Bordetella pertussis-associated disease were noted by AFHSC investigators, with a total of 476 confirmed cases reported 90 among military personnel. Subsequent analysis for the period of January 2012 through June 2014 revealed continued pertussis activity in the military, with 39 confirmed and 124 probable cases among military personnel ; A. Cost, unpublished data, 10 March 2015. Additionally, increased risks and outbreaks have been documented for Israeli Defense Forces recruits and French military boarding school students , who are not routinely immunized upon arrival at training sites. These illnesses in young adults, although generally mild , have been quite incapacitating. Deployed personnel can also be at high risk of B. During the recent engagement of U. Infection was clearly documented in 3 of 21 British HCPs during Operation Herrick as well as in a large serosurvey of U. Clinical spectrum of illness. The incubation period for pertussis is usually 9 to 10 days, with a wide range of 6 to 20 days. In otherwise healthy adults, pertussis usually presents with a gradual onset of a paroxysmal, nonproductive, unrelenting, hacking cough. The cough can result in cyanosis or posttussive emesis, which in adults is highly suggestive of pertussis. Nasal congestion and headache may accompany the cough. There is often a protracted course of illness, ranging from 1 to 8 weeks or longer. Some complications of pertussis may include pneumonia, otitis media, rib fractures, urinary incontinence, and syncope ,. The method of choice for rapid diagnosis is PCR of a NP swab or aspirate sample. Specimens should be collected in a patient care area that is separate from where vaccination occurs in order to avoid cross-contamination. Testing is not recommended for asymptomatic persons, given the high false-positive rate. However, testing after 5 or more days of antimicrobial therapy may result in a false-negative test result. While commercially available assays are desirable, the above-mentioned FDA-approved nested PCR assays for the detection of B. The CDC and several state public health laboratories offer PCR and serologic testing support and should be consulted when clinically suspicious cases or clusters of clinically compatible illnesses are seen. For serologic anti-pertussis toxin IgG ELISA testing, blood should ideally be collected between 2 and 8 weeks following symptom onset but can be collected as long as 12 weeks after symptoms have begun. Treatment should be started prior to the return of any test results if the clinical history is strongly suggestive of, or if the patient is at risk for, severe or complicated disease e. For infants, azithromycin is preferred. Trimethoprim-sulfamethoxazole is an alternative agent for patients 2 months of age or older. The choice of agent should be based on tolerability, drug-drug interactions, cost, and ease of adherence. An alternative drug to azithromycin should be used in patients with a predisposition to arrhythmias, such as a prolonged QT interval. Vaccination policies in the past decade. For many years, whole-cell pertussis vaccines were recommended for children under the age of 7 years. Initial acellular vaccines approved for use in 1997 were associated with reduced rates of rare severe side effects seen with whole-cell vaccines. Unfortunately, these vaccines were also associated with waning immunity and pertussis resurgence, as mentioned above. The impact that these acellular vaccines and associated immunization policies will have on the control of this disease in civilian communities or among military service members and the potential increase in the number of breakthrough cases due to reduced immunogenicity are not known at this time. Background historical information, epidemiology, and transmission. Tuberculosis TB is a public health concern to the military. During WWI and WWII, there were high rates of disease, mainly due to exposure within the United States prior to military service rather than overseas exposure ,. Rates of TB disease declined rapidly during the Korean and Vietnam conflicts and leveled off with TB disease rates in the civilian population of the United States ,. In the 1980s and 1990s, further declines in incidence were noted in the U. More recently, during deployment in Afghanistan, where TB is hyperendemic, concerns about TB exposures were raised. Prisoners of war have been the only other military group where higher rates of TB disease have been documented after military deployment. TB is uncommon in the United States, with the incidence of TB disease in 2014 being 3. The TB disease incidence rate in the U. Only 128 active TB cases were diagnosed 119 pulmonary and 9 extrapulmonary during the years 1998 through 2012, an average of only 9 cases per year. The principal risk factors for M. The risk of infection may also be higher among military members who engage in activities that expose them to local populations, such as personnel involved in humanitarian assistance and health care operations ,. In 90% to 95% of healthy adults, the infection remains latent for decades; disease develops, or reactivates, in 5% to 10% of untreated infected adults, most often in the lung apex, where the ratio of ventilation to blood perfusion is highest. Secondary cases of infection in close contacts can occur in up to 2% to 3% of those exposed, usually within 6 to 12 months postexposure , ,. Active TB is most commonly seen in settings with extreme crowding and poor hygiene, such as berthing areas in ships, prisons, or disciplinary barracks, or in foreign-trainee settings where disease is imported. Clinical spectrum of illness. Once an individual is infected with M. Individuals who are infected and considered to have latent TB infection LTBI are defined as those who are infected but have no signs or symptoms of TB disease and cannot spread the disease. Pulmonary TB is, by far, the most common form of disease presentation in the military. However, TB can affect any organ system in the body, with extrapulmonary manifestations including meningitis, lymphadenitis, pericarditis, peritonitis, spondylitis, mediastinitis, and laryngitis, among others. Pulmonary TB in association with influenza virus infection is also associated with increased mortality. Symptoms are insidious and may progress over the course of months. Physical examination may not be helpful, as findings are often nonspecific. Chest radiographs are almost always abnormal in otherwise healthy individuals, and abnormalities include hilar adenopathy, infiltrates, and atelectasis; cavitation occurs later in the disease course. To detect active TB disease, acid-fast bacillus AFB sputum smear staining should be performed, notwithstanding its poor sensitivity 45% to 80% , followed by culture, which often takes up to 8 weeks to provide a result, as M. At least three sputum samples need to be taken from persons suspected of having TB disease, each collected in 8- to 24-h intervals, one of which should be an early-morning specimen. Cultures positive for M. Culture examinations should be done on all diagnostic specimens, regardless of AFB smear or NAAT results. Commercially available broth culture systems allow the detection of most mycobacterial growth in 4 to 14 days, compared to 3 to 6 weeks for solid media. Thus, laboratories performing TB cultures should routinely use a broth-based system. NAAT-based methods are not as sensitive for smear-negative samples but have been demonstrated to have a sensitivity of 50% to 80% compared with culture ,. Diagnosis of extrapulmonary TB is generally based on clinical suspicion with subsequent microbiological confirmation with fluid or tissue culture. The TST represents the principal mode or first line of diagnosis for LTBI. A TST reading should be evaluated by using the CDC's and the military's risk-stratified interpretation, which establishes cutoffs depending on the patient's risk factors for TB infection or progression to TB disease , ,. There are currently two TST formulations, Tubersol Sanofi, Bridgewater, NJ and Aplisol JHP Pharmaceuticals, Rochester, MI , that can be used. Tubersol is the preferred skin test product in the U. Aplisol has been associated with false-positive results in military and civilian populations. Although less desirable in military populations, Aplisol may be used for TB testing during shortages of Tubersol. In addition, two brands of interferon gamma release assays IGRAs have been developed and could be used in place of a TST; these newer diagnostic tests are outlined further in the TB screening section, below. The development of diagnostic tools that take advantage of molecular amplification of the M. The development of FDA-cleared molecular tests has played an important role in improving patient outcomes. An enclosed cartridge-based NAAT for TB and rifampin resistance has been used widely. This assay has both very high sensitivity 99. In comparison, this assay has a moderately high sensitivity 76. This reduced sensitivity in smear-negative patients means that this assay cannot replace existing methods for TB detection but can augment the clinical testing routine. The FDA-cleared assay has a rapid turnaround and is easy to use; however, the cost of this assay can limit usage in resource-poor areas ,. Additionally, this assay has been found to have reduced sensitivity as much as 30% in detecting rifampin-resistant strains due to strains with an rpoB gene encoding an I-to-F mutation at position 491 rpoB-I491F in Swaziland. In the military, this NAAT-based assay is not widely used given its high cost; it is used as an adjunct to sputum smear and TB culture. The CDC recommends that NAAT-based methods be used on at least one respiratory sample from any patient suspected of having M. There are at least three FDA-cleared assays to choose from , , ,. One of these assays can also detect M. The choice of regimen should take into consideration the patient's medical history, treatment setting, adherence considerations, and patient preference. For treatment of active pulmonary TB, every effort should be made to obtain a specimen for microbiological confirmation and drug susceptibility testing. Treatment should be started as directly observed therapy with four active drugs usually isoniazid, rifampin, pyrazinamide, and ethambutol when drug resistance is not suspected and drug sensitivity is later confirmed by cultures, in accordance with WHO treatment guidelines. Treatment with these drugs is continued for the first 2 months of therapy, which is subsequently followed by at least 4 months of treatment with two active drugs, most commonly isoniazid and rifampin. Shorter 4-month regimens have been shown to be inferior to the standard 6-month regimen and should not be used ,. Treatment of multidrug-resistant MDR TB consists of at least five drugs to which the organism is sensitive, for 18 months or longer. Sputum examination for AFB and culture for M. Treatment of extrapulmonary TB is similar to treatment of active pulmonary TB with streptomycin being substituted for ethambutol in cases of TB meningitis ; however, the treatment duration is longer, at 9 to 12 months or more. Drug toxicity may become an issue during therapy, and several measures can be taken to prevent it. For example, pyridoxine vitamin B 6 should be coadministered with isoniazid to prevent peripheral neuropathy. It is also important to perform liver function tests regularly, as many of the anti-TB drugs can cause hepatotoxicity. Finally, regular eye exams are recommended for individuals receiving ethambutol given its potential for ocular toxicity. Recently, a new anti-TB drug, bedaquiline, was approved by the FDA as an alternative for the treatment of MDR TB. Bedaquiline may be used for a period of 6 months for treatment of adults with laboratory-confirmed MDR TB when effective treatment cannot otherwise be provided. Use of this drug in children, HIV-infected persons, pregnant women, and patients with extrapulmonary MDR TB needs to be judged on a case-by-case basis. To lessen the emergence of resistance to bedaquiline, this drug should be used only in combination with at least 3 to 4 other antimicrobials to which M. Patients who take bedaquiline should be monitored closely for suspected and severe adverse events involving the liver, kidneys, or cardiac organ systems by periodic electrocardiogram, serum transaminase, and renal clearance function testing. In general, patients should be isolated until they have met the following criteria: i treatment with an effective regimen for at least 2 weeks, ii three negative sputum smears on consecutive days, and iii clinical response to therapy. Thereafter, sputum smears should be obtained at a minimum at monthly intervals until cultures of two consecutive specimens are negative , ,. For individuals at risk for TB in the health care setting, initial baseline TST or IGRA results should be obtained. Upon exposure, those who were negative at baseline should be retested within 4 to 8 weeks after exposure and treated with daily isoniazid preemptively if conversion has taken place. In addition, if exposure was heavy or the HCP is HIV positive, therapy should be initiated before the person is retested, even if the person is asymptomatic. For HIV-negative persons, if the retest result is negative, isoniazid can be discontinued at that time ,. Vaccine development and challenges. Two French scientists, Calmette, a physician, and Guérin, a veterinarian, began studies on a TB vaccine in 1908. The live attenuated Bacille- Calmette-Guérin BCG vaccine was developed from a Mycobacterium bovis isolate, and the first human BCG vaccination was given in 1921. That said, this vaccine has not been free of controversy, especially given the variable efficacy 0% to 70% in eight controlled clinical trials of BCG against pulmonary TB in adults. Given the low risk of M. TB elimination will require newer, more effective vaccines developed by using modern molecular genetics and biotechnology techniques. The following approaches are being pursued: i subunit vaccines, ii DNA-based vaccines, iii virus-delivered vaccines, iv attenuated auxotrophs and mutants, and v recombinant BCG vaccines. These newer technologies offer promising advances, which are extensively discussed by Connelly Smith et al. TB screening and prevention in the military setting. The risk of developing LTBI is variable and dependent on host-specific factors, the types of exposure during service, and the diagnostic test used, whether a TST or an IGRA. Cutoffs for a positive TST result depend on i the individual's risk for TB exposure and ii his or her risk for developing active TB, if he or she is infected. For most healthy individuals in the military as well as HCPs, this cutoff is 10 mm. Two FDA-approved IGRAs are available. Some advantages of IGRAs include the need for only a single patient visit to conduct the test, greater specificity for M. On the other hand, IGRAs are more costly, are logistically difficult to implement in mass testing settings, and create a substantial burden on the supporting laboratory; therefore, their use in military settings is limited at this time. Until recently, routine TST screening was performed upon arrival at recruit training centers. In late 2013, however, U. Existing policy also gives priority for screening of high-risk groups involving personnel deployed to areas where TB is endemic and health care workers, for whom annual screening is recommended. Treatment of individuals with LTBI who are deployed should be a priority. Individual risk factors that should be checked include foreign birth, visit to friends and relatives in areas of the world where TB is endemic, evidence of engagement in health care activities with potentially infective patients, and HIV infection or other immunosuppressive conditions. In personnel with suspected clinical findings of or epidemiological risk factors for M. If either is positive, the patient should be evaluated for the possibility of active TB. If the chest X ray is normal, the patient should be treated for LTBI. If the patient has been in contact with potentially infective cases, treatment for suspected LTBI should also be started. Such treatment is critical in order to limit infectiousness and secondary transmission as well as to prevent the development of active TB. Standard therapy with daily isoniazid for 6 or 9 months, daily isoniazid and rifampin for 3 months, shortened therapy with weekly isoniazid plus rifapentine for 3 months, or daily rifampin therapy for 3 to 4 months are the four main options at this time , , , , ,. Above all, public health practices of TB control, such as timely contact investigation, treatment of infected contacts, and early diagnosis of active TB cases, are important to achieve TB control in the military setting. RESPIRATORY DISEASE SURVEILLANCE EFFORTS IN THE U. MILITARY From the early 1970s through the late 1990s, scientists at the WRAIR maintained the Acute Respiratory Disease Surveillance Program. During the past decade 2000 to 2014 , U. Army medical officials have maintained this program, which also monitors trainees with uncomplicated febrile ARD e. All cases are monitored, especially those who have been removed from training and managed in self-care settings e. Daily inpatient admission and outpatient surveillance logs rosters from hospitals, troop medical clinics, or emergency departments of trainees are also kept by public health officials at each recruit training center, and a weekly ARD surveillance report is generated, which outlines unit- and gender-based cases by i week of training, ii type of training, and iii barracks type. These data are summarized on a weekly basis at the local level, and a monthly graphical outline is produced , which outlines weekly trends in ARD and streptococcal disease activity at training centers. This program has been immensely valuable in identifying clusters of respiratory disease among U. Army trainees for almost 50 years. Understanding the need for a laboratory-based surveillance system that provides early detection of emerging respiratory pathogens, the NHRC established a febrile respiratory illness FRI surveillance program for recruits in 1998. This program has been very successful and is still operational. Weekly tracking of respiratory pathogen morbidity is done. This system identified the return of significant respiratory disease morbidity across all services during the period of adenovirus vaccination cessation spring of 1999 through fall of 2011. Data from this project, as well as from a large, 4,000-subject, phase 3 RCT of adenovirus 4 and 7 vaccines led by NHRC and WRAIR investigators see section on adenovirus vaccines and the military, below , have been critical in assessing adenoviral morbidity among recruits and associated Ad4 and Ad7 vaccine efficacy. FRI surveillance data have also been leveraged to estimate annual influenza vaccine effectiveness among recruits, as shown in , , , as well as to conduct targeted serologic and vaccine strain genetic studies and to characterize influenza virus strain circulation each season in a timely and consistent manner. Seasonal influenza vaccine effectiveness in U. Navy ships and vessels represent settings in which crowded work and berthing conditions predispose individuals to respiratory infections. Thus, the NHRC has been conducting shipboard FRI surveillance since 2002. Individuals on ships traveling to foreign ports may be susceptible to emerging illnesses, such as infections due to new influenza virus strains. This program now allows the military to monitor the incidence of and etiologies responsible for respiratory illnesses aboard U. Navy ships and provides a laboratory-based system for the rapid identification of important pathogens that would otherwise be undetected in this highly mobile population. The value of this shipboard surveillance is best exemplified by the early detection and rapid control within a week of an H3N2-associated influenza outbreak in a U. Navy minesweeper, where intense transmission in closed quarters led to 25 cases among a crew of 102 highly immunized personnel in a 7-day period in February 2014. Department of Defense DoD Global Emerging Infections Surveillance and Response System mission. Presently executed out of the U. This program provides a weekly assessment of influenza activity , allows early influenza virus strain detection and subtyping, provides comprehensive influenza virus genomic sequencing and characterization, and facilitates influenza vaccine effectiveness estimations. This program has allowed U. Since the creation of the AFHSC in early 2008, centralized U. This system, which complements the MTF-based system operated by the USAFSAM, has significantly enhanced the U. Key among this system's contributions is the identification of the initial pH1N1 influenza virus strains in the United States, which have been subsequently used in support of large-scale production of pandemic and seasonal vaccines since 2009. Additionally, this AFHSC-supported system has allowed medical officials to enhance medical policy on influenza vaccination by periodically conducting influenza vaccine effectiveness evaluations , ,. Weekly summaries of worldwide U. Adenovirus Vaccines and the Military: Lessons Relearned U. These oral vaccines effectively controlled adenovirus-associated respiratory disease in recruit training camps for almost 3 decades until 1999 , when remaining supplies were exhausted after the manufacturer Wyeth Labs ceased production in 1994. Although there was considerable discussion about the need to resume production or find a new source, administrative mechanisms by which to fund a new FDA-approved manufacturer could not be found. In addition, the enormous success of the adenovirus vaccine in controlling adenovirus disease among recruits may have lessened any sense of urgency regarding the need to replace the adenovirus vaccine. Following the loss of adenovirus vaccine production and exhaustion of remaining supplies, adenovirus-associated febrile respiratory disease promptly returned to pre-vaccine-era levels. Occasional deaths were also documented, and the diversity of adenovirus strains in circulation also increased , ,. This situation was not tolerable, knowing that a vaccine that would strongly impact infection rates could be produced. Vaccine restoration efforts finally began in 2001 with a decision by the Army Surgeon General to fund a new production contract. The old vaccine constructs were provided by Wyeth Labs, and Army contracting selected Barr Labs as the contractor to build a new facility and obtain FDA approval of the replacement oral Ad4 and Ad7 vaccine, which was to be as close a replica of the Wyeth Labs products as possible. A new facility was built, and new equipment was used to formulate the oral vaccine product. Finally, in late October 2011, after 12 years of efforts, the oral Ad4 and Ad7 vaccine was again given to all U. The impact was dramatic, with an extreme drop in the numbers of Ad4 and Ad7 cases as well as non-Ad4- or non-Ad7-associated cases. A recent estimate by NHRC investigators attributed adenovirus vaccination with a 100-fold 99% decline in adenovirus-associated disease burden from 5. Impact of adenovirus type 4 and 7 vaccination among recruits at eight training centers. Vaccination was reinstituted in late October 2011. The graph illustrates the number of adenovirus-positive specimens along with the rate of diagnosed FRIs expressed... The loss of the adenovirus vaccine program in the late 1990s demonstrates that institutional memory regarding the potential impact of disease can be lost once a control program that is nearly 100% effective is in place. The adenovirus vaccine program was successfully implemented for almost 30 years, far longer than the term of any U. Convincing the high-ranking U. Perhaps more importantly than all of these recommendations, the formal requirement for the vaccine was established by the Vice Chief of Staff of the Army. Response to Emerging Respiratory Pathogens: Diagnostic and Surveillance Test Development in the Military and the Case of MERS-CoV The U. Laboratory capabilities include genetic sequencing and assay development, which can be used in the face of an emerging threat to quickly develop both diagnostic and surveillance testing capacities for novel pathogens. In the case of the emerging MERS-CoV, these capabilities have been used to support not only military medical personnel but also national and international public health authorities in their goals of understanding and controlling this threat. In April 2012, a hospital in Amman, Jordan, experienced an outbreak of severe, acute respiratory infections among its staff. The Jordan Ministry of Health MoH requested assistance to investigate this outbreak from the U. Naval Medical Research Unit No. Respiratory samples were taken from 6 of the 11 hospitalized patients, including 5 HCPs and 1 student; 2 of these patients 1 HCP and 1 student died soon after hospitalization. Nasal swab samples were tested for influenza virus, HCoVs including SARS-CoV , adenovirus, hMPV, and parainfluenza types 1 through 3 via PCR. All test results were negative, leaving investigators without an explanation as to what had been observed. After the emergence of MERS-CoV became widely known in September 2012, and after they received specific conventional and real-time PCR reagents from the CDC, NAMRU-3 scientists consulted with Jordanian MoH authorities and decided to retest samples from the outbreak for genetic material from MERS-CoV. Bronchial lavage specimens from both deceased patients tested positive for all three MERS-CoV-specific genes. In retrospect, these samples had been collected from the earliest-known cases of MERS-CoV. Subsequent full genomic sequencing of one of the isolates from these Jordanian samples was successfully accomplished by NAMRU-3 and Naval Medical Research Command scientists in collaboration with the NIH ,. Samples from the four nondeceased patients were found to be negative. NAMRU-3 scientists, with the consent of the Jordanian MoH, shared these samples with the CDC and other U. Until that point, U. Navy's Biological Defense Research Directorate using reported MERS-CoV genetic sequences for biosurveillance purposes. Obtaining a patient's positive sample allowed test development and positive-control validation and led to the widespread distribution of MERS-CoV-specific RT-PCR diagnostic test kits in coordination with the CDC. Laboratories throughout the U. Influenza Virus Transmission and Severity Prediction Modeling Efforts The U. An extension of this work has included the development of influenza transmission and severity prediction models. These modeling efforts have taken advantage of the AFHSC's Defense Medical Surveillance System DMSS , which contains demographic, deployment, inpatient, outpatient, and immunization data that allow military-unique analyses. The DoD Epidemiologic Modeling Working Group was established in February 2013 in an effort to identify, coordinate, and assess current military efforts and provide recommendations to improve them. These models afford researchers the opportunity to examine the relative importance of specific variables regarding defined outcomes. One of the benefits of this kind of analysis is that it allows the examination of the predictor variable effects individually while holding effects of other predictor variables or covariates constant. In addition, these kinds of models also allow the examination and control of interactions between explanatory variables. Forecasting of influenza, including estimating its predicted severity in military populations, has been another area of interest for U. In this area, explanatory variables are used to predict how disease may occur given a set of parameters of interest. For example, if an epidemiologist was interested to know how many hospitalizations a state health department could expect during a future influenza pandemic, he or she could do this by using statistical modeling techniques and assumptions about the virulence of the infection given certain other important parameters e. In addition, such efforts have resulted in the estimation of influenza transmission rates and clinical ARs for novel influenza viruses in military populations and the estimation of morbidity and mortality associated with pH1N1 among military personnel. Reduction of airborne transmission from the primary infectious source is of paramount importance in respiratory disease control. Interventions are best defined for influenza virus and M. Implementation of personal protective measures, such as the use of face masks, the use of N95 respirators, as well as early treatment, has proven to be of some relevance for these two pathogens but less so for others. In addition, personal hygiene measures, especially hand washing HW and hand hygiene HH , as well as cohorting of at-risk personnel and isolation of potentially infected patients have shown variable efficacy in preventing the spread of viral infections ,. There are some airborne pathogens that are particularly problematic to control, such as SARS-CoV, which can be transmitted at longer distances of up to 200 m ,. Others, such as adenoviruses and M. In these cases, environmental engineering controls such as high-volume ventilation systems and high-efficiency particulate air HEPA filtration systems, which remove viral pathogens 0. Fomite-related transmission, hand washing, and hand hygiene. Fomite-related transmission can occur with most viral agents and most certainly with TB but not with group A streptococcus, pneumococcus, Mycoplasma, or Chlamydophila. For the control of fomite-related transmission, HW and other HH practices, such as the use of alcohol-based hand sanitizers and alcohol-based swabs, are particularly relevant. Three salient studies of the efficacy of HH measures have been conducted in U. Military investigators reported a significant reduction in the occurrence of respiratory diseases: a 45% decrease in respiratory disease rates was reported in the Navy studies, and 33% to 40% reductions in clinic visits for ARD and sore throats, respectively, were seen in the Air Force study. Microbiologically speaking, it has been shown that even in the absence of any intervention, influenza virus load on hand surfaces naturally is decreased within 1 to 2 h. The use of soap and alcohol-based hand rub preparations has also been shown to achieve an almost immediate reduction in culture- and PCR-detectable influenza virus on the hands of human volunteers. Thus, implementation of HW and HH measures within 15 to 30 min of patient or surface contact is particularly important, in order for these measures to have any beneficial effect in curtailing transmission. At least two recent civilian-based, well-controlled studies have shown the efficacy of HW measures in decreasing influenza virus contamination of household surfaces, with a concomitant decrease in the number of influenza cases in Bangkok, Thailand ,. Consistent with these studies and with the concept of decreases in virus load and transmissibility via fomites, HW and HH practices have been found to provide a 55% reduction in the risk of transmission of respiratory viruses, including influenza viruses, in three recent large systematic reviews in the literature , ,. Additionally, two recent studies of school-age populations have shown that HH interventions can reduce ILI and laboratory-confirmed influenza infection ,. Nonetheless, while these HW and HH measures have the potential to reduce the transmission of influenza and other respiratory pathogens, their effectiveness is greatly dependent on the study setting e. The key factors that seem to dictate success are the implementation and monitoring of strict compliance with these measures. Face masks and N95 respirators. There are few issues as contentious in respiratory medicine as the dilemma surrounding whether face masks or N95 respirators work in reducing respiratory pathogen transmission. Well-designed and reproducible studies supporting or refuting the clinical effectiveness of N95 respirators are lacking ,. A proper evaluation of face masks or respirators in military settings is logistically difficult, and masks are not routinely provided to military recruits, even in times of epidemics. N95 respirators have a greater filtration capacity than do face masks; thus, they are thought to provide greater protection to the uninfected recipient user , especially in health care settings ,. However, adequate data to pass judgment are lacking. Face masks by themselves have not been clearly proven to be efficacious in household or community settings ,,. To emphasize this point, a recent systematic review of HH measures found that face masks may be beneficial in preventing laboratory-confirmed influenza infections in community settings but only if combined with HW and HH measures. Moreover, cloth masks have actually been found to increase the risk of ILI and influenza virus infection rates compared to face masks among health care workers in the first RCT conducted in Vietnam. Future studies are urgently needed in military trainee as well as in health care settings in order to assess the effectiveness of face masks and respirators. The best data supporting the use of face masks in the prevention of respiratory disease are probably for reducing the risk of SARS-CoV infection. Data are not as solid for influenza, however. A large controlled study of HCPs in Beijing, China, during the winter of 2008 to 2009 found inconclusive evidence of the efficacy of face masks in preventing influenza infection. Subsequent data from that same trial indicated that continuous use of N95 respirators, but not face masks, was associated with greater protection of HCPs against clinical respiratory illness as well as lower rates of bacterial colonization and bacterium-virus coinfections than with just intermittent use of N95 respirators or face masks ,. Given the large number of personal, environmental, and pathogen-specific factors that have an impact on aerosol transmission of respiratory pathogens, there is no consensus at present, and the relative superiority of face masks versus N95 respirators cannot be truly determined. At the time of this publication, N95 respirators are being recommended only for the control of TB transmission in health care settings. The CDC recommends that susceptible personnel should wear an N95 respirator upon entering a room with a patient known or suspected to be infected with TB ,. Above all, what is certainly most relevant with face masks and N95 respirators is that they be used early, consistently, and correctly. Guidelines for their use can be found at the CDC website. Effect of crowding and administrative controls. Five well-conducted studies of U. The first study looked at recruits in Fort Humphreys, VA, during the 1918-1919 pandemic and documented higher rates among units training in crowded environments than elsewhere. The second and third studies looked at a cross-sectional analysis of U. Navy recruits at Great Lakes, IL, during WWII and in the 1950s and early 1960s and found increased ARD rates among units with greater numbers of recruits per sleeping bay area. The fourth investigation constituted an observational study of ARD rates among recruits at Fort Benning, GA, who experienced an Ad4 outbreak in April through May 2000. These military space allocation guidelines, and associated crowding reduction measures, require formal evaluation in a controlled fashion before clearer, evidence-based recommendations can be provided. At least four observational studies in the military have looked at the practice of cohorting e. Thus, these studies support the notion that interruption of outbreaks may be possible if contact between members of separate training companies can be avoided early e. Unfortunately, military training schedules often involve frequent and constant physical interactions between trainees in barracks, classrooms, and dining facilities and at recreational events. Thus, these conditions present a real obstacle to the effective implementation of cohorting control measures. Environmental UV light measures. As an additional environmental control measure of potential use in the military, the use of glycol vapors has been evaluated in one military barracks-based study, with positive results showing reduced ARD rates in intervention barracks compared to those in untreated control barracks. UV lighting devices have also been formally evaluated in four U. Navy recruit training settings; all four studies demonstrated a reduction in ARD rates. In spite of these encouraging findings, it should be noted that the beneficial effects of UV light irradiation were deemed to be too small to support this recommendation as a viable one ,. These measures still meet with great administrative and logistic challenges to be of widespread use in the military today. Comprehensive approach to respiratory disease control. In situations with a high risk of pathogen transmission, such as during ARD epidemics in recruit training, not just one but many of the above-described control measures would need to be applied concomitantly. A comprehensive approach that incorporates the implementation of physical barrier measures, such as face masks, as well as prompt isolation of potentially infective cases and cohorting of military units should be implemented. Additional control measures in closed, crowded settings in the military, such as emphasis on personal hygiene measures, including hand washing practices, antiseptic cleaning of surfaces, and the use of antimicrobial hand wipes to prevent transmission from infected secretions and fomites, are also recommended. Of greatest importance is the immediate reduction of transmission from acutely ill individuals, especially within the first 1 to 5 days of illness, when the level of transmissibility is highest. Additionally, frequent education and oversight of HW, HH, and respiratory hygiene of nonmedical military personnel are required. Nonvaccine, nonpharmacologic interventions to prevent ARD in military settings have been summarized in a very practical guide. Other measures such as head-to-toe sleeping arrangements, physical barriers, as well as limiting interactions between training cohorts in order to reduce the risk of respiratory pathogen transmission should be considered. Clearly, further research is needed to determine the effectiveness and efficacy of the different types of HW, HH, masks, and other personal protective measures for reducing the transmission of influenza virus and other respiratory pathogens. CONTRIBUTIONS TO THE PREVENTION OF RESPIRATORY INFECTIONS, FUTURE CHALLENGES, AND CONCLUSIONS The U. Preeminent scientists, such as Gorgas and Welch, embarked on the investigation of these infections, describing their epidemiology and clinical features among military personnel in WWI and during the interwar period. This was followed by the establishment of the Commission on Acute Respiratory Diseases and the Armed Forces Epidemiological Board during WWII, led by Woodward, which conducted salient studies on the epidemiology and prevention of acute respiratory infections among military trainees. Rammelkamp and colleagues led the way in the late 1940s and early 1950s in describing the epidemiology and treatment of streptococcal infections, most notably defining the importance of nasopharyngeal carriage and its eradication in the prevention of acute rheumatic fever ,. Bass subsequently led studies in the 1960s that defined the epidemiology of pertussis and concluded that there was no role for a chronic asymptomatic carrier state as the importance of early erythromycin treatment was realized ,. Other salient public health endeavors that are described above include i the development of the first influenza vaccine in the late 1930s and the requirement for universal vaccination in the 1940s; ii investigation of the epidemiology of and clinical treatment strategies for RSV infection; iii the identification of adenovirus infection and its key role in the etiology of FRI epidemics and the development of adenovirus vaccination with documentation of its efficacy in the 1950s through 1970s and again during the past decade; iv the initial identification of pandemic influenza virus pH1N1 infection in April 2009 in the United States; and v the initial identification and isolation of MERS-CoV as the cause of severe acute respiratory illnesses in Jordan in 2012. In the 21st century, efforts to conduct comprehensive laboratory-based surveillance and research are of paramount importance to military public health officials as well as to military training leaders. Significant enhancements in respiratory disease surveillance and research have taken place in the United States, and worldwide, in the past 2 decades. Toward the end of the 1990s and in the early part of the past decade, the advent of electronic surveillance systems and molecular-based testing for a majority of respiratory pathogens facilitated and refined the conduct of these activities on a broader scale. These efforts have resulted in major contributions to global public health, such as the early detection of the initial sentinel events that led to the identification of the 2009 pandemic pH1N1 virus in the United States as well as among many other U. Great progress has been attained through a flexible, centrally coordinated, worldwide network of partners who promote, maintain, coordinate, and enhance an informative and responsive system in support of emerging infectious disease surveillance worldwide. Continued intensive surveillance will provide data as a basis for military public health officials to make recommendations for reducing morbidity and mortality due to epidemic respiratory disease threats outlined in this and other relevant military reviews. Given the continued threat of emergence of influenza and other respiratory pathogens, such as H7N9 and MERS-CoV, there is a continued need to maintain the forward movement in developing and sustaining comprehensive surveillance programs and systems that allow better assessment of these threats and the associated response and control efforts. These efforts need to be implemented in such a way that they cross the domestic-international boundaries in order for them to be effective. Hopefully, these efforts will result in expedient and cost-effective approaches to better understand respiratory diseases in the military and support the development of policies to lessen their impact. A closing comment is warranted. Substantial virus shedding and transmission, particularly of influenza virus and adenoviruses, may occur in persons not yet ill or with mild or subclinical infections, making routine, compulsory influenza virus and adenovirus immunizations the most important control measures available to the U. Additional control efforts outlined in this review need to be emphasized by military medical and public health officials if control of these infections is to be attained. Prevention programs must be supported by sound epidemiological data and the constant attention of public health professionals. The adenovirus vaccine story may be a cautionary tale. Effective prevention programs, especially immunization programs, may be lost without our strong advocacy. We thank the numerous individuals who are involved in the routine conduct of disease surveillance activities as part of the AFHSC and associated collaborators and partners. Nikki Jordan at the U. Army Public Health Command USAPHC , Anthony Hawksworth at the Naval Health Research Center, and Susan Federinko at the U. Air Force School of Aerospace Medicine were kind enough to provide critical surveillance and outbreak data to complement our data. Hiser's work in collating routine surveillance data, reports, and publications included in this project was partially supported by an appointment to the Postgraduate Research Participation Program administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U. Department of Energy and USAPHC. This work was funded by the Global Emerging Infections Surveillance and Response Division at the Armed Forces Health Surveillance Center. The opinions stated are those of the authors and do not represent the official position of the U. Department of Defense, the Mayo Clinic, or other contributing network partner organizations. Mention of any commercial product does not imply an endorsement or official recommendation for or against the use of any such product. No infringement on the rights of the holders of the registered trademarks is intended. Sanchez is a graduate of the University of Puerto Rico and Johns Hopkins University School of Hygiene and Public Health. He completed his Preventive Medicine residency training at the Walter Reed Army Institute of Research, and for the past 35 years, he has dedicated his efforts to infectious disease epidemiology, surveillance, outbreak investigation, and applied biomedical research. He has been involved in the conduct of studies defining the epidemiology of respiratory infections, HIV and other sexually transmitted infections, diarrheal diseases, malaria, leptospirosis, and hepatitis as well as the role of emerging infectious disease surveillance and capacity-building efforts by the U. He now works as Team Leader, Division of Global Emerging Infections Surveillance and Response GEIS , Armed Forces Health Surveillance Center, providing oversight to U. Cooper is a graduate of Pennsylvania State University and the Epidemiology Intelligence Service, U. Centers for Disease Control and Prevention. For the past 15 years, he has dedicated his efforts to the public health control and surveillance of infectious diseases. He has been involved in the conduct of studies defining the epidemiology of various infectious disease pathogens, including respiratory and vector-borne infections, with considerable experience in international settings such as the South Pacific, Europe, and Africa. He now works as Chief, Respiratory Disease Surveillance, Division of GEIS, Armed Forces Health Surveillance Center, providing oversight to more than 30 respiratory disease surveillance and research projects worldwide. For the past 10 years, he has provided guidance and support as NHRC has added molecular diagnostic assays to their surveillance program, which monitors disease burdens in U. At the NHRC, he has led the analytical and clinical evaluations of diagnostics that are of particular concern to the U. Cummings is a graduate of Georgetown University School of Medicine. He completed his Internal Medicine residency and Infectious Disease fellowship training at the Walter Reed Army Medical Center, and for the past 10 years, he has dedicated his efforts to infectious disease clinical and vaccine research and translational medicine research. He now serves as the U. Army Surgeon General's Consultant for Medical Research and Development and also serves as Director, Division of GEIS, Armed Forces Health Surveillance Center, providing leadership and oversight to U. Vest is a graduate of Oklahoma State University and Johns Hopkins University School of Hygiene and Public Health. He completed his doctorate in public health at the Uniformed Services University of the Health Sciences, and for the past 28 years, he has dedicated his efforts to veterinary and infectious disease epidemiology, surveillance, and research of military relevance. He has been involved in the conduct of studies defining the epidemiology of respiratory and zoonotic diseases and has vast experience in international settings such as Honduras, Panama, and Japan. He now works as a Veterinary Epidemiologist and Deputy Chief of Staff, Armed Forces Health Surveillance Center, responsible for coordinating operating decisions, providing advice and expertise in public health policy matters, as well as providing advice on infectious disease surveillance priorities and initiatives. Russell is a graduate of the University of Texas at San Antonio Medical School in 1990 with a Family Practice internship that was followed by U. Navy Undersea Medicine training. He worked in diving medicine research from 1991 through 1995. After a Preventive Medicine Residency and a master's degree in Tropical Medicine and Hygiene, he became head of the Virology Laboratory at the U. Navy Medical Research laboratory in Lima, Peru, where he engaged in arbovirus and HIV surveillance studies throughout South America. In 2001 to 2008, at the Naval Health Research Center in San Diego, CA, he conducted surveillance in recruits, shipboard personnel, border clinics, and outbreak support and became the U. Navy's principal investigator for a phase 3 FDA trial of oral adenovirus vaccine types 4 and 7. In July 2008, Dr. Russell became Director, Global Emerging Infections Surveillance and Response System, and Deputy Director, Armed Forces Health Surveillance Center. He subsequently served as Director, Armed Forces Health Surveillance Center, from June 2011 through April 2015, responsible for all levels of health surveillance in the U. Sanchez is a graduate of the University of Maryland and the Johns Hopkins University School of Medicine. She completed her residency in Internal Medicine at Johns Hopkins Hospital. Her fellowship training in Infectious Diseases was completed at Stanford Hospital and the University of Minnesota. Prior to medical school, she obtained a B. In 2014, she joined the Division of General Internal Medicine at Mayo Clinic, where she provides consultative, patient-centered care. Her interests include medical education, HIV pathogenesis, and infections in solid-organ transplant recipients. Hiser is a graduate of George Mason University, where she completed a master's degree in Public Health with a focus in epidemiology. Prior to her graduate degree, she obtained a B. In 2013, she joined the Division of GEIS at the Armed Forces Health Surveillance Center as a fellow with a focus on surveillance and research of respiratory and sexually transmitted infections in the U. Gaydos is a Professor in the Division of Infectious Diseases, Johns Hopkins University; Director of the North American Branch for the International Union Against Sexually Transmitted Infections; and a member of the Center for Global Health. She is the Director of the International STI, Respiratory Diseases, and Biothreat Research Laboratory. Gaydos has conducted clinical trials for new diagnostics for sexually transmitted infections STIs and respiratory pathogens and developed multiple DNA amplification tests. Internet recruitment of home-collected samples for STI screening has been an effective outreach program she has engaged in. She serves on the editorial board of the journal Sexually Transmitted Diseases and the executive committee of the American STD Association. She is a Principal Investigator of an NIH Center grant to develop point-of-care tests for STIs. 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