3. ganization (WHO) (5) ranks lower respiratory infections as the
third leading annual cause of death globally, accounting for
ϳ4.25 million deaths (7.1% of deaths overall), mainly in very
young, elderly, and immunocompromised individuals in the
developing world (6, 7). Acute respiratory diseases (ARDs) are
also the leading cause of outpatient illness, with significant
impact in terms of disability-adjusted life years, accounting for
115.23 million disability-adjusted life years worldwide (8). In
the United States alone, lower respiratory tract infections ac-
count for ϳ85,000 deaths each year (3.2% of all deaths) and
constitute the leading infectious cause of death (9).
HISTORICAL BACKGROUND AND RELEVANCE OF
RESPIRATORY INFECTIONS TO THE U.S. MILITARY
The Military Trainee Environment and Increased Risks
Related to Training
ARDs have been particularly problematic in recruit and other mil-
itary training environments, where close and crowded living con-
ditions (10), physical and psychological stresses (11), environ-
mental challenges (12), and demanding physical training (13) lead
to more intense exposure as well as a state of relative immune
compromise (14). 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) (15). 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 docu-
mented 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 (15, 16).
Subsequently, U.S. Navy investigators clearly documented train-
ee-related ARD outbreaks in winter at the Great Lakes Naval
Training Center in Illinois (17). A principal finding of naval re-
cruit studies in the 1950s and 1960s was the observed direct cor-
relation of pneumonia and ARD rates with greater degrees of
crowding (18, 19).
ARD continue to have a substantial impact among military re-
cruits and newly mobilized troops. In the past 2 decades, U.S.
Navy (3, 12, 20) and Armed Forces Health Surveillance Center
(AFHSC) (21–23) investigators have been able to quantify the
military burden of ARD. The incidence of hospitalizations for
respiratory disease among recruits exceeds that among compara-
ble civilian adults in the United States by at least 3- to 4-fold,
accounting for 25% to 30% of infectious disease-related hospital-
izations (20). Severe ARD is seen mostly in recruit and advanced
individual training phases early in a military career. Respiratory
infections represent the most commonly diagnosed medical con-
dition in these groups, estimated to be responsible for ϳ36,000 to
100,000 medical encounters affecting an estimated 25,000 to
80,000 recruits each year. These infections also impact training in
a major way, accounting for ϳ12,000 to 27,000 days of lost train-
ing time as well as 1,000 to 3,000 hospital bed-days each year
(21–23, 699).
Nontrainee and Deployed Military Environment
Respiratory infections are also of significance among active-
duty, nonrecruit personnel, where they were estimated to ac-
count for 300,000 to 400,000 medical encounters affecting
200,000 to 600,000 service members each year during the in-
fluenza seasons in the years 2012 through 2014 (24, 25, 700).
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 (26).
Throughout U.S. military history, the numbers of nonbattle
injuries and illnesses have exceeded the numbers of battle
wounds (27, 28). 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 (29).
U.S. Navy personnel onboard ships prior to the Iraq war in
2000 to 2001 sustained respiratory illness rates of ϳ3% per
month (30). More recently, U.S. military personnel deployed
to Iraq and Afghanistan (2003 to 2006) sustained significant
morbidity from respiratory infections (30–32). During the ini-
tial stages of the Iraq and Afghanistan deployments in 2003 to
2004, respiratory illnesses were documented in ϳ17% of de-
ployed forces, ranking as the third most common diagnosis
after diarrheal illnesses (ϳ48%) and noncombat injuries
(ϳ31%). Moreover, wartime respiratory illness rates estimated
at ϳ15% per month were seen in Iraq and Afghanistan in 2003
to 2004 (27) and in 2005 to 2006 (32); overall rates were esti-
mated to be ϳ69% and ϳ40%, respectively. Military personnel
performance was affected in 14% and 34% of respiratory illness
cases in 2003 to 2004 and 2005 to 2006, respectively (27, 32).
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.g., hot and cold); and
high altitude may play a role in the susceptibility of military per-
sonnel to respiratory infections (33). Physiologic and immuno-
logic 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 (33, 34). Other im-
portant factors, such as the nature of the military mission (e.g., less
availability of medical care), length of deployment (e.g., short ver-
sus long), and location of deployment (e.g., exposure to pathogens
from host country nationals), also play an important, yet unde-
fined, role.
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 (32). In
another study during the Persian Gulf War (35), no such associa-
tions were found. Respiratory infection rates tend to be higher
among troops billeted in tightly constructed air-conditioned
buildings (35, 36). Empirical evidence of transmission of human
adenovirus in enclosed settings, such as schools and military train-
ing camps, seems to indicate that close proximity of personnel
(e.g., crowding) and the environmental persistence of some of
these pathogens may also play important roles in their transmis-
sion (37, 38).
Respiratory Infections in the U.S. Military
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4. ACUTE RESPIRATORY DISEASE: GENERAL CONCEPTS
Clinical Presentations and Seasonality
Some key clinical features and epidemiological characteristics of
respiratory pathogens to consider in military settings are outlined
in Table 1 (39–48). Military-relevant respiratory infections can
present as (i) a “common cold” syndrome, with symptoms of
feverishness, nasal congestion, cough, and rhinorrhea; (ii) acute
bronchitis with persistent cough, with or without fever; (iii) pneu-
monia with acute onset of fever and respiratory compromise; (iv)
influenza-like illness (ILI); and (v) tuberculosis (TB)-related dis-
ease. Clinical symptoms resulting from infection by different
pathogens may overlap, so a specific etiologic diagnosis based on
clinical grounds only is often inaccurate.
The “common cold” syndrome is most often due to infection with
rhinoviruses (ϳ50% of cases), followed by human coronaviruses
(HCoVs) in ϳ10% of cases; adenovirus, influenza virus, parainflu-
enzavirus(PIV),andrespiratorysyncytialvirus(RSV)in10%to15%
of cases; human metapneumovirus (hMPV) in Ͻ5% of cases; as well
TABLE 1 Clinical features of and epidemiological clues for respiratory pathogens in military settingsa
Pathogen(s) Incubation period Clinical presentation and/or epidemiological clue(s)
Adenoviruses 4–8 days Acute onset with nonexudative pharyngitis and fever; conjunctivitis may be prominent;
may be associated with secondary viral (but not bacterial) pneumonia with certain
strains (usually in no more than 5% of cases); associated with clusters among
nonimmune recruits; not a significant problem in vaccinated individuals
Influenza (parainfluenza) viruses 1–4 days (2–6 days) Acute onset with fever, cough, headaches, and malaise (ILI), which can last for 1–5
days; may be complicated by secondary bacterial infections in as many as 20% to
30% of cases; associated with clusters among nonimmune recruits (early in basic
training prior to development of vaccine-induced immunity) and among older
veterans
RSV 3–7 days Acute onset of coryza, pharyngitis, nonproductive cough, sore throat, nasal congestion,
and low-grade fever; wheezing is seen in Ͼ60% of cases who have lower respiratory
tract involvement; often detected in association with influenza virus and/or
adenovirus among nonimmune recruits
hMPV 3–5 days Acute onset of ILI or “common cold” syndrome (feverishness, nasal congestion, cough,
and rhinorrhea); may be associated with community clusters of asthma,
conjunctivitis, pharyngitis, laryngitis, or pneumonia; infrequently associated with
CAP (Ͻ5% of cases)
Human rhinoviruses 2–4 days Acute onset of “common cold” syndrome (accounts for 50% of common colds) and
additional symptoms such as headache and sore throat; high rates of infection
among recruits (20%–70%), with lower respiratory tract symptoms such as shortness
of breath and higher risk of pneumonia
HCoVs 2–10 days Acute onset of “common cold” syndrome (in the case of non-SARS CoVs) lasting 3 to
18 days; may present as SARS with onset of pneumonia as long as 10–14 days after
exposure (in the case of SARS-CoV or MERS-CoV)
Streptococcus pneumoniae 1–3 days Pneumonia highlighted by acute onset of high fever, rigors, productive cough with
rusty sputum, and shortness of breath; often seen in conjunction with viral
infections; affects nonimmune recruits and other highly stressed, very fatigued
military trainees (such as Navy Seals or Army Rangers)
Streptococcus pyogenes 2–4 days Acute onset of fever and suppurative, patchy sore throat in nonimmune recruits and
other highly stressed, very fatigued military trainees (such as Navy Seals or Army
Rangers); tendency to occur in clusters at any time of the year rather than
sporadically
Mycoplasma pneumoniae 6–32 days Gradual onset of dry, nonproductive cough, malaise, and chills with low-grade fever;
may result in atypical pneumonia; underrecognized cause of respiratory illness
among trainees and service academy cadets or students; ϳ50% present with positive
cold agglutinin test
Chlamydophila pneumoniae 10–30 days Acute or gradual onset of nonexudative pharyngitis, dry and nonproductive cough,
hoarseness, and low-grade fever; may result in atypical pneumonia; illness is
generally milder than those caused by other pathogens; underrecognized cause of
respiratory illness among trainees and service academy cadets or students
Bordetella pertussis 6–20 days Gradual onset of unrelenting, hacking cough with paroxysms, whoop or postcough
vomiting, nasal congestion, or headaches, which can last for 1–8 wk in deployed
personnel exposed to local nationals; uncommon in recruits due to effective
immunization upon arrival
Mycobacterium tuberculosis Weeks to months Ͼ90% of cases are pulmonary with persistent cough (Ͼ3 wk), with subsequent spiking
fever, sputum production, shortness of breath, and weight loss; often misdiagnosed
as bronchitis or atypical pneumonia; secondary cases may occur in up to 2%–3% of
those exposed as long as 6–12 mo postexposure
a
Adapted from reference 41 with permission. ILI, influenza-like illness; CAP, community-acquired pneumonia; SARS, severe acute respiratory syndrome; HCoVs, human
coronaviruses; MERS-CoV, Middle East respiratory syndrome coronavirus.
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5. as group A streptococcus (GAS) in 5% to 10% of cases (49). Pharyn-
gitis is often prominent in adenovirus, influenza virus, and strepto-
coccalinfections.Adenoviralandstreptococcalinfectionsmayalsobe
accompanied by tonsillar exudate, while human rhinovirus
(HRV), influenza virus, HCoV, and RSV infections usually are
not. Severe and prolonged cough may be found in patients
infected with adenovirus, influenza virus, Mycoplasma pneu-
moniae, Chlamydophila pneumoniae (formerly known as Chla-
mydia pneumoniae) (http://www.bacterio.net/chlamydophila
.html), and Bordetella pertussis.
Pneumonia is most often caused by infection with Streptococcus
pneumoniae, adenovirus, or influenza virus (50). M. pneumoniae
and C. pneumoniae may cause clusters of pneumonia cases that
have been deemed atypical, since typical bacterial pathogens are
not isolated from these cases. Pneumococcal pneumonia was of-
ten observed during large influenza epidemics in 1918 at many
military training camps (51) and at Fort Bragg, NC, in 1944 (52).
Pneumonia epidemics due to adenovirus type 14 (Ad14) have
been well documented among U.S. military recruits as recently as
2006 through 2009 (53–55).
ILIs are characterized by the presence of fever, cough, chills,
muscle aches, and headaches, which can last 1 to 5 days. They are
most often seen with infection by influenza virus and PIV and less
often with adenoviruses and RSV. When accompanied by cough
and fever, such illnesses are commonly associated with circulation
of influenza viruses (56).
In a separate section below, we discuss TB symptomatology and
clinical presentation. Respiratory infections due to Mycobacte-
rium tuberculosis may result in persistent cough (Ͼ3 weeks in
duration) with spiking fever, sputum production, and shortness
of breath and initially may be misdiagnosed as chronic bronchitis
or atypical pneumonia (43, 45).
Knowledge of seasonality patterns may be helpful in distin-
guishing among these pathogens. For example, in temperate cli-
mates, 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 (57–59).
In tropical regions, respiratory infections with all these pathogens
tend to be more frequent during wet and cold weather (42).
Pathogen Transmission and Shedding
Respiratory pathogens are spread by (i) large droplet nuclei (Ն5 to
10 m in diameter), often referred to as “person-to-person”
transmission; (ii) small droplet nuclei (Ͻ5 m in diameter), often
referred as “airborne” transmission; and (iii) self-inoculation
onto the nasal mucosa or conjunctiva from contaminated surfaces
(e.g., fomites) (42). 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 syn-
drome 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 (42, 57). 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.g.,
streptococcus) or long-term active disease (e.g., TB).
RESPIRATORY PATHOGENS OF MAJOR MILITARY CONCERN
Adenoviruses
Background historical information and epidemiology. Adeno-
virus derives its name from “adenoids,” a term derived from the
tissue from which the virus was first isolated in 1953 by Rowe et al.
at the National Institutes of Health (60). Soon thereafter, Hille-
man and Werner, working at the Walter Reed Army Institute of
Research (WRAIR), identified cytopathic effects in HeLa and hu-
man tracheal cell cultures (61) 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. at Western Reserve University, the presently accepted term
“adenoviruses” was coined, in accord with the original cells from
which the virus was first isolated (62).
There are Ͼ50 adenovirus types that cause a wide variety of
clinical syndromes, including febrile ARD, pharyngoconjunctival
fever, epidemic keratoconjunctivitis, and pneumonia in healthy
persons and disseminated infection with hepatitis, hemorrhagic
cystitis, and renal failure in immunocompromised patients (49).
Adenoviruses caused significant morbidity among military re-
cruits prior to the advent of Ad4 and Ad7 vaccination in the early
1970s. In the 1960s, investigators at the WRAIR documented
widespread adenoviral infection (ϳ80%) among recruits, who
also experienced very high hospitalization rates (ϳ20%) during
their first 2 months of training (63). 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-spe-
cific attack rate (AR) estimates being as high as 50% to 80% (64).
Prior to these studies, in the 1950s, adenovirus infection rates in
the recruit setting were documented to range widely from a low of
4% to 9% to as high as 54% to 79%; hospitalization rates were
documented to be ϳ33 times higher among recruits than among
nonrecruits (65). For further historical details and relevant stud-
ies, the reader is referred to an excellent review by Russell (12).
Humoral, antibody-mediated immunity plays a key role in ad-
enovirus epidemiology. A lack of preexisting, type-specific immu-
nity 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 re-
cruits were noted in the mid- to late 1970s (66) and subsequently
in the mid-1990s by other Army investigators (67, 68), where it
was estimated that 76% to 88% of incoming recruits were nonim-
mune to Ad4 or Ad7 upon arrival in training. A subsequent pro-
spective study of recruits at Fort Jackson, SC (69), definitively
confirmed the important protective role of humoral immunity;
anti-Ad4 immunity (defined as neutralization titers of Ն1:32) was
found to provide 60% protection from adenovirus-associated
hospitalization and 98% protection from infection.
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 1.4 to 1.5 times and 3.6 times
higher than those for women, respectively (69). Smoking has also
been found to increase the risk of hospitalization (odds ratio
[OR] ϭ 1.9); tropical birthplace has also been associated with a
higher level of immunity (68, 69).
Outbreak potential during nonvaccination periods. A sum-
mary of the most notable adenovirus-related outbreaks, studies,
and deaths in military populations undergoing training during the
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6. past 2 decades is presented in Table 2 (3, 53–55, 68–104, 107). In
summary, thousands of cases and nine deaths were documented
by U.S. military medical officials. 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 ex-
hausted, 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 (94, 107).
Adenovirus-associated FRI outbreaks have also affected other
non-U.S. military and police forces in the past 2 decades; out-
breaks and deaths have been documented for Finnish (78), Chi-
nese (80), South Korean (88, 101–103), and Singaporean (87) mil-
itary recruits as well as for Turkish expatriates conducting military
training in Turkey (85), Chinese nonrecruits (98–100, 104), and
Malaysian police trainees (95). 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 (105). 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 (89). The most notable
military Ad14 outbreak took place in the spring of 2007 at the U.S.
Air Force recruit training center in Lackland, TX, where a cluster
of trainees with severe FRI was identified (55, 92). Many trainees
were hospitalized, and several were in intensive care. Sporadic
Ad14 cases were identified at other U.S. military training sites
starting in late 2006, but Ad14 was not associated with unusually
severe morbidity prior to this outbreak (54, 106). Ad14 subse-
quently went on to affect recruits in all eight training centers dur-
ing the years 2006 through 2009 (53). 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
(55, 89). 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. However, surveil-
lance data to date show that Ad14 activity remains low Ͼ3 years
after the introduction of the vaccine (107).
Clinical spectrum of illness. The incubation period for natu-
rally acquired adenovirus disease of the respiratory tract is 4 to 8
days (median, 6 days) but may be up to 2 weeks (44, 49). Viral
shedding begins shortly before the onset of symptoms (within 1 to
2 days) and continues for up to a week after symptom resolution
(12). Adenovirus-associated respiratory disease in the military set-
ting 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 conjuncti-
vitis, which may be prominent and may serve as a useful diagnos-
tic finding compared to other pathogens (12, 49). Until the rein-
troduction of vaccination in October 2011, adenoviruses were a
common cause of viral pneumonia among military recruits, oc-
curring in as many as 5% to 10% of adenovirus-associated FRI
cases, especially in association with certain types, such as Ad14
(55, 108). The characteristics of adenovirus-associated pneumo-
nia are similar to those due to other pathogens, thus making it
difficult to establish a diagnosis using clinical or radiographic
findings alone.
Diagnostic modalities. Diagnosis of adenovirus infection may
be achieved by virus isolation or by direct detection of viral anti-
gens or nucleic acids from appropriate specimens of respiratory
secretions, conjunctival swabs, stool, and urine, depending on the
clinical syndrome (49). An enzyme-linked immunosorbent assay
(ELISA) or an immunofluorescence assay (IFA) can be used to
directly detect viral antigen in clinical specimens. The time re-
quired 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 detec-
tion by nucleic acid amplification tests (NAATs) have led to their
increased use in clinical laboratories (109). Several commercial
PCR-based assays detect adenovirus from purified extracts of re-
spiratory samples (110–112). Adenoviruses can also be rapidly
detected by several relatively new NAATs that are multiplexed to
detect several viruses at the same time (113–115). These assays
include (i) a multiplex PCR whose resulting products are labeled
by a primer extension step and then hybridized to detection mi-
crobeads that can be specifically sorted based on their internal dye
content (116); (ii) a multiplex PCR whose resulting products are
converted to a single-stranded form and hybridized to both a cap-
ture probe and signal probes, which allows electrochemical detec-
tion (117); 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
(118–120).
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 intermedi-
ate adenovirus strains; this algorithm is of particular relevance in
investigations of outbreaks and clusters of unusually severe ade-
novirus-associated disease (121). This method relies upon hexon
sequencing and a gel-based PCR method for fiber determination
of genotype. Discrepant results are resolved by individual plaque
isolation and amplification followed by sequencing and/or restric-
tion enzyme analysis. Serologic diagnosis is primarily of epidemi-
ological relevance, and type-specific neutralizing antibody titer
determinations have been helpful in investigating outbreaks
among military personnel (122).
Treatment modalities. There are no U.S. Food and Drug Ad-
ministration (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 (49, 123). Brincidofovir, a lipid-linked
derivative of cidofovir, has also been used in the treatment of
disseminated infections among immunocompromised patients
(124, 125). Intravenous ribavirin or ribavirin combined with im-
munoglobulin has been used in specific cases; unfortunately, fail-
ures with these drugs are common (126, 127).
Adenovirus vaccination. The U.S. military is unique in the
world in requiring adenovirus vaccination of military recruits (2).
Resumption of this program at military training centers took place
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7. TABLE 2 Notable adenovirus-associated outbreaks, studies, and deaths in military-related populations from 1995 to 2012a
Time period(s) Military population Ad serotypes(s) involved and description Reference(s)
Apr–May 1995 U.S. recruits Ad4 identified among 7 of 73 hospitalized unvaccinated recruits at Fort Jackson
with viral culture data; first outbreak reported during initial period of
vaccine unavailability during May 1994–March 1995
70–72
Jan 1996–Nov 1997 U.S. recruits Ad4 identified in 71 (90%) of 79 patients hospitalized at Fort Jackson during a
9-day period in November 1997; low anti-Ad4 immunity (15–22%) in new
recruits; higher Ad infection rates in males (OR ϭ 2.1) and smokers (OR ϭ
1.9); estimated ϳ8,903 ARD hospitalizations (rate, 0.6% per week) in
ϳ200,000 recruits in January 1996–September 1999, with units with rates as
high as 8–10% per wk; clear increase in ARD rates in the 1998-1999 period
compared to the 1996-1997 time frame (RR ϭ 1.8–2.2); overcrowding in
barracks suspected to be predominating environmental factor (sleeping
density of Ͼ40 recruits/bay); outbreak halted by resumption of vaccination
in late November 1997
68
Oct 1996–May 1998 U.S. recruits Ad4 and Ad7 predominant strains in FRI-based surveillance at 5 recruit
training centers (3,212 throat cultures); cases due to Ad4 (46%), Ad7 (32%),
Ad3 (13%), and Ad21 (5%); unvaccinated recruits at much greater risk of
culture-positive Ad4/Ad7 infection than vaccinated recruits (OR ϭ 41.2)
3
Jan 1997–Dec 2003 U.S. recruits Ad4 accounted for ϳ98% of Ad-associated ARD cases; elegant genotyping
study involving 724 Ad4 strains at 8 recruit training sites showing
heterogeneity of 7 distinct Ad4 genome types despite homogeneity of recruit
source population; highly suggestive of ongoing environmental reservoirs (as
opposed to reintroductions by incoming recruits)
53
Jan 1997–Mar 2013 U.S. recruits Largest, year-of-entry, cohort-based surveillance study of enlisted recruits at 10
training centers involving 2.4 million recruits; ARD rates much higher in the
initial 3 mo of BCT than in the subsequent 9 mo post-BCT (IRR was 3.3–6.1
times higher for outpatient visits and 1.6–5.1 times higher for
hospitalizations); clear decrease in ARD rates in 2012 recruit cohort,
suggesting vaccine-related effect in initial 3 mo of BCT but not in subsequent
9 mo of military service (e.g., post-BCT)
73
May–Dec 1997 U.S. recruits Initial Ad4 isolate on 22 May 1997, ϳ7 wk after cessation of vaccination; 673
(66%) of 1,018 recruits with ARD at Fort Jackson; outbreak halted by
resumption of vaccination in late November 1997
74
Jun–Oct 1997 U.S. recruits Ad4 responsible for ϳ200 cases; spillover of infections from Fort Jackson to
Fort Gordon among AIT trainees; prolonged epidemic period due to
nonvaccination policy (given only during the period from 1 October–31
March)
75, 76
Aug–Dec 1997 U.S. recruits First outbreak due to a non-Ad4 serotype in postvaccine era involving 541 Ad
infections (70% due to Ad7; 24% due to Ad3) at GLNTC; suspected
introduction of Ad7d2 genotype from the Chicago area; FRI rates peaked at
5.2% per wk; prolonged epidemic period due to nonvaccination policy
(given only during the period from 1 October–31 March); FRI risk 17–19
times higher among unvaccinated recruits; outbreak halted by resumption of
vaccination in late October 1997
77
Oct–Nov 1998 U.S. recruits Intensive 8-wk clinicoepidemiological prospective study of 678 recruits at Fort
Jackson; 17% of recruits hospitalized for an ARD (hospitalization rates of
0.9–3.8% per wk), with significant rates of isolation of Ad4 (72%), Ad3
(7%), and Ad21 (2%); low anti-Ad4 immunity of incoming recruits as main
risk factor; younger individuals (Ͻ20 yr old), males, and recruits from
temperate regions at increased risk of Ad4 infection
69
1999 Finnish recruits Ad3, Ad4, Ad14; no vaccination 78
Jul 1999–Jun 2004 U.S. recruits Most comprehensive evaluation of FRI in association with Ad infection among
recruits at 8 training sites; estimated 73,748 Ad cases (70%) among 110,172
FRI cases; mostly Ad4; peak at wk 3–5 of training; highest FRI rates in Navy
and Air Force recruits (rates of 1.2–1.4% per wk); Ad rates averaged 0.5–
0.8% per wk, 33% higher in the latter 2 years (2002–2004) of surveillance
79, 90
2000 Chinese recruits Ad3, Ad7; no vaccination 80
2000–2011 U.S. recruits (9 deaths) Ad4 (n ϭ 3), Ad4 and Ad7 (n ϭ 2), Ad14 (n ϭ 2), and ND (n ϭ 2); period of
vaccine cessation due to unavailability; first 2 deaths in military recruits at
GLNTC since vaccination started in 1971–1972
81–83; R. N. Potter,
unpublished data
Apr–May 2000 U.S. recruits Ad4 (n ϭ 43) identified among 47 (43%) of 109 hospitalized recruits at Fort
Benning with viral culture data; lack of ventilation (nonfunctioning air
handlers), younger age, sleeping density of Ͼ50/bay, unit cohorting (1
company), and white race associated with increased risk
84
2004 Turkish expatriates
training in Turkey
Ad11; no vaccination 85
2004 South Korean recruits Ad7 identified in 26 (42%) of 62 recruits with ARD at Korean Air Force
training center; 138 (6%) of 2,155 recruits admitted developed pneumonia
in January–December 2004; no vaccination
C. H. Yoon, unpublished
data
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8. in late October 2011 after a 12-year hiatus (128). Adenovirus Type
4 and Type 7 Vaccine, Live, Oral (1 dose), is administered to en-
listed recruits 17 to 50 years of age. This vaccine can be adminis-
tered simultaneously or at any interval before or after other vaccines,
including live vaccines. There are specific contraindications, includ-
ing 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 (129). Additional details of this vaccination program and its
large impact on the U.S. military are outlined below.
Influenza Viruses
Influenza pandemics of major importance to the military. Dur-
ing 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, 1.2% to 8.4%); however, for pneumo-
nia cases, it was much higher, at 20% to 50% (51, 130). In fact, the
impact of influenza during World War I (WWI) was actually
larger than that of combat wounds and injuries; ϳ792,000 soldiers
were hospitalized in the United States and France, and Ͼ57,000
(e.g., 1 in 67 soldiers) died from influenza and its secondary
(mostly pneumococcal) pneumonia complications, which ex-
ceeded the number of combat-related deaths (n ϭ 50,280) during
this conflict. Moreover, an estimated 8.7 million days of duty were
lost due to influenza, with a substantial impact on operational
readiness (131, 132). 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 (133).
The novel A(H1N1)pdm09 virus (2009 pandemic influenza
virus; henceforth referred to as “pH1N1”) affected the U.S. mili-
tary in a significant way (134). During the 2009 pandemic, the U.S.
military experienced high levels of influenza infection, with as
many as 200 to 300 cases per week being reported to the Military
Health System (MHS); of these cases, 20 to 30 (ϳ10%) were hos-
pitalized (135). 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).
TABLE 2 (Continued)
Time period(s) Military population Ad serotypes(s) involved and description Reference(s)
Feb 2004–Mar 2005 U.S. recruits Ad4 estimated to cause ϳ81% of FRI cases among Marine Corps recruits at
MCRD-SD; FRI rates of ϳ3.5% per wk, with higher rates in closed units and
larger units (76–88 recruits; FRI rates, 3.5–4.0 per wk) than in smaller units
(44–75 recruits; FRI rates, 2.5–3.2% per wk); viable Ad cultured from ϳ5–
9% of surface samples; strong suggestion of environmental source of Ad
outbreaks (as opposed to reintroductions by incoming recruits)
86
Jan–Oct 2005 Singaporean recruits Ad11a detected in 30 (13%) of 226 male ARD cases in February through June
2005; 2–13 cases per mo due to a genomic variant resulting from
recombination of parental Ad11 and Ad14 strains in southeast Asia; no
vaccination
87
Feb–May 2006, Apr
2011–Mar 2012
South Korean recruits In 2006, Ad7 identified in 122 (76%) of 200 recruits with ARD during 4-wk
basic military training; overall, 24,004 ARD cases identified among ϳ60,000
recruits, with ARD rates of ϳ10% per wk; in 2011–2012, Ad found to be
responsible for most acute LRTIs (63%) among a group of 87 personnel
admitted to the Armed Forces Capital Hospital in Seongnam; no vaccination
88, 101–103
Mar 2006–Mar 2009 U.S. recruits Ad14 emergence of infections at several recruit training centers in 2006–2007;
expansion from U.S. West Coast (appearance in 2003) to all recruit training
centers by mid-2009; more severe pneumonia-associated disease
presentation documented at Lackland AFB (Mar–Apr 2007) and CGTC
(Mar 2009); low baseline anti-Ad14 immunity a risk factor
53–55, 89, 91, 92
Apr 2007–Jun 2008 U.S. recruits Study of 234 pneumonia cases among 42,254 Air Force recruits conducting 6.5
wk of training at Lackland AFB; demonstrated widespread distribution of
Ad14 serotypes among hospitalized (63%) and outpatient (59%) pneumonia
cases; similar severities in Ad14 and non-Ad14 cases; Ad14-infected females
found to have a higher risk of hospitalization (83% vs 40%) and clinical
severity, as reflected by ICU stay (80% vs 9%), than males
93
Jan 2008–Dec 2012 U.S. recruits Dramatic and sustained reduction in ARD and Ad4 isolation rates since
resumption of vaccination in late October 2011
94
Mar 2011 Malaysian police
trainees (3 deaths)
Ad7 identified in 10 (48%) of 21 trainees at Kuala Lumpur Police Training
Centre hospitalized with ARD at Kuala Lumpur Hospital; overcrowding and
physical stress may have played a role; no vaccination
95
2000–2012 U.S. recruits Clear documentation of impact of Ad vaccination on drastic reduction of Ad-
related outcomes (ϳ85% FRI rate reduction; Ͼ90% reduction in Ad
isolation rates); 100-fold (99%) decline in Ad-associated disease burden
96, 97, 107
Feb 2012 Chinese military Ad55 identified in several hundred soldiers hospitalized at Boading City PLA
252 military hospital; possible link with reemergent Ad55 strain with Ad11-
Ad14 hexon recombination in China in 2009–2010; no vaccination
98–100
Feb–Mar 2012 Chinese recruits Ad7 strain found in 15 (83%) of 18 trainee samples; similar to a strain isolated
in a previous civilian-based outbreak in Shaanxi, China, in 2009; first well-
documented report of Ad7 in Chinese military; no vaccination
104
a
Classification is done by date of observation or outbreak when available; when not available, publication dates are provided. Reports may represent studies of acute respiratory
disease (ARD) in selected military populations and not necessarily outbreak investigations. ND, not determined; OR, odds ratio; RR, relative risk; GLNTC, Great Lakes Naval
Training Center, Chicago, IL; AIT, advanced individual training; FRI, febrile respiratory illness; MCRD-SD, Marine Corps Recruit Depot, San Diego, CA; AFB, Air Force Base;
CGTC, Coast Guard Training Center, Cape May, NJ; ICU, intensive care unit; BCT, basic combat training (months 1 to 3 of military service); IRR, ratio of the incidence rate for
recruits in months 1 to 3 compared to that for recruits in months 4 to 12 of military service; LRTI, lower respiratory tract infections; PLA, People’s Liberation Army.
Sanchez et al.
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9. 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 pre-
sented in Table 3 (83, 134, 136–159). The U.S. military’s labora-
tory-based respiratory disease surveillance efforts were responsi-
ble for the initial detection of pH1N1 virus, which occurred in
four military dependents who presented with ILI symptoms at
U.S. military treatment facilities (MTFs) and U.S.-Mexico border
clinics in San Diego, CA, and San Antonio, TX (134, 136–140).
In general, there is great variability in terms of the ARs experi-
enced; 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 (160), including large outbreaks at Fort Riley,
KS; Fort Hood, TX; Fort Lewis, WA; and Fort Bliss, TX, with
subsequent spread to U.S. forces in Kuwait and Iraq (138).
Intervention control measures were evaluated in the course of
these pH1N1-related outbreak investigations. These measures in-
cluded (i) the use of mass antiviral oseltamivir chemoprophylaxis
in a ship crew, shown by U.S. Navy investigators to limit pH1N1
spread (145); (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 mil-
itary members and the civilian populace in New York City (144);
(iii) evaluation of patient isolation and restriction measures in
shipboard personnel, with limitation of influenza spread (138,
145); (iv) early fever screening (i.e., within 24 h of arrival) of U.S.
troops in SWA, which was shown to be of limited utility given the
low specificity of the case definition and ongoing, asymptomatic
virus shedding (146); (v) implementation of electronic reporting
systems, patient isolation measures, the use of hand sanitizers and
face masks for ill individuals, and the use of rapid influenza diag-
nostic tests (RIDTs), leading to outbreak control in a Peruvian
Navy ship (147, 148); (vi) evaluation of oseltamivir “ring chemo-
prophylaxis” of coworkers and same-unit members, with clearly
documented efficacy in a semiclosed, crowded recruit setting in
Singapore (150); (vii) demonstration of prolonged pH1N1 virus
shedding, leading to secondary spread among closed-unit mem-
bers in the setting of a service academy (153); and (viii) the initial
recognition and control of pH1N1 virus transmission in Afghan-
istan, Serbia, and Switzerland by the local military (157–159).
Seasonal influenza in the U.S. military. Seasonal influenza vi-
rus 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 (161). Dur-
ing the latest 5-year period (2007 to 2012) for which there are
reported data from the AFHSC, influenza was found to be respon-
sible 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
(162). Although pH1N1 viruses have continued to circulate
worldwide (163), drifted H3N2 viruses have begun to predomi-
nate, causing an increase in the number of laboratory-confirmed
influenza-associated hospitalizations among both U.S. civilians
and military personnel in 2014 to 2015 (164; our unpublished
data, 19 March 2015). These drifted H3N2 viruses have also been
associated with increased mortality, especially among individuals
Ͼ64 years of age (165–167).
It appears that influenza-associated respiratory illnesses are
also common among dependents of military personnel (e.g.,
spouses and children), although underreporting of these condi-
tions may underestimate their impact in this group. The influen-
za-related mortality rate among military personnel has been very
low, with only nine influenza-associated deaths being docu-
mented during the past 16 years (1998 to 2014), three of which
occurred during the 2009-2010 pandemic period (83; R. N. Potter,
personal communication). 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 mil-
itary deaths is in place. Unfortunately, even though autopsies were
performed on these cases, the data were often limited to the phy-
sician-determined cause of death, without additional pathogen
laboratory workup or tissue analyses to better assess the underly-
ing contributing factors or the role of other coinfections. There is
no adequate dependent-based mortality registry to estimate the
mortality impact for this group.
Emerging avian-derived influenza viruses of concern: H5N1,
H3N2/H1N1 swine variants, H7N9, and others. Human infec-
tions with other avian-derived influenza viruses (AIVs) such as
H5N1 have been reported since 1997 and are of concern to the
military (168). As of May 2015, a total of 840 laboratory-con-
firmed human cases and 447 deaths have been reported to the
WHO from 16 countries (169). Despite the high mortality rate
(CFR of ϳ53%), human cases of H5N1 infection remain rare to
date, even among persons exposed to infected sick or dead poul-
try. Sporadic infections or small family clusters have been de-
tected, especially among individuals living in the same household
or those exposed to infected household poultry or contaminated
environments (170, 171). Fortunately, H5N1 does not appear to
transmit easily among humans, and the risk of community-level
spread remains low (172, 173). To date, there have been no re-
ported H5N1 infections in the U.S. military, and the risk to mili-
tary personnel is deemed to be low (our unpublished data, 6 May
2015).
Novel, triple-reassortant, swine-origin H3 variant viruses
(here referred to as “H3N2v”), first detected in swine in 2007, have
been responsible for Ͼ300 cases in the United States since the
summer of 2011 (174). 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.g., hand
washing [HW]) appears to represent a principal risk factor for
infection (175). 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 (175, 176). H3N2v viruses are considered to be
of human concern, with potential for epidemic spread among
highly susceptible, younger age groups (177). Enhanced vigilance
among swine-exposed populations, increased sanitation, and sim-
ple personal hygiene measures are believed to play an important
role in the containment of these viruses (178). As of May 2015,
there have been no reported cases among U.S. military personnel,
although one case was reported in Ohio, that of a 10-year-old
female dependent exhibiting ILI after exposure to swine at a
county fair. The risk to military personnel is deemed to be low
(U.S. Air Force School of Aerospace Medicine [USAFSAM], un-
published data, 16 to 17 October 2014).
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10. TABLE 3 Notable influenza deaths, outbreaks, and clusters in military-related populations due to pH1N1 virus from 2009 to 2010a
Time frame Population
No. of individuals
affected (AR [%]) Major finding(s) and/or highlight(s) Reference(s)
2009–2010 U.S. military personnel
(deaths)
3 (ND) Only 3 of 9 influenza-associated deaths in the 1998-2013 period
were attributed to pH1N1 virus during pandemic period
(April 2009 to August 2010)
83; R. N. Potter,
unpublished data
Apr 2009 U.S. military dependents 4 (ND) First detection of pH1N1 virus among dependent children in
San Diego, CA (2 cases), and San Antonio, TX (2 cases);
subsequent development of rRT-PCR assay for rapid testing
by the CDC in late April 2009; initial peak of 10–20 cases/day
during 25 April–1 May 2009 among dependents in MHS
134, 136–140
Apr–May 2009 U.S. military dependents 97 (0.1) Among Ͼ96,000 beneficiaries, a total of 761 ILI patients tested
by rRT-PCR, 97 (13%) of which had confirmed pH1N1 virus
infection, with 68 (70%) of those infected patients
epidemiologically linked in San Diego, CA, area
141
Apr–Jun 2009 U.S. military personnel 30 (2) Outpatient clinic-based testing of patients with ILI at Randolph
AFB and Lackland AFB in San Antonio, TX, on 1 April–7
June 2009; 30 of 56 influenza infections due to pH1N1 virus
(low prevalence of ϳ2% among ILI patients); documented
low reliability of rapid antigen-based RIDT in screening
142
Apr–May 2009 U.S. military shipboard
personnel
32 (8) A total of 46 (11%) crew members suffered ILI; 32 (70%) had
confirmed pH1N1 virus infection; secondary AR among
family members was ϳ6% (2 of 34 persons); crew exposed to
civilian Mexican maintenance workers while at dock in San
Diego, CA; effective use of mass antiviral chemoprophylaxis
led to outbreak control
141
May 2009 Engineer military
students
79 (12) First evidence of community transmission of pH1N1 virus in
Spain; AR for ILI moderately high (17%) among 636 recruits
within a 2-wk period; wide range in ARs depending on class
(3–19%)
143
May–Jun 2009 U.S. military shipboard
personnel
135 (12) Aborted an outbreak aboard the USS Roosevelt (crew of 280)
by hospitalizing 1 case at local VA medical center; exposure
of personnel at New York City Harbor resulted in an
outbreak involving 135 cases among ϳ1,100 personnel on
the USS Iwo Jima during a 3-wk period; strict isolation,
active case finding, early oseltamivir treatment of ill and
chemoprophylaxis of medical staff, and placement of ill
patients on sick leave ashore likely reduced the magnitude of
the outbreak
144
May–Aug 2009 U.S. military shipboard
personnel
Several hundred (ND) 7 separate clusters in shipboard platforms, evaluation of patient
isolation and restriction measures; largest outbreak at USS
Boxer with Ͼ200 cases over a 5-wk period following
deployment to Phuket, Thailand, in June–July 2009
138, 145
May–Aug 2009 U.S. military deploying
and in SWA
Several hundred (ND) First reported cases and outbreaks among U.S. military
deploying to SWA at 9 of 15 deploying installations in the
U.S., including large outbreaks at Fort Riley, KS (n ϭ 33);
Fort Hood, TX (n ϭ 44); Fort Lewis, WA (n ϭ 144); and
Fort Bliss, TX (n ϭ 188), with eventual spread to U.S. forces
in Kuwait and Iraq
138
May 2009 Deployed U.S. military 44 (20) First reported cases in Kuwait; rRT-PCR screening of 2 units
upon arrival at Camp Buehring (n ϭ 217); use of fever plus
cough or sore throat as screening criteria had low sensitivity
of only 5%, with a PPV of 100% and NPV of 80%;
phylogenetic analyses revealed a composition of the HA gene
similar to those of other worldwide-circulating pH1N1
viruses in April–May 2009
146
Jun–Jul 2009 Peruvian military
shipboard personnel
78 (22) Large outbreak among 355 nonimmune crew members over a
4-wk period following deployment to San Francisco, CA, in
late June 2009; serological infection rate found to be more
than twice as high as the symptomatic AR (49.1%); early
detection with an electronic reporting system, isolation of ill,
use of hand sanitizers and masks for ill, and rapid testing led
to outbreak control, with an estimated decrease in
infectiousness of 86.7%
147, 148
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11. TABLE 3 (Continued)
Time frame Population
No. of individuals
affected (AR [%]) Major finding(s) and/or highlight(s) Reference(s)
Jun–Oct 2009 Singaporean military
personnel
292 (29) One of the first large serologic cohort studies to document the
effectiveness of combined public health interventions against
pandemic influenza; prospective seroepidemiological study
of public health measures to control pH1N1 involving 1,166
personnel in 3 groups of units, including infantry (control),
essential personnel, and HCPs; overall infection rate was
29%, with higher documented rates for control personnel
(44%) than for essential personnel (17%) and HCPs (11%);
symptomatic infection rates also higher for control personnel
(12%) than for essential personnel (5%) and HCPs (2%)
149
Jun 2009 Singaporean military
personnel
82 (7) Large study of efficacy of daily oseltamivir ring
chemoprophylaxis in reducing symptomatic pH1N1
infections at 4 military camps; AR was 6.4% before
intervention, compared to only 0.6% after intervention
(Ͼ90% reduction); first documentation of efficacy of such an
intervention in a large-scale, crowded setting
150
May–Sep 2009 Italian military
shipboard personnel
83 (39) postcruise A total of 52 (22%) crew members sustained an ARI, 1 of which
was confirmed pH1N1 virus infection; 83 (39%) of 211 crew
members found to have significant anti-pH1N1 HAI/CF
titers (Ն1:10) postcruise; crowding associated with higher
prevalence of anti-pH1N1
151
Jun–Aug 2009 U.S. military shipboard
personnel
142 (32) High rate of asymptomatic infection (53%) and higher risk of
illness for females (OR ϭ 2.2), Marine Corps (OR ϭ 1.7),
and younger personnel (19–24 yr old) (OR ϭ 3.9); improved
infection control measures such as preembarkation illness
screening, isolation of ill, quarantine of exposed contacts,
and prompt antiviral chemoprophylaxis of close contacts and
treatment of ill
152
Jun–Jul 2009 U.S. military service
academy students
Several hundred overall
(ND), 148 (11) at
USAFA outbreak
Post-4th-of-July social-mixing event at the U.S. Air Force
Academy in Colorado Springs, CO, led to a rapid peak in
pH1N1 transmission within 48 h; variable secondary ARs
(7% to 18%) among 10 squadron units; 1st report of
prolonged (Ͼ7 days postonset) pH1N1 virus shedding by
virus culture; documented outbreaks at other U.S. service
academies (U.S. Naval Academy, MD; US Military Academy,
NY; U.S. Coast Guard Academy, CT)
138, 153
Jun–Oct 2009 Singapore armed forces 312 (29) Random sample of 1,213 military personnel from 15 units (n ϭ
1,570) with serology done on 3 occasions between 22 June
and 9 October 2009; baseline immunity of ϳ9%; rapid
seroconversion and military epidemic peak 2 to 3 wk prior to
community peak; infection rate much higher in military
(29%) than in community members (13%) or hospital staff
(7%); younger age, lower baseline titer, and proportion
infection rate associated with increased risk of infection;
receipt of seasonal influenza vaccine associated with a 59%
decreased risk of infection
154
Aug–Oct 2009 U.S. military recruits Several hundred (ND) Few cases in first wave in June–July 2009 (outbreaks at U.S.
Navy, Marine Corps, and Air Force recruit camps); larger
peak in no. of cases in second wave in August–October 2009
affecting all 8 recruit training centers
138
May 2009–Apr
2010
French military ND (0.4/wk) Peak in transmission rates (0.4% per wk) in early December
2009; much lower than national rates in the civilian
population (attributed to the “healthy worker effect”)
155
Jul–Nov 2009 Afghan national and
foreign forces
703 (ND) First imported case in multinational force military member on
or about 3 July 2009; 313 cases in foreign and 390 in Afghan
national forces
156
Oct–Nov 2009 Afghan recruits 6,344 of ϳ9,000 (70) Most recruits (n ϭ 5,954 [94%]) sustained mild to moderate
ILI and returned to duty when asymptomatic, 319 (5%) were
isolated until asymptomatic for 24 h, and 61 (1%) were
hospitalized with severe ILI and/or pneumonia
157
(Continued on following page)
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12. On 31 March 2013, the first three human infections with H7N9
virus were reported to the WHO by Chinese authorities (179).
These viruses, which have become enzootic in China (180, 181),
have spread efficiently among live-poultry market (LPM) work-
ers, close household contacts, and health care providers (HCPs) in
China and Hong Kong (182, 183) and constitute a significant
threat to the military. These novel triple-reassortant viruses cause
severe disease in humans (184). 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 (184, 185).
H7N9 viruses appear to be more readily transmissible from
animals to humans than H5N1 viruses, although human-to-hu-
man transmission continues to be limited (186, 701, 702). 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 (173, 187–189, 703). 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 (190).
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 (191). 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 (169, 183, 192–194; our
unpublished data, 6 May 2015). Preliminary studies in mice indi-
cate that infection with these H7N9 viruses is associated with in-
creased lethality (160), similar to that seen with 1918 H1N1 virus
infection. To date, there have been no reported cases of H7N9
infection in the U.S. military, and the risk to military personnel
appears to be low (our unpublished data, 20 May 2015).
Additional AIVs continue to emerge or reemerge in East and
Southeast Asia (169, 195). 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
(196, 197). 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. Addition-
ally, one ILI case due to H6N1 was reported in China, and three ILI
cases due to H9N2 were reported in China and Egypt (173). Hu-
man 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 (198).
Elsewhere, two asymptomatic H1N2 infections in swine farmers
in Sweden were reported in April 2014; no further swine-to-hu-
man or human-to-human transmission has been documented in
this instance (169). Lastly, but of great concern in the United
States, 18 human infections (1 death) due to influenza A(H1N1)v
viruses (134) have been detected since December 2005 (173, 704,
705). Thus, these novel subtypes may continue to spread, and
additional surveillance of high-risk populations is needed to re-
veal the extent of their circulation (197, 199–201, 706). No cases
due to these additional AIVs have been identified in the U.S. mil-
itary to date (our unpublished data, 6 May 2015).
Clinical spectrum of illness. Seasonal influenza viruses (H1N1,
H3N2, and B subtypes) have a very short incubation period (me-
dian, 2 days; range, 1 to 4 days), which may be longer (up to 8 to 9
days) for infections caused by other AIVs (44, 202). 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. Hospital-
ized adults may shed infectious virus for up to a week or longer
after illness onset. Viremia rarely occurs in uncomplicated influ-
enza, except in cases of H5N1-infected patients, for whom detec-
tion of viral RNA in blood is associated with a worsened prognosis
(202).
Most adults with symptomatic influenza virus infection have
uncomplicated illness, with sudden onset of fever, cough, head-
aches, 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 (203). Although most persons
with influenza virus infection do not develop critical illness, those
who are pregnant (204, 205) or obese (204, 206) 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 dys-
function (207, 208), an illness which is the result of an intense
inflammatory host response to the virus (209). Influenza infec-
tions may also be complicated by secondary bacterial pneumonia,
TABLE 3 (Continued)
Time frame Population
No. of individuals
affected (AR [%]) Major finding(s) and/or highlight(s) Reference(s)
Oct–Nov 2009 Serbian military students 44 (15) 1st confirmed outbreak in Serbia; AR for ARI very high (71%)
among 288 students; most pH1N1-infected cases had mild
illness with relative absence of sore throat (21%); receipt of
2008-2009 seasonal TIV was documented to be ϳ30%
effective in reducing pH1N1 infection and ϳ22% effective in
reducing ARI rates
158
Dec 2010 Swiss recruits 105 (14) Rapid amplification of pH1N1 virus transmission within
military boot camp setting; affected 5 company-sized units
(n ϭ 750) in 4 separate military barracks; initial influenza
outbreak in Switzerland in 2010-2011 season
159
a
pH1N1, novel influenza A pdm09 virus; AR, estimated attack rate; ILI, influenza-like illness, defined as fever with cough or sore throat; ND, not determined; AFB, Air Force Base;
SWA, Southwest Asia; CDC, U.S. Centers for Disease Control and Prevention; MHS, U.S. Military Health System; OR, odds ratio; rRT-PCR, real-time reverse transcriptase PCR;
PPV, positive predictive value; NPV, negative predictive value; HA, hemagglutinin; RIDT, rapid influenza diagnostic test; ARI, acute respiratory illness; HAI, hemagglutination
inhibition assay; CF, complement fixation; TIV, trivalent inactivated influenza vaccine; HCPs, health care providers; USAFA, U.S. Air Force Academy.
Sanchez et al.
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13. especially with Staphylococcus aureus (including methicillin-resis-
tant S. aureus), S. pneumoniae, or Streptococcus pyogenes, in up to
20% to 30% of cases (209).
Diagnostic modalities. Influenza virus can be readily isolated
in tissue culture (rhesus monkey kidney cells, Madin-Darby ca-
nine kidney cells, cynomolgus monkey kidney cells, and Vero
cells) of nasal aspirates or nasopharyngeal (NP) swabs (49, 210).
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 diagno-
sis can also be facilitated by commercially available RIDTs (211).
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 de-
pendent largely on the type of sample as well as on the patient’s age
and phase of illness (211). RIDT sensitivity is lower in adults and
elderly patients than in young children, whose nasal secretions
may contain larger quantities of virus (212, 213). 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 (214). RIDT
specificity, on the other hand, has been very good, ranging from
85% to 100%; thus, they are good tests for “ruling in” rather than
“ruling out” influenza infection, especially when influenza activity
is high in the community (211). 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 im-
prove the sensitivity and specificity of RIDTs (215).
The gradual dissemination of NAATs, including real-time RT-
PCR (rRT-PCR), in clinical laboratories has shifted the focus of
laboratory diagnosis of influenza infection from dependency on
virus culture, which takes several days, to a highly specific
(Ͼ99.9%) and highly sensitive (86% to 100%) diagnosis available
within several hours (216). Sample processing automation, com-
bined with user-friendly platforms for NAATs and information
management systems, facilitates high-throughput molecular di-
agnostics for the detection of viral nucleic acids, including those of
influenza A virus, from a variety of respiratory tract samples. Mo-
lecular assays can be used in conjunction with other diagnostic
assays, and with clinical and epidemiological information, to assist
in patient management and treatment (217).
The U.S. military has been an active participant in the devel-
opment of PCR-based platforms for the detection of influenza
virus and other respiratory pathogens in the past decade. A mo-
lecular-based testing platform, termed the Joint Biological Agent
Identification and Diagnostic System (JBAIDS) (Fig. 1), was de-
veloped by the U.S. military to detect select agents, such as those
responsible for anthrax and tularemia. Subsequently, its use was
expanded to the rapid diagnosis of influenza A and B viruses in
field operational settings (218). Additionally, in 2013 to 2014, U.S.
Navy scientists at the Naval Health Research Center (NHRC)
(219), in collaboration with the Swiss Armed Forces (Spiez Labo-
ratory, Spiez, Switzerland) and the University of Hong Kong, eval-
uated an H7N9 influenza virus detection rapid test. By using clin-
ical 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 (220). This rapid detection test is intended for use by
the U.S. military’s network of laboratories, or by other U.S. Gov-
ernment (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.
New FDA-cleared multiplex PCR tests that also allow the si-
multaneous detection of influenza virus as well as other respira-
tory agents, either as single viruses or as copathogens, have been
made available (113–115, 118–120, 221–223). Among adult pa-
tients 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
(707). One influenza virus typing kit based on the RT-PCR elec-
trospray ionization mass spectrometry (PCR-ESI-MS) platform
allows the detection of 16 hemagglutinin (HA) and 9 neuramini-
dase (NA) subtypes (224) as well as detection of drift of specific
genes over time (224–227). Because of its ability to detect recom-
bination, drifting, or shifting events, PCR-ESI-MS typing analysis
can be useful in detecting newly emerging influenza virus strains
(228). However, this test is currently performed as a service only
by AthoGen (Carlsbad, CA). New PCR-based point-of-care tests
that are more sensitive (Ͼ90%) than older RIDTs have been de-
veloped and cleared by the FDA for laboratory-based and physi-
cian-based office use (229–231).
As with adenoviruses, serologic assays for influenza A and B
viruses exist but are not routinely used for clinical diagnosis. How-
ever, 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 (152, 232,
233).
FIG 1 Joint Biological Agent Identification and Diagnostic System. This rug-
gedized, deployable, and portable system for the field environment was first
developed by the U.S. military for the identification of biological agents (e.g.,
anthrax, plague, tularemia, and brucella). Influenza virus detection reagents
and other testing materials were developed to identify generic subtypes A and
B as well as to identify specific subtypes H1 (seasonal and pandemic variants),
H3, H5, H7, H9 (avian variants), and H3 (swine variant).
Respiratory Infections in the U.S. Military
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