Acute Respiratory Disease Associated with Adenovirus Serotype 14

Acute Respiratory Disease Associated with Adenovirus Serotype 14 ---
Four States, 2006—2007

November 16, 2007 / 56(45);1181-1184

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5645a1.htm?s_cid=mm5645a1_e%0A

Adenovirus serotype 14 (Ad14) is a rarely reported but emerging
serotype of adenovirus that can cause severe and sometimes fatal
respiratory illness in patients of all ages, including healthy young
adults. In May 2006, an infant in New York aged 12 days died from
respiratory illness caused by Ad14. During March--June 2007, a total
of 140 additional cases of confirmed Ad14 respiratory illness were
identified in clusters of patients in Oregon, Washington, and Texas.
Fifty-three (38%) of these patients were hospitalized, including 24
(17%) who were admitted to intensive care units (ICUs); nine (5%)
patients died. Ad14 isolates from all four states were identical by
sequence data from the full hexon and fiber genes. However, the
isolates were distinct from the Ad14 reference strain from 1955,
suggesting the emergence and spread of a new Ad14 variant in the
United States. No epidemiologic evidence of direct transmission
linking the New York case or any of the clusters was identified. This
report summarizes the investigation of these Ad14 cases by state and
city health authorities, the U.S. Air Force, and CDC. State and local
public health departments should be alert to the possibility of
outbreaks caused by Ad14.

New York

In May 2006, a fatal case of Ad14 illness occurred in New York City in
an infant girl aged 12 days. The infant was born after a full-term
pregnancy and uncomplicated delivery. She was found dead in bed, where
she had been sleeping. The infant had been examined 3 days after birth
and noted to have lost weight but was otherwise healthy. The next week
she had decreased tears with crying, suggesting early dehydration.
Physical activity and feeding progressively decreased during the week
before her death.

Postmortem tracheal and gastric swabs from the infant were sent to the
Wadsworth Center laboratory of the New York State Department of
Health, where adenovirus was detected by polymerase chain reaction
(PCR). Adenovirus also was isolated by culture, confirmed by
immunofluorescence assay (IFA), and typed as Ad14 by antibody
neutralization assay. Analysis at CDC identified the same unique
genetic sequences in this isolate as were later identified in the Ad14
isolates from the three 2007 clusters.

Autopsy and histologic findings at the Office of the Chief Medical
Examiner in New York City included presence in the lung of chronic
inflammatory cells with intranuclear inclusions, consistent with
adenoviral bronchiolitis and acute respiratory distress syndrome.
Investigation by the New York City Department of Health and Mental
Hygiene has not identified any other local cases of Ad14 illness.

Oregon

In early April 2007, a clinician alerted the Oregon Public Health
Division (OPHD) regarding multiple patients at a single hospital who
had been admitted with a diagnosis of severe pneumonia during March
3--April 6. A total of 17 specimens were obtained from patients; 15
(88%) yielded isolates that were identified by CDC as Ad14. Through
retrospective examination of laboratory reports from the three
clinical laboratories in the state that have virology capacity and the
Oregon State Public Health Laboratory (OSPHL), OPHD identified 68
persons who tested positive (by culture, PCR, or IFA) for adenovirus
during November 1, 2006--April 30, 2007. Isolates from 50 (74%) of
these patients were available for further adenovirus typing at either
CDC or OSPHL. Of the 50 patient isolates, 31 (62%) were identified as
Ad14, and 15 (30%) were identified as another adenovirus type
(Figure); four (8%) did not test positive for adenovirus.

Among 30 Ad14 patients (i.e., all but one) whose medical charts were
reviewed, 22 (73%) were male; median age was 53.4 years (range: 2
weeks--82 years). Five cases (17%) occurred in patients aged <5 years,
and the remaining 20 (83%) occurred in patients aged >18 years.
Twenty-two patients (73%) required hospitalization, sixteen (53%)
required intensive care, and seven (23%) died, all from severe
pneumonia. Median age of the patients who died was 63.6 years; five
(71%) were male. One death occurred in an infant aged 1 month. Of the
30 Ad14 cases with patient residence information available, 28 (93%)
occurred in residents of seven Oregon counties, and two cases occurred
in residents of two Washington counties. No link was identified in
hospitals or the community to explain transmission of Ad14 from one
patient to another.

In comparison with the Ad14 patients, among the 12 adenovirus non-type
14 patients (i.e., all but three) whose medical charts were reviewed,
nine (75%) were male. Median age was 1.1 years, and 11 (92%) patients
were aged <5 years. Two (17%) adenovirus non-type14 patients required
hospitalization; no ICU admissions or deaths were reported in this
group.

Washington

On May 16, 2007, the Tacoma-Pierce County Health Department notified
the Washington State Department of Health (WADOH) of four residents
housed in one unit of a residential-care facility who had been
hospitalized recently for pneumonia of unknown etiology. The patients
were aged 40--62 years; three of the four were female. One patient had
acquired immunodeficiency syndrome (AIDS); the three others had
chronic obstructive pulmonary disease. All four were smokers.

The patients had initial symptoms of cough, fever, or shortness of
breath during April 22--May 8, 2007. Three patients required intensive
care and mechanical ventilation for severe pneumonia. After 8 days of
hospitalization, the patient with AIDS died; the other patients
recovered. Respiratory specimens from all four patients tested
positive for adenovirus by PCR at the WADOH laboratory; isolates were
available from three patients, and all three isolates were identified
as Ad14 by CDC. Ad14 had last been identified in an isolate from a
patient from Washington in May 2006, marking the first identification
of Ad14 in the state since 2004. Active surveillance among facility
residents and staff did not identify any other cases of Ad14 illness.

Texas

Since February 2007, an outbreak of cases of febrile respiratory
infection* associated with adenovirus infection has been reported
among basic military trainees at Lackland Air Force Base (LAFB).
During an initial investigation, conducted from February 3 to June 23,
out of 423 respiratory specimens collected and tested, 268 (63%)
tested positive for adenovirus; 118 (44%) of the 268 were serotyped,
and 106 (90%) of those serotyped were Ad14. Before this outbreak, the
only identification of an Ad14 isolate at LAFB occurred in May 2006
(1).

During February 3--June 23, 2007, a total of 27 patients were
hospitalized with pneumonia (median hospitalization: 3 days),
including five who required admission to the ICU. One ICU patient
required extracorporeal membrane oxygenation for approximately 3 weeks
and ultimately died. All 16 hospitalized patients from whom throat
swabs were collected, including the five patients admitted to the ICU,
tested positive for Ad14. Fifteen of these hospitalized patients
tested negative for other respiratory pathogens, and one patient had a
sputum culture that was positive for Haemophilus influenzae.

All health-care workers from hospital units where trainees had been
admitted were offered testing for Ad14, regardless of history of
respiratory illness. Of 218 health-care workers tested by PCR, six
(3%) were positive for Ad14; five of the six reported direct contact
with hospitalized Ad14 patients.

Prevention measures implemented during the outbreak included
increasing the number of hand-sanitizing stations, widespread
sanitizing of surfaces and equipment with appropriate disinfectants,
increasing awareness of Ad14 among trainees and staff members, and
taking contact and droplet precautions for hospitalized patients with
Ad14. Beginning on May 26, trainees with febrile respiratory illness
were confined to one dormitory and both patients and staff members
were required to wear surgical masks.

Cases reported postinvestigation. Since the investigation, new cases
of febrile respiratory illness have continued to occur at LAFB, but
the weekly incidence has declined from a peak of 74 cases with onset
during the week of May 27--June 2, to 55 cases with onset during the
week of September 23--29 (the most recent period for which data were
available). In addition, during March--September 2007, three other
military bases in Texas that received trainees from LAFB reported a
total of 220 cases of Ad14 illness (Air Force Institute for
Operational Health, personal communication, 2007). However, whether
Ad14 spread from LAFB to these three bases has not been determined.
Ad14 also was detected in April in an eye culture from an outpatient
in the surrounding community who had respiratory symptoms and
conjunctivitis. No link between this case and the LAFB cases was
identified.

Reported by: Oregon Dept of Human Svcs. Washington State Dept of
Health Communicable Diseases. 37th Training Wing, 59th Hospital Wing,
Air Force Institute for Operational Health, Epidemic and Outbreak
Surveillance, US Air Force. Naval Health Research Center, US Navy.
Texas Dept of State Health Svcs. New York City Dept of Health and
Mental Hygiene. Div of Viral Diseases, National Center for
Immunization and Respiratory Diseases; Div of Healthcare Quality
Promotion, National Center for Preparedness, Detection, and Control of
Infectious Diseases; Career Development Div, Office of Workforce and
Career Development, CDC.

Editorial Note:

Adenoviruses were first described in the 1950s and are associated with
a broad spectrum of clinical illness, including conjunctivitis,
febrile upper respiratory illness, pneumonia, and gastrointestinal
disease. Severe illness can occur in newborn or elderly patients or in
patients with underlying medical conditions but is generally not
life-threatening in otherwise healthy adults. Adenoviruses are known
to cause outbreaks of disease, including keratoconjunctivitis, and
tracheobronchitis and other respiratory diseases among military
recruits (2,3). Although adenovirus outbreaks in military recruits are
well-recognized (3), infection usually does not require
hospitalization and rarely requires admission to an ICU. Beyond the
neonatal period, deaths associated with community-acquired adenovirus
infection in persons who are not immunodeficient are uncommon and
usually sporadic.

Fifty-one adenovirus serotypes have been identified (4). The cases
described in this report are unusual because they suggest the
emergence of a new and virulent Ad14 variant that has spread within
the United States. Ad14 infection was described initially in 1955 (5)
and was associated with epidemic acute respiratory disease in military
recruits in Europe in 1969 (6) but has since been detected
infrequently. For example, during 2001--2002, Ad14 was associated with
approximately 8% of respiratory adenoviral infections in the pediatric
ward of a Taiwan hospital, with approximately 40% of Ad14 cases in
children aged 4--8 years manifesting as lower airway disease (7).

The National Surveillance for Emerging Adenovirus Infections system
includes military and civilian laboratories at 15 sites. During
2004--2007, this surveillance system detected 17 isolates of Ad14 from
seven sites (8). Ten of the 17 isolates (60%) were collected from
three military bases (8). Despite this surveillance, adenovirus
infections often go undetected, because few laboratories routinely
test for adenovirus and even fewer do serotyping. Wider circulation of
Ad14 might have occurred in recent years and might still be occurring.

Further work is needed to understand the natural history of Ad14, risk
factors for severe Ad14 disease, and how Ad14 transmission can be
prevented effectively. Vaccines against adenovirus serotypes four and
seven (i.e., Ad4 and Ad7) were used among military recruits during
1971--1999, before vaccines were no longer available. Adenoviral
disease among U.S. military recruits subsequently increased (9). Ad4
and Ad7 oral vaccines have been redeveloped and are being evaluated in
clinical trials. Work is ongoing to determine whether the new Ad4 and
Ad7 vaccines will protect against Ad14 infection. Management of
adenoviral infections is largely supportive. A number of antiviral
drugs, including ribavirin, vidarabine, and cidofovir, have been used
to treat adenoviral infections such as Ad14, but none have shown
definitive efficacy against adenoviruses (2).

Control of adenovirus outbreaks can be challenging because these
viruses can be shed in both respiratory secretions and feces and can
persist for weeks on environmental surfaces. Guidelines for the care
of patients with pneumonia (10) should be followed in cases of
suspected adenoviral pneumonia.

Clinicians with questions related to testing of patients for
adenovirus or Ad14 infection should contact their state health
departments, which can provide assistance. State health departments
and military facilities should contact CDC to report unusual clusters
of severe adenoviral disease or cases of Ad14 or to obtain additional
information regarding laboratory testing.

References

1. Metzgar D, Osuna M, Kajon AE. Abrupt emergence of diverse species
B1 and B2 adenoviruses in US military recruit training centers. J
Infect Dis. In press.

2. Adenovirus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles
and practice of infectious disease. 6th edition. Philadelphia, PA:
Churchill Livingstone; 2004.

3. Dingle JH, Langmuir AD. Epidemiology of acute, respiratory disease
in military recruits. Am Rev Respir Dis 1968;97(Suppl):1--65.

4. Kajon AE, Moseley JM, Metzgar D, et al. Molecular epidemiology of
adenovirus type 4 infections in US military recruits in the
postvaccination era (1997--2003). J Infect Dis 2007;196:67--75.

5. Van der Veen J, Kok G. Isolation and typing of adenoviruses
recovered from military recruits with acute respiratory disease in The
Netherlands. Am J Hyg 1957;65:119--29.

6. Hierholzer JC, Pumarola A. Antigenic characterization of
intermediate adenovirus 14-11 strains associated with upper
respiratory illness in a military camp. Infect Immun 1976;13:354--9.

7. Chen H, Chiou S, Hsiao H, et al. Respiratory adenoviral infections
in children: a study of hospitalized cases in southern Taiwan in
2001--2002. J Trop Pediatr 2002;50:279--84.

8. National Surveillance for Emerging Adenovirus Infections. Available
at http://www.public-health.uiowa.edu/adv.

9. Russell KL, Hawksworth AW, Ryan MA, et al. Vaccine-preventable
adenoviral respiratory illness in US military recruits, 1999--2004.
Vaccine 2006;24:2835--42.

10. CDC. Guidelines for preventing health-care--associated pneumonia,
2003. Recommendations of CDC and the Healthcare Infection Control
Practices Advisory Committee. MMWR 2004;53(No. RR-3).

* Defined as 1) fever >100.5°F (>38.1°C) plus at least one other sign
or symptom of respiratory illness or 2) diagnosis of pneumonia.