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

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).

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Date last reviewed: 11/14/2007