Outbreak of Adenovirus 14 Respiratory Illness --- Prince of Wales Island, Alaska, 2008

On September 22, 2008, a physician on Prince of Wales Island, Alaska, notified the Alaska Department of Health and Social Services (ADHSS) of an unusually high number of adult patients with recently diagnosed pneumonia (n = 10), including three persons who required hospitalization and one who died. ADHSS and CDC conducted an investigation to determine the cause and distribution of the outbreak, identify risk factors for hospitalization, and implement control measures. This report summarizes the results of that investigation, which found that the outbreak was caused by adenovirus 14 (Ad14), an emerging adenovirus serotype in the United States that is associated with a higher rate of severe illness compared with other adenoviruses. Among the 46 cases identified in the outbreak from September 1 through October 27, 2008, the most frequently observed characteristics included the following: male (70%), Alaska Native (61%), underlying pulmonary disease (44%), aged ≥65 years (26%), and current smoker (48%). Patients aged ≥65 years had a fivefold increased risk for hospitalization. The most commonly reported symptoms were cough (100%), shortness of breath (87%), and fever (74%). Of the 11 hospitalized patients, three required intensive care, and one required mechanical ventilation. One death was reported. Ad14 isolates obtained during the outbreak were identical genetically to those in recent community-acquired outbreaks in the United States which suggests the emergence of a new, and possibly more virulent Ad14 variant. Clinicians should consider Ad14 infection in the differential diagnosis for patients with community-acquired pneumonia, particularly when unexplained clusters of severe respiratory infections are detected.

On October 1, 2008, epidemiologists from ADHSS arrived at Prince of Wales Island to identify cases and help collect clinical specimens from patients at clinics A and B. On October 6, CDC confirmed that six of 13 nasopharyngeal samples collected from patients at clinics A and B from September 1 through October 6 tested positive for Ad14 infection. Before the outbreak (October 2005--August 2008), only six sporadic cases of Ad14 infection had been identified by the Alaska State Virology Laboratory. On October 12, ADHSS and CDC investigators returned to the island to conduct additional investigations. Investigators reviewed hospital and clinic medical records using a CDC data collection form* to ascertain demographic characteristics of patients, symptom information, past medical history, and clinical outcomes. A probable case of Ad14 infection was defined by a clinically diagnosed acute lower respiratory tract infection in a resident of Prince of Wales Island who had been treated at clinic A or B from September 1 through October 27. A confirmed case was defined by laboratory-confirmed Ad14 infection by polymerase chain reaction, viral culture, or serology during the same period. Sera were collected at the time of the clinic or home visit and tested for Ad14-specific neutralizing antibodies using a standardized neutralization assay for Ad14; a titer of ≥1:80 was considered evidence of recent Ad14 infection (1). Paired sera were not collected. Patients who met the probable or confirmed case definitions completed a written questionnaire on risk factors for hospitalization, smoking status, travel history, and social history.

From September 1 through October 27, 46 cases of Ad14 infection (20 probable and 26 confirmed) were identified at clinics A and B; symptom onset ranged from August 29 to October 19 (Figure). Patients ranged in age from 2 to 95 years (median: 47 years); 70% were male, 61% were Alaska Native, and 48% were current smokers. The most common symptoms included cough in 46 patients (100%), shortness of breath in 40 (87%), and self-reported fever in 34 (74%) (Table 1). Chest radiographs were obtained for 39 (85%) patients; 30 (77%) of the radiographs were consistent with acute lower tract respiratory illness, most commonly patchy or interstitial infiltrates. The median duration of illness was 14 days (range: 1--41 days). Most of the 46 patients received one or more of the following treatments: antibiotics (91%), bronchodilators (41%), or corticosteroids (28%) (Table 1); none received antiviral therapy.

Among the 11 (24%) patients who were hospitalized, ages ranged from 33--78 years (median age: 68 years); nine patients were medically evacuated off the island. One patient with a history of underlying chronic obstructive pulmonary disease (COPD) requiring supplemental oxygen refused hospitalization and died within 10 days of symptom onset. Postmortem testing for adenovirus was not performed.

Among the 46 cases identified, 28 (61%) also had pulmonary disease (including COPD, asthma, or lung cancer) or another chronic condition (including cardiovascular disease, diabetes, cancer, and liver disease) (Table 2). Patients aged ≥65 years had a five-fold increased risk for hospitalization on univariate analysis (p<0.01) (Table 2). In a multivariate logistic regression model that included age, current smoking status, race, underlying pulmonary disease, and comorbid condition, only age ≥65 years remained a statistically significant predictor of hospitalization (odds ratio [OR] = 13.7; p<0.01).

Serum and nasal/oral swabs were obtained from September 1 through October 27, and submitted to ASVL and CDC's Gastroenteritis and Respiratory Viruses Laboratory Branch for testing. Respiratory specimens were cultured for respiratory syncytial virus, influenza viruses, parainfluenza viruses, adenoviruses, herpes simplex virus, rhinoviruses, coxsackie viruses, echoviruses, and enteroviruses. Respiratory specimens were also tested for Ad14 DNA using an Ad14-specific real-time polymerase chain reaction assay and viral isolates were sequenced.

Serum and/or nasal/oral swabs were collected from 39 (85%) patients (25 serum samples, 39 nasal/oral swabs). Among the 39 respiratory specimens submitted for testing, 16 (41%) tested positive for Ad14. Among the 25 serum specimens submitted for testing, 12 (48%) had elevated Ad14 neutralizing antibody titers. In total, 26 (67%) of 39 patients tested had laboratory-confirmed Ad14 infection. The genetic sequences of the Ad14 viruses isolated from this outbreak were identical with those found in other outbreak strains in the United States (2,3). No other pathogens were identified.

Reported by

J McLaughlin, MD, D Fearey, MS, SA Jenkerson, MSN, K Martinek, MPH, Alaska Section of Epidemiology. C Panozzo, MPH, E Schneider, MD, J Tate, PhD, Div of Viral Diseases, National Center for Immunization and Respiratory Diseases; CL Robbins, PhD, D Esposito, MD, TJ Gardner, PhD, EIS officers, CDC.

Editorial Note

This report documents the first recognized community outbreak of Ad14 infection in Alaska. Adenoviruses have been associated with acute respiratory infections, pharyngoconjunctival fever, gastrointestinal illness, and hemorrhagic cystitis (4). Although adenovirus infections are typically mild, some persons, including infants and immunocompromised persons, are at increased risk for severe disease (2). Before 2003, U.S. outbreaks of Ad14 most often occurred among U.S. military recruits, and most cases were mild (3,5). However, recent U.S. reports of Ad14 outbreaks, including the Alaska outbreak, describe severe and sometimes fatal respiratory illness in persons of all ages (2,3). The genetic sequences of the isolated Ad14 viruses in these recent outbreaks are identical and are distinct from the Ad14 reference strain of 1955, which suggests the emergence of a new and possibly more virulent Ad14 variant (2,3).

During this outbreak, certain groups were more frequently affected, including males, persons aged ≥65 years, and persons with underlying pulmonary disease. In addition, 22 (48%) patients were current smokers. Smoking has not been associated with Ad14 infection previously. As part of a separate investigation of this outbreak, a case-control study was conducted on Prince of Wales Island during September and October 2008. Cases were patients with clinical or radiological evidence of pneumonia in an island resident aged >1 year who sought care from September 1 through October 27, 2008. Age-matched controls were randomly selected from the community. Controls with self-reported signs of febrile acute upper respiratory infection or acute lower respiratory tract illness in the 2 weeks preceding onset of symptoms in the case-patient to whom they were matched were excluded. Preliminary results indicate that smoking (OR = 13.0, p = 0.002), comorbid condition (OR = 3.5, p = 0.03), and contact with an Ad14-infected person (OR = 18.0, p<0.001) to be risk factors for disease (CDC, unpublished data; 2009). Although smoking prevalence for the Prince of Wales Island was unavailable, the 48% rate of smoking among patients in this report was substantially higher than the smoking prevalence in the general Alaska public (22%) and the Alaska Native population (38%).† This finding, when combined with the preliminary results of the case-control study, suggests that smoking was associated with Ad14 illness in this outbreak. In addition, 70% of the patients who met the case definition were Alaska Natives, a group that constitutes only 33% of the Prince of Wales Island population. Alaska Natives living in rural Alaska have been shown to be at increased risk for many respiratory infections, likely due to multiple risk factors, including lack of modern sanitation services, crowded housing conditions, and barriers to health care (6).

During this outbreak, 11 of 46 (24%) patients were hospitalized. In the multivariable analysis, the only statistically significant independent risk factor for hospitalization was advanced age (≥65 years). In other studies of Ad14, additional risk factors for hospitalization have included certain underlying medical conditions, such as pulmonary and cardiovascular disease (7). No such associations were found in this investigation, but the ability to assess the individual effect of these risk factors was limited by small sample size.

Among the 46 patients, 42 (91%) were prescribed antibiotics at the time of their clinic visit. Although cidofovir, gancyclovir, and ribavirin might be beneficial (4), no specific antiviral medication is recommended for the treatment of severe adenovirus disease, and none of the patients received antiviral medications. No licensed vaccine for Ad14 currently exists. However, initial studies to assess the safety and immunogenicity of newly manufactured adenovirus 4 (Ad4) and 7 (Ad7) vaccines have shown promise in study populations (8). Ad4 and Ad7 vaccine safety and efficacy trials are in progress, and vaccines for these adenovirus serotypes might offer some cross-immunity to Ad14 (3,9).

Adenovirus infections continue to be identified in communities throughout Alaska; the last reported cases of Ad14 were in August 2009. Health-care providers should consider Ad14 in their differential diagnosis for patients with community-acquired pneumonia, obtain respiratory and serologic specimens for laboratory confirmation, and report suspected Ad14 outbreaks to public health officials. Patients with symptoms of severe viral respiratory infections and those diagnosed with adenovirus infection should be placed in private rooms or share a room with other patients with the same infection to help control the spread of respiratory infections (10). Health-care providers should follow standard contact and droplet precautions when caring for persons hospitalized with an adenoviral infection (10).

Acknowledgments

The findings in this report are based, in part, on contributions by M Fribush, MD, who initially reported this outbreak, and by E Funk, Alaska Section of Epidemiology; T Schmidt, Alaska State Virology Laboratory; C Watson, Alaska Public Health Nursing; L Thomas; health-care providers and staff members of clinics A and B, Prince of Wales Island; L Anderson, G Armstrong, A Curns, D Erdman, G Fischer, X Lu, Div of Viral Diseases; and D Bensyl, B Gunnels, Office of Workforce and Career Development, CDC.

References

1. Lu X, Erdman DD. Molecular typing of human adenoviruses by PCR and sequencing of a partial region of the hexon gene. Arch Virol 2006;151:1587--602.
2. CDC. Acute respiratory disease associated with adenovirus serotype 14---four states, 2006--2007. MMWR 2007;56:1181--4.
3. Tate JE, Bunning ML, Lott L, et al. Outbreak of severe respiratory disease associated with emergent human adenovirus serotype 14 at a US Air Force training facility in 2007. J Infect Dis 2009;199:1419--26.
4. Baum SG. Adenovirus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious disease. 6th ed. Philadelphia, PA: Churchill Livingstone; 2004.
5. Metzgar D, Osuna M, Kajon AE, Hawksworth AW, Irvine M, Russell KL. Abrupt emergence of diverse species B adenoviruses at US military recruit training centers. J Infect Dis 2007;196:1465--73.
6. Hennessy TW, Ritter T, Holman RC, et al. The relationship between in-home water service and the risk of respiratory tract, skin, and gastrointestinal tract infections among rural Alaska natives. Am J Public Health 2008;98:2072--8.
7. Lewis PF, Schmidt MA, Lu X, et al. A community-based outbreak of severe respiratory illness caused by human adenovirus serotype 14. J Infect Dis 2009;199:1427--34.
8. Lyons A, Longfield J, Kuschner R, et al. A double-blind placebo-controlled study of the safety and immunogenicity of live, oral type 4 and type 7 adenovirus vaccines in adults. Vaccine 2008;26:2890--8
9. Barraza EM, Ludwig SL, Gaydos JC, Brundage JF. Reemergence of adenovirus type 4 acute respiratory disease in military trainees: report of an outbreak during a lapse in vaccination. J Infect Dis 1999;179:1531--3.
10. CDC. Guidelines for preventing health-care--associated pneumonia, 2003. MMWR 2004;53(No. RR-3).

All MMWR HTML versions of articles are electronic conversions from typeset documents. This conversion might result in character translation or format errors in the HTML version. Users are referred to the electronic PDF version (http://www.cdc.gov/mmwr) and/or the original MMWR paper copy for printable versions of official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices.

**Questions or messages regarding errors in formatting should be addressed to [email protected].