Adenovirus 14: An Emerging Threat
By Amesh A. Adalja, MD, April 17, 2009
The Journal of Infectious Diseases has just published 2 papers by teams of researchers describing separate, severe outbreaks of Adenovirus 14 (Ad14), a historically rare serotype of adenovirus that has not been known to cause severe disease.1, 2 Until now, adenoviruses have been thought of as minor pathogens for normal immunocompetent hosts. Similarly, until the SARS outbreak, coronaviruses were considered just another virus capable of causing the common cold. However, as the experience with SARS illustrated, new variants of well-characterized pathogens can emerge and spark outbreaks that cause significant morbidity and mortality. This now appears to be the case with Ad14.
Outbreak in U.S. Air Force (USAF) Training Facility
In 2007, trainees at a Texas USAF base experienced increasing rates of severe pneumonia and febrile respiratory illnesses caused by Ad14. This cluster of illnesses prompted an investigation that included an analysis of weekly surveillance data on febrile respiratory illness occurring in 2007, and a review of administrative and medical records of all trainees hospitalized with pneumonia in 2007. A retrospective cohort investigation was also conducted to quantify rates of Ad14 infection, spectrum of illness, and risk factors.1
In 2007, 1,147 cases of febrile respiratory infection were detected in trainees. Respiratory samples were collected for 42% of those cases; 55% of those samples were positive for adenovirus, and 87% were positive for Ad14. Sixty-six trainees were hospitalized for pneumonia, and 35% of them had evidence of Ad14 infection. Intubation was required in 3 of the Ad14 victims, and one trainee died.1
In response to the alarming rates of Ad14 infection, enhanced infection control protocols were implemented, including: an increased number of hand-sanitizing stations; widespread use of surface disinfectant; education of staff and recruits; and contact and droplet precautions for hospitalized patients. In addition, febrile trainees were kept in an isolation bay rather than being returned to their living quarters.1
In the cohort analysis, males were found twice as likely as females to be infected with Ad14, and infection was more likely during the second half of training, which was the more physically arduous portion. Cohort investigations revealed that only 3% of trainees had preexisting Ad14 antibodies, while 50% demonstrated evidence of infection during training (positive sample for adenovirus or rise in titer of antibody). Of those who were exposed to Ad14, 40% reported a febrile respiratory illness, 51% reported mild illness, and 9% were asymptomatic. Trainees with pre-existing Adenovirus 7 antibodies were less likely to contract severe Ad14 disease.1
Oregon Community Outbreak
Occurring almost simultaneously with the outbreak at the Texas military base was a community outbreak in Oregon detected by physicians caring for patients who were afflicted with severe Ad14 pneumonia. This provoked deeper analysis of Ad14 infection, which involved analysis of samples stored from 1993 through 2007 at the Oregon State Public Health Laboratory and the Providence Portland Infectious Disease Laboratory. Investigators found that Ad14 virus infections occurred only after 2005, during which Ad14 represented 17% of the adenovirus isolates. By 2007, Ad14 represented 55% of the adenoviruses tested. In a retrospective analysis of cases occurring between November 2006 and July 2007, 40 Ad14 cases were identified, and 38 were characterized further and compared with non-Ad14 adenovirus infection.2
The comparisons gave rise to several salient points:
While 75% of non-Ad14 cases occurred in patients under 5 years of age, 61% of Ad14 patients were older than 40.
The proclivity for males, identified in the USAF study, was also demonstrated in the Oregon cases.
No military links were uncovered among case patients in Oregon.
Underlying disease was found in approximately 50% of the Ad14 patients, and 60% had smoked cigarettes in the month prior.
Fever, cough, and shortness of breath were the most common symptoms in Ad14 patients, but vomiting and diarrhea also occurred.
More than 75% of those infected with Ad14 were hospitalized, with 39% requiring intubation. Of those hospitalized, 90% had an abnormal chest radiograph. Lymphocyte counts >1,000 cells/microliter were also common. Antiviral treatment with cidofovir was instituted in 21% of hospitalized patients, 67% of whom survived.
Cases continued to accrue, though at a lower rate, through July 2008. In all, 18% of the patients in Oregon died.2
Is Adenovirus a Threat?
An editorial accompanying these two papers carries the admonition that Ad14 “serves to remind us that we are at least equally likely . . . to soon experience large-scale morbidity through epidemics of emergent pathogens” as we are to experience a biological weapons attack.3 The emergence of fulminant adenovirus infections in the military and in the community during 2006/2007 indicates that the host-pathogen interplay has changed to favor the pathogen. Possible explanations include the cessation of routine vaccinations of military recruits against Ad4 and Ad7, a practice that was implemented from 1971 through 1996. This may have provided sufficient immunity to keep Ad14 at bay, as indicated by the protective role played by Adenovirus 7 immunity in the USAF study.2 Also, a 2 amino acid deletion detected in the current Ad14 strain, now termed Ad14a, may differ enough from historical isolates to promote increased transmissibility and/or virulence.1
Accordingly, the emergence of Ad14 infections should prompt military decision makers to consider re-implementing adenovirus vaccinations. It should also prompt consideration of immunization for high-risk members of the general population (patterned on Pneumovax), since immunization against Adenovirus 7 appears to be protective against severe Ad14 disease. Also, the development and utilization of an Ad14 vaccine should also become a priority, given the role of the virus in military illness.
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. http://www.journals.uchicago.edu/doi/full/10.1086/598520. Accessed April 13, 2009.
Lewis PF, Schmidt MA, Lu X, et al. A community-based outbreak of severe respiratory illness caused by human adenovirus 14. J Infect Dis 2009; 199. http://www.journals.uchicago.edu/doi/full/10.1086/598521. Accessed April 13, 2009.
Gray GG, Chorazy ML. Human Adenovirus 14a: A new epidemic threat. J Infect Dis 2009; 199. http://www.journals.uchicago.edu/doi/full/10.1086/598522. Accessed April 13, 2009.