Acute respiratory illness (ARI) associated with human adenovirus (HAdV) usually occurs in infants and children [1], with severe cases reported sporadically in adults [2]. Outbreaks of HAdV-associated ARI (HAdV-ARI) in adults have been reported in communal living populations, including school, hospital, and military populations [3-8]. HAdV-55, a novel recombinant strain of HAdV-11 and HAdV-14 that causes ARI in adults [9], emerged as an epidemic strain in Asian and European countries from 2004 [6,8,10-18]. In the Republic of Korea, fatal cases of HAdV-55 pneumonia among military personnel have been reported since 2012 [19], and a large military outbreak associated with HAdV-55 was observed in the winter of 2014 [20]. Although several outbreak studies at different sites have been conducted [21-24], epidemiologic evaluation of the entire military population has yet to be conducted. To assess the current status of the HAdV outbreak, we designed an epidemiologic study for all 14 military hospitals in the Republic of Korea and compared these data to nationwide surveillance data for the Korean civilian population.

The first epidemiologic study of RVs in the Korean military in 2006 reported a predominance of HAdV-7 [26], which was associated with a large HAdV outbreak in Korean children in 1996 and subsequent small outbreaks [27]. Although detection of HAdV-7 was as high as 61.0%, severe HAdV-ARI cases were not reported [26,28]. From January 2011 to March 2013, six cases of severe adenoviral pneumonia were identified with 50% mortality, while such severe adenoviral pneumonia was not reported previously in the Korean military [25,28]. An epidemiologic study based on HAdV molecular typing was conducted from January 2013 to April 2014, and HAdV-55 (42.0%) was the most frequently identified strain, followed by HAdV-4 (13.0%), HAdV-5 (1.4%), and HAdV-6 (1.4%) [23]. Severe HAdV-ARIs requiring MV support were exclusively due to HAdV-55 in that period [19,23]. From the winter to spring seasons of 2014 to 2015, a large HAdV outbreak occurred in the military and persisted into the next season [20]. Molecular typing of HAdV was performed for 74 samples collected in 2016; all were identified as HAdV-55 [20]. In other unpublished data from ongoing studies in the military, HAdV-55 was strongly predominant during the 2016 to 2017 and 2017 to 2018 periods. According to a surveillance study evaluating 1,079 ARI cases in four military training centers from the 37th week of 2016 to the 36th week of 2018, 509 of 518 HAdV-ARIs (98.3%) were caused by HAdV-55, and HAdV-2 was detected in nine cases (1.8%, data acquired by personal communication with J.Y.H.). In a cytokine study of 23 HAdV pneumonia patients admitted to Hospital J from September 2017 to June 2018, 100% of cases were due to HAdV-55 (data acquired by personal communication with J.U.L.). The predominance of HAdV55 was also observed in a serologic study evaluating 52 HAdV-ARIs from April 2018 to June 2018; 100% of cases were HAdV-55 positive (data acquired by personal communication with S.H.K.). Although molecular typing of HAdV was not performed in the present study, the abovementioned findings suggest the following plausible scenario: after introduction of HAdV-55 to the Korean military in 2006, it became predominant in the early 2010s and is currently causing the largest ongoing outbreak that started in winter 2014.

In addition to epidemicity in the adult population, rapidly progressive and potentially fatal acute respiratory distress syndrome is a key concern of HAdV-55 infection [13]. Many studies have reported severe cases [6,8,14,15,29,30], and large outbreak studies have reported case fatality rates of approximately 0.4% [8,20]. In the present analysis of 6,646 HAdV-ARI cases, the overall case fatality rate was 0.075%, less than 0.1%. This can explain why previous outbreaks in China involving fewer than 1,000 patients did not report mortality [14], while sporadic reports of fatality due to HAdV-55 have persisted [13]. Reports of several severe or fatal cases may imply a large outbreak of HAdV-55 in the background community [13]. Although the fatality rate is not as high as for emerging respiratory viruses such as Middle East respiratory syndrome coronavirus (MERS-CoV) [31-33], it is important for public health officials to recognize that a pathogen responsible for the common cold may cause severe and potentially fatal infections.

Of note, case fatality of HAdV patients with respiratory failure was as high as 15.6%. For fatal cases, the median time of MV and ECMO support was 6 days from symptom onset, suggesting a rapidly progressive disease. The times to MV and ECMO support were markedly shorter than those documented for MERS patients (12 and 16 days, respectively) [31]. Although cidofovir was administered in three patients, it was administered after progression to respiratory failure. While early administration of cidofovir has been reported to be associated with favorable outcomes, the chance for early administration is slim in rapidly progressive cases [2,19,34]. Because there are few efficacy-proven treatment modalities for HAdV-ARI, control of outbreaks is emphasized to reduce the overall burden of the disease. To control HAdV outbreaks, AFMC has implemented several measures, including emphasis of hand hygiene, use of personal masks, cohort-isolation of trainees with ARI, and early referral of febrile patients to hospitals. Because HAdV outbreaks are more prominent among trainees and low-rank soldiers recently discharged from training centers [20,21,34], such measures have been emphasized in training centers for new recruits [24]. Although an oral vaccine for HAdV-4 and -7 successfully controlled HAdV-ARI outbreaks in the United States military [35], it has not been adopted in the Korean military because HAdV-ARI is known to exhibit type-specific immunity, and HAdV-55 shares immunogenicity with HAdV-14 [9,36,37]. Several multi-valent HAdV vaccines targeting HAdV-55 are currently under development, but clinical application of these vaccines will take time [36,38]. More resources should be focused on vaccine development, and HAdV molecular typing must be implemented in surveillance systems for proper selection of HAdV vaccines in the future.

The present epidemiologic study had several limitations. First, we mainly used reported data of RV-PCR tests without molecular typing. However, the present ongoing HAdV outbreaks are likely primarily due to HAdV-55, considering the previously reported studies, seasonal outbreak patterns, and data from ongoing unpublished studies. Second, because we could not review EMRs of all HAdV cases, clinical presentation of HAdV-55 infections was based on previous studies [20,22]. Third, as only patients visiting hospitals were evaluated, the proportion of RVs is likely biased. Nevertheless, this bias would have been similar in surveillance studies of civilian hospitals and would not critically affect epidemiologic comparisons between military and civilian hospitals.

In conclusion, a large HAdV outbreak that started in 2014 is currently ongoing in the Korean military, and HAdV-55 is likely the predominant strain. Efforts to control this outbreak should be strengthened, and implementation of HAdV molecular typing for surveillance and vaccine development is required.