Adenovirus Transmission—Worthy of Our Attention

The report by Russell et al. [1] in this issue of the Journal of Infectious Diseases is likely the most comprehensive adenovirus transmission study ever performed. Through aggressive clinical surveillance, serological assays, viral culture, frequent environmental sampling, and—most importantly—high-throughput molecular diagnostics, the authors clearly demonstrate the ease of respiratory virus transmission in a crowded, susceptible population. Their study is remarkable for a number of findings. They demonstrate that the introduction of asymptomatic viral shedders among recycled trainees to a susceptible new cohort is very likely a primary cause of continual transmission of adenovirus serotype 4 (Ad-4) in a recruit camp. They document the nearly ubiquitous environmental contamination that is concomitant with active disease in a closed cohort and its likely role as an accelerant in disease transmission. Over the course of a 4-week period (changes in titer were recorded over the course of 6 weeks), they recorded an incredible 98% rate of Ad-4 infection among 180 susceptible persons. They show that simply counting study subjects who seek medical attention will miss an astounding 69% of symptomatic adenovirus infections. They report surprisingly high heterotypic cross-neutralization effects, with Ad-4 exposures causing neutralizing antibodies against adenovirus serotype 7 (Ad-7), especially for those subjects with low titers to both serotypes at enrollment. In short, their research is a model for epidemiologists to follow, and it strongly supports policy decisions to provide vaccines and other aggressive prophylaxis to such crowded susceptible populations.

The history of adenovirus prevention among military trainees is worth reflection. Live enteric-coated vaccines against Ad-4 and Ad-7 were routinely used among US military trainees beginning in the 1970s; these had efficacy rates of 82%–95% and safety profiles that would enchant any pharmaceutical company [2]. However, adenovirus disease was so well controlled by these vaccines that severe morbidity and explosive epidemics were nearly forgotten. For multiple reasons, not the least of which was complacency [3], the vaccines were lost in the late 1990s [4]. Subsequent to this loss, US military trainees have had considerable preventable morbidity caused by adenovirus infection [5-11], including deaths [12]. However, there is good news to report. In 2001, the US Department of Defense identified a new adenovirus vaccine manufacturer, and recent phase 1 studies of Duramed Pharmaceuticals' Ad-4 and Ad-7 vaccines were very encouraging, with good percentages of seroconversion and safety profiles [13]. After a little more clinical trial work, it is expected that these vaccines will soon be available to prevent disease in future US military populations.

Our understanding of adenovirus transmission is valuable to populations other than US military trainees. Dutch, Finnish, and Turkish military personnel have had considerable morbidity caused by adeno-virus infection [14-17]. A 2004 outbreak of adenovirus in Germany affected hundreds of international military personnel, some very severely [17]. Adenoviruses frequently cause epidemics among children, especially newborns [18], institutionalized persons [19], and immunocompromised persons [20, 21]. Transplant recipients and other immunocompromised patients seem to be among the most severely affected, with mortality rates as high as 60% [20, 21]. Now that certain serotypes of human adenovirus may respond to antiviral therapy in vitro [22], physicians need not only to understand adenovirus transmission, but also to know the adenovirus serotype affecting their patients and whether the virus is a nosocomially acquired strain, a community-acquired strain, a donor-associated strain, or reactivation of a latent strain.

In addition, mounting evidence suggests that some adenovirus genotypes may be associated with more severe morbidity and have a competitive advantage [23]. In South America, Ad-7h strains have been noted to be associated with more severe respiratory disease requiring more frequent hospital care [24, 25]. Ad-7d2 strains have been implicated in a number of recent US epidemics that have resulted in deaths [26]. In Iowa, Ad-7d2 strains have supplanted all other Ad-7 strains [23]. These and other novel genotypes and their severe morbidity qualify human adenoviruses as emerging pathogens.

Because of the wider use of molecular diagnostics, understanding adenovirus transmission is also important for the investigation of newly reported possible associations of adenovirus with a number of acute and chronic conditions. Some studies have suggested that adenovirus infections may be involved with chronic airway obstruction [27] and pulmonary dysplasia [28], myocarditis and dilated cardiomyopathy [29], mononucleosis-like syndromes [30], intussusception [31], sudden infant perinatal death [32], and, perhaps most intriguingly, the development of obesity [33, 34]. Although these associations may or may not be causal, understanding adenovirus transmission seems to be key to their further study.

Were these reasons not enough, the value of the recent adenovirus transmission research is increased by the recognition that adenoviruses are the most UV-resistant viruses [35], and their detection is now a key indicator of water quality. The US Environmental Protection Agency and water-treatment companies are developing protocols to best detect and eliminate adenoviral contamination in water sources and systems. Hence, it seems that whether one serves as a public-health professional concerned about preventing adenovirus epidemics, a clinician concerned about protecting immunocompromised patients or preventing chronic disease, or a water-quality engineer, one needs to understand how adenoviruses interact with the environment and move from person to person. The research of Russell et al. [1] serves as an excellent example in pursuing such knowledge.