European Journal of Microbiology and Immunology 4 (2014) 1, pp. 26–33 DOI: 10.1556/EuJMI.4.2014.1.2 HUMAN ADENOVIRUS: VIRAL PATHOGEN WITH INCREASING IMPORTANCE B. Ghebremedhin1,2,* 1 Faculty of Health, University of Witten/Herdecke, 58448 Witten, Germany 2 HELIOS Clinic Wuppertal, Institute of Medical Laboratory Diagnostics, 42283 Wuppertal, Germany Received: December 12, 2013; Accepted: December 21, 2013 The aim of this review is to describe the biology of human adenovirus (HAdV), the clinical and epidemiological characteristics of adenoviral epidemic keratoconjunctivitis and to present a practical update on its diagnosis, treatment, and prophylaxis. There are two well-defined adenoviral keratoconjunctivitis clinical syndromes: epidemic keratoconjunctivitis (EKC) and pharyngoconjuncti- val fever (PCF), which are caused by different HAdV serotypes. The exact incidence of adenoviral conjunctivitis is still poorly known. However, cases are more frequent during warmer months. The virus is endemic in the general population, and frequently causes severe disease in immunocompromised patients, especially the pediatric patients. Contagion is possible through direct con- tact or fomites, and the virus is extremely resistant to different physical and chemical agents. The clinical signs or symptoms of conjunctival infection are similar to any other conjunctivitis, with a higher incidence of pseudomembranes. In the cornea, adenovi- ral infection may lead to keratitis nummularis. Diagnosis is mainly clinical, but its etiology can be confirmed using cell cultures, antigen detection, polymerase chain reaction or immunochromatography. Multiple treatments have been tried for this disease, but none of them seem to be completely effective. Prevention is the most reliable and recommended strategy to control this contagious infection. Keywords: human adenovirus (HAdV), serogroups, epidemic keratoconjunctivitis (EKC), pharyngoconjunctival fever (PCF) Introduction genicity [1]. An additional serotype 52 constitutes a new HAdV species and has recently been reported after genom- Human adenoviruses (HAdVs) are classifi ed in the genus ic sequencing and phylogenetic analysis of an isolate in the Mastadenovirus, which contains seven known HAdV spe- U.S. [5, 6]. New HAdV types have since been identifi ed by cies HAdV-A to HAdV-G [1–3]. In 1953, adenoviruses several authors based on genomic data, including several were fi rst isolated by Rowe and colleagues while studying emerging and recombinant viruses [7–14]. Most recently, the growth of polioviruses in adenoidal tissue [4]. During a primate adenovirus from New World monkeys was de- this study, a transmissible agent was identifi ed which was tected which crossed the species barrier to infect humans capable of causing cytopathic changes in tissues in the ab- [15, 16]. The majority of new HAdV types are homolo- sence of poliovirus. Traditionally, the HAdV species were gous recombination within the same subgenus, and as a classifi ed by hemagglutination and serum neutralization result, certain new serotypes acquire different pathogenic- reactions into different serotypes [1, 2]. Today, there have ities. Recombination is a common evolutionary way for been reported 67 HAdV types. However, according to the HAdV; however, the mechanism of recombination and the genebank (http://hadvwg.gmu.edu/) [3] for human adeno- potential hazards to human beings remain unknown [1]. virus genotype classifi cation, HAdV type 68 – belonging Adenoviruses can cause an array of clinical diseases, to subgroup B – has been reported in 2012. The discovery including conjunctivitis, gastroenteritis, hepatitis, myo- and division of the HAdV types 52–68 are based on the carditis, and pneumonia (Table 1). Most of these occur in genomic sequencing and bioinformatic analysis and differ- children younger than the age of 5 years and are gener- ent from the pre-existing 51 HAdV serotypes identifi ed by ally self-limiting illnesses. They commonly present with traditional serological methods in composition and patho- mild gastrointestinal symptoms, respiratory symptoms, *Corresponding author: Beniam Ghebremedhin, MD, MSc, University of Witten/Herdecke, Faculty of Health, Alfred-Herrhausen-Straße 50, 58448 Witten, HELIOS Clinic Wuppertal, Institute of Medical Laboratory Diagnostics, Heusnerstr. 40, 42283 Wuppertal, Germany; E-mail: [email protected] ISSN 2062-509X / $ 20.00 © 2014 Akadémiai Kiadó, Budapest Human adenovirus: Viral pathogen with increasing importance 27 Table 1. Adenovirus serotypes and associated clinical diseases [5–7, 17, 34–37] HAvD subgroup Serotype Type of infection A 12, 18, 31 gastrointestinal, respiratory, urinary B, type 1 3, 7, 16, 21 keratoconjunctivitis, gastrointestinal, respiratory, urinary B, type 2 11, 14, 34, 35 gastrointestinal, respiratory, urinary C 1, 2, 5, 6 respiratory, gastrointestinal including hepatitis, urinary D 8–10,13,15,17,19,20,22–30,32,33,36–39,42–49 keratoconjunctivitis, gastrointestinal E4 keratoconjunctivitis, respiratory F 40, 41 gastrointestinal G 52 gastrointestinal or a combination of both. Globally, 5–7% of respiratory not known to be oncogenic. However, it has been shown tract infections in pediatric patients are ascribed to HadV that the cells transformed by non-oncogenic HAdV can [17–19]. cause tumors in immunocompromised host, indicative of Some serotypes, such as HAdV type 14, have been the host immune system rejecting those transformed by the associated with severe and potentially fatal outbreaks of non-oncogenic adenoviruses [31–33]. pneumonia in residential facilities and military bases [20]. HAdV type 8 (HAdV-8) is a major causative agent of Of the seven HAdV subgroups (A to G), subgroup A has epidemic keratoconjunctivitis which is frequently associ- been associated with the gastrointestinal tract [21, 22], ated with community, military, industrial, and nosocomial while subgroups B and C are more common to the respira- outbreaks. To date, HAdV-8A, B, E, and I have been found tory tract [21], though conjunctivitis outbreaks have been in Japan as variants of HAdV-8. In the recent time, two associated with HAdV type 3 (subgroup B-1, Table 1). novel HAdV types causing nosocomial EKC were report- HAdV subgroup D overwhelmingly causes conjunctivitis ed from Japan [38–40]. One of these has been misclassi- [21, 23, 24], and subgroup E is associated with respiratory fi ed as HAdV-8 in some cases because of its similarity to and ocular infections, but more commonly in conjuncti- HAdV-8, according to neutralization test and phylogenetic vitis [21]. Finally, subgroups F and G are the causative analyses. However, the virus showed completely different agents of gastroenteritis [17, 21]. restriction patterns from those of other published HAdV- 8 genome types, revealing it is a novel serotype and is named as HAdV-54 [38]. Adenovirus: biology, classification, Epidemic keratoconjunctivitis (EKC) is caused by a and associated diseases group of HAdVs of different serotypes that can also cause pharyngoconjunctival fever (PCF) and nonspecifi c follicu- lar conjunctivitis. EKC is highly contagious, has a tenden- Adenoviruses are non-enveloped double-stranded DNA cy to occur in epidemics, and has been reported worldwide viruses that can infect a variety of human tissues. They such as epidemic outbreaks in hospitals, swimming pools, range in size from 65 to 80 nm in diameter. The virion is military bases, schools, and other community settings; in composed of a protein capsid, made up of 252 capsomeres, Asia, this disease is endemic [41–45]. In 1955, Jawetz et and a nucleoprotein core that contains the DNA viral ge- al. [25] were the fi rst to attribute the etiology of EKC to the nome (26–46 kbp long, containing 23–46 protein-coding infection of ocular surface tissue caused by HAdV. EKC genes) and internal proteins. The capsid has an icosohedral is one of the most common causes of acute conjunctivitis, shape, consisting of 240 hexon components and 12 pen- with characteristic clinical features such as sudden onset tons per virus particle [25, 26]. Each penton contains a of acute follicular conjunctivitis, with watery discharge, base plate with fi ber. The length of the fi bers varies among hyperemia, chemosis, and ipsilateral pre-auricular lym- the different serotypes [27]. DNA homology within the phadenopathy [46]. HAdV subgroups ranges from 48% to 99%. HAdV sub- group C serotypes revealed the highest DNA homology (up to 99%) as compared to other HAdV subgroups. How- Epidemiology of epidemic ever, the DNA homology between HAdV subgroups is less keratoconjunctivitis (EKC) than 20% [17]. There is a varying degree of oncogenicity among the HAdV serotypes. For instance, HAdV subgroup A types, EKC is one of the most frequent ocular diseases, exhibit- such as HAdV type 12, are highly oncogenic [28–30] with ing ubiquitous distribution. Due to its high frequency and the ability to induce tumors in new born rodents within that many of the cases do not obtain medical help, it is 4 months. On the other hand, HAdV subgroup B are weak- most diffi cult to acquire precise statistical data. The ac- ly oncogenic, and fi nally HAdV subgroups C, E, and F are tual prevalence and incidence of EKC in countries, such as European Journal of Microbiology and Immunology 4 (2014) 1 28 B. Ghebremedhin Germany, is well documented [41–44, 46–48]. EKC cases ter the onset, focal epithelial keratitis develops with cen- have to be reported to the medical authority in Germany. tral ulceration and irregular borders with gray-white dots. However, the prevalence and incidence of EKC at the in- These epithelial changes are related to active viral infec- ternational level are unknown. The infection is more com- tion. These lesions persist for 1 to 2 weeks. About 2 weeks mon in adults, but all age groups can be affected with no post-onset, subepithelial infi ltrates can appear beneath specifi c gender affi nity as has been reported by Adlhoch et the focal epithelial lesions, persisting for weeks to years. al. [48]. Their analysis did not show a disproportionately These resolve spontaneously, usually without scarring. In affected gender or age group, but many infections were rare cases, disciform keratitis or anterior uveitis can occur.