We present eight cases and review the literature of concurrent urethritis and conjunctivitis where adenovirus was identified as the causative pathogen. The focus of this review concerns the identification of specific sexual practices, symptoms, signs and any serotypes that seem more commonly associated with such adenovirus infections. We discuss the seasonality of adenovirus infection and provide practical advice for clinicians to give to the patient.
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Adenovirus is a double stranded DNA virus first isolated by Rowe et al1 in 1953 from surgical specimens of adenoid tissue. Since then, 67 serotypes in seven subgroups, A to G,2 have been identified and these cause a variety of clinical diseases such as respiratory tract infection, keratoconjunctivitis, cystitis, hepatitis and gastroenteritis.3 Primary adenovirus infection or reactivation of infection can be severe in the immunocompromised such as paediatric, HIV and transplant patients.4
The first article to report adenovirus causing concurrent urethritis and conjunctivitis was in 1981 when Harnett and Newnham7 identified two cases of adenovirus type 19 from urethral and conjunctival swabs. A further four of their cases were swab positive for adenovirus type 19 from the urethra and had reported conjunctivitis. At this time, they felt that the data were insufficient to attribute adenovirus serotype 19 as a cause of NGU. Since then, 32 cases of concurrent urethritis and conjunctivitis have been reported in the literature.
We present eight additional cases of men with urethritis and conjunctivitis where adenovirus DNA was detected by PCR on either urethral swab or conjunctival swab or both.
Our eight cases presented with urethritis and concurrent conjunctivitis between June 2012 and April 2014 at Camberwell Sexual Health Centre, King's College Hospital, London.
In each, we performed the following tests: Hologic GenProbe Aptima Combo-2 nucleic acid amplification test for Chlamydia trachomatis and Neisseria gonorrhoeae on urine sample and conjunctival swab, serum 4th generation HIV antibody/antigen assays and treponemal antibody. Urethral discharge was swabbed for gonococcal culture and gram stain was performed. An additional urethral sample was taken for herpes simplex virus (HSV) types 1 and 2 DNA and adenovirus DNA.8 ,9 Conjunctival swab for adenovirus DNA was also performed. Samples for HSV and adenovirus DNA were placed in viral transport media and assessed by inhouse real time PCR. Where sufficient clinical material was available, adenovirus DNA positive samples were further assessed for serotyping by nucleic sequencing of two regions (460 and 477 bp) of the adenovirus hexon gene at the Virus Reference Department, Public Health England Microbiology Services at Colindale, London.10 Similarity of nucleotide sequences obtained to adenovirus sequences in databases was performed using the BLAST tool at the National Centre for Biotechnology.11
The results from our case series together with the other 32 published cases of concurrent urethritis and conjunctivitis are summarised in tables 1⇓–3. Our eight cases correspond to column ‘a’ and are highlighted in italics.
In addition to those previously reported in the current literature, we have presented a further eight cases where adenovirus was identified as the cause of urethritis and bilateral conjunctivitis. Specific clinical features have previously been recognised that should alert the clinician to considering adenovirus as the cause of NGU13 ,14 ,17 and our case series adds further support to this. Tables 1⇑–3 demonstrate the many similarities that occur in patients diagnosed with concurrent adenovirus infection of the urethra and conjunctiva.
Patients typically present with dysuria which can be severe,13–15 ,17 clear or mucoid urethral discharge and evidence of meatitis. Perhaps unexpectedly, constitutional symptoms were common, occurring in 20% of cases (table 2). In our eight cases, conjunctivitis was bilateral, spreading from one eye to the other 2–5 days thereafter (figure 1). Conjunctivitis was also bilateral in a further three cases but it was not commented on in the remaining 29 cases. All of our cases had more than five polymorphonuclear leucocytes per high-powered field and this was a consistent finding in other case reports (table 3). Azariah and Reid14 and Tønsberg and Hartgill18 comment on the identification of large numbers of mononuclear cells on urethral smear and postulate that this could indicate a viral aetiology. We did not look at this in our case series; however, if the patient is symptomatic but does not have microscopic evidence of urethritis, then finding mononuclear cells may alert the clinician to consider adenovirus as the cause.
Oral sex is the likely route of acquisition of urethral adenovirus infection.13–17 The virus can be transmitted by direct exposure to infected tissue. Furthermore, oral secretions infected with adenovirus contain very high levels of viral particles (100 000–1 000 000/mL). Of the case reports that stated the type of sex, including our eight cases, 100% of patients had received oral sex in the 2–28 days preceding the onset of symptoms. Adenovirus can also be spread by autoinoculation which could explain the development of conjunctivitis following initial urethral infection. Vaginal sex was also commonly reported (table 2). Adenovirus has been isolated from the female genital tract on several occassions7 ,12 ,21–23 and therefore provides another possible route for acquiring urethral infection.
Of the 40 adenovirus DNA positive samples, successful molecular serotyping was performed in 27 (table 3). Subgroup D was identified in 26 samples and there was just one subgroup B2 virus. Analysis of sequences of both hexon gene regions from an eye and a penile swab from one of our cases showed 100% similarity to adenoviruses in species D type 56. In a second case, samples from the eye, urine and urethra showed 99%–100% similarity to two adenoviruses in species D types 19 and 64. We were unable to discriminate further exactly which serotype was responsible for the patient’s symptoms on the basis of the sequence data obtained. Azariah and Reid also reported cross reaction of more than one adenovirus serotype in their study.14 Of note, type 64 has not been previously identified in the literature as causing urethritis and/or conjunctivitis. Further research is required to determine if infection with type 64 can result in urethritis and conjunctivitis. The commonest serotypes overall were 19 and 37. Subgroup D adenoviruses are well known to cause keratoconjunctivitis,3 and types 8, 19 and 37 have been responsible for large epidemics.24 This review supports the role of adenovirus subgroup D, and in particular types 19 and 37, as the cause of concurrent urethritis and conjunctivitis.
Subgroup B2 also has an affinity for the genital tract but is not thought to cause conjunctivitis. In another of our cases, a sequence from one of the targeted hexon gene regions from a conjunctival swab showed closest genetic similarity (99%) to two adenoviruses in species B2, types 11 and 35. Again, we were unable to distinguish which serotype was causative. This does however highlight another potential clinical disease that subgroup B adenoviruses are responsible for that has not previously been reported.
Adenovirus infections are endemic throughout the year. However, 14 (74%) of the cases where information was available occurred in the autumn and winter months in comparison with only 5 (26%) in the spring and summer (table 1). Although this does not provide conclusive evidence that adenovirus typically causes concurrent urethritis and conjunctivitis in the autumn and winter, it may be prudent for clinicians to have a high index of suspicion during this time.
Diagnosing adenovirus as the cause of NGU allows the clinician to reassure the patient that the urethritis and conjunctivitis are self-limiting. The mean length of time for symptoms to resolve was 14.2 days. Adenovirus is contagious, and therefore advice concerning good hand hygiene, avoidance of sharing towels and no sexual contact until symptoms have resolved should be provided. Artificial tears can help with the symptoms of conjunctivitis. Antibiotics are not indicated. Testing for adenovirus DNA should be considered in patients who have ongoing symptomatic NGU despite initial antibiotic treatment if not performed at the first visit.
Serotyping was unable to be performed in five of our cases due to insufficient sample in three and a technical error in two. Table 3 identifies an additional eight cases where adenovirus was untypeable. Reasons include the adenovirus isolate being unavailable for typing,12 typing not performed on samples tested by PCR alone or on some tested by culture,13 technical issues,14 cross reactivity14 and a negative urethral swab for adenovirus following a delay in sampling.15 Despite this, we were still able to identify the commonest serotypes as typing was successful in 27 cases.
Missing data in tables 1⇑–3 of the Results section are a further limitation. Each publication presented varying degrees of information regarding their cases and therefore our conclusions are based on small numbers. However, we were still able to recognise specific sexual practices, symptoms, signs and seasons commonly associated with adenoviral urethritis and conjunctivitis.
Concurrent urethritis and conjunctivitis caused by adenovirus are transmitted by oral sex and possibly vaginal sex. Symptoms include dysuria, which may be severe, urethral discharge and a fifth of patients will experience constitutional symptoms. Examination findings include meatitis and conjunctivitis which are often bilateral. In most cases, microscopic evidence of urethritis will be present and urethral and conjunctival swabs should be taken and adenovirus DNA testing specifically requested. Subgroup D types 19 and 37 are the most common; however, we have identified a case of subgroup B2 adenovirus infection which has not previously been reported. Clinicians should have a higher index of suspicion during the autumn and winter months. Patients should be reassured that the infection is self-limiting.
Concurrent urethritis and conjunctivitis caused by adenovirus are transmitted by oral sex.
Adenovirus infection of the urethra and conjunctiva results in distinct clinical characteristics that should alert the clinician to test for adenovirus DNA.
Adenovirus subgroup D types 19 and 37 are the most common causes of concurrent urethritis and conjunctivitis.
Further research in relation to subgroup B2 adenovirus infection as a cause of concurrent urethritis and conjunctivitis is warranted.
The authors would like to thank Dr Kayi Chan at Public Health England for her technical assistance.
Handling editor Jackie A Cassell
Contributors MIS suggested the topic and identified the cases. OL conducted the literature review, drafted the manuscript and is the guarantor. MIS, MS, JE and CT provided advice, suggestions and comments on the writing of the manuscript.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.