Evidence review

Clinical and technical evidence

Regulatory bodies

A search of the Medicines and Healthcare Products Regulatory Agency website revealed no manufacturer Field Safety Notices or Medical Device Alerts for this device. No reports of adverse events were identified from a search of the US Food and Drug Administration (FDA) database: Manufacturer and User Device Facility Experience (MAUDE).

Clinical evidence

Studies evaluating the Adeno Detector test (the predecessor of AdenoPlus) were excluded from further assessment because it has a higher limit of detection and a partly different design, so limiting the generalisability of findings. This briefing includes 2 prospective diagnostic accuracy studies (Sambursky et al. 2013; Kam et al. 2015) and 1 conference abstract and its respective poster (Tuil et al. 2015a, 2015b), which reported interim analyses of an observational epidemiological study.

The study by Sambursky et al. (2013; presented in tables 1 and 2) was a prospective, multicentre diagnostic accuracy study conducted in 8 private ophthalmology practices and academic centres in the USA. It compared the sensitivity and specificity of the AdenoPlus test with polymerase chain reaction (PCR) and viral cell culture with confirmatory immunofluorescence assay (CC‑IFA), to detect adenovirus in tear fluid from 128 consecutive people presenting with a clinical diagnosis of acute viral conjunctivitis.

Compared with PCR, AdenoPlus showed a sensitivity of 85% (29/34), a specificity of 98% (89/91), a negative predictive value (NPV) of 95% (89/94), and a positive predictive value (PPV) of 94% (29/31). The overall agreement was 94% (118/125).

Compared with CC‑IFA, AdenoPlus showed a sensitivity of 90% (28/31), a specificity of 96% (93/97), a NPV of 97% (93/96), a PPV of 88% (28/32), and an overall agreement of 95% (121/128).

Compared with the combination of CC‑IFA and PCR, AdenoPlus showed a sensitivity of 93% (27/29) and a specificity of 98% (88/90).

The Kam et al. (2015) study (presented in tables 3 and 4) was a prospective, single‑centre diagnostic accuracy study done in a walk‑in ophthalmic accident and emergency service in the UK. It assessed the diagnostic accuracy of the AdenoPlus test compared with PCR in 109 consecutive people presenting to the emergency eye unit with a clinical indication of acute adenoviral conjunctivitis.

Using PCR as the reference standard, the sensitivity of the AdenoPlus test in detecting adenovirus was 39.5% (95% confidence interval [CI] 25 to 56) and the specificity was 95.5% (95% CI 87 to 99). The authors report the positive (8.7; 95% CI 2.71 to 27.9) and negative (0.63; 95% CI 0.49 to 0.81) likelihood ratios incorrectly as PPV and NPV. The authors of the briefing have calculated the correct PPV and NPV as 85% (95% CI 62.11 to 96.79) and 70.79% (95% CI 60.19 to 79.95) respectively. No adverse events from doing the AdenoPlus or PCR tests were reported.

The conference abstract (Tuil et al. 2015a) reported an interim analysis of an ongoing observational epidemiology study (ADVISE), which is being done in France, Germany, Spain, Italy and the UK (Duquesroix et al. 2014). The information presented in table 5 was extracted from the conference poster (Tuil et al. 2015b), which includes more detail than the abstract. The investigators assessed the clinical characteristics and incidence of adenovirus conjunctivitis in people who presented with symptoms of acute conjunctivitis. The interim analysis was based on 334 patients from 16 sites in France (all but 1 were hospital ophthalmology departments).

Before using the AdenoPlus test, the investigators believed that the conjunctivitis was of viral origin in 89% of the people. This was confirmed by the AdenoPlus test in only half of these people. AdenoPlus test results were reported (0.6%), for which no further definition was stated. No further information was reported that would allow the calculation of any test accuracy measures.

Recent and ongoing studies

Five ongoing or in‑development studies on AdenoPlus for adenoviral conjunctivitis detection were identified in the preparation of this briefing. Four of the ongoing trials are part of the international ADVISE (ADenoVirus Initiative Study in Epidemiology) study with different trial registrations per country (France, Germany, Spain, Italy and the UK). The study has completed recruitment in France (Clinicaltrials.gov identifier: NCT02054234). It is currently recruiting in Spain and Germany (Clinicaltrials.gov identifiers: NCT02254330; NCT02054273) and is not yet recruiting in the UK (Clinicaltrials.gov identifier: NCT02112773). ADVISE trial registration for Italy could not be found. Interim results of the ADVISE study carried out in France are presented in this briefing. The other ongoing US study aims to determine the specificity of AdenoPlus compared with quantitative PCR testing (Clinicaltrials.gov identifier: NCT02472223).

Costs and resource consequences

No published evidence on the resource consequences of the AdenoPlus test was identified. If the AdenoPlus test accurately excludes a bacterial cause of infectious conjunctivitis at its early stages, it has the potential to reduce inappropriate antibiotic use, reduce the number of work days and school days lost, and help to better manage the condition. Using AdenoPlus in primary care, pharmacy and emergency settings could also provide efficiencies to the NHS by reducing the number of unnecessary referrals to ophthalmologic units.

Strengths and limitations of the evidence

Two published diagnostic accuracy studies, and 1 conference abstract and its respective poster were identified.

In the Sambursky et al. (2013) study the patients were recruited consecutively from multiple sites, suggesting that they were likely to be representative of the population studied. The study was done in the USA, and so the results may not be generalisable to a NHS setting.

In this study, the AdenoPlus test results were compared with those of PCR and of CC‑IFA, which seem to be appropriate reference standards because they are commonly used measures for detecting adenovirus. The authors stated that the AdenoPlus test results were analysed by an independent, blinded healthcare professional. It was unclear what the healthcare professional was blinded to when analysing the AdenoPlus test results. The AdenoPlus test result seems objective, with 1 red line and 1 blue line indicating the result as positive, and a single blue line indicating the test as negative. The authors stated that AdenoPlus was done first because this test uses direct sampling, which prohibits splitting a single sample between the reference methods; the second and third samples collected were used for the reference analyses. It was unclear whether the analyses of the PCR and CC‑IFA results were done by investigators blinded to the AdenoPlus results.

The Kam et al. (2015) study was done in an emergency eye unit in the UK, indicating that the results are likely to be generalisable to the UK NHS setting. Recruiting consecutive patients into the study minimised potential selection bias. PCR was used as the standard reference test, and either automatically generated or manually entered into the database by qualified biomedical staff blinded to the result of the AdenoPlus test. AdenoPlus test results were analysed by a qualified independent member of clinical staff who had no previous contact with the patients or the clinical notes. Using the blinding methods, the study minimised potential measurement bias. According to the manufacturer's instructions for use, the AdenoPlus test is best done within 7 days of developing a red eye consistent with infectious conjunctivitis, although this study included patients who had an onset of symptoms of up to 2 weeks. This might have contributed to the observed differences in the test accuracy results between this study and that of Sambursky et al. (2013), which included patients presenting within 7 days of developing a red eye. The authors incorrectly report positive and negative likelihood ratios as positive predictive value and negative predictive value in the paper.

In both studies, the AdenoPlus test was done first and then other samples were collected for the reference analyses. As the authors of the Sambursky et al. (2013) study pointed out, this could result in a negative test result for the reference tests because the subsequent samples may contain fewer viruses than the first swab, causing an artificial increase of the AdenoPlus sensitivity.

The manufacturer pointed out that the hospital where the Kam et al. (2015) study took place did not accept any advice from the manufacturer on training to use the test and this might indicate that inadequate sampling methods were used in the study. The authors state that they trained all specialist nurse practitioners and ophthalmologists in using the AdenoPlus test, but it is unclear if the authors themselves had any training.

In the conference abstract and its respective poster reporting the epidemiology study (Tuil et al. 2015a; Tuil et al. 2015b), 7.2% of the 334 people had protocol deviations at inclusion, mostly for using topical corticosteroids. It is not clear if the same investigators did both the initial assessment and the AdenoPlus test, or if the investigators who carried out the AdenoPlus test were blinded to the initial diagnosis. No relevant data on the diagnostic accuracy of the AdenoPlus test was given in either the conference abstract or the poster.

The Sambursky et al. (2013) study was supported by the manufacturer and the main author has an affiliation with the manufacturer. The first and last authors of the Tuil et al. (2007b) poster act as consultants for the manufacturer. The manufacturer provided the AdenoPlus test for the Kam et al. (2015) study at no cost.

Overall, the current evidence was based on 2 diagnostic accuracy studies with reasonable methodological quality.