Underascertainment of Respiratory Syncytial Virus Infection in Adults Due to Diagnostic Testing Limitations: A Systematic Literature Review and Meta-analysis

Abstract

Background Most observational population-based studies identify RSV by nasal/nasopharyngeal swab RT-PCR only. We conducted a systematic review and meta-analyses to quantify specimen and diagnostic testing-based under-ascertainment of adult RSV infection. Methods EMBASE, PubMed and Web of Science were searched (Jan2000–Dec2021) for studies including adults using/comparing >1 RSV testing approach. We quantified test performance and RSV detection increase associated with using multiple specimen types. Results Among 8066 references identified, 154 met inclusion. Compared to RT-PCR, other methods were less sensitive: rapid antigen detection (pooled sensitivity, 64%), direct fluorescent antibody (83%), and viral culture (86%). Compared to singleplex PCR, multiplex PCR’s sensitivity was lower (93%). Compared to nasal/nasopharyngeal swab RT-PCR alone, adding another specimen type increased detection: sputum RT-PCR, 52%; 4-fold rise in paired serology, 44%; and oropharyngeal swab RT-PCR, 28%. Sensitivity was lower in estimates limited to only adults (for RADT, DFA and Viral culture), and detection rate increases were largely comparable. Conclusions RT-PCR, particularly singleplex testing, is the most sensitive RSV diagnostic test in adults. Adding additional specimen types to nasopharyngeal swab RT-PCR testing increased RSV detection. Synergistic effects of using ≥3 specimen types should be assessed, as this approach may improve the accuracy of adult RSV burden estimates.

Estimation of the number of RSV-associated hospitalisations in adults in the European Union

“…We have based this work on regression model estimates [which are not so dependent on high levels of RSV testing] to increase the comparability of the Stage 1 estimates [41] and to limit the risk of underestimating the RSV disease burden in adults (as there is less testing in this age group) [13]. Considering that the review of the literature found no eligible recent studies, there is a need for more data from more countries to generate improved estimates with less uncertainty as the uncertainty intervals given here are falsely narrow and do not capture all sources of uncertainty.…”

“…Previous studies have reported varying estimates of the incidence of RSV infections in hospitalised adults [5, 11, 12]. Estimating the incidence of RSV infection in hospitalised adults remains challenging as there are no dedicated RSV surveillance systems, RSV is not routinely screened for in patients with an ARI and only the more severe cases are commonly diagnosed [13]. RSV-associated mortality among older adults is reportedly substantial and comparable to influenza [14] with the majority of deaths occurring among persons aged ≥60 years [8].…”

Adjusting for Case Under-Ascertainment in Estimating RSV Hospitalisation Burden of Older Adults in High-Income Countries: a Systematic Review and Modelling Study

“…We calculated the proportion of detection by each possible combination of testing approach(es) compared with the gold standard, as reported by Falsey and colleagues [ 9 ] (assuming that any positives by any of the three methods—PCR, culture and paired serology—were true positives); as a result, the detection proportion should range from 0 (lowest sensitivity) to 1 (perfect sensitivity). We also calculated the proportion of detection by rapid antigen testing compared with the gold standard through a systematic review of RSV diagnostic accuracy comparison [ 10 ]. As the second step, we focused on adjusting for clinical specimen conditioning on testing method.…”

“…For example, a study that compared different diagnostic tests of RSV among adults found that only half of the RSV cases confirmed by reverse transcription polymerase chain reaction (RT-PCR) had a positive viral culture result [ 9 ]. Furthermore, a growing body of literature recently summarised in a systematic review and meta-analysis suggests that use of nasopharyngeal (NP) or nasal swabs alone to identify RSV infection yields downwardly biased estimates of RSV disease rates [ 10 ]. Compared to NP/nasal swab alone, RSV detection increased by 52% when adding RT-PCR of sputum, 28% when adding RT-PCR of oropharyngeal swabs, and 42% when adding serology testing of paired specimens.…”

Respiratory syncytial virus infection in the modern era

“…In contrast, a retrospective cohort study from Eastern Finland in 2017–2018 showed that RSV-infected patients were older and had an increased risk of hospitalization and mortality in comparison to influenza virus-infected adults [26 ▪▪ ]. The level of RSV infection in adults and older adults may also be underestimated due to limitations in diagnostic testing, a situation that could be alleviated by the collection and testing of three or more specimen types from patients [27]. The burden of RSV-infection in healthy term infants has also been recently assessed in a prospective birth cohort study performed in five locations in Europe [28].…”