Respiratory Syncytial Virus Infections in Recipients of Bone Marrow Transplants: A Systematic Review and Meta-Analysis

Abstract

Human Respiratory Syncytial Virus (RSV) is a common cause of respiratory tract infections. Usually associated with infants and children, an increasing amount of evidence suggests that RSV can cause substantial morbidity and mortality in immunocompromised individuals, including recipients of bone marrow transplantation (BMT). The present systematic review was therefore designed in accordance with the PRISMA guidelines to collect available evidence about RSV infections in BMT recipients. Three medical databases (PubMed, Embase, and MedRxiv) were therefore searched for eligible observational studies published up to 30 September 2023 and collected cases were pooled in a random-effects model. Heterogeneity was assessed using I² statistics. Reporting bias was assessed by means of funnel plots and regression analysis. Overall, 30 studies were retrieved, including 20,067 BMT cases and 821 RSV infection episodes. Of them, 351 were lower respiratory tract infections, and a total of 78 RSV-related deaths were collected. A pooled attack rate of 5.40% (95% confidence interval [95%CI] 3.81 to 7.60) was identified, with a corresponding incidence rate of 14.77 cases per 1000 person-years (95%CI 9.43 to 20.11), and a case fatality ratio (CFR) of 7.28% (95%CI 4.94 to 10.60). Attack rates were higher in adults (8.49%, 95%CI 5.16 to 13.67) than in children (4.79%, 95%CI 3.05 to 7.45), with similar CFR (5.99%, 95%CI 2.31 to 14.63 vs. 5.85%, 95%CI 3.35 to 10.02). By assuming RSV attack rates as a reference group, influenza (RR 0.518; 95%CI 0.446 to 0.601), adenovirus (RR 0.679, 95%CI 0.553 to 0.830), and human metapneumovirus (RR 0.536, 95%CI 0.438 to 0.655) were associated with a substantially reduced risk for developing corresponding respiratory infection. Despite the heterogeneous settings and the uneven proportion of adult and pediatric cases, our study has identified high attack rates and a substantial CFR of RSV in recipients of BMT, stressing the importance of specifically tailored preventive strategies and the need for effective treatment options.

Keywords: RSV; bone marrow transplantation; differential diagnosis; viral pneumonia.

Figure A1

Correlation between attack rates for respiratory syncytial virus (RSV) and influenza virus (a), adenovirus (b), and human metapneumovirus (hMPV) (c). The correlation was significant for RSV and influenza virus (Spearman’s rho = 0.790, 95%, p < 0.001) and RSV and adenovirus (rho = 0.650, p = 0.026), but not for RSV and hMPV (rho = 0.559, p = 0.098) [46,51,61,68,70,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].

Figure A2

Time trend of the proportion of LRTI over the total number of RSV cases. A non-significant negative association was eventually identified (rho = −0.366; p = 0.055) [46,51,61,68,70,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].

Figure A3

Correlation between sample size and the ratio between upper and lower respiratory tract infections (URTI; LRTI) occurring in 20,067 cases of bone marrow transplantation collected in the present survey. No actual association was found (rho = 0.833; p = 0.724) [46,51,61,68,70,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].

Figure A4

Correlation of case fatality ratio and proportion of lower respiratory tract infections (LRTI) in sampled cases of bone marrow transplantation [46,51,61,68,70,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104]. A positive correlation was eventually found (Spearman’s rho = 0.445, p = 0.018).

Figure A5

Sensitivity analysis for pooled attack rates of RSV [46,51,61,68,70,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].

Figure A6

Sensitivity analysis for pooled incidence rate for RSV cases [46,51,61,68,70,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].

Figure A7

Sensitivity analysis for pooled case fatality ratio (CFR) [46,51,61,68,70,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].

Figure A8

Sensitivity analysis for pooled odds ratio (OR) [81,94,101].

Figure A9

Time trend of the case fatality ratio (CFR). A non-significant negative association was eventually identified (rho = −0.178; p = 0.346) [46,51,61,68,70,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].

Figure A10

Correlation between attack rate for respiratory syncytial virus infections and number of cases included in the studies. A significant negative association was eventually identified (rho = −0.663; p < 0.001) [46,51,61,68,70,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].

Figure A11

Correlation between case fatality ratio (CFR) for respiratory syncytial virus infections and number of cases included in the studies. A non-significant association was eventually identified (rho = 0.048; p = 0.803) [46,51,61,68,70,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].

Figure 1

Flowchart of included studies.

Figure 2

Summary of risk of bias assessment for included studies [46,51,61,68,70,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104], performed according to the National Toxicology Program (NTP)’s Office of Health Assessment and Translation (OHAT) handbook and respective risk of bias (ROB) tool [74,75].

Figure 3

Forest plot for RSV attack rates among 20,067 subjects having undergone a bone marrow transplantation procedure. An overall estimate of 5.40% (95% confidence interval [95%CI] 3.81 to 7.60) was identified, with high heterogeneity (94.4%, 95%CI 93.0 to 95.6; p < 0.001) [46,51,61,68,70,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].

Figure 4

Forest plot for RSV incidence among 20,067 subjects having received a bone marrow transplantation procedure (pooled observation time: 130,622.81 person-years). An overall incidence of 14.77 cases per 1000 person-years (95% confidence interval [95%CI] 9.43 to 20.11) was identified, with high heterogeneity (91.6%, 95%CI 89.1; 93.5; p < 0.001) [46,51,61,68,70,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].

Figure 5

Forest plot for case fatality ratio (CFR) among 821 cases of RSV infections in people having undergone a bone marrow transplantation procedure. A total of 78 deaths were reported, for a pooled CFR of 7.28% (95% confidence interval [95%CI] 4.94 to 10.60) with low heterogeneity (I² = 0.0, 95%CI 0.0 to 40.8; τ² = 0.389, Q = 22.26, p = 0.809) [46,51,61,68,70,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].

Figure 6

Forest plot for the odds ratio (OR) of the occurrence of Respiratory Syncytial Virus (RSV) infections in children (individuals aged 0 to 18 years) vs. adults (individuals older than 18 years). Ultimately, an OR of 2.941 (95%CI 1.689 to 5.122) was identified, with an I² value of 4.8%, 95%CI 0.0 to 90.1 [81,94,101].

Figure 7

Funnels plots for the whole of the studies reported in the present meta-analysis in terms of attack rates (a), incidence rates for RSV (b), and their corresponding CFR (c).

Figure 8

Radial plots for included studies, assessed by the calculation of attack rates (a); Egger’s test: t = 0.65, df = 28, p-value = 0.519), incidence rates (b); t = 8.76, df = 28, p-value < 0.001), and case fatality ratio (c); t = −4.78, df = 28, p-value < 0.001) [46,51,61,68,70,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].