Disease Burden Estimates of Respiratory Syncytial Virus related Acute Respiratory Infections in Adults With Comorbidity: A Systematic Review and Meta-Analysis

Abstract

Background

Respiratory syncytial virus related acute respiratory infection (RSV-ARI) constitutes a substantial disease burden in adults with comorbidities. We aimed to identify all studies investigating the disease burden of RSV-ARI in this group.

Methods

We estimated the incidence, hospitalization rate, and in-hospital case fatality ratio (hCFR) of RSV-ARI in adults with comorbidities based on a systematic review of studies published between January 1996 and March 2020. We also investigated the association between RSV-ARI and any comorbidity in adults. Meta-analyses based on random effects model were carried out.

Results

Overall, 20 studies were included. The annual incidence rate of RSV-ARI in adults with any comorbidity was 37.6 (95% confidence interval [CI], 20.1–70.3) per 1000 persons per year in industrialized countries and the seasonal incidence rate was 28.4 (11.4–70.9) per 1000 persons per season. The hCFR in industrialized countries was 11.7% (5.8%–23.4%). There were no studies in developing countries. There were insufficient data to generate the meta-estimate of hospitalization rate. The likelihood of experiencing RSV-ARI for those with any comorbidity compared to those without was estimated to be 4.1 (odds ratio [OR], 1.6–10.4) and 1.1 (OR, 0.6–1.8) from studies using univariable and multivariable analysis respectively.

Conclusion

The disease burden of RSV-ARI among adults with comorbidity is substantial with limited data available.

respiratory syncytial virus, adults, comorbidity, acute respiratory infection

Acute respiratory infections (ARI), including pneumonia, constitute a substantial disease burden in adults [1]. The Global Burden of Disease, Injuries, and Risk Factors (GBD) Study 2015 estimated that in 2015 lower respiratory infections have caused 1.7 million deaths (uncertainty range [UR], 1.6–1.8) and 32.3 million disability-adjusted life-years (UR, 29.9–33.9) in adults [2]. Respiratory syncytial virus (RSV) is one of the important viral pathogens identified in adults with ARI [3] and is increasingly recognized as a cause of illness in high-risk adults, including those with chronic lung and heart disease. A 4-year prospective cohort study indicated that RSV infection was observed annually in 3%–7% of healthy older adults and in 4%–10% of adults with chronic cardiopulmonary disease [3]. In this study, RSV infection was found in 10.6% of hospitalizations with pneumonia, 11.4% of hospitalizations with chronic obstructive pulmonary disease (COPD), 5.4% of hospitalizations with congestive heart failure (CHF), and 7.2% of hospitalizations with asthma in adults ≥65 years. Previously, we estimated that in 2015, there were about 1.5 million (95% confidence interval [CI], .3–6.9) episodes of RSV-ARI in older adults ≥65 years in industrialized countries (data unavailable in developing countries), and of these 214 000 (approximately 14.5%; 95% CI, 100 000–459 000) were admitted to hospitals [4]. The global number of hospital admissions for RSV-ARI in older adults was estimated at 336 000 (UR, 186 000–614 000). We also estimated that about 14 000 (UR, 5000–50 000) in-hospital deaths in older adults were related to RSV-ARI globally. However, the disease burden in adults with comorbidity is not well characterized in spite of being increasingly recognized. In this study, we aimed to estimate the incidence, hospital admission rate, and in-hospital case fatality ratio associated with RSV-ARI in adults with comorbidity, as well as the strength of association between RSV-ARI and comorbidities.

METHODS

Search Strategy and Selection Criteria

We conducted a systematic review across 7 databases (including 3 Chinese language databases) following the approach detailed in the PRISMA guidelines [5]. Tailored search strategies were developed and applied to search Medline, Embase, Global Health, LILACS, China National Knowledge Infrastructure, Wanfang Data, and Chongqing VIP databases (Supplementary Table 1). All searches were restricted to articles with publication dates between January 1996 and March 2020. No publication status criteria or language restrictions were applied. We included studies that fulfilled the selection criteria as indicated in Supplementary Material.

Four investigators (T. S., S. V., F. J., and R. B.) conducted the search in the databases independently and extracted data using standardized data extraction templates. Any disagreements were resolved upon discussion. The protocol of this review was published in the PROSPERO database (No. CRD42020172051).

Definitions

We adopted the case definitions of pneumonia and (very) severe pneumonia, which were adapted from the WHO Integrated Management of Adolescent and Adult Illness guidelines [6]. The details of the definitions are displayed in Supplementary Table 2. RSV infection was laboratory confirmed. We categorized countries as either industrialized or developing on the basis of UNICEF’s classification 2015 [7] and used this regional classification to report our results.

Statistical Analysis

We calculated incidence rate, hospitalization rate, or in-hospital case fatality ratio (hCFR). We performed meta-analyses (using Stata version 14.0) by region for RSV-ARI incidence and hCFR and reported pooled estimates (with 95% CIs). Meta-analysis was carried out when there were at least 3 studies. We applied a random effects model (DerSimonian-Laird method) because in-study and between-study data heterogeneity was anticipated [8].

We calculated odds ratios (ORs) of experiencing RSV-ARI for adults with comorbidity compared to the control group (without comorbidity) with accompanying 95% CIs. ORs from univariable analysis and adjusted ORs from multivariable analysis were extracted and reported separately. Using STATA (version 14.0), we performed a meta-analysis of comorbidity-associated ORs and reported pooled estimates with corresponding 95% CIs using the random effects model due to the heterogeneity across studies, as mentioned above.

RESULTS

Study Characteristics

We identified 2026 records, and 20 articles fulfilled our selection criteria (Supplementary Figure 1) [3, 9–27]. Eighteen studies were from industrialized countries and 2 from developing countries. Nineteen studies were from urban areas and one from a mixed population. Among all studies, 7 reported the community-based incidence rates in adults with comorbidity, 2 reported hospital admission rates, 8 had hCFR data, and 5 reported odds ratios for comparison of patients with and without a comorbidity. The definitions of comorbidity in these studies are presented in Supplementary Table 3. The full descriptions of study characteristics and reported outcomes are available in Supplementary Table 4. Half (10/20) of the included studies reported data in patients ≥18 years and some focused on an older age group (eg, ≥50 years). One study stratified the data by narrower age bands [15].

Incidence

Seven community-based studies (with 8 data points) reported RSV-ARI incidence in adults with comorbidity (Table 1) [3, 9–14]. All of them came from industrialized countries and reported incidence rate in adults with cystic fibrosis, CHF, COPD, or those with immunocompromised status due to hematopoietic stem cell transplantation. The incidence rate of RSV-ARI in adults with any comorbidity from industrialized countries was 30.3 (95% CI, 15.3–59.9) per 1000 persons per year/season. Three studies reported annual incidence rate for adults with cystic fibrosis and immunocompromised status and its meta-estimate was 37.6 (95% CI, 20.1–70.3) per 1000 persons per year. Four studies reported seasonal incidence rate for adults with CHF, COPD, and immunocompromised status and its meta-estimate was 28.4 (95% CI, 11.4–70.9) per 1000 persons per season.

Table 1.

Meta-Estimates of the Incidence, hCFR, and OR of RSV-ARI in Adults With Any Comorbidity From Industrialized Countries

Measure	Meta-Estimate
Incidence rate of RSV-ARI
No. of studies (No. of data points)	7 (8)
Incidence rate, annual (95% CI)	37.6 (20.1–70.3)
Incidence rate, seasonal (95% CI)	28.4 (11.4–70.9)
hCFR of RSV-ARI
No. of studies (No. of data points)	6 (7)
hCFR, % (95% CI)	11.7 (5.8–23.4)
OR of RSV-ARI, univariable
No. of studies (No. of data points)	4 (16)
OR (95% CI)	4.1 (1.6–10.4)
OR of RSV-ARI, multivariable
No. of studies (No. of data points)	2 (6)
OR (95% CI)	1.1 (.6–1.8)

Incidence rate annual is presented as per 1000 persons per year. Incidence rate seasonal is presented as per 1000 persons per season.

Abbreviations: ARI, acute respiratory infection; CI, confidence interval; hCFR, in-hospital case fatality ratio; OR, odds ratio; RSV, respiratory syncytial virus.

Hospitalizations

Two hospital-based studies reported hospitalization rate for RSV-ARI in adults with comorbidities [15, 16]. One came from South Africa and another one from the United States. Moyes et al [15] estimated the hospitalization rate of RSV-ARI in adults with human immunodeficiency virus (HIV) in 3 age bands (18–44 years, 45–64 years, and ≥65 years). The rate in the age band of ≥65 years was 4.8 (95% CI, 1.6–11.2) per 1000 persons per year in 2012, while in the age band of 45–64 years, the rate was 2.0 (95% CI, 1.5–11.2) per 1000 persons per year and in those aged 18–44 years, the rate was 2.0 (95% CI, 1.5–11.2) per 1000 persons per year. In the study by Falsey et al [16], the hospitalization rate in adults with CHF or COPD aged ≥65 years was 13.2 (95% CI, 6.8–23.0) per 1000 persons per year.

In-Hospital Case Fatality Ratio

Eight studies reported hCFR of RSV-ARI in adults with comorbidities [3, 15, 17–20, 26, 27]. Six studies (with 7 data points) came from industrialized countries and another 2 from developing countries. Four studies reported data in adults ≥18 years and the rest focused on an older age group, for example, >45 years. Comorbidities such as HIV, CHF, COPD, and immunocompromised status were reported. Overall, the hCFR meta-estimate was 11.0% (95% CI, 6.8%–17.9%) in adults with any comorbidity. In industrialized countries, it was 11.7% (95% CI, 5.8%–23.4%).

Associations

Five studies reported the associations between the occurrence of RSV-ARI and the history of comorbidity(ies) in adults [21–25]. All of them were hospital-based studies and came from industrialized countries. Three studies reported the results using univariable analysis, 1 study used multivariable analysis and 1 study reported both. Three studies reported data in adults ≥18 years, while 1 focused on ≥21 years and another 1 focused on ≥50 years. Comorbidities such as asthma, CHF, COPD, diabetes, and immunocompromised status were reported. Their comparison groups were adults without this comorbidity. The meta-estimate OR from studies using univariable analysis was 4.1 (95% CI, 1.6–10.4) based on 16 data points, while it was 1.1 (95% CI, .6–1.8) from those using multivariable analysis based on 6 data points for RSV-ARI hospitalization in patients with a comorbidity comparing to those without the comorbidity. When focusing on CHF, the meta-estimate OR was 3.3 (95% CI, .2–44.9) based on univariable analysis from 3 data points.

DISCUSSION

This is the first systematic review to evaluate and summarize the available literature that estimates the burden of RSV-ARI in adults with comorbidities. Our review summarized data from about 11 000 cases of RSV-ARI in adults with comorbidities reported in 20 articles. Our study shows a substantial disease burden of RSV-ARI in adults with comorbidities. We estimated that the annual incidence rate was 37.6 (95% CI, 20.1–70.3) per 1000 persons per year and seasonal incidence rate was 28.4 (95% CI, 11.4–70.9) per 1000 persons per season in industrialized countries. The hCFR was 11.7% (95% CI, 5.8–23.4) for industrialized countries. The overall hCFR was 11.0% (95% CI, 6.8–17.9) in adults with any comorbidity. The association between RSV-ARI and a comorbidity in adults was 4.1 (95% CI, 1.6–10.4) based on univariable analysis and 1.1 (95% CI, .6–1.8) from multivariable analysis.

The incidence rate of RSV-ARI in adults with comorbidities in our study was much higher than the rate reported in the general population (with or without comorbidities): 37.6 (95% CI, 20.1–70.3) compared to 6.7 (95% CI, 1.4–31.5) per 1000 persons per year in industrialized countries [4]. However, the latter estimate was focusing on those aged ≥65 years, while our estimate included also younger patients. We observed a similar pattern for hCFR. In industrialized countries, hCFR of RSV-ARI was 11.7% (95% CI, 5.8–23.4) for adults with comorbidity, while it was 1.6% (95% CI, .7–3.8) for the general population [4]. This indicates that adults with comorbidities could have a higher risk of experiencing RSV-ARI infection and tend to have a poorer outcome. We could not reliably estimate any data for developing countries due to paucity of data from this region (none reported incidence rate, 1 reported hospitalization rate, and 2 reported hCFR).

Variations in estimates from different studies should be interpreted with caution, because several factors may affect the estimates: methodological differences across studies (eg, differences in enrolment criteria, case definitions for ARI, case ascertainment method, definition of comorbidity, age group of study population, and sample size of included studies), annual variations in RSV activity, clinical specimen, sensitivity and specificity of RSV diagnostic tests, variation in RSV epidemiology between study populations, and health care seeking behavior of the underlying population. Although we did not include fever as part of the case definition, 1 study used severe acute respiratory infection that required history of fever or measured fever of ≥38°C, which could result in missing some RSV cases [28]. Moreover, the in-hospital CFR was defined as 90-day overall mortality or death at 100 days in 2 studies, which might have overestimated the actual in-hospital CFR. Therefore, considering the variations across study sites, the true uncertainties around these estimates are larger than those expressed in the standard 95% CI that we reported.

There are a few limitations of this study. First, our estimates of RSV-ARI morbidity and mortality in adults with comorbidity are limited by data availability in developing countries where outcomes may be poorer. Of the 20 studies, only 2 were from developing countries, reporting the hospitalization rate or hCFR. We expect that many adults with severe or very severe RSV-ARI in developing countries do not receive prompt hospital care. Further estimates of RSV-ARI morbidity and mortality from population-based studies with demographic surveillance could provide additional data to allow more robust estimates. Better surveillance systems, including standard case definitions and reporting practices, would substantially reduce the uncertainty in the RSV-ARI morbidity and mortality estimates in both industrialized and developing countries. Second, most studies (4/5) used RSV-negative ARI patients as the control group to investigate the strength of association, which might not reflect the true association between RSV-ARI and comorbidity in the general population. Third, most studies did not report age-group–specific rate except Moyes’ study, where the hospitalization rate in adults with HIV seemed to increase with age: 1.1 (95% CI, .9–1.2) per 1000 persons per year in adults aged 18–44 years, 1.4 (95% CI, 1.0–1.9) aged 45–64 years, and 3.9 (95% CI, .8–11.3) aged ≥65 years. This indicates that age might be an important risk factor for RSV-ARI–related hospital admissions among adults with HIV. More studies with age-specific data are required to provide more robust evidence for HIV and other comorbidities (eg, COPD, cardiorespiratory) [29, 30]. Fourth, we only included laboratory-confirmed RSV cases, which could miss a number of cases with late presentation or lower viral loads [31]. In addition, the estimate from this report on RSV-ARI could underestimate the overall disease burden attributable to RSV infection. For example, it would be helpful to include exacerbation of underlying heart and lung disease rather than only those diagnosed as ARI. Fifth, there were insufficient data to provide regional incidence or hospitalization rate estimate. Also, estimates by RSV subtype or gender-specific estimates were missing.

In conclusion, this study provides a review of the existing evidence regarding RSV-ARI burden in community and hospital settings in adults with comorbidities. RSV-ARI is an important disease among this population. Further research into the high-risk profiles of adults will improve the disease burden estimate on RSV-ARI morbidity and mortality in adults with comorbidities. This will help guide management strategies and guide targeted interventions such as vaccination against RSV.

Supplementary Data

Supplementary materials are available at The Journal of Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

RESCEU investigators. Harish Nair, Harry Campbell, Ting Shi, You Li (University of Edinburgh); Peter Openshaw (Imperial College London); Philippe Beutels (Universiteit Antwerpen); Louis Bont (University Medical Centre Utrecht); Andrew Pollard (University of Oxford); Eva Molero (Team-IT Research); Federico Martinon-Torres (Servicio Galego de Saude); Terho Heikkinen (Turku University Central Hospital); Adam Meijer (National Institute for Public Health and the Environment); Thea Kølsen Fischer (Statens Serum Institut); Maarten van den Berge (Academisch Ziekenhuis Groningen); Carlo Giaquinto (Fondazione PENTA for the treatment and care of children with HIV-ONLUS); Michael Abram (AstraZeneca); Kena Swanson (Pfizer); Sonia K Stoszek, Jean-Yves Pircon (GlaxoSmithKline); Scott Gallichan, Clarisse Demont (Sanofi Pasteur); Jeroen Aerssens, Arnaud Cheret, Gabriela Ispas, Paul Peeters (Janssen); Brian Rosen, Robert Fuentes (Novavax); Ann Falsey (University of Rochester Medical Center); Rafael Mikolajczyk (Martin-Luther University Halle-Wittenberg); and Larry Anderson (Emory University School of Medicine).

Financial support. This work was supported by Innovative Medicines Initiative 2 Joint Undertaking (grant number 116019 to RESCEU). This Joint Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation Programme and European Federation of Pharmaceutical Industries and Associations. The content in this article reflects only the authors' view, and the EC is not responsible for any use that may be made of the information it contains.

Supplement sponsorship. This article appears as part of the supplement “Results from RESCEU study: Evidence for Policy,” sponsored by RESCEU.

Author notes

Potential conflict of interest. H. N. reports grants and personal fees from Sanofi Pasteur, personal fees from Janssen, personal fees from AbbVie, grants and personal fees from World Health Organization, personal fees from Bill and Melinda Gates Foundation, and grants from National Institute for Health Research, outside the submitted work. All other authors report no potential conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.