Respiratory syncytial virus in cirrhosis: Time to separate data from dogma?

Abstract

Respiratory syncytial virus (RSV) vaccination recommendations now include adults with chronic liver disease, but there is still limited direct evidence of increased RSV risk and benefit in cirrhosis. In a single Australian center, the rate of RSV-related hospitalization among cirrhotic patients was low (0.3% of 744 cases over 8 years)—lower than that for chronic obstructive pulmonary disease, chronic kidney disease, or heart failure, but similar to diabetes—and cirrhosis did not independently predict mortality among RSV-positive inpatients. These surprising findings challenge the use of RSV vaccine trial data, where liver disease was under-represented, and population models were limited by low event counts, questioning whether cirrhosis should be treated as a high-risk condition alongside better-documented cardiopulmonary comorbidities. Clinicians should have vaccination discussions on a case-by-case basis, considering age and comorbidities. Multicenter studies are urgently needed to define RSV burden, vaccine effectiveness, and decompensation risk in cirrhosis to justify policy decisions. This review argues for separating empirical data from pathophysiological assumptions in an era of expanding adult RSV prevention.

Key Words: Respiratory syncytial virus; Cirrhosis; Vaccine; Influenza virus; SARS-CoV-2; COVID-19

Core Tip: Although cirrhosis is frequently categorized as a high-risk condition for respiratory syncytial virus (RSV) infection in adults, direct evidence supporting this classification remains limited. Recent real-world data indicate that RSV-related hospitalizations among patients with cirrhosis are uncommon and not independently associated with increased mortality, in contrast to the well-established risk observed in cardiopulmonary and renal diseases. Consequently, current RSV vaccination recommendations for individuals with cirrhosis rely largely on extrapolation rather than robust cirrhosis-specific evidence. Until stronger data become available, RSV vaccination in cirrhosis should be individualized, considering age and co-morbidities, while prioritizing multicenter studies to better define true risk and clinical benefit.

INTRODUCTION

Respiratory syncytial virus (RSV) has quickly become a target of adult vaccines, but its true effect on cirrhosis remains poorly understood. Walia et al[1] challenge the common belief that all immunocompromised individuals face the same risk of RSV infection. By comparing cirrhosis with other known high-risk conditions in a real-world hospital setting, the authors encourage liver specialists and decision-makers to reconsider how much current RSV vaccination guidelines for liver disease are based on actual data rather than assumptions from studies of RSV and vaccination in the general adult population. Current recommendations still rely largely on findings from studies of RSV and vaccination in the general adult population rather than on condition-specific data; recent reviews and trials emphasize variation in vaccine effectiveness and risk across different high-risk groups, including older adults[2-6], transplant recipients[7], and patients with cancer[8].

Hospital-based comparison, together with the limited literature specifically addressing vaccination in cirrhosis, suggests that liver specialists and policy makers should re-examine guideline assumptions and consider condition-specific evidence when updating RSV vaccination recommendations[1,9].

QUIET SIGNAL IN A NOISY FIELD

The main point of this single-center retrospective analysis is both straightforward and thought-provoking: Over eight years, hospitalization for RSV infection among patients with cirrhosis was rare. It accounted for only two cases among 744 cirrhotic inpatients (0.3%) and 1.2% of 163 RSV-positive admissions[1]. Although this percentage was higher than that in obesity, ischemic heart disease, and diabetes, it was still lower than that in chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), and congestive heart failure—conditions that dominate the adult RSV burden literature and vaccine trial populations (Figure 1).

Figure 1 Respiratory syncytial virus hospitalization rates in chronic conditions and vaccination considerations for cirrhotic patients. A: Comparative bar chart showing a low respiratory syncytial virus (RSV)-related hospitalization rate in cirrhosis (0.3%, according to Walia et al[1]) compared with higher rates in chronic kidney disease, heart failure, and chronic obstructive pulmonary disease, based on real-world Australian hospital data over 8 years; B: Case-by-case considerations for RSV vaccination decisions, prioritizing age > 60 years and cardiopulmonary comorbidities, challenging uniform high-risk classification. COPD: Chronic obstructive pulmonary; CKD: Chronic kidney disease; RSV: Respiratory syncytial virus; CHF: Congestive heart failure; DM: Diabetes mellitus.

Systematic reviews focused on chronic respiratory conditions report a high burden of RSV-related hospitalizations and complications among older adults with COPD and asthma[10,11]. Large surveillance and cohort analyses corroborate these findings and additionally show increased RSV severity in older adults with cardiovascular and other chronic diseases[12-14]. Together, these reviews and recent policy updates underscore the public-health rationale behind current RSV vaccination recommendations for older adults[2,15].

This, in a way, underscores the findings of a somewhat low signal from Walia et al’s study[1] on RSV infection in cirrhosis, as captured in adult data from other populations[10,16].

A recent modeling and cohort study found that multimorbidity clusters, including cardiopulmonary and renal conditions, predict increased RSV-related severity[17,18]. Systematic reviews and meta-analyses highlight particularly poor outcomes among immunocompromised and transplant populations[17,19]. Patient-level research also identifies clinical and sociodemographic factors that affect RSV vaccination uptake and disease outcomes[20,21]. This again highlights that within the “high-risk” category, vulnerability specific to different organs is not uniform.

EXTRAPOLATION ON TRIAL: HOW STRONG IS THE CASE FOR RSV VACCINATION IN CIRRHOSIS?

Regulatory endorsements of adult RSV vaccination for patients with chronic liver disease reflect concern about cirrhosis-associated immune dysfunction and altered vaccine responsiveness[22-24]. Recommendations are also informed by clinical experience with other respiratory viruses, notably influenza and severe acute respiratory syndrome coronavirus 2, which demonstrate both increased infection risk and variable vaccine effectiveness or immunogenicity in patients with liver disease[24-26]. Finally, guidance and review articles advocating vaccination in liver disease and transplantation populations emphasize the heightened morbidity from respiratory infections and support proactive immunization strategies in this group[27,28].

Yet, Walia et al[1] carefully demonstrate how slender the RSV-specific cirrhosis data underlying these recommendations truly are, and how heavily practice relies on extrapolation from populations in whom RSV risk is far better documented.

In pivotal pre-F protein RSV vaccine trials in older adults and in high-risk younger adults, chronic pulmonary disease, cardiovascular disease, and diabetes were common[29-31]. In contrast, only a small minority of participants had liver disease, with explicit reporting that fewer than 5% had underlying hepatic conditions in some studies[2,10]. Similarly, modelling work estimating roughly a two-fold increase in RSV-associated hospitalization risk in cirrhosis relative to the general population has been hampered by very low event counts and, in some settings, an inability to analyze liver disease separately at all, amplifying uncertainty about cirrhosis-specific vaccine impact[2,10,32] (Figure 1).

Against this backdrop, the Australian data presented here act less as a definitive refutation of risk than as a reminder that current cirrhosis-focused RSV vaccination policies rest on an uneasy mixture of pathophysiological reasoning, analogies with other viruses, adult RSV data from non-hepatic comorbidities, and very sparse direct observations. This invites a more explicit, transparent discussion—both in clinics and in guidelines—about where evidence ends and extrapolation begins when cirrhosis is placed alongside COPD, CKD, and congestive heart failure in RSV risk tables.

THE TYRANNY OF SMALL NUMBERS AND WHY THEY STILL MATTER

From a methodological perspective, the study by Walia et al[1] is limited by its single-center design, reliance on international classification diseases based case ascertainment, and a very small number of RSV-positive cirrhotic admissions. These constraints restrict causal inference and prevent detailed subgroup analyses by liver disease stage, etiology, or decompensation status.

However, dismissing the study solely on this basis would overlook its relevance in a field where cirrhosis-specific RSV data are almost absent[1].

First, the rarity of RSV-related admission among cirrhotic patients in this large chronic-disease inpatient cohort is itself a meaningful observation in an era when viral testing has become routine, and adult RSV surveillance is more sensitive, as highlighted by recent burden and severity comparisons with influenza and coronavirus disease 2019 (COVID-19) in older adults[33,34] (Figure 1).

Second, by systematically comparing the relative RSV burden across multiple chronic conditions within one health system, the authors implicitly argue for a prioritization framework[1,13,35]. If adult RSV vaccines are to be deployed under budgetary or logistic constraints, should cirrhosis sit alongside COPD and CKD, or closer to diabetes and ischemic heart disease in risk-based hierarchies[2,36,37]? That question cannot be answered definitively here, but the rank ordering presented forces the field to confront it explicitly rather than accept a flat, undifferentiated “high risk” label for all comorbidities[38-40].

BETWEEN THE PRINCIPLES AND THE REAL WORLD: HOW SHOULD DOCTORS ACT NOW

In the absence of strong population-level evidence, Walia et al[1] recommend a balanced, case-by-case approach to RSV vaccination in cirrhosis, based on local standards but adjusted for age and other high-risk factors. Their stance is intentionally pragmatic: It recognizes the favorable safety and tolerability profile of current RSV vaccines and the practical cost considerations that support broader adult use[2,41]. They nevertheless concede that the absolute risk reduction for many patients with cirrhosis remains unclear, whereas systematic reviews and meta-analyses document more clearly defined burden and benefit-risk relationships for cardiopulmonary disease and frail older adults[1,42-45].

The review can be read alongside the growing literature on COVID-19 vaccination in patients with cirrhosis, which shows that although cirrhosis is associated with altered innate and adaptive immunity and chronic inflammation, most affected individuals mount satisfactory responses to vaccination[32,46-49], particularly after booster or heterologous schedules[50-52]. This comparison suggests that, for RSV vaccination in cirrhosis, the primary unknown is not only immunogenicity but whether vaccination delivers a large enough clinical benefit to justify universal prioritization[1,2]. Accordingly, prioritization might reasonably be targeted to cirrhotic patients with additional risk factors (for example, older age, cardiopulmonary disease, or diabetes) while awaiting more effectiveness and outcome data[53-56].

Also notable is the pattern of vaccine hesitancy and low coverage in patients with chronic liver issues, well known for influenza and COVID-19, and now likely to recur with RSV unless hepatology clinics adopt more integrated, liver-centered vaccination policies.

Surveillance data show suboptimal coverage for influenza, COVID-19, and RSV among adults, with the largest gaps in older people and socioeconomically deprived groups[57-60]. Work in clinical populations, including patients with chronic liver disease and cirrhosis, documents vaccine hesitancy and variable serological/clinical responses, highlighting further missed opportunities for prevention[61-63]. Taken together, these findings support the authors’ call for active, systematized interventions (rather than opportunistic, small-scale efforts) to increase uptake and reduce inequities[1].

RESEARCH AGENDA FOR A “NEGATIVE” STUDY

Perhaps the greatest contribution of this work lies in the research agenda that it sketches when read against the broader RSV and vaccination literature. The authors highlight critical gaps: Under-ascertainment of community-managed RSV, the inability of administrative coding to capture decompensation events or dynamic liver function, and the lack of prospective data linking RSV infection to acute-on-chronic liver failure or hepatic decompensation. Multicenter, registry-linked or population-wide studies that integrate virological testing, detailed cirrhosis phenotyping, vaccination status, and comparison with other respiratory viruses are now needed to move beyond the constraints of small-number hospital cohorts[1,41].

Moreover, vaccine-effectiveness studies specifically powered for cirrhosis, rather than subsuming liver disease into broad “immunocompromised” categories, will be essential to determine whether the theoretical benefits inferred from other viral infections are realized for RSV and to define which subgroups (e.g., older patients with decompensated cirrhosis and cardiopulmonary comorbidity) derive the greatest marginal benefit. Designing such studies will require collaboration among hepatologists, infectious disease specialists, and respiratory physicians, as well as a willingness among regulators and funders to treat cirrhosis not merely as an a priori high-risk label but as a population whose true RSV risk profile remains to be properly defined[1,2].

CONCLUSION

Walia et al[1] thus provide more than a local audit; situated alongside emerging adult RSV burden data, vaccine policy statements, and the rich experience with other vaccines in cirrhosis, their work offers a carefully argued provocation to a field rapidly moving from vaccine development to policy implementation. Their data do not close the debate on RSV vaccination in cirrhosis—rather, they open it, challenging readers to interrogate assumptions, refine risk stratification, and design the next generation of studies that will determine whether current recommendations are proportionate to the actual disease burden in this complex population[1,2,41].