Evaluating cirrhosis and respiratory syncytial virus infection: Should we vaccinate?

Abstract

BACKGROUND

Respiratory syncytial virus (RSV) is a common respiratory infection with significant morbidity and mortality amongst patients with certain comorbidities. A vaccination for RSV has recently been developed and is being considered in patients with cirrhosis given its association with an immunocompromised state. There is a paucity of research, however, evaluating the risks of RSV in cirrhosis.

AIM

To assess the burden of RSV in cirrhosis and compare it to other conditions included in vaccination recommendations.

METHODS

We performed a retrospective, single-center study at an Australian tertiary hospital from 2017 to 2024. Patients hospitalised with RSV and either cirrhosis, ischaemic heart disease, congestive heart failure, chronic kidney disease, chronic obstructive pulmonary disease, obesity and diabetes were identified using International Statistical Classification of Diseases codes. Prevalence of RSV alongside co-morbidities was documented, and predictors of in-hospital mortality among RSV-positive patients were assessed using multivariable logistic regression.

RESULTS

Among 163 patients hospitalised with RSV, two had cirrhosis (1.2%). In contrast, a higher proportion had other comorbidities. Of 744 individual patients with cirrhosis known to our service over the 8-year study period, 0.3% were hospitalised with RSV. This was higher than obesity (0.0%), ischaemic heart disease (0.1%) and diabetes (0.2%), but lower than congestive heart failure (0.5%), chronic obstructive pulmonary disease (0.7%) and chronic kidney disease (0.7%). Of 50 RSV-positive patients died during their admission, including one patient with cirrhosis. Independent risk factors for inpatient mortality included age (odds ratio: 1.05, 95% confidence interval: 1.02-1.09, P < 0.001) and diabetes (odds ratio: 2.19, 95% confidence interval: 1.01-4.84, P = 0.049), but not cirrhosis.

CONCLUSION

The burden of RSV amongst patients with cirrhosis appears to be low, but may be higher than other at-risk conditions. Further population-level data is required to inform RSV vaccination strategies.

Key Words: Cirrhosis; Respiratory syncytial virus; Respiratory tract infection; Vaccination; Hospitalisation

Core Tip: Respiratory syncytial virus (RSV) is an increasingly recognised cause of hospitalisation in adults, but its impact in patients with cirrhosis remains poorly defined. In this hospital-based study, RSV-related admissions among patients with cirrhosis were relatively infrequent and were not associated with the degree of healthcare utilisation or mortality observed in several other chronic disease groups. These findings suggest that the burden of RSV in cirrhosis requires further evaluation, and further research is required on the relationship between RSV and cirrhosis to help inform vaccination strategies.

INTRODUCTION

Respiratory syncytial virus (RSV) is a common and highly contagious respiratory tract infection, which is associated with considerable morbidity and mortality in high-risk patient groups, including older adults and those with certain health conditions[1-3]. Pulmonary conditions such as chronic obstructive pulmonary disease (COPD) predispose patients to RSV-related respiratory complications due to baseline airway damage, structural changes and impaired mucociliary clearance[4]. Patients with cardiac conditions such as congestive heart failure (CHF) are at an increased risk of cardiac decompensation, due in part to the increased cardiac demands in those infected[5]. Patients with chronic kidney disease (CKD) and metabolic conditions such as diabetes and obesity are at an increased risk in less direct ways, owing to the immune dysregulation associated with these conditions, predisposing them to more severe infection[6-8].

Similarly, patients living with cirrhosis have notable immune dysfunction[9], with impaired innate and adaptive immune systems alongside chronic systemic inflammation. This leads to reduced pathogen clearance and a disposition towards exaggerated systemic responses[10]. These patients may additionally have clinically significant portal hypertension, hyperdynamic circulation, risk of fluid overload and an overall reduced physiological reserve[11]. For these reasons, patients with cirrhosis are also felt to be at increased risk of severe RSV, though direct data is limited.

Given the risk of severe RSV in high-risk populations, RSV vaccines have been developed, and recent trials have demonstrated their safety and efficacy[12-14]. Regulatory authorities, such as the European Medicines Agency[15], United States of America’s Center for Disease Control and Food and Drug Administration[16], Japan’s Ministry of Health, Labour and Welfare[17], and Australia’s Therapeutic Goods Administration[18,19] have therefore approved and recommend RSV vaccination for adults of varying age groups with comorbidities that increase the risk of severe infection, including cirrhosis.

Despite this, evidence for cirrhosis as a significant risk factor for severe RSV is limited compared with other health conditions[14,20], and vaccination recommendations may instead be extrapolated from evidence detailing the increased risks of other respiratory tract infections in cirrhosis[21]. Increased testing for viral illnesses including RSV in recent years allow for greater identification and assessment of associated harms. The aim of this study was to assess the burden of RSV among patients with cirrhosis, and to evaluate the impact of cirrhosis on the severity of RSV-related outcomes in comparison to other chronic health conditions.

MATERIALS AND METHODS

Study design, setting and population

This was a retrospective, single-center study conducted at a tertiary hospital in Melbourne, Australia. Patients hospitalized with RSV and/or cirrhosis were identified from January 2017 to December 2024. Patients admitted with other major chronic health conditions identified as being risk factors for severe RSV infection, including ischaemic heart disease (IHD), CHF, CKD, COPD, obesity and diabetes, were also identified and included for comparison.

Data collection

International Statistical Classification of Diseases-Australian Modification codes were used to extract patient admission episodes with a diagnosis of RSV (J12.1), cirrhosis (K74.6 or K70.3) or other chronic health conditions (Supplementary Table 1). Patient age, sex, duration of hospitalization and inpatient mortality were collected. The study received approval from the Northern Health Research Development and Governance Unit (approval No. 63.2024).

Statistical analysis

Statistical analyses were conducted using R software version 4.3.2[22]. Comparisons between RSV positive and negative patients were conducted using χ² or Fisher’s exact test where appropriate for categorical variables, and the Mann-Whitney U test for continuous variables due to non-normal distributions. The relative burden of RSV in each chronic health condition was calculated as the proportion of patients hospitalised with RSV and that heath condition, out of the total number of individuals hospitalised with that health condition during the study period. To identify predictors of in-hospital mortality in patients with RSV, multivariable logistic regression was conducted including age, sex, cirrhosis and other chronic health conditions.

RESULTS

Patient characteristics

A total of 163 patients hospitalised with RSV were identified [median age 75, interquartile range (IQR): 67-75]. Of these, 109 had at least one chronic health condition (Supplementary Figure 1). The most common chronic health condition was diabetes (38.7%), followed by CHF (17.8%) and COPD (14.7%) (Table 1). Only two patients with cirrhosis were hospitalised with RSV (1.2%) during the study period.

Table 1 Characteristics of patients hospitalised with respiratory syncytial virus, n (%)/median (interquartile range).

Characteristics	n = 163
Age, years	75 (67-84)
Sex, female	99 (60.7)
Duration of hospitalization, days	4.7 (2.5-8.4)
Chronic health condition
Cirrhosis	2 (1.2)
Ischaemic heart disease	10 (6.1)
Congestive heart failure	29 (17.8)
COPD	24 (14.7)
Chronic kidney disease	17 (10.4)
Obesity	0 (0.0)
Diabetes	63 (38.7)
Number of chronic health conditions
0	54
1	82
2	19
3	7
4	1

COPD: Chronic obstructive pulmonary disease.

A total of 49758 unique inpatients with at least one pre-specified chronic health condition were identified over the study period (Table 2, Supplementary Figure 2). Cirrhosis was identified in 744 (1.5%) of these patients. Diabetes was the most common chronic health condition (n = 33602), followed by IHD (n = 7316), CHF (n = 5551) and COPD (n = 3246). The median age of cirrhosis patients was 53 (IQR: 63-73) and were mostly male (69.2%) - similar to IHD [median age 53 (64-75), 65.4% male]. Patients with CHF, diabetes, COPD and CKD were generally older and were more likely to be male. Patients with obesity were youngest overall [median age 28 (22-39)] and were less likely to be male (9.7%).

Table 2 Chronic health conditions assessed and incidence of respiratory syncytial virus (n = 49758), n (%)/median (interquartile range).

	n	Age	Female	RSV+ (n)	RSV+ (%)
Cirrhosis	744	53 (63-73)	229 (30.8)	2	0.3
Ischaemic heart disease	7316	53 (64-75)	2534 (34.6)	10	0.1
Congestive heart failure	5551	66 (79-87)	2664 (48.0)	29	0.5
COPD	3246	64 (74-82)	1551 (47.8)	24	0.7
Chronic kidney disease	2590	71 (81-88)	1314 (50.7)	17	0.7
Obesity	1089	28 (22-39)	983 (90.3)	0	0
Diabetes	33602	57 (68-78)	15536 (46.2)	63	0.2

RSV: Respiratory syncytial virus; COPD: Chronic obstructive pulmonary disease.

Burden of RSV

Of 49758 patients with at least one chronic health condition, 109 were hospitalised with RSV over the study period. Only 0.3% of patients with cirrhosis (2 of the 744) had a hospitalisation with RSV over the 8-year study period (Table 2). This was higher than diabetes (0.2%), IHD (0.1%) and obesity (0.0%), but lower than all other health conditions, with CKD and COPD leading (0.7%). As can be seen in Table 3, patients hospitalised with RSV were significantly older [78 (71-85) years vs 68 (56-79) years, P < 0.001], and more likely to have a diagnosis of CHF (26.6% vs 11.1%, P < 0.001), COPD (22.0% vs 6.5%, P < 0.001), CKD (15.6% vs 5.2%, P < 0.001) but not cirrhosis (1.8% vs 1.5%, P = 1.000).

Table 3 Characteristics of patients hospitalised with and without respiratory syncytial virus, n (%)/median (interquartile range).

	RSV+	RSV-	P value
Age, years	78 (71-85)	68 (56-79)	< 0.001
Sex (female)	58 (53.2)	22879 (46.1)	0.163
Cirrhosis	2 (1.8)	742 (1.5)	1.000
Ischaemic heart disease	10 (9.2)	7306 (14.7)	0.135
Congestive heart failure	29 (26.6)	5522 (11.1)	< 0.001
COPD	24 (22.0)	3222 (6.5)	< 0.001
Chronic kidney disease	17 (15.6)	2573 (5.2)	< 0.001
Obesity	0 (0.0)	1089 (2.2)	0.217
Diabetes	63 (57.8)	33539 (67.6)	0.039

From a cohort of patients with specific chronic health conditions (n = 49758), 109 with respiratory syncytial virus. RSV: Respiratory syncytial virus; COPD: Chronic obstructive pulmonary disease.

Mortality

A total of 50 patients with RSV experienced in-hospital mortality. As can be seen in Supplementary Table 2, patients who died had a higher median age 81 (IQR 74-88) compared to those who survived [72 (63-82), P < 0.001]. There were no significant differences in the proportions of patients with each comorbidity in those who experienced in-hospital mortality and those who survived. Multivariable logistic regression identified age (odds ratio: 1.05, 95% confidence interval: 1.02-1.09, P = 0.002), diabetes (odds ratio: 2.19, 95% confidence interval: 1.01-4.84, P = 0.049) but not cirrhosis, as independent risk factors for in-hospital mortality in patients hospitalised with RSV (Table 4).

Table 4 Multivariable logistic regression: Independent risk factors for mortality in patients hospitalised with respiratory syncytial virus.

Variable	Adjusted OR	95% confidence interval	P value
Age (years)	1.05	1.02-1.09	0.002
Sex (female)	1.01	0.48-2.16	0.980
Cirrhosis	8.56	0.3-245.53	0.154
Ischaemic heart disease	1.72	0.38-7.32	0.460
Congestive heart failure	0.9	0.3-2.63	0.853
COPD	0.72	0.2-2.29	0.588
Chronic kidney disease	2.02	0.63-6.44	0.229
Diabetes	2.19	1.01-4.84	0.049

OR: Odds ratio; COPD: Chronic obstructive pulmonary disease.

DISCUSSION

Due to its association with an immunocompromised state, chronic liver disease is increasingly being considered as an indication for RSV vaccination in certain age groups worldwide[15-19]. Despite this, direct data evaluating the risk of severe RSV in patients with cirrhosis remains scarce. The need for further data evaluating the morbidity and mortality of RSV infection in patients with cirrhosis is essential and will help inform vaccination discussions in clinical practice.

In this study, RSV hospitalisation among patients with cirrhosis was uncommon. Of the two hospitalised patients with cirrhosis and RSV, the first had an additional diagnosis of COPD and was discharged within 24 hours. The second unfortunately died (the only mortality with RSV and cirrhosis recorded in our health service), but had additional risk factors for severe disease, including advanced age (> 85 years) and several other co-morbidities. Despite the prevalence of hospitalisation with RSV being lower in our cirrhosis cohort compared to other high-risk conditions such as CKD, COPD, CHF - it was comparable to IHD and diabetes, and is likely to be higher than adults without any risk factors for severe disease[21].

A population-wide study by Osei-Yeboah et al[21] assessed RSV-associated hospitalisations in patients with comorbidities, including cirrhosis, across two European countries. The authors estimated a 2.0 relative risk of RSV-associated hospitalisation in patients with cirrhosis compared to the general population, but this risk was considerably lower than other chronic health conditions assessed.

Similar to the limitations present in our study, Osei-Yeboah et al[21] encountered issues with overall low numbers of RSV infections in patients with liver disease. One of the two countries studied, Scotland, had limited subgroup analysis with respect to RSV-associated admissions in patients with chronic liver disease, and the other, Denmark, needed to exclude analysis on liver disease entirely due to lack of numbers. These limitations, alongside the limited RSV event rates in our own cohort, highlight the challenges in assessing the relationship between RSV and cirrhosis outcomes.

It has been suggested that patients with RSV and cirrhosis would experience worse outcomes and would benefit from vaccination, but evidence is scarce. Instead of research assessing cohorts of patients with liver disease and RSV, much of the concern around RSV in chronic liver disease is extrapolated from other sources. This includes evidence detailing how cirrhosis represents an immunocompromised state[23], as well as existing research demonstrating the risk of other viral infections such as influenza[24-27] and more recently, coronavirus disease 2019[28] in patients with cirrhosis.

Similarly, research which has supported the approval of RSV vaccination in adults with comorbidities designated as high-risk - including cirrhosis - have included limited numbers of patients with advanced liver disease. In a phase III trial published by Davis et al[14] of the 678 participants included, just 4.9% had liver disease, whereas 52.4% had chronic pulmonary disorders, 42.8% had diabetes mellitus, and 8.0% cardiovascular condition - all conditions which have a greater body of evidence detailing the increased risk of RSV infections[13,29-31]. Consequently, current recommendations for RSV vaccination in cirrhosis are largely extrapolated from overall trial efficacy and the broader infection risk to which cirrhosis is associated.

Despite the relative novelty of our study, our findings are limited by their retrospective and single center nature. International Statistical Classification of Diseases coding was used to identify RSV cases and chronic health conditions, which is not always accurately reflective of patient’s true comorbidities. Lack of testing for RSV may have similarly resulted in reduced case identification. Although hospitalisation rates were low, this study could not capture the morbidity experienced in non-hospitalised patients. Given the increasing numbers of vaccinations being recommended to patients with cirrhosis, alongside the high refusal and low vaccinations rates documented in the cirrhosis population[32,33] - all in the context of persistent vaccination misinformation and skepticism - dedicated prospective research highlighting the risk of RSV in cirrhosis, and the benefits of vaccination, is required.

Until such data are available, patients with cirrhosis should be offered RSV vaccination on a case-by-case basis, in-line with local guidelines, particularly if they are advanced in age or have other high risk chronic health conditions. The safety, tolerability and relative low cost of vaccination[12-14], alongside the potential risk of severe disease as observed with other infections[34], support its consideration in this population.

CONCLUSION

RSV hospitalisation among patients with cirrhosis was uncommon in our health service, but was limited by low event rates and a lack of population-level data and outcomes. Although patients with cirrhosis and RSV may be more likely to have adverse outcomes and benefit from vaccination, further research in this cohort is required to help inform vaccination recommendations.