We read with interest the work by Jachs et al, reporting the benefits of non-selective beta blockers (NSBBs) in reducing systemic inflammation in individuals with cirrhosis, with an associated reduced rate of acute decompensation and mortality.1 Systemic inflammation is a hallmark of cirrhosis-associated immune dysfunction, representing pathological translocation of bacteria and/or bacterial products from the gut.2
Cirrhotics have an increased risk of developing infection,3 with substantially increased mortality when such infections occur.4 5 Secondary infections significantly contribute to this, and predict 30-day mortality independently of disease severity.6 7 Extending on the work of Jachs et al, we here report a beneficial impact of NSBB on clinical and microbiological outcomes of decompensated cirrhotics in both a specialist outpatient setting and inpatients. We also report the novel finding of a reduction in circulating bacterial DNA (bDNA) levels in a subset of cirrhotics with primary infections on NSBB.
We retrospectively analysed 138 patients with Child-Pugh grade B/C cirrhosis attending a specialist cirrhosis outpatient clinic at St Mary’s Hospital, London, over a 2-year period. Patients were included at the point of clinic attendance, with records of adverse events (including hospitalisation) and mortality collected from electronic notes. Baseline characteristics of this cohort are shown in table 1. The indication for NSBB for all patients in this cohort was for either primary or secondary prophylaxis of varices. NSBB use (89/138) was associated with improved survival (p=0.01), lower 1-year incidence of infection requiring hospitalisation (p=0.03), and reduced need for all-cause admission (p=0.02). On binary logistic regression; factors independently associated with 1-year survival were NSBB use (OR 5.18, 95% CI 1.67 to 16.01, p=0.004), lower baseline Model For End-Stage Liver Disease score (OR 1.25, 95% CI 1.11 to 1.41, p=0.0001) and lower infection rates (OR 1.72, 95% CI 1.17 to 2.58, p=0.007).
Table 1.
Baseline characteristics of NSBB users and non-users attending a specialist cirrhosis clinic at St Mary’s Hospital, London, UK
| Demographics | NSBB (n=89) | Non-NSBB (n=49) | P value |
| Sex (%) | 0.39 | ||
| Male | 64 (71.9) | 31 (63.3) | |
| Female | 25 (28.1) | 18 (36.7) | |
| Age (years) (IQR) | 58 (49–66) | 59 (52–67) | 0.47 |
| Main aetiology (%) | 0.52 | ||
| Alcohol | 48 (53.9) | 31 (63.3) | |
| Hepatitis C | 16 (18.0) | 7 (14.3) | |
| Non-alcoholic steatohepatitis | 6 (6.7) | 6 (12.2) | |
| Disease severity (IQR) | |||
| Child-Pugh Score | 8 (8–10) | 8 (7–10) | 0.39 |
| Model For End-Stage Liver Disease score | 13.50 (11.40–15.80) | 11.80 (9.40–14.40) | 0.006 |
| Ascites (%) | |||
| None | 38 (42.7) | 17 (34.7) | 0.12 |
| Mild | 24 (27.0) | 9 (18.4) | |
| Moderate | 18 (20.2) | 11 (22.4) | |
| Severe | 9 (10.1) | 12 (24.5) | |
| Hepatic encephalopathy (%) | 24 (27.0) | 10 (20.4) | 0.52 |
| Hepatocellular carcinoma (%) | 6 (6.7) | 1 (2.0) | 0.42 |
| Laboratory parameters (IQR) | |||
| Sodium (mmol/L) | 137 (133–139) | 137 (135–138) | 0.91 |
| Creatinine (μmol/L) | 70 (62–84) | 63 (57–73) | 0.03 |
| Albumin (g/L) | 29 (25–33) | 30 (26–33) | 0.33 |
| Bilirubin (µmol/L) | 39 (23–59) | 30 (15–52) | 0.06 |
| International normalised ratio | 1.3 (1.2–1.5) | 1.3 (1.2–1.4) | 0.03 |
| Platelets (×109/L) | 96 (66–144) | 127 (83–136) | 0.03 |
NSBB, non-selective beta blocker.
Subsequently, we prospectively investigated the impact of NSBB use on bDNA levels and the 28-day incidence of secondary infection. We assessed bDNA levels in 22 consecutive cirrhotics admitted with primary infection with follow-up at day 28. At this point, they were assessed for secondary infection development, defined as per the North American Consortium for the Study of End-Stage Liver Disease criteria,6 with blood sampling for 16S rRNA gene count (bacterial DNA load) analysis using PCR. Further details are included in the online supplemental material. Of the 22 patients, 50% (n=11) were already established on NSBB therapy at enrolment and 50% were not (n=11). There was no significant difference in median MELD scores between the two groups. Demographic and clinical details are summarised in table 2.
flgastro-2021-101818supp001.pdf (67.6KB, pdf)
Table 2.
Baseline characteristics of patients with bDNA according to the use of NSBB
| Demographics | NSBB group (n=11) | Non-NSBB group (n=11) | P value |
| Age (years) (IQR) | 57 (51–68) | 51 (44–56) | 0.14 |
| Gender, % (n) | 0.65 | ||
| Male sex | 63.6 (7/11) | 72.7 (8/11) | |
| Female sex | 36.4 (4/11) | 27.3 (3/11) | |
| Aetiology, % (n) | |||
| Alcoholic liver disease | 54.5 (6/11) | 72.7 (8/11) | 0.38 |
| Viral hepatitis (hepatitis B or C) | 27.3 (3/11) | 9.1 (1/11) | 0.27 |
| Non-alcoholic steatohepatitis | 18.2 (2/11) | 18.2 (2/11) | 1.00 |
| Model For End-Stage Liver Disease score (IQR) | 14.9 (11.4–19.9) | 14.5 (12.7–23.1) | 0.72 |
| Comorbidities, % (n) | |||
| Ischaemic heart disease | 9.1 (1/11) | 9.1 (1/11) | 1.00 |
| Lung disease | 18.2 (2/11) | 18.2 (2/11) | 1.00 |
| Diabetes mellitus | 36.4 (4/11) | 18.2 (2/11) | 0.34 |
| Primary infection site, % (n) | |||
| Spontaneous bacteraemia | 27.3 (3/11) | 36.4 (4/11) | 0.65 |
| Spontaneous bacterial peritonitis | 18.2 (2/11) | 9.1 (1/11) | 0.53 |
| Respiratory infection | 27.3 (3/11) | 18.2 (2/11) | 0.61 |
| Cellulitis | – | 18.2 (2/11) | – |
| Urinary tract infection | 18.2 (2/11) | – | – |
| Other abdominal infections | 9.1 (1/11) | 18.2 (2/11) | 0.53 |
bDNA, bacterial DNA; NSBB, non-selective beta blocker.
Disease severity stratified by MELD score correlated with bDNA concentrations (Spearman’s r=0.550, p=0.0145) and also with C reactive protein (Spearman’s r=0.543, p=0.0162). Notably, circulating levels of bDNA at baseline were significantly lower in the NSBB group versus the non-NSBB group (73.0 pg/mL of whole blood vs 133.8 pg/mL, p=0.01).
The incidence of secondary infection development at 28 days was 22.7% (5/22), comparable to previous studies.6 Circulating levels of bDNA at baseline in patients who developed secondary infection, all of whom were not on NSBB, were higher (109.0 pg/mL) compared with those who did not develop secondary infections (66.3 pg/mL, p=0.02).
Our findings build on those from Jachs et al, suggesting that NSBB therapy within the context of a specialist decompensated cirrhosis service can benefit patients by reducing mortality, need for admission and infection rates. Additionally, we have shown that NSBB therapy can result in lower levels of bDNA during episodes of primary infection and may protect against the development of secondary infections. More broadly, our data support the concept that NSBB may have added beneficial effects beyond the pure reduction of portal pressures. Mechanisms may include NSBB-related improvement in gut barrier integrity, potentially via an impact on gut motility. Finally, we agree with Jachs et al that in clinical trials involving cirrhotic patients, where inflammatory/infective outcome measures are being assessed, consideration needs to be given to patient stratification by NSBB use to allow optimal study design and interpretation of results.
Acknowledgments
The authors thank and dedicate this work in memory of Dr Harry Antoniades.
Footnotes
Twitter: @RooshiNathwani, @bhmullish
Contributors: RN: lead author of the manuscript, involved with data collection, analysis and experimental work. DK and BM: data collection and manuscript write-up. AC: data collection. ML, CGA, MRT and AD: conceptualised the work, provided intellectual support and edited the manuscript. AD: overall responsibility for the carried out work. All authors reviewed and approved the final version of the manuscript.
Funding: The Division receives financial support from the National Institute of Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. BHM is the recipient of an NIHR Academic Clinical Lectureship (CL-2019-21-002).
Competing interests: None declared.
Provenance and peer review: Not commissioned; internally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
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References
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Supplementary Materials
flgastro-2021-101818supp001.pdf (67.6KB, pdf)