Letter to the editor: vaccination against upper respiratory infections is a matter of survival in alcoholic liver disease

We read with great interest the report on SARSCoV2 infection in patients with primary biliary cholangitis (PBC) by Ampuero et al. An independent association of chronic liver disease with adverse clinical outcome in patients with COVID19 was previously reported in this journal. However, the impact of SARSCoV2 and upper airway infections in general on patients with alcoholic liver disease (ALD) remains widely unknown. Yet, those data would be of high relevance to global public health and vaccination campaigns since alcohol related diseases are endemic. 57% of the population over age 15 has consumed alcohol in the last 12 months, and 2.3 billion people are current drinkers. With respect to upper airway respiratory infections, patients with chronic liver disease, including those with ALD, are particularly susceptible to infections as the immune system is dysfunctional through several pathological mechanisms including decreased opsonisation, reticuloendothelial dysfunction, neutrophils impairment and abnormal immunoglobulin synthesis. 5 Moreover, alcohol abuse, independently from other factors, depresses the immune system by decreasing the lymphocytes and antibodies and the production of cytokines as TNFalpha, IL1 and IL6. Several human and murine studies have reported that patients with chronic alcohol consumption are at higher risk of severe influenza. Thus, respiratory infections such as seasonal flue or SARSCoV2 represent a major threat to these patients. Unfortunately, despite general recommendations for seasonal influenza vaccinations, systematic evaluations of the efficacy of such vaccinations are widely lacking. Even more, the general perception appears, that influenza vaccination is less beneficial in patients with ALD due to a lack of conclusive information (no randomisation, small sample sizes). In order to determine the benefit of influenza vaccination in (chronic) ALD, we analysed a large cohort of 4667 US patients with ALD for vaccination efficacy between 2000 and 2020. Patient data were obtained through the Observational Health Data Sciences and Informatics (OHDSI) consortium, an opensource, multistakeholder and interdisciplinary collaborative effort. This analysis demonstrated a highly significant benefit of influenza vaccinations, no matter what available strain or year were investigated during the last decade. Vaccinations against seasonal influenza A variants (H1N1 (p=0.000), H3N2 (p=0.000)), influenza B virus (p=0.000), Massachusetts2–2010liver variant (p=0.000) and BWisconsin12010 (p=0.006) variant all demonstrated a highly significant survival benefit for ALD patients (figure 1). Our data clearly demonstrate the benefit of vaccination against upper airway respiratory (viral) infections, even in a severely ill cohort with 63% of all patients suffering from liver cirrhosis, 32% from ascites and 16% encephalopathy. A similar trend was observed in an independent Korean cohort of 7339 patients with ALD, which slightly failed statistical significance (p=0.082, figure 2) but showed a clear separation of survival curves. This may be particularly due to a better survival of the nonvaccinated control group. The reasons for that may be manifold: First of all, the Ajou cohort of patients obviously were not as sick as the US cohort as measured by means of symptoms of decompensation. Also, number of patients with mental disorders was clearly lower in South Korean patients, which may well result in a better selfprotecting behaviour in order to prevent influenza infections. Finally, generally more people have been wearing masks over the past two decades in Asia. By reporting these data, we aimed to contribute urgently needed evidence on vaccination against upper airway infections in ALD. We conclude, that vaccination against ongoing or seasonal viral Letter