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COVID-19 vaccination among cirrhotics in Italy: High coverage and effectiveness of 3 doses versus 2 in preventing breakthrough infection and hospitalization

Published:December 16, 2022DOI:https://doi.org/10.1016/j.dld.2022.11.016

      Abstract

      Background and Aims

      Few reports, all retrospective, have evaluated vaccine coverage against COVID-19 infection in cirrhotic subjects. No data are available for European Countries. We aimed to explore this topic and potential independent predictors of lack of vaccination.

      Methods

      Between January 1st and June 30th 2022, 1512 cirrhotic subjects of any etiology were consecutively enrolled in an observational - prospective study in 8 referral centers in Italy. Adjusted Odds Ratios (O.R.) for the association with lack of vaccination and with occurrence of breakthrough infection were evaluated by multiple logistic regression analysis.

      Results

      Overall vaccine coverage was 89.7% (80% among people born abroad). Among the 1358 vaccinated people, 178 (13.1%) had a breakthrough infection; of them 12 (6.7%) were hospitalized, but none died. Independent predictors associated with lack of vaccination were birth abroad, age <65 years and lower years of schooling. Child stage B/C was the only independent predictor of breakthrough infection. Occurrence of breakthrough infection was more likely reported in subjects who received 2 doses of vaccine than in those who received 3 doses (33.9% versus 9.0%; P<0.001).

      Conclusion

      High vaccine coverage against COVID-19 infection is observed among cirrhotic subjects in Italy. Vaccine is effective in preventing severe outcomes. Three doses are more effective than two, even in cirrhotic subjects.

      Lay Summary

      This large cohort study evidenced high vaccine coverage against COVID-19 infection among cirrhotic subjects in a European country and the effectiveness of vaccine in preventing severe outcomes. Three doses of vaccine are more effective than two in preventing breakthrough infection and hospitalization. Informative campaigns targeting people younger than 65 years of age and those with lower years of schooling may increase these excellent results.

      Keywords

      1. Introduction

      Subjects with liver cirrhosis, once infected with COVID-19 virus, have high rate of hospitalization, liver decompensation and death [
      • Marjot T.
      • Moon A.M.
      • Cook Ja
      • et al.
      Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: an international registry study.
      ]. Among patients with cirrhosis, COVID-19 was associated with a 2.38-fold (95% C.I., 2.18–2.59) increased risk of a 30-day mortality, and among patients with COVID-19 and chronic liver disease, presence of cirrhosis was associated with a 3.31-fold (95% C.I., 2.91–3.77) risk of 30-day mortality [
      • Ge J.
      • Pletcher M.J.
      • Lai J.C.
      • et al.
      Outcome of SARS-CoV-2 infection in patients with chronic liver disease and cirrhosis: a national COVID cohort collaborative study.
      ]. A key point of these severe outcomes is the innate and adaptive immune dysregulation present in subjects with liver cirrhosis [
      • Albillos A.
      • Lario M.
      • Alvarez-Moh M.
      Cirrhosis associated immune dysfunction: distinctive features and clinical relevance.
      ]. Another important step is played by bacterial translocation from the intestinal lumen to mesenteric lymph nodes, able to increase the level of endotoxins and cytokines [
      • Bonnel A.R.
      • Bunchorntavakul C.
      • Reddy K.R.
      Immune dysfunction and infections in patients with cirrhosis.
      ].
      Development of effective vaccines against COVID-19 has been rapid. These have been highly effective in phase 3 clinical trials, offering a 94 to 95% protection from infection [
      • Polack F.P.
      • Thomas S.J.
      • Kitchin N.
      • et al.
      C4591001 Clinical Trial Group
      Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine.
      ,
      • Baden L.R.
      • El Sahly H.M.
      • Essink B.
      • et al.
      COVE Study Group
      Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine.
      ]. As for the other vaccines (such as those against Streptococcus pneumoniae [
      • Mccashland T.M.
      • Preheim L.C.
      • Gentry M.J.
      Pneumococcal vaccine response in cirrhosis and livertransplantation.
      ], influenza [
      • Harmala S.
      • Parisinos C.A.
      • Shallcross L.
      • et al.
      Effectiveness of influenza vaccines in adults with chronic liver disease: a systematic review and meta-analysis.
      ] and hepatitis B virus [
      • Aggeletopoulou I.
      • Davoulou P.
      • Konstantakis C.
      • et al.
      Response to hepatitis B vaccination in patients with liver cirrhosis.
      ], subjects with liver cirrhosis show a suboptimal antibodies response even against COVID-19 vaccine [
      • Thuluvath P.J.
      • Robarts P.
      • Chauhan M.
      Analysis of antibody responses after COVID-19 vaccination in liver transplant recipients and those with chronic liver diseases.
      ] as consequence of their immune dysfunction [
      • Albillos A.
      • Lario M.
      • Alvarez-Moh M.
      Cirrhosis associated immune dysfunction: distinctive features and clinical relevance.
      ].
      A cohort study of US veterans with cirrhosis showed that administration of 2 doses of mRNA vaccines was associated with a 100% reduction in hospitalization and death. However, this reduced schedule had a delayed and lower (78.6%) efficacy against COVID-19 breakthrough infection [
      • John B.V.
      • Deng Y.
      • Scheinberg A.
      • et al.
      Association of BNT162b2 mRNA and mRNA-1273 vaccines with COVID-19 infection and hospitalization among patients with cirrhosis.
      ]. A more recent survey has confirmed the strong reduction of mortality in subjects with post vaccination COVID-19 infection, among both those with either compensated (HR, 0.19: 95% C.I. 0.08–0.45) and decompensated (HR, 0.27: 95% C.I. 0.08–0.90) cirrhosis [
      • John B.V.
      • Deng Y.
      • Schwartz K.B.
      • et al.
      Postvaccination COVID-19 infection is associated with reduced mortality in patients with cirrhosis.
      ]. Accordingly, international liver societies guidelines (i.e. AASLD and EASL) recommend COVID-19 vaccination for subjects with chronic liver disease [
      • Fix O.K.
      • Blumberg E.A.
      • Chang K.M.
      • et al.
      AASLD expert panel consensus statement: vaccines to prevent coronavirus disease 2019 infection in patients with liver disease.
      ,
      • Cornberg M.
      • Buti M.
      • Eberhardt C.S.
      • et al.
      EASL position paper on the use of COVID-19 vaccines in patients with chronic liver diseases, hepatobiliary cancer and liver transplant recipients.
      ].
      Thus, knowledge of COVID-19 vaccine coverage and characteristics of subjects unvaccinated are of paramount importance to address and improve vaccination policy.
      Few and retrospective reports have explored this topic. National data from the Veterans Health Administration in US has shown that 60% of cirrhotic patients received a SARS-COVID-2 vaccination [
      • Mahmud N.
      • Chapin S.E.
      • Kaplan D.
      • et al.
      Identifying patients at highest risk of remaining unvaccinated against severe acute respiratory syndrome coronavirus 2 in a large veterans health administration cohort.
      ]. In eastern China only 37.1% of decompensated cirrhotic subjects received at least one dose of vaccination, while 62.9% remained unvaccinated despite vaccination in this population has been shown to be safe [
      • Cao Z.
      • Zhang C.
      • Zhao S.
      • et al.
      COVID-19 vaccines in patients with decompensated cirrhosis: a retrospective cohort on safety data and risk factors associated with unvaccinated status.
      ].
      Aim of this survey was to evaluate, for the first time in a European country, vaccine coverage and potential predictors associated with lack of vaccination against COVID-19 infection in a large sample of cirrhotic subjects recruited in 8 liver units across Italy. Attention has also been addressed to the rate and predictors of breakthrough infection among subjects with completion of the primary vaccination cycle.

      2. Patients and methods

      2.1 Study design and patients

      This is a multicentre observational study, prospectively enrolling all consecutive patients with cirrhosis of any etiology. The study was performed in 8 tertiary centers (3 in the North, 1 in the centre, 3 in the South and 1 in Sicily) during a six-month period, from January 1st to June 30th, 2022. Seven liver units and 1 infectious disease unit participated. All cirrhotic subjects, regardless of the etiology, aged 18 years or older, consecutively observed as either inpatients or outpatients, were prospectively recruited. Incident cases were defined as those who were first diagnosed with liver cirrhosis during the study period; “prevalent cases” as those observed during the study period but with an already known diagnosis of liver cirrhosis. Subjects with hepatocellular carcinoma and/or liver transplantation were excluded from the study.
      Subjects were classified as being vaccinated if they reported that they had received Coronavirus vaccine in the past. Patients were classified as having post-vaccination COVID-19 if the infection was diagnosed more than 14 days after the full vaccination. Ascertainment of COVID-19 infection was determined by a protease COVID-19 polymerase chain reaction (PCR) obtained by nasal swab.
      Patients were evaluated only once at their first observation. In this occasion, a questionnaire was administered to subjects. Once evaluated, subjects were no longer followed-up.
      Data were collected on an anonymous form at each participating center. The questionnaire contained information on socio-demographic characteristic of subjects, etiology and stage (Child score) of liver cirrhosis, referral pattern, self-reported history of vaccination, outcomes in vaccinated subjects, and potential reasons for vaccination or not vaccination against COVID-19.
      All subjects gave their written consent to participate to the study, which was carried out in conformity with the 2013 revision of the Declaration of Helsinki. The study was approved by the ethic committee of Casa Sollievo della Sofferenza Hospital – IRCCS – San Giovanni Rotondo.

      2.2 Diagnostic criteria

      Liver cirrhosis was based on the presence of the peculiar clinical, biochemical, ultrasound signs [
      • Gaiani S.
      • Gramantieri L.
      • Venturoli N.
      • et al.
      What is the criterion for differentiating chronic hepatitis from compensated cirrhosis? A prospective study comparing ultrasonography and percutaneous liver biopsy.
      ] and transient elastometry performed by Fibroscan [
      • Chon Y.E.
      • Choi E.H.
      • Song K.J.
      • et al.
      Performance of transient elastography for the staging of liver fibrosis in patients with chronic hepatitis B: a meta-analysis.
      ]. Etiology of liver cirrhosis was based on the criteria stated in a previous published survey [
      • Stroffolini T.
      • Sagnelli E.
      • Gaeta G.B.
      • et al.
      Characteristics of liver cirrhosis in Italy: evidence for a decreasing role of HCV aetiology.
      ].

      2.3 Serological assays

      Viral hepatitis serum markers (HBsAg and HCV) were determined by commercial immune-enzymatic assays (ELISA) in the laboratories of the eight hospital participating in the survey. The kits used were: HBsAg EIA Abbott for HBsAg detection and Ortho HCV 3.0 ELISA for HCV detection.
      Clinical COVID-19 infection was laboratory-confirmed by a positive result of COVID-19 PCR by nasal swab.

      2.4 Statistical analysis

      Differences in proportions were evaluated by the Chi-squared test. A p value <0.05 was considered to be significant.
      Crude Odds Ratio (OR) and their 95% Confidence Intervals (CI) for the association of outcome variable (vaccination status) with the socio-demographic and clinical characteristics of the subjects, were calculated by univariate analysis. In order to control for the disturbing influence of confounders, the independent predictors of lack of Coronavirus vaccination were identified by multiple logistic regression analysis. In the model, lack of vaccination was the outcome variable; age, area of birth, area of residence, years of schooling, etiology and Child stage were the forced variables. For the Odds ratios estimates, the reference category for each variable was that reporting the higher vaccination coverage rate.
      A further logistic regression analysis was applied only to 3 doses vaccinated people to identify characteristics of subjects independently associated with breakthrough infection. In the model occurrence of breakthrough infection was the outcome variable, while sex, age, etiology and Child stage were the forced variables.

      3. Results

      3.1 Main characteristic of subjects

      A total of 1512 cirrhotic subjects were recruited during the 6-months enrolment period. The male to female ratio was 2.3; mean age was 64.2 years, with most cases (49.7%) being older than 64 years of age. People born abroad were 10.3%. A low rate (9.1%) of subjects were incident cases. The majority were outpatients (80.0%). Nearly three quarter of cases (74.6%) had a viral etiology. Most subjects (83.7%) had compensated cirrhosis (Child A). (Table 1).
      Table 1Baseline characteristics of 1512 subjects with liver cirrhosis. Italy, 2022.
      CharacteristicN.
      For some variables, inconsistencies are due to missing values.
      %
      SexMale105269.6
      Female46030.4
      Sex ratio (M/F)2.3
      AgeMean64.2
      Standard Deviation13.1
      Median64
      Range21–97
      Age distribution≤ 50 years20113.3
      50–64 years55937.0
      ≥ 65 years75049.7
      Area of birthItaly135689.7
      Abroad15510.3
      Area of residenceNorth/Center81053.6
      South/Islands70246.4
      Years of schooling≤8 years70346.7
      > 8 years80352.3
      Type of caseIncident1379.1
      Prevalent137490.9
      Referral patternInpatient30220.0
      Outpatient121080.0
      Etiology
      Several cases had more than 1 etiological factor.
      Viral112974.6
      Alcoholic25316.8
      NAFLD/NASH23515.6
      Other1369.0
      ChildA126483.7
      B19012.6
      C573.8
      low asterisk For some variables, inconsistencies are due to missing values.
      low asterisklow asterisk Several cases had more than 1 etiological factor.

      3.2 Vaccination status

      In Italy, the third dose of mRNA vaccine was available for high-risk subjects since August 2021.
      As many as 1358 (89.8%) subjects reported previous vaccination against COVID-19; 1137 (83.7%) of them received 3 or more doses of vaccine, 221 (16.3%) 2 doses, while none had received only one dose. Almost all (95.7%) had received RNA messenger vaccines. Among the 1358 people vaccinated, 178 (13.1%) had a breakthrough infection; 12 (6.7%) of them were hospitalised, but none died.
      The mean time elapsed since the administration of the latest dose of vaccine and occurrence of breakthrough infection was 122 days (range 102–156). In the 12 subjects requiring hospitalization, the clinical presentation was respiratory distress in 9 cases, and liver decompensation in 3 cases (data not shown). Subjects who had received 2 doses of vaccine more likely reported breakthrough infection and hospitalization than those who had received 3 dose of vaccine (33.9% vs. 9.1%, P<0.001 and 4.6% vs. 0.5%, P<0.001, respectively).
      Refusal of vaccination was reported by 133 (86.4%) of the 154 unvaccinated people; negative advice from the General Practitioner (G.P.s) against vaccination was reported by 10.4% of subjects. (Table 2)
      Table 2Vaccination status against COVID-19 of 1512 subjects with liver cirrhosis. Italy, 2022.
      CharacteristicN.%
      VaccinatedYes135889.8
      No15410.2
      Vaccinated
      None received 1 dose of vaccine.
      < 3 doses22116.3
      ≥ 3 doses113783.7
      Type of vaccineAdeno/vector423.1
      RNA messenger129995.7
      Both171.3
      Infection in vaccinatedYes
      P<0.001.
      17813.1
      No118086.9
      Infection by vaccination dose
      P<0.001.
      With < 3 doses7533.9
      With ≥ 3 doses1039.1
      Hospitalization in vaccinatedYes126.7
      No16693.3
      Hospitalization by vaccinationWith < 3 doses74.6
      Dose
      P<00.1.
      ,/
      None died.
      With ≥ 3 doses50.5
      Reason of vaccinationAdvised by the G.P.27320.1
      (n = 1358)Advised by the specialist70151.6
      Self-reporting38428.3
      Reason of not vaccinationLack of information53.2
      (n = =154)Refusal13386.4
      Advised against by the G.P.1610.4
      low asterisk None received 1 dose of vaccine.
      low asterisklow asterisk P<0.001.
      low asterisklow asterisklow asterisk P<00.1.
      low asterisklow asterisklow asterisklow asterisk None died.
      Prevalence of vaccination coverage was lower in patients younger than 65 years of age (86.1% vs. 93.6%; p <0.001), in those born abroad (80.0% vs. 90.9%; p <0.001), in South Italy and Sicily residents (86.3% vs. 92.8%; p<0.001), in subjects with lower years of schooling (86.6% vs. 92.8%; p<0.001), among those with an alcoholic etiology (84.9% vs. 91.0%; p<0.05), and in patients with Child B/C stages (83.8% vs. 91.0%; p<0.05) (Table 3). Sex was the only significantly different characteristic among the 154 unvaccinated people by area of birth (54.8% in males and 45.2% in females; p<0.05) (Table 4).
      Table 3Prevalence of anti COVID-19 vaccination coverage in 1512 subjects with liver cirrhosis. .Italy, 2022.
      Characteristicp value
      N.vaccinatedN. subjects%Chi-square test
      SexMale944105289.7>0.05
      Female41446090.0
      Age< 65 years65476086.1<0.001
      ≥ 65 years70275093.6
      Area of birthItaly1233135690.9<0.001
      Abroad12415580.0
      Area of residenceNorth/Center75281092.8<0.001
      South/Islands60670286.3
      Years of schooling≤8 years60970386.6<0.001
      > 8 years74580392.8
      Etiology
      143 subjects with mixed etiology were excluded.
      Not alcoholic1126123791.0<0.05
      Alcoholic11213284.9
      ChildA1150126491.0<0.05
      B/C20724783.8
      low asterisk 143 subjects with mixed etiology were excluded.
      Table 4Frequencies (%) of characteristics in 154 not vaccinated subjects by area of birth, Italy 2022.
      CharacteristicItalians (N = 123)Foreigners (N = 31)p value

      Chi-square
      N.%N.%Test
      SexMale9174.01754.8<0.05
      Female3226.01445.2
      Age< 65 years8266.72477.4>0.05
      ≥ 65 years4133.3722.6
      Etiology
      23 subjects with mixed etiology were excluded.
      Not alcoholic8885.42382.1>0.05
      Alcoholic1514.6517.9
      ChildA9274.82271.0>0.05
      B/C3125.2929.0
      Reasons of notRefusal10585.42890.3>0.05
      vaccinationOther1914.639.7
      low asterisk 23 subjects with mixed etiology were excluded.

      3.3 Independent predictors of lack of vaccination

      The crude O.R.s for the association of the characteristics of subjects not undergoing COVID-19 vaccination, evidenced a link with all the variables considered (age, area of birth, area of residence, years of schooling, etiology and Child stage). After adjustment by multiple logistic analysis for the confounding effect of all variables considered, age <65 years (OR = 2.88; CI 95% = 1.91–4.36), being born abroad (OR = 2.31; CI 95% = 1.43–3.75), and lower years of schooling (OR = 1.91; CI 95% = 1.25–2.92) resulted independent predictors of lack of vaccination. Area of residence, etiology and Child stage were no longer associated (Table 5).
      Table 5Crude and adjusted Odds Ratios (O.R.) derived by multiple logistic regression analysis for the association of different variables with lack of anti COVID-19 vaccination in cirrhotics. Italy, 2022.
      FactorCrude O.R.95% CIAdjusted O.R.
      Adjusted for the confounding effect of all listed variables.
      95% CI
      Age≥ 65 years1.001.00
      < 65 years2.371.66 - 3.392.881.91 - 4.36
      Area of birthItaly1.001.00
      Abroad2.511.62 - 3.872.311.43 - 3.75
      Area of residenceNorth/Center1.001.00
      South/Islands2.051.46 - 2.891.330.86 - 2.06
      Years of schooling>8 years1.001.00
      ≤ 8 years1.981.41 - 2.801.911.25 - 2.92
      Etiology
      143 subjects with mixed etiology were excluded.
      Not alcoholic1.001.00
      Alcoholic1.811.08 - 3.031.080.61 - 1.90
      ChildA1.001.00
      B/C1.951.32 - 2.881.590.99 - 2.56
      low asterisk Adjusted for the confounding effect of all listed variables.
      low asterisklow asterisk 143 subjects with mixed etiology were excluded.

      3.4 Independent predictors of breakthrough infection

      The 1137 subjects who had received 3 or more doses of vaccine were compared by occurrence of breakthrough infection. Baseline liver disease stage (i.e. Child class B/C) was the only independent predictor of this outcome (adjusted O.R. 2.30; CI 95% = 1.37–3.86). No association was found with sex, age, and etiology. (Table 6)
      Table 6Frequencies (%) of characteristics of subjects with ≥ 3 doses of COVID vaccine with or without breakthrough infection. Adjusted Odds Ratios (O.R.) derived by multiple logistic regression analysis. Italy, 2022.
      FactorWith Breakthrough (n = 103)Without Breakthrough (n = 1034)Adjusted O.R.
      Adjusted for the confounding effect of all listed variables.
      95% CI
      N.%N.%
      SexFemale2625.231330.31.00
      Male7774.872169.71.250.76 - 2.05
      Age≥ 65 years4644.748246.71.00
      < 65 years5755.355153.30.830.53 - 1.29
      Etiology
      89 subjects with mixed etiology were excluded.
      Not alcoholic8287.288592.81.00
      Alcoholic1212.8697.21.560.80 - 3.07
      ChildA7673.890587.51.00
      B/C2726.212912.52.301.37 - 3.86
      low asterisk Adjusted for the confounding effect of all listed variables.
      low asterisklow asterisk 89 subjects with mixed etiology were excluded.

      4. Discussion

      In Italy, immunization with COVID-19 vaccine was strongly recommended for patients with chronic diseases, including those with cirrhosis, from March 2021. Thereafter, a third and a fourth dose of vaccine were recommended for these subjects since August 2021 and March 2022, respectively. Consequently, subjects enrolled in the study period (January-June 2022) may have received 3 or 4 doses of vaccine.
      This is the first study assessing vaccine coverage against COVID-19 among cirrhotic subjects in a European country. The nearly 90% overall vaccine coverage is strong evidence for a very successful vaccination campaign against COVID-19 infection. Even subjects belonging to groups at lower vaccine coverage reported uptake vaccination rates from 80 to 90%. Of particular interest is the 80% rate among people born abroad, which reflects how regular immigrated have the same chance of access to our health care system as the native people in Italy do.
      The present figures largely exceed those (all from retrospective surveys) of 60% observed in USA [
      • Mahmud N.
      • Chapin S.E.
      • Kaplan D.
      • et al.
      Identifying patients at highest risk of remaining unvaccinated against severe acute respiratory syndrome coronavirus 2 in a large veterans health administration cohort.
      ] among cirrhosis of any stage, and 37.1% in China [
      • Cao Z.
      • Zhang C.
      • Zhao S.
      • et al.
      COVID-19 vaccines in patients with decompensated cirrhosis: a retrospective cohort on safety data and risk factors associated with unvaccinated status.
      ] among decompensated cirrhosis.
      Identification of risk factors associated with unvaccinated status is critical to target interventions and further improve vaccine coverage. As in the U.S. study [
      • Mahmud N.
      • Chapin S.E.
      • Kaplan D.
      • et al.
      Identifying patients at highest risk of remaining unvaccinated against severe acute respiratory syndrome coronavirus 2 in a large veterans health administration cohort.
      ], subjects younger than 65 years of age were nearly 3-fold less likely vaccinated, reflecting an attitude of younger people to underestimate the risk of severe infection and thus defer vaccination. Even subjects with lower years of schooling are at increased risk (adj. O.R. 1.91; CI 95% = 1.25–2.92) of lack of vaccination, probably because of vaccine hesitancy stemming from personal or political beliefs. The finding that 86.4% of cases reported refusal as reason for not undergoing vaccination, further supports the previous consideration. Moreover, subjects with lower educational level may be the most at risk of falling prey to vaccine misinformation. Of notice is the observation that nearly 10% of subjects remained unvaccinated since they were not provided correct medical advice by their G.P.s, who probably did not consider vaccines against COVID-19 effective and safe for cirrhotic subjects. Thus, we suggest that counselling on the risks and benefits of COVID-19 vaccination should be specifically addressed to both cirrhotic patients and G.P.s to correct their attitude against vaccination [
      • Abbasi J.
      COVID-19 conspiracies and beyond: how physicians can deal with patients’ misinformation.
      ]. Correct counselling will also counter the vaccine misinformation provided by some media outlets and online social media [
      • Abbasi J.
      COVID-19 conspiracies and beyond: how physicians can deal with patients’ misinformation.
      ].
      Though breakthrough infections may occur after completion of the primary vaccination cycle, these are associated with a reduced COVID-19 related hospitalization and mortality [
      • John B.V.
      • Deng Y.
      • Scheinberg A.
      • et al.
      Association of BNT162b2 mRNA and mRNA-1273 vaccines with COVID-19 infection and hospitalization among patients with cirrhosis.
      ,
      • John B.V.
      • Deng Y.
      • Schwartz K.B.
      • et al.
      Postvaccination COVID-19 infection is associated with reduced mortality in patients with cirrhosis.
      ]. Our findings further strengthen the favourable effect of vaccination on severe outcomes even in cirrhotic subjects. Indeed, among the 178 subjects with breakthrough infection, only 12 (6.7%) required hospitalization and none died. Moreover, the observed better effectiveness of a third vaccine dose in preventing breakthrough infection and hospitalization, confirms the results of a recent U.S. study [
      • John V.B.
      • Ferreira R.D.
      • Doshi A.
      • et al.
      Third dose of COVID –19 mRNA vaccine appears to overcome vaccine hyporesponsiveness in patients with cirrhosis.
      ]. This latter study supports the importance of a third dose of mRNA vaccine among patients with cirrhosis, suggesting that it can also overcome their vaccine hyperresponsiveness [
      • John V.B.
      • Ferreira R.D.
      • Doshi A.
      • et al.
      Third dose of COVID –19 mRNA vaccine appears to overcome vaccine hyporesponsiveness in patients with cirrhosis.
      ].
      Decompensated cirrhosis (i.e. advanced Child stage) was the only factor independently associated (adj. O.R. 2.30; CI 95% 1.37–3.86) with breakthrough infection, suggesting that liver status is the major determinant to acquire the infection in vaccinated subjects.

      5. Limitations

      We acknowledge some potential limitations to our study. The true proportion of breakthrough infections may be underestimated because asymptomatic infections, which more likely occur in vaccinated people [
      • Aschwanden C.
      Five reasons why COVID herd immunity is probably impossible.
      ], weren't identified. Moreover, subjects vaccinated may be less likely to receive COVID-19 PCR testing in the presence of symptoms, and thus their positive status might go undetected. However, these points may have affected the incidence rate of breakthrough infections, but not that of severe outcomes such as hospitalization and death.

      6. Strength

      The study is characterized by several strong points which are worth underlying. First, the observational study design, with the enrolment of all consecutive patients, generates a more accurate ascertainment than retrospective studies, generally affected by selection and ascertainment biases. Second, the large cohort (1512 cases) enrolled allows an accurate estimate of Odds Ratios for the associations explored. Third, participating centers were scattered all over the country, assuring representativeness to the observed findings. Finally, the enrolment period lasting 6 months corresponds to the interval time recommended by the Italian Association for the Study of Liver (AISF) for surveillance of cirrhotic subjects; consequently, nearly all cirrhotic subjects referring to the participating centres had the chance to be observed.

      7. Conclusions

      Our findings evidence very high vaccine coverage against COVID infection in Italy among patients with liver cirrhosis. Educational campaigns targeting subjects younger than 65 years of age and with lower years of schooling may further improve vaccination coverage. Patients with decompensated cirrhosis are at higher risk of breakthrough infection. Vaccine is effective in protecting against hospitalization and death. Three doses of vaccine are more effective than two in preventing breakthrough infection and hospitalization.

      Conflict of interest

      All authors have no conflict of interests.

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