key: cord-1055076-3v8zquyb authors: Vaishnav, Manas; Elhence, Anshuman; Biswas, Sagnik; Pathak, Piysuh; Anand, Abhinav; Sheikh, Sabreena; Singh, Vishwajeet; Maitra, Souvik; Goel, Amit; Shalimar title: The Outcome after Hospital Discharge in Cirrhosis is Not Worsened with COVID-19 Infection: A Propensity Score-matched Analysis date: 2021-11-24 journal: J Clin Exp Hepatol DOI: 10.1016/j.jceh.2021.11.009 sha: 0d175e916c37321ad189112a8c716467d595566b doc_id: 1055076 cord_uid: 3v8zquyb BACKGROUND: Patients with cirrhosis and coronavirus disease-2019 (COVID-19) have high in-hospital mortality. The information on outcome of cirrhosis patients in post-hospitalization period are limited. AIMS: We aimed to study the outcome of cirrhosis patients with COVID-19 after hospital discharge. METHODS: The records of the cirrhosis patients discharged after COVID-19 were reviewed. Their data were compared with a similar number of cirrhosis patients without COVID-19 after propensity score matching for age, sex, etiology of cirrhosis, and model for end-stage liver disease (MELD) score. RESULTS: Cirrhosis patients with (n=92) or without (n=92) COVID-19 were included in 1:1 ratio. The mortality among COVID-19 (22; 23.9%) and non-COVID-19 (19; 20.7%) were comparable (HR 1.224; 95% CI 0.663-2.263, P=0.520), over a similar duration of follow-up [186 (86-271) vs 183 (103-274)]. Among COVID-19 patients, 45; 48.9% developed a new acute decompensation-increased ascites (40; 43.5%), hepatic encephalopathy (20; 21.7%), or variceal bleeding (8; 8.7%) whereas 25 (27.2%) patients needed re-hospitalization. A proportion of participants continued to have either fatigue/weakness (24/80; 30.0%), sleep disturbances (11/80; 13.7%), or joint pains (16/80; 20.0%). The most common causes of death in patients of both groups were end-stage liver disease: 16 (72.7%) vs 9 (47.4%), followed by multiorgan dysfunction: 4 (18.2%) vs 6 (31.6%), GI bleeding: 2 (9.1%) vs. 4 (21.0%), P=0.484. A lower albumin level, higher international normalized ratio, bilirubin, Child-Turcotte-Pugh, and MELD scores at discharge predicted mortality in the COVID-19 group. CONCLUSION: Short-term outcomes of patients with cirrhosis who survive the initial insult of COVID-19 are not different from patients without COVID-19, and survival is determined by the severity of liver disease at discharge. The Coronavirus disease-2019 (COVID-19) has high mortality rates among those with risk factors such as old age, diabetes mellitus, renal failure, obesity, and chronic liver disease. [1] [2] [3] Waning pandemic has surfaced the problem of its consequences such as multiorgan inflammatory syndrome and long COVID syndrome. [4] [5] [6] [7] Now, COVID-19 is accepted as a multisystem disease with long-lasting consequences and not just an acute respiratory illness. 8 Over 50% of those discharged after COVID-19 have troublesome symptoms related to various organ systems such as fatigue, loss of taste and/or smell, or a plethora of neuropsychiatric, pulmonary, and cardiovascular symptoms. 5, 9, 10 The risk of developing post-COVID-19 symptoms is higher in old age. 11 The exact pathogenesis of these symptoms is not clear. The post-COVID syndrome may result from ongoing organ damage secondary to prolonged subclinical inflammation, continued viral-mediated organ damage, immune complex-mediated injury or induction of autoimmunity by antigen mimicry. 7, 11 Liver injury is common during active COVID-19 disease. Liver enzyme elevations are seen in up to 50-60% of patients. 12 This high rate of liver injury can be explained by the high expression of ACE2 receptors on cholangiocytes, sinusoidal endothelial cells, and hepatocytes. 13 There is a possibility of prolonged injury to hepatocytes or cholangiocytes, resulting in significant damage to the liver. Cirrhosis patients have limited residual hepatocytes, and any additional injury could lead to decompensation and death after discharge from the hospital. At present, the data are J o u r n a l P r e -p r o o f We retrospectively reviewed the records of the cirrhosis patients admitted between January 2018 and April 2021 to select the cases and controls. Cirrhosis patients discharged after recovery from COVID-19 were selected as cases. Controls were selected from those who were admitted with cirrhosis-related complications without COVID-19. RT-PCR testing was available only for the controls admitted after the onset of the COVID-19 pandemic. The cases and controls were subjected to propensity score matching. Diagnosis of cirrhosis was made with a combination of clinical features, laboratory parameters, radiological and endoscopic evaluation. The diagnosis of COVID-19 was made with symptoms compatible with coronavirus infection supported with positive RT-PCR results in samples collected from nasal and/or throat swabs. The clinical severity of COVID-19 was defined according to the Ministry of Health and Family Welfare (MOHFW) criteria: mild disease as patients with only upper respiratory tract symptoms without any signs of breathlessness and hypoxia. Moderate severity was defined as the presence of pneumonia with the respiratory rate (RR) between 24 and 30/min and SpO2 between 90% and 94% on room air, while the severe disease was defined by the presence of pneumonia with RR > 30/min or SpO2 < 90% on room air or severe respiratory distress. 14 J o u r n a l P r e -p r o o f The relevant clinical, laboratory, radiological and endoscopic data information was retrieved to assess the liver disease severity. The liver disease severity was assessed with Child-Turcotte-Pugh (CTP) 15 and MELD 16 scores. All parameters available at hospital discharge were considered as baseline parameters for those with and without COVID-19 infection. The CTP and MELD score at discharge was recorded as the baseline value to assess the outcomes. The follow-up data were retrieved for all the participants to assess the outcomes. Data were collected with either video call or physical visit to the hospital, with preference to the latter. The collected data included the appearance of new symptoms of decompensation, worsening of preexisting decompensation. Patients were asked about any post-COVID complications like persistent fatigue/weakness, anosmia/dysgeusia, dyspnea, joint pains, difficulty in sleeping, cough, and headache. If the patient had died after discharge, verbal autopsy was done after discussion with the closest possible attendant who was with the patient during the last seven days before his/her death. Ethical clearance with a waiver of consent was obtained from the Institutional Ethics Committee. Propensity score matching (PSM) was used for matching the groups. The propensity scores were based on the potential confounding variables, including age, sex, etiology of cirrhosis, and MELD score at the time of discharge. The patients were matched 1:1 from both the groups based on the propensity scores with a caliper width of 0.20 SD. PSM was also performed using Kernel Qualitative data were expressed as number and percentage, and quantitative variables were expressed as median (interquartile range, IQR). Qualitative data were compared using the Chisquare test or Fisher's Exact test as appropriate, while quantitative data were compared between two groups with the Mann-Whitney U test. Univariable and multivariable analysis was done for assessing independent predictors of the outcome using the Cox-regression method. Survival Overall, patients with cirrhosis and COVID-19 (n=92) as compared to those without COVID-19 (n=226) had higher age and hemoglobin. The platelet count, serum creatinine, alkaline phosphatase, and MELD score were lower in the COVID-19 patients ( Table 1 ). The rest of the variables between the 2 groups were similar. The mortality in the two groups was similar, 23.9% vs. 25.7% (P=0.778). Post-matching balance assessment is represented using covariate balance plots ( Figure 2 ). The standardized percentage differences in covariates were nearly eliminated by propensity matching. The differences in platelet count, serum creatinine, and alkaline phosphatase persisted after matching the groups (Table 1) . Overall, among patients with COVID-19, the COVID severity was graded as mild in 76 (82.6%), moderate 9 (9.8%), and severe 7 (7.6%). The liver disease severity was as follows-CTP-A 27 ( In the pre-matched group, independent predictors of mortality on unadjusted Cox-proportional hazard analysis included international normalized ratio, HR, 1.191 The HR for mortality with COVID-19 infection compared to those without COVID-19 was 1.224 (0.663-2.263), P=0.520 (Table 3) . On multivariate analysis adjusting for age, sex, etiology, and MELD score/CTP score, the presence of COVID-19 infection was not associated with mortality in both the whole cohort and PSM cohort. In the COVID-19 group, 22 died during follow-up. On univariate analysis, the only significant predictors of mortality included CTP score/CTP class and individual components of Child score, namely INR, bilirubin, and albumin. MELD score also independently predicted outcome (Table 3 ). Multivariate analysis was not done as the significant factors included MELD/CTP and their components. For predicting mortality, the area under the receiver operating characteristic curve (AUROC) of MELD and CTP score was 0.708 (0.597-0.820) and 0.714 (0.594-0.834), respectively. On follow-up, the mortality was higher in patients with Child C: 38.5% (10/26) than those with The patients we could not contact for follow-up had a higher MELD score (statistically not significant), and a significantly larger proportion of them had alcohol as the etiology of cirrhosis compared to patients we could contact. Other clinical and laboratory variables were comparable between the two groups ( Table 4 ). The CTP score scores and COVID-19 disease severity were comparable between the two groups. This study aimed to assess the outcomes of cirrhosis patients with COVID-19 after discharge from the hospital. In order to reduce the effect of various confounding variables which could influence the outcome in cirrhosis patients, we used propensity score matching. Study groups were matched for age, gender, etiology, and MELD score. These factors are known to influence outcomes in patients with cirrhosis and COVID-19. 3, 17 Our results suggest that post-hospital discharge, survival of cirrhosis patients with COVID-19 is similar to those without COVID-19. There were no differences in the survival across Child classes among patients with and without COVID-19. Post-COVID-19 recovery was associated with significant morbidity. Almost half of the patients developed new acute decompensation, and one-fourth required hospital admission. The most common new acute decompensation was ascites, followed by HE and GI bleeding. The risk of acute decompensation development on follow-up in patients with cirrhosis and SARS-CoV2 infection was similar to that reported for patients with cirrhosis without SARS-CoV2 J o u r n a l P r e -p r o o f infection. 18, 19 In contrast, an episode of bacterial infection independent of the MELD score alters patients' natural history and reduces survival. 20 The outcomes of cirrhosis patients are also affected by the underlying etiology of liver disease. 21 Projections suggest that the COVID-19 pandemic will be responsible for increased mortality in cirrhosis patients, both directly and indirectly, due to care delivery issues. 22, 23 A study from China reported persistence of abnormal liver enzymes up to 2 months after infection and association with worse recovery of COVID-19 patients. 24 Our results suggest that persistent fatigue/weakness, difficulty sleeping, joint pains, and dyspnea are prevalent post-recovery in patients with cirrhosis and COVID-19 infection. These findings are consistent with those reported in the literature. [25] [26] [27] We did not compare these symptoms in patients and controls, as the recall for such symptoms may be fallacious. We may have overestimated the prevalence of these symptoms as these were leading questions to patients. Nevertheless, it is important to note that post-recovery cirrhosis patients have sequelae that need to be addressed. In addition, other symptoms/signs reported in COVID-19 patients on follow-up include cardiac arrhythmias, myocarditis, pulmonary fibrosis, seizures, encephalitis, mood swings, brain fog, chronic fatigue syndrome, depression, anxiety, post-traumatic stress disorder, and substance abuse. 9,10,28, 29 We could not contact almost 20% of our patients who were discharged from the hospital. Unfortunately, we could not trace these patients despite multiple attempts. These patients had higher MELD scores, which is an important determinant of outcomes in patients with cirrhosis. [30] [31] [32] It is, therefore, possible that the overall mortality in this sub-group would have J o u r n a l P r e -p r o o f been higher than 25%. Nonetheless, our analysis suggests a similar short-term outcome in COVID-19 and those without COVID-19 patients with similar MELD scores. Our results indicate that the MELD and Child scores and their components independently predict the outcome after discharge from the hospital. We are aware of the following limitations of our study. First, many patients with high MELD scores were not contactable at the last follow-up, possibly because a large population migration occurred at the time of lockdown. We did not assess for the quality of life and symptoms such as depression and anxiety. We could not correlate the outcomes with markers of disease severity such as IL-6, ferritin, CRP due to the non-availability of these investigations. Post-discharge from the hospital, MELD and CTP scores were unavailable as many patients could not get a repeat blood investigation. The indications of hospital admission for the controls may have been different from the COVID-19 patients, where respiratory causes may have been more common (20% of patients had moderate or severe COVID-19). The causes of death were ascertained by verbal autopsy, which has its limitations. In conclusion, the short-term outcome of patients with cirrhosis who survive the initial insult of COVID-19 is not different from patients without COVID-19, and survival is determined by the severity of liver disease at discharge. Figure 4A . The mortality was higher in Child C than in Child A and B (log-rank test, P<0.001). Figure 4B . The mortality among mild, moderate, and severe COVID-19 at admission was similar (log-rank test, P=0.619). Figure 4C . The mortality was higher in patients with MELD scores ≥15 than <15 (log-rank test, P=0.005). Note: Qualitative and quantitative data are expressed as proportions and median (interquartile range), respectively. Abbreviations: AIH, autoimmune hepatitis; HBV, hepatitis B virus; HCV, hepatitis C virus; NAFLD, non-alcoholic fatty liver disease; TLC, total leukocyte count; INR, international normalized ratio; ALT, alanine aminotransferase; Alk P, alkaline phosphatase; AST, aspartate aminotransferase; CTP, Child-Turcotte-Pugh; MELD, model for end-stage liver disease. Qualitative and quantitative data are expressed as proportions and median (interquartile range), respectively. Factors associated with COVID-19-related death using OpenSAFELY Poor outcomes in patients with cirrhosis and Corona Virus Disease-19 Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: An international registry study Sick-Samuels AC. 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