key: cord-318920-njurbf3d authors: Romana Ponziani, Francesca; Del Zompo, Fabio; Nesci, Antonio; Santopaolo, Francesco; Ianiro, Gianluca; Pompili, Maurizio; Gasbarrini, Antonio title: Liver involvement is not associated with mortality: results from a large cohort of SARS‐CoV‐2 positive patients date: 2020-07-06 journal: Aliment Pharmacol Ther DOI: 10.1111/apt.15996 sha: doc_id: 318920 cord_uid: njurbf3d BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection is frequently associated with liver tests abnormalities. AIMS: To describe the evolution of liver involvement during SARS‐CoV‐2 infection and its effect on clinical course and mortality. METHODS: Data of 515 SARS‐CoV‐2 positive patients were collected at baseline and during follow‐up, last evaluation or death. Stratification based on need for hospitalization, severe disease and admission to intensive care unit (ICU) was performed. The association between liver tests abnormalities (baseline and peak values) and ICU admission or death was also explored. RESULTS: Liver tests abnormalities were found in 161 (31.3%) patients. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) were increased in 20.4%, 19% and 13.6% of patients, respectively. Baseline liver tests abnormalities were associated with increased risk of ICU admission (OR 2.19 [95%CI 1.24‐3.89], p=0.007) but not with mortality (OR 0.84 [95%CI 0.49‐1.41], p=0.51). Conversely, ALP peak values were correlated with the risk of death (OR 1.007 [95%CI 1.002‐1.01], p=0.005) along with age, multiple comorbidities, acute respiratory distress syndrome (ARDS), ICU admission, and C‐reactive protein. Alterations of liver tests worsened within 15 days after hospitalization; however, in patients with the longest median follow‐up, the prevalence of liver tests alterations decreased over time, returning similar to that of baseline. CONCLUSIONS: In SARS‐CoV‐2 positive patients without pre‐existing severe chronic liver disease, baseline liver tests abnormalities are associated with the risk of ICU admission and tend to normalize over time. ALP peak value seems to be predictive of a worse prognosis. On December 31, 2019, Chinese authorities reported a group of pneumonia cases in Wuhan. A zoonotic infection was suspected, and a novel pathogenic human coronavirus (CoV) with a certain homology with respect to severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV was sequenced and identified as SARS-CoV-2. The human-to-human transmission of SARS-CoV-2 was rapid, and due to the increase in the number of cases outside China, the World Health Organization (WHO) defined the infection as a pandemic on March 12, 2020. Italy was the second country to be hit after China, but Spain, Germany, France and other European countries, as well as the United States, are also facing the heavy consequences of this pandemic. During the past SARS outbreak, hepatic impairment was described in up to 60% of patients (1) , and was associated with elevation of serum transaminases, hypoproteinemia and prolongation of prothrombin time. Chinese data on patients with SARS-CoV-2 infection report a prevalence of abnormal liver tests as high as 76.3%, while the prevalence in Western patients seems to be lower [1] [2] [3] [4] . However, these studies report baseline or short-term follow-up evaluations. Therefore, the evolution of liver involvement, its correlation with patients' mortality or resolution of SARS-CoV-2 infection is still unknown. In this paper, we report the experience of a tertiary care center in Italy facing the emergency of the SARS-CoV-2 infection, describing the prevalence and the evolution of liver involvement over time and its impact on patients' clinical course and mortality. All patients aged > 18 years tested positive for SARS-CoV-2 infection at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome from March 6 th to April 16 th , 2020 were included in this retrospective study. Nasopharyngeal swabs for SARS-CoV-2 diagnostic testing were obtained according to the WHO guidelines 5 and analyzed by the Microbiology Laboratory of our Hospital (Real-time PCR, This article is protected by copyright. All rights reserved AllplexTM 2019-nCoV Assay [Seegene] ). To exclude the infection or to confirm its resolution, two negative samples must be obtained at least 48 h apart. According to the Italian Society for Infectious and Tropical Diseases (SIMIT) guidelines 6 , patients were treated with antivirals (lopinavir/ritonavir or darunavir/ritonavir) plus hydroxychloroquine whereas the anti-interleukin 6 (IL-6) agent tocilizumab was used in selected patients. Acute respiratory distress syndrome (ARDS) was defined as the ratio of arterial oxygen partial pressure (PaO2) to fractional inspired oxygen (FiO2) ≤ 100 mmHg 7 . To investigate the prevalence of liver damage in our cohort of patients, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), total bilirubin and albumin were collected at baseline, then on the date closest to 15 days from the admission. At the same timepoints, lactate dehydrogenase (LDH), C-reactive protein (CRP), fibrinogen, D-dimer as inflammatory markers and international normalized ratio (INR), platelets (PLTS), white blood cells (WBC), neutrophils and lymphocytes counts were also recorded. In a subgroup of 53 patients with a longer follow-up (> 1 month), a third data timepoint was recorded at the last available evaluation. Peak values of AST, ALT, GGT, ALP and bilirubin achieved during the hospitalization were recorded. History of liver disease and comorbidities were also assessed. The study was approved by the Institutional Ethics Committee of the Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome (ID number: 3042) and was conducted according to the principles of the Declaration of Helsinki. Patients' characteristics and laboratory examinations were reported as median and interquartile range (continuous variables) or as frequencies and percentages (categorical variables). Baseline serum levels of liver function tests (i.e. AST, ALT, GGT), which were the main object of our study, were also stratified according to 3 cut-offs (>ULN; >ULN but up to 3 x ULN) for a better definition of possible alterations. Missing data for each variable in the database accounted for <5% except for AST (12.1%). Descriptive and inferential statistics were initially carried out on the overall population, then on three different subgroups identified on the basis of a) need for hospitalization b) severity of the This article is protected by copyright. All rights reserved disease c) admission to intensive care unit (ICU The analyses were performed using R statistics program version 3.6.2. During the study period, 515 patients tested positive for SARS-CoV-2 infection were admitted to the Emergency Department of our Hospital and included in the following analysis ( Four-hundred-forty-eight (87%) patients required hospitalization, and, among them, 146 (32.6%) presented with ARDS and 77 (15%) required ICU admission. Overall, liver tests abnormalities were found in 161 (31.3%) patients. Increase in AST, ALT and GGT above ULN was found in 20.4%, 19% and 13.6%, respectively; these alterations were mild/moderate (lower than 3 x ULN), and in only 5% of cases a more severe increase, above 3 x ULN, was observed. Relevant alterations in ALP or bilirubin serum levels were observed in a minority of patients ( Table 1 ). The prevalence of liver tests alteration was higher in patients with ARDS (62 [42.5%]) and in those requiring admission to ICU (41 [53.2%]). AST or ALT elevation was more frequent than GGT elevation, being present in up to 30% of those with ARDS and 35% of those admitted to ICU. Conversely, only 10.4% of the patients who were not hospitalized presented liver involvement ( Table 1 ). The peak values of liver function tests occurred during hospitalization were the following: AST This article is protected by copyright. All rights reserved After a median follow-up of 16 (10-26) days, 77 (15%) of the hospitalized patients died, 410 (79.6%) were discharged and 28 (5.4%) were still hospitalized. Liver tests alterations at baseline were associated with higher risk of ICU admission ], p=0.007; Table 2) but not with death (OR 0.84 [95%CI 0.49-1.41], p=0.51; Table 3 ). As shown in Figure 1 , the cumulative incidence of death or discharge was similar between patients with or without liver tests abnormalities at baseline. Older age, the presence of multiple comorbidities, ICU admission, high CRP and ALP peak values were, instead, associated with an increased risk of mortality in our multivariate regression model (Table 3) . We then analyzed the evolution of liver involvement during hospitalization. Liver tests recorded within 15 (±3) days after admission or at the last evaluation for patients who were discharged or died, showed a worsening trend in all groups (Table 4) This study demonstrates that in patients without severe chronic liver disease liver involvement during SARS-CoV-2 infection is usually mild, is not associated with increased risk of ICU admission or mortality, and tends to resolve over time. We found a 31.3% prevalence of liver tests abnormalities in patients with SARS-CoV-2 infection, which was slightly lower than that reported in previous Western 2,3 or Chinese series 4 . Pure cholestatic alterations characterized by the increase of both ALP and GGT were extremely rare, whereas GGT elevation was present in 13.6% of patients. Noteworthy, all the recorded This article is protected by copyright. All rights reserved alterations were mild, did not require any intervention, except withdrawal of antiviral therapy in a single case. While previous studies mainly addressed liver tests abnormalities at baseline or few days after the admission 2,4 , this is the first analysis to include patients with a longer follow-up and to evaluate liver involvement at more than 1 month after the admission. Our study revealed that liver tests initially increase during hospitalization and then improve over time, finally reaching values similar to baseline or even lower, as shown in Figure 2 by the trend of the proportion of patients with liver tests abnormalities. This was to be expected in a population of patients affected by a viral disease, but the reasons for liver involvement in patients with SARS-COV-2 infection can be multiple. The virus itself may probably exert a direct damage to the liver. Post-mortem liver tissue This article is protected by copyright. All rights reserved whereas a parallel decrease in serum albumin is usually observed. Although in our population the association between liver tests and indirect markers of inflammation was weak, we recently reported a strict correlation with serum levels of IL-6, with the highest increase recorded within 15 days after patients' admission 15 . Probably, IL-6 serum levels are more sensitive indicators of the persistence of the inflammatory response than non-specific inflammatory parameters. In our series, abnormal liver tests were correlated with ICU admission, probably reflecting a more severe evolution of the disease, as previously reported 4 . We also demonstrated that age, multiple comorbid conditions, ARDS, ICU admission and CRP serum levels, but not abnormal baseline liver tests, were associated with the risk of death. Therefore, the presence of other negative prognostic factors is crucial to increase the risk of mortality during SARS-CoV-2 inflammatory syndrome, of which abnormal liver tests are a collateral manifestation. The prognostic significance of ALP peak value should be underscored, as also other studies reported an association between clinical deterioration and increased ALP serum levels, but not with other liver tests 16, 17 . As previously discussed, SARS-CoV-2 cause cholangiocytes injury in experimental models 12 ; ALP peak value could be a marker of virus-related liver injury and, therefore, this event could be associated with an unfavorable prognosis. Although this hypothesis is intriguing, multiorgan failure and drug-induced cholangiocellular damage could also explain the association between ALP peak values and mortality. This study is one of the few large available series exploring the outcome of liver involvement during SARS-CoV-2 infection in Western patients. Although data were collected in a single center, being a guarantee of their homogeneity and of treatment approach, this study suffers of the generic limitations related to the retrospective collection of data. In particular, the prevalence of chronic liver disease was low in our series, but we cannot exclude that some patients (e.g. those with metabolic comorbidities) could be affected by liver disease. However, patients' records were accurately revised, and based on laboratory examinations, radiological findings and clinical data, we can reasonably rule out that patients with pre-existing advanced liver disease were included in the study group. Therefore, our conclusions can only be applied to patients with SARS-CoV-2 infection without severe chronic liver disease or cirrhosis, for whom high morbidity and mortality have been reported 3, 18 . In conclusion, SARS-CoV-2 infection is not associated with clinically-meaningful liver injury in Western patients without advanced chronic liver disease. Baseline liver tests abnormalities can be found in more than 30% of cases, especially in patients with ARDS; these alterations are associated with the risk of ICU admission but not with mortality, and tend to normalize over time. ALP could be a surrogate marker of virus-related liver injury and its peak value seems to be predictive of a worse prognosis. Cai This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis Liver Biochemistries in Hospitalized Patients With COVID-19 Clinical Characteristics and Outcomes of COVID-19 Among Patients with Pre-Existing Liver Disease in United States: A Multi-Center Research Network Study ARDS=acute respiratory distress syndrome; AST=aspartate aminotransferase GGT=gamma glutamyl transferase; ALP=alkaline phosphatase; WBC=white blood cells Laboratory examinations reference range: AST 7-45 IU/L; ALT 7-45 IU/L; GGT 8-61 IU/L; ALP 40-129 IU/L; Bilirubin 0.3-1.2 mg/dL CRP <5 mg/L; Fibrinogen 200-400 mg/dL; D-dimer <500 ng/mL. 656)