COVID-19 and chronic liver disease: results from the 1219 patients French registry

doi:10.21203/rs.3.rs-4800973/v1

The negative impact of Coronavirus SARS CoV-2 related Disease (COVID-19) in patients with chronic liver disease (CLD) has been described in several cohorts. We report here the results from the largest French cohort in “real-life”. The primary outcome was 30-days mortality.

Patients with CLD regardless of etiology, who developed COVID-19 confirmed by a positive PCR and/or an evocative chest CT scan were included. The prognostic influence of clinical and biological features was assessed and multivariate analyses were made.

Between 08/05/2020 and 31/12/2021, 1219 patients were included, mostly men (62%), median age 61 years, with advanced liver fibrosis in 46%, alcohol-related in 21% of the cases, complicated by liver failure (CHILD-PUGH B/C) in 170 of patients with cirrhosis (40%). Moreover 366 patients (30%) were immunocompromised, including 271 organ transplant recipients.

Hospitalization in intensive care unit was required in 11% of the patients and 159 patients (13%) died, 70% of them from extra-hepatic causes.

Overall, the independent risk factors for death were age > 61 years, diabetes, advanced liver fibrosis, and alcoholic etiology of the liver disease. Immunosuppression was not a prognostic factor in multivariate analysis.

The results of this cohort confirm a significant vulnerability of COVID-19 patients with CLD. On the other hand, they confirm the absence of excess mortality related to immunosuppression, particularly in liver transplant recipients.

Health sciences/Gastroenterology/Hepatology

Health sciences/Biomarkers/Predictive markers

Health sciences/Risk factors

cirrhosis

chronic liver disease

COVID-19

SARS-Cov2

immunosuppression

transplantation

The coronavirus disease 2019 (COVID-19) pandemic that has evolved since the end of 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been responsible for more than 6.9 million deaths worldwide, including 163000 in France as of June 2023. Chronic liver diseases (CLD) in the broadest sense include pathologies of widely varying severity, but cirrhosis is implicated in 1.32 million annual deaths worldwide (1). Several international cohorts have demonstrated the negative impact of CLD on COVID-19 prognosis (2, 3, 5, 6). In addition, a large French retrospective study based on the Hospital Discharge database (Programme de Médicalisation des Systèmes d’Information) emphasized that therapeutic effort limitation may have contributed to COVID-19-related death in French residents with a liver-related complication or an alcohol use disorder (6). A large study also showed an increase in liver-related mortality during the COVID-19 period in the United States (7). In addition, liver test abnormalities during SARS-CoV-2 infection are very common (20–65% depending on the study) and are associated with more severe SARS-CoV-2 infection (8, 9). The systemic inflammatory response induced by the virus would also be deregulated because of the immune dysfunction secondary to cirrhosis (5). The impact of COVID-19 on liver transplant recipients has been assessed and no over-mortality was showed (10–11).

Metabolic syndrome and excessive alcohol consumption are compounding factors associated to COVID-19 mortality (12, 13).

In this context, the French Liver Society (Association Française pour l'Etude du Foie-AFEF) has set up a national multicentric registry of patients followed for chronic liver disease infected by SARS-CoV-2 in order to describe the characteristics of their underlying liver pathologies and their evolution after infection by SARS-CoV-2 and to identify possible risk factors of death, focusing particularly on the roles of fibrosis and immunosuppression.

Data source

The COVID19-FOIE National Observatory is a French multicenter registry. The registry has been approved and validated by ethics committee (Comité d'Evaluation de l'Ethique des projets de Recherche Biomédicale (CEERB IRB 00006477), in accordance with reference method MR-004 of the Commission Nationale de l'Informatique et des Libertés.

This study was registered in the ClinicalTrials.gov database (NCT 04375670). As this was a noninterventional study, patients were informed and a note and nonobjection was distributed to each patient included, without the need for written consent. We confirm that all methods were carried out in accordance with relevant guidelines and regulations.

The inclusion criteria were as follows: i) age older than 18 years; ii) previous chronic liver disease of any cause and severity previously diagnosed and followed by one of the hepatologists involved in the study; iii) infection with SARS-CoV-2 diagnosed accordingly to current recommendations by a positive nasopharyngeal swab PCR test and/or chest CT scan suggestive of COVID-19 whether the patient was symptomatic or not. Patients without chronic liver disease who had abnormal liver function tests or cytolytic hepatitis in the setting of SARS-CoV-2 infection were not included in the registry.

Organ transplant patients were included prospectively in the registry from October 2020 and retrospectively using the liver transplant database from the French Transplant Society (SFT), which identified cases during the first wave of the epidemic (April 2020-September 2020). Inclusion criteria for the SFT transplant database were i) symptomatic patients over 18 years of age; ii) history of solid organ transplantation (liver, kidney, heart or bi-organ); iii) infection with SARS-CoV-2 diagnosed by PCR and typical imaging. The etiologies of pretransplant hepatopathy were not detailed. Immunosuppression was defined as a history of organ transplantation, immunosuppressive treatment, HIV infection regardless of CD4 count, hematologic malignancy or extrahepatic solid cancer that was under treatment.

A dedicated e-CRF created by AFEF in May 2020 on the CleanWeb platform entitled "COVID and Liver" was accessible to all investigators (physicians or clinical research associates from hospitals, university hospitals, clinics) who requested an access code from the clinical research unit of Saint Louis Fernand Vidal Lariboisière. The medical information systems program was used in some centers to optimize the inclusion of hospitalized patients by cross-referencing the "COVID-19" code with different diagnostic codes for liver diseases from the International Classification of Diseases version 10 (ICD-10). Patients were included ambispectively (retrospective and prospective) between 05/08/2020 and 12/31/21, and the data were regularly updated.

Baseline variables recorded prior to SARS CoV-2 infection included demographic, clinical, and laboratory characteristics on etiology and severity of underlying liver disease.

Advanced liver fibrosis was assessed by the hepatologist of each patient based on either i) clinical, biological and morphological stigmate of cirrhosis; or ii) noninvasive tests results (Livers stiffness measure and/ or specialized biological tests); or iii) liver biopsy.

In addition, we collected clinical and biological variables at the time of SARS-CoV-2 infection diagnosis and during follow-up.

The date of the last visit was recorded, as were the date and cause of death.

All the variables collected are summarized in Supplementary Table 1, but a number of data could not be interpreted, as a result of missing data.

Statistical Analyses

Categorical variables are presented as the number (%) of patients with the characteristic of interest, while continuous data are reported as mean +/- standard deviation or the median with interquartile range (IQR), as appropriate. The Mann‒Whitney U test was run to compare nonnormally distributed continuous variables between two groups. Group comparisons of categorical variables were made using Pearson’s chi-squared test or Fisher’s exact test. The primary outcome was short-term (30-days) mortality. To study possible associations between selected variables (age, sex, body mass index, mild fibrosis, Child-Pugh, significant cardiovascular history, liver cirrhosis, and diabetes mellitus) and 30-days mortality, we built univariate and different stepwise multiple logistic regression models. The results are expressed as the odds ratio (OR) with its 95% confidence interval (CI). Time to event was analyzed by Kaplan–Meier survival curves and compared by the log-rank test. All analyses were done with a 5%, two-sided risk level in SAS software version 9.4.

Population Description

Between 05/08/2020 and 12/31/2021, 1219 adults were included from 30 different hospitals (24 university, 5 general public, 1 private). The geographical distribution of the participating centers is shown in Fig. 1. Seventy-nine percent of the patients were included from 10 centers, 9 of which were university hospitals (Fig. 1). Among the 1219 enrolled patients, 1132 (93%) were input directly into the registry, and 87 were included from the SFT transplant database. The main baseline characteristics of patients prior to SARS-CoV-2 infection are described in Table 1. Sixty-two percent of patients (n = 754) were male, with a median age of 61 years and frequent comorbidities (diabetes in 313 patients (26%), cardiovascular history in 248 patients (20%), obesity in 257 patients (21%), and dialysis renal failure in 26 patients (2%)).

Table 1

Baseline patients’ characteristics prior to SARS Cov-2 infection.
	Missing data (n)	Population n = 1219
Male (%)	26	754 (61.9%)
Age (years; median, Q1-Q3)	12	61.0 (49.0–69.0)
Tobacco use (active, n %)	308	127 (10,4%)
Alcohol use (active, %)
Comorbidities (%)
Immunosuppression*	172	366 (30.0%)
Organ transplant	172	271 (22.2%)
Diabetes mellitus	178	313 (25.7%)
Cardiovascular events (HBP¹/stroke/ coronaropathy)	182	248 (20.3%)
BMI² > 30 kg / m2 (%)	246	257 (21.1%)
Chronic respiratory failure	182	60 (4.9%)
Dialysis renal failure	268	26 (2.1%)
Liver fibrosis (%)	0
F0 / F1 / F2 (%)		557 (53.9%)
F3 / F4 (%)		477 (46.1%)
Child Pugh (patients with cirrhosis)	4	421
Grade A (%)		251 (59.1%)
Grade B (%)		125 (29.4%)
Grade C (%)		45 (10.6%)
Etiologies (%)
Alcohol		169 (13,9%)
Viruses		199 (16.3%)
NASH		160 (13,1%)
Combined (alcohol, NASH, viruses)		165 (13.5%)
Others (of which healthy liver and liver graft)		526 (43.2%)
Primary Liver tumors (%)
HCC³ (active / cured)	261	184 (15.1%)
Cholangiocarcinoma (active / cured)	265	13 (1.1%)
¹HBP: High Blood Pressure, ²BMI: Body Mass Index, ³ HCC: Hepatocellular carcinoma
*Immunosuppression: immunosuppressive treatments, malignant hemopathy, organ transplant recipients, HIV

Description of underlying liver disease

In our population, 557 patients (54%) had no to mild fibrosis (F0, F1, F2), and 477 (46%) had advanced liver fibrosis (including 52 patients F3). The degree of fibrosis was assessed by non-invasive tests in 861 patients (71%) and histology in 312 patients (26%).

Among the 425 patients with cirrhosis (35%), 251 were Child‒Pugh A (59%), 125 Child‒Pugh B (29%), and 45 Child‒Pugh C (11%). The median MELD score was 9 (IQR 5–15).

The reported etiologies of liver disease were viral infection (active or cured HCV and active or inactive HBV) in 199 patients (16%), nonalcoholic steatohepatitis (NASH) in 160 patients (13%), and/or past or current excessive alcohol consumption (OH) in 169 patients (14%). The majority of etiologies were mixed (association NASH ± OH ± virus) (14%) or other (liver transplantation, autoimmune chronic hepatitis, biliary disease, hemochromatosis, porto-sinusoidal liver disease) (43%). In the year preceding infection, 37 patients had digestive bleeding.

A primary malignant liver tumor (current or past) was recorded in 197 patients (16.2%), mostly hepatocellular carcinoma (HCC) (n = 184), among them 115 patients with active HCC and 69 “cured” HCC and more rarely cholangiocarcinoma (n = 13), among them 10 patients with active cholangiocarcinoma and 3 patients in long term remission.

Description of the immunosuppressed patients

Thirty percent of the 1219 enrolled patients (n = 366) were immunocompromised, including 271 (22%) organ transplant recipients (among them 258 liver transplants), 60 patients with treated autoimmune hepatitis, 10 patients with HIV infection, and 11 patients with treated hematologic malignancies.

Description of COVID-19 cases

SARS-CoV-2 infection was diagnosed by positive PCR in 80% of cases (976 patients) and/or was associated with a suggestive chest CT scan in 28% of cases. Patients were symptomatic in 63% of cases. The diagnosis was incidental in the context of systematic screening before the medical procedure or visit in 32% of cases (Table 2).

Table 2

COVID diagnosis criteria, management and liver complications.
Table 2	Pourcentages
Symptoms	772 (63.3%)
Cough / expectorations	388 (31.8%)
Fever / chills	505 (41.3%)
Dyspnea / chest pain	313 (25.7%)
Systematic screening before treatment / contact	391 (32.1%)
Diagnostic methods
Nasal swabbing : PCR / positive	976 (80.1%)
Thoracic CT-scan in favor — n (%)	340 (27.9%)
Serology (n/ positive)	79 (6.4%)
Hospitalization	514 (42.1%)
Intensive care unit	128 (10.5%)
Medecine unit	355 (29.1%)
Occurrence of hepatic complication
Acute hepatitis (ALAT or PAL > 10ULN)	36 (2.9%)
Liver failure (TP < 70%)	64 (5.3%)
Ascitis	75 (6.2%)
Encephalopathy	73 (6%)
Death	159 (13%)
Liver-related cause	48 (30.2%)
Non-liver-related cause	111 (69.8%)

Among the 425 cirrhotic patients, edematous decompensation was reported in 75 patients (18%) and encephalopathy was reported in 73 patients (17%). Within the limits of the eCRF information, immunosuppressive therapy would have been modified or stopped in 60 patients (16% of the immunosuppressed).

At the time of diagnosis of SARS-CoV-2 infection, acute cytolytic hepatitis (liver enzymes > 10 times the upper limit of normal (ULN)) was recorded in 36 patients.

Outcome and short-term mortality?

The median follow-up time was 65 days (IQR 21–154 days).

A total of 514 patients were hospitalized (42%), including 128 in intensive care (11%); among them, 54 patients were cirrhotic (45%).

The majority of patients remained at home or returned home (83%), 51 patients were still hospitalized at the time of inclusion (4%) and finally 159 patients died (13%), and 119 patients were dead at 30 days. Most of the patients died (111 patients, 70%) from non-liver-related causes and less often (48 patients, 30%) from hepatic causes. The median time from inclusion in the observatory to death was 15 days (IQR 6–31 days).

Prognostic factors for short-term mortality

In univariate analysis, the factors associated with 30-days mortality were male gender (p = 0.049), age (p < 0.0001), advanced liver fibrosis (p < 0.0001), type 2 diabetes (p = 0,006), chronic respiratory failure (p = 0.03), alcohol-related etiology (alone or mixed) (p < 0.0001), Child-Pugh score B/C (p < 0,0001) (Table 3).

Table 3

Univariate analysis for 30-days mortality.
Table 3	p
Male gender	0.0049
Age (years; median, IQR)	< 0.0001
Obesity (BMI¹ > 30 kg / m2)	0.085
Fibrose hépatique	< 0.0001
F 0 / F1 - F2
F3 / F4
Initial ChildPugh grade – cirrhotic patients F4	< 0.0001
A Grade
B /C Grade
Comorbidities
Dialysis renal failure	0.342
Cardiovascular events	0.197
Diabetes mellitus	0.0064
Immunosuppression*	0.138
Organ transplant	0.205
Chronic respiratory failure	0.033
Extra-hepatic solid tumors	0.394
Etiology
Alcohol (pure or combined)	< 0.0001
Other etiologies
Primary liver tumors
HCC² Active/ cured	0.241
Cholangiocarcinoma Active/ cured	0.259
¹BMI: Body Mass Index, ²HCC: Hepatocellular carcinoma
*Immunosuppression: immunosuppressive treatments, malignant hemopathy, organ transplant recipients, HIV

To illustrate the prognostic impacts of liver fibrosis and hepatic failure, Fig. 2 presents the overall survival according to liver fibrosis in the entire population, and Fig. 3 presents the overall survival according to Child‒Pugh score in the subgroup of patients with cirrhosis.

Immunocompromised status was not associated with a significant risk of short-term mortality (p = 0.138) in univariate analysis, or hospitalization (p = 0.64) compared to immunocompetent status. These results were similar in the whole immunocompromised group and in the transplanted patients’ group (p = 0,205) (Table 3).

In multivariate analysis, 3 populations were analyzed (Tables 4a, b and c): i) overall population (n = 1219), ii) cirrhotic patients (n = 425) and iii) compensated patients (n = 1049) defined as (fibrosis F0 to F3 and F4 with Child Pugh Score A, excluding decompensated patients with Child-Pugh score B/C). In the overall population of 1219 patients, the 3 independent prognostic factors of mortality were advanced fibrosis F3/F4, alcohol-related etiology and age. Among the cirrhotic patients’ group of 425 patients, the 3 independent prognostic factors identified were Child‒Pugh score B/C, male sex and age.

Table 4

a-
Risk Factors	p	OR	95% CI
Age	< 0.0001	1.046	1.024	1.068
Fibrosis F3-4 vs F0-1-2	0.0027	2.688	1.41	5.127
Others vs alcohol-related liver disease (alone or combined)	< 0.003	0.383	0.228	0.644

Table 4

b-
Risk factors	p	OR	95% CI
Age	0.0018	1.043	1.020	1.066
Child-Pugh B/C vs A	< 0.0001	4.691	2.795	7.872
Male vs Female sex	0.0388	1. 979	1.036	3.782

Lastly, among the compensated patients’ group of 1049 patients with compensated liver disease, the only independent prognostic factor identified were age.

This registry is the only French multicenter “real life” cohort, mainly prospective, and the largest one, describing 1219 SARS-CoV-2-infected patients with underlying chronic liver disease. Indeed, other international registries have been reported, the largest of which, reported by Marjot et al., included 745 patients followed for chronic liver disease but excluded liver transplant patients (3). Other concordant results come from public health databases (6, 14, 15, 16, 17) including a French retrospective study (6) based on Hospital Discharge database without detailed clinical characteristics of the patients.

The primary outcome confirms the major prognostic impact of advanced liver fibrosis on COVID-19-related short-term mortality. In particular, the results confirm the excess risk of death induced by the presence of cirrhosis, a fortiori by liver failure (assessed by the Child‒Pugh score B or C). Thus, advanced fibrosis was the main independent prognostic factor in this observational study, with an odds ratio of 2.688, regardless of the Child‒Pugh score. Age was also a hazardous factor in the entire population and the subgroups studied.

These results confirm previous data from other registries and cohorts that also showed an excess mortality of patients with cirrhosis of approximately 30% (3, 14, 15). In the French national hospital discharge database report by Mallet et al. (6), it seemed that the reduced access to intensive care and mechanical ventilation might have resulted in the excess mortality of patients with cirrhosis.

Nevertheless, according to Brozat et al. (14), the excess mortality of cirrhotic patients could be explained in part by the frequent comorbidities in these patients (diabetes, obesity, hypertension, chronic renal failure, etc.). On the other hand, a Swedish study of a population of patients with chronic liver disease showed that the presence of chronic liver disease was associated with an increased risk of hospitalization for COVID-19, but COVID-19-related mortality was not increased (16).

This result was a key argument behind our French liver society convincing the national health authorities to prioritize vaccination of patients with compensated cirrhosis in March 2021 before vaccination became universal.

The other major finding of the study was the absence of excess mortality risk in the subpopulation of immunocompromised patients, particularly in the subgroup of liver transplant patients, which represented 22% of the overall population, probably because, after transplant, the recipient has a normal and functional liver. This study is the largest cohort of liver transplant recipients with COVID-19 and confirms the results of several studies on liver transplant patients (10, 11, 18), in contrast to the results on kidney transplant patients, which have been associated with an increase in mortality related to COVID-19, probably because of their numerous associated comorbidities (chronic kidney failure, cardiovascular, type 2 diabetes, arterial hypertension, advanced age) and their high level of immunosuppression. There was no excess mortality in patients followed for autoimmune hepatitis, confirming the data of Marjot et al. (19).

Regarding the etiology of chronic liver disease, we found alcohol to be a factor associated with excess mortality in multivariate analysis, as did the registry studies of Marjot et al. and the French database from Mallet et al. (3, 6).

Other studies have shown that the prevalence of MAFLD (metabolism-associated fatty liver disease) ranges from 28 to 37% of patients infected with SARS-CoV-2 (14). MAFLD was associated with greater severity of COVID-19 (20), particularly in the subgroup of patients under 65 years of age in the meta-analysis by Wang et al. (13), and with increased mortality in these patients, with an OR of 2.93 (95% CI 1.87–4.6) (21), though there were no details on the degree of liver fibrosis.

The presence of a primary liver tumor was a collected data, but was not associated with mortality in our study. Some studies have investigated the impact of COVID-19 on the management and prognosis of HCC, one large international study showing a change in management (screening, diagnosis or treatment) in 80% of cases (22). In a French study of 670 patients (in two periods, 2019 vs. 2020), the number of new HCCs presented to the multidisciplinary consultation meeting was lower during the COVID-19 period, and the time to treatment was extended by one month in 20% of patients (23). More generally, the number of patients newly treated for digestive cancer, especially for HCC, fell drastically during the lockdown period (-42%) in a large population of patients over 65 years of age (24).

Our study has several limitations. The registry is not exhaustive in part because the inclusions were nonconsecutive and made by voluntary investigators, thus leading to a selection bias. Moreover, the observational was partially retrospective and was of a declarative nature, resulting in a large number of missing data, particularly biological data, which must be taken into account in interpreting the results.

Thus, although data from several large studies, including a meta-analysis of 64 studies involving more than 11,000 patients, showed that abnormalities on liver tests, mainly cytolysis, were frequent (> 20% of infected patients) (9) and were associated with excess mortality in hospitalized infected patients (8), in our study the biochemical data and the prognostic effect of disturbances of liver homeostasis were not interpretable.

Moreover, fibrosis was not assessed by the same methods in patients and only 26% of patients had liver biopsy as a reflect of nowadays clinical practice.

We did not collect information regarding the occurrence of post-COVID-19 cholangitis in the follow-up of patients, as there were too many missing biological data. This complication of chronic post-COVID-19 cholangitis has been regularly reported in the literature (25, 26, 27). The pathophysiology could be multifactorial, combining at least a direct viral toxicity, ischemic cholangitis similar to resuscitation cholangiopathies and a drug toxicity, in particular from ketamine.

Finally, as the observation was initiated before the start of universal vaccination programs against SARS-CoV-2, information on the vaccination status of the patients was not available. In addition, given the inclusion period, a minority of patients had an optimal vaccination schedule as currently recommended.

In this large cohort of 1219 patients who were previously followed for liver disease and infected with SARS-CoV-2, 159 patients died (13%). The presence of advanced fibrosis was associated with excess mortality whether or not liver function was impaired. On the other hand, immunocompromised status, particularly in the transplant subpopulation, was not associated with excess mortality. Our registry results are consistent with the management guidelines recently issued by the EASL (28).

AFEF

Association Française de l’Etude du Foie / French Liver Society

EASL

European Association for the Study of the Liver

COVID-19

Coronavirus SARS-Cov2 related Disease

HCC

hepatocellular carcinoma

MAFLD

metabolic associated fatty liver disease

NASH

Non-alcoholic steato-hepatitis

Author Contribution

Study concept, design and supervision: N. G-C., J. D., M. B., E. V.Acquisition of data: all authorsAnalysis and interpretation of data: L. B., N. G.-C., J. D., M. B., E. V.Statistical analysis: E. V., B. M.Drafting of the manuscript: L. B., N. G.-C., J. D., M. B.Administrative, technical and material support: Z. T.Critical revision of the manuscript for important intellectual content: all authors

Acknowledgement

Thanks to all investigators and to AFEF for the logistic support.

Data Availability

The data used to support the findings of this study are included within the article.

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No competing interests reported.

tablesupparticleCOVIDAFEF.docx

COVID-19 and chronic liver disease: results from the 1219 patients French registry

Status:

Version 1

Abstract

Figures

Introduction

Methods

Data source

Statistical Analyses

Results

Population Description

Description of underlying liver disease

Description of the immunosuppressed patients

Description of COVID-19 cases

Outcome and short-term mortality?

Prognostic factors for short-term mortality

Discussion

Conclusion

Abbreviations

Declarations

Author Contribution

Acknowledgement

Data Availability

References

Additional Declarations

Supplementary Files

Status:

Version 1