key: cord-0915347-1zz3mzsl authors: Singh, Shailendra; Khan, Ahmad title: Clinical Characteristics and Outcomes of COVID-19 Among Patients with Pre-Existing Liver Disease in United States: A Multi-Center Research Network Study date: 2020-05-04 journal: Gastroenterology DOI: 10.1053/j.gastro.2020.04.064 sha: 3741b22acb658b1f9fd490f4b84185fd8e90ae21 doc_id: 915347 cord_uid: 1zz3mzsl nan Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a global public health crisis. Liver injury has been reported during the COVID-19 disease progression 1 . However, previous studies did not examine in detail the interaction of pre-existing liver disease and COVID-19 1 . Therefore, we aimed to study the impact of pre-existing liver disease on outcomes in a large cohort of COVID-19 patients in the United States. A real-time search and analysis were performed for patients (> 10 years age) diagnosed with COVID-19 using the TriNETX (Cambridge, MA, USA) Research Network with COVID-19 specific diagnosis and terminology recommended by WHO and CDC. TriNetX provided real-time access to electronic medical records (EMR) of more than 49 million patients from 37 healthcare organizations (HCOs). Identified COVID-19 patients were then stratified into two groups based on the presence (LD) or absence (Non-LD) of pre-existing liver disease. The LD group consisted of patients with a diagnosis of chronic liver disease, cirrhosis, or related complications either at the time of diagnosis of COVID-19 or anytime before that. The outcomes studied were mortality, hospitalization, and laboratory findings in the time window up to 30 days from the diagnosis of COVID-19. All statistical analyses were performed using TriNetX. TriNetX obfuscates patient counts to safeguard protected health information by rounding patient counts in analyses up to the nearest 10. Details of the data source, search criteria, diagnosis, study variables, statistical analysis, and limitations of the methodology are available in Supplementary Methods. We identified a total of 2,780 COVID-19 patients across 34 HCOs in the United States. 250 (9%) patients with pre-existing liver disease were included in the LD group and the remaining 2530 in the non-LD group. Among the LD patients, 50 (1.8%) were also diagnosed with cirrhosis. LD patients were older than the Non-LD group (55.2 ± 14.6 vs. 51.6 ± 17.8, p-value <0.01). LD patients had substantially higher comorbidities, and a large proportion had hypertension (68%), diabetes (48%). Fatty Liver Disease or Nonalcoholic Steatohepatitis (42%) was the most common among LD group patients. Therefore, we performed (1:1) propensity score matching for BMI, hypertension, and diabetes, in addition to age, race, and nicotine use. The groups were relatively balanced after propensity matching (N=250 each group) (Table and Supplementary were also seen. Concentrations of ferritin, C reactive protein, Lactate dehydrogenase, Interleukin-6, creatine kinase, and D-dimer were also elevated in both groups (Table) . Patients in the LD group had a significantly higher risk of mortality (RR 2.8, 95% CI 1.9-4.0, pvalue <0.001), and the risk remained high even after the propensity matching of two groups (RR 3.0, 95% CI 1.5-6.0, p-value 0.001). In the subgroup analysis of the LD group, patients with cirrhosis had an even higher relative risk of mortality as compared to patients in the Non-LD group (RR 4.6, . Similarly, the risk of hospitalization was higher in the LD group before and after the matching of cohorts (Table 1 ). We compared outcomes of patients with pre-existing liver disease and without liver disease in a large and diverse cohort of 2780 COVID-19 patients in the United States. Elevation in liver chemistries was seen in the vast majority of patients suggesting possible liver injury in COVID-19. We found that patients with pre-existing liver disease were at increased risk for mortality (RR 2.8, 95% CI 1.9-4.0, p-value <0.001) as compared to patients without liver disease, and the relative risk was markedly higher in patients with cirrhosis (RR 4.6, 95% CI 2.6-8.3, p-value <0.001). Our findings are similar to those reported for other comorbidities such as hypertension, diabetes, or cardiovascular disease, yielding poor outcomes 2 . Many comorbidities overlap in patients or have a similar profile; a large proportion of patients in the pre-existing liver disease group had fatty liver disease along with diabetes and hypertension. Therefore, we performed propensity matching of the groups and still found a higher risk for mortality and hospitalization in patients with pre-existing liver disease. The possible reasons for poor outcomes among COVID-19 with pre-existing liver disease need further investigation; however, it appears to be an interplay of local liver injury and systemic disturbances. SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) receptor to gain entry and damage the target organ 3 . The expression of ACE2 receptors has been suggested in both liver and bile duct cells 4.5 . Previous studies have reported abnormalities in transaminases in 14-53% cases of COVID-19 patients 1 . We also noticed elevations in liver chemistries from baseline values, suggesting possible liver injury from SARS-CoV-2. However, we cannot rule out medications or other possible etiologies for these abnormalities and are unable to specify a pattern of liver injury. Hypoxia often seen in COVID-19 can induce diminished cellular activity and high-level oxygen free radical resulting in liver injury and organ failure 1,6 . COVID-19 patients with pre-existing liver dysfunction, especially with cirrhosis, are theoretically more susceptible to poor outcomes from these direct injuries to liver. Moreover, the immune deficiency and accompanying persistent systemic inflammation reflected by the activated circulating immune cells and increased serum levels of pro-inflammatory cytokines that occurs in patients with advanced liver disease can predispose them to uncontrollable pro-inflammatory cytokines production 6, 7 . Many patients with cirrhosis can also have underlying hepatopulmonary syndrome, portopulmonary hypertension, or hepatic hydrothorax that can increase the risk of respiratory failure in itself 8 . In conclusion, liver injury can be seen in the majority of patients with COVID-19. However, patients with pre-existing liver disease, notably cirrhosis, are at higher risk for hospitalizations and mortality. Early isolation, intensive surveillance, and timely diagnosis are essential in these patients. Further research identifying interventions to reduce poor outcomes in high-risk Table Legends Table: Outcomes, baseline characteristics, and laboratory findings among COVID-19 patients stratified into pre-existing Liver Disease and without Liver Disease. Outcomes and baseline characteristics are compared before and after propensity score matching of groups. Laboratory findings are compared before and after COVID-19 diagnosis. Table: Outcomes, baseline characteristics, and laboratory findings among COVID-19 patients stratified into pre-existing Liver Disease and without Liver Disease. Outcomes and baseline characteristics are compared before and after propensity score matching of groups. Laboratory findings are compared before and after COVID-19 diagnosis. Ferritin (ng/mL) 371 ± 94 (130) 1,925 ± 2,567 TriNetX (Cambridge, MA, USA) COVID-19 Research Network for HCOs actively seeking to participate in coronavirus research was recently created. TriNETX fast-tracked data inflow to incorporate COVID-19 specific diagnosis and terminology following the World Health Organization (WHO) and Centers for Disease Control (CDC) COVID-19 criteria. As a federated network, TriNetX received a waiver from Western IRB since only aggregated counts, statistical summaries of de-identified information, but no protected health information is received, and no study-specific activities are performed in retrospective analyses. TriNetX cloud-based features allow real-time access to the de-identified longitudinal clinical data along with the analytics to analyze research questions. The de-identified clinical data is aggregated directly from the electronic medical records of the participating HCOs continuously. Both the patients and HCO's as data sources stay anonymous. Participating HCO's include a mix of inpatient, outpatient, and specialty care services and provide care to a diverse patient population from different geographical regions. The search was conducted (April 12, 2020) following the criteria provided by the TriNETX to identify The diagnosis of COVID-19 was defined as the index event. Baseline comorbidities were estimated based on diagnosis any time before or at the time of index event. The patient presenting signs and symptoms were estimated from the index event to 14 days before the index event. Baseline laboratory values were the most recent findings from anytime 14 days before the index event. The time window to estimate all outcomes were from the day of diagnosis of COVID-19 up to 30 days after that. All statistical analyses were performed in real-time using TriNetX. TriNetX obfuscates patient counts to safeguard protected health information (PHI) by rounding patient counts in analyses up to the nearest 10. Rounding may influence measures of association results for small cohorts and infrequent outcomes. The means, standard deviations, and proportions of clinical facts were used to describe and compare patient characteristics. We performed 1:1 propensity score matching using a greedy nearest-neighbor matching algorithm with a caliper of 0.1 pooled standard deviations to account for confounding variables. For each outcome, the risk difference and risk ratio were calculated to compare the association of the liver disease with the outcome. A-priori defined two-sided alpha of less than <0.05 was used for statistical significance. The data derived from EMR based database is susceptible to errors in coding or data entry when patient information is translated into ICD-10 code. However, the ability of TriNetX to aggregate the data directly from the EMRs in a real-time fashion minimizes the risk of data collection errors at the investigator's end. Patients with mild disease who remained undiagnosed or were treated at home and did not present to any HCOs were missed; therefore, our cohort may represent the more severe spectrum of the disease. Data on the exposure history, incubation time, specific radiographic findings, and dynamic changes in patients' clinical condition could not be estimated. The laboratory findings were not performed for all patients, and hence their role might be undervalued. Patient counts were rounded up to the nearest 10 in our analysis to protect PHI. Rounding may influence measures of association results for small cohorts and infrequent outcomes. Liver injury in COVID-19: management and challenges Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases from the Chinese Center for Disease Control and Prevention Clinical Characteristics of 138 Hospitalized Patients with Novel Coronavirus-Infected Pneumonia in Wuhan, China Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection Liver injury during highly pathogenic human coronavirus infections the USA) were included. The B97.29 code was specifically included based on the recommendation from the general guidance of the ICD-10-CM Official Coding Guidelines released by the CDC on Queries for liver disease patients were made using the ICD-10-CM codes alone or in combination Alcoholic liver disease K74 Fibrosis and cirrhosis of liver Primary sclerosing cholangitis Hepatic failure, unspecified; K71 Toxic liver disease; K75.81 Nonalcoholic steatohepatitis, K76.0 Fatty (change of) liver, not elsewhere classified, B18 Chronic viral hepatitis, B19.1 Unspecified viral hepatitis B, K73 Chronic hepatitis Inflammatory liver disease, unspecified; K76.6 Portal hypertension; K65.2 Spontaneous bacterial peritonitis Hepatopulmonary syndrome; K76.7 Hepatorenal syndrome Supplementary Figure 2: Distribution of the values of Alanine aminotransferase (ALT) after COVID-19 in patients with pre-existing Liver Disease and without Liver disease We acknowledge the West Virginia Clinical and Translational Science Institute to provide us access, and training to the TriNETX global healthcare network.We also acknowledge the TriNETX (Cambridge, MA, USA) healthcare network for design assistance to complete this project.