key: cord-0752377-l7tep07v
authors: Xiang, Fangfei; Sun, Jing; Chen, Po-Hung; Han, Peijin; Zheng, Haipeng; Cai, Shuijiang; Kirk, Gregory D
title: Early elevation of FIB-4 liver fibrosis score is associated with adverse outcomes among patients with COVID-19
date: 2020-11-09
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa1710
sha: 28a41a03d58fe9de9e3091366cf0e9df3c87a45a
doc_id: 752377
cord_uid: l7tep07v

BACKGROUND: Limited prior data suggest that pre-existing liver disease was associated with adverse outcomes among patients with COVID-19. FIB-4 is a noninvasive index of readily available laboratory measurements that represents hepatic fibrosis. We sought to evaluate the association between FIB-4 at an early stage of infection and COVID-19 outcomes. METHODS: FIB-4 was evaluated at admission in a cohort of 267 patients admitted with early-stage COVID-19 confirmed through RT-PCR. Hazard of ventilator use and of high-flow oxygen was estimated using Cox regression models controlled for covariates. Risk of progress to severe cases and of death/prolonged hospitalization (>30 days) were estimated using logistic regression models controlled for same covariates. RESULTS: Forty-one (15%) patients progressed to severe cases, 36 (14%) required high-flow oxygen support, 10 (4%) required mechanical ventilator support, and 1 died. Patients with high FIB-4 score (>3.25) were more likely to be older with pre-existing conditions. FIB-4 between 1.45-3.25 was associated with over 5-fold (95% CI: 1.2-28) increased hazard of high-flow oxygen use, over 4-fold (95% CI: 1.5-14.6) increased odds of progress to severe stage, and over 3-fold (95% CI: 1.4-7.7) increased odds of death or prolonged hospitalization. FIB-4>3.25 was associated with over 12-fold (95% CI: 2.3-68. 7) increased hazard of high-flow oxygen use and over 11-fold (95% CI: 3.1-45) increased risk of progress to severe disease. All associations were independent of sex, number of comorbidities, and inflammatory markers (D-dimer, C-reactive protein). CONCLUSIONS: FIB-4 at early-stage of COVID-19 had an independent and dose-dependent association with adverse outcomes during hospitalization. FIB-4 provided significant prognostic value to adverse outcomes among COVID-19 patients.

Patients infected with Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), the virus causing Coronavirus Disease 2019 (COVID- 19) , present a wide spectrum of disease severity, from asymptomatic to mild to critically ill requiring organ support and associated with high mortality [1, 2] . Early predictors of disease progression are critical for COVID-19 disease management; identifying high risk individuals can inform appropriate triage and allocate limited healthcare resources appropriately during this global pandemic. Previous studies identified that patients with multi-morbidities and of older age had worse prognosis [1, [3] [4] [5] . However, the role of liver disease in COVID-19 remains unclear.

Recent studies have reported that liver enzyme abnormalities and acute liver injury were common among patients with severe COVID-19 infection [6] [7] [8] [9] [10] . Liver dysfunction is likely multifactorial, and could result from liver injury directly by the SARS-CoV-2 virus, by the associated cytokine storm, by resulting multi-organ failure, or by medications used to manage patients with COVID-19 [7, 11] . Acute liver decompensation following COVID-19 infection could also represent exacerbation of pre-existing chronic liver diseases [12] . Liver dysfunction and cirrhosis are associated with innate immune dysfunction which could enhance susceptibility to acute proinflammatory responses [13] . These pathways are hypothesized to lead to severe outcomes among patients with COVID-19.

Current guidelines recommend prioritizing testing for COVID-19 and early admission for patients with chronic liver disease [12] . However, there remain limited data explaining whether individuals with pre-existing liver disease might have elevated risk of severe symptoms and worse clinical outcomes with COVID-19 [7, 11, 12, 14- M a n u s c r i p t 16] . Routine clinical encounters often do not include detailed imaging evaluation of liver function, which increases the challenge of identifying pre-existing liver condition in early COVID-19 disease stage. Further, while liver injury is a prominent feature of severe COVID-19, the impact of liver injury at early-stage COVID-19 remains largely unexplored.

The Fibrosis-4 (FIB-4) index was developed to leverage inexpensive and routinely available laboratory results (platelet count, aspartate transaminase [AST] , and alanine transaminase [ALT]) along with age to noninvasively identify liver fibrosis among patients with viral hepatitis [17] [18] [19] . FIB-4 has demonstrated a high predictive value for multiple liver-related outcomes (hepatocellular carcinoma, severe fibrosis, cirrhosis verified by biopsy) in patients with viral hepatitis [20, 21] . FIB-4 also predicts all-cause inpatient mortality and all liver-related outcomes among individuals without known chronic liver diagnosis [22, 23] . A recent study reported that high FIB-4 among hospitalized COVID-19 patients was associated with ICU admission [24] .

However, the disease stage and potential exposure to medication prior to the FIB-4 measurements were unclear. These factors could significantly impact the FIB-4 scores as liver enzyme and platelet count abnormalities fluctuate during COVID-19 disease course [25] . We sought to evaluate the association of FIB-4 scores at an early-stage of SARS-CoV-2 infection with adverse outcomes during hospitalization.

This study was approved by the Institutional Review Board of Guangzhou No. 8

People's Hospital. We conducted a retrospective cohort study of adults with confirmed SARS-CoV-2 infection admitted to a leading hospital specializing in A c c e p t e d M a n u s c r i p t infectious diseases (Guangzhou No. 8 People's Hospital) in the capital of Guangdong province, China from January 20 to February 10, 2020. During this time period, suspected cases of COVID-19 in Guangzhou city were evaluated at the hospital and admitted immediately after confirmed diagnosis, regardless of the presence of symptoms. Suspected cases were identified through (1) symptom presentation, (2) contact tracing of confirmed cases, (3) testing individuals with a recent travel history to Wuhan, China whom were under mandatory quarantine. All cases included in this analysis were confirmed by RT-PCR (Daan Gene Co., Sun Yat-sen University) of nasopharyngeal swabs. A total of 274 patients were admitted during the recruitment period. As our focus was on early-stage disease, we excluded 7 patients with respiratory decompensation (room air oxygen saturation <93% or respiratory rate ≥30 breaths per minute) at admission. Compared to the 267 persons included in the analysis, the 7 patients excluded with respiratory decompensation at admission were more likely to be older, diabetic, and have liver disease (all p<0.05; data not shown).

Outcomes, exposures of interest, and other covariates were identified through standardized abstraction from medical records by three trained physicians. 

FIB-4 score was calculated using age, AST (U/L), ALT (U/L), and platelet count ( ) using standard methods [17] [18] [19] . All laboratory values were obtained within 24 hours of admission to the hospital. FIB-4 scores were categorized according to prior cutpoints validated to be a proxy of Ishak stage of normal (0-1), significant (2-

3), and advanced (4-6) hepatic fibrosis (<1.45, 1.45-3.25, and >3.25, respectively) [17] [18] [19] .

Symptoms and signs on admission were obtained through self-report (diarrhea, fatigue, coughing, mucus) or physical examination (fever, rales). Self-report of pre- 

The patient population studied included individuals tested because of potential A c c e p t e d M a n u s c r i p t

The majority of ALT and AST levels were within the normal range at admission Table 2 ). In addition to higher AST and lower platelet counts that are incorporated into the FIB-4 index, patients with higher FIB-4 scores were more likely to have higher direct bilirubin and lower albumin; ALT or prothrombin time were not different by FIB-4 score. Several biochemical and hematologic abnormalities differed by FIB-4 scores in a dosedependent manner, notably including reduced total lymphocyte count and hemoglobin levels and increased C-reactive protein (CRP), lactic acid dehydrogenase, creatinine kinase and serum cystatin C ( Table 2) .

As demonstrated in Figure 1 6.8-98) increased hazard of using high-flow oxygen, ~21-fold (95% CI: 6.9-60.8)

increased risk of progress to severe cases, and over 5-fold (95% CI: 1.9-13.2) increased odds of death or prolonged hospitalization. All associations were independent from sex, number of total comorbidities at admission, and time from symptoms onset to admission. After controlling for inflammatory markers (D-dimer, A c c e p t e d M a n u s c r i p t CRP), the associations between FIB-4 and adverse outcomes were attenuated but not eliminated ( Table 3) . Similar associations were observed among patients with FIB-4 between 1.45-3.25 compared to those with FIB-4 <1.45, although the magnitude of association was lower compared to patients with FIB-4 >3.25 ( Table   3 ). Further demonstrations in Figure 2 showed patients with higher FIB-4 were associated with higher hazard of using ventilators (p-value of test for trend of cumulative hazard functions<0.001). These results suggested a strong, dosedependent association between high FIB-4 score at an early-stage of infection and adverse clinical outcomes among patients with COVID-19, and this association was not completely driven by acute inflammation.

Self-reported liver disease (N=6) was associated with higher probability of death or prolonged hospitalization (Supplementary Table S The current study has several limitations. We were not able to confirm liver fibrosis using ultrasound, elastography, or biopsy to better characterize liver disease severity among patients. Therefore, the association should be interpreted with caution. Finally, this is a single-site study with relatively low sample size. Thus, the external validity should be further evaluated in other cohorts with larger sample sizes.

However, despite the limited sample size, we were still able to observe strong associations between high FIB-4 scores early on and multiple adverse outcomes during follow-up.

There are also several strengths to our study. Most studies on liver disease and COVID-19 were focused on liver injury during COVID-19 infection, and many were conducted among patients with progressive disease [9, 10, 24] . In contrast, our cohort admitted all individuals as soon as they received a positive result of COVID-19, regardless of the presence of symptoms, which provided a unique opportunity for us to evaluate the natural history of disease progression based on early symptoms and characteristics. In addition, although this is a single-site study, we were able to A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 3.25 (0.96-11.0) 0.06 *Risk estimates for use of ventilator and high-flow oxygen were hazard ratios based on Cox regression models; risk estimates for severe/critical cases and death/prolonged hospitalization were odds ratios-based logistics regression models. a Model adjusted for sex, comorbidities (none vs. only 1 vs. 2 or more), and time from admission to symptom onset date. 

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