key: cord-0695392-5osucst1
authors: Kim, Sung-Woo; Jeon, Jae-Han; Moon, Jun Sung; Kim, Mi Kyung
title: High Fibrosis-4 Index Is Related with Worse Clinical Outcome in Patients with Coronavirus Disease 2019 and Diabetes Mellitus: A Multicenter Observational Study
date: 2021-08-20
journal: Endocrinol Metab (Seoul)
DOI: 10.3803/enm.2021.1040
sha: 1bc6c488ffabe99a16d4ce8aaba3dcd7fc307db2
doc_id: 695392
cord_uid: 5osucst1

BACKGROUND: Based on recent evidence on the importance of the presence of diabetes mellitus (DM) and fibrosis-4 (FIB-4) index in coronavirus disease 2019 (COVID-19) mortality, we analyzed whether these factors could additively predict such mortality. METHODS: This multicenter observational study included 1,019 adult inpatients admitted to university hospitals in Daegu. The demographic and laboratory findings, mortality, prevalence of severe disease, and duration of quarantine were compared between patients with and without DM and/or a high FIB-4 index. The mortality risk and corresponding hazard ratio (HR) were analyzed using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: The patients with DM (n=217) exhibited significantly higher FIB-4 index and mortality compared to those without DM. Although DM (HR, 2.66; 95% confidence interval [CI], 1.63 to 4.33) and a high FIB-4 index (HR, 4.20; 95% CI, 2.21 to 7.99) were separately identified as risk factors for COVID-19 mortality, the patients with both DM and high FIB-4 index had a significantly higher mortality (HR, 9.54; 95% CI, 4.11 to 22.15). Higher FIB-4 indices were associated with higher mortality regardless of DM. A high FIB-4 index with DM was more significantly associated with a severe clinical course with mortality (odds ratio, 11.24; 95% CI, 5.90 to 21.41) than a low FIB-4 index without DM, followed by a high FIB-4 index alone and DM alone. The duration of quarantine and hospital stay also tended to be longer in those with both DM and high FIB-4 index. CONCLUSION: Both DM and high FIB-4 index are independent and additive risk factors for COVID-19 mortality.

for type 2 DM of the Korean Diabetes Association [19] . Release from quarantine was defined using the instructions from the Korean Central Disease Control Headquarters: (1) absence of a fever, without the need for an anti-pyretic agent, and an improvement in symptoms; (2) negative results of RT-PCR tests performed twice at a 24-hour interval (http://ncov.mohw.go.kr/ baroView); and (3) severe disease defined as the necessity for the use of a high-flow nasal cannula, mechanical ventilation, continuous renal replacement therapy, or extracorporeal membrane oxygenation or admission to an intensive care unit.

The FIB-4 index was calculated using the following equation [age×AST level (IU/L)]/[(platelet count×10 9 )×√ALT level (IU/L)] based on the blood test results obtained at the time of hospital admission, before starting any specific COVID-19 therapies. Specifically, a FIB-4 index of over 3.25 or 2.0 and an age of >65 years were associated with a high risk for advanced fibrosis; the patients meeting these criteria were categorized into the high FIB-4 index group. Conversely, those with a FIB-4 index of below 3.25 or 2.0 aged >65 years were assigned to the low FIB-4 index group [20] .

Statistical analyses were performed using SPSS Statistics version 18.0 (SPSS Inc., Chicago, IL, USA). Continuous data were presented as mean±standard deviation and categorical data as frequency rates and percentages. Comparisons between the two groups were performed using Student's t test for continuous data and the chi-square test for categorical data. The risk of mortality and the corresponding hazard ratio (HR) were analyzed using the Kaplan-Meier method and Cox proportional hazard models. A multivariate logistic analysis of the initial laboratory findings was performed to identify the prognostic factors for severe disease and mortality from COVID-19. Differences were considered to be statistically significant at a two-sided α of <0.05.

The baseline characteristics of the patients are presented in Table 1 . Based on recent literature indicating higher mortality in patients with DM [21] [22] [23] and the FIB-4 index as a novel indicator of COVID-19 mortality [16, 24] , we measured the FIB-4 index in the patients with COVID-19. As expected, the patients with DM had a significantly higher FIB-4 index (2.93±3.76 vs. Table 3 ). The patients with a high FIB-4 index with DM were the oldest, followed by those with a high FIB-4 index without DM, low FIB-4 index with DM, and low FIB-4 index without DM ( Table 3 ). The rates of mortality and severe clinical course, as well as the duration of hospital stay and quarantine, followed the same trend ( Table 3 ). The patients with DM and patients with a high FIB-4 index exhibited a higher mortality than did those without DM and those with a lower FIB-4 index, respectively, as illustrated by the cumulative mortality (HR, 2.66 and 4.20, respectively) ( Fig. 1A, B) .

Notably, the patients with both DM and high FIB-4 index (n= 88) had a significantly higher mortality than the other patients ( Table 3 , Fig. 1C ). To determine the independent effect of the presence of DM on mortality, we evaluated mortality according to the presence of DM in the patients with a low FIB-4 index ( Fig. 2A) and a high FIB-4 index (Fig. 2B ). In the low FIB-4 index group, the presence of DM did not affect the mortality (HR, 0.98; 95% confidence interval [CI], 0.28 to 3.46) ( Fig. 2A) . However, in the high FIB-4 index group, the presence of DM was associated with a higher mortality (HR, 3.28; 95% CI, 1.84 to 5.83) (Fig. 2B ). In the analysis of mortality according to the FIB-4 index in the patients without DM (Fig. 3A ) and those with DM ( Fig. 3B) , we observed that a high FIB-4 index increased the mortality in the patients with DM (HR, 6.09; 95% CI, 2.38 to 15.56) compared with that in those without DM (HR, 2.63; 95% CI, 1.05 to 6.60).

In addition, the odds ratio (OR) for a severe clinical course ( severe clinical course and mortality). The duration of quarantine, defined as the period from confirmation of COVID-19 to release from quarantine, and the duration of hospital stay were compared among the four groups. The duration of quarantine was the longest in the high FIB-4 index with DM group, although no significant difference was observed (32.5±1.9 days) (Fig. 5A) . Meanwhile, the duration of hospital stay was significantly longer in the high FIB-4 index groups (28.5±1.2 and 30.8±1.9 days for those without DM and with DM, respectively) than in the low FIB-4 index group without DM (23.8±0.6 days), even after adjusting for multiple confounding factors (Fig. 5B) . Collectively, the presence of DM and a high baseline FIB-4 index were related with worse COVID-19 clinical outcome in a complementary and independent manner.

Herein, we showed that both presence of DM and high FIB-4 index are related with higher mortality of COVID-19 infection. This study was an extension of our previous report, which showed that patients with DM have a higher mortality [9] . In addition to these results, we identified that the patients with DM had a higher FIB-4 index, and among those with a low FIB-4 index, DM exhibited a minimal relationship with mortality. In contrast, regardless of the presence of DM, a high FIB-4 index reflected a higher mortality. In particular, the patients with DM with a high FIB-4 index tended to show the most severe clinical course and mortality than did those with DM only or a high FIB-4 index only, suggesting a complementary role in predict- ing COVID-19 mortality. Several pieces of evidence suggest the prognostic value of the FIB-4 index in COVID-19 cases [12, 16, 24, 25] . Liver injury in COVID-19 cases has been observed more frequently in severe cases [26] . Although the mechanism remains elusive, it is very likely that liver enzyme level elevation may be related to aberrant cytokine release, which is frequently observed in severe pneumonia [27] . Angiotensin-converting enzyme 2 (ACE-2) receptors have been reported to be present in both cholangiocytes and hepatocytes. Therefore, it is likely that this leads to cellular injury [28] . Conversely, advanced liver disease accompanies persistent stimulation of immune cells by pathogen-associated molecular patterns or damage-associated molecular patterns that are responsible for the activation of immune cells [29] . Immune cell-driven upregulation of cytokine production activates additional inflammatory cells, forming a low-grade inflammatory milieu [29] .

FIB-4 index is a non-invasive panel to assess underlying liver fibrosis, and recently widely accepted as inexpensive and accurate tool in patients with hepatic disorders such as viral hepatitis and NAFLD/NASH. Especially, NAFLD/NASH encompass various stages from simple steatosis to cirrhosis, and progression to advanced stage such as steatohepatitis and fibrosis is known to increase morbidity and mortality as well as cardiovascular risk. Recent guideline recommended scoring for advanced fibrosis in NAFLD suspected individuals [20, 30] , and FIB-4 is one of the constitute predictive models. Interestingly, FIB-4 was closely associated with the disease severity and mortality of extrahepatic disorders as well as liver stiffness in previous studies [13] [14] [15] . As we commented above, worse outcomes have been reported in patients with underlying liver disease and cirrhosis, it is easily speculated the subjects having higher FIB-4 are vulnerable to SARS-CoV-2 infection. Consistently to our results, Park et al. [16] demonstrated that the survival rate was significantly lower in high FIB-4 group compare to the low FIB-4 group. These findings supported the predictive role of FIB-4 as we shown in our study, and would be useful to effective delivery of healthcare resources in COVID-19 pandemic era.

Our results show that although DM alone is a critical risk factor, the addition of the FIB-4 index can more specifically predict COVID-19 mortality and severity. This trend was valid even after adjusting for age, sex, and underlying disease. This is consistent with recent findings from previous studies in which the proportion of severe COVID-19 cases was higher in patients with MAFLD [31] . The risk was reported to have a wide range of OR (1.10 to 31.2), and this variability among studies is probably attributed to the different study designs, prevalence of CO-VID-19, quarantine strategies, and definitions of MAFLD or NAFLD/NASH. Nevertheless, the findings from all relevant studies indicate that hepatic fibrosis is a crucial factor in determining the outcomes of patients with SARS-CoV-2 infection, and the risk is synergistically increased in the presence of DM. In this regard, it can be postulated that among patients with DM, those with a high FIB-4 index are at a higher risk of developing a more severe inflammatory status.

Because of the considerable increase in the number of patients with COVID-19 in Daegu, we had no opportunity to examine the prevalence of NAFLD among them either via medical history- Copyright © 2021 Korean Endocrine Society taking or via abdominal ultrasonography. Therefore, we were unable to discriminate NAFLD from infection-related acute liver injury. Although we excluded patients who had ALT levels of ≥ 80 IU/L at the time of admission or died within 3 days from diagnosis with COVID-19 who were more likely to have COVID-19-related liver injury, these arbitrary criteria cannot fully exclude acute liver injury. Nevertheless, it has been reported that even in populations that are clinically not diagnosed with NAFLD, the FIB-4 index correlates with disease severity [32, 33] , suggesting that apart from the presence of NAFLD or NASH, the FIB-4 index per se might serve as a disease severity marker. Our study had some limitations. First, because of a shortage of infrastructure and medical staff, there was incomplete documentation regarding exposure history and lack of timely laboratory examinations being conducted. In particular, as mentioned above, the acquisition of demographic information to account for NAFLD/NASH as a comorbidity was not performed. Second, of the confirmed cases of COVID-19 in Daegu, 65.6% were associated with a single religious group, and these patients were admitted to university hospitals because of their disease severity; therefore, the data are more likely to be representative of patients with COVID-19 with moderate-to-severe disease, which indicates a lack of heterogeneity. Lastly, other prognostic markers, such as the D-dimer, lactate dehydrogenase, or ferritin level, were not measured and compared with the FIB-4 index.

Nevertheless, our study findings strongly suggest that DM and the FIB-4 index can play independent roles in the prediction of COVID-19 mortality and disease severity. Patients with DM and a high FIB-4 index could have an almost 10-fold higher mortality risk than those without DM and a low FIB-4 index. Furthermore, it is noteworthy that among patients with DM, the FIB-4 index could be used in further stratifying the risk. Therefore, special attention is required for patients with DM and a high FIB-4 index upon admission.

No potential conflict of interest relevant to this article was reported.

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We would like to express sincere gratitude to all the members of the Daegu-Gyeongbuk Diabetes and Endocrinology Society who actively participated in the study.