key: cord-0764386-p4fq72p5
authors: Targher, Giovanni; Mantovani, Alessandro; Byrne, Christopher D.; Wang, Xiao-Bo; Yan, Hua-Dong; Sun, Qing-Feng; Pan, Ke-Hua; Zheng, Kenneth I.; Chen, Yong-Ping; Eslam, Mohammed; George, Jacob; Zheng, Ming-Hua
title: Detrimental effects of metabolic dysfunction-associated fatty liver disease and increased neutrophil-to-lymphocyte ratio on severity of COVID-19
date: 2020-06-04
journal: Diabetes Metab
DOI: 10.1016/j.diabet.2020.06.001
sha: 6b0bfcbbd6b65f8d1d0e8604135b08e2a869581e
doc_id: 764386
cord_uid: p4fq72p5

nan

known marker of systemic inflammation integrating the detrimental effects of neutrophilia and lymphopenia, is strongly associated with poorer in-hospital outcomes in patients with coronavirus disease-2019 (COVID-19) [1] . Previous studies also reported a significant association between increased NLR and the histological severity of liver fibrosis in non-alcoholic fatty liver disease (recently renamed metabolic dysfunction-associated fatty liver disease (MAFLD) [2] ) [3, 4] . We therefore postulated that MAFLD might contribute to the COVID-19induced inflammatory "storm", and that patients with MAFLD and increased NLR are at greater risk for severe COVID-19 illness.

We studied a multicentre cohort of 310 patients with laboratory-confirmed COVID-19, who were consecutively hospitalized at four sites in Whenzou, Zhejiang Province (China), between January and February 2020. These patients have been included in a prior study examining the relationship between MAFLD with increased non-invasive fibrosis scores and risk of COVID-19 severity [5] . Patients with viral hepatitis, excessive alcohol consumption, active cancers or chronic pulmonary diseases were excluded. Clinical and laboratory data were collected in all patients at hospital admission, including NLR that was calculated by dividing the absolute number of neutrophils by the absolute number of lymphocytes. Obesity was diagnosed as body mass index >25 kg/m 2 . Pre-existing diabetes was defined as self-reported history of disease or use of glucose-lowering medications. All patients were screened for hepatic steatosis by computed tomography and subsequently diagnosed as MAFLD, according to the recently proposed diagnostic criteria [2] . The severity of COVID-19 was assessed during hospitalization and classified as severe and non-severe based on the current management guideline [6] . The study protocol was approved by the local ethics committees of the four hospitals. The requirement for written informed consent was waived due to the retrospective and anonymous nature of the study design.

In our cohort of 310 (48.1% men; mean age 47 years) consecutive cases of COVID-19, the median values of NLR were 2.53 (inter-quartile range: 1.7-3.8), and 94 (30.3%) patients had imaging-defined MAFLD. We stratified our cohort of patients by both presence/absence of MAFLD and high/low values of NLR; we adopted a cut-point value of 2.80 that was found to be the optimal cut-point value of NLR in a ROC curve analysis, using the Youden's index, for predicting severe COVID-19 in the patient cohort. After stratifying patients by both presence/absence of MAFLD and high/low NLR values at hospital admission, those with MAFLD and increased NLR were older and more likely to have diabetes, obesity and hypertension, and had higher serum liver enzymes, higher leucocyte and neutrophil counts, higher C-reactive protein, longer prothrombin time and higher D-dimer levels, as well as lower lymphocyte counts and lower high-density lipoprotein-cholesterol concentrations compared with their counterparts without MAFLD and normal NLR. Notably, as shown in Figure 1 , the severity of COVID-19 illness markedly increased across the groups of patients. Almost identical results were found when we used a different cut-off value of NLR for stratifying the COVID-19 cases, i.e., 3.2 that corresponds to the upper tertile of distribution of NLR values in the entire cohort (data not shown).

In binary logistic regression analysis, compared to those without MAFLD and NLR ≤ 2.8 at hospital admission, patients with MAFLD and NLR ≤2.8 (adjusted-odds ratio [OR] 5.32, 95%

confidence intervals [CI] 0.98-29.9, P = 0.053), those without MAFLD and NLR > 2.8 (adjusted-OR 17.7, 95%CI 3.89-80.6, P < 0.001), and those with MAFLD and NLR > 2.8 (adjusted-OR 25.9, 95%CI 5.32-127, P < 0.001) were associated with greater severity of COVID-19 illness, even after adjustment for age, sex, pre-existing diabetes, obesity and hypertension. In this multivariable regression model, older age (adjusted-OR 1.03, 95%CI 1.01-1.06, P < 0.05), male sex (adjusted-OR 2.63, 95%CI 1.22-5.01, P < 0.01) and hypertension (adjusted-OR 2.68, 95%CI 1.20-5.98, P < 0.01) were also independently associated with greater risk of having severe COVID-19.

Our study has some limitations, including the relatively modest sample size, the Asian ancestry of the cohort, and the lack of any data on lymphocyte subsets (by flow cytometry) and serial monitoring of NLR during the hospital stay. Despite these limitations, our study is the first to examine the differential effects of MAFLD and increased NLR on severity of COVID-19. It has been shown that increased NLR (and T lymphopenia) is strongly associated with poorer inhospital outcomes amongst patients with COVID-19 [1, 7] , and also predicts with reasonable accuracy the fibrosis stage and other histological features of MAFLD [3, 4] .

Our multicentre preliminary analysis confirms the prognostic value of NLR in hospitalized patients with COVID-19, and shows for the first time that patients with imaging-defined MAFLD and increased NLR values on admission are at substantially higher risk of severe illness from COVID-19, irrespective of age, sex and metabolic comorbidities. It is possible that the presence of MAFLD with increased NLR exacerbates the virus-induced inflammatory "storm", possibly

Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis

A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement

Neutrophil to lymphocyte ratio: a new marker for predicting steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease

The role of neutrophil to lymphocyte ratio for the assessment of liver fibrosis and cirrhosis: a systematic review

Risk of severe illness from COVID-19 in patients with metabolic dysfunction-associated fatty liver disease and increased fibrosis scores

National Health Commission & State Administration of Traditional Chinese Medicine. Diagnosis and treatment protocol for novel coronavirus pneumonia

Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19

FIGURE LEGEND Figure 1. Proportion of severe COVID-19 illness among patients, stratified by presence/absence of metabolic dysfunction-associated fatty liver disease (MAFLD) and values of neutrophil-to-lymphocyte ratio (NLR) at hospital admission