COVID-19 Severity and Mortality Among Chronic Liver Disease Patients

A Systematic Review and Meta-Analysis

Ramya Nagarajan, MD; Yuvaraj Krishnamoorthy, MD; Sathish Rajaa, MD; Vishnu Shankar Hariharan, MD

Prev Chronic Dis. 2022;19(8):e53

Abstract and Introduction

Abstract

Introduction: Pre-existing comorbid conditions in COVID-19 patients are risk factors for developing severe disease and death. We aimed to determine the association of chronic liver disease (CLD), a comorbid condition, with severity of disease and death among COVID-19 patients.

Methods: We searched for studies reporting COVID-19 outcomes among CLD and non-CLD patients in databases including Medline, EMBASE, ScienceDirect, Google Scholar, and Cochrane Library from inception of the pandemic until February 2022. Risk of bias assessment was conducted by using the Newcastle-Ottawa Scale for assessing the quality of nonrandomized studies in meta-analyses. We conducted a meta-analysis with a random-effects model and reported pooled odds ratios (ORs) with 95% CIs.

Results: We included 40 studies with 908,032 participants. Most studies were conducted in China and the US. COVID-19 patients with CLD had significantly higher odds of having a severe form of COVID-19 (pooled OR = 2.44; 95% CI, 1.89–3.16) and death (pooled OR = 2.35; 95% CI, 1.85–3.00) when compared with COVID-19 patients without CLD.

Conclusion: The presence of CLD is significantly related to adverse clinical outcomes among COVID-19 patients in terms of severity and mortality. Clinicians should develop a comprehensive intervention plan to manage these high-risk patients and reduce COVID-19–related deaths.

Introduction

A coronavirus is a group of viruses that causes mild to severe respiratory tract infections in humans and animals.^[1] In recent times, we have witnessed outbreaks of severe acute respiratory syndrome (SARS) virus (2004), Middle East Respiratory Syndrome coronavirus (MERS-CoV) (2012), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (2019) that belong to this group of viruses.^[2] The SARS-CoV-2 outbreak is the most recent and was declared a global pandemic by the World Health Organization (WHO) on March 11, 2020.^[3] As of May 16, 2021, 162 million cases and 3 million deaths were reported globally due to COVID-19.^[4] The clinical features range from asymptomatic infection to severe pneumonia and death. However, patients who have comorbidities are more likely to have a severe form of the condition or to die.^[5]

Chronic liver disease (CLD) is marked by the gradual destruction of liver parenchyma over time. Various factors cause it; the most common are alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), chronic viral hepatitis, and genetic and autoimmune causes.^[6] Understanding the conditions that lead to severe disease and death among COVID-19–infected people is critical with the evolving pandemic.^[7] COVID-19 infection highlights the pre-existing weaknesses of the individual organ systems,^[8] making it logical to postulate that people with CLD may be susceptible to more severe respiratory infections or be at increased risk of death. In addition, it has been proposed that metabolic-associated fatty liver disease (MAFLD) or NAFLD is associated with significant or advanced fibrosis that might exacerbate the "cytokine storm" induced by the COVID-19 infection.^[9] The mechanism behind this is probably through the release of various proinflammatory hepatokines, which might contribute mechanistically to developing a severe form of COVID-19 infection.^[9] Several studies have found that hospitalized COVID-19 patients with CLD had an acute rise in liver enzymes, which results in a severe condition requiring mechanical ventilation and even leading to death.^[10–12] Existing evidence on COVID-19 outcomes among CLD patients has reported mixed results, making it difficult to determine a prognosis for these patients.^[10–13] Hence, we conducted a systematic review and meta-analysis to find the association between CLD and the severity of and mortality caused by COVID-19.

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Abstract and Introduction
Methods
Results
Discussion
References
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Table. Characteristics of the Included Studies (N = 40)
Reference no.	Study	Country	Design	Mean age, y	Sample size	CLD criteria	COVID-19 severity criteria	Outcome assessed	Study quality
49	Afify et al (2021)	Egypt	RCS	NA	125	NA	ICU admission	Severity and mortality	Poor
9	Bahardoust et al (2021)	Iran	Case-control study	60	1,002	Previous medical records	Patients with respiratory rate >30 breaths/min, SpO₂ <93% or PaO₂/FiO₂ ≤300 mm Hg	Severity	Good
10	Bajaj et al (2020)	US	Matched cohort study	61	145	Prior liver biopsy, evidence of frank hepatic decompensation, radiologic evidence of a nodular liver and/or features of portal hypertension or endoscopic evidence of varices	ICU transfer	Severity and mortality	Good
8	Berenguer et al (2020)	Spain	RCS	70	3,998	Previous medical records	NA	Mortality	Poor
12	Chen et al (2020)	China	RCS	62	274	Previous medical records	NA	Mortality	Poor
11	Frager et al (2021)	US	RCS	64.8	3,352	FIB-4 of >3.25 and/or Fibro Scan transient elastography results of >12.5 kPa	NA	Mortality	Poor
15	Galiero et al (2020)	Italy	RCS	65	618	Previous records and laboratory examination	NA	Mortality	Good
36	Gao et al (2020)	China	Cohort study	46	130	Presence of steatosis by histology or imaging	Patients with respiratory rate >30 breaths/min, SpO₂ <93% or PaO₂/FiO₂ ≤300 mm Hg/mech ventilation/shock/ICU	Severity	Good
50	Ge et al (2021)	US	Cohort study	NA	38,387	Documentation of at least 1 OMOP concept identifier corresponding to previously validated ICD-10-CM codes for liver diseases at any time before the index date	NA	Severity and mortality	Good
43	Guan et al (2020)	China	RCS	47	1,099	Previous medical records	American Thoracic Society guidelines for community-acquired pneumonia	Severity	Poor
29	Guan et al (2020)	China	RCS	48.9	1,590	Previous medical records	American Thoracic Society guidelines for community-acquired pneumonia	Severity and mortality	Poor
35	Harrison et al (2020)	US	RCS	50	31,731	Previous medical records	NA	Mortality	Poor
51	Hashemi et al (2020)	US	RCS	63.4	363	Manual review of laboratory, imaging and/or histopathological data	ICU admission	Severity and mortality	Good
37	Huang et al (2020)	China	Cohort study	49	41	Laboratory investigation (LFT)	ICU admission	Severity	Poor
19	Ioannou et al (2020)	US	Cohort study	NA	10,131	Previous medical records	Need for mechanical ventilation	Severity and mortality	Good
23	Ji et al (2020)	China	Cohort study	44.5	202	Hepatic steatosis index (HSI = 8 × [ALT/AST] + BMI [+2 if type 2 diabetes yes, +2 if female]) >36 points and/or by abdominal ultrasound examination	Patients with respiratory rate >30 breaths/min, SpO₂ <93% or PaO₂/FiO₂ ≤300 mm Hg	Severity	Good
38	Kim et al (2020)	US	Cohort study	56.9	847	Previous medical records	NA	Mortality	Good
20	Lee et al (2020)	South Korea	Cohort study	61	1,005	Laboratory investigations	ICU admission	Severity and mortality	Good
40	Lei et al (2020)	China	Cohort study	56	5,771	Previous medical records	Patients with respiratory rate >30 breaths/min, SpO₂ <93%	Severity	Fair
26	Li et al (2020)	China	Cohort study	59	104	Laboratory investigations	NA	Mortality	Poor
52	Mahamid et al (2020)	Israel	RCS	51	71	Radiologic examination	Patients with respiratory rate >30 breaths/min, SpO₂ <93% or PaO₂/FiO₂ ≤300 mm Hg	Severity	Poor
24	Mallet et al (2021)	France	RCS	70	259,110	NA	Mechanical ventilation	Severity and mortality	Good
44	Mushtaq et al (2020)	Qatar	Case-control study	NA	589	HSI index of 36 and above	NA	Severity and mortality	Poor
39	Navarathnam et al (2021)	England	RCS	NA	91,541	Previous medical records	NA	Mortality	Good
45	Posso et al (2020)	Spain	RCS	78.2	834	Previous medical records	NA	Mortality	Fair
30	Rodriguez-Gonzalez et al (2021)	Spain	Case-control study	65	1,255	Laboratory investigations	NA	Mortality	Fair
41	Sarin et al (2020)	13 Asian countries	Cohort study	NA	228	Clinical and laboratory examination	Patients with respiratory rate >30 breaths/min, SpO₂ <93% or PaO₂/FiO₂ ≤300 mm Hg	Severity and mortality	Poor
46	Schonfeld et al (2021)	Argentina	Cohort study	42.9	207,079	NA	ICU admission	Severity and mortality	Fair
27	Simon et al (2021)	Sweden	Cohort study	60.9	224,467	Liver biopsy	ICU admission	Severity	Good
47	Singh et al (2020)	US	Cohort study	NA	2,780	NA	NA	Mortality	Poor
31	Sun et al (2020)	China	Matched cohort study	47	63	Clinical and laboratory examination	Patients with respiratory rate >30 breaths/min, SpO₂ <93% or PaO₂/FiO₂ ≤300 mm Hg; need for mechanical ventilation, ICU	Severity	Poor
42	Targher et al (2020)	China	Cohort study	NA	310	Laboratory investigations	ICU admission	Severity	Poor
21	de la Tijera et al (2021)	Mexico	Cross-sectional study	50.6	166	Previous medical records	Require invasive mechanical ventilation	Severity	Poor
33	Tobolowsky et al (2021)	US	Cohort study	83	101	NA	NA	Mortality	Poor
22	Veloz et al (2021)	Spain	Case- control study	NA	447	Historical medical records, radiology or analytic records within the last 24 months	NA	Mortality	Poor
25	Wang et al (2020)	China	Cohort study	69	339	Previous medical records	NA	Mortality	Good
48	Wang et al (2021)	US	RCS		16,960	Previous medical records	NA	Mortality	Poor
32	Yang et al (2020)	China	Cohort study	55	495	Laboratory investigations	Patients with respiratory rate >30 breaths/min, SpO₂ <93% or PaO₂/FiO₂ ≤300 mm Hg	Severity	Poor
34	Zhang et al (2021)	China	Case- control study	47.9	172	Laboratory investigations	Patients with respiratory rate >30 breaths/min, SpO₂ <93% or PaO₂/FiO₂ ≤300 mm Hg	Severity	Poor
28	Zhou et al (2020)	China	Cohort study	42.1	110	Previous medical records	COVID-19 management guidance 7th edition	Severity	Fair