Liver Involvement in Children With SARS-COV-2 Infection

Two Distinct Clinical Phenotypes Caused by the Same Virus

Adriana Perez MD; Amanda Cantor MD; Bryan Rudolph MD, MPH; Jonathan Miller MD; Debora Kogan-Liberman MD; Qi Gao PhD; Bernardo Da Silva; Kara G. Margolis MD; Nadia Ovchinsky MD, MBA; Mercedes Martinez MD

Disclosures

Liver International. 2021;41(9):2068-2075.

Abstract and Introduction

Abstract

Background and Aims: Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) associated acute liver injury (ALI) has been linked to poor outcomes in adults. Here we compare characteristics in children with elevated ALT (E-ALT) in two distinct manifestations of the infection, multisystem inflammatory syndrome-children (MIS-C) and coronavirus disease 2019 (COVID-19).

Methods: This is a retrospective study of patients ≤21 years of age with positive for SARS-CoV-2 PCR. E-ALT was defined as alanine aminotransferase (ALT) > 40 U/L. Bivariate analysis and multivariable logistic regression were obtained to describe differences in children with and without E-ALT in COVID-19 and MIS-C.

Results: E-ALT was detected in 36% of the 291 patients; 31% with COVID-19, and 51% with MIS-C. E-ALT in COVID-19 was associated with obesity (P < .001), immunocompromised status (P = .04), and chronic liver disease (P = .01). In the regression models, E-ALT in COVID-19 was associated with higher c-reactive protein (OR 1.08, P = .01) after adjusting for common independent predictors. Children with E-ALT and MIS-C were more often boys (P = .001), Hispanic (P = .04), or Black (P < .001). In MIS-C, male gender (OR 5.3, P = .02) and Black race (OR 4.4, P = .04) were associated with increased odds of E-ALT. Children with E-ALT in both cohorts had significantly higher multiorgan dysfunction, longer hospitalization, and ICU stay. Children with MIS-C had 2.3-fold increased risk of E-ALT compared to COVID-19. No association was found between E-ALT and mortality.

Conclusion: E-ALT with SARS-CoV-2 presents as elevated transaminases without hepatic synthetic dysfunction. Patients with either manifestation of SARS-CoV-2 infection and E-ALT experienced more severe disease.

Introduction

The clinical manifestations of severe acute respiratory syndrome (SARS)-associated coronavirus 2 (SARS-CoV-2) infection are typically mild in children.^[1–7] However, severe symptoms and even deaths from Coronavirus Disease 2019 (COVID-19) can occur.^[8,9] A separate pediatric-specific clinical presentation arises in the form of an entity termed Multisystem Inflammatory Syndrome (MIS-C), characterized by a persistent acute febrile illness progressing to multiorgan dysfunction.^[10,11]

The prevalence of acute liver injury (ALI) in adult patients with COVID-19 ranges from 15%-78%, with most studies reporting 20%-30% among hospitalized patients.^[12–14] ALI, defined as an elevation in aminotransferases and typically presenting as hepatocellular histological injury with mild acute cholestasis, has been documented in adults and children with SARS-CoV-2 infection. Most adult patients experience transient mild to moderate elevation of liver enzymes.^[12–16] Severe ALI (alanine aminotransferase [ALT] values 5x above the upper limit of normal [ULN]) was reported to correlate with disease severity and poor outcomes in adults, including death.^[13,17]

In contrast, less is known about the association between elevated ALT (E-ALT) and disease severity in children with SARS-CoV-2. In this study, we looked at elevations in ALT (E-ALT), as a surrogate marker for liver injury, similar to what has been done in adult studies.^[13] We previously published a focused description of the association of hepatitis with disease severity in a cohort of 44 patients with MIS-C included within this report.^[18] We now further expand the scope of understanding of liver involvement in two clinical presentations of SARS-CoV-2. We provide critical data on its associating factors, epidemiology, and their contribution to the consequences of elevated ALT in children with COVID-19 versus MIS-C.

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Abstract and Introduction
Methods
Results
Discussion
References
Sidebar

Table 1. Patient characteristics in children *with COVID-19* and *MIS-C* with and without Elevated ALT
	COVID-19			MIS-C			COVID-19 vs MIS-C^a
	ALT ≤ 40 U/L (n = 151)	ALT > 40 U/L (n = 69)	P-value	ALT ≤ 40 U/L (n = 35)	ALT > 40 U/L (n = 36)	P-value	P-value
Demographics
Age (years), median (IQR)	11 (2–17)	16 (8–20)	0.001	6 (2–10)	9.5 (6.0–13.5)	0.01	0.01
Male sex, n (%)	87 (58)	49 (71)	0.06	11 (31)	25 (69)	0.001	0.87
Hispanic ethnicity, n (%)	50 (43)	19 (31)	0.13	14 (48)	16 (53)	0.69	0.04
Black race, n (%)	26 (26)	7 (14)	0.08	6 (24)	13 (59)	0.01	<0.001
Comorbidities
Asthma, n (%)	25 (17)	17 (25)	0.16	2 (6)	6 (17)	0.26	0.35
Chronic liver disease, n (%)	4 (3)	9 (13)	0.01	0	0	-	0.03
Congenital heart disease, n (%)	10 (7)	2 (3)	0.35	0	0	-	0.54
Diabetes mellitus, n (%)	11 (7)	7 (10)	0.48	0	1 (2.8)	1.00	0.26
Immunosuppression, n (%)	9 (6)	11 (16)	0.02	0	0	-	0.01
Malignancy, n (%)	5 (3)	10 (15)	0.01	0	0	-	0.01
Obesity, n (%)	28 (23)	34 (54)	<0.001	6 (19)	11 (31)	0.26	0.02
Clinical course characteristics
ICU admission, n (%)	28 (19)	24 (35)	0.01	15 (43)	23 (64)	0.08	0.01
ICU length of stay (days)^b	2.1 (±6.8)	5.3 (±12.1)	0.01	1.8 (±2.6)	3.6 (±3.9)	0.04	0.08
Hospital length of stay (days)^b	6.1 (± 12.1)	15.8 (± 27.1)	<0.001	5 (3–7)	8 (5–10)	0.001	0.48
Multiorgan dysfunction, n (%)	6 (4)	12 (17)	0.001	5 (14)	11 (31)	0.10	0.12
Respiratory failure, n (%)	18 (12)	21 (30)	0.001	1 (3)	11 (31)	0.01	0.99
Cardiac dysfunction, n (%)	13 (9)	12 (17)	0.06	16 (46)	20 (56)	0.41	<0.001
Kidney dysfunction, n (%)	12 (8)	5 (7)	0.85	5 (14)	10 (28)	0.16	0.01
Death, n (%)	4 (3)	3 (4)	0.68	0	0	-	0.55
Therapeutic agent use
Remdesivir, n (%)	7 (5)	7 (10)	0.23	0	3 (8)	0.24	1.0
Systemic steroids, n (%)	17 (11)	23 (33)	<0.001	26 (74)	29 (81)	0.53	<0.001
Antibiotics, n (%)	44 (51)	31 (76)	0.01	8 (80)	15 (88)	0.61	0.48

Abbreviations: ICU, intensive care unit; IQR, interquartile ranges; SD, standard deviation.
For additional variables, please see supplemental tables.
^acompares children with elevated ALT values defined as ALT >40 U/L in COVID-19 vs MIS-C.
^bValues reported as mean (±SD).

Table 2. Laboratory characteristics in children *with COVID-19* and *MIS-C* with and without elevated ALT
	COVID-19			MIS-C			COVID-19 vs MIS-C^a
	ALT ≤ 40 U/L (n = 151)	ALT > 40 U/L (n = 69)	P-value	ALT ≤ 40 U/L (n = 35)	ALT > 40 U/L (n = 36)	P-value	P-value
Liver tests
Median (IQR)
ALT (U/L), peak	19 (15–25)	98 (58–197)	<0.001	23 (15–31)	77 (58–117)	<0.001	0.16
AST (U/L), peak	31 (21–43)	78 (53–137)	<0.001	30 (26–34)	88 (62–124)	<0.001	0.84
Total bilirubin (mg/dL), peak	0.4 (0.2–0.8)	0.6 (0.4–1.0)	0.001	0.4 (0.3–0.6)	0.8 (0.6–1.8)	<0.001	0.02
Albumin (g/dL), nadir	4.3 (3.7–4.8)	3.5 (2.9–4.2)	<0.001	3.3 (2.5–4.0)	2.7 (2.3–3.2)	0.02	<0.001
Coagulation tests
Median (IQR)
INR, peak n = 127	1.2 (1.1–1.3)	1.2 (1.1–1.3)	0.51	1.2 (1.1–1.4)	1.3 (1.2–1.4)	0.23	0.01
D Dimer (ug/mL), peak	1.2 (0.5–3.2)	2.2 (0.9–6.3)	0.05	3.0 (1.5–4.5)	4.8 (3.2–15.3)	0.01	0.01
Complete blood count
Mean (±SD)
White blood cell count (10³/mm³), peak	11.0 (±6.5)	14.3 (±14.5)	0.02	16.4 (±9.7)	21.1 (±13.8)	0.11	0.02
Acute lymphocytic count (cells/mm³), nadir	2,295 (±1,641)	1,380 (±1,150)	<0.01	2,005 (±1967)	1,382 (±1234)	0.33	0.99
Platelet count (10³/mm³), peak	250 (±129)	210 (±120)	0.03	235 (±136)	134 (±96)	0.001	0.01
Inflammatory markers
Median (IQR)
CRP (mg/dL), peak	1.4 (0.5–5.7)	13.6 (3.6–23.4)	<0.001	14.0 (2.9–25.2)	19.0 (6.0–30.0)	0.07	0.06
Ferritin (ng/mL), peak	144 (71–382)	1208 (368 −2629)	<0.001	344 (171–531)	759 (508–1641)	<0.001	0.69
IL 6 (pg/mL), peak	22.9 (7.3–78.7)	61.4 (9.0–315.0)	0.30	213.1 (31.0–315.0)	234.6 (86.6–315.0)	0.51	0.04
LDH (U/L), peak	287 (217–386)	464 (353–738)	<0.001	315 (288–409)	370 (300–482)	0.07	0.19
Other tests
Median (IQR)
CK (IU/L), peak	138 (77–226)	223 (100–662)	0.12	120 (67–168)	280 (78–983)	0.18	0.93

Note: Clinically relevant and significant values depicted.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; CRP, c-reactive protein; g/dL, gram per deciliter; ICU, intensive care unit; IL 6, interleukin 6; INR, international normalized ratio; IU/L, international units per liter; k/uL, kilo per microliter; LDH, lactate dehydrogenase; mg/dl, milligram per deciliter; mg/L, milligrams per liter; mm³, cubic millimeter; ng/mL, nanogram per milliliter; pg/ml, picograms per milliliter; U/L, unit per liter; ug/mL, microgram per milliliter.
For additional variables, please see supplemental tables.
^acompares children with elevated ALT defined as ALT > 40 U/L in COVID-19 vs MIS-C.

Table 3. Predictors of ALT elevations comparing Children with *COVID-19 and MIS-C*
	COVID-19			MIS-C
	OR	95% Confidence interval	P-value	OR	95% Confidence interval	P-value
Age	1.02	0.94–1.11	0.64	1.14	0.97–1.34	0.11
Male sex	2.34	0.73–7.46	0.15	5.29	1.25–22.43	0.02
Black race	0.28	0.06–1.30	0.10	4.43	1.01–18.81	0.04
Obesity	1.67	0.55–5.07	0.37	-	-	-
Chronic liver disease	2.39	0.32–17.95	0.40	-	-	-
ICU admission	2.63	0.66–10.44	0.17	-	-	-
Peak CRP	1.08	1.03–1.15	0.01	1.02	0.96–1.08	0.63

Note: Multivariable logistic regression comparing children without and with elevated ALT. E-ALT defined as ALT > 40 U/L. Obesity defined as body mass index ≥95th percentile in patients <18 years-old or ≥30 kg/m² in patients 19–21 years-old, COVID-19 cohort: ALT ≤ 40 U/L (n = 151) and ALT > 40 U/L (n = 69)
MIS-C cohort: ALT ≤ 40 U/L (n = 35) and ALT > 40 U/L (n = 36).
Abbreviations: ALT, alanine aminotransferases; CI, Confidence interval; COVID-19, coronavirus disease-2019; CRP, c-reactive protein; MIS-C, multisystem inflammatory syndrome in children; OR, odds ratio.

Table 4. Predictors of elevated ALT among children comparing *COVID-19 vs MIS-C*
	OR	95% Confidence interval	P value
Age	1.05	0.99–1.11	0.06
Male sex	2.33	1.22–4.47	0.01
Black race	0.84	0.42–1.69	0.62
Presence of MIS-C	2.30	1.10–4.87	0.03

Note: Multivariable logistic regression comparing ONLY children with elevated ALT defined as ALT >40 U/L in COVID-19 (n = 69) versus MIS-C (n = 36).
Abbreviations: ALT, alanine aminotransferase; COVID-19, coronavirus disease-2019, OR: odds ratio; MIS-C, multisystem inflammatory syndrome in children.