key: cord-0765324-ggnec1w5
authors: Perez, Adriana; Cantor, Amanda; Rudolph, Bryan; Miller, Jonathan; Kogan‐Liberman, Debora; Gao, Qi; Da Silva, Bernardo; Margolis, Kara G.; Ovchinsky, Nadia; Martinez, Mercedes
title: Liver involvement in children with SARS‐COV‐2 infection: Two distinct clinical phenotypes caused by the same virus
date: 2021-04-22
journal: Liver Int
DOI: 10.1111/liv.14887
sha: 8a530845d9989f4f179a0bbcc043fa95e7ec597a
doc_id: 765324
cord_uid: ggnec1w5

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.

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] [13] [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] [13] [14] [15] [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.

In this retrospective study, we included patients ≤21 years old 19 We excluded children without liver tests.

Clinical, demographic, laboratory, and anthropometric data were collected. We have defined E-ALT as a peak elevation of ALT >40 U/L, as these values were reported to fall above the 97th percentile for all ages and both sexes in a large cohort of healthy children. 20 

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.

acute liver failure, acute liver injury and MISC, COVID-19 ALI in children, elevated ALT, liver involvement in SARS-CoV2

• Children with either COVID-19 or MIS-C who developed concomitant elevated alanine aminotransferase were at risk of a more severe disease course including longer hospitalization and ICU stay.

• Obese children immunocompromised and children with chronic liver disease with COVID-19

were more frequently to develop hepatitis.

• Children with MIS-C had overall higher chances of getting hepatitis compared to children with COVID-19 (ALT > 40 U/L) or absent (ALT ≤ 40 U/L) within each cohort. We also evaluated AST, bilirubin, albumin, and INR values. Obesity was defined as body mass index (BMI) above 95th percentile and/or BMI ≥30 kg/m 2 as applicable. An immunocompromised state was defined by the presence of malignancy requiring chemotherapy or radiation, recipients of bone marrow or solid organ transplant, or among patients receiving other immunosuppressive therapy or biologics including those with inflammatory bowel disease.

Student's t-test or Mann-Whitney U-test was performed for continuous variables. Chi-square or Fisher's exact test was used for categorical variables to identify differences between the presence or absence of E-ALT within each cohort (COVID-19 and MIS-C) and to compare the differences between them. Variables were presented as frequency (percentage), mean with standard deviation (SD), or median with interquartile range (IQR), as appropriate.

Multivariable logistic regression was used to examine the potential risk factors for E-ALT by cohort (COVID-19 and MIS-C) and for the combined data set. Clinically significant variables and/ or those with P < .25 in bivariate analysis were selected. Due to the small sample size in each cohort, the association between the potential risk factors and E-ALT was tested sequentially, while controlling for age, gender, and race in each model, as well as for other predictors. Backward variable selection was used to compare E-ALT in MIS-C to E-ALT in COVID-19 until all variables were significant, while controlling for age, gender, and race. P-values <0.05 were considered statistically significant. All analyses were performed using SAS 9.4.

A total of 291 patients were included in the study: 220 (76%) and 71 (24%) were diagnosed with COVID-19 and MIS-C respectively Table S1 ) and MIS-C respectively. One child with MIS-C developed acute liver failure and recovered.

Flow-chart of study cohort demonstrating the differences of ALI in the COVID-19 and MIS-C cohorts; A total of 291 patients were included in the study: 220 (76%) and 71 (24%) were diagnosed with COVID-19 and MIS-C, respectively. ALI was detected in 31% (n = 69) of children with COVID-19 and 51% (n = 36) of children with MIS-C. Severe injury defined as ALT > 200 U/L was noted in 8% of children with COVID-19 and 4% of children with MIS-C, respectively. Abbreviations: ALI, acute liver injury; ALT, alanine aminotransferase; COVID-19, Coronavirus disease 2019; MIS-C, system inflammatory syndrome in children

Children with E-ALT were significantly older, with a median age of 16 vs 11 years (P =.001). No differences were observed in race, gender, or ethnicity. E-ALT was associated with obesity (P <.001), immunocompromised status (P =.04), presence of any malignancy (P =.01), and chronic liver disease (CLD) (P =.01). Underlying CLD was present in 13% of children with E-ALT. The etiologies of CLD in patients in whom prior medical history could be discerned were non-alcoholic fatty liver disease (NAFLD) (six patients), biliary atresia (1), liver transplant recipient (1), and glycogenic hepatopathy (1) ( Tables 1, 2; Tables S1 and S2).

Children with E-ALT were also significantly older, with a median age of 9.5 vs 6 years (P = .01). E-ALT was associated with Black race (P = .01) and male gender (P = .001). Most children had no prior medical history and no differences in BMI were noted (Tables 1, 2; Tables S3).

Liver involvement in both cohorts was characterized by statistically significant elevation of median ALT above 2x ULN with mild cholestasis. MIS-C hepatitis was associated with decreased albumin (median 2.7, P < .001) and thrombocytopenia (mean 134, P = .01). Children with E-ALT and MIS-C were more frequently Hispanic (P = .04) and

of Black race (P < .001). Cardiac dysfunction (P < .001), kidney injury (P = .01), elevated troponin (P = .03), higher pro-B natriuretic peptide (P < .001), higher median D-dimer levels (P = .01), and higher peak interleukin-6 (P = .04) were more frequently recorded in the MIS-C cohort with E-ALT (Tables 1, 2; Tables S4). Children with E-ALT in both cohorts had a more severe disease course with a greater prevalence of multiorgan dysfunction (P = .001 in both cohorts), respiratory failure (P = .001 and 0.01 in COVID-19

and MIS-C, respectively), longer hospitalization (P < .001 and .001), and longer ICU stay (P = .01 and 0.04). No significant association was found between E-ALT and mortality in COVID-19 (see Table S6 for details), and no deaths were recorded in the MIS-C cohort. In multivariable analysis, E-ALT in the COVID-19 cohort was associated with an increase in c-reactive protein (CRP) level (OR 1.08 with 95% confidence interval [CI] [1.03-1.15]) after adjustment for age, gender, race, obesity, CLD, and ICU admission (Table 3 ). In the MIS-C cohort, male gender and Black race were associated with more than 5-and 4-fold increased E-ALT odds, respectively, when adjusted for age and CRP ( Table 3 ). The association with gender was consistent in all multivariable regression models; Black race was also associated with E-ALT when adjusted for obesity but did not reach statistical significance in other models (Table S5) .

Children with MIS-C had 2.3× increased odds of elevated ALT levels than children with COVID-19 after adjusting for age and race (Table 4 ).

In our study, 36% of children developed E-ALT, which was also Obesity was present in both cohorts, albeit significantly more prevalent in children with E-ALT in COVID-19. Among them, only six children were previously diagnosed with NAFLD. We cannot exclude the possibility of a higher prevalence of NAFLD within this cohort due to our retrospective design limitations. It has been proposed that patients with NAFLD may be susceptible to a worsening viral oxidative stress when infected with a hepatotoxic virus. 29 It is worth noting that the three patients who died of COVID-19

and developed E-ALT and the single patient in the MIS-C cohort who developed acute liver failure were obese (Table S6) . Adult literature also highlights the association between clinical course severity and obesity in COVID-19. It further implies that increased morbidity may be due to obesity-related impact on cytokine dysfunction or impaired immune response in leptin resistance, raising concerns that obesity influences disease behavior. 30 -32 This observation is particularly relevant given the increasing prevalence of obesity in our children and is an essential practical point for the bedside physician. 33 Racial disparities in SARS-CoV-2 infection, including a higher disease prevalence and mortality among adult Blacks and Hispanics, have been noted, but these observations are based on limited data. 34 Population-based data from MIS-C in NYC also concluded a disproportionate MIS-C burden among Black and Hispanic children. 35 It is unclear whether this finding represents an actual phenomenon or skewness due to missing race/ethnicity data for most confirmed, non-hospitalized, and nonfatal cases. 35 We did not identify any racial differences pre- In conclusion, liver involvement associated with SARS-CoV-2 infection typically leads to a temporary moderate elevation of liver tests without significant hepatic synthetic function impairment.

Patients with SARS-CoV-2 infection and E-ALT are at risk of a more severe disease course including longer hospitalization and ICU stays.

Children require careful management and monitoring throughout their hospitalization and thereafter to establish resolution of elevated ALT values. Further studies need to provide mechanistic insights into the pathophysiology of underlying liver injury in both conditions.

The authors declare no conflict of interest related to this study.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Abbreviations: ALT, alanine aminotransferase; COVID-19, coronavirus disease-2019, OR: odds ratio; MIS-C, multisystem inflammatory syndrome in children.

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