Liver abnormalities following SARS-CoV-2 infection in children under 10 years of age (preprint)

ObjectiveBeginning in October 2021 in the US and elsewhere, cases of severe pediatric hepatitis of unknown etiology were identified in young children. While the adenovirus and adenovirus-associated virus have emerged as leading etiologic suspects, we attempted to investigate a potential role for SARS-CoV-2 in the development of subsequent liver abnormalities. DesignWe conducted a study utilizing retrospective cohorts of de-identified, aggregated data from the electronic health records of over 100 million patients contributed by US health care organizations. ResultsCompared to propensity-score-matched children with other respiratory infections, children aged 1-10 years with COVID-19 had a higher risk of elevated transaminases (Hazard ratio (HR) (95% Confidence interval (CI)) 2.16 (1.74-2.69)) or total bilirubin (HR (CI) 3.02 (1.91-4.78)), or new diagnoses of liver diseases (HR (CI) 1.67 (1.21-2.30)) from one to six months after infection. Patients with pre-existing liver abnormalities, liver abnormalities surrounding acute infection, younger age (1-4 years), or illness requiring hospitalization all had similarly elevated risk. Children who developed liver abnormalities following COVID-19 had more pre-existing conditions than those who developed abnormalities following other infections. ConclusionThese results indicate that SARS-CoV-2 may prime the patient for subsequent development of liver infections or non-infectious liver diseases. While rare ([~]1 in 1,000), SARS-CoV-2 is a risk for subsequent abnormalities in liver function or the diagnosis of diseases of the liver. What is already known on this topicClusters of severe hepatitis in children in 2022 coincident with the increase in COVID-19 infections in children raised the question of the contribution of SARS-CoV-2 to the hepatitis outbreak, though it was soon determined that SARS-CoV-2 was not the primary etiologic agent. What this study addsSARS-CoV-2 may prime the patient for subsequent development of liver infections or non-infectious liver diseases. How this study might affect research, practice or policyDespite the mild initial disease in children, there may be longer term consequences of COVID-19, such as liver abnormalities, that warrants further investigation.

Primary Liver Rhabdomyosarcoma in a Burnt-out disease: An unusual presentation (preprint)

Rhabdomyosarcoma is the most common soft tissue sarcoma in children. However, Primary hepatic RMS is rare and less than 20 cases are reported in literature. We present the case of a neonate who presented to us with a lumbar mass and lost follow-up during COVID pandemic. She came back to us with a Primary liver Rhabdomyosarcoma in the setting of a burnt out disease. In the setting of a diagnostic dilemma, we found histopathology as the cornerstone to diagnosis. Multimodality therapy based on the experience of similar case reports is the answer is such rare cases where specific guidelines are not yet defined.

Effect Of Molnupiravir On Ichemia/Reperfusion Damage In Rat Liver, An Experimental Study (preprint)

Background Ischemia occurs when blood supply to tissues is limited, resulting in cellular dysfunction and necrosis. Reperfusion, or the process of restoring blood flow, can result in an overabundance of reactive oxygen species (ROS) and toxic byproducts. The I/R (Ischemia / Reperfusion) technique used in liver resection and transplantation has been linked to liver damage. Molnupiravir, a non-hepatotoxic oral medicine, is converted into N-hydroxycytidine (NHC). The purpose of this study is to see how molnupiravir affects I/R-induced damage of liver in rats.Methods We divided the rats into three groups: Sham operation (SG) (n = 6), Liver I/R (LIR) (n = 6), and Molnupiravir + Liver I/R (MIR) (n = 6) groups. The MIR group (n = 6) received 40 mg/kg of molnupiravir. All animals were subjected to laparotomy, hepatic ischemia (1 hour), and reperfusion (6 hours). At the end of the trial, liver tissue samples were tested for IL-1β, tGSH, NF-κB, MDA, and TNF-α levels, as well as histopathological examination. The levels of ALT and AST in the blood were determined. The MIR group's results were in comparison to the SG and LIR groups.Results Biochemical examination revealed that NF-ƘB, MDA, TNF-α, IL-1β, ALT, and AST measurements were higher in the LIR and MIR groups than in the SG group. The SG group had the highest tGSH values. Histopathological examinations revealed that the MIR group had the most damage.Conclusion While molnupiravir, which is included in COVID-19 treatment regimen since it has no projected liver toxicity, does not affect healthy liver tissue, it does exacerbate ischemia/reperfusion injury in stressed liver tissue. Molnupiravir should be used with caution because it has the potential to aggravate liver damage during procedures such as liver transplantation or resection.

A clustering and graph deep learning-based framework for COVID-19 drug repurposing (preprint)

Drug repurposing (or repositioning) is the process of finding new therapeutic uses for drugs already approved by drug regulatory authorities (e.g., the Food and Drug Administration (FDA) and Therapeutic Goods Administration (TGA)) for other diseases. This involves analyzing the interactions between different biological entities, such as drug targets (genes/proteins and biological pathways) and drug properties, to discover novel drug-target or drug-disease relations. Artificial intelligence methods such as machine learning and deep learning have successfully analyzed complex heterogeneous data in the biomedical domain and have also been used for drug repurposing. This study presents a novel unsupervised machine learning framework that utilizes a graph-based autoencoder for multi-feature type clustering on heterogeneous drug data. The dataset consists of 438 drugs, of which 224 are under clinical trials for COVID-19 (category A). The rest are systematically filtered to ensure the safety and efficacy of the treatment (category B). The framework solely relies on reported drug data, including its pharmacological properties, chemical/physical properties, interaction with the host, and efficacy in different publicly available COVID-19 assays. Our machine-learning framework reveals three clusters of interest and provides recommendations featuring the top 15 drugs for COVID-19 drug repurposing, which were shortlisted based on the predicted clusters that were dominated by category A drugs. The anti-COVID efficacy of the drugs should be verified by experimental studies. Our framework can be extended to support other datasets and drug repurposing studies, given open-source code and data availability.

The impact of the COVID-19 pandemic on treatment for domestic violence injuries: evidence from medical claims (preprint)

Previous studies have observed heterogeneous changes in domestic violence-related 911 calls, police incident reports, and arrests at the onset of the COVID-19 pandemic. In this study, we use a large-scale medical claims database with coverage of over 100 million patients to examine the impact on domestic violence victims’ use of emergency department care for their injuries in the early weeks of the pandemic compared to the corresponding weeks in previous years. We find a 35% decrease in utilization of emergency medical services by domestic violence victims between March and June of 2020. Based on this finding, it is essential to use caution when using medical claims to measure domestic violence in future research covering this time period. Decreases in care utilization also have important implications for the detection, screening, and treatment of domestic violence injuries during future public health crises.

Ivermectin drug induced liver injury.

Ivermectin remains a popular, albeit unproven, therapy used in both the prevention and treatment of COVID-19. We discuss a patient who developed jaundice and a liver injury 3 weeks after initiating ivermectin for COVID prevention.  Liver histology demonstrated a pattern of injury that was both portal and lobular, with a bile ductulitis as well with marked cholesasis. She was managed with low dose corticosteroids, later tapered and withdrawn. She remains well a year after presenting.

[Treatment of toxic hepatitis in COVID-19 patients].

BACKGROUND: The article reflects the clinical significance of the early diagnosis of toxic hepatitis in patients who have undergone a new coronavirus infection with the determination of clinical and laboratory predictors of the response to therapy. A dynamic analysis of the effectiveness of toxic hepatitis therapy in patients of three experimental groups and a control group is presented. AIM: The aim of the present study is to increase the effectiveness of the treatment of toxic hepatitis in patients who have undergone COVID-19. MATERIALS AND METHODS: On the basis of the newly created infection centers of the Central Clinical Hospital "RZhD-Medicine" and Vishnevsky 3-rd Central Military Clinical Hospital 996 patients with COVID-19, who had clinical and laboratory signs of toxic liver damage (cytolytic and/or cholestatic syndromes) against the background of COVID-19 therapy. RESULTS: On the 14th day from the start of therapy in group 3, there was a significant decrease in the clinical manifestations of jaundice in 163 (72.8%) patients, on the 21st day of treatment, this symptom was stopped in all patients. In groups 1 and 2, the decrease in clinical manifestations of jaundice was significantly lower - 122 (55.2%) and 134 (58.8%); p<0.05. At the end of therapy, no manifestations of jaundice were observed in all experimental groups, while in the control group, symptom reduction was achieved only in 47 (14.5%) patients. CONCLUSION: The use of drugs with hepatoprotective effect in the form of monotherapy in groups 1 (UDCA) and 2 (ademethionine) showed a low therapeutic effect with positive dynamics of clinical and laboratory indicators of toxic hepatitis activity. The use of combined treatment in group 3 (UDCA and ademethionine) demonstrated the maximum therapeutic effect, pronounced positive dynamics in the form of normalization of clinical and laboratory indicators of toxic hepatitis activity.

Early treatment with N-acetylcysteine reduces hepatotoxicity in acute acetaminophen poisoning.

During the outbreak of COVID19 measures taken to contain the spread of the virus have influenced the mental well-being of adults and adolescents. Acetaminophen overdose is the major cause of drug intoxication among children and adolescents. We reported a case of a 15-year- old girl referred to our Emergency Department 3 hours after ingestion of 10 g of paracetamol for suicidal purposes. She promptly started the administration of intravenous N-acetylcysteine (NAC) and the patient was discharged after 5 days of hospitalization in good clinical condition and with neuropsychiatric follow-up. Our case shows that the timing of the intravenous NAC administration is considered the most important factor in the prevention of acetaminophen-induced hepatic failure, despite high serum levels after acetaminophen ingestion.

The Prophylactic Effect of Vitamin C and Vitamin B12 against Ultraviolet-C-Induced Hepatotoxicity in Male Rats.

Ultraviolet C (UVC) devices are an effective means of disinfecting surfaces and protecting medical tools against various microbes, including coronavirus. Overexposure to UVC can induce oxidative stress, damage the genetic material, and harm biological systems. This study investigated the prophylactic efficacy of vitamin C and B12 against hepatotoxicity in UVC-intoxicated rats. Rats were irradiated with UVC (725.76, 967.68, and 1048.36 J/cm2) for 2 weeks. The rats were pretreated with the aforementioned antioxidants for two months before UVC irradiation. The prophylactic effect of vitamins against UVC hepatotoxicity was evaluated by monitoring the alteration of liver enzyme activities, antioxidant status, apoptotic and inflammatory markers, DNA fragmentation, and histological and ultrastructural alterations. Rats exposed to UVC showed a significant increase in liver enzymes, oxidant-antioxidant balance disruption, and increased hepatic inflammatory markers (TNF-α, IL-1ß, iNOS, and IDO-1). Additionally, obvious over-expression of activated caspase-3 protein and DNA fragmentation were detected. Histological and ultrastructural examinations verified the biochemical findings. Co-treatment with vitamins ameliorated the deviated parameters to variable degrees. In conclusion, vitamin C could alleviate UVC-induced hepatotoxicity more than vitamin B12 by diminishing oxidative stress, inflammation, and DNA damage. This study could provide a reference for the clinical practice of vitamin C and B12 as radioprotective for workers in UVC disinfectant areas.

Improving modelling for epidemic responses: reflections from members of the UK infectious disease modelling community on their experiences during the COVID-19 pandemic (preprint)

The COVID-19 pandemic both relied and placed significant burdens on the experts involved from research and public health sectors. The sustained high pressure of a pandemic on responders, such as healthcare workers, can lead to lasting psychological impacts including acute stress disorder, post-traumatic stress disorder, burnout, and moral injury, which can impact individual wellbeing and productivity. As members of the infectious disease modelling community, we convened a reflective workshop to understand the professional and personal impacts of response work on our community and to propose recommendations for future epidemic responses. The attendees represented a range of career stages, institutions, and disciplines. This piece was collectively produced by those present at the session based on our collective experiences. Key issues we identified at the workshop were lack of institutional support, insecure contracts, unequal credit and recognition, and mental health impacts. Our recommendations include rewarding impactful work, fostering academia-public health collaboration, decreasing dependence on key individuals by developing teams, increasing transparency in decision-making, and implementing sustainable work practices. Despite limitations in representation, this workshop provided valuable insights into the UK COVID-19 modelling experience and guidance for future public health crises. Recognising and addressing the issues highlighted here is crucial, in our view, for ensuring the effectiveness of epidemic response work in the future.

AMA-positive hepatitis induced by the SARS-CoV-2 vaccine.

We present the case of a 56-year-old female admitted to our centre for hepatitis. She had recieved the first dose of the BNT162b2 vaccine against SARS-CoV-2 10 days before the admission. Etiologic study was negative. The patient was diagnosed with vaccine-induced hepatitis.

Impact of COVID-19 lockdowns on pediatric injury attendances in different population groups in Israel: an interrupted time-series analysis, 2018-2022. (preprint)

Background Lockdowns and quarantines during the COVID-19 pandemic influenced healthcare services’ usage patterns such as emergency department (ED) attendances. During the pandemic, Israel issued three lockdowns (March-May 2020, September-October 2020, December 2020-February 2021) to mitigate the spread of COVID-19. Little is known about the impact of these lockdowns on ED attendance for injuries in the diverse population of Northern Israel.Methods We conducted a retrospective time series analysis. We extracted data from medical records of all northern Israeli children aged 0–17 years old who attended Ziv Medical Center (ZMC) emergency department (ED) due to injury, between 01/01/2018 and 10/02/2022. We compared volume and characteristics of ED attendances during lockdown periods to the same time periods in the 2 years before the pandemic and 1 year after the lockdowns, using chi-square tests.Results 7,619 northern children attended ZMC ED during the time periods of the study for injuries and were analyzed. Mean attendance numbers during lockdowns decreased compared to previous years, with an increase in injuries proportion (67.8% (1502/2216) vs. 52.7% (2038/3868) p < 0.001). The proportion of 0–4 years old attending for injuries during the lockdown increased compared to pre-pandemic (39.68% vs. 30.7%, p < 0.0001). Minority populations attendances decreased (27.47% vs. 30.71% p = 0.02). Hospitalization rates increased (13.21% vs. 10.65% p = 0.01). Post-lockdown periods saw a return to the pre-pandemic age and ethnicity distribution.Conclusions Compared to previous years, the volume of injuries was lower during lockdowns for all ages. Older children’s injuries may have been prevented by lockdowns, possibly because of restrictions on outdoor activities. A lower proportion of attendance from minority groups suggest different health seeking behavior patterns during emergencies compared to the general population. Understanding these differences will help better plan for future emergencies.

In Silico Investigation of Komaroviquinone as a Potential Inhibitor of Sars-Cov-2 Main Protease (Mpro): Molecular Docking, Molecular Dynamics, and Qm/Mm Approaches (preprint)

COVID-19 has highlighted the urgent need for new therapeutic agents to combat the spread of the virus. The main protease of SARS-CoV-2 (Mpro) has emerged as a promising target. In this study, we conducted an in silico investigation to explore the potential of Komaroviquinone, an icetexane diterpene, as a therapeutic agent against COVID-19. We employed molecular docking, molecular dynamics, and QM/MM methodologies to compare the binding affinity, molecular interactions, and stability of Komaroviquinone and the FDA-approved antiviral drug Nirmatrelvir with the SARS-CoV-2 Mpro protein. The study demonstrated that Komaroviquinone exhibits strong interaction with Mpro, with a binding energy comparable to Nirmatrelvir. The ADMET analysis revealed that Barbatusol, Brussonol, and Komaroviquinone possess superior solubility, permeability, and intestinal absorption compared to Nirmatrelvir, as well as more favorable distribution properties and lower toxicity profiles. Notably, Nirmatrelvir displayed toxicity and hepatotoxicity, which were not present in the natural compounds. Thus, it is suggested that Komaroviquinone may be a promising candidate for the development of effective and safer therapeutic agents against COVID-19. Experimental validation is necessary to confirm its potential as a treatment for the disease.

Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors.

Antiviral protease inhibitors are peptidomimetic molecules that block the active catalytic center of viral proteases and, thereby, prevent the cleavage of viral polyprotein precursors into maturation. They continue to be a key class of antiviral drugs that can be used either as boosters for other classes of antivirals or as major components of current regimens in therapies for the treatment of infections with human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, sustained/lifelong treatment with the drugs or drugs combined with other substance(s) often leads to severe hepatic side effects such as lipid abnormalities, insulin resistance, and hepatotoxicity. The underlying pathogenic mechanisms are not fully known and are under continuous investigation. This review focuses on the general as well as specific molecular mechanisms of the protease inhibitor-induced hepatotoxicity involving transporter proteins, apolipoprotein B, cytochrome P450 isozymes, insulin-receptor substrate 1, Akt/PKB signaling, lipogenic factors, UDP-glucuronosyltransferase, pregnane X receptor, hepatocyte nuclear factor 4α, reactive oxygen species, inflammatory cytokines, off-target proteases, and small GTPase Rab proteins related to ER-Golgi trafficking, organelle stress, and liver injury. Potential pharmaceutical/therapeutic solutions to antiviral drug-induced hepatic side effects are also discussed.

Evaluating the Association of Depressive Disorder Symptoms and Moral Injuries in Healthcare Workers during COVID-19 Pandemic (preprint)

Abstract Background: Moral injury occurs when negative distressing emotions appear and are suppressed. This could lead to several mental health problems such as depression and post-traumatic stress disorder, and result in long-lasting emotional, behavioral, and social problems. Moral injury, a term more commonly used in war contexts, has come into the spotlight during COVID-19 pandemic. We aimed to evaluate the rate of moral injury and its association with psychological injuries during this healthcare crisis. Methods: We assessed the rates of depression, anxiety, stress, and their association with moral injury among 333 nurses, medical interns, and residents between December 2020 and January 2021. This study was done using validated versions of Depression Anxiety Stress Scales (DASS-21) and Moral Injury Symptom Scale-Healthcare Professionals (MISS-HP) scores. Results: Totally 333 healthcare professionals participated in this study, mostly aged between 26 to 30 years old. Nearly half of the participants had a clinically significant moral injury. The average scores of anxiety and stress were significantly higher in women. The participants who were single showed higher rates of depression and moral injury than married ones. Moreover, anxiety, stress, depression, and moral injury were higher in nurses than other healthcare professionals. The scarcity of personal protective equipment at the workplace and giving care to patients with end-stage COVID-19 diagnosis were among the factors associated with a higher risk of developing mental health problems. Conclusion: The results of this study showed that anxiety, stress, depression, and moral injury were prevalent among healthcare professionals during COVID-19 pandemic. Also, the rates of anxiety, stress, and depression were associated with moral injuries.

Recovery from post-COVID-19 vaccination biliary ductopenia and multiorgan inflammation: A case with insight from angiotensin II type 1 receptor antibody- mediated injury (preprint)

Background The coronavirus disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality. Spike messenger RNA (mRNA)–based vaccines against severe acute respiratory syndrome coronavirus 2 may contribute to immune-mediated injuries. Here we present a case of marked cholangiopathy with multiorgan injury and investigate the potential mechanisms associated with mRNA-based vaccines. Case summary and investigation A previously healthy 47-year-old man developed progressive jaundice 2 weeks after receiving his 3rd COVID-19 vaccination (1st mRNA-based vaccine). Apart from elevated serum total bilirubin levels (peaked at >70 mg/dL), deteriorating renal (blood urea nitrogen: peak, 108.5 mg/dL; creatinine: peak, 6 mg/dL) and exocrine pancreas (amylase: peak, 1717 U/L; lipase: peak, 5784 U/L) profiles were also seen. Vanishing bile duct syndrome characterized by ductopenia and cholangiocyte vacuolation, positive C4d deposition, and high titer of anti-angiotensin II type 1 receptor antibody consistently explain the overall antibody-mediated pathogenesis resembling antibody-mediated “rejection” in the solid organ transplant setting. Corticosteroids and plasmapheresis were administered, leading to gradual resolution of the symptoms, and the jaundice completely resolved 2 months later. Conclusion Here we reported a case of antibody-mediated multiorgan injury after an mRNA COVID-19 vaccine characterized by severe cholangiopathy. The patient recovered with corticosteroids and plasmapheresis, and long-term follow-up is needed.

Highlights of the drug-induced liver injury literature for 2021.

INTRODUCTION: In 2021, over 3,000 articles on Drug-Induced Liver Injury (DILI) were published, nearly doubling the annual number compared to 2011. This review selected DILI articles from 2021 we felt held the greatest interest and clinical relevance. AREAS COVERED: A literature search was conducted using PubMed between 1 March 2021 and 28 February 2022. 86 articles were included. This review discusses new and established cases of hepatotoxins, including new FDA approvals and COVID-19 therapeutics. Developments in biomarkers and causality assessment methods are discussed. Updates from registries are also explored. EXPERT OPINION: DILI diagnosis and prognostication remain challenging. Roussel Uclaf Causality Assessment Method (RUCAM) is the best option for determining causality and has been increasingly accepted by clinicians. Revised Electronic Causality Assessment Method (RECAM) may be more user-friendly and accurate but requires further validation. Quantitative systems pharmacology methods, such as DILIsym, are increasingly used to predict hepatotoxicity. Oncotherapeutic agents represent many newly approved and described causes of DILI. Such hepatotoxicity is deemed acceptable relative to the benefit these drugs offer. Drugs developed for non-life-threatening disorders may not show a favorable benefit-to-risk ratio and will be more difficult to approve. As the COVID-19 landscape evolves, its effect on DILI deserves further investigation.

Drug-induced liver injury in COVID-19 patients during hospitalization.

Since coronavirus disease 2019 (COVID-19) outbreaks in December 2019 in Wuhan, almost no studies have systematically described drug-induced liver injury (DILI) in COVID-19 patients. This study aimed to assess the characteristics of liver test abnormality or liver injury in patients with COVID-19, and further to explore DILI in COVID-19 patients during hospitalization. It was a single-center retrospective analysis of confirmed severe acute respiratory syndrome coronavirus 2 infected patients in the hospital from January 2020 to March 2020. Univariate and multivariate logistic regression analysis were used to assess the risk factors associated with liver test abnormality or liver injury. At admission, 148 (48.8%, 148/303) patients had abnormal liver test results and 7 (2.4%, 7/303) had liver injury, while 195 (64.4%, 195/303) had abnormal liver test results and 17 (5.6%, 17/303) had liver injury during hospitalization. After excluding these patients with liver disease and liver function abnormalities or liver injury at admission, 15 (11.1%, 15/135) patients developed DILI during hospitalization. Further regression analysis indicated that methylprednisolone (odds ratio = 4.177, 95% confidence interval [1.106-15.771], P = .035), but not Chinese herbal medicine or other used drug, was associated with DILI in patients during hospitalization. Abnormal liver function results were in more than half of patients with COVID-19, and the incidence of DILI in COVID-19 patients was 11.1% during hospitalization. Liver test abnormality or liver injury in patients might be directly caused by the viral infection at admission, but the detrimental effects on liver injury mainly related to certain medications used during hospitalization, particularly methylprednisolone. Severe COVID-19 could increase the occurrence of liver injury (P = .007) during hospitalization, but not a risk factor of liver injury. However, Chinese herbal medicine was a protective factor for liver injury.