Case Of Severe Acute Hepatitis Research Articles

Severe acute hepatitis of unknown origin in children: Is it still amystery? What role does adenovirus play?

On March 31, 2022, severe acute hepatitis of unknown origin was first reported from the Royal Glasgow Children's Hospital in Scotland. According to the criteria by WHO-ECDC, a probable case of unknown acute hepatitis in children is defined as a subject under 16 years of age, who tested negative for viral hepatitis and transaminases >500 U/L, starting from the 1st of October 2021. WHO invites Member States to participate in the global effort to collect anonymized clinical data on probable cases of severe acute hepatitis of unknown aetiology. As of May 26, 2021, 650 cases were already registered on the platform worldwide, of whom at least 38 cases have required liver transplants. Several hypotheses such as previous SARS-CoV-2 infection or coinfection or infection with another virus were examined and a strong association was found between adenovirus (41F) and acute hepatitis of unknown aetiology cases. This review article summarizes the global epidemiological evidences on acute hepatitis of unknown origin in children, analysing their incidence and characteristics.

Task Force for a rapid response to an outbreak of severe acute hepatitis of unknown aetiology in children in Portugal in 2022.

On 5 April 2022, the United Kingdom reported an increase of cases of severe acute hepatitis of unknown aetiology in children, several needing hospitalisation and some required liver transplant or died. Thereafter, 35 countries reported probable cases, almost half of them in Europe. Facing the alert, on 28 April, Portugal created a multidisciplinary Task Force (TF) for rapid detection of probable cases and response. The experts of the TF came from various disciplines: clinicians, laboratory experts, epidemiologists, public health experts and national and international communication. Moreover, Portugal adopted the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO) case definition and recommendations. By 31 December 2022, 28 probable cases of severe acute hepatitis of unknown aetiology were reported: 16 male and 17 aged under 2 years. Of these cases, 23 were hospitalised but none required liver transplant or died. Adenovirus was detected from nine of 26 tested cases. No association was observed between adenovirus infection and hospital admission after adjusting for age, sex and region in a binomial regression model. The TF in Portugal may have contributed to increase awareness among clinicians, enabling early detection and prompt management of the outbreak.

Signatures of AAV-2 immunity are enriched in children with severe acute hepatitis of unknown etiology.

Severe acute hepatitis of unknown etiology in children is under investigation in 35 countries. Although several potential etiologic agents have been investigated, a clear cause for the liver damage observed in these cases remains to be identified. Using VirScan, a high-throughput antibody profiling technology, we probed the antibody repertoires of nine cases of severe acute hepatitis of unknown etiology treated at Children's of Alabama and compared their antibody responses with 38 pediatric and 470 adult controls. We report increased adeno-associated dependoparvovirus A (AAV-A) breadth in cases relative to controls and adeno-associated virus 2 (AAV-2) peptide responses that were conserved in seven of nine cases but rarely observed in pediatric and adult controls. These findings suggest that AAV-2 is a likely etiologic agent of severe acute hepatitis of unknown etiology.

English

In the current New Normal Era, people are starting to be free to do activities outside the house, with the condition of wearing a mask to prevent the coronavirus. After the number of cases of the Covid-19 pandemic began to decline, the World Health Organization (WHO) received a report on April 5, 2022, from the United Kingdom regarding cases of acute hepatitis that began to spread in children and whose aetiology was unknown. The spread of the disease can be through the air, so everyone must wear a mask outside the house. Through the Ministry of Health, the Indonesian government reported that as of June 16, 2022, at 16.00, there were 28 suspected cases of severe acute hepatitis with unknown or mysterious causes for Indonesian children. This number increased by three cases from the June 9, 2022 report. Of the 28 cases, there were 13 probable and 15 pending classifications in classifying hepatitis. This research aims to design a mask detector that assists in monitoring health protocols by detecting the use of masks in public areas or office buildings so that they can continue to carry out everyday activities during the pandemic. The design of this mask detection tool uses the Viola-Jones Algorithm, where this method has four primary keys, namely the Haar feature, Integral Image, adaboost, and cascade classifier. Based on the test results, this mask detector can detect mask objects at a distance of 1 to 2 meters, with a limit of the number of people detected up to 3. Future research is expected to be able to develop a mask detection device using raspberry pi hardware to replace the arduino uno to better suit system needs and also add a sound system.

Clinical pattern of checkpoint inhibitor-induced liver injury in a multicentre cohort

Immune checkpoint inhibitors (ICIs) have changed the landscape of cancer therapy. Liver toxicity occurs in up to 25% of patients treated with ICIs. The aim of our study was to describe the different clinical patterns of ICI-induced hepatitis and to assess their outcome. We conducted a retrospective observational study of patients with checkpoint inhibitor-induced liver injury (CHILI) discussed in multidisciplinary meetings between December 2018 and March 2022 in three French centres specialised in ICI toxicity management (Montpellier, Toulouse, Lyon). The hepatitis clinical pattern was analysed by the ratio of serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) (R value= (ALT/ULN)/(ALP/ULN)) for characterisation as cholestatic (R ≤2), hepatocellular (R ≥5), or mixed (2 <R <5). We included 117 patients with CHILI. The clinical pattern was hepatocellular in 38.5%, cholestatic in 36.8%, and mixed in 24.8% of patients. High-grade hepatitis severity (grade ≥3 according to the Common Terminology Criteria for Adverse Events system) was significantly associated with the hepatocellular hepatitis (p <0.05). No cases of severe acute hepatitis were reported. Liver biopsy was performed in 41.9% of patients: granulomatous lesions, endothelitis, or lymphocytic cholangitis were described. Biliary stenosis occurred in eight patients (6.8%) and was significantly more frequent in the cholestatic clinical pattern (p < 0.001). Steroids alone were mainly administered to patients with a hepatocellular clinical pattern (26.5%), and ursodeoxycholic acid was more frequently used in the cholestatic pattern (19.7%) than in the hepatocellular or mixed clinical pattern (p <0.001). Seventeen patients improved without any treatment. Among the 51 patients (43.6%) rechallenged with ICIs, 12 (23.5%) developed CHILI recurrence. This large cohort indicates the different clinical patterns of ICI-induced liver injury and highlights that the cholestatic and hepatocellular patterns are the most frequent with different outcomes. ICIs can induce hepatitis. In this retrospective series, we report 117 cases of ICI-induced hepatitis, mostly grades 3 and 4. We find a similar distribution of the different patterns of hepatitis. ICI could be resumed without systematic recurrence of hepatitis.

Multi-country outbreak of severe acute hepatitis of unknown origin in children, 2022.

To describe epidemiological characteristics of multi-country outbreak of severe acute hepatitis of unknown origin in children in 2022. A descriptive epidemiological study design was used. The review based on the available information concerning this multi-country outbreak aims to summarise the current knowledge about the severe acute hepatitis of unknown origin in children, highlights the suggested working hypotheses, introduces some of the potential explanations for its occurrence and reports on public health measures undertaken to control the disease. Since the first 10 cases of severe acute hepatitis of unknown origin in children in the United Kingdom on 5 April 2022, and up until the 29 August 2022, more than 1000 probable cases have been reported in 35 countries in the world. Up to today, 22 children died in this multi-country outbreak. Despite the numerous theories that have been suggested on the possible underlying causes of the outbreak, an association with hepatitis A-E viruses has been excluded. Adenovirus serotype 41 has been detected in numerous cases, which makes it the most likely underlying cause of the disease. Efficient surveillance and comprehension advancements of the epidemiology of this disease are especially important for effective prevention and outbreak response.

Transplantation in Pediatrics Liver Failure Associated with Acute Hepatitis of Unknown Etiology

Introduction. On 5th April 2022, some cases of severe acute hepatitis of unknown etiology in children were reported in the United Kingdom. Since then, the number has increased rapidly, with 650 probable cases identified worldwide. This review focuses on available information about managing acute liver failure (ALF) in pediatrics with acute hepatitis of unknown etiology through the perspective of hepatobiliary surgery. Method. A literature review proceeded on some databases, namely PubMed and Google Scholar. Epidemiological data and technical policy were obtained from World Health Organization and some government institutions. Results. Severe acute hepatitis can progressively develop into acute liver failure, thus requiring a liver transplantation procedure immediately. There are about 30 patients have received a liver transplant. Fourteen patients reported had died. Liver transplantation is necessary to treat acute liver failure in children with acute hepatitis of unknown etiology. The need for a liver transplant can be avoided if ALF is prevented. Conclusion. The decision to perform or not to perform a liver transplant procedure may consider indications, contraindications, possible outcomes, patient status, availability of donors, and access to transplant centers' facilities and resources.

Acute hepatitis of unknown origin in children: A combination of factors.

On 5 April 2022, the World Health Organization was notified of 10 cases of severe acute hepatitis of unknown etiology in children under 10years of age in the United Kingdom. Although the exact cause of a proportion of pediatric acute hepatitis and acute liver failure cases was unclear, the above event has caused widespread concern worldwide. As of 14 September 2022, approximately 1,296 probable cases of acute hepatitis of unknown etiology have been reported from 37 countries/regions, of which approximately 55 required or received liver transplantation and 29 died. Although the etiology of acute hepatitis of unknown origin in children remains unclear, many hypotheses have been proposed about the disease. Instead of individual factors such as "adenovirus infection," "SARS-CoV-2 related," and "Adeno-associated virus 2 with helper virus coinfection," it is more likely due to a combination of factors. Accordingly, there is an urgent need for more data and research to clarify the disease etiology. This review aims to provide a historical perspective of acute hepatitis of unknown etiology in children in the past decades and summarize the current hypothesis and evidence on this emerging disease.

An Epidemic of Acute Hepatitis of Unknown Etiology in Children

An Epidemic of Acute Hepatitis of Unknown Etiology in Children

Severe Acute Hepatitis of Unknown Etiology in Indonesia: What Has Been Learned?

The world has witnessed increased incidences of severe acute hepatitis in children since early 2021, in which the total number of global cases was over 1,000 in July 2022. Those cases of severe acute hepatitis were intriguing, as they were not caused by the common hepatitis A-E viruses. Additionally, the cause remains unknown to date, thus named as severe acute hepatitis of unknown etiology. The World Health Organization, supported by regional and national health agencies, has issued the working case definitions in order to closely monitor the development of this disease worldwide. As one of its member states, Indonesia has also adopted the case definitions and subsequently issued a health decree to increase public awareness and to conduct an early surveillance on this illness. It remains to be seen whether this updated public health policy would be successful to control the numbers of cases of severe acute hepatitis of unknown etiology in Indonesia.

S3204 Turmeric-Induced Liver Injury: A Rare Case of DILI

Introduction: Turmeric, a plant prevalent in South Asia, is often marketed to be safe, with many benefits including antioxidant and anti-inflammatory effects. Hepatotoxicity, a rare adverse effect, has only been documented in a few case reports. Here we present a case of turmeric Drug Induced Liver Injury (DILI) with normalization of liver function tests after its cessation. Case Description/Methods: A 62-year-old female with a history of hypertension presented with nausea and generalized abdominal pain for five days. She denied taking medications other than hydrochlorothiazide. Further interview noted that she initiated turmeric tea over the preceding three weeks. On physical exam, she had scleral icterus and right upper quadrant tenderness. Laboratory workup showed AST 1510 U/L, ALT 1889 U/L, total bilirubin 13.9 mg/dL, direct bilirubin 8.1 mg/dL, ALP 134 U/L, LDH 542 U/L, with an ALT/LDH ratio of 3.49. INR was normal. Ultrasound revealed findings consistent with acute hepatitis. Ferritin, ceruloplasmin, and acetaminophen levels were normal. Alpha-1-antitrypsin, anti-mitochondrial, and anti-smooth muscle antibodies were unremarkable. Viral serologies were normal. The patient improved with turmeric cessation, with complete resolution of abnormal liver enzymes on follow-up. Discussion: Turmeric, previously considered safe, has now been reported to be associated with DILI in a few case reports. Our case adds to the growing body of evidence supporting turmeric induced DILI. Although we could not uncover the exact dose, we do establish a high probability of adverse effects from turmeric using the validated Roussel Uclaf Causality Method (RUCAM) scoring system. Our patient scored 9, with a score >8 representing a high probability. Turmeric induced DILI is thought to be both dose dependent and associated with formulations that contain supplements or nanoparticles that increase turmeric’s bioavailability. Lombardi et al. and Sohal et al. for example both report several cases of acute hepatitis associated with turmeric preparations developed with piperine (black pepper), which has been shown to increase the absorption of turmeric by 2000%. In our case, the patient’s turmeric tea also included black pepper, which likely explains the hepatotoxicity. This case underscores the importance of supplement history, with an emphasis on turmeric, when evaluating for potential causes of DILI.

Acute hepatitis (Non Hepa A-E) of unknown origin among pediatrics.

Several clusters and individual cases of acute hepatitis have been reported in the US, Europe and recently in Asia and Central America since October 2021. A laboratory investigation of the common viral hepatitis agents (HAV, HBV, HCV, HDV and HEV) yielded negative results prompting the use of the term "acute non HepA-E hepatitis" to describe this condition. As of 24 June of 2022, WHO have reported 920 probable cases of severe acute hepatitis of unknown origin among pediatrics in 33 countries in five WHO regions. Since the previous reports on 27 May 2022, 270 new probable cases have been increased, including from four new countries, some of whom were also found to be positive for SARS-CoV-2. All the patients showed symptoms such as vomiting, diarrhea, jaundice, and abdominal pain. The patients' liver enzymes were remarkably increased. No connection with SARS-CoV-2 or its vaccine has been found so far. However, the suspected cause is adenovirus, including its genomic variations, because its pathogenesis and laboratory investigations have been positively linked. Until further evidence emerges, hygiene precautions could be helpful to prevent its spread.

Hepatitis of unknown aetiology in children - epidemiological overview of cases reported in Europe, 1 January to 16 June 2022.

Following the report of an excess in paediatric cases of severe acute hepatitis of unknown aetiology by the United Kingdom (UK) on 5 April 2022, 427 cases were reported from 20 countries in the World Health Organization European Region to the European Surveillance System TESSy from 1 January 2022 to 16 June 2022. Here, we analysed demographic, epidemiological, clinical and microbiological data available in TESSy. Of the reported cases, 77.3% were 5 years or younger and 53.5% had a positive test for adenovirus, 10.4% had a positive RT-PCR for SARS-CoV-2 and 10.3% were coinfected with both pathogens. Cases with adenovirus infections were significantly more likely to be admitted to intensive care or high-dependency units (OR = 2.11; 95% CI: 1.18–3.74) and transplanted (OR = 3.36; 95% CI: 1.19–9.55) than cases with a negative test result for adenovirus, but this was no longer observed when looking at this association separately between the UK and other countries. Aetiological studies are needed to ascertain if adenovirus plays a role in this possible emergence of hepatitis cases in children and, if confirmed, the mechanisms that could be involved.

Non-hepatotropic viral hepatitis and its causative pathogens: The ongoing need for monitoring in children with severe acute hepatitis of unknown etiology.

Non-hepatotropic viral hepatitis and its causative pathogens: The ongoing need for monitoring in children with severe acute hepatitis of unknown etiology.

Severe Acute Hepatitis of Unknown Origin in Children: What Do We Know Today?

In May 2022, the UK International Health Regulations National Focal Point notified World Health Organization of 176 cases of severe acute hepatitis of unknown etiology in children under 10 years of age. From that moment on, cases of severe acute hepatitis of unknown origin in children began to be reported in several countries. As of June 17, 2022, a total of 991 cases had been reported in 35 countries worldwide, 50 children needed a liver transplant and 28 patients died. According to information published by ECDC, 449 cases have been detected in 21 EU countries. The children were between 1 month and 16 years of age. Adenovirus was detected in 62.2% of the analyzed samples. So far, the cause of these cases is unknown and many hypotheses remain open, but hepatitis A–E viruses and COVID-19 vaccines have been ruled out. A possible hypothesis has been published to explain the cause of these cases of severe hepatitis, according to which it could be a consequence of adenovirus infection in the intestine in healthy children previously infected with SARS-CoV-2. No other clear epidemiological risk factors have been identified to date. Thus, at this time, the etiology of the current cases of hepatitis remains under active investigation.

A case of severe acute hepatitis of unknown etiology requiring liver transplantation in a child with adenovirus infection

The article presents a clinical observation of severe acute hepatitis of unknown aetiology with liver transplantation in a 16-year-old child, which occurred in October 2021. Initial symptoms were abdominal pain, diarrhea. The general wellbeing of the girl did not suffer, there was no fever, no intoxication syndrome. Over the next days, she began to notice the appearance of edema on the legs, an increase in the size of the abdomen. From the 10-11th day of illness – darkening of urine, acholia of feces, jaundice were observed. She was examined by a pediatrician, a biochemical blood test was performed, according to the results the girl was hospitalized with a diagnosis of acute hepatitis. According to the severity of the condition, she was hospitalized in the ICU. On admission she complained of abdominal pain, jaundice, edema, and weakness. On examination: jaundice, scleral icterus, hemorrhagic rash at the site of the tourniquet, bleeding from injection sites, hepatomegaly, anasarca. In blood tests: progressive anemia, thrombocytopenia, increased AST (with a decrease in dynamics against the background of progression of liver failure), a decrease in total protein and albumin, fibrinogen, prothrombin according to Quick. Laboratory excluded viral hepatitis A-E. The only infectious agent diagnosed was group F adenovirus in feces. By the third day of hospitalization developed of multiple organ failure, DIC. On the 4th day of hospitalization, the child was transferred to a specialized hospital, where an emergency liver transplantation was performed. The operation was successful, the child was discharged in a stable condition.

Severe acute hepatitis of unknown causes in children - Current findings, questions, opinions, and recommendations, a mini-review.

ABSTRACTSince October 2021 in Alabama, the United States, and March 2022 in central Scotland, the United Kingdom, the number of cases of severe acute hepatitis of unknown etiology/causes in children was found to increase, and the total number of cases has reached 920 worldwide by June 22 this year, 45 cases (5%) required liver transplantation, and 18 cases (2%) died according to World Health Organization (WHO). To understand the basic characteristics of this disease/syndrome, a literature search was performed at PubMed, websites of WHO, UK Health Security Agency, and US and European Centers for Disease Control and Prevention, and more than 20 reports were enrolled as references for this review. The main clinical manifestations are anorexia, vomiting, fatigue, jaundice, and so forth. Most of the cases seemed to have a self‐limited course of the disease, about 6% of cases may develop life‐threatening acute liver failure. The disease seems to be transmissible from person to person. Human adenovirus was detected in up to 75% of cases, but this virus seems not to be the only and major etiologic agent, other cofactors probably are involved. Researchers proposed many hypotheses concerning the etiology and pathogenesis, and many important works and studies are ongoing. This mini‐review is aimed at summarizing, reviewing, and further understanding the characteristics of the disease, raising some clinically relevant questions, and trying to discuss some questions that may be related to the treatment of the disease for consideration.

Development and application of LAMP assays for the detection of enteric adenoviruses in feces.

ABSTRACTLoop-mediated isothermal amplification (LAMP) is an alternative to PCR that is faster and requires fewer resources. Here, we describe two LAMP assays for the detection of human adenoviruses in the feces of children with acute intestinal infections. We designed сolorimetric LAMP (c-LAMP) and real-time LAMP (f-LAMP) with fluorescent probes to detect the DNA of the adenovirus F human adenovirus 40/41 (hAdV40/41) hexon gene. The detection limit of both developed methods was 103 copies/mL, which is comparable to the sensitivity of PCR. The specificities of both c-LAMP and f-LAMP were high, with no false-positive results for clinical samples that do not contain adenovirus F, when testing other viruses and microorganisms. Comparative tests of PCR and LAMP on clinical samples from patients with acute gastroenteritis were carried out. For all samples with a PCR threshold cycle (CT) of up to 36, the PCR and LAMP results completely coincided; however, at low viral loads, the diagnostic sensitivity of LAMP, especially c-LAMP with colorimetric detection, was inferior to that of PCR. The combination of LAMP with modern methods of nucleic acid extraction, both in manual and automatic modes, can reduce the time for a complete study, including extraction of nucleic acid material and amplification, to 60 min.IMPORTANCE In April 2022, several cases of acute hepatitis of unknown origin were reported in children from 12 countries. In many cases, enteric adenovirus or SARS-CoV-2 and adenovirus coinfection were detected. It is known that human adenoviruses can cause different infections of varying severity, from asymptomatic to severe cases with lethal outcomes. There is a need to increase the diagnostic capabilities of clinical laboratories to identify such an underestimated pathogen as adenovirus. Although PCR remains the gold standard for pathogen detection, this method requires specialized equipment and has a long turnaround time to process samples. Previously, LAMP assays for the detection of human adenovirus have been based on measuring the turbidity, the fluorescence of intercalated dyes, or electrophoretic separation. Herein, we present LAMP-based assays with colorimetric or fluorescent detection and perform a detailed assessment of their sensitivity, specificity, and diagnostic performance.

Expert symposium on severe acute hepatitis of unknown cause in children, a paradigm of exchanges and sharing between Chinese and Western medicine professionals.

Expert symposium on severe acute hepatitis of unknown cause in children, a paradigm of exchanges and sharing between Chinese and Western medicine professionals.

The relationship between adenovirus infection and severe acute hepatitis of unknown etiology

Adenovirus infection can occur in all regions or countries of the world, with no obvious seasonality, but pandemics mostly occur in winter or early spring. Adenovirus infection is self-limited among immunocompetent host with supportive care, however fatal infection can occur among immunocompromised patients, mainly affecting respiratory, gastrointestinal tract and adjunctiva and very rarely causing hepatitis, cholecystitis, pancreatitis, hemorrhagic cystitis, myocarditis, meningitis or encephalitis. Adenovirus hepatitis mainly occur in malignant tumors or organ transplantation patients, but acute severe hepatitis can occur even in immunocompetent children or adults. On 5 April 2022, WHO was notified of 10 cases of severe acute hepatitis of unknown etiology in children. As of 21 April 2022, at least 169 cases of acute hepatitis of unknown origin have been reported from 12 countries (including 11 WHO European Region countries and the United States). Adenovirus has been detected in at least 74 cases; SARS-CoV-2 was identified in 20 cases of those that were tested. Furthermore, 19 were detected with a SARS-CoV-2 and adenovirus co-infection. At present, the etiology has not been fully elucidated. The leading hypotheses center around adenovirus, and the relationship with SARS-CoV-2 needs to be further ruled out.