[Adenovirus-related acute liver failure treated with intravenous immunoglobulin]. / Insuficiencia hepática aguda por adenovirus tratada con inmunoglobulina intravenos.

BACKGROUND: Acute liver failure in pediatric age is a serious multisystem disease, characterized by a failure of the synthesis and detoxification function of the liver. Among the etiologies, viral infection should be investigated. Treatment is supportive and some cases require liver transplantation. CASE REPORT: A 2-year-old girl was admitted for acute liver failure. The PCR viral panel was positive for Adenovirus 41 and IgG antibodies to SARS-CoV-2 were also found. Supportive treatment was started without improvement, so intravenous immunoglobulin was administered, with resolution of the liver failure. CONCLUSIONS: Immunoglobulin has immunomodulatory mechanisms in children with severe acute hepatitis of infectious etiology, so in some cases, its administration can be considered as adjuvant therapy.

ANTECEDENTES: La insuficiencia hepática aguda en pacientes pediátricos es una enfermedad multisistémica grave, caracterizada por falla de la función de síntesis y detoxificación del hígado. Dentro de su origen debe investigarse alguna infección viral. El tratamiento es de soporte y algunos casos requieren trasplante hepático. REPORTE DE CASO: Paciente pediátrica de 2 años, que ingresó al servicio médico por insuficiencia hepática aguda. El panel viral por PCR fue positivo para adenovirus 41 y anticuerpos IgG para SARS-CoV-2. Se inicio tratamiento de soporte sin reacción satisfactoria, por lo que se administró inmunoglobulina intravenosa, con resultados adecuados y curación de la insuficiencia hepática. CONCLUSIONES: La inmunoglobulina tiene mecanismos inmunomoduladores en pacientes pediátricos con hepatitis aguda grave de origen infeccioso, por lo que en algunos casos puede considerase su administración como terapia adyuvante.

Histologic Manifestations of Gastrointestinal Adenovirus Infection After Stem Cell Transplant.

Adenovirus can cause severe disease in hematopoietic stem cell transplant (HSCT) patients. Histopathologic features of this infection in gastrointestinal biopsies and their distinction from graft-versus-host disease (GVHD) have been incompletely studied. We retrospectively identified patients with gastrointestinal adenovirus infection. H&E-stained sections were reviewed and the histologic features were recorded. The extent of immunostaining was determined using a semiquantitative scale and a maximum number of positive cells per high-power field. Information regarding the clinical course and endoscopic findings were obtained from the electronic medical records. The study group included 32 HSCT patients. Most (81%) presented with diarrhea and detectable virus in the serum. Twenty patients had multiorgan involvement in the gastrointestinal tract, mostly in the duodenum (62%) and colon (56%). Characteristic features included apoptotic epithelial cells with nuclear disarray (84%) and tufted aggregates of degenerating epithelial cells (69%), the latter of which was more commonly seen in the study population more than a control group of HSCT patients with GI involvement by GVHD. Viral inclusions were limited to the superficial epithelium in 59% of samples, and the density of viral inclusions within biopsies was variable (grade 1: 40%, grade 2: 38%, and grade 3: 22%). Following therapy, 10 patients (30%) improved and 14 (42%) had progressive disease. Patients with disease progression were often older (64 vs. 36 years, P =0.01) with higher serologic viral loads, prior history of GVHD, multifocal involvement, and increased number and density of immunoreactive nuclei. Adenovirus infection elicits a spectrum of histologic changes that can simulate or occur in combination with gastrointestinal GVHD. Patients with progressive disease are more likely to have high viral loads and more extensive infection of the gastrointestinal tract.

Monitoring of adenoviremia in pediatric patients undergoing hematopoietic stem cell transplantation: Is it alone sufficient to predict adenoviral disease?

BACKGROUND: We aimed to evaluate our pediatric HSCT recipients routinely monitored for adenoviremia and to determine the adequacy of this monitoring in predicting adenoviral disease (AD). METHODS: A retrospective cohort of patients who underwent allogeneic HSCT between January 2021 and August 2022, and routinely monitored for adenoviremia by real-time PCR was included in our survey. Demographic and clinical data of the patients were recorded. Incidence rates, risk factors, and mortality rates related to adenoviremia, and AD were analyzed. RESULTS: Among 104 HSCTs performed in 94 patients adenovirus (AdV) was revealed in 27 (26%) episodes and adenoviremia in 18 (17.3%) HSCT episodes. AD without adenoviremia developed in nine episodes (8.6%). Disseminated disease was significantly more frequently detected in episodes with adenoviremia (p = .008). GVHD was independent risk factor for AdV detection (OR: 8.6, 95% CI: 2.03-33.7, p = .001). Viremia developed within a shorter time interval after HSCT in isolated episodes of adenoviremia compared to those with concomitant AD (p = .006). Initial and peak viral loads were significantly higher in adenoviremia with AD (p < .001). Mortality was higher in the AdV-detected episodes (p < .001) than in the AdV-undetected episodes. AdV-related mortality was found to be 22.2%. Adenoviremia increased the risk of mortality (OR: 1.2, 95% CI: 0.22-1.33, p = .01). CONCLUSIONS: Adenoviremia monitoring is an important process in the detection of AD. Since some patients may develop AD without accompanying by adenoviremia, monitoring for AdV in blood samples should be supported with other monitoring methods in order to evaluate the probable involvement of different organs or systems.

The Role of Adenovirus in Hepatitis of Unknown Etiology Among Children in Turkey, July 2022 to January 2023.

BACKGROUND: In the first half of 2022, the increase in cases of severe acute hepatitis in children with no epidemiological link and unknown cause has aroused concern worldwide. In this study, we aimed to determine the frequency of adenovirus in children with hepatitis of unknown origin in Turkey. METHODS: In this study, which was conducted with the participation of 16 centers from Turkey, between July 2022 and January 2023, 36 pediatric patients under the age of 18 who met the definition of acute hepatitis were included. RESULTS: Twenty (55,6%) of patients were female and 16 (44,4%) were male, with a mean age of 41.55 ± 39.22 (3-192) months. The most common symptoms were fever (66.7%), weakness (66.7%), loss of appetite (66.7%), fatigue (61.1%), vomiting (61.1%), and diarrhea (47.2%). Six (16 %) children had acute hepatic failure. Eight of the 15 children (46%) had respiratory viral infections (rhinovirus/enterovirus, n = 4; rhinovirus + parainfluenza, n = 1; parainfluenza, n = 1, SARS-CoV-2 n = 2). Adenovirus was detected in 16 (44%) patients. Adenovirus and coinfections were detected in 7 patients. History of diarrhea and fatigue in the last month was significantly higher in the adenovirus group ( P = 0.023 and 0.018). One child who had both adenovirus and rhinovirus infection required liver transplantation; all others recovered with supportive care. CONCLUSION: There were no deaths in our series; however, the number of cases, etiology, and severity of the clinical course may have differed between countries owing to differences in case definitions, laboratory facilities, or regional genetic differences.

Immunity in the balance: Fatal disseminated adenovirus infection in a patient undergoing plasma exchange and immunosuppressive chemotherapy for anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (anti-GBM) disease (formerly known as Goodpasture's syndrome) is a rare autoinflammatory condition that affects the renal and/or pulmonary capillaries. The standard therapeutic regimen for anti-GBM disease involves therapeutic plasma exchange (TPE), cyclophosphamide, and corticosteroids to rapidly remove and inhibit autoantibody production and reduce organ inflammation. Herein we report an 82-year-old female who developed anti-GBM disease but expired despite therapy, secondary to multi-organ failure in the setting of disseminated adenovirus disease. We discuss the utility and potential adverse effect of daily TPE for a protracted course (ie, 10-14 days), the recommended TPE intensity in the 2023 American Society for Apheresis guidelines, updated from every-other-day TPE in the 2019 guidelines, despite no new data. We also highlight the potential for unusual infections to occur in these patients due to the profound immunosuppression, and discuss the importance of balancing immunosuppression to treat the disease with close surveillance of any potential opportunistic infections.

Kawasaki disease, multisystem inflammatory syndrome in children, and adenoviral infection: a scoring system to guide differential diagnosis.

Children with Kawasaki disease (KD), Multisystem Inflammatory Syndrome in Children (MIS-C), and Adenovirus infections (AI) of the upper respiratory tract show overlapping features. This study aims to develop a scoring system based on clinical or laboratory parameters to differentiate KD or MIS-C from AI patients. Ninety pediatric patients diagnosed with KD (n = 30), MIS-C (n = 26), and AI (n = 34) admitted to the Pediatric Emergency Unit of S.Orsola University Hospital in Bologna, Italy, from April 2018 to December 2021 were enrolled. Demographic, clinical, and laboratory data were recorded. A multivariable logistic regression analysis was performed, and a scoring system was subsequently developed. A simple model (clinical score), including five clinical parameters, and a complex model (clinic-lab score), resulting from the addition of one laboratory parameter, were developed and yielded 100% sensitivity and 80% specificity with a score ≥2 and 98.3% sensitivity and 83.3% specificity with a score ≥3, respectively, for MIS-C and KD diagnosis, as compared to AI. CONCLUSION: This scoring system, intended for both outpatients and inpatients, might limit overtesting, contribute to a more effective use of resources, and help the clinician not underestimate the true risk of KD or MIS-C among patients with an incidental Adenovirus detection. WHAT IS KNOWN: • Kawasaki Disease (KD), Multisystem Inflammatory Syndrome in Children (MIS-C) and adenoviral infections share overlapping clinical presentation in persistently febrile children, making differential diagnosis challenging. • Scoring systems have been developed to identify high-risk KD patients and discriminate KD from MIS-C patients. WHAT IS NEW: • This is the first scoring model based on clinical criteria to distinguish adenoviral infection from KD and MIS-C. • The score might be used by general pediatricians before referring febrile children to the emergency department.

Clinicopathologic Features of Severe Acute Hepatitis Associated With Adenovirus Infection in Children.

A recent increase in reports of severe acute hepatitis of unknown etiology in children is under investigation. Although adenovirus has been frequently detected, its role remains unclear, and systematic histopathologic analysis is lacking. We conducted a retrospective study of 11 children hospitalized between October 2021 and May 2022 with unexplained acute hepatitis and concurrent adenovirus infection. Liver biopsies collected shortly after admission demonstrated moderately to severely active hepatitis in 8/11 (73%) cases, characterized by marked portal mixed inflammation, moderate-to-severe interface activity, and milder lobular inflammation. Clusters of plasma cells were present in 6/11 (55%) cases, mimicking autoimmune hepatitis. Semiquantitative scoring of 17 discrete histologic features found that greater degrees of portal inflammation, interface activity, bile duct injury, bile ductular reaction, lobular inflammation, Kupffer cell activation, and hepatocyte focal necrosis were significantly more common in these cases in comparison to the control group of unexplained acute severe hepatitis without adenovirus infection. Liver biopsy immunohistochemistry was negative for adenovirus in all cases. Polymerase chain reaction testing of liver tissue was positive for the enteric adenovirus serotypes 41 (species F) in 10/11 (91%) cases. An immunoprofile study of hepatic infiltrating lymphocytes in 1 patient revealed the presence of large numbers of CD3 + and CD4 + lymphocytes. Nine patients received supportive treatment without steroids and recovered without the need for liver transplantation. In summary, liver injury in children with severe acute hepatitis and adenovirus infection is characterized by a hepatitic pattern that resembles severe autoimmune hepatitis and may represent an immune-mediated process associated with viral infection.

Human adenovirus infection induces pulmonary inflammatory damage by triggering noncanonical inflammasomes activation and macrophage pyroptosis.

Introduction: Human adenovirus (HAdV) is a common respiratory virus, which can lead to severe pneumonia in children and immunocompromised persons, and canonical inflammasomes are reported to be involved in anti-HAdV defense. However, whether HAdV induced noncanonical inflammasome activation has not been explored. This study aims to explore the broad roles of noncanonical inflammasomes during HAdV infection to investigate the regulatory mechanism of HAdV-induced pulmonary inflammatory damage. Methods: We mined available data on GEO database and collected clinical samples from adenovirus pneumonia pediatric patients to investigate the expression of noncanonical inflammasome and its clinical relevance. An in vitro cell model was employed to investigate the roles of noncanonical inflammasomes in macrophages in response to HAdV infection. Results: Bioinformatics analysis showed that inflammasome-related genes, including caspase-4 and caspase-5, were enriched in adenovirus pneumonia. Moreover, caspase-4 and caspase-5 expression levels were significantly increased in the cells isolated from peripheral blood and broncho-alveolar lavage fluid (BALF) of pediatric patients with adenovirus pneumonia, and positively correlated with clinical parameters of inflammatory damage. In vitro experiments revealed that HAdV infection promoted caspase-4/5 expression, activation and pyroptosis in differentiated THP-1 (dTHP-1) human macrophages via NF-κB, rather than STING signaling pathway. Interestingly, silencing of caspase-4 and caspase-5 in dTHP-1 cells suppressed HAdV-induced noncanonical inflammasome activation and macrophage pyroptosis, and dramatically decreased the HAdV titer in cell supernatants, by influencing virus release rather than other stages of virus life cycle. Discussion: In conclusion, our study demonstrated that HAdV infection induced macrophage pyroptosis by triggering noncanonical inflammasome activation via a NF-kB-dependent manner, which may explore new perspectives on the pathogenesis of HAdV-induced inflammatory damage. And high expression levels of caspase-4 and caspase-5 may be a biomarker for predicting the severity of adenovirus pneumonia.

Keratouveitis in juvenile dogs and its presumed association with canine adenovirus infection.

OBJECTIVE: We hypothesized that keratouveitis still occurs despite current widespread use of Canine adenovirus (CAV)-2 vaccinations and assessed the utility of CAV-1 and CAV-2 titers in elucidation of its etiopathogenesis. ANIMALS STUDIED: Nine dogs with unexplained keratouveitis (14 eyes) and nine control dogs. PROCEDURES: The Animal Health Trust clinical database was searched between 2008 and 2018 to identify cases of keratouveitis. Inclusion criteria included known vaccination status, interval from vaccination to development of clinical signs and availability of CAV titers. Cases were excluded if they were older than 1 year of age, or other causative ocular pathology for corneal edema was identified. Nine age-matched dogs without corneal edema but with CAV titers were included as controls. RESULTS: Mean CAV-1 and CAV-2 titers were not statistically different between dogs with keratouveitis and controls (p = .16 and p = .76, respectively). Three cases had CAV-1 titers >5000 and two of these cases had rising convalescence titers (greater than an 11-fold increase) suggesting infection with wild-type CAV-1. The six other cases did not appear to be associated with CAV infection or vaccination. CONCLUSION: Keratouveitis continues to occur despite the advent of CAV-2 vaccinations. While this study found no evidence to indicate CAV-2 vaccination causes keratouveitis, the data indicates that in a proportion of cases, contemporaneous wild-type CAV-1 infection is a possible cause.

Síndrome del ocho y medio como manifestación de enfermedad desmielinizante aguda por adenovirus / Eight-and-a-half syndrome as manifestation of acute disseminated adenovirus encephalomyelitis

La encefalomielitis diseminada aguda es una enfermedad inflamatoria-desmielinizante inmunomediada que suele manifestarse tras una infección o vacunación en niños en edad escolar. Típicamente presenta una fase prodrómica con un cuadro pseudogripal seguida de una fase con clínica muy variada, pudiendo aparecer alteraciones neurooftalmológicas como oftalmoplejía o neuritis óptica.La etiología es variada, incluyendo enfermedades tumorales, vasculares, infecciosas, inflamatorias y desmielinizantes. El diagnóstico se basa en la historia clínica y en las características de la resonancia magnética cerebral, prueba de imagen de elección. El estudio del líquido cefalorraquídeo puede servir de ayuda en la orientación del cuadro clínico.El pronóstico es favorable, con excelente respuesta a los corticoides e inmunoglobulinas y con mínimas secuelas a largo plazo en la mayoría de los casos.Presentamos el caso de un varón de 8años con enfermedad desmielinizante aguda por adenovirus cuya manifestación fue un síndrome del ocho y medio. (AU)

Acute disseminated encephalomyelitis is an immune mediated inflammatory-demyelinizing disease that usually manifests after infection or vaccination in school-age children. It typically presents a prodromal phase with flu-like symptoms, followed by a phase with varied clinical symptoms, neuro-ophthalmological alterations such as ophthalmoplegia or optic neuritis may occur.The differential diagnosis includes tumor, vascular, infectious, inflammatory and demyelinating diseases. Diagnosis is based on the clinical history and the characteristics of brain magnetic resonance imaging, the gold standard test. The study of the cerebrospinal fluid can help to guide the clinical picture.The prognosis is favorable, with an excellent response to corticosteroids and immunoglobulins, with minimal long-term sequelae in most cases.We report the case of an 8-year-old male with acute demyelinating disease due to adenovirus whose manifestation was an eight-and-a-half syndrome. (AU)

Construction and analysis of a nomogram prediction model for post-infectious bronchiolitis obliterans in children with adenovirus pneumonia after invasive mechanical ventilation.

BACKGROUND: Post-infectious bronchiolitis obliterans (PIBO) is the most common sequelae in children with adenovirus pneumonia (ADVP). However, there are few studies on the risk factors for PIBO occurrence. This study aims to investigate the risk factors for PIBO in pediatric patients with severe ADVP, especially after invasive mechanical ventilation (IMV), as well as to build a nomogram prediction model. METHODS: The clinical data, laboratory and imaging features, and treatment of 863 children with ADVP under 3 years old who were admitted to our hospital from January to December 2019 were retrospectively analyzed. Among them, 66 children with severe ADVP received IMV treatment. The situation and the influencing factors of PIBO in children with severe ADVP were explored, and a nomogram prediction model was constructed. RESULTS: Among the 863 cases of ADVP, 46 cases (5.33%) developed PIBO. Duration of fever, IMV, complications, and neutrophil percentage were independent risk factors for PIBO in children with ADVP. Among the 66 patients with ADVP who underwent IMV, 33 patients (50.0%) developed PIBO. Gender, duration of fever, adenovirus (ADV) load, and mixed fungal coinfections were independent risk factors for PIBO. In the nomogram prediction model analysis, the area under the curve (AUC) was 0.857; in addition, Hosmer‒Lemeshow (H-L) detection reflected good alignment (χ2 = 68.75, P < 0.01). CONCLUSIONS: A nomogram prediction model, which can be utilized to predict PIBO occurrence in pediatric patients with ADVP after IMV at an early time period, was successfully built.

Outbreak of indeterminate acute liver failure in children with adenoviraemia - Not a new disease.

BACKGROUND & AIMS: In the year 2022, an outbreak of indeterminate acute hepatitis and indeterminate paediatric acute liver failure (ID-PALF) in association with adenoviraemia in immunocompetent children was reported in the UK. We postulate that this association is not a new disease in immunocompetent children. METHODS: Children with acute hepatitis during the outbreak who were referred to King's College Hospital, London for advice and management were included in the study. Data on the frequency of ID-PALF in 2022, as well as transplantation rates and the association with adenovirus infection, were obtained from electronic health records. The clinical presentation, histology and outcomes of children with ID-PALF and adenoviraemia in 2017-2021 were compared with those in 2022. RESULTS: From January to June 2022, 65 patients with acute hepatitis were referred. Ten children were admitted with ID-PALF. ID-PALF constituted 26% of all PALF cases in 2017-2021, in contrast to 58.8% during the 2022 outbreak. During the outbreak, adenoviraemia was present in 52% of children with acute hepatitis without liver failure (in whom adenoviraemia test results were available) and in 100% of ID-PALF cases. Adenoviraemia was seen in immunocompetent children in 6/13 (46%) of all ID-PALF cases between 2017-2019, with a clear absence of adenoviraemia in the 6 ID-PALF cases during 2020-2021. Compared to ID-PALF with adenoviraemia in 2017-2019 (n = 6), ID-PALF with adenoviraemia during the outbreak (n = 10) was associated with more frequent hepatic encephalopathy, hypotension requiring vasoactive medications and higher plasma ammonia levels (admission and peak), with similar native liver survival. CONCLUSIONS: The recent outbreak of ID-PALF with adenoviraemia in immunocompetent children does not appear to be a new disease, contrary to perception and other reports. The frequency of such cases over the years could be linked to background rates of adenovirus infections. IMPACT AND IMPLICATIONS: Indeterminate paediatric acute liver failure (ID-PALF) associated with adenoviraemia in immunocompetent children is not a new disease specific to 2022. The exclusive role of human adenovirus infection in the causation of this outbreak of acute hepatitis seems unlikely. Indeed, we provide histological data from explants in transplanted patients that do not support direct viral cytotoxicity. The disease is probably mediated by immunological injury directed towards adenovirus infection and/or adeno-associated virus-2.

Acute Liver Failure in a Child With Adenovirus Detected by PCR in the Explanted Liver.

As of June 15, 2022, the Centers for Disease Control and Prevention has reported 296 pediatric patients under investigation for hepatitis of unknown etiology in the United States; the World Health Organization has reported 650 probable cases worldwide. One of the leading hypotheses for this cluster of cases is adenovirus, a virus that commonly causes respiratory or gastrointestinal symptoms in healthy children but rarely causes severe hepatitis or acute liver failure in immunocompetent children. The other leading hypothesis is that prior infection with SARS-CoV-2 may predispose children to developing liver injury from a normally innocuous agent. We describe a case of a previously healthy child presenting with acute liver failure who had detectable adenovirus DNA in his stool, whole blood, and in liver explant tissue, suggesting adenovirus as the likely etiology for the liver failure. He had no evidence of prior or current SARS-CoV-2 infection, nor had he received COVID vaccination, suggesting that SARS-CoV-2 did not play a role. Additionally, we report on the ability to provide rapid evaluation of a living donor within 72 hours and successfully perform a lifesaving, left-lobe, living donor liver transplant.

Adenovirus infection is a risk factor for recurrent intussusception in pediatric patients.

BACKGROUND: Human adenoviruses are the most common pathogens to be isolated from cases of pediatric intussusception. However, the specific clinical characteristics of pediatric intussusception associated with adenovirus infection are poorly known. METHODS: We reviewed the medical records of pediatric patients (≤18 years of age) with intussusception treated between January 2014 and December 2020. We enrolled patients with febrile episodes, 27 with and 29 without adenovirus infections (the latter serving as control group). The demographic data, clinical characteristics, and the diagnoses and management strategies were evaluated. RESULTS: The adenovirus group exhibited a significantly longer febrile duration (4.3 ± 1.9 vs. 3.3 ± 1.1 days, p = 0.020) than the control group, with an odds ratio (OR) of 5.098 (95% confidence interval [CI] 1.223-21.254, p = 0.025). The recurrence rates were 48.1% and 13.8% in the two groups (OR 5.804; 95% CI: 1.585-21.245, p = 0.008). Most adenoviruses were non-enteric (85.2%). CONCLUSION: Adenovirus-related intussusception is associated with a longer febrile period and a higher rate of intussusception recurrence. It is recommended that patients suspected of adenovirus-related intussusception should be observed for longer than others prior to discharge.