Search

Background: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. Objective: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. Methods: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. Results: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4−CD8−) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. Conclusion:: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

Background It has been demonstrated that children who had been breastfed remain better protected against various infections, and notably respiratory tract infections, well beyond infancy. Since the role of breastfeeding to explain why children are less affected by COVID-19 has not been studied until now, the aim of this study was to determine whether any history of breastfeeding reduces the incidence rate of COVID-19 in children. Methods This was a secondary analysis of an observational study on clinical and epidemiological characteristics of pediatric COVID-19 in Majorca. A total of 691 children were recruited during the 5 months of August–December 2020. Eligible participants were children under 14 who were tested for SARS-CoV-2 in pediatric emergency services. The independent explanatory variable was any breastfeeding. Bivariate analyses were conducted through the Chi-square test, the Fisher’s Exact test or the Student’s T test. All children had the same demographic, epidemiological and clinical data collected through a study team member interview and via the participants medical records. Results Within the sample of children who visited emergency services with symptoms of potential COVID-19, we found higher prevalence of positive SARS-CoV-2 RT-PCR test results among those who were exclusively formula fed compared with those who were ever breastfed (OR 2.48; 95% CI 1.45, 3.51; P = 0.036). Conclusions The present study suggests that ever breastfeeding reduces the risk of COVID-19 among children, as documented for other infections.

The timing of caloric intake plays an important role in the long-term process that leads to communicable diseases. The primary objective of this study was to analyse whether children who ate dinner early were at lower risks of acute respiratory infections than children who ate dinner late during the COVID-19 pandemic. Methods: This cross-sectional study was conducted from July to December 2020 on children attending Majorcan emergency services. Our survey on dinner time habits was carried out by using self-administered questionnaires. Results: A total of 669 children were included in this study. The median dinner time was 8:30 pm. Late dinner eaters accounted for a higher proportion of acute otitis media (7% vs. 3%; p = 0.028) than early dinner eaters. Other infectious diseases were not associated with dinner time habits. Conclusions: We make a preliminary estimate of the link between late dinner habits and acute otitis media in children. However, no conclusions about causality can be established due to the observational design of the study, and further research is needed in order to confirm the different issues raised by our initial exploration of an emerging research area.

[Introduction] Since the first description of gain of function (GOF) mutations in signal transducer and activator of transcription (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, their indications, dosing, and monitoring remain to be established., [Methods] A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature., [Results] Ten children (median age 8.5 years (3–18), receiving JAKinibs (ruxolitinib (n = 9) and baricitinib (n = 1)) with a median follow-up of 18 months (2–42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune deficiency and dysregulation activity scores were 15.99 (5.2–40) pre and 7.55 (3–14.1) under therapy (p = 0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response., [Conclusions] Our study supports the potentially beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries., Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by the Job Research Foundation (NY, USA); the Consejería de Salud de la Junta de Andalucía (SA0051/2020 to O.N.); Agencia de Innovación y Desarrollo de Andalucía (PI-0184–2018 to P.O); Instituto de Salud Carlos III, Madrid, Spain (Sara Borrell, CD20/00124 to P.B.L, Juan Rodés JR18/00042 to P.O, FIS PI19/01471 to O.N. and P.O); the projects PI18/00223, FI19/00208, and PI21/00211 to LA, integrated in the Plan Nacional de I + D + I and co-financed by the ISCIII—Subdirección General de Evaluación y Fomento de la Investigación Sanitaria—and the Fondo Europeo de Desarrollo Regional (FEDER), by Pla Estratègic de Recerca i Innovació en Salut (PERIS), Departament de Salut, Generalitat de Catalunya (SLT006/17/ 00199 to LA), by a 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (IN[17]_BBM_CLI_0357) to LA, by a 2017 Beca de Investigación de la Sociedad Española de Inmunología Clínica Alergología y Asma Pediáatrica to LA, by a 2021 Beca de Investigación de la Sociedad Española de Inmunología Clínica, Alergología y Asma Pediátrica to ADM and by the Ministry of Health, Czech Republic (NV18-05–00162 to M.B and NV19-05–00332 to V.K).

Running at odds with the timing imposed by the circadian clock plays an important role in the process that leads to communicable and non communicable diseases. The primary objective of this study was to analyse whether early dinner eater children were at lower risks of acute respiratory infections than late dinner eater children, during the COVID-19 pandemic. Methods: This cross sectional study was conducted from July to December 2020 on children attending Majorcan emergency services. Clinical data collected included timing, symptoms, laboratory tests and imaging studies of current illness. Each diagnosis was validated by general paediatricians. Our survey on dinner time habits was carried out by using self-administered questionnaires. Results: A total of 669 children under age 18 were included in the study. The median of dinner time was 8:30 pm. Late dinner eaters accounted for a higher proportion of acute otitis media than early dinner eaters (7% vs 3%; P=0.028). Other infectious diseases were not associated with dinner time habits. Conclusions: We make a preliminary estimate of the link between late dinner habits and acute otitis media in children. However, no conclusions about causality can be established due to the observational design of the study.

Introduction: In 2014 the Consensus Document produced by the Spanish Paediatric Societies (SEIP-SERPE-SEOP) was published to help in the diagnosis and treatment of osteoarticular infections (OAI). In 2015 the RIOPed was considered as a multidisciplinary national network for the investigation into OAI. The aim of this study was to assess the level of adaption to the recommendations established in the Consensus during one year of follow-up. Material and methods: A prospective, national multicentre study was carried out in 37 hospitals between September 2015 and September 2016. The study included patients >16 years-old with a diagnosis of OAI, confirmed by microbiological isolation, or probable: septic arthritis (SA) with >40,000 white cells in synovial fluid, or osteomyelitis (OM)/spondylodiscitis (SD) with a compatible imaging test. The results were compared with those obtained in a retrospective study conducted between 2008 and 2012. Results: A total of 235 cases were included, of which 131 were OM, 79 SA, 30 OA, and 15 SD. As regards the complementary tests that the Consensus considered mandatory to perform, radiography was carried out on 87.8% of the cases, a blood culture on 91.6%, and culture of the synovial fluid in 99% of SA. A magnetic resonance (MR) was performed on 71% of the OM cases. The choice of intravenous empirical antibiotic treatment was adapted to the recommendations in 65.1% of cases, and in 62.3% for the oral treatment. Surgery was performed in 36.8% of SA cases (85.7% arthrotomy), with a significant decrease compared to the retrospective study (P = .014). Only 58.5% of cases followed the recommendations on the duration of the treatment; however, a lower duration of intravenous treatment was observed. Conclusions: In general, the level of adaptation to the recommendations that were set by the Expert Group, is good for the complementary tests, and acceptable as regards the choice of antibiotic treatment, although inadequate in almost 40% of cases. A decrease in hospital stay was achieved. Resumen: Introducción: En 2014 se publicó el Documento de Consenso desarrollado por SEIP-SERPE-SEOP para el diagnóstico y el tratamiento de las infecciones osteoarticulares (IOA). En 2015 se constituyó RIOPed como red nacional multidisciplinar para la investigación en IOA. El objetivo del estudio ha sido valorar el grado de adecuación a las recomendaciones establecidas en el consenso durante un año de seguimiento. Material y métodos: Estudio prospectivo multicéntrico nacional realizado entre septiembre de 2015 y septiembre de 2016 en 37 hospitales con inclusión de pacientes menores de 16 años diagnosticados de IOA, confirmada mediante aislamiento microbiológico, o probable: artritis séptica (AS) con >40.000 leucocitos en líquido sinovial u osteomielitis (OM)/osteoartritis (OA)/espondilodiscitis (ED) con prueba de imagen compatible. Los resultados se compararon con los obtenidos en el estudio retrospectivo realizado entre 2008 y 2012. Resultados: Se incluyeron 255 casos: 131 OM, 79 AS, 30 OA y 15 ED. Respecto a las pruebas complementarias que el consenso consideró de obligada realización, la radiografía se llevó a cabo en el 87,8% de los casos, el hemocultivo en el 91,6% y el cultivo de líquido sinovial en el 99% de AS. Se realizó RM en el 71% de las OM. La elección del tratamiento antibiótico intravenoso empírico se adecuó a las recomendaciones en el 65,1% de los casos, y en el 62,3% para el tratamiento oral. Se llevó a cabo cirugía en el 36,8% de las AS (85,7% artrotomía), con un descenso significativo respecto al estudio retrospectivo (P = ,014). Solo el 58,5% de casos se ajustaron a las recomendaciones de duración del tratamiento; sin embargo, se comprobó una menor duración del tratamiento intravenoso. Conclusiones: En general, el grado de adecuación a las recomendaciones que marcaron el grupo de expertos es bueno para las pruebas complementarias y aceptable respecto a la elección del tratamiento antibiótico, aun detectándose casi un 40% de inadecuación. Se ha conseguido un descenso de la estancia hospitalaria.

[EN] Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available., [ES] Las inmunodeficiencias primarias (IDP) son unas enfermedades raras, frecuentemente infradiagnosticadas y potencialmente fatales. Las manifestaciones clínicas de las IDP pueden ser muy graves y ocasionar secuelas que empeoran la calidad de vida de los pacientes. Tradicionalmente, el tratamiento de las IDP ha sido fundamentalmente de soporte, con excepción del trasplante de progenitores hematopoyéticos y, más recientemente, la terapia génica. El descubrimiento de nuevos mecanismos patogénicos, el desarrollo de nuevas moléculas y fármacos biológicos y los avances en el conocimiento de las bases moleculares de estas enfermedades han abierto oportunidades para el tratamiento de esta afección. El objetivo de este documento es revisar el conocimiento actual y aportar recomendaciones para el diagnóstico y el tratamiento clínico de los pacientes adultos y pediátricos con IDP basado en la evidencia científica disponible y teniendo en cuenta la actual práctica y los retos futuros. Se realizó una revisión sistemática, que justifica los niveles de evidencia para cada recomendación.

Background: It has been demonstrated that children who had been breastfed remain better protected against various infections, and notably respiratory tract infections, well beyond infancy. Since the role of breastfeeding to explain why children are less affected by COVID-19 has not been studied until now, the aim of this study was to determine whether any history of breastfeeding reduces the incidence rate of COVID-19 in children.Methods: This was a secondary analysis of an observational study on clinical and epidemiological characteristics of pediatric COVID-19 in Majorca. A total of 691 children were recruited. Eligible participants were children under 14 who were tested for SARS-CoV-2 in pediatric emergency services. The independent explanatory variable was initial breastfeeding. Bivariate analyses were conducted through the Chi-square test, the Fisher's Exact test or the Student’s T test. All children had the same demographic, epidemiological and clinical data collected through a study team member interview and via the participants medical records. Aspredicted Trials Registry number is #62721. Results: Within the sample of children who visited emergency services with symptoms of potential COVID-19, we found higher prevalence of positive SARS-CoV-2 RT-PCR test results among those who were exclusively formula fed compared with those who were ever breastfed (OR, 2.48; 95%CI, 1.45-3.51; P=0.036). Conclusions: Since approximately 1 in 60 ever breastfed symptomatic children had tested positive for SARS-CoV-2 versus 1 in 25 never breastfed symptomatic children, this study shows that initially breastfed children remain at lower risk of COVID-19.

Abstract Background H syndrome (HS) is a rare autoinflammatory disease caused by a mutation in the solute carrier family 29, member 3 (SCL29A3) gene. It has a variable clinical presentation and little phenotype-genotype correlation. The pathognomonic sign of HS is cutaneous hyperpigmentation located mainly in the inner thighs and often accompanied by other systemic manifestations. Improvement after tocilizumab treatment has been reported in a few patients with HS. We report the first patient with HS who presented cardiogenic shock, multiorgan infiltration, and digital ischemia. Case presentation 8-year-old boy born to consanguineous parents of Moroccan origin who was admitted to the intensive care unit during the Coronavirus Disease-2019 (COVID-19) pandemic with tachypnoea, tachycardia, and oliguria. Echocardiography showed dilated cardiomyopathy and severe systolic dysfunction compatible with cardiogenic shock. Additionally, he presented with multiple organ dysfunction syndrome. SARS-CoV-2 polymerase chain reaction (PCR) and antibody detection by chromatographic immunoassay were negative. A previously ordered gene panel for pre-existing sensorineural hearing loss showed a pathological mutation in the SCL29A3 gene compatible with H syndrome. Computed tomography scan revealed extensive alveolar infiltrates in the lungs and multiple poor defined hypodense lesions in liver, spleen, and kidneys; adenopathy; and cardiomegaly with left ventricle subendocardial nodules. Invasive mechanical ventilation, broad antibiotic and antifungal coverage showed no significant response. Therefore, Tocilizumab as compassionate use together with pulsed intravenous methylprednisolone was initiated. Improvement was impressive leading to normalization of inflammation markers, liver and kidney function, and stabilising heart function. Two weeks later, he was discharged and has been clinically well since then on two weekly administration of Tocilizumab. Conclusions We report the most severe disease course produced by HS described so far in the literature. Our patient’s manifestations included uncommon, new complications such as acute heart failure with severe systolic dysfunction, multi-organ cell infiltrate, and digital ischemia. Most of the clinical symptoms of our patient could have been explained by SARS-CoV-2, demonstrating the importance of a detailed differential diagnosis to ensure optimal treatment. Although the mechanism of autoinflammation of HS remains uncertain, the good response of our patient to Tocilizumab makes a case for the important role of IL-6 in this syndrome and for considering Tocilizumab as a first-line treatment, at least in severely affected patients.

Accumulation of genetic alterations in hepatocarcinogenesis is closely associated with chronic inflammatory liver disease. 8-oxo-2′-deoxyguanosine (8-oxo-dG), the major promutagenic DNA adduct caused by reactive oxygen species (ROS), leads to G:C → T:A transversions. These lesions can be enzymatically repaired mainly by human MutT homolog 1 (hMTH1), human 8-oxo-guanine DNA glycosylase (hOGG1) and human MutY homolog (hMYH). The aim of this study was to evaluate the extent of oxidative damage and its dependence on the cellular antioxidative capacity and the expression of specific DNA repair enzymes in tumor (tu) and corresponding adjacent nontumor (ntu) liver tissue of 23 patients with histologically confirmed hepatocellular carcinoma. 8-oxo-dG levels, as detected by high-pressure liquid chromatography with electrochemical detection, were significantly (P = .003) elevated in ntu tissue (median, 129 fmol/μg DNA) as compared to tu tissue (median, 52 fmol/μg DNA), and were closely associated with inflammatory infiltration. In ntu tissue, the hepatic iron concentration and malondialdehyde levels were significantly (P = .001) higher as compared to tu tissue. Glutathione content, glutathione peroxidase activity and manganese superoxide dismutase messenger RNA (mRNA) expression did not show statistical differences between ntu and tu tissue. Real-time reverse transcription polymerase chain reaction revealed in tu tissue significantly (P = .014) higher hMTH1 mRNA expression compared to ntu tissue. In contrast, hMYH mRNA expression was significantly (P < .05) higher in ntu tissue. No difference in hOGG1 mRNA expression was seen between tu and ntu. In conclusion, these data suggest that ROS generated by chronic inflammation contribute to human hepatocarcinogenesis. The role of DNA repair enzymes appears to be of reactive rather than causative manner. (HEPATOLOGY 2004;39:1663–1672.)

Chronic neutrophilic inflammation leads to oxidative damage, which may play an important role in the pathogenesis of cystic fibrosis lung disease. Bronchoalveolar lavage levels of the antioxidant glutathione are diminished in patients with cystic fibrosis. Here we evaluated the effects of glutathione aerosol on lower airway glutathione levels, lung function, and oxidative status. Pulmonary deposition of a radiolabeled monodisperse aerosol generated with a Pari LC Star nebulizer (Allergy Asthma Technology, Morton Grove, IL) connected to an AKITA inhalation device (Inamed, Gauting, Germany) was determined in six patients. In 17 additional patients bronchoalveolar lavage fluid was assessed before and after 14 days of inhalation with thrice-daily doses of 300 or 450 mg of glutathione. Intrathoracic deposition was 86.3 +/- 1.4% of the emitted dose. Glutathione concentration in lavage 1 hour postinhalation was increased three- to fourfold and was still almost doubled 12 hours postinhalation. FEV(1) transiently dropped after inhalation but increased compared with pretreatment values after 14 days (p0.001). This improvement was not related to the lavage content of oxidized proteins and lipids, which did not change with treatment. These results show that, using a new inhalation device with high efficacy, glutathione treatment of the lower airways is feasible. Reversion of markers of oxidative injury may need longer treatment, higher doses, or different types of antioxidants.

In murine models, overexpression of interleukin (IL)-12 and interferon (IFN)-γ can induce severe liver damage, whereas IL-10 has anti-inflammatory and hepatoprotective properties. To analyze the potential role of these cytokines in human fulminant hepatitis B, we used immunohistochemistry to study expression of IL-12, IFN-γ, and IL-10 in explant livers of 11 patients with fulminant hepatitis B, 5 patients with fulminant hepatitis due to other etiologies, 37 patients with chronic liver disease (CLD; hepatitis B virus, n = 15; hepatitis C virus, n = 10; primary biliary cirrhosis, n = 12), and 10 normal controls (NCs). Furthermore, cytokine messenger RNA (mRNA) levels were determined in the liver specimens by quantitative real-time polymerase chain reaction (PCR). In NCs, faint IL-12 expression was detected in only a few Kupffer cells, whereas sinusoidal endothelial cells, hepatic stellate cells, bile ducts, and lymphocytes expressed IL-12 in CLD and, more conspicuously, in fulminant hepatitis B. In contrast, expression of IFN-γ and IL-10 was restricted to lymphocytes and Kupffer cells, respectively. In fulminant hepatitis B, numbers of IL-12– and IFN-γ–positive cells markedly exceeded those found in CLD and NCs. A close correlation existed between IL-12 and IFN-γ expression (r = 0.68; P < .001). In contrast, IL-10 expression was not significantly different in CLD and fulminant hepatitis. The quantitative differences in immunohistologic cytokine expression closely corresponded to the mRNA levels. In conclusion, our data indicate massive induction of the proinflammatory cytokines IL-12 and IFN-γ in fulminant hepatitis B, which is apparently not counterbalanced by the anti-inflammatory cytokine IL-10. This cytokine imbalance may play an important role in promoting inflammatory reactions leading to massive liver damage in fulminant hepatitis B. (HEPATOLOGY 2002;36:1001-1008.)

Background & Aims: The tumor necrosis factor (TNF)-α/TNF receptor system is critical for liver development because hepatocytes undergo apoptosis if the antiapoptotic cascades resulting in RelA NF-κB activation are not effective. Therefore, we studied the role of TNF-α in fulminant hepatic failure (FHF) and developed a new therapeutic strategy. Methods: Serum levels and hepatic expression of TNF-α and both TNF receptors were determined by enzyme-linked immunosorbent assay and immunohistochemistry. Adenoviral vectors were constructed expressing dominant-negative proteins interfering with intracellular TNF-α–dependent pathways. The relevance of these constructs was studied in primary mouse hepatocytes and in a murine model of FHF. Results: Serum levels of TNF-α and TNF receptors are significantly increased in FHF; this increase correlates with patient prognosis. In livers of patients with FHF, infiltrating mononuclear cells express high amounts of TNF-α and hepatocytes overexpress TNF receptor 1 (TNF-R1). Apoptotic hepatocytes are significantly increased in FHF, and there is a strong correlation with TNF-α expression, which is even more pronounced in areas of mononuclear infiltrates. In an in vivo FHF model, the Fas-associated death domain (FADD), adenovirus selectively blocked the intracellular pathway, leading to mitochondrial cytochrome c release, caspase-3 activation, and, thus, apoptosis of hepatocytes. Conclusions: The results show that the TNF-α/TNF-R1 system is involved in the pathogenesis of FHF in humans. Studies in this animal model indicate that FADD may serve as a molecular target to prevent liver cell death in vivo. GASTROENTEROLOGY 2000;119:446-460

In murine models, overexpression of interleukin (IL)-12 and interferon (IFN)-gamma can induce severe liver damage, whereas IL-10 has anti-inflammatory and hepatoprotective properties. To analyze the potential role of these cytokines in human fulminant hepatitis B, we used immunohistochemistry to study expression of IL-12, IFN-gamma, and IL-10 in explant livers of 11 patients with fulminant hepatitis B, 5 patients with fulminant hepatitis due to other etiologies, 37 patients with chronic liver disease (CLD; hepatitis B virus, n = 15; hepatitis C virus, n = 10; primary biliary cirrhosis, n = 12), and 10 normal controls (NCs). Furthermore, cytokine messenger RNA (mRNA) levels were determined in the liver specimens by quantitative real-time polymerase chain reaction (PCR). In NCs, faint IL-12 expression was detected in only a few Kupffer cells, whereas sinusoidal endothelial cells, hepatic stellate cells, bile ducts, and lymphocytes expressed IL-12 in CLD and, more conspicuously, in fulminant hepatitis B. In contrast, expression of IFN-gamma and IL-10 was restricted to lymphocytes and Kupffer cells, respectively. In fulminant hepatitis B, numbers of IL-12- and IFN-gamma-positive cells markedly exceeded those found in CLD and NCs. A close correlation existed between IL-12 and IFN-gamma expression (r = 0.68; P.001). In contrast, IL-10 expression was not significantly different in CLD and fulminant hepatitis. The quantitative differences in immunohistologic cytokine expression closely corresponded to the mRNA levels. In conclusion, our data indicate massive induction of the proinflammatory cytokines IL-12 and IFN-gamma in fulminant hepatitis B, which is apparently not counterbalanced by the anti-inflammatory cytokine IL-10. This cytokine imbalance may play an important role in promoting inflammatory reactions leading to massive liver damage in fulminant hepatitis B.

Interferon-alpha (IFN-α) has potent pro-inflammatory and anti-viral functions. It exerts its effects by inducing intracellular proteins such as MxA. To analyse the role of intrahepatic interferon activation, IFN-α and MxA expression was studied by immunohistochemistry in explant livers of 20 patients with fulminant hepatic failure (FHF), 41 patients with chronic liver disease (CLD), and ten normal controls (NCs). In NCs only small numbers of Kupffer cells, but no hepatocytes, showed IFN-α and MxA expression. In contrast, significantly enhanced numbers of IFN-α- and MxA-positive Kupffer cells, along with small numbers of MxA-positive and larger numbers of IFN-α-positive lymphocytes, were found in CLD and in FHF. MxA protein was also expressed on hepatocytes and bile ducts in the vicinity of IFN-α-positive inflammatory infiltrates (hepatocytes: NCs: 0%, CLD: 8%, FHF: 68%; bile ducts: NCs: 19%, CLD: 46%, FHF: 83%). A significant correlation was found between the numbers of IFN-α- and MxA-positive cells (r=0.67, p