To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR.
Objective To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. Methods This international multidisciplinary initiative included four phases: (1) Phase I, criteria generation by surveys and literature review; (2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; (3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and (4) Phase IV, validation using independent adjudicators’ consensus as the gold standard. Results The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1–7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti–β2-glycoprotein I antibodies). Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria vs the 2006 revised Sapporo classification criteria had a specificity of 99% vs 86%, and a sensitivity of 84% vs 99%. Conclusion These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.
Background Biobanking biospecimens and consent are common practice in paediatric research. We need to explore children and young people’s (CYP) knowledge and perspectives around the use of and consent to biobanking. This will ensure meaningful informed consent can be obtained and improve current consent procedures. Methods We designed a survey, in co-production with CYP, collecting demographic data, views on biobanking, and consent using three scenarios: 1) prospective consent, 2) deferred consent, and 3) reconsent and assent at age of capacity. The survey was disseminated via the Young Person’s Advisory Group North England (YPAGne) and participating CYP’s secondary schools. Data were analysed using a qualitative thematic approach by three independent reviewers (including CYP) to identify common themes. Data triangulation occurred independently by a fourth reviewer. Results One hundred two CYP completed the survey. Most were between 16–18 years (63.7%, N = 65) and female (66.7%, N = 68). 72.3% had no prior knowledge of biobanking ( N = 73). Acceptability of prospective consent for biobanking was high (91.2%, N = 93) with common themes: ‘altruism’, ‘potential benefits outweigh individual risk’, 'frugality', and ‘(in)convenience’. Deferred consent was also deemed acceptable in the large majority (84.3%, N = 86), with common themes: ‘altruism’, ‘body integrity’ and ‘sample frugality’. 76.5% preferred to reconsent when cognitively mature enough to give assent ( N = 78), even if parental consent was previously in place. 79.2% wanted to be informed if their biobanked biospecimen is reused ( N = 80). Conclusion Prospective and deferred consent acceptability for biobanking is high among CYP in the UK. Altruism, frugality, body integrity, and privacy are the most important themes. Clear communication and justification are paramount to obtain consent. Any CYP with capacity should be part of the consenting procedure, if possible.
Children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) usually present minimal symptoms or are asymptomatic. Nevertheless, a subset of children 2-6 weeks after the initial SARS-CoV-2 infection develops a postinfectious SARS-CoV-2-related multisystem inflammatory syndrome in (MIS-C). Recently, transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation, however, the underlying pathophysiology of MIS-C is not fully understood [1].The purpose of our project is to characterize the complexity of cell populations and capture cellular heterogeneity to uncover the regulatory networks and interactions that are disrupted during MIS-C flare with simultaneous profiling of gene expression and open chromatin regions from the same nuclei.Samples of peripheral blood mononuclear cells from patients with MIS-C diagnosed at the University Children’s Hospital, University Medical Center Ljubljana, were collected during the initial presentation before any treatment and at 6-12 months in remission. The primary aim is to identify which regulatory networks are driving inflammation in MIS-C flare, for which we are performing single cell Multiome ATAC + Gene Expression Sequencing. To enable simultaneous profiling of epigenomic landscape and gene expression from the same nuclei, we are using Chromium Next GEM Single Cell Multiome ATAC + Gene Expression kit from 10X Genomics.We included 32 patients with MIS-C from whom we collected paired blood samples during the initial presentation before treatment and at 6-12 months in remission. In single cell multiomic experiment we included 10 patients with paired samples, with the most viable cell count prior cryopreservation. All samples that are included into multiomic single cell analysis have 75% - 99% viability prior cryopreservation. In the protocol the key is to remove remaining granulocytes causing high mitochondrial RNA burden and extensively optimize the dilution factor of lysis buffer and the length of cell lysis step in order to get intact nuclei with no significant blebbing. Afterward, the single cell ATAC libraries as well as single-cell gene expression libraries are constructed and sequenced. Data are undergoing pairwise analysis to compare the cell population heterogeneity, expression profile and open chromatin landscape in the time of the initial presentation of MIS-C and in the remission, with Cell ranger software as well as with R package scREG [2], and custom scripting. In the second step we will inspect if the resulting altered transcriptomic signature from single-cell experiment is present on larger cohort. In that regard, we will perform bulk transcriptomic profiling on all paired collected samples during the initial presentation of MIS-C before treatment and at 6-12 months in remission.The results of this project are expected to enlighten the underlying pathophysiology of MIS-C flare and thus support clinical decision on more targeted treatment. The identified disrupted networks during MIS-C flare could lead the way to establish an early diagnosis and improve long-term outcome, including prevention of myocardial and neuropsychological impairment. Moreover, a better understanding of the disrupted regulatory networks that are driving inflammation in MIS-C, could lead to new insights into diseases with similar clinical presentations as is Kawasaki Disease.[1]Sacco, K., Castagnoli, R., Vakkilainen, S.et al.Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19.Nat Med28, 1050–1062 (2022).[2]Duren, Z., Chang, F., Naqing, F.et al.Regulatory analysis of single cell multiome gene expression and chromatin accessibility data with scREG.Genome Biol23, 114 (2022).This research was supported by Slovenian research agency grant J3-3061 and Interreg ITA-SLO project Cattedra.None Declared.
Juvenile systemic sclerosis (jSSc) is an orphan disease with a prevalence of 3 in 1 000 000 children. In adult patients there are significant differences between the clinical presentation of diffuse and limited subtypes. We reviewed clinical differences in presentation of subtypes in patients in the juvenile systemic scleroderma inception cohort (jSScC).To study the clinical presentation of jSSc patients with diffuse (djSSc) and limited (ljSSc) subtypes.We reviewed the baseline clinical characteristics of the patients, who were recruited to the jSScC till December 2022. jSScC is a prospective cohort of jSSc patients, who developed the first non-Raynaud´s symptom before the age of 16 years and are under the age of 18 years at the time of inclusion.The JSScC included 232 patients, 68% (n=159) had diffuse subtype. The median age at onset of Raynaud phenomenon was 10.4 years (7.3-12.9), at the first non-Raynaud symptom 10.9 years (7.3-13.0) and median disease duration 2.5 years (1.0-4.6). The female/male ratio was significantly lower in the djSSc subtype (3:1 versus 5:1, p<0.001). Antibody profile was similar, with the exception of a significantly higher number of anticentromere positive patients in the ljSSc. Decreased FVC<80% was found in approximately 30% and decreased DLCO<80% was found in around 40% in both subtypes. Abnormal HRCT findings were found in 44% of patients. Pulmonary hypertension assessed by ultrasound occurred in approximately 5% in both groups and gastrointestinal involvement in 43% of djSSc and 36% in ljSSc (p=0.303). Patients with djSSc had significantly higher modified Rodnan Skin Score, more frequently sclerodactyly, a history of digital ulceration active ulceration, telangiectasia, a decreased Body Mass Index z score ≤ -2 and decreased joint range of motion. Patients with ljSSc had significantly higher rate of cardiac involvement. Regarding patient related outcomes assessed by VAS 0-100 djSSc patients had more severe disease also physician related outcome assessed by VAS 0-100 were significantly higher in djSSc (see Table 1).Table 1.Comparison of subtypes at time of inclusion in the cohortWhole Group N=232Diffuse Subtype N=159Limited Subtype N=73P value Anticentromere5% (7/156)2% (2/106)10% (5/50)0.022 MRSS, median (IQR)10 (4 – 20)16 (8 - 27)4 (0 – 8)0.001 Gottron Papules26% (59/228)31% (48/155)15% (11/73)0.011 Sclerodactyly75% (165/219)85% (127/150)55% (38/69)<0.001 Telangiectasia37% (77/209)44%(62/141)22% (15/68)0.002 History of ulceration52% (119/229)62% (98/158)30% (21/71)<0.001 Active ulceration17% (39/229)21% (33/158)8% (6/71)0.021 Only Cardiac involvement5% (12/232)3% (4/159)11% (8/73)0.007 BMI<- 2 z score15% (33/217)20% (29/148)6% (4/69)0.008 Joints with decreased range59% (136/231)64% (101/158)48% (35/73)0.022Physician Reported (Median, IQR) Physician global disease activity30 (20 – 45)n=19735 (20– 50)n=13820 (10 – 30)n=590.001 Physician global disease damage30 (15 – 40)n=19530 (20 – 45)n=13820 (5 – 30)n=570.004 Physician ulceration activity0 (0 – 16)n=2165 (0 – 20)n=1540 (0 – 0)n=620.018Patient Reported (Median, IQR) Patient global disease activity40 (20 – 50)n=17840 (20 – 50)n=12930 (15 – 55)n=490.024 Patient global disease damage30 (15 – 60)n=17740 (20 – 60)n=12825 (5 – 55)n=490.001 Patient Raynaud activity30 (10 – 60)n=20230 (10 – 60)n=14515 (0 – 55)n=570.001 Patient ulceration activity0 (0 – 30)n=20310 (0 – 30)n=1450 (0 – 20)n=580.001In the largest jSSc cohort in the world, djSSc patients have a significantly more severe disease. Patients and physician related outcomes were significantly more severe in djSSc group. Interestingly, we found no differences regarding interstitial lung disease, pulmonary hypertension or gastrointestinal involvement, although the number of patients with decreased BMI ≤ -2 z score was significantly higher in the djSSc patients.NIL.NIL.None Declared.
Background Paediatric patients with autoimmune rheumatic diseases (pARD) are often immunocompromised because of the disease and/or the therapy they receive. At the beginning of COVID-19 pandemic there was a great concern about the possibility of severe SARS-CoV-2 infection in these patients. The best method of protection is vaccination, so as soon as vaccine was licenced, we aimed to vaccinate them. Data on disease relapse rate after COVID-19 infection and vaccination are scarce, but they play important role in everyday clinical decisions. Methods The aim of this study was to determine the relapse rate of autoimmune rheumatic disease (ARD) after COVID-19 infection and vaccination. Data on demographic, diagnosis, disease activity, therapy, clinical presentation of the infection and serology were collected from pARD who had COVID-19 and from pARD who were vaccinated against COVID-19, from March 2020 to April 2022. All vaccinated patients received two doses of the BNT162b2 BioNTech vaccine, on average, 3.7 (S.D.=1.4) weeks apart. Activity of the ARD was followed prospectively. Relapse was defined as a worsening of the ARD in a time frame of 8 weeks after infection or vaccination. For statistical analysis, Fisher’s exact test and Mann-Whitney U test were used. Results We collected data from 115 pARD, which we divided into two groups. We included 92 pARD after infection and 47 after vaccination, with 24 in both groups (they were infected before/after vaccination). In 92 pARD we registered 103 SARS-CoV-2 infections. Infection was asymptomatic in 14%, mild in 67% and moderate in 18%, 1% required hospitalization; 10% had a relapse of ARD after infection and 6% after vaccination. There was a trend towards higher disease relapse rate after infection compared to vaccination, but the difference was not statistically significant (p = 0.76). No statistically significant difference was detected in the relapse rate depending on the clinical presentation of the infection (p = 0.25) or the severity of the clinical presentation of COVID-19 between vaccinated and unvaccinated pARD (p = 0.31). Conclusions There is a trend towards a higher relapse rate in pARD after infection compared to vaccination and connection between the severity of COVID-19 and vaccination status is plausible. Our results were, however, not statistically significant.
Background Postgraduate rheumatology training programmes are already established at a national level in most European countries. However, previous work has highlighted a substantial level of heterogeneity in the organisation and, in part, content of programmes. Objective To define competences and standards of knowledge, skills and professional behaviours required for the training of rheumatologists. Methods A European Alliance of Associations for Rheumatology (EULAR) task force (TF) of 23 experts, including two members of the European Union of Medical Specialists (UEMS) section of rheumatology, was convened. The mapping phase consisted of the retrieval of key documents on specialty training in rheumatology and other related specialties across a broad set of international sources. The content of these documents was extracted and represented the foundation for the document draft that underwent several rounds of online discussion within the TF, and afterwards was also distributed to a broad group of stakeholders for collecting feedback. The list of generated competences was voted on during the TF meetings, while the level of agreement (LoA) with each statement was established by anonymous online voting. Results A total of 132 international training curricula were retrieved and extracted. In addition to the TF members, 253 stakeholders commented and voted on the competences through an online anonymous survey. The TF developed (1) an overarching framework indicating the areas that should be addressed during training, (2) 7 domains defining broad areas that rheumatology trainees should master by the end of the training programme, (3) 8 core themes defining the nuances of each domain and (4) 28 competences that trainees should acquire to cover each of the areas outlined in the overarching framework. A high LoA was achieved for all competences. Conclusion These points to consider for EULAR–UEMS standards for the training of European rheumatologists are now defined. Their dissemination and use can hopefully contribute to harmonising training across European countries.
OBJECTIVES CLIPPER2 was an 8-year, open-label extension of the phase 3 b, 2-year CLIPPER study on the safety and efficacy of etanercept in patients with juvenile idiopathic arthritis (JIA), categorized as extended oligoarticular arthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). METHODS Participants with eoJIA (2-17 years old), ERA, or PsA (each 12-17 years old) who received ≥1 etanercept dose (0.8 mg/kg weekly; maximum 50 mg) in CLIPPER could enter CLIPPER2. Primary end point was occurrence of malignancy. Efficacy assessments included proportions achieving JIA American College of Rheumatology (ACR) 30/50/70/90/100 criteriaand ACR inactive disease criteria, and clinical remission (ACR criteria) or Juvenile Arthritis Disease Activity Score (JADAS) ≤1. RESULTS Overall, 109/127 (86%) CLIPPER participants entered CLIPPER2 (n = 55 eoJIA, n = 31 ERA, n = 23 PsA; 99 [78%] on active treatment); 84 (66%) completed 120 months' follow-up (32 [25%] on active treatment). One malignancy (Hodgkin's disease in 18-year-old patient with eoJIA treated with methotrexate for 8 years) was reported; there were no cases of active tuberculosis or deaths. Numbers and incidence rates [events per 100 patient-years] of TEAEs (excluding infections/ISRs) decreased from 193 [173.81] in Year 1-9 [27.15] in Year 10; TE infections and serious infections also decreased. Over 45% of participants (N = 127) achieved JIA ACR50 responses from Month 2 onwards; 42 (33%) and 17 34 (27%) participants achieved JADAS and ACR clinical remission, respectively. CONCLUSIONS Etanercept treatment up to 10 years was well tolerated, consistent with the known safety profile, with durable response in the participants still on active treatment. The benefit-risk assessment of etanercept in these JIA categories remains favorable. CLINICALTRIALS.GOV IDS CLIPPER (NCT00962741); CLIPPER2 (NCT01421069).
Introduction Although children seem to be less susceptible to COVID-19, some of them develop a rare but serious hyperinflammatory condition called multisystem inflammatory syndrome in children (MIS-C). While several studies describe the clinical conditions of acute MIS-C, the status of convalescent patients in the months after acute MIS-C is still unclear, especially the question of persistence of changes in the specific subpopulations of immune cells in the convalescent phase of the disease. Methods We therefore analyzed peripheral blood of 14 children with MIS-C at the onset of the disease (acute phase) and 2 to 6 months after disease onset (post-acute convalescent phase) for lymphocyte subsets and antigen-presenting cell (APC) phenotype. The results were compared with six healthy age-matched controls. Results All major lymphocyte populations (B cells, CD4 + and CD8+ T cells, and NK cells) were decreased in the acute phase and normalized in the convalescent phase. T cell activation was increased in the acute phase, followed by an increased proportion of γ/δ-double-negative T cells (γ/δ DN Ts) in the convalescent phase. B cell differentiation was impaired in the acute phase with a decreased proportion of CD21 expressing, activated/memory, and class-switched memory B cells, which normalized in the convalescent phase. The proportion of plasmacytoid dendritic cells, conventional type 2 dendritic cells, and classical monocytes were decreased, while the proportion of conventional type 1 dendritic cells was increased in the acute phase. Importantly the population of plasmacytoid dendritic cells remained decreased in the convalescent phase, while other APC populations normalized. Immunometabolic analysis of peripheral blood mononuclear cells (PBMCs) in the convalescent MIS-C showed comparable mitochondrial respiration and glycolysis rates to healthy controls. Conclusions While both immunophenotyping and immunometabolic analyzes showed that immune cells in the convalescent MIS-C phase normalized in many parameters, we found lower percentage of plasmablasts, lower expression of T cell co-receptors (CD3, CD4, and CD8), an increased percentage of γ/δ DN Ts and increased metabolic activity of CD3/CD28-stimulated T cells. Overall, the results suggest that inflammation persists for months after the onset of MIS-C, with significant alterations in some immune system parameters, which may also impair immune defense against viral infections.
Objectives: Juvenile systemic sclerosis is a rare childhood disease. Three disease activity indices have been published for adult patients with systemic sclerosis: the European Scleroderma Study Group Index, a modified version of the European Scleroderma Study Group Index and the revised European Scleroderma Trials and Research index. The objective of this study was to determine the feasibility and performance of the three disease activity indices in a prospectively followed cohort of patients with juvenile systemic sclerosis. Methods: The analysis cohort was selected from the prospective international inception cohort enrolling juvenile systemic sclerosis patients. The correlation of the disease activity indices with the physicians’ and the patients’ global assessment of disease activity was determined. The disease activity indices were compared between patients with active and inactive disease. Sensitivity to change between 6- and 12-month follow-up was investigated by mixed models. Results: Eighty percent of the 70 patients had a diffuse cutaneous subtype. The revised European Scleroderma Trials and Research index was highly correlated with the physician-reported global disease activity/parents-reported global disease activity (r = 0.74/0.64), followed by the European Scleroderma Study Group activity index (r = 0.61/0.55) and the modified version of the European Scleroderma Study Group activity index (r = 0.51/0.43). The disease activity indices significantly differed between active and inactive patients. The disease activity indices showed sensitivity to change between 6- and 12-month follow-up among patients who improved or worsened according to the physician-reported global disease activity and the parents-reported global disease activity. Conclusion: Overall, no disease activity score is superior to the other, and all three scores have limitations in the application in juvenile systemic sclerosis patients. Furthermore, research on the concept of disease activity and suitable scores to measure disease activity in patients with juvenile systemic sclerosis is necessary in future.
International interest in development of treat-to-target (T2T) in both childhood-onset systemic lupus erythematosus (cSLE) and adult-onset SLE (aSLE) is increasing. T2T could facilitate more effective and structured use of treatments, aggressively controlling disease activity, preventing organ damage, and improving health-related quality of life. The first step is the selection of an appropriate target. Remission is deemed the ultimate target, but may not be attainable by all. Low disease activity (LDA), based on the principle of “tolerable” disease activity on stable treatment, with low corticosteroid dosage, may be more appropriate for some patients. The aim of this study was to derive a consensus-based cSLE appropriate definition of LDA, building upon existing aSLE definitions to improve applicability to cSLE, whilst maintaining sufficient unity to ensure that future T2T studies including adolescents and adults together are possible. The International cSLE T2T Task Force, including 18 specialists from paediatric rheumatology/nephrology, and adult rheumatology undertook a series of Delphi surveys, exploring views on aSLE LDA targets. Two virtual consensus meetings were held, utilising a modified nominal group technique to debate, modify, and vote upon topics underpinning the cSLE LDA target and its criteria. Agreement of > 80% was considered consensus. The task force agreed that the LDA target should encompass cSLE as a whole and be based upon the aSLE Lupus Low Disease Activity State definition (LLDAS), with modifications to make it more applicable to cSLE (cLLDAS, all 100% agreement). A conceptual definition of cLLDAS was defined: ‘A state, which if sustained, is associated with a low likelihood of adverse outcome (considering disease activity, damage, and medication toxicity)’ (100% agreement). Five cLLDAS criteria were agreed, as detailed within Table 1. The final cLLDAS definition was endorsed by the Paediatric Rheumatology European Society (PReS) Executive Council and PReS cSLE Working Party Chair, on behalf of the Society. A cSLE, age-appropriate definition of cLLDAS has been generated, preserving sufficient unity with the aSLE LLDAS definition to encourage life-course research. The development and validation of targets has been a key enabler for T2T trials, therefore this initiative represents a significant step forward for cSLE. Disclosure E.M.D. Smith: None. A. Aggarwal: None. J. Ainsworth: None. E. Al-Abadi: None. T. Avcin: None. L. Bortey: None. J. Burnham: None. C. Ciurtin: None. C.M. Hedrich: None. S. Kamphuis: None. D. Levy: None. L. Lewandowski: None. N. Maxwell: None. E. Morand: None. S. Ozen: None. C. Pain: None. A. Ravelli: None. C. Saad Magalhaes: None. C. Pilkington: None. D. Schonenberg: None. C. Scott: None. K. Tullus: None. M.W. Beresford: None.
An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology. Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK^ 1 . Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.
An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland^ 1 in April 2022 and has now been identified in 35 countries^ 2 . Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case–control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4^+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10^−12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a ‘helper virus’ to support AAV2 replication) and disease susceptibility related to HLA class II status. A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.
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