Invasive Fungal Diseases in Adult Patients in Intensive Care Unit (FUNDICU): 2024 consensus definitions from ESGCIP, EFISG, ESICM, ECMM, MSGERC, ISAC, and ISHAM.

PURPOSE: The aim of this document was to develop standardized research definitions of invasive fungal diseases (IFD) in non-neutropenic, adult patients without classical host factors for IFD, admitted to intensive care units (ICUs). METHODS: After a systematic assessment of the diagnostic performance for IFD in the target population of already existing definitions and laboratory tests, consensus definitions were developed by a panel of experts using the RAND/UCLA appropriateness method. RESULTS: Standardized research definitions were developed for proven invasive candidiasis, probable deep-seated candidiasis, proven invasive aspergillosis, probable invasive pulmonary aspergillosis, and probable tracheobronchial aspergillosis. The limited evidence on the performance of existing definitions and laboratory tests for the diagnosis of IFD other than candidiasis and aspergillosis precluded the development of dedicated definitions, at least pending further data. The standardized definitions provided in the present document are aimed to speed-up the design, and increase the feasibility, of future comparative research studies.

Neuropsychological evaluation of phenoconversion risk in REM sleep behaviour disorder: A scoping review.

The objective of this study was to assess the role of cognitive evaluation in the prediction of phenoconversion in polysomnography-confirmed idiopathic or isolated rapid eye movement sleep behaviour disorder, through a scoping review focussing on a longitudinal comprehensive neuropsychological assessment of patients with idiopathic REM sleep behaviour disorder. A literature search (2006-2022) yielded 1034 records, and 20 were selected for analysis. The sample included 899 patients from eight different cohorts and five countries. We extracted data on clinical evolution, mild cognitive impairment diagnosis, neuropsychological tests used, and classification of cognitive domains. Tests, cognitive domains, and mild cognitive impairment definitions were heterogeneous across the studies, precluding a meta-analysis. Ten studies (50%) evaluated the presence of mild cognitive impairment; 14 studies (70%) grouped neuropsychological tests into between three (6 studies, 21.4%) and seven (1 study, 7.1%) cognitive domains. The most frequently used tests were semantic fluency, Stroop colour word test, trail making test A and B, digit span, Rey auditory verbal learning test, and Rey-Osterrieth figure. All except digit span showed a role in predicting phenoconversion. The authors did not consistently assign tests to specific cognitive domains. In conclusion, we discuss methodological differences between the studies and highlight the need for a standardised framework for neuropsychological data acquisition and presentation, based on a multilevel approach covering test selection, domain assignment, and mild cognitive impairment diagnostic criteria.

Performance of existing clinical scores and laboratory tests for the diagnosis of invasive candidiasis in critically ill, nonneutropenic, adult patients: A systematic review with qualitative evidence synthesis.

BACKGROUND: The Fungal Infections Definitions in Intensive Care Unit (ICU) patients (FUNDICU) project aims to provide standard sets of definitions for invasive fungal diseases in critically ill, adult patients. OBJECTIVES: To summarise the available evidence on the diagnostic performance of clinical scores and laboratory tests for invasive candidiasis (IC) in nonneutropenic, adult critically ill patients. METHODS: A systematic review was performed to evaluate studies assessing the diagnostic performance for IC of clinical scores and/or laboratory tests vs. a reference standard or a reference definition in critically ill, nonneutropenic, adult patients in ICU. RESULTS: Clinical scores, despite the heterogeneity of study populations and IC prevalences, constantly showed a high negative predictive value (NPV) and a low positive predictive value (PPV) for the diagnosis of IC in the target population. Fungal antigen-based biomarkers (with most studies assessing serum beta-D-glucan) retained a high NPV similar to that of clinical scores, with a higher PPV, although the latter showed important heterogeneity across studies, possibly reflecting the targeted or untargeted use of these tests in patients with a consistent clinical picture and risk factors for IC. CONCLUSIONS: Both clinical scores and laboratory tests showed high NPV for the diagnosis of IC in nonneutropenic critically ill patients. The PPV of laboratory tests varies significantly according to the baseline patients' risk of IC. This qualitative synthesis will provide the FUNDICU panel with baseline evidence to be considered during the development of definitions of IC in critically ill, nonneutropenic adult patients in ICU.

Efficacy, immunogenicity, and safety of available vaccines in children on biologics: A systematic review and meta-analysis.

Vaccinations are essential for preventing infectious diseases in children with chronic diseases as they have increased risk of infection from frequent use of biologics. Response to immunizations in this group is not well known. OBJECTIVE: A systematic review was performed to evaluate three primary outcomes: efficacy; immunogenicity; and safety of vaccines in children with chronic conditions treated with biologics. METHODS: The protocol for our systematic review and meta-analysis was registered and published with PROSPERO. We searched electronic bibliographic databases for studies published from 2009 to 2019, focusing on vaccinations in children with chronic conditions treated with biologics. RESULTS: We retrieved 532 records. Thirty-one full-text articles were selected, and 14 were included in the meta-analysis. No significant publication bias was found. EFFICACY: limited data are available regarding the efficacy of vaccination, as most studies have focused on immunogenicity as surrogate outcome for efficacy. Immunogenicity: patients receiving anti-TNF-alpha therapy had a statistically significant risk of poor seroconversion (p = 0.028) and seroprotection by the serotype B influenza vaccine [inflammatory bowel disease (IBD) p = 0.013; juvenile idiopathic arthritis (JIA) p = 0.004]. We found adequate responses with H1N1 and H3N2 serotypes. Few studies existed for pneumococcal, hepatitis A virus, hepatitis B virus, varicella-zoster virus, Measles Mumps Rubella virus, and multiple vaccine administration. SAFETY: vaccine administration was not associated with serious side effects, but JIA patients on anti-TNF alpha therapy had a statistically significant risk of presenting with myalgia or arthralgia postinfluenza vaccine (p = 0.014). CONCLUSIONS: More evidence concerning efficacy, immunogenicity, and safety of vaccinations is needed to guide physicians in the vaccine decision process for this pediatric population.

Global Meta-Analysis on the Association between Behcet Syndrome and Polymorphisms from the HLA Class I (A, B, and C) and Class II (DRB1, DQB1, and DPB1) Genes.

Behcet syndrome (BS) is a multisystemic perivasculitis whose genetic susceptibility is linked to HLA region. We first meta-analysed all HLA class I and II genes involved in BS susceptibility in all ethnic groups worldwide. We identified 1141 articles and finally included 31 case-control studies after multiple rounds of selection. We analysed frequencies for 24 HLA-A alleles (3 alleles for HLA-A∗26 at four digits), 50 HLA-B alleles (11 alleles for HLA-B∗51 at four digits), 15 HLA-C alleles, 16 HLA-DRB1 alleles, 6 HLA-DQB1 alleles, and 15 HLA-DPB1 alleles. We meta-analysed only HLA allelic frequencies from at least three studies; therefore, we investigated 21 alleles out of 140. Going from 7.00 to 1.6 OR, we found 11 class I alleles conferring risk for BS: B∗51 : 08, B∗51, B∗51 : 01, B∗51 : 02, DQB1∗03, A∗26 : 01, Cw∗14, Cw∗15, Cw∗16, B∗15, and A∗26. Overall, the studies included populations from Europe (Greece, Spain, Italy, Germany, and Ireland), Asia (Korea, China, China Han, and Thailand), Middle East (Israel, Saudi Arabia, and Iran), and Morocco (as no other North-African population was included). We collected a number of ethnical groups sufficient to conduct an ethnic-specific meta-analysis where Europeans showed 11.25 OR for B∗51:08 and Japan 3.50 OR for A∗26 : 01. A remarkable result was that the most frequent HLA - B∗51 two-digit alleles associated with BS were different among populations: HLA - B∗51 : 08 in Europe, HLA - B∗51 : 01 in Turkey, and HLA - B∗51 : 02 in Japan. Overall, we discussed our real-world results with other imputation studies.

Performance of Existing Definitions and Tests for the Diagnosis of Invasive Fungal Diseases other than Invasive Candidiasis and Invasive Aspergillosis in Critically Ill, Adult Patients: A Systematic Review with Qualitative Evidence Synthesis.

The Fungal Infections Definitions in Intensive Care Unit (ICU) patients (FUNDICU) project aims to provide standard sets of definitions for invasive fungal diseases (IFDs) in critically ill, adult patients, including invasive aspergillosis (IA), invasive candidiasis (IC), Pneumocystis jirovecii pneumonia (PJP), and other non-IA, non-IC IFDs. The first step of the project was the conduction of separated systematic reviews of the characteristics and applicability to critically ill, adult patients outside classical populations at risk (hematology patients, solid organ transplant recipients) of available definitions and diagnostic tests for IFDs. We report here the results of two systematic reviews exploring the performance of available definitions and tests, for PJP and for other non-IA, non-IC IFDs. Starting from 2585 and 4584 records for PJP and other IFDs, respectively, 89 and 61 studies were deemed as eligible for full-text evaluation. However, only two studies for PJP and no studies for other IFDs met the FUNDICU protocol criteria for inclusion in qualitative synthesis. Currently, there is no sufficient solid data for directly evaluating the performance of existing definitions and laboratory tests for the diagnosis of PJP and other non-IA, non-IC IFDs in critically ill adult patients outside classical populations at risk.

The role of trimethoprim/sulfametoxazole in reducing relapses and risk of infections in ANCA-associated vasculitis: a meta-analysis.

OBJECTIVES: To assess available evidence from randomized controlled trials (RCTs) and observational studies including a control group regarding the role of trimethoprim/sulfametoxazole (TMP/SMX) in reducing the relapse rate in patients with granulomatosis with polyangiitis (GPA) and the risk of infections in patients with ANCA-associated vasculitis (AAV). METHODS: MEDLINE, EMBASE, The Cochrane Library databases, Scopus, Web of Science and ClinicalTrials.gov were searched from inception until 15 January 2020 to identify controlled studies assessing the role of TMP/SMX in reducing the rate of relapse in patients with GPA (primary outcome) and the number and/or severity of infections in patients with AAV (secondary outcome). Two reviewers independently selected eligible studies and extracted data. Cumulative risk ratios (RRs) with 95% CI were calculated using a random effect meta-analysis. RESULTS: Eight studies were selected out of 2907 records. Seven studies (520 patients) (of which two were RCTs) assessed the role of TMP/SMX in the relapse rate in patients with GPA. TMP/SMX was not associated with a reduced risk of relapse (RR = 1.15, 95% CI: 0.51, 2.55; I2 = 78.5%; P < 0.001). Sensitivity analysis according to the dose of TMP/SMX (960 mg twice daily vs three times/week) confirmed the results. One retrospective cohort study (192 patients) was identified demonstrating a significant reduction of severe infections in patients with AAV receiving prophylaxis with TMP/SMX in association with rituximab. CONCLUSION: TMP/SMX was not associated with a reduced risk of relapse in patients with GPA. TMP/SMX might be useful in the reduction of infectious complications. PROSPERO DATABASE REGISTRATION CODE: CRD42019118983.

Quality of care indicators in the MAnageMent of BlOOdstream infections caused by Enterobacteriaceae (MAMBOO-E study): state of the art and research agenda.

OBJECTIVES: The impact on outcome of five interventions was reviewed in order to investigate the state of the art for management of Enterobacteriaceae bloodstream infection (E-BSI). METHODS: We searched for randomised controlled trials (RCTs) and observational studies published from January 2008 to March 2019 in PubMed, EMBASE and Cochrane Library. Populations consisted of patients with E-BSI. Interventions were as follows: (i) performance of imaging to assess BSI source and/or complications; (ii) follow-up blood cultures (FU-BCs); (iii) use of loading dose followed by extended/continuous infusion (E/CI) of ß-lactams; (iv) duration of treatment (short- versus long-term); and (v) infectious diseases (ID) consultation. Patients without intervention were considered as controls. The main outcome was 30-day mortality. RoB 2.0 and ROBINS-I tools were used for bias assessment. RESULTS: No study was eligible for interventions i, iii and v. For FU-BCs, one observational study including 901 patients with E-BSI was considered. Intervention consisted of repeating BCs within 2-7 days after index BCs. All-cause 30-day mortality was 14.2% (35/247) in the intervention group versus 14.7% (96/654) in the control group. For short treatment duration, two RCTs and six observational studies were included comprising 4473 patients with E-BSI. All-cause mortality was similar in the short and long treatment groups (OR = 1.10, 95% CI 0.83-1.44). CONCLUSION: Of the assessed interventions, only short treatment duration in non-immunocompromised patients with E-BSI is supported by current data. Studies investigating the use of systematic imaging, FU-BCs, E/CI ß-lactams and ID consultation in patients with E-BSI are needed.

Carrier frequency of HLA-DQB1*02 allele in patients affected with celiac disease: A systematic review assessing the potential rationale of a targeted allelic genotyping as a first-line screening.

BACKGROUND: Celiac Disease (CD) is an immune-mediated disorder, in which the HLA immunogenetic background (DQ2 and DQ8 heterodimers) and environmental trigger (gluten) are well established. Indeed, both factors are necessary - but not sufficient - to develop CD. However, it is very likely that CD is underdiagnosed in both developing and developed countries, due to several aspects, including the fact that a lot of patients present mild and/or atypical symptoms, without the presence of any recognized risk factors. Therefore, the possibility and feasibility of widened screening strategies to identify CD patients are debated. AIM: To provide further evidence of the main epidemiological importance of HLA-DQB1*02 allele in the population of CD patients. METHODS: We performed a systematic search in PubMed, EMBASE, Cochrane, Web of Science and Scopus databases, in order to produce a systematic review assessing the carrier frequency of HLA-DQB1*02 allele in the celiac population. Following the PRISMA guidelines, we retrieved all the original articles describing CD patients' HLA-DQB1 genotype in such a way that could allow to assess the HLA-DQB1*02 carrier frequency among CD patients, along with the evidence of the appropriate diagnostic work-up to achieve a correct and final diagnosis of CD. RESULTS: The final output of this systematic search in the medical literature consisted of 38 studies providing the appropriate HLA-DQB1 genotype information of the respective CD population. According to this systematic review, including a pool of 4945 HLA-DQ genotyped CD patients, the HLA-DQB1*02 carrier frequency was 94.94%, meaning that only 5.06% of CD patients were completely lacking this allelic variant. Interestingly, if we consider only the studies whereby the prevalence of CD patients affected with type 1 diabetes mellitus was supposed or clearly established to be very low, the frequency of non-HLA-DQB1*02 carriers among CD patients dropped to 3.65%. CONCLUSION: Such a high carrier frequency of the HLA-DQB1*02 allelic variant (which is > 95%-96% in CD patients without risk factors, like type 1 diabetes mellitus comorbidity) might be exploited to consider a cost-effective and widened screening approach. If a sustainable strategy could be implemented through a low-cost targeted genetic test to detect the individual presence of HLA-DQB1*02 allele, an appropriate algorithm for serological screening in individuals resulting to be genetically predisposed to CD, might be considered.

Epidemiology of Nonesophageal Eosinophilic Gastrointestinal Diseases in Symptomatic Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Primary eosinophilic gastrointestinal diseases (EGIDs) are increasingly described disorders that include eosinophilic esophagitis (EoE), eosinophilic gastritis, gastroenteritis, and colitis. The exact epidemiology of nonesophageal EGIDs (non-EoE EGIDs) is still unclear. OBJECTIVE: To evaluate the epidemiology of non-EoE EGIDs in adults and children referred to outpatient clinics for gastrointestinal symptoms. METHODS: We conducted a systematic review and meta-analysis using a protocol registered and published with the international prospective register of systematic reviews (PROSPERO CRD42018111437). We searched PubMed, EMBASE, Web of Science, Scopus, and CINAHL for cohort or cross-sectional studies published since 1990, evaluating the incidence and prevalence of non-EoE EGIDs. We assessed study quality and risk of bias using items derived from the Strengthening the Reporting of Observational Studies in Epidemiology statement. RESULTS: A total of 576 articles were identified. Ten studies with 13,377 participants were included in the analysis, with the results showing high heterogeneity. No significant publication bias was found. The overall prevalence of non-EoE EGIDs in patients with gastrointestinal symptoms was 1.9% (95% confidence interval: 0.575-3.894; I2 = 92.72%; P < .001). Because none of the examined studies were prospectively designed, incidence rates could not be determined. CONCLUSIONS: More prospective, large-scale, multicenter studies are needed to evaluate reported data and to further investigate the epidemiology of non-EoE EGIDs and their possible risk factors and comorbidities.

In vivo studies on antibiotic combination for the treatment of carbapenem-resistant Gram-negative bacteria: a systematic review and meta-analysis protocol.

OBJECTIVE: There is poor evidence to determine the superiority of combination regimens versus monotherapy against infections due to carbapenem-resistant (CR) Gram-negative bacteria. In vivo models can simulate the pathophysiology of infections in humans and assess antibiotic efficacy. We aim to investigate in vivo effects of antibiotic combination on mortality and disease burden for infections due to CR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae and provide an unbiased overview of existing knowledge. The results of the study can help prioritising future research on the most promising therapies against CR bacteria. METHODS AND ANALYSIS: This protocol was formulated using the Systematic Review Protocol for Animal Intervention Studies (SYRCLE) Checklist. Publications will be collected from PubMed, Scopus, Embase and Web of Science. Quality checklists adapted by Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies and SYRCLE's risk of bias tool will be used. If the meta-analysis seems feasible, the ES and the 95% CI will be analysed. The heterogeneity between studies will be assessed by I2 test. Subgroup meta-analysis will be performed when possible to assess the impact of the studies on efficacy of the treatments. Funnel plotting will be used to evaluate the risk of publication bias. DISSEMINATION: This systematic review and meta-analysis is part of a wider research collaboration project, the COmbination tHErapy to treat sepsis due to carbapenem-Resistant bacteria in adult and paediatric population: EvideNCE and common practice (COHERENCE) study that includes also the analyses of in vitro and human studies. Data will be presented at international conferences and the results will be published in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42019128104(available at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019128104).

Relevance of HLA-DQB1*02 Allele in the Genetic Predisposition of Children with Celiac Disease: Additional Cues from a Meta-Analysis.

Background and Objectives: Celiac disease (CD) is a multifactorial immune-mediated disorder, triggered by the ingestion of gluten in genetically-predisposed subjects carrying MHC-DQ2 and -DQ8 heterodimers, which are encoded by four HLA-DQ allelic variants, overall. This meta-analysis aims at providing further epidemiological support to the predominant relevance of one specific allele, namely HLA-DQB1*02, in the predisposition and genetic risk of CD. Materials and Methods: We performed a search of MEDLINE/PubMed, Embase, Web of Science, and Scopus, retrieving all publications (case-control study, cross-sectional, and retrospective cohort study) on the association between HLA class II polymorphisms and first-degree relatives (FDRs) of children with CD. After a critical reading of the articles, two investigators independently performed data extraction according to the following inclusion criteria: HLA class II genes, any DQ and DR molecules, and CD diagnosed following the current clinical guidelines. A third participant was consulted for discussion to reach an agreement concerning discrepancies. Results: Our search strategy selected 14 studies as being eligible for inclusion, and those were submitted for data extraction and analysis. These studies were published between 1999 and 2016 and, collectively, enrolled 3063 FDRs. Positive and negative likelihood ratios (LR+ and LR-, respectively) for CD diagnosis, according to the presence of the HLA-DQ genotype coding a complete MHC-DQ2 and/or MHC-DQ8 molecules, were 1.449 (CI 1.279-1.642) and 0.187 (CI 0.096-0.362), respectively. If only the isolated presence of HLA-DQB1*02 allele is considered, the pooled estimation of LR+ was 1.659 (CI 1.302-2.155) and, importantly, the LR- still showed a very good discriminatory power of 0.195 (CI 0.068-0.558). Conclusions: Through our differential meta-analysis, comparing the presence of the genotype coding the full MHC-DQ2 and/or DQ8 molecules with the isolated presence of HLA-DQB1*02 allelic variant, we found that the LR- of the latter analysis maintained the same value. This observation, along with previous evidences, might be useful to consider potential cost-effective widened screening strategies for CD in children.

Diagnostic Performance and Accuracy of the 3 Interpreting Methods of Breast Strain Elastography: A Systematic Review and Meta-analysis.

There are 3 methods of interpreting breast strain elastography: the elastographic-to-B-mode length ratio (E/B), a 5-point color scale (5P), and the strain ratio (SR). This meta-analysis assessed which method is superior to the others. A systematic search of the medical literature was performed in July 2017. Studies were eligible for inclusion if they fulfilled the following criteria: (1) had biopsy-proven or long-term stability as the reference standard; (2) used either the E/B, 5P, or SR to interpret results; and (3) had at least 50 cases. A total of 220 records were retrieved; 60 full-text articles were examined, and 46 were included in the meta-analysis. Publication years ranged from 2007 and 2017. The quality of studies was generally high. The mean age of women was 48 years; 12,398 lesions (4242 malignant) were analyzed. For the 5P method, the sensitivity was 77%; specificity, 87%; positive likelihood ratio (LR), 5.3; and negative LR, 0.24. For the SR method, sensitivity was 87%; specificity, 81%; positive LR, 4.8; and negative LR, 0.16. For the E/B method, sensitivity was 96%; specificity, 88%; positive LR, 7.1; and negative LR, 0.03. Of the 3 methods, the E/B had the highest sensitivity, and the E/B and 5P had the highest specificity. With a negative LR of 0.03, the E/B method can downgrade lesions with a pretest probability of 50% to a 2% probability of malignancy.

Developing definitions for invasive fungal diseases in critically ill adult patients in intensive care units. Protocol of the FUNgal infections Definitions in ICU patients (FUNDICU) project.

BACKGROUND: The reliability of diagnostic criteria for invasive fungal diseases (IFD) developed for severely immunocompromised patients is questionable in critically ill adult patients in intensive care units (ICU). OBJECTIVES: To develop a standard set of definitions for IFD in critically ill adult patients in ICU. METHODS: Based on a systematic literature review, a list of potential definitions to be applied to ICU patients will be developed by the ESCMID Study Group for Infections in Critically Ill Patients (ESGCIP) and the ESCMID Fungal Infection Study Group (EFISG) chairpersons. The proposed definitions will be evaluated by a panel of 30 experts using the RAND/UCLA appropriateness methods. The panel will rank each of the proposed definitions on a 1-9 scale trough a dedicated questionnaire, in two rounds: one remote and one face-to-face. Based on their median rank and the level of agreement across panel members, selected definitions will be organised in a main consensus document and in an executive summary. The executive summary will be made available online for public comments. CONCLUSIONS: The present consensus project will seek to provide standard definitions for IFD in critically ill adult patients in ICU, with the ultimate aims of improving their clinical outcome and facilitating the comparison and generalizability of research findings.

Guidelines for biomarkers in autoimmune rheumatic diseases - evidence based analysis.

Autoimmune rheumatic diseases are characterised by an abnormal immune system response, complement activation, cytokines dysregulation and inflammation. In last years, despite many progresses in managing these patients, it has been shown that clinical remission is reached in less than 50% of patients and a personalised and tailored therapeutic approach is still lacking resulting in a significant gap between guidelines and real-world practice. In this context, the need for biomarkers facilitating early diagnosis and profiling those individuals at the highest risk for a poor outcome has become of crucial interest. A biomarker generally refers to a measured characteristic which may be used as an indicator of some biological state or condition. Three different types of medical biomarkers has been suggested: i. mechanistic markers; ii. clinical disease markers; iii. therapeutic markers. A combination of biomarkers from these different groups could be used for an ideal more accurate diagnosis and treatment. However, although a growing body of evidence is focused on improving biomarkers, a significant amount of this information is not integrated on standard clinical care. The overarching aim of this work was to clarify the meaning of specific biomarkers during autoimmune diseases; their possible role in confirming diagnosis, predicting outcome and suggesting specific treatments.

[Genotyping in patients affected by HLA-related diseases. App development for diagnostic support.] / Tipizzazione genetica nelle patologie HLA-correlate. Sviluppo di una app per il supporto diagnostico.

HLA typing requests for association studies of immune-mediated diseases are often redundant and inadequate. We designed a series of meta-analyses to evaluate the accuracy of typing and distribution of HLA alleles predisposing to diseases, aiming at developing an app that can help doctors in choosing the most suitable molecular analysis. The first study was on celiac disease (CD) and HLA-DQ in children. We searched all english articles published in the main bibliographic databases up to May 2016. The search strategy has been developed using controlled terms (e.g. MeSH) and free terms. We identified 1885 articles. 1334 abstracts were examined. 46 manuscripts were evaluated, and 13 studies were included in the meta-analysis (740 CD and 943 controls). The risk of developing CD in children with allelic variants encoding the HLA-DQ2.5 and/or HLA-DQ8 molecules has been confirmed. The greatest CD risk resides in carriers of two DQ2.5 molecules, i.e. subjects homozygous for the DQB1*02:01 and DQA1*05 alleles (OR=5.4, 95 % CI=4.1-6.8) compared to any other DQ genotype. Carriers of two DQB1*02:01 (chain ß2) alleles and one DQA1*05 (chain α5) allele have the same risk (p=0.8089) of DQ2.5 homozygotes (OR=5.3%, 95 CI=4,1 to 6.5). We found no differences between DQ8/ß2 and DQ2.5/DQ8, nor between ß2/DQX and DQ2.5/X. We suggest a two-step process: first typing the DQB1*02:01 allele and, in case of a negative result, full typing of HLA-DQ.

HLA-DQ genetics in children with celiac disease: a meta-analysis suggesting a two-step genetic screening procedure starting with HLA-DQ ß chains.

BackgroundSpecific HLA-DQ genes have been recognized as necessary - but not sufficient - factors for the occurrence of Celiac Disease (CD). Through a meta-analysis, evaluating the distribution of CD-related HLA genotypes in children, we aimed at providing insights for a potential widened screening strategy.MethodsAfter a systematic search on the association between class II HLA genes and CD in children, 46 publications were obtained and assessed for eligibility. A total of 13 eligible studies were submitted to data extraction and analysis (10 case-control studies and 3 cohort studies). Case-control studies collectively enrolled 740 CD patients and 943 controls.ResultsIn the population-stratified analysis, the following alleles conferred a significantly increased risk for CD: HLA-DQB1*02 (odds ratio [OR]=10.28) and HLA-DQB1*03:02 (OR=2.24). By drafting a risk gradient to develop CD according to HLA genetic background, the highest risk is confirmed to exist for DQ2/DQ2 homozygous subjects, regardless of the ethnicities (OR=5.4). Actually, the genotype DQ2/ß2 showed basically the same risk (OR=5.3). Indeed, no differences have been found in CD risk between DQ2/ß2 and DQ2/DQ2, as well as between DQ8/ß2 and DQ2/DQ8, and between ß2/DQX and DQ2/X.ConclusionThe HLA-DQB1*02:01 allele is present in more than 90% CD children. In the perspective of a widened pediatric population screening for CD, a double-step process might be suggested: HLA-DQB1*02:01 might be investigated first and, only if this result is positive, children might be candidate for a prospective serologic screening, as a second step.

HLA-DRB1 alleles and juvenile idiopathic arthritis: Diagnostic clues emerging from a meta-analysis.

Juvenile Idiopathic Arthritis (JIA) is characterized with a variable pattern of articular involvement and systemic symptoms and, thus, it has been classified in several subtypes. Genetic predisposition to JIA is mainly due to HLA class II molecules (HLA-DRB1, HLA-DPB1), although HLA class I molecules and non-HLA genes have been implicated, too. Here, we carried out a meta-analysis including selected studies designed to assess HLA genetic background of JIA patients, compared to healthy controls; particularly, we focused our attention on HLA-DRB1. In summary, our meta-analysis showed four main findings regarding HLA-DRB1 locus as a genetic factor of JIA: i) HLA-DRB1*08 is a strong factor predisposing to JIA, both for oligo-articular and poly-articular forms (oJIA>pJIA); ii) HLA-DRB1*01 and HLA-DRB1*04 may be involved in the genetic predisposition of Rheumatoid Factor (RF) positive forms of JIA; iii) HLA-DRB1*11 was confirmed to be predisposing to oligo-articular JIA; iv) HLA-DRB1*04 was confirmed to have a role in systemic JIA. Importantly, RF positivity seems to select the JIA clinical subset with the strongest immunogenetic similarities with adult rheumatoid arthritis.