Autoinflammatory Research Articles

Macrocephaly and Finger Changes: A Narrative Review

Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals.

Chronic Osteomyelitis of Clavicle as a Primary Manifestation of CRMO in an Adolescent: A Case Report

Background: Chronic recurrent multifocal osteomyelitis (CRMO) is an auto-inflammatory bone disorder characterized by aseptic, mono- to multi-focal inflammation of the bones, yet its etiology remains undetermined. Diagnosis of CRMO is often challenging due to its overlapping signs and symptoms with other bone disorders, leading to potential long-term deformities. Increasing awareness of the various presentations of CRMO is crucial for timely diagnosis and management. Case presentation: A 14-year-old girl presented to our center with recurrent left clavicle pain, persisting for more than 3 years before referral. She had received multiple courses of analgesics. Physical examination revealed a hard, fixed mass in the medial third of the left clavicle, painless to palpation, with no inflammatory signs. MRI showed diffuse multiple hypo-signal lesions of the medial third of the left clavicle, blowing the bone cortex with infiltration of the soft tissues. Differential diagnoses were ruled out through bone biopsy, and laboratory tests. The patient responded favorably to treatment with Methotrexate, and Indomethacin, with no relapse observed during one year of follow-up. Conclusions: Uncommon presentations of CRMO can pose challenges in diagnosis, potentially leading to prolonged diagnostic processes. Increasing awareness among specialists regarding these presentations can facilitate earlier diagnosis and more effective treatment of CRMO patients.

Monitoring of Adverse Events and Safety in Autoinflammatory Diseases: Real-Life Data from the Eurofever Registry.

The study is aimed to evaluate the impact of safety events in the Eurofever registry for Autoinflammatory diseases. This was a retrospective and longitudinal observational multicentre study. Data were retrieved from the international registry Eurofever, starting patients' enrolment since 2009. All moderate, severe, or very severe AEs reported by treating physician in Eurofever were analyzed regardless of a possible suspected causal relationship to any therapies and according to the latest release of the Medical Dictionary for Regulatory Activities. Complete information on safety were available in 2464 patients enrolled in the registry. In 1499 of them retrospective data encompassing the period from disease onset to enrolment were available, whereas 965 consecutive patients entered in the longitudinal part of the study. A total of 479 AEs have been reported in 275 patients. Eighty-two AEs were reported as serious and 99 were drug-related according to the physicians. Infections or infestations (94; 19.6%), gastrointestinal disorders (66; 13.8%), nervous system disorders (41; 8.6%) and systemic disorders or administration site reactions (35; 7.3%) were the most frequent reported events. The highest absolute number of drug-related AEs were related to biologic DMARDs (40/99 reports, 40,4%) and colchicine (31/99 reports, 31.3%). Present study shows the importance of a longitudinal and homogeneous registration of the AEs in rare conditions, with a particular focus on the safety profile of the treatments used in these conditions.

Unravelling the clinical heterogeneity of undefined recurrent fever over time in the European registries on Autoinflammation

BackgroundSystemic autoinflammatory disorders (SAIDs) represent a growing spectrum of diseases characterized by dysregulation of the innate immune system. The most common pediatric autoinflammatory fever syndrome, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA), has well defined clinical diagnostic criteria, but there is a subset of patients who do not meet these criteria and are classified as undefined autoinflammatory diseases (uAID). This project, endorsed by PRES, supported by the EMERGE fellowship program, aimed to analyze the evolution of symptoms in recurrent fevers without molecular diagnosis in the context of undifferentiated AIDs, focusing on PFAPA and syndrome of undifferentiated recurrent fever (SURF), using data from European AID registries.MethodsData of patients with PFAPA, SURF and uSAID were collected from 3 registries including detailed epidemiological, demographic and clinical data, results of the genetic testing and additional laboratory investigations with retrospective application of the modified Marshall and PRINTO/Eurofever classification criteria on the cohort of PFAPA patients and preliminary SURF criteria on uSAID/SURF patients.ResultsClinical presentation of PFAPA is variable and some patients did not fit the conventional PFAPA criteria and exhibit different symptoms. Some patients did not meet the criteria for either PFAPA or SURF, highlighting the heterogeneity within these groups. The study also explored potential overlaps between PFAPA and SURF/uAID, revealing that some patients exhibited symptoms characteristic of both conditions, emphasizing the need for more precise classification criteria.ConclusionsPatients with recurrent fevers without molecular diagnoses represent a clinically heterogeneous group. Improved classification criteria are needed for both PFAPA and SURF/uAID to accurately identify and manage these patients, ultimately improving clinical outcomes.

IFIH1 loss of function predisposes to inflammatory and SARS-CoV-2-related infectious diseases.

The IFIH1 gene, encoding melanoma differentiation-associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation in weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain-of-function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi-Goutieres and Singleton-Merten syndromes, while biallelic loss causes immunodeficiency. In this study, nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) were identified with putative loss-of-function IFIH1 variants by whole-exome sequencing. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. There was a significant association between IFIH1 monoallelic loss of function and susceptibility to infections in males. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with Poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss-of-function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS-CoV-2-related disorders.

Antibiotic prescriptions to children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis.

To investigate the rate of dispensed antibiotic prescriptions to children and adolescents with PFAPA and compare this with the rate for children in the general population. Furthermore, to compare dispensed antibiotic prescription rates before and after a diagnosis of PFAPA was established. Patients aged 0-17 years and diagnosed with PFAPA between 1 January 2006 to 31 October 2017 were included retrospectively. Data on dispensed drug prescriptions were obtained from the Swedish National Prescribed Drug Register. The PFAPA cohort received more antibiotic prescriptions than the general population in all but one of the age groups and time periods that were analysed. The largest difference was seen in 2014-2017 in the youngest age group (0-4 years) when children with PFAPA received 1218 antibiotic prescriptions per 1000 person years compared to 345 in the general population (IRR 3.5; 95% CI 2.8-4.4). The yearly number of antibiotic prescriptions to PFAPA patients was reduced from 2.1 before diagnosis to 0.8 after diagnosis, a reduction of 62%. This study shows higher rates of dispensed antibiotic prescriptions for children with PFAPA than in the general population. The reduction of prescriptions after an established PFAPA diagnosis indicates that antibiotics were previously incorrectly prescribed for PFAPA episodes.

How to quantify developmental synchrony in malaria parasites

Malaria infections represent an iconic example of developmental synchrony, where periodic fevers can result when the population of parasites develops synchronously within host red blood cells. The level of synchrony appears to vary across individual hosts and across parasite species and strains, variation that—once quantified—can illuminate the ecological and evolutionary drivers of synchrony. Yet current approaches for quantifying synchrony in parasites are either biased by population dynamics or unsuitable when population growth rates vary through time, features ubiquitous to parasite populations in vitro and in vivo. Here we develop an approach to estimate synchrony that accounts for population dynamics, including changing population growth rates, and validate it with simulated time series data encompassing a range of synchrony levels in two different host-parasite systems: malaria infections of mice and human malaria parasites in vitro. This new method accurately quantifies developmental synchrony from per capita growth rates using obtainable abundance data even with realistic sampling noise, without the need to sort parasites into developmental stages. Our approach enables variability in developmental schedules to be disentangled from even extreme variation in population dynamics, providing a comparative metric of developmental synchrony.

Interrupting an IFN-γ-dependent feedback loop in the syndrome of pyogenic arthritis with pyoderma gangrenosum and acne

ObjectivesTo study the molecular pathogenesis of PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome, a debilitating hereditary autoinflammatory disease caused by dominant mutation in PSTPIP1.MethodsGene knock-out and knock-in mice were...

The Systemic Score May Identify Life-Threatening Evolution in Still Disease: Data from the GIRRCS AOSD-Study Group and the AIDA Network Still Disease Registry.

We aimed to evaluate the clinical usefulness of the systemic score in the prediction of life-threatening evolution in Still disease. We also aimed to assess the clinical relevance of each component of the systemic score in predicting life-threatening evolution and to derive patient subsets accordingly. A multicenter, observational, prospective study was designed including patients included in the Gruppo Italiano Di Ricerca in Reumatologia Clinica e Sperimentale Adult-Onset Still Disease Study Group and the Autoinflammatory Disease Alliance Network Still Disease Registry. Patients were assessed to see if the variables to derive the systemic score were available. The life-threatening evolution was defined as mortality, whatever the clinical course, and/or macrophage activation syndrome, a secondary hemophagocytic lymphohistiocytosis associated with a poor prognosis. A total of 597 patients with Still disease were assessed (mean ± SD age 36.6 ± 17.3 years; male 44.4%). The systemic score, assessed as a continuous variable, significantly predicted the life-threatening evolution (odds ratio [OR] 1.24; 95% confidence interval [CI] 1.07-1.42; P = 0.004). A systemic score ≥7 also significantly predicted the likelihood of a patient experiencing life-threatening evolution (OR 3.36; 95% CI 1.81-6.25; P < 0.001). Assessing the clinical relevance of each component of the systemic score, liver involvement (OR 1.68; 95% CI 1.48-2.67; P = 0.031) and lung disease (OR 2.12; 95% CI 1.14-4.49; P = 0.042) both significantly predicted life-threatening evolution. The clinical characteristics of patients with liver involvement and lung disease were derived, highlighting their relevance in multiorgan disease manifestations. The clinical utility of the systemic score was shown in identifying Still disease at a higher risk of life-threatening evolution in a large cohort. Furthermore, the clinical relevance of liver involvement and lung disease was highlighted.

Var3PPred: variant prediction based on 3-D structure and sequence analyses of protein-protein interactions on autoinflammatory diseases

We developed a pathogenicity classifier, named Var3PPred, for identifying pathogenic variants in genes associated with autoinflammatory disorders. Our comprehensive approach integrates protein-protein interaction analysis and 3D structural information. Initially, we collected a dataset of 702 missense disease-associated variants from 35 genes linked to systemic autoinflammatory diseases (SAIDs). This dataset, sourced from the Infevers database, served as the training and test sets. We used the SMOTE algorithm to balance the dataset comprising 130 benign and 572 pathogenic variations. Our approach included 3D docking analysis of protein-protein interactions, utilizing data from the STRING and Intact databases. We weighted ZDOCK and SPRINT values in accordance with HGPEC gene rank scores for robustness. Additionally, we integrated sequential and structural features, such as changes in folding free energies (ΔΔ G), accessible surface area, volume, per residue local distance difference test (pLDDT) scores, and position specific independent count (PSIC) scores. These features, calculated using PyRosetta and AF2 computed structures, provided insights into amino acid conservation at variant positions and the impact of variants on protein structure and stability. Through extensive hyperparameter tuning of six machine learning algorithms, we found the random forest classifier to be the most effective, yielding an AUROC of 99% on the test set. Var3PPred outperformed three other classifiers, SIFT, PolyPhen, and CADD, on an unseen test set of a SAID-related gene. This demonstrates its capacity for pathogenicity classification of SAID variations. The source code for Var3PPred and the predictions for all 420 missense variants of uncertain significance from the Infevers database are available on GitHub: (https://github.com/alperbulbul1/Var3PPred).

3D clustering of gene expression data from systemic autoinflammatory diseases using self-organizing maps (Clust3D)

Background and objectiveSystemic autoinflammatory diseases (SAIDs) are characterized by widespread inflammation, but for most of them there is a lack of specific biomarkers for accurate diagnosis. Although a number of machine learning algorithms have been used to analyze SAID datasets, aiding in the discovery of novel biomarkers, there is a growing recognition of the importance of SAID timeseries clustering, as it can capture the temporal dynamics of gene expression patterns. MethodologyThis paper proposes a novel clustering methodology to efficiently associate three-dimensional data. The algorithm utilizes competitive learning to create a self-organizing neural network and adjust neuron positions in time-dependent and high dimensional feature space in order to assign them as clustering centers. The quantitative evaluation of the clustering was based on well-known clustering indices. Furthermore, a differential expression analysis and classification pipeline was employed to assess the capability of the proposed methodology to extract more accurate pathway-specific genes from its clusters. For that, a comparative analysis was also conducted against a heuristic timeseries clustering method. ResultsThe proposed methodology achieved better overall clustering indices scores and classification metrics using genes derived from its clusters. Notable cases include a threefold increase in the Calinski-Harabasz clustering index, a twofold improvement in the Davies–Bouldin clustering index and a ∼60% increase in the classification specificity score. ConclusionA novel clustering methodology was developed and applied on several gene expression timeseries datasets from systemic autoinflammatory diseases, and its ability to efficiently produce well separated clusters compared to existing heuristic methods was demonstrated.

C-reactive protein is more suitable than Serum Amyloid A to monitor crises and attack-free periods in Systemic Auto-Inflammatory Diseases.

BackgroundWith their broad presentations and no global biomarker to discriminate crises and attack-free periods, Systemic Auto-Inflammatory Diseases (SAID) are difficult to manage. This study assessed Serum Amyloid A (SAA), C-reactive protein (CRP) and serum calprotectin as potential biomarkers to monitor patients with SAID. MethodSAA (already studied in Familial Mediterranean Fever (FMF)), CRP and serum calprotectin were measured on SAID adult patients from Juvenile Inflammatory Rheumatism (JIR) cohort during their follow-up visits between 2020 and 2022. Crises and attack-free periods were clinically determined. Results96 measures, mainly from FMF (43 %) and Unclassified SAID (USAID) (37 %) patients were included. Using ROC curves, a threshold with sensitivity and specificity of/over 75 % was determined for SAA (9 mg/L) and CRP (9 mg/L) but not for serum calprotectin, not investigated further. With this threshold, the results were similar in FMF and USAID patients’ subgroups. SAA and CRP showed a positive correlation with crises and attack-free periods in SAID patients (r = 0.4796, p < 0.001 and r = 0.5525, p < 0.001, respectively) as in FMF and USAID patients, with no significant difference between both markers in diagnosis value and ROC curves Area Under Curve (AUC) (p = 0.32). Only the CRP results were not influenced by obesity. ConclusionSAA and CRP can discriminate crisis and attack-free periods in our cohort of SAID patients mainly composed of FMF and USAID patients. However, only CRP can be used regardless of body mass index. It is the first report of common biomarkers for all SAID, including USAID patients, with CRP widely accessible in routine worldwide.

Primary Immunodeficiency Disorders (PIDs) and its Rheumatologic Manifestations Mohammad Imnul Islam

The hallmark of Primary Immunodeficiency Disorders (PIDs) is increased susceptibility to recurrent infections, which are often poorly responsive to therapy, prolonged and life-threatening. The infections can involve bones and joints. PIDs may also predispose to allergic, autoimmune, autoinflammatory and malignant disorders. Arthritis is the most common rheumatological manifestation of PIDs. Recurrent septic arthritis, arthritis with increased susceptibility to infection, skeletal changes, autoimmune disease or systemic lupus erythematosus with negative antinuclear antibody (ANA) are the essential clinical clues that could be considered rheumatologic manifestations of PIDs. This is considerable concern that early detection of PIDs patients invariably improves the quality of life and life expectancy through the prompt implementation of appropriate medical intervention. BANGLADESH J CHILD HEALTH 2022; VOL 46 (2) : 82-85

The gut microbiome and HLA-B27-associated anterior uveitis: a case-control study

BackgroundThe human gut microbiome (GM) is involved in inflammation and immune response regulation. Dysbiosis, an imbalance in this ecosystem, facilitates pathogenic invasion, disrupts immune equilibrium, and potentially triggers diseases including various human leucocyte antigen (HLA)-B27-associated autoinflammatory and autoimmune diseases such as inflammatory bowel disease (IBD) and spondyloarthropathy (SpA). This study assesses compositional and functional alterations of the GM in patients with HLA-B27-associated non-infectious anterior uveitis (AU) compared to healthy controls.MethodsThe gut metagenomes of 20 patients with HLA-B27-associated non-infectious AU, 21 age- and sex-matched HLA-B27-negative controls, and 6 HLA-B27-positive healthy controls without a history of AU were sequenced using the Illumina NovaSeq 6000 platform for whole metagenome shotgun sequencing. To identify taxonomic and functional features with significantly different relative abundances between groups and to identify associations with clinical metadata, the multivariate association by linear models (MaAsLin) R package was applied.ResultsSignificantly higher levels of the Eubacterium ramulus species were found in HLA-B27-negative controls (p = 0.0085, Mann-Whitney U-test). No significant differences in microbial composition were observed at all other taxonomic levels. Functionally, the lipid IVA biosynthesis pathway was upregulated in patients (p < 0.0001, Mann-Whitney U-test). A subgroup analysis comparing patients with an active non-infectious AU to their age- and sex-matched HLA-B27-negative controls, showed an increase of the species Phocaeicola vulgatus in active AU (p = 0.0530, Mann-Whitney U-test). An additional analysis comparing AU patients to age- and sex-matched HLA-B27-positive controls, showed an increase of the species Bacteroides caccae in controls (p = 0.0022, Mann-Whitney U-test).ConclusionIn our cohort, non-infectious AU development is associated with compositional and functional alterations of the GM. Further research is needed to assess the causality of these associations, offering potentially novel therapeutic strategies.

Effect of Colchicine Treatment on Clinical Course in Children with PFAPA Syndrome.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA) is the most common periodic fever condition in children. There is no consensus on treatment to prevent attacks and reduce their frequency. In this study, we aimed to evaluate the effectiveness of colchicine treatment in PFAPA syndrome. In addition, we described the demographic and clinical features of PFAPA patients. We retrospectively analyzed 58 PFAPA patients who were started on colchicine treatment between January 2017 and January 2022. Demographic data, clinical features, laboratory tests, genetic analysis of MEditerranean FeVer (MEFV) mutations, and autoinflammatory disease activity index (AIDAI) scores of all patients were evaluated. In addition, patients were divided into two groups according to MEFV variants and compared. Attack frequency, duration, and AIDAI scores decreased in all patients after colchicine treatment. Duration of follow-up was 13.53±6.65 months. The median±IQR age at diagnosis was 3.2 (2-5) years. Thirty three (56.9%) patients had heterozygous mutations of MEFV. The most common MEFV variants were M694V (63.6%). There was no significant difference between the two groups in terms of colchicine responses. Colchicine treatment is effective and safe in patients with PFAPA who have frequent attacks. No association was established between the presence of heterozygous mutations of MEFV and colchicine response.

Monogenic and acquired autoinflammatory diseases

Monogenic and acquired autoinflammatory diseases

Adult-onset Still’s disease: analysis of a monocentric cohort of patients

Objective Adult-onset Still’s disease (AOSD) is a multigenic autoinflammatory disease with a severe systemic involvement. Because of the rarity of the disease, most published cohorts are multicentric. The aim of this report is to describe a monocentric cohort of AOSD patients, reporting clinical features and response to therapy in a long follow-up. Method Thirty-eight patients, attending the Clinical Immunology Unit and fulfilling Yamaguchi, Fautrel, or Daghor-Abbaci classification criteria for AOSD, were recruited for this study. In all patients, clinical and serological data were collected at diagnosis and every 6 months thereafter. The Pouchot score was calculated at every visit. Results Fever, arthromyalgia, and skin rash were the most frequent manifestations, followed by lymphadenopathy, sore throat, arthritis, splenomegaly, hepatic involvement, pleuropericarditis, and weight loss. As far as the disease course is concerned, 25% presented a monocyclic and 35% a polycyclic pattern, and 40% developed chronic articular involvement. Severe complications were observed at disease onset in 21% of the patients. All of the patients were treated with steroids; 74% also received conventional synthetic disease-modifying anti-rheumatic drugs (methotrexate in most cases) and 71% biological disease-modifying anti-rheumatic drugs (interleukin-1 inhibitors in most cases). Therapeutic switching for lack/loss of efficacy or adverse drug reactions was necessary in 66%. Conclusion The analysis of this cohort confirms that AOSD is a complex, severe, and heterogeneous disease. However, despite long-term treatment and comorbidities, therapies are effective and well tolerated. The therapeutic armamentarium now available allows long-lasting remission with low immunosuppression to be achieved in most patients.

Relapsing polychondritis: clinical updates and new differential diagnoses.

Relapsing polychondritis is a rare inflammatory disease characterized by recurrent inflammation of cartilaginous structures, mainly of the ears, nose and respiratory tract, with a broad spectrum of accompanying systemic features. Despite its rarity, prompt recognition and accurate diagnosis of relapsing polychondritis is crucial for appropriate management and optimal outcomes. Our understanding of relapsing polychondritis has changed markedly in the past couple of years with the identification of three distinct patient clusters that have different clinical manifestations and prognostic outcomes. With the progress of pangenomic sequencing and the discovery of new somatic and monogenic autoinflammatory diseases, new differential diagnoses have emerged, notably thevacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS)syndrome, autoinflammatory diseases and immune checkpoint inhibitor-related adverse events. In this Review, we present a detailed update of the newly identified clusters and highlight red flags that should raise suspicion of these alternative diagnoses. The identification of these different clusters and mimickers has a direct impact on the management, follow-up and prognosis of patients with relapsing polychondritis and autoinflammatory syndromes.

Association of autoimmune and autoinflammatory disorders with chronic rhinosinusitis in children

BackgroundIncreasing evidence suggests that autoimmune disorders and their immunomodulating medications may increase the risk of rhinosinusitis. The goal of this study is to determine if autoimmune and autoinflammatory diseases are associated with increased risk of chronic rhinosinusitis (CRS) in children. MethodsA retrospective case-control study of pediatric patients (age 2–18 years) seen in the West Virginia University Hospitals System in the past 10 years was performed. Cases were children with autoimmune or autoinflammatory diseases. Controls were children without any autoimmune or autoinflammatory disorders. Query of our electronic medical record (Epic) was performed using ICD-10 codes. Univariate (unadjusted) and multivariate (adjusted) logistic regression were used to calculate the strength of association of autoimmune or autoinflammatory disorders with CRS and the other airway disorders while adjusting for age, sex, and race. Results420582 pediatric patients were queried with mean age of 10.8 years (SD of 4.8, range of 2–18 years), and 47.9% being female. 1956 (0.5%) had autoimmune disorders and 293 (0.07%) had autoinflammatory disorders. Both autoimmune and autoinflammatory disorders increase the odds of having CRS in the unadjusted [OR = 3.36, p < 0.001 and 5.69, p < 0.001 for the respectively] and the adjusted [OR = 2.90, p < 0.001 and OR = 5.07, p < 0.001 respectively after adjusting for age, sex, and race] models. ConclusionAutoimmune and autoinflammatory disorders increase the risk of CRS and chronic rhinitis in children.

The Etiologic Landscape of Lymphoproliferation in Childhood: Proposal for a Diagnostic Approach Exploring from Infections to Inborn Errors of Immunity and Metabolic Diseases.

Lymphoproliferation is defined by lymphadenopathy, splenomegaly, hepatomegaly, or lymphocytic organ and tissue infiltration. The most common etiologies of lymphoproliferation are represented by infectious diseases and lymphoid malignancies. However, it is increasingly recognized that lymphoproliferative features can be the presenting sign of rare conditions, including inborn errors of immunity (IEI) and inborn errors of metabolism (IEM). Among IEI, lymphoproliferation is frequently observed in autoimmune lymphoproliferative syndrome (ALPS) and related disorders, common variable immunodeficiency (CVID), activated phosphoinositide 3-kinase δ syndrome, and Epstein-Barr virus (EBV)-related disorders. Gaucher disease and Niemann-Pick disease are the most common IEMs that can present with isolated lymphoproliferative features. Notably, other rare conditions, such as sarcoidosis, Castleman disease, systemic autoimmune diseases, and autoinflammatory disorders, should be considered in the differential diagnosis of patients with persistent lymphoproliferation when infectious and malignant diseases have been reasonably ruled out. The clinical features of lymphoproliferative diseases, as well as the associated clinical findings and data deriving from imaging and first-level laboratory investigations, could significantly help in providing the correct diagnostic suspicion for the underlying etiology. This paper reviews the most relevant diseases associated with lymphoproliferation, including infectious diseases, hematological malignancies, IEI, and IEM. Moreover, some practical indications to orient the initial diagnostic process are provided, and two diagnostic algorithms are proposed for the first-level assessment and the approach to persistent lymphoproliferation, respectively.