Managing granulomatous-lymphocytic interstitial lung disease in common variable immunodeficiency disorders : e-GLILDnet International Clinicians Survey

Background Granulomatous-lymphocytic interstitial lung disease (GLILD) is a rare, potentially severe pulmonary complication of common variable immunodeficiency disorders (CVID). Informative clinical trials and consensus on management are lacking. Aims The European GLILD network (e-GLILDnet) aims to describe how GLILD is currently managed in clinical practice and to determine the main uncertainties and unmet needs regarding diagnosis, treatment and follow-up. Methods The e-GLILDnet collaborators developed and conducted an online survey facilitated by the European Society for Immunodeficiencies (ESID) and the European Respiratory Society (ERS) between February-April 2020. Results were analyzed using SPSS. Results One hundred and sixty-one responses from adult and pediatric pulmonologists and immunologists from 47 countries were analyzed. Respondents treated a median of 27 (interquartile range, IQR 82-maximum 500) CVID patients, of which a median of 5 (IQR 8-max 200) had GLILD. Most respondents experienced difficulties in establishing the diagnosis of GLILD and only 31 (19%) had access to a standardized protocol. There was little uniformity in diagnostic or therapeutic interventions. Fewer than 40% of respondents saw a definite need for biopsy in all cases or performed bronchoalveolar lavage for diagnostics. Sixty-six percent used glucocorticosteroids for remission-induction and 47% for maintenance therapy; azathioprine, rituximab and mycophenolate mofetil were the most frequently prescribed steroid-sparing agents. Pulmonary function tests were the preferred modality for monitoring patients during follow-up. Conclusions These data demonstrate an urgent need for clinical studies to provide more evidence for an international consensus regarding management of GLILD. These studies will need to address optimal procedures for definite diagnosis and a better understanding of the pathogenesis of GLILD in order to provide individualized treatment options. Non-availability of well-established standardized protocols risks endangering patients

Appropriate lung management in patients with primary antibody deficiencies

Introduction: Human primary immunodeficiency diseases (PIDs) include a broad spectrum of more than 350 disorders, involving different branches of the immune system and classified as 'rare diseases.' Predominantly antibody deficiencies (PADs) represent more than half of the PIDs diagnosed in Europe and are often diagnosed in the adulthood. Areas covered: Although PAD could first present with autoimmune or neoplastic features, respiratory infections are frequent and respiratory disease represents a relevant cause of morbidity and mortality. Pulmonary complications may be classified as infection-related (acute and chronic), immune-mediated, and neoplastic. Expert opinion: At present, no consensus guidelines are available on how to monitor and manage lung complications in PAD patients. In this review, we will discuss the available diagnostic, prognostic and therapeutic instruments and we will suggest an appropriate and evidence-based approach to lung diseases in primary antibody deficiencies. We will also highlight the possible role of promising new tools and strategies in the management of pulmonary complications. However, future studies are needed to reduce of diagnostic delay of PAD and to better understand lung diseases mechanisms, with the final aim to ameliorate therapeutic options that will have a strong impact on Quality of Life and long-term prognosis of PAD patients

Precision Medicine: The Use of Tailored Therapy in Primary Immunodeficiencies

Primary immunodeficiencies (PID) are rare, complex diseases that can be characterised by a spectrum of phenotypes, from increased susceptibility to infections to autoimmunity, allergy, auto-inflammatory diseases and predisposition to malignancy. With the introduction of genetic testing in these patients and wider use of next-Generation sequencing techniques, a higher number of pathogenic genetic variants and conditions have been identified, allowing the development of new, targeted treatments in PID. The concept of precision medicine, that aims to tailor the medical interventions to each patient, allows to perform more precise diagnosis and more importantly the use of treatments directed to a specific defect, with the objective to cure or achieve long-term remission, minimising the number and type of side effects. This approach takes particular importance in PID, considering the nature of causative defects, disease severity, short- and long-term complications of disease but also of the available treatments, with impact in life-expectancy and quality of life. In this review we revisit how this approach can or is already being implemented in PID and provide a summary of the most relevant treatments applied to specific diseases.info:eu-repo/semantics/publishedVersio

Immunopathogenesis of Granulomas in Chronic Inflammatory Diseases : Relevance to diagnostics, biomarkers and treatment

Granulomas are formed in chronic immune mediated diseases such as sarcoidosis and Crohn’s disease as a sign of chronic inflammation. These diseases present with different clinical features, yet overlap in treatment and possibly immunopathogenesis. In this thesis we studied the involvement of B cells in Crohn’s disease in peripheral blood and inflamed intestinal tissue. As B cells showed to be numerously present in granulomatous tissue we analyzed whether additional B-cell staining would lead to an increase in granuloma detection in patients with Crohn’s disease. The effect of infliximab on B-and T-cell subsets was studied in patients with sarcoidosis before and during therapy in order to find immunological markers predicting therapeutic success. Furthermore, the effect of infliximab in patients with neurosarcoidosis was described in a multicenter cohort. With this thesis, we provide new evidence for the involvement of B cells in the immunopathogenesis of granulomatous inflammatory diseases. This opens new targeted treatment options for these disorders, by either targeting B cells or through B-T cell interactions

ESCMID-ECMM guideline : diagnosis and management of invasive aspergillosis in neonates and children

ACKNOWLEDGEMENT Prof Warris is supported by the Wellcome Trust Strategic Award (grant 097377) and the MRC Centre for Medical Mycology (grant MR/N006364/1) at the University of Aberdeen. FUNDING European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the European Confederation of Medical Mycology (ECMM)Peer reviewedPostprintPostprin

Peripheral Blood Gene Expression as a Novel Genomic Biomarker in Complicated Sarcoidosis

Sarcoidosis, a systemic granulomatous syndrome invariably affecting the lung, typically spontaneously remits but in ∼20% of cases progresses with severe lung dysfunction or cardiac and neurologic involvement (complicated sarcoidosis). Unfortunately, current biomarkers fail to distinguish patients with remitting (uncomplicated) sarcoidosis from other fibrotic lung disorders, and fail to identify individuals at risk for complicated sarcoidosis. We utilized genome-wide peripheral blood gene expression analysis to identify a 20-gene sarcoidosis biomarker signature distinguishing sarcoidosis (n = 39) from healthy controls (n = 35, 86% classification accuracy) and which served as a molecular signature for complicated sarcoidosis (n = 17). As aberrancies in T cell receptor (TCR) signaling, JAK-STAT (JS) signaling, and cytokine-cytokine receptor (CCR) signaling are implicated in sarcoidosis pathogenesis, a 31-gene signature comprised of T cell signaling pathway genes associated with sarcoidosis (TCR/JS/CCR) was compared to the unbiased 20-gene biomarker signature but proved inferior in prediction accuracy in distinguishing complicated from uncomplicated sarcoidosis. Additional validation strategies included significant association of single nucleotide polymorphisms (SNPs) in signature genes with sarcoidosis susceptibility and severity (unbiased signature genes - CX3CR1, FKBP1A, NOG, RBM12B, SENS3, TSHZ2; T cell/JAK-STAT pathway genes such as AKT3, CBLB, DLG1, IFNG, IL2RA, IL7R, ITK, JUN, MALT1, NFATC2, PLCG1, SPRED1). In summary, this validated peripheral blood molecular gene signature appears to be a valuable biomarker in identifying cases with sarcoidoisis and predicting risk for complicated sarcoidosis.</p

Eye and Periocular Skin Involvement in Herpes Zoster Infection

Herpes zoster ophthalmicus (HZO) is a clinical manifestation of the reactivation of latent varicella zoster virus (VZV) infection and is more common in people with diminished cell-mediated immunity. Lesions and pain correspond to the affected dermatomes, mostly in first or second trigeminal branch and progress from maculae, papules to vesicles and form pustules, and crusts. Complications are cutaneous, visceral, neurological, ocular, but the most debilitating is post-herpetic neuralgia. Herpes zoster ophthalmicus may affect all the ophthalmic structures, but most severe eye-threatening complications are panuveitis, acute retinal necrosis (ARN) and progressive outer retinal necrosis (PORN) as well. Antiviral medications remain the primary therapy, mainly useful in preventing ocular involvement when begun within 72 hours after the onset of the rash. Timely diagnosis and management of HZO are critical in limiting visual morbidity. Vaccine in adults over 60 was found to be highly effective to boost waning immunity what reduces both the burden of herpes zoster (HZ) disease and the incidence of post-herpetic neuralgia (PHN)

Is the skin microbiota a modifiable risk factor for breast disease?: A systematic review

Purpose: High prevalence, unreliable risk discrimination and poor clinical outcomes are observed in malignant and benign breast diseases (BD). The involvement of microbial communities in the development of BD has become topical, and distal influences of microbial dysregulation in the breast have been well established. Despite advances, the role of the breast skin microbiota in BD remains unclear. Interactions between the skin microbiota and the underlying mucosal immune system are complex. In homeostasis, the skin offers a physical barrier protecting underlying breast tissue from skin commensals and noxious environmental triggers. Our review aims to illuminate the role of the skin microbiota in the development of BD. Methods: Adhering to the PRISMA protocol, a systematic review was conducted utilising the Medline and Embase search engines. Results: Through a comprehensive search of the last ten years, twenty-two studies satisfied the inclusion criteria. Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes were identified as the most prevalent phyla of both breast tissue and skin in healthy controls and BD. High abundance of skin commensals, specifically some species of Staphylococcus, have been linked in breast cancer and metastases. Similarly, dysregulated microbial abundance is also seen in inflammatory and implant-associated BD. These findings raise the hypothesis that the skin microbiota plays a role in tissue homeostasis and may contribute to a range of breast pathologies. Several mechanisms of microbial transfer to underlying tissue have been proposed, including retrograde transfer through ductal systems, breakdown of the skin barrier, and migration through nipple-aspirate fluid. Conclusion: Our review provides preliminary insights into the skin microbiota as a modifiable risk factor for BD. This raises opportunities for future studies in antimicrobials/probiotics as an adjunct to, or replacement of surgery; a diagnostic and/or prognostic tool for BD; and the possibility of conditioning the microbiota to manage BD

The Diagnostic Approach to Monogenic Very Early Onset Inflammatory Bowel Disease

Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histological features of Crohn’s disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects