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Recurrent Infection, Pulmonary Disease, and Autoimmunity As Manifestations of Immune Deficiency Property of Presenter Not for Re

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Recurrent Infection, Pulmonary Disease, and Autoimmunity As Manifestations of Immune Deficiency Property of Presenter Not for Re Recurrent Infection, Pulmonary Disease, and Autoimmunity as Manifestations of Immune Deficiency Presenter of Erwin W. ReproductionGelfand, M.D. Professor, Departmentfor of Pediatrics PropertyNational Jewish Health Professor ofNot Immunology and Pediatrics University of Colorado School of Medicine Presenter of Reproduction for Property Not • Investigator: Boehringer Ingelheim Disclosures Learning Objectives • To understand the interplay between immunodeficiency and allergic and pulmonary disorders. Presenter • To recognize the increasingof numbers of monoallelic immune systemReproduction mutations that have allergic and pulmonaryfor manifestations. • To incorporateProperty genetic testing in the clinical Not evaluation of patients with seemingly common diseases. Presenter of Reproduction for Property Not Hypogammaglobulinemia (Immunodeficiency) Autoimmunity HypersensitivityAllergy Host Defense Specific Non-Specific Presenter of • Adaptive immunity • Innate immunity Reproduction • Barriers for Property Not The Innate and Adaptive Immune Response Specific antigen receptors Presenter of Reproduction for Property Pattern Not recognition receptors Dranoff G. Nature Reviews Cancer 2004;4:11-22. Presenter of Reproduction for Property Not Primary Immunodeficiency Diseases Infection Malignancy Autoimmunity Atopy Primary Immunodeficiency Diseases Infection Autoimmunity Malignancy Presenter of Deficient/defective Deficient/defective effector cells Reproductionregulatory cells for Property Not Primary Immunodeficiency Diseases Infection Autoimmunity Atopy Malignancy Presenter of Deficient/defective Deficient/defective effector cells regulatoryReproduction cells for Property Not T Cell Receptor Signaling Signal StrongWeak Absent Presenter of Adaptive IR Atopy Immunodeficiency Reproduction for Th17 Th1 Property Th2 Not Neutrophilia IFN IgE Eosinophilia T Cell Receptor Signaling Signal StrongWeak Absent Presenter of Adaptive IR Atopy Immunodeficiency Reproduction for Th17 Th1 Property Th2 Not Autoimmunity Neutrophilia IFN IgE Eosinophilia Pulmonary Complications Associated with PID • Infectious – Bacterial – Fungal Viral – Opportunistic Presenter of • Non-infectious Reproduction – Allergy for Property – AutoimmunityNot – Interstitial lung disease (ILD) • Granulomatous-lymphocytic ILD (GLILD) Presenter of Reproduction for Property Not Sinopulmonary Signs Suggesting an Immune Defect Busse PJ, et al. Ann. All ergy Asthma Immunol. 98:1-9, 2007 Presenter of Reproduction for Property Not Presenter of Reproduction for Property Not Immunodeficiency Allergy Pulmonary Immunodeficiency Diseases with Eosinophilia Elevated Serum IgE and Eczema - The Triad – – Hyper-IgE syndrome (HIES) Presenter of – DOCK8 deficiency Reproduction for Property Not Immunodeficiency Diseases with Eosinophilia Elevated Serum IgE and Eczema - The Triad – and lung disease – Hyper-IgE syndrome (HIES) Presenter of – DOCK8 deficiency Reproduction for Property Not A Classification of HIES HIES Inheritance Molecular Genetic Testing Type Type 1 •Sporadic (more • STAT3 mutations than 90% of cases) Presenter •Familial with of autosomal dominant Reproduction inheritance (rare) for Type 2 •Familial withProperty • TYK2 deficiency autosomal Not recessive inheritance •Rare Hyper-IgE (HIES) Syndrome (Job’s Syndrome) Triad: Cold abscesses, pneumonia, high IgE • Chronic eczema-like rash/atopic dermatitis – Onset - newborn rash Presenter – Staphylococcal superinfectionof • High IgE - often >2,000 IU/mL Reproduction • Eosinophilia - usually >700 cells/mL for Property *Generally free fromNot other allergic manifestations (rhinitis, asthma, urticaria, anaphylaxis). Allergic skin testing usually negative Hyper-IgE (HIES) Syndrome (Job Syndrome) • Characteristic facial appearance-coarse features, prominent forehead, broad nasal bridge • Distinct abnormalities of the connective tissue, skeleton, dentition Presenter • Pneumonia, pneumatocelesof • Mucocutaneous candidiasis • Coronary and CNS arteryReproduction aneurysms for • Fractures Property • Retained primaryNot teeth • Scoliosis • Joint hyperextensibility Presenter of Reproduction for Property Not Presenter of Reproduction for Property Not Presenter of Reproduction for Property Not Chest Radiograph Showing Right Lower Lobe Infiltrate With Cystic Lesions (Arrow) Venkata C et al. Chest 2008;133:1026-1029 Presenter of Reproduction for Property Not Chest CT Scan Showing Extensive Consolidation and Cystic Changes in the Right Lung With Right Pleural Thickening and Left Pleural Effusion With Compressive Atelectasis and Early Infiltrates in the Left Lower Lobe Venkata C et al. Chest 2008;133:1026-1029 Immunodeficiency Diseases with Eosinophilia and Elevated Serum IgE – Hyper IgE syndrome Presenter(HIES) AD-HIES of Reproduction – DOCK8 deficiency AR-HIES for Property Not Combined Immunodeficiency Associated With DOCK8 Mutations • Severe atopy – Atopic dermatitis – High IgE levels – Moderate eosinophilia – Food sensitivities Presenter • Otitis media of • Sinusitis Reproduction • Pneumonia for • Recurrent staphylococcalProperty skin infections with otitis externa • Recurrent H. simplex/H.Not zoster • Molluscum • Low T, B, and NK cell numbers • CNS vasculitis* Clinical Features of DOCK8 Deficiency Atopic dermatitis 91% Asthma 41% Allergies 66% High serum IgE Presenter 100% Eosinophilia of 90% Bacterial skin infections 78% Mucocutaneous candidiasisReproduction 72% Any viral infection-HSV,HPV,VZV,for MCV 88% Respiratory tractProperty infections 97% CNS vasculitis Not 6% Malignancy 19% Autoimmune hemolytic anemia 6% Common Variable Immunodeficiency Disease (CVID) Clinical Manifestations of CVID Infectious Manifestations Noninfectious Manifestations •Pneumonia (atypical and Autoimmune cytopenias typical organisms) GranulomatousPresenterdisease •Otitis media •Lymphadenopathyof •Sinusitis •Splenomegaly •Conjunctivitis •EnteropathyReproduction •Enteritis •forNodular regenerative hyperplasia Property •Polyarthritis Not •Interstitial lung disease/GLILD •Malignancy (lymphoma/MALToma) Clinical and Laboratory Criteria for Diagnosis of CVID Clinical criteria for a probable diagnosis At least one of the following: • Increased susceptibility to infection • Autoimmune manifestations • Granulomatous disease • Unexplained polyclonal lymphoproliferationPresenter • Affected family member with antibody deficiency of Laboratory criteria for a probable diagnosis - Marked decrease of IgG and markedReproduction decrease of IgA with or without low IgM levels (measured at least twice;for <2SD of the age-normal levels AND at least one of the following:Property •Poor antibody response to vaccinesNot (and/or absent isohaemagglutinins); i.e. absence of protective levels despite vaccination where defined • Low switched memory B cells (<70% of age-related normal value) GLILD • Lymphocytic interstitial pneumonia (LIP) • Follicular bronchiolitisPresenter of • Granulomatous lung diseaseReproduction for Property • Organizing pneumonia Not Silent Radiological Features of GLILD • Plain X-ray – Diffuse interstitial infiltrates Presenter of • HRCT – Consolidation Reproduction for – Ground glassProperty opacities – Reticular abnormalitiesNot Presenter of Reproduction for Property Not Imaging in Common Variable Immunodeficiency Bronchiectasis • Most common radiologic abnormality in CVID (25-73%), usually in lower lobes • Associated with mucous plugging Presenter and tree-in-bud nodules of • Bronchiectasis is related to history of recurrent infections Reproduction • Bronchiectasis is rare in young for patients. Prevalence Propertyincreases over time, correlating to number of infections Not • However, presence of bronchiectasis does not correlate with IgG levels Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) • GLILD is a unique Pathology entity, occurring only in •Non-necrotizing the setting of CVID and Presentergranulomas of CVID-like illnesses •LIP • Mixed Reproduction•FB restrictive/obstructive for •Lymphocyte hyperplasia physiology Property •MALToma • Associated with aNot poorer prognosis than CVID without GLILD Bates CA, et al. J. Allergy Clin. Immunol. 114:415-421, 2004 Presenter of Reproduction for Property Not GLILD - Pathology Nodular dense lymphoid hyperplasia. Underlying architecture is preserved. Non-necrotizing granuloma GLILD - Radiology • Characterized uniquely by a combination of ground glass and consolidative opacities with septal thickening, nodularity, and Presenter adenopathy of • Usually lower lung predominant, often peribronchovascular in Reproduction distribution for Property • May progress to fibrosis Not • Radiologic findings may wax and wane over time Lymphoproliferative Disease in CVID • Increased risk of lymphoma up to 30x • Most commonly non-Hodgkin lymphoma, B-cell subtype Presenter of • Often extra-nodal and associated with mucosal tissues Reproduction for • MALT (mucosa-associatedProperty lymphoid tissue) lymphomaNot or MALToma, a subset of B-cell non-Hodgkin lymphoma Lymphocytic infiltration in pulmonary MALToma effaces the normal architecture, destroying the bronchiole (arrows) Presenter of Reproduction for Property Not Maglione PJ, et al. J. Allergy Clin. Immunol. Pract. 3:941-950, 2015 Presenter of Reproduction for Property Not Comparison of Initial Clinical and Laboratory Characteristics Maglione PJ, et al. J. Allergy Clin. Immunol. Pract. 3:941-950, 2015 Presenter of Reproduction for Property Not Univariate Analyses of Granulomatous Lymphocytic Interstitial Lung Diseae Predictors Mannina A, et al. Ann. Am. Thorac. Soc. 13;1042-1049, 2016 Treatment
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