A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside

Abstract

The number of genetically defined Primary Immunodeficiency Diseases (PID) has increased exponentially, especially in the past decade. The biennial classification published by the IUIS PID expert committee is therefore quickly expanding, providing valuable information regarding the disease-causing genotypes, the immunological anomalies, and the associated clinical features of PIDs. These are grouped in eight, somewhat overlapping, categories of immune dysfunction. However, based on this immunological classification, the diagnosis of a specific PID from the clinician's observation of an individual clinical and/or immunological phenotype remains difficult, especially for non-PID specialists. The purpose of this work is to suggest a phenotypic classification that forms the basis for diagnostic trees, leading the physician to particular groups of PIDs, starting from clinical features and combining routine immunological investigations along the way. We present 8 colored diagnostic figures that correspond to the 8 PID groups in the IUIS Classification, including all the PIDs cited in the 2011 update of the IUIS classification and most of those reported since.

Fig. 1

Combined T- and B- cell immunodeficiencies. ADA: Adenosine Deaminase; Adp: adenopathy; AIHA: Auto-Immune Hemolytic Anemia; AR: Autosomal Recessive inheritance; CBC: Complete Blood Count; CD: Cluster of Differentiation; CID: Combined Immunodeficiency; EBV: Ep-stein-Barr Virus; EDA: Anhidrotic ectodermal dysplasia; EO: Eosinophils; FISH: Fluorescence in situ Hybridization; HIGM: Hyper IgM syndrome; HLA: Human Leukocyte Antigen; HSM: Hepatosplenomegaly; Ig: Immunoglobulin; N: Normal, not low; NK: Natural Killer; NN: Neonate; NP: Neutropenia; PT: Platelet; SCID: Severe Combined ImmunoDeficiency; TCR: T-Cell Receptor; XL: X-Linked

Fig. 2

Well-defined syndromes with immunodeficiencies. These syndromes are generally associated with T-cell immunodeficiency. αFP: alpha- fetoprotein; AD: Autosomal Dominant inheritance; AR: Autosomal Recessive inheritance; CNS: Central Nervous System; FCM*: Flow cytometry available; FISH: Fluorescence in situ Hybridization; HSM: Hepatosplenomegaly; Ig: Immuno-globulin; NK: Natural Killer; XL: X-Linked inheritance

Fig. 3

Predominantly antibody deficiencies. Ab: Antibody; Anti PPS: Anti- pneumococcal polysaccharide antibodies: AR: Auto-somal Recessive inheritance; CD: Cluster of Differentiation; CVID: Common Variable Immunodeficiency Disorders; CT: Computed Tomography; Dip: Diphtheria; FCM*: Flow cytometry available; GI: Gastrointestinal; Hib: Haemophilus influenzae se-rotype b; Hx: medical history; Ig: Immunoglobulin; subcl: IgG subclass; Tet; Tetanus; XL: X-Linked inheritance

Fig. 4

Diseases of immune dysregulation. AD: Autosomal Dominant inheritance; AR: Autosomal Recessive inheritance; CD: Cluster of Differentiation; CTL: Cytotoxic T-Lymphocyte; EBV: Epstein-Barr Virus; FCM*: Flow cytometry available; HSM: Hepatosplenomegaly; Ig: Immunoglobulin; IL: interleukin; NK: Natural Killer; NKT: Natural Killer T cell; TL: T lymphocyte; XL: X-Linked inheritance

Fig. 5

Congenital defects of phagocyte number, function, or both. For DHR assay, the results can distinguish XL-CGD from AR-CGD, and gp40phox defect from others AR forms. AD: Autosomal Dominant inheritance; AML: Acute Myeloid Leukemia; AR: Autosomal Recessive inheritance; CBC: Complete Blood Count; CD: Cluster of Differentiation; CGD: Chronic Granulomatous Disease; CMML: Chronic Myelo-monocytic Leukemia; DHR: DiHydroRhodamine; LAD: Leukocyte Adhesion Deficiency; MSMD: Mendelian Susceptibility to Mycobacteria Disease; NP: Neutropenia; PNN: Neutrophils; WBC: White Blood Cells; XL: X-Linked inheritance

Fig. 6

Defects in innate immunity. AD: Autosomal Dominant inheritance; AR: Autosomal Recessive inheritance; BL: B lymphocyte; EDA-ID: Anhidrotic Ectodermal Dysplasia with Immunodeficiency; Ig: Immunoglobulin; PNN: Neutrophils; XL: X-Linked inheritance

Fig. 7

Autoinflammatory disorders. AD: Autosomal Dominant inheritance; AR: Autosomal Recessive inheritance; CAPS: Cryopyrin-Associated Periodic syndromes; CINCA: Chronic Infantile Neurologic Cutaneous and Articular syndrome; DA: Duration of Attacks; FA: Frequency of Attacks; FCAS: Familial Cold Autoinflammatory Syndrome; HIDS: Hyper IgD syndrome; Ig: Immunoglobulin; IL: interleukin; MKD: Mevalonate Kinase deficiency; MWS: Muckle-Wells syndrome; NOMID: Neonatal Onset Multisystem Inflammatory Disease; PAPA: Pyogenic sterile Arthritis, Pyoderma gangrenosum, Acne syndrome; SPM: Splenomegaly; TNF: Tumor Necrosis Factor; TRAPS: TNF Receptor-Associated Periodic Syndrome

Fig. 8

Complement deficiencies. Def: deficiency; SLE: Systemic Lupus Erythematosus