Introduction
Disease category | Diagnosesa
|
---|---|
Combined B- and T-cell immunodeficiencies (predominantly T-cell) | (Severe) combined immunodeficiency, (S)CID; many different genetic defects |
CD40L deficiency | |
Predominantly antibody deficiencies | X-linked or AR agammaglobulinemia |
Common variable immunodeficiency disorders (CVIDs) | |
Specific antibody deficiencies | |
IgG-subclass deficiency | |
Selective IgA deficiency | |
Other well-defined immunodeficiency syndromes | Wiskott Aldrich syndrome |
Ataxia telangiectasia and other DNA repair disorders | |
Hyper-IgE syndromes | |
Disease of immune dysregulation | Immunodeficiencies with hypopigmentation |
Familial hemophagocytic lymphohistiocytosis syndromes (HLH) | |
X-linked lymphoproliferative syndrome | |
Autoimmune lymphoproliferative syndrome (ALPS) | |
Congenital defects of phagocyte number, function, or both | Severe congenital neutropenia |
Cyclic neutropenia | |
X-linked or AR chronic granulomatous disease (CGD) | |
Defects in innate immunity | Anhidrotic ectodermal dysplasia with immunodeficiency |
IL-1 receptor-associated kinase 4 deficiency (IRAK-4 deficiency) | |
Chronic mucocutaneous candidiasis | |
Autoinflammatory disorders | Familial Mediterranean fever |
TNF receptor-associated periodic fever (TRAPS) | |
Hyper-IgD syndrome | |
Cryopyrin-associated periodic syndromes | |
Complement deficiencies | Broad spectrum of deficiencies of classical and alternative pathway complement factors |
Hereditary angioedema (C1 esterase inhibitor deficiency) |
A diagnostic strategy for PIDs
Clinical presentation and diagnosis of PID
Medical history |
Recurrent (proven) bacterial infections |
Two ore more severe infections (pneumonia, sepsis, meningitis, osteomyelitis) |
Atypical presentation of infection |
Unusually severe course of infection or impaired response to treatment |
Infections caused by an unexpected or opportunistic pathogen |
Recurrent infections with the same type of pathogen |
Abscesses of internal organs or recurrent subcutaneous abscesses |
Failure to thrive with prolonged or recurrent diarrhea |
Generalized long-lasting warts or mollusca contagiosa |
Extensive prolonged candidiasis (oral/skin) |
Delayed (>4 weeks) separation of the umbilical cord |
Delayed shedding of primary teeth |
Family history of immunodeficiency, unexplained infant deaths, or consanguinity of the parents |
Difficult-to-treat obstructive lung disease, unexplained bronchiectasis |
Atypical autoimmune disease and/or lymphoproliferation |
Physical examination |
Dysmorphic features, especially facial abnormalities and microcephaly |
Partial albinism, abnormal hair, severe eczema, dermatitis |
Telangiectasia, ataxia |
Gingivitis, oral ulcers/aphthae |
Abnormal wound healing |
Absence of immunological tissue (lymph nodes, tonsils) |
Lymphadenopathy |
Organomegaly |
Digital clubbing |
Vasculitis |
Clinical presentation | Suspected immunodeficiency | Non-immunological differential diagnosis (most frequent on top) | First-line immunologic diagnostic work-up |
---|---|---|---|
Recurrent ENT and airway infections | Antibody deficiency | Normal frequency in infants and young children | Full blood count and differential |
Phagocyte deficiency | Asthma, allergy, bronchial hyperreactivity | IgG, IgA, IgM | |
HIV | Adenoidal hypertrophy | In case of agammaglobulinemia: lymphocyte subpopulations (B-cells present?) | |
PID related to eponymous syndrome | Gastro-esophageal reflux | In case of hypogammaglobulinemia or persistent problems: IgG-subclasses, specific antibody responses, CH50, AP50, lymphocyte subpopulations | |
Wiskott Aldrich Syndrome | Inhaled foreign body | ||
Complement deficiency | Cystic fibrosis | ||
Primary ciliary dyskinesia | |||
Congenital anomaly | |||
Failure to thrive from early infancy (often combined with intractable diarrhea) | T-lymphocyte deficiency: (S)CID | Wide variety of other causes, see appropriate textbooks | Exclude SCID and HIV infection: |
HIV | Full blood count and differential, IgG, IgA, IgM | ||
HIV test | |||
Lymphocyte subpopulations (decreased T-cells?) | |||
Recurrent pyogenic infections (e.g., abscesses of internal organs or recurrent subcutaneous abscesses) | Congenital defects of granulocyte number, function, or both | Disrupted skin (eczema, burns) | Full blood count and differential |
Carriage of virulent strain of Staphylococcus aureus
| Perform repeatedly in case of cyclic pattern of fever: | ||
Drug-related neutropenia | 3×/week for 3–6 weeks | ||
Alloimmune neutropenia, benign neutropenia of infancy (autoimmune neutropenia) | In case problems persist and there is no neutropenia, antibody or complement deficiency: phagocyte function tests | ||
Hematological malignancy | |||
Unusual infections or unusually severe course of infections (e.g., opportunistic infections) | T-lymphocyte deficiency: (S)CID | Secondary immunodeficiency: | Full blood count and differential, |
HIV | Malignancy, malnutrition, chronic disease, immunosuppressive therapy | IgG, IgA, IgM | |
Wiskott Aldrich Syndrome | HIV test | ||
Defects of innate immunity | Lymphocyte subpopulations (decreased T-cells?) | ||
Recurrent infections with the same type of pathogen | Encapsulated bacteria: antibody deficiency | Increased exposure | Full blood count and differential |
Meningococci: complement deficiency | Inadequate treatment of first infection | IgG, IgA, IgM, follow diagnostic work-up for recurrent ENT and airway infections | |
Candida: T-lymphocyte deficiency | Anatomical defects, e.g., CSF fistula in case of recurrent meningitis | In case of meningococcal disease: CH50, AP50 | |
Mycobacteria: macrophage–T-cell interaction problem | In case of mycobacteria: consult immunologist | ||
Autoimmune or chronic inflammatory disease; lymphoproliferation | CVIDs | Other systemic autoimmune diseases like autoimmune cytopenias | Initial work-up depends upon clinical presentation |
Hemophagocytic lymphohistiocytosis (HLH) | SLE | ||
Autoimmune lymphoproliferative syndrome (ALPS) | |||
Characteristic combinations of clinical features in eponymous syndromes and PID warning signs | DNA-repair defects | See appropriate textbooks for syndrome characteristics | Initial work-up depends upon the suspected syndromes |
Hyper-IgE syndromes | |||
Microdeletion 22q11 (DiGeorge) | |||
Angioedema | C1 esterase inhibitor deficiency | Allergy, malignancy, autoimmunity, drug-related | C1 esterase inhibitor |