PID - Human Inborn Errors of Immunity D81.-D84.

Theterm primary immun odeficiencies (synonym: PID/immunodeficiency syndromes/immunodeficiency diseases) covers more than 400 different diseases of the immune system, which are characterized by a temporary or irreversible disturbance of the immune function, in which the immunodeficiency is congenital, occurs in families and/or can be inherited.

Secondary or acquired immunodeficiencies: The PID group with congenital defects is contrasted with acquired or secondary immunodeficiencies. The best known example of this is AIDS (acquired immune deficiency syndrome). Naturally, we are most often concerned with immunodeficiencies induced by immunosuppressive therapy.

Clinically, primary immunodeficiencies usually, but not always (e.g. fever syndromes), appear by a pathological susceptibility to infections, which can also be specific in the case of various mutations. E.g. IL-ILRA defect (chronic mucocutaneous candidiasis), interleukin-12/IL-23RB1 defects (medelian susceptibility to macobacerial diseases) or STAT1/STAT2 defects leading to a predisposition for severe viral infections.

Typical warning signs are hidden behind the acronyms:

• ELVIS(pathogen: unusual; localization: atypical; course: long; intensity: severe; sum: very common)

and

• GARFIELD(granulomas, autoimmunity, recurrent fever, eczema, lymphoproliferation, intestinal inflammation).

PID can manifest in all organs, but the surface epithelia of the skin, lungs, intestines, and genitourinary tract are most commonly affected.

For children, the following symptoms are considered warning signs(12 Warning Signs in Children):

1. Positive family history of congenital immunodeficiency.
2. 8 or more purulent otitis per year, mastoiditis
3. 2 or more sinusitis per year
4. 2 or more pneumonias within one year
5. indicated antibiotic therapy for 2 or more months without effect
6. Vaccination complications with live vaccinations (especially BCG, rotavirus and polio according to Sabin)
7. recurrent or systemic infections with atypical mycobacteria
8. recurrent deep skin or organ abscesses
9. 2 or more visceral infections (meningitis, osteomyelitis, septic arthritis, empyema, sepsis)
10. persistent Candida infections on skin or mucosa beyond 1 year of age
11. unexplained erythema/erythroderma in newborns and young infants (e.g., chronic graft vs. host reaction, Omenn phenotype, etc.)
12. Failure to thrive in infancy, with or without chronic diarrhea.

For adults, the following 6 warning signs are indicative:

1. 4 or more infections within a year that had to be treated with antibiotics.
2. Recurrent infections or an infection requiring prolonged antibiotic therapy
3. 2 or more severe bacterial infections
4. 2 or more radiologically proven pneumonias within three years
5. Infection with unusual localization or with unusual causative agent
6. Primary immunodeficiency in the family

The following table shows, based on the biological findings , the currently valid classification of primary immunodeficiencies according to the IUIS Classification 2021. It is constantly expanding, as about 10 new primary immunodeficiencies are described each year. The individual clinical pictures are summarized here in groups. The individual entities can be found under the linked group names.

Primary immunodeficiencies (PID) according to IUIS classification (2021)

1.PID /combined T/B/NK cell immunodeficiencies incl. "SCID and CID".

• 1.1.SCID (T-/B+)
• 1.2.SCID (T-/B-)
• 1.3 Combined immunodeficiencies (CID, less severe than SCID)

2. PID /T- and B-cell immunodeficiencies with syndromal features

• 2.1 PID with congenital thrombocytopenia
• 2.2. DNA repair defects
• 2.3. thymic defects with additional abnormalities
• 2.4. immunosseous dysplasias
• 2.5. hyper IgE syndromes
• 2.6. disorders of vitamin B12 and folic acid metabolism
• 2.7 Anhidrotic ectodermal dysplasias with immunodeficiencies (EDA-ID)
• 2.8 Calcium channel defects
• 2.9. other defects (Ig decreased, IgA absent)

3) PID/antibody deficiency as leading symptom (see also Common variable immunodeficiency - CVID)

• 3.1. severe reduction of all immunoglobulin isotypes with severely reduced or absent B cells
• 3.2. severe reduction of at least 2 Ig isotypes (IgG and IgA)B cell count normal or decreased
• 3.3. reduction of IgG and IgA with normal/increased IgM and normal B cell count
• 3.4. isotype or light chain deficiency with normal B cells

4. PID/Immundysregulations

• 4.1.Familial hemophagocytic lymphohistiocytoses (FHL)
• 4.1.1.Familial hemophagocytic lymphohistiocytoses (FHL)
• 4.1.2 Familial hemophagocytic lymphohistiocytoses with hypopigmentation
• 4.2 Genetic defects of regulatory T cells
• 4.3 Autoimmunity with or without lymphoproliferation
• 4.4. immune dysregulation with colitis
• 4.5 Autoimmune lymphoproliferative syndromes (ALPS; Canale Smith syndrome)
• 4.6. immunodysregulation with abnormalities towards EBV/lymphoproliferation

5. PID/Defects of phagocytes

• 5.1. defects of neutrophil development, congenital neutropenias
• 5.2. defects of motility
• 5.3. defects in the respiratory burst
• 5.4 Other non-lymphocytic defects

6. PGD/Defects of intrinsic and natural immunity

• 6.1 Mendelian Susceptibility to Mycobacterial Disease (MSMD)
• 6.2 Epidermodysplasia verruciformis
• 6.3. predisposition to severe viral infections
• 6.4. herpes simplex encephalitis
• 6.5. disposition to invasive fungal infections
• 6.6 Chronic mucocutaneous candidiasis (CMC)
• 6.7. disorders of TIR (Toll-like and Interluekin-IR) signaling with susceptibility
• 6.8. other congenital defects of immunity involving non-hematopoietic tissues
• 6.9 Other congenital defects in leukocytes

7. PGD/autoinflammatory diseases

• 7.1 Type I interferonopathies
• 7.2 Defects of the inflammasome
• 7.3. non-inflammasome-dependent autoinflammation

8. PGD/complement defects

9. PID/bone marrow failure

10. PGD/phenocopies (as DD of primary immunodeficiencies)

• 10.1.phenocopies associated with somatic mutations
• 10.2.phenocopies associated with autoantibodies

There are no precise figures on the frequency of primary immunodeficiencies (PID) in Germany. Estimates are that one in 1,000 people has a PID.

So far, about 340 PID diseases are known in which defined mutations in a gene have been detected, and about 10 new PID are described worldwide every year. These genotypes are characterized by different phenotypes. However, it is not uncommon for different genotypes to be associated with a uniform phenotype. Leading clinical symptoms of all PID syndromes are chronic and recurrent infections, preferentially affecting the skin, digestive tract, bronchial system and genitourinary tract, and central nervous system.

The growing diversity of phenotypes and genotypes attributed to primary immunodeficiency disorders (PID) makes primary immunodeficiencies a rapidly expanding field of medicine (see classification below).

After a detailed anamnesis and clinical examination, the further diagnostic procedure is performed according to consensus and evidence-based guidelines. In individual complex cases that cannot be clarified with previous methods, a so-called "whole exome sequencing" may be indicated.

Numerous forms of therapy are now available (e.g. regular administration of antibody preparations, enzyme replacement therapy, modern antibiotics or antimycotics, transplantation of stem cells from bone marrow or peripheral blood, and gene therapy approaches).

Note: Since August 2019, newborns are screened for severe congenital immunodeficiencies (SCID).

The classification of primary immunodeficiencies is published at multi-year intervals as a report of a scientific working group of the International Union of Immunological Societies (IUIS). The present classification is based on the work of Tangye SG et al (2020) and Tangye SG et al (2021).

1. Bousfiha A et al. (2015) The 2015 IUIS Phenotypic Classification for Primary Immunodeficiencies. J Clin Immunol 35:727-738.
2. Bousfiha A et al (2020) Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification. J Clin Immunol 40:66-81.
3. Tangye SG et al (2020) Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 40:24-64.
4. Tangye SG et al. (2021) The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee. J Clin Immunol 41:666-679.