Primary immunodeficiency disorders (PIDD)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU

Since Bruton described X-linked agammaglobulinemia in 1952, more than 180 different primary immunodeficiencies have been described.

10 Warning Signs of Primary Immunodeficiency in Children

1. Four or more new ear infections within one year.
2. Two or more sinus infections within one year, or chronic sinusitis.
3. Two or more months on antibiotics with little effect.
4. Two or more pneumonias within one year, or pneumonia twice over any time.
5. Failure of an infant to gain weight or grow normally.
6. Recurrent, deep skin or organ abscesses.
7. Persistent thrush in mouth or fungal infection on skin.
8. Need for intravenous antibiotics to clear infection.
9. Two or more deep-seated infections including septicemia.
10. A family history of primary immunodeficiency.

10 Warning Signs of Primary Immunodeficiency in Adults

1. Two or more new ear infections within one year.
2. Two or more serious sinus infections within one year, in the absence of an allergy; or chronic sinusitis.
3. One pneumonia per year for more than one year, or pneumonia twice over any time.
4. Chronic diarrhea with weight loss.
5. Recurrent viral infections (colds, herpes, warts, condyloma).
6. Recurrent need for intravenous antibiotics to clear infections.
7. Recurrent, deep abscesses of the skin or internal organs.
8. Persistent thrush or fungal infection on skin or elsewhere.
9. Infection with normally harmless tuberculosis-like bacteria.
10. A family history of primary immunodeficiency.

Source: PDF handouts: Children PIDD, Children PIDD (illustrated), Adult PIDD, 4 Stages of Immunologic Testing when PIDD is suspected.

Primary immunodeficiency disorders (PIDD) (click to enlarge the image).

Definition of PIDD: Genetically determined immunodeficiency.

The World Health Organization recognizes more than 100 PIDD. Most of PIDD are rare but selective IgA deficiency is relatively common, prevalence 1:500.

4 Major Host Defense Mechanisms:

- B-cell immunity
- T-cell immunity
- Phagocytic cells
- Complement system

Phagocyte immunodeficiencies (click to enlarge the image):

Read more:

Phagocyte Deficiencies
Chronic Granulomatous Disease (CGD)
Chediak-Higashi Syndrome (CHS)
Leukocyte adhesion deficiency (LAD)
Leukocyte adhesion deficiency type I (LAD I)
Leukocyte adhesion deficiency type II (LAD II)
Leukocyte adhesion deficiency type III (LAD III)
Hyper IgE Syndrome (HIES)

Humoral immunodeficiency (click to enlarge the image).

B and T cells "talk" constantly in T-dependent immune responses where a host of enzymes are involved in class switching - AICD, UNG, CD40, CD40L - if there is a defect in any of these enzymes, B cells cannot class switch - Ig gets "stuck" at IgM level and hyper-IgM immonodeficiency develops.

T-cell Immunodeficiencies (click to enlarge the image).

The autoimmune regulatory gene (AIRE) is expressed in the thymus. AIRE promotes expression of non-thymic tissue antigens in the thymus - a key part of the thymic education of T cells.

Mutation in the AIRE gene produces disorders such as autoimmune polyglandular syndrome or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). In this syndrome, T cells do not develop tolerance to self-antigens. The endocrine organs are attacked by autoreactive T cells. The AIRE mutation was the first report of a single-gene defect causing a systemic human autoimmune disease.

Mutations in FAS or caspase 10 manifest as autoimmune lymphoproliferative syndrome (ALPS). In ALPS, lymphocytes do not get a signal to "die" and they accumulate in the lymphoid organs.

Read more:

IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X linked) syndrome
Autoimmune lymphoproliferative syndrome (ALPS)
Chronic Mucocutaneous Candidiasis (CMCC)
Diagnosis of T-cell Immunodeficiency

Combined Immunodeficiencies (click to enlarge the image).

Bare lymphocyte syndromes include MHC class I and MHC class II deficiencies. These are primary immune deficiency disorders (PIDD) due to a lack of expression of either MHC I or MHC II. MHC class I deficiency leads to CD8 lymphopenia. MHC class II deficiency leads to CD4 lymphopenia.

Read more:

DiGeorge Syndrome (DGS)
Wiskott-Aldrich Syndrome (WAS)
Ataxia-Telangiectasia (A-T)

Severe Combined Immunodeficiency (SCID) (click to enlarge the image).

In SCID, the younger the age of the patient at the time of transplantation, the better the prognosis. There is a 95% survival rate in an infant who undergoes a transplant before 3 months of age. After six months, the survival rate decreases dramatically, to 50%.

Receptor editing reactivates RAG-1 and RAG-2 when a high affinity self-antigen is recognized by a B cell receptor (BCR). RAG-1 and RAG-2 defects lead to Omenn syndrome, a form of SCID.

Severe combined immunodeficiency (SCID) - 4 groups according to T/B/NK cells (click to enlarge the image).

Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 contain γ chain, which is affected in X-linked SCID.

Cytokine receptors (click to enlarge the image)

Complement deficiencies (click to enlarge the image).

Read more in Complement Deficiencies.

Tests and Workup of Suspected Immunodeficiency - mostly primary immunodeficiency disorders (PIDD)

B-cell PIDD

Flow Cytometry: CD19 and CD20
Ig G, A, M, E
IgG subclasses (IgG1, IgG2, IgG3, IgG4)
IgG titer for Tetanus
IgG titer for Diphtheria
IgG titer for Haemophilus influenzae type B
IgG titer for Mumps
IgG titers for Pneumococcus
IgG titers for Pneumococcal conjugated vaccine (if given PCV7 or PCV13, Prevnar in the U.S.)
IgG titers for Pneumococcal unconjugated vaccine (if given PSPV, Pneumovax in the U.S.)
Blood group Isohemagglutinins (for diagnosis of CVID)
Mitogen stimulation assays for B- and T-cells

T-cell PIDD (T-cell and NK cell)

Absolute lymphocyte count (CBC-Diff)
Flow Cytometry: CD3CD4, CD3CD8, and CD16CD56
Delayed-type hypersensitivity
Enzyme assays (ADA and PNP)
NK cytolysis assay
Mitogen stimulation assays for B- and T-cells

Phagocyte PIDD (neutrophils, macrophages and monocytes)

CBC-Diff with peripheral smear
Absolute neutrophil count
Flow Cytometry: LFA-1 (CD11a or CD18) and CD15
Oxidative function (DHR or NBT or chemiluminescence)
Enzyme assays (MPO and G6PDH)
Phagocyte function assay - chemotaxis and bactericidal function

Complement PIDD

C3 and C4
C1 esterase inhibitor (C1-INH) - qualitative and quantitative
CH50 (classic pathway)
AH50 (alternative pathway)


Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol 2005 May;94(5 Suppl 1):S1-63.

Algorithm 1: General Approach for the Diagnosis of Primary Immunodeficiency
Algorithm 2: Diagnosis of Humoral Immunodeficiency
Algorithm 3: Diagnosis of Cellular and Combined Immunodeficiencies
Algorithm 4: Diagnosis of Phagocyte Defects
Algorithm 5: Diagnosis of Complement Deficiency
Algorithm 6: General Considerations for Therapy of Primary Immunodeficiency
Classification of primary immunodeficiencies: Need for a revised approach?

Published: 08/29/2009
Updated: 03/02/2014

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