Dr. Marwan Jabr Alwazzeh
Assoc. Prof. of Medicine
Consultant Internist/ Infectious Diseases
University of Dammam
Why me?!
 A 18-year-old youth
admitted three times
between 2004 and
2012 for
meningococcal
meningitis.
This patient
presents to your
clinic and asks:
Why me?!
Why Primary Immunodeficiencies (PIDs)
Diagnostic Delay
 The perception of PIDs as rare, difficult to
manage congenital diseases.
 It can take many years for PIDs to be diagnosed.
 Clinicians consider signs and symptoms (eg,
bronchitis, pneumonia, sinusitis, diarrhea) to be
infection related without taking the underlying
immunological process into account, even in
specialized centers.
Why Primary Immunodeficiencies
(PIDs)
 Morbidity and mortality
 Economic Impact
 Treatment Options
Primary Immunodeficiencies (PIDs)
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Identification of PIDs
Epidemiology
Classifications
General approach
PIDs in adults
 Which PIDs Can Present in Adults?
 Patterns of Clinical Presentation of PIDs in Adults
 Diagnostic Approach to an Adult with Suspected
PID.
 Take-home messages
Primary Immunodeficiencies (PIDs)
 Genetic diseases cause alterations in the
immune response and present with an
increased rate of infection, allergy,
autoimmune disorders, and cancer.
 More than 150 PIDs are known, and the
genetic basis of many of them has been
identified.
Primary immunodeficiencies (PIDs)
Epidemiology
 PIDs prevalence in the European Union
is estimated to be 1 case/10 000 people.
 Recent North American population
study revealed an estimated prevalence
for PIDs of 1 case/1200-2000 people.
 Between 25% and 40% of all PIDs are
diagnosed in adulthood.
Traditional Classification of PIDs
1 Defects in humoral immunity Recurrent respiratory infections by encapsulated
(antibody deficiencies)
microorganisms
2 Defects in cellular immunity Severe infections by viruses, fungi, and other
opportunistic pathogens such Pneumocystis jiroveci
and mycobacteria
3 Defects in phagocytosis
Recurrent cutaneous and deep-seated abscesses due to
Staphylococcus aureus, gramnegative bacteria
(Escherichia coli, Serratia marcescens, Burkholderia
species, Pseudomonas species), fungi (Aspergillus
species), Nocardia species or mycobacteria
4 Defects in the complement
system
Streptococcus pneumoniae and Neisseria species
Categories of PID according to the International Union of Immunological Societies (IUIS)
Disease category
1 Combined B- and T-cell
immunodeficiencies
(predominantly T-cell)
2 Predominantly antibody
deficiencies
3 Other well-defined
immunodeficiency
syndromes
4 Disease of immune
dysregulation
5 Congenital defects of
phagocyte number,
function, or both
6 Defects in innate
immunity
7 Autoinflammatory
disorders
8
Complement deficiencies
Diagnoses
(Severe) combined immunodeficiency, (S) CID; many different genetic defects
CD40 and CD40L deficiencies
Common variable immunodeficiency disorders (CVIDs)
X-linked agammaglobulinemia (XLA, or ‘Bruton disease’)
Selective IgA deficiency
IgG-subclass deficiency
Deficiencies in the production of specific antibodies
Wiskott Aldrich syndrome
Ataxia telangiectasia
Hyper-IgE syndrome
Immunodeficiencies with hypopigmentation
Familial hemophagocytic lymphohistiocytosis syndromes (HLH)
X-linked lymphoproliferative syndrome
Autoimmune lymphoproliferative syndrome (ALPS)
Severe congenital neutropenia
Cyclic neutropenia
X-linked or autosomal recessive chronic granulomatous disease (CGD)
Anhidrotic ectodermal dysplasia with immunodeficiency
IL-1 receptor-associated kinase 4 deficiency (IRAK-4 deficiency)
Chronic mucocutaneous candidiasis
Familial Mediterranean fever
TNF receptor-associated periodic fever (TRAPS)
Hyper-IgD syndrome
Cryopyrin-associated periodic syndromes
Broad spectrum of deficiencies of classical and alternative pathway complement
factors
Start from clinical presentations
European Society for Immunodeficiencies
(ESID)
developed Patient-centered screening for
primary immunodeficiency: a multistage diagnostic protocol designed for
non-immunologists in 2005 and updated
in 2011.
Start from clinical presentations
History (Symptoms that could point to potential PID)
 The hallmark of PID: infection history
 Recurrent (probably) bacterial infections (more frequent than expected
at the patient’s age)
 More than one severe infection (e.g. meningitis, osteomyelitis,
pneumonia, sepsis)
 Infections that present atypically, are unusually severe or chronic or fail
regular treatment (especially if i.v. antibiotics are needed)
 Abscess of internal organ
 Recurrent subcutaneous abscesses (especially in children)
 Prolonged or recurrent diarrhoea
 Any infection caused by an unexpected or opportunistic pathogen (e.g.
pneumocystis)
 Severe or long-lasting warts, generalized mollusca contagiosa
 Extensive candidiasis, recurrent oral thrush in children >1 year
 Complications of vaccination (disseminated BCG or varicella infection,
paralytic polio, rotavirus infection)
Start from clinical presentation
History (Symptoms that could point to potential PID)
 Remember the family history!
 PID in the family; familial occurrence of similar
symptoms (affected males related by the female line, or
another clear pattern of inheritance)
 Unexplained early infant deaths, deaths due to infection
 Consanguinity in the (grand) parents (known or
suspected)
 Autoimmune disease or haematological malignancy in
several family members
Start from clinical presentations
History (Symptoms that could point to potential PID)
 Other (could point to PID, but may not)
 Aplasia or hypoplasia of thymus (X-ray)
 Angioedema
 Auto-immune disease (especially autoimmune cytopenias, SLE)
 Bleeding tendency
 Congenital cardiac anomalies (mainly
conotruncal defects)
 Chronic diarrhoea, malabsorption,
pancreatic insufficiency
 Delayed separation of umbilical cord ( >4
weeks)
 Delayed shedding of primary teeth
 Developmental delay (progressive)
 Difficult-to-treat obstructive lung disease
 Eczema, dermatitis (severe, atypical)
 Failure to thrive (child) or wasting (adult)
 Graft-versus-host reaction after blood
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transfusion, or mother-to-child
(infant) engraftment
Granulomas
Haemolysis
Hypersensitivity to sunlight
Hypocalcaemic seizures
Inflammatory bowel disease (atypical)
Malignancy (mainly lymphoma)
Non-allergic oedema
Poor wound healing; scarring
Recurrent fever
Rib or other skeletal anomalies (X-ray)
Thymoma
Unexplained bronchiectasis,
pneumatoceles, interstitial lung
disease
Vasculitis
Start from clinical presentations
Physical examination (Signs that could point to potential PID)
Skin and
appendages
Abnormal hair or teeth. Eczema. Neonatal erythroderma. (Partial)
albinism. Pale skin. Incontinentia pigmenti. Nail dystrophy. Extensive
warts or molluscae. Congenital alopecia. Vitiligo. Petechiae (early onset,
chronic). Cold abscesses. Telangiectasia. Absence of sweating.
Oral cavity
Eyes
Gingivostomatitis (severe). Periodontitis. Aphthae (recurrent). Giant
oral ulcers. Thrush. Dental crowding. Conical incisors. Enamel
hypoplasia. Persistent deciduous teeth
Retinal lesions. Telangiectasia
Lymphoid
tissue
Absence of lymph nodes and tonsils. Lymphadenopathy (excessive).
Asplenia. Organomegaly (liver, spleen)
Neurological
Ataxia. Microcephaly. Macrocephaly
Other
Angioedema (without urticaria). Digital clubbing. Dysmorphism.
Stunted growth or disproportional growth
Primary Immunodeficiencies
(PIDs) in adults
Which PIDs Can Present in Adults?
Almost all PIDs can present in adults
Selective IgA deficiency
Common variable immunodeficiency disorders (CVIDs)
IgG-subclass deficiency
Deficiencies in the production of specific antibodies
Defects of the classic and alternative activation pathways (C1 to C4, factors D, I, H, and P)
Defects of the terminal complement pathway (membrane attack complex)
Defects in the lectin pathway (MBL, mannose-binding protein-associated serine protease 2 [MASP2])
Defects of the interleukin (IL) 12/23–IFN- γ pathway
(Severe) combined immunodeficiency, (S) CID; many different genetic defects
X-linked agammaglobulinemia (XLA, or ‘Bruton disease’)
Wiskott Aldrich syndrome
Ataxia telangiectasia
Hyper-IgE syndrome
Cyclic neutropenia
X-linked or autosomal recessive chronic granulomatous disease (CGD)
Familial Mediterranean fever
TNF receptor-associated periodic fever (TRAPS)
Hyper-IgD syndrome
Thymoma-associated immunodeficiency
Patterns of Clinical Presentation of PIDs in Adults
Infections with special characteristics
1
• Recurrent or persistent upper and lower respiratory infections,
unexplained bronchiectasis
• Antibody deficiencies
Common variable immunodeficiency disorders (CVIDs)
Selective IgA deficiency
IgG-subclass deficiency
Deficiencies in the production of specific antibodies
Thymoma with immunodeficieny
X-linked agammaglobulinemia (XLA, or ‘Bruton disease’)
Patterns of Clinical Presentation of PIDs in Adults
Infections with special characteristics
Antibody deficiencies
Association
Common variable immunodeficiency disorders (CVIDs)
Selective IgA deficiency
Higher incidence autoimmune diseases
Higher incidence celiac disease
IgG-subclass deficiency
Deficiencies in the production of specific antibodies
Thymoma with immunodeficieny
Hypogammaglobulinemia, myasthenia
gravis.
X-linked agammaglobulinemia (XLA, or ‘Bruton
disease’)
They can affect the digestive tract (diarrhea and malabsorption, inflammatory bowel disease) and
produce inflammatory symptoms (granuloma) in the lungs and intestine.
May have a higher incidence of lymphoproliferative disorders, solid tumors (gastric carcinoma)
Patterns of Clinical Presentation of PIDs in Adults
Infections with special characteristics
1
•Recurrent or persistent upper and lower respiratory infections,
unexplained bronchiectasis
• Complement deficiencies
• defect in C1 to C4, factors I, D, and H, and P.
• C2 deficiency is the most common (incidence of 1 case in 10 000 people).
• Occur with infections by encapsulated germs such Neisseria species and associated
with lupus-like syndromes.
Patterns of Clinical Presentation of PIDs in Adults
Infections with special characteristics
1
•Recurrent or persistent upper and lower respiratory
infections, unexplained bronchiectasis
• Phagocytic defects
Chronic Granulomatous Disease (CGD)
Neutropenia
Hyper-IgE syndrome
Patterns of Clinical Presentation of PIDs in Adults
Infections with special characteristics
2
• Recurrent abscesses–both superficial (cutaneous, mucosal)
and deep-seated (lung, bone, liver, lymph nodes)
• Phagocytic defects
Chronic Granulomatous Disease (CGD)
Neutropenia
Hyper-IgE syndrome
Patterns of Clinical Presentation of PIDs in Adults
Infections with special characteristics
3
• Diarrhea and malabsorption
• Antibody deficiencies
Common variable immunodeficiency disorders (CVIDs)
Selective IgA deficiency
They may also occur secondary to infection by Giardia species, enterovirus, and cytomegalovirus
(CMV), or associated with celiac disease and inflammatory bowel disease.
Patterns of Clinical Presentation of PIDs in Adults
Infections with special characteristics
4
• Especially severe or opportunistic infections (P jiroveci, Aspergillus species,
Cryptococcus species, Cryptosporidium species, Nocardia species, severe
infections by viruses such as CMV, Epstein-Barr virus [EBV], varicella-zoster
virus [VZV], human herpes virus [HHV])
(Less severe) forms of cellular or combined immunodeficiencies
Wiskott-Aldrich syndrome
Isolated poorly defined deficiencies in cellular immunity
Patterns of Clinical Presentation of PIDs in Adults
Infections with special characteristics
5
• Infections by certain pathogens suggest specific defects.
Recurrent meningococcal meningitis,
or by rare serogroups (not B or C)
Terminal complement pathway (membrane
attack complex C5-C9)
Infections by Pneumococcus and other
encapsulated species
Signaling deficiencies of Toll-like receptors
(TLRs) (IRAK4/NEMO/MyD88)
Invasive pneumococcal infections
EBV
Chronic mucocutaneous candidiasis
Asplenia
X-linked lymphoproliferative syndrome
Mutation in the AIRE gene
Patterns of Clinical Presentation of PIDs in Adults
Immunopathologic manifestations
1
• Asthma and food allergy
IgA deficiency
Wiskott-Aldrich syndrome
Hyper-IgE syndrome
Patterns of Clinical Presentation of PIDs in Adults
Immunopathologic manifestations
2
• Autoimmunity and inflammation
Systemic lupus erythematosus, rheumatoid arthritis
Periodic fever syndromes
Cytopenia
Autoimmune polyendocrinopathy-candidiasis-ectodermal
dystrophy (APECED)
Autoimmune features and polyclonal or monoclonal
lymphoproliferation
Selective IgA deficiency
Complement deficiencies
DiGeorge syndrome
hyper-IgD syndrome
Familial Mediterranean fever
Common variable immunodeficiency disorders (CVIDs)
Selective IgA deficiency
AIRE gene mutations
Autoimmune lymphoproliferative syndrome (defects of
apoptosis pathways)
Patterns of Clinical Presentation of PIDs in Adults
Immunopathologic manifestations
3
• Cancer
CVID (lymphoma, gastric cancer)
Advanced Wiskott-Aldrich syndrome
Ataxia telangiectasia
Autoimmune lymphoproliferative syndrome
Patterns of Clinical Presentation of PIDs in Adults
Typical associations with rare phenotypic characteristics
DiGeorge syndrome
cardiopathy, hypoparathyroidism,
dysmorphic features, severe cellular
immunodeficiency, or more frequently a mild
form associated with allergy and/or
autoimmunity
WiskottAldrich
syndrome
eczema, thrombocytopenia,
immunodeficiency, risk of
lymphoproliferative disease
Ataxia telangiectasia with variable immunodeficiency, lymphoma
Patterns of Clinical Presentation of PIDs in Adults
Abnormal laboratory findings
Neutropenia
Lymphocytosis
Eosinophilia
X-linked agammaglobulinemia
Hyper-IgM syndrome
Autoimmune syndrome
Leukocyte adhesion deficiency
Cellular or combined immunodeficiency, especially
adenosine deaminase deficiency (ADA-SCID)
SCID
Hyper-IgE syndrome, Wiskott-Aldrich syndrome
Hypocalcemia
Hypouricemia
Hypergammaglobulinemia
DiGeorge syndrome
Purine nucleoside phosphorylase deficiency (SCID)
Defects in phagocytosis
Defects in complement system
Neutrophilia
Lymphopenia
Patterns of Clinical Presentation of PIDs in Adults
Diagnostic Approach to the Adult
with Suspected PIDs
History
 Infections with specific characteristics.
 Present of autoimmune diseases,
allergy, or cancer.
 The causal microorganisms.
Diagnostic Approach to the Adult
with Suspected PIDs
Family History
 Recurrent infections, autoimmune processes, cancer,
or higher infant mortality.
 Absence does not rule it out:
 Family history found in only 18% of cases.
 25% of cases linked to the X chromosome are caused by de
novo mutations.
 Autosomal dominant diseases may have incomplete
penetration.
 May be associated with factors that result in major
variability in clinical expression within the same family.
Diagnostic Approach to the Adult
with Suspected PIDs
Physical examination
 Data on chronic diseases (pallor, thinness,
acropachy, lung sounds)
 Nonspecific suggestive conditions
(hepatosplenomegaly and lymphadenopathy)
 Absence of lymphoid tissue and tonsil hypoplasia
(agammaglobulinemia and many forms of SCID)
 The phenotypic traits
The 6 Warning Signs for Adult Primary
Immunodeficincies Diseases
1. Four or more infections requiring antibiotics within 1 year
(otitis, bronchitis, sinusitis, pneumonia).
2. Recurring infections or infection requiring prolonged
antibiotic therapy.
3. Two or more severe bacterial infections (osteomyelitis,
meningitis, septicemia, cellulitis).
4. Two or more radiologically proven pneumonia within 3 years.
5. Infection with unusual localization or unusual pathogen.
6. PID in the family.
European Society of Immunodeficincies (ESID)
Diagnostic Approach to the Adult with
Suspected PIDs
Differential diagnosis
 Secondary immunodeficiencies: aging, malnutrition,
metabolic diseases, surgery, trauma, environmental
conditions, radiation, altitude, chronic hypoxia,
infection, AIDS, hypogammaglobulinemia secondary to
protein-losing syndromes, hypercatabolism, or drugs
 Localized processes
 Generalized processes
 Hereditary diseases other than PIDs
Diagnostic Approach to the Adult with
Suspected PIDs
Investigations-Level 1
 Complete blood count, with a manual
count of leukocytes and careful
verification of absolute values
 Quantification of IgG, IgA, IgM, and
IgE
Diagnostic Approach to the Adult with
Suspected PIDs
Investigations-Level 2
 Repeated quantification of IgG, IgA, IgM, and IgE, and IgG
 Antibody response investigations:
 Antitetanus and/or antidiphtheria (protein antigens): Levels
are related to vaccine status; if they are low, a booster dose of
the vaccine and further tests to determine the presence of
these antibodies are necessary. To consider a response
normal, the baseline titer must increase at least 4-fold.
 Natural antibodies (isohemagglutinin, anti-ABO,
antistreptolysin O titer).
 Antipneumococcal antibody and monitoring after
polysaccharide vaccine (Pneumo 23): normal response is a 2fold increase in the baseline titer.
Diagnostic Approach to the Adult with
Suspected PIDs
Investigations-Level 2
 IgG subclasses
 IgD
 Study of complement: C3, C4, CH50 (integrity
of the classic and terminal complement
pathway).
Diagnostic Approach to the Adult with
Suspected PIDs
Investigations-Level 2
• Lymphocyte subpopulations (basic protocol)
CD3+
CD3+/CD4+
CD3+/CD4+/CD27+/CD45RA+
CD3+/CD8+
CD3+/HLA-DR+
CD3+/TCR-αβ+/CD4-/CD8CD3+/TCR-γδ+
CD19+ or CD20+
CD19+/CD27+/IgM-/IgDCD3-/CD16+ and/or CD56+
T lymphocytes
Helper-T lymphocytes
Naive helper-T lymphocytes
Cytotoxic T lymphocytes
Activated T lymphocytes
‘Double-negative’ TCR-αβ+ T cells
TCR-γδ+ subset of T lymphocytes
B lymphocytes
Switched memory-B lymphocytes
NK cells
Diagnostic Approach to the Adult with
Suspected PIDs
Invistegations-Level 3
 Oxidative capacity of neutrophils (burst test).
 Quantification of other complement factors
and of the activity of the alternative and
lectin pathways.
 Lymphocyte subpopulations (extended
protocol).
Diagnostic Approach to the Adult with
Suspected PIDs
Investigations-Level 3
 Lymphocyte cultures (stimulation and measurement of
response), as follows:
 Mitogen stimulation assays (PHA, ConA)
 Tritiated thymidine incorporation assay.
 Special studies:
 Standard karyotype, karyotype with methotrexate, FISH
(study of deletion of 22q11.2 to investigate DiGeorge
syndrome), alpha fetoprotein/carcinoembryonic antigen.
 Parathormone.
 Biopsy (intestinal, lymph nodes), bone marrow
examination.
Diagnostic Approach to the Adult with
Suspected PIDs
Invistegations-Level 4
 Lymphocyte cultures (stimulation and response measurement),
with several variables:
 Stimulation with mitogens (PWM, PMA/ionoCa), monoclonal
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antibodies (anti-CD3 or anti-CD2+ anti-CD28), and antigens (tetanus
toxoid, Candida).
Addition of IL-2 or other cytokines.
Measurement of activation markers, cytokines, and/or
immunoglobulins in supernatant fluids.
Intracellular cytokines (eg, IL-2, IFN- γ, IL-4)
IL-12/IL-12Rß/IFN- γ R
Proteins (flow cytometry, Western blot [eg, ZAP 70, Jak3, TAP1/2])
Genetic studies (eg, BTK, RAG1/2, CD40L/CD40, IFN γ R, ATM, WASP)
Diagnostic Approach to the Adult with
Suspected PIDs
Invistegations-Level 4
• Protocol for determination of granulocyte function
Flow cytometric analysis using dihydrorhodamine (DHR)
Nitroblue tetrazolium test (NBT) to a stimulant (PMA, LPS)
Chemoluminescence test
Immunophenotyping (CD18, CD11b, sLeX, kindlin3)
Chemotaxis, granule contents, bacterial killing, phagocytosis
Migration to a chemoattractant (e.g. fMLP)
Immunohistochemistry of granule contents, electron microscopy
Bacterial killing (e.g. of Staphylococcus aureus)
Take-home messages
 PIDs not so rare in adult.
 The key to detect a PID is to consider the
possibility.
 Timely recognition of antibody deficiency
prevents future organ damage.
 PIDs almost always present with one or more
of clinical presentations; these can be used as
the starting point to enter the appropriate
diagnostic protocol.
Take-home messages
 If PID is suspected or runs in the family,
delay live attenuated vaccinations and
do not postpone immunological
investigations.
 Use age-matched reference values to
avoid misinterpretation of
immunological test results.