Primary Immune Deficiencies =

Inborn Error of Immunity

Nia Kurniati
nia.kurniati@ui.ac.id
Bubble Boy
 Term and Definition
• Immunodeficiency diseases are clinically and pathologically
heterogeneous, because different diseases involve different
components of the immune system.
• Also known as Human Inborn Error of Immunity
• Diagnosis and management need extensive laboratory
procedure
 Milestone of PID
• 1926 Ataxia-teleangiectasia
• 1928 Chronic Mucocutaneus Candidiasis
• 1937 Wiskott-Aldrich Syndrome
• 1950-58 “Swiss” type SCID described
• 1962 “American” type SCID recognized
• 1953 Bruton – XLA (X-linked Agammaglobulinemia)
• 1967 CGD (Chronic Granulomatous Disease)
• -> ADA, DNA-breakage, lymphokines, LAD, WASP, neutropenia
genes, FOXP3, STATs >300 PID-related and 20 SCID genes
Epidemiology
 Function of Major Immune Component

B Cell T Cell Phagocyte Complement NK Cells

Differentiates TH cells provide B

into plasma cells with signals Opsonization Destroys
necessary to
cells Engulf and Terminal virally
generate Ab
(producing Ab) production destroy components infected
Opsonization Cytotoxic T cells microbes to create cells and
destroy virally MAC tumor cells
Complement infected cells and
activation tumor cells
Treg suppresses
Toxine auto-reactive cells
neutralization
 Immune Deficiency

Primary 90% Secondary

Intrinsic <10% Underlying disease

nMissing enzyme (ADA) nLymphoid malignancy

nMissing cell type (lig CD40) nHIV infection

nNonfunctioning component nMalnutrition

Congenital nImmunosuppressant drug

Acquired

Manifest since early age Manifest in any age

Stiehm 2005
 PID Classification
• PID comprise at least 430 genetically-defined inborn errors of
immunity and 406 distinct disorders
• The International Union of Immunological Societies (IUIS) PID
proposed PID classification: grouped into ten categories based
on the principal mechanism
Boushifa AA et al. Human Inborn Error of Immunity: 2019 update of the IUIS Phenotypical Classification
J Clin Immunology 2020;40:66-81
 2019 IUIS IEI
I. Immunodeficiency affecting cellular and humoral immunity
II. CID with associated or syndromic features
III. Predominantly antibody deficiency
IV. Diseases of Immune dysregulations
V. Congenital defects of phagocytes number, function or both
VI. Defects in intrinsic and innate immunity
VII. Autoinflammatory disorders
VIII.Complement deficiency
IX. Bone marrow failure
X. Phenocopies of PID
Distribution
 When should you be concerned?

• C hronic
• R ecurrent
• U sual pathogens
• I nvasive
• S evere
• E valuate!
10 Warning Signs of PID
• 8+ AOM in 1 year
• 2+ sinus infections in 1 year
• 2+ months on antibiotic with little effect
• 2+ pneumonias in 1 year
• FFT, chronic diarrhea
• Recurrent, deep skin or organ abscesses
• Persistent thrush after age 1
• Need for IV antibiotic to clear infections
• 2+ deep seated infections
• Positive family history

Jeffrey Modell Foundation

PID may be part of adulthood
Approach to cases of possible IEI
 History
• Recurrent/persistent infections of unusual severity
• Infections affecting multiple sites
• Infections that rapidly progress with fulminant, life-threatening
clinical course
• Frequent use of antibiotics and suboptimal treatment response
• Infections caused by opportunistic organisms
• Failure to thrive
• Parental consanguinity
• Family history of recurrent infections or early infant deaths
Lee PPW, Lau YL. Asian Pac J Allergy Immunol. 2013;31:217-26.
 Other history that may or may not sign of IEI
• Aplasia or hypoplasia of thymus (X-ray)
Angioedema
Auto-immune disease (especially auto-immune
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
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
 Physical Examination
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 Gingivostomatitis (severe). Periodontitis. Aphthae (recurrent). Giant oral
ulcers. Thrush. Dental crowding. Conical incisors. Enamel hypoplasia. Persistent
deciduous teeth
Eyes 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

deVries with ESID. Clin Experimental Immunol 2011; 167: 108-19

Recognition of common patterns of Infection in IEI
• Recurrent sinopulmonary infections
• Chronic diarrhea
• Recurrent cutaneous or soft tissue abscess/fistula
• Chronic mucocutaneous candidiasis
• Severe or long-lasting warats, generalized molluscum contagiosum
• Invasive infections e.g meningitis, osteomyelitis, deep organ abscess,
bacteremia
• Opportunistic pathogens eg PJP, Cryptosporodium sp, non tuberculous
mycobacteria, disseminated varicella, recurrent herpes zoster
• Systemic fungal infection eg. Candidemia, invasive aspergillosis
• Complication of live vaccines eg. BCG, oral polio, rotavirus, varicella

Lee PPW, Lau YL. Asian Pac J Allergy Immunol. 2013;31:217-26.

 Beware of:
Acquired Immunodeficiency
• HIV
• Drug induced: eg chemotherapy, immunosuppression in
transplant patients, etc
• Infection induced immunodeficiency: eg severe sepsis, viral
suppression of the immune system
• Others: eg protein losing enteropathy

DON’T FORGET ABOUT THEM in your differential

Diagnostic procedure (Jakarta adaptation)

Genetic

Quantitative Ig
(A,E,G,M)
Baseline blood test: Lymphocyte subtype
CBC with leucocyte (B, T, NK)
differential, Complement
Chemistry:
electrolytes, lipid,
fibrinogen, ferritin,
CRP We miss: Ig titers of Tetanus, Diphteria, Pneumococcal; Qualitative study
eg. burst assay
Antibody Deficiency
 Normal Immunoglobulin Levels for Age

•Adult levels of IgG are reached during the 3rd trimester

•Premature infants < 28 wks GA have low IgG
•Healthy neonates have low/absent IgM and IgA
 Ig Level Reference (g/l)

Adapted from: Vademecum diagnostisch onderzoek Sanquin, 2008, pp 90. Clinical chemistry
1982, 28:127. European Journal of Clinical Chemistry and Clinical Biochemistry 1996; 34-517.
Infection in Ab-deficiencies
 Humoral Immunodeficiency
Abnormalities include:
• Abnormal B cell maturation resulting in low B cell
numbers, eg Bruton agammaglobulinemia
• A defect in the Ab making ability of B cells,
e.g. AR hyper IgM syndrome
• A defect in the ability of B cells to respond to antigen (Ag)
resulting in abnormal Ab production, eg X-linked hyper
IgM syndrome
Hyper IgM Syndromes

Defects in Ab production
and
Response to Ag
 Hyper IgM Syndrom:
Defects in Ab production
• Disorders with abnormal class switching from IgM to other isotypes
• Eg AR hyper IgM syndrome, a defect of the AID enzyme expressed
only in B cells and required for class switching and somatic
hypermutation
• Normal to high serum IgM with low IgG and IgA
• Disrupted B cell maturation results in massive enlargement of
lymph node germinal centers, including intestinal lymphoid
hyperplasia
• Risk for autoimmune hematologic diseases
 Hyper IgM Syndrome:
Defects in B cell response to Ag
• Due to abnormal second signal molecules required by B cells for
production of Ab
• (Defect of CD40 ligand on T cells in X-linked hyper IgM syndrome,
or CD40 on B cells in AR hyper IgM syndrome)
• Normal to elevated IgM, low IgG, IgA
• Lymphoid hyperplasia
• Also at risk for opportunistic infections
including PJP, CMV, cryptosporidium
• Increased risk of malignancies
• BMT is indicated for cure
 IgA Deficiency
• The most common form of PID
• 1/600 in Europeans and N. Americans
• Increased susceptibility to sinopulmonary infections, though most are
asymptomatic
• Associated with GI diseases (celiac, giardia), atopy, autoimmune disease
• Can also have selective IgG subclass deficiency
• Specific Ab production is usually normal
• Definition: IgA < 0.7 g/L in a patient > 4 yo
Normal IgG and IgM

May develop anaphylaxis if given IVIG!!

 Hyper IgE Syndrome

• Very high IgE serum level

• Eosinophilia
• Allergy testing usually negative
• Chemotactic defect (secondary, inconsistent) • Immature B cells
• Abnormal antibody responses
• Abnormal cytokine production
• Lack of Th17 cells, low IL-17
 Hyper IgE Syndrome (Job syndrome)

• Chronic eczematous rash

• Recurrent skin and sinopulmonary infections
• S. aureus infections
• Mucocutaneous candidiasis
• Skeletal and dental abnormalities
• Pathologic fractures, shark teeth
• Asymmetric facies
• Lung cysts
• IgE usually >2000
• AD inheritance with incomplete penetrance
• STAT3 mutation
• Abnormal neutrophil chemotaxis
 Wiskott Aldrich Syndrome
• X-linked recessive disorder
• Thrombocytopenia/small platelets
• Eczema; Elevated IgE
• Recurrent infections
• Abnormal B and T cell functions
• Autoimmune diseases
• Malignancies
 Selective Antibody Deficiency
• Normal Ig’s but abnormal response to Ag
• Usually defect in response to polysaccharide Ag, eg
pneumococcus
• Poor response to pneumovax®, though may have an adequate
response to Prevenar®, the conjugated pneumococcal
vaccination
• Up to 25% of PID diagnoses!
 Other Humoral Immune Deficiencies

Transient hypogammaglobulinemia of infancy

– ‘delayed’ maturation of the immune system
– Rarely have difficulty with infections
– Usually resolves by 3-5 yo
– Rarely requires therapy
– Do need to treat fevers, bacterial infections more
aggressively
 Management of Humoral Deficiencies

• Prophylactic IVIG is the mainstay of therapy (400-500 mg/kg q3-4wks)

• Only indicated for patients with significant difficulties with
recurrent infections; continue therapy only if there is
improvement!
• SC Ig commonly used in Europe
• Weekly SC infusions of Ig
• Can be done at home
• Gives more steady state levels of IgG
 Management of Humoral Deficiencies

• Prophylactic Antibiotics
• Aggressive antibiotics therapy for infections
• Monitoring for long term complications:
• High index of suspicion for malignancy
• Monitoring for chronic lung disease – YEARLY PFTs
• Watch for autoimmune complications: CBCD, liver enzymes, screening for SLE,
thyroid disease
Cellular Immune Deficiencies
 Cellular Immune Deficiencies
• Very few abnormalities ONLY affect the cellular system, most
are combined (T, B and other)
• Defects of the interferon-g and IL-12 axis
• Both required for the TH1 pathway, which activates cytotoxic T
and NK cells
• Susceptible to intracellular organisms: atypical mycobacteria,
salmonella
• Includes chronic mucocutaneous candidiasis
 Chronic Mucocutaneous Candidiasis

• Persistent or recurrent infections of the skin, nails, mucous

membranes by Candida
• Rarely develop Candida sepsis or organ infection
• 7 defined subgroups
• Responds to antifungals but recurs once therapy stopped
 Combined Immune Deficiencies
• The most profound immune defects
• Recurrent bacterial, viral and fungal infections
• Opportunistic infections, eg PJP
• Diarrhea, FTT
• Autoimmune/atopic phenomena
• Risk of maternal engraftment and associated GVHD
• Usually present in the first few months of life
• SCID: documented abnormal of humoral and cellular immune system
coupled with life-threatening complications
• The earlier the diagnosis the better!!!
 Combined Immune Deficiencies
X-linked SCID
• The most common type is X-linked SCID due to a
defect of the common g chain receptor (44% of
SCID)
• Protein required for the cytokine receptors of IL-2,
IL-4, IL-7, IL-9, IL-21
• Results in arrest of T and NK cell development and
a B cell maturation defect
• Lymphoid hypoplasia and recurrent infections
• Risk for autoimmune complications
• BMT is required for cure, the earlier the better!!
 SCID
Adenosine Deaminase Deficiency
• The most common type of SCID
with AR inheritance (16%)
• Defective enzyme in the purine
salvage pathway results in
progressive lymphopenia due to
metabolic poisoning of the cells
• Skeletal abnormalities in 50%
• PEG-ADA can partially correct
• BMT is the only cure
• Similar phenotype in PNP
deficiency
Phagocytic Disorders
 Innate Immunity
Phagocytic Disorders
The first line of defense
• Present mainly with bacterial infections +/- fungal infections
• Sepsis, Fever without source
• Aphthous ulcers/gingivostomatitis
• Perineal abscesses
• Skin infections
• Sinopulmonary infections
Phagocyte Disorders:
Abnormal Function
 Chronic Granulomatous Disease
• Defective neutrophil oxidation
• Susceptible to catalase + bacteria
• Soft tissue infections, adenitis, liver abscesses, osteomyelitis,
pneumonia, sepsis,
• Aspergillus infections
• granulomas
• Colitis in 17%
• Most X-linked, also AR types
• Diagnosed with NBT/DHR/oxidative burst
• Confirm with protein flow cytometry and genetic sequencing
 Leukocyte Adhesion Deficiency
• Delayed umbilical cord separation
• Persistent leukocytosis
• Reduced pus formation
• Impaired wound healing
• Recurrent life-threatening bacterial and sometimes viral
infections
• Two types
I – defect of integrins CD11, CD18
II – defect of sialyl Lewis X, component of L-selectin
 Phagocytic Disorders
Lab Evaluation
First line: CBC, differential and smear

Second line:
• Cyclic neutropenia workup if indicated
• NBT/dihydrorhodamine/oxidative burst to rule out CGD
• LAD workup if indicated (CD11/CD18 expression)
• Neutrophil function and chemotaxis assays if indicated and
available
 Phagocytic Disorders
Management
• Infection prevention
• Avoid hay, dirt, aspergillus spores for CGD
• Prophylactic antibiotics if indicated
• Cotrimoxazole for S. aureus in CGD, hyper IgE
• Fungal prophylaxis for CGD, usually itraconazole
• Aggressive treatment of infections
• G-CSF if indicated/effective
• Monitoring for complications
• Eg malignancy in Kostmann (severe congenital neutropenia)
• Disease specific treatments
• Eg IFN-G for CGD
 Take Home Message
• The key to detect a PID is to consider the possibility.
• PIDs almost always present with one or more of eight clinical presentations;
these can be used as the starting-point to enter the appropriate diagnostic
protocol.
• SCID is an emergency.
• Timely recognition of antibody deficiency prevents future organ damage.
• 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.
Thank You