1 When to think about primary immunodeficiency
1.1 Primary immunodeficiency deficiency
- Incidence PID 1:500 – 1:5000.000 > depends on disease
- >330 genetic mutations
- Signs and symptoms: asymptomatic > live threatening
o Immunodeficiency
o Auto-immune disease
o Predisposition to malignancy
European society for immunodeficiencies (ESID) registry; biggest part is
antibody disorders (also T-cell, phagocyte disorders, complement
deficiencies, auto-immune and immune dysregulation syndromes, auto-
inflammatory syndromes, other well defined and unclassified PIDS)
- Pathophysiology: infection susceptibility, clinical features of PID < absence or altered
function of one of more gene products.
- Clinical manifestation: infections, autoimmunity, malignancy, other (e.g. dysmorphic
features, skeletal manifestation, skin/mucosal manifestation, bleeding tendency, delayed
shedding primary teeth, hypersensitivity to sunlight, delayed separation of umbilical cord,
poor wound healing)
PID categories
- Humoral
o Agamma – or hypogammaglobulinemia: not enough gamma globulins are produced
in the blood > lower ab count, impairs the immune system, increased risk of infection
o IgA and/or IgG-subclass deficiency
IgA def: undetectable serum IgA level in the presence of normal serum levels
of IgG/IgM (<4 yo) (type of hypogamma)
IgG def: form of dysgammaglobulinemia, levels of the IgG isotype are
reduced relative to other immunoglobulin isotypes
o Specific antibody synthesis problem
- Humoral + cellular (20-30%):
o Severe combined immunodeficiency (SCID): disturbed development of functional T
cells and B cells caused by numerous genetic mutations > defective ab response due
to direct involvement with B lymphocytes or through improper B lymphocyte
activation due to non-functional T-helper cells.
o Combined immunedeficiency (CID): distinguished from SCID by low but not absent T-
cell function.
o Hyper-IgM: defective CD40 signaling > elevated IgM, deficient IgG-A-E
- Phagocytes (20%)
o Neutropenia
o Chronic granulomatous disease (CGD): NADPH oxidase defect which phagocytes
need to kill certain bacteria and funghi
o Hyper-IgE (Th17): elevated serum IgE, rash and recurrent bacterial infections of the
skin and lung; 2 forms; a dominant form mutations in STAT3, recessive form genetic
cause is unclear
- Complement/MBL
o Deficiency
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,Characteristics of infection
- solitary episode vs recurrent infections
- Primary pathogen vs opportunistic (e.g. pneumocystis jeroveci, CMV, candida spp.,
aspergillus spp., mycobacteria spp., nocardia spp. M. tuberculosis, S. Pneumoniae, H.
influenzae, S. aureus)
- Normal presentation & course vs atypical presentation & unusual course
Localisation of infection
- Respiratory tract 91% - Urinary tract 5%
- Gut 21% - Bone 5%
- Central nervous system 13% - Other 8%
Immunological work-up / warning signs
The key to detect a PID is to consider the possibility.
1. >8 URT infections/year 7. 2 or more deep-seated infections
2. >2 severe sinusitis/year including septicaemia
3. >2 pneumonia/year 8. Failure to gain weight or grow
4. >2 month on AB with little help normally
5. Recurrent skin- and/or organ 9. Need for IV to clear infection
abscesses 10. Family history positive for
6. Therapy resistant trust or candida immunodeficiency
infections 11. Opportunistic infections
Physical examination
- Skin and appendages
o Abnormal hair/teeth o Vitiligo
o Eczema o Petechia
o Neonatal erythroderma o Cold abscesses
o (Partial) albinism o Telangiectasia (=blijvende
o Extensive warts or mollusca verwijde capillairen)
(=waterwratjes) o Absence of sweating
o Congenital alopecia o Nail dystrophy
- Oral cavity
o Gingivostomatitis (Severe, o Giant oral ulcers (=lesions in
=ontsteking your mouth)
mond/tandvleesvlies) o Thrush (=yeast infection)
o Periodontitis (= gumdisease) o Dental crowding
o Aphthae o Conical incisors
- Eyes
o Retinal lesions, telangiectasia
- Lymphoid tissue
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, o Absence of lymph nodes and o Asplenia
tonsils lymphadenopathy o Organomegaly
(massive)
- Neurological
o Ataxia (=poor muscle control) o Dysmorphism
o Micro-, macrocephaly o Stunted growth or
- Other disproportional growth
1.2 Diagnostic approach
Clinical presentations
1. Recurrent ENT (=KNO) and airway infections
2. Failure to thrive from early infancy
3. Recurrent pyogenic infections
4. Unusual infections or unusually severe course of infections
5. Recurrent infections with same pathogen
6. Autoimmune or chronic inflammatory disease and/or lymphoproliferation
7. Characteristic combinations of clinical features in eponymous syndromes
8. Angioedema (=swelling underneath the skin)
PID almost always present with one or more of these 8 clinical presentations
Relation with causative pathogen
Opsonisation defects Pathogens
IgA-deficiency, IgG-subclass deficiency or defect H. influenzae, S. pneumonia
in specific Ab-production
Agammaglobulinemie H. Influenzae, S. pneumoniae, M. pneumoniae,
U. urealyticum
Deficiency C2, C3, C4, Mannose-binding lectin H. influenzae, S. pneumoniae, Meningococcen
(MBL, loe levels MBL in blood)
Phagocyte dysfunction, hyper-IgE-syndrome S. aureus, gram (-) rods, candida spp (deep
seated infections), A. fumigatus
T-lymphocyte dysfunction Mycobacterium spp, viruses, candida spp
(superficial infections), pneumocystis jiroveci
Hyper-IgM-syndrome Pneumocystis juroveci
- Opsonisation defect: Recurrent infections of the RT and the ear-nose-throat
- T-cell disfunctions: Unusual or opportunistic infections and general malaise, loss of weight
and failure to thrive
- Phagocyte dysfunction: Severe recurrent infections of the skin, oral cavity and mucosa and
the internal organs (longs and liver) and the skeleton.
Pattern recognition is the key to identification!
Immunodeficiencies
- Primary immunodeficiency: inborn error, abnormal immune system, low prevalence
- Secondary immunodeficiency: acquired, abnormalities not within the immune system itself,
high prevalence
Cells Primary ID Secondary ID
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, B-cells XLA, CVID Loss of protein by gut or
kidney
T-cells DiGeorge syndrome HIV Viruses: CMV, herpes
Fungi: Aspergillus species,
Candida albicans
Bacteria: mycobacteria
Parasites: Pneumocystis
jiroveci
B-&T-cells SCID Drugs or malignancies
Phagocytes Chronic granulomatous disease Drugs Bacteria: Stafylococci,
Gram-negative bacteria
Fungi: Aspergillus species,
Candida albicans
Complement C2-degivirny Auto-immune disorders Meningococcal spp.,
Pyogenic bacteria
Antibody deficiencies: Pyogenic bacteria, some viruses
Immunological work-up depends on the causative agents and additional symptoms.
Diagnostics
- Cell differential in peripheral blood
- Lymphocyte subpopulations (T,B,NK), functional tests
- Immunoglobulins
- Phagocytic functional assays
- Complement activation assays
- Genetics
1.2.1 IL-12R1 Deficiency
- Homozygous defect
- Curable infections (usually)
- Most common cause of Mendelian susceptibility to mycobacterial diseases (MSMD)
worldwide
o Il-12/23 subunit p40 (IL12B)
o IL-12/23 receptor beta1 (IL12RB1)
o Interferon-gamma receptor 1 (IFNGR1)
o Interferon-gamma receptor 2 (IFNGR2)
o Signal transducer and activator of transcription (STAT) 1
2 A glance into the daily practice
2.1 X-linked dyskeratosis congenita
- Incidence: 1:1million, young males (<10 yo)
- Symptoms: abnormal skin pigmentation, nail dystrophy, leucoplakia of the oral mucosa,
abnormalities of the eyes, teeth, hair and gut
- Increased risk of malignancies, lung- and liver diseases, bone marrow failure
- Main cause of early mortality > progressive bone barrow failure
- Pathophysiology: 50% mutations (14 genes) > missense mutation DKC1 Xq28 > X-linked
recessive form
o Codes for telomeric maintenance protein (dyskerin)
o Premature telomere shortening and subsequent replicative senescence
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