Primary immunodeficiencies

Asist.univ.dr.Alexis Cochino

Immune system
Non specific
Monocytes-macrophages
Phagocytosis

NK cells Complement system (C1-C9):

membranes lysis antigen-antibody complex binding mediators of inflammation, phagocyte recruitment

Immune system
Specific
Lymphocytes:
B (BL)plasmocytes: antibody production T (TL)
Helper (hTL), CD4+: BL-TL +ve cooperation Cytotoxic (cTL), CD8+: killing tumoral or viral infected cells Supressor (sTL), CD8+: BL-TL -ve cooperation Regulator (Tregs), CD4CD25Foxp3+

Antibodies (Ig)
D, M, G, A, E

Immunodeficiencies
Primary Secondary
HIV/AIDS Malnutrition
Protein/caloric Zinc Vit. A, D, B12

Leukemia, lymphoma
Iatrogenic (CST, chemo)

Classification of Immunodeficiency
1. Antibody deficiencies (B-cell) quantitative or qualitative defects in antibody production account for more than 50% of defects. Cellular (T-cell) usually combined with Ab def.; account for 20-30%. Phagocytic defects in number, migration, or killing; account for ~18%. Complement account for ~2%

2. 3. 4.

Recurrent Infections Vs. Frequent Infections

Immuno-competent kids may have:
up to six URIs/year ten URIs/year if they attend daycare. Illness duration: 7-10 days + 1-3 weeks of residual cough

Key-questions: How often? What kind of cold How long do they last?

Common errors: Limited history taking Default antibiotic prescription

Recurrent Infections Vs. Frequent Infections

Common Risk Factors for Frequent Infections
Day-care, school-aged siblings Second-hand smoke Atopy Anatomic abnormalities including ciliary defects Retained foreign body Gastroesophageal reflux

Recurrent Infections Vs. Frequent Infections

Frequent or recurrent sinopulmonary infections, malabsorption, nasal polyps Cystic Fibrosis
1:2500 More common than most of the immunodeficiencies

10 signs of PID*
1. 8 ear infections/year 2. 8 serious sinus infections/year 3. 2 months of AB treatment/year with little effect 4. 2 pneumonias/year 5. Unsatisfactory growth curve 6. Recurrent, deep skin or organ abscesses. 7. Persistent thrush in mouth or elsewhere on skin, after age 1. 8. Need for intravenous antibiotics to clear infections 9. Two or more deep-seated infections (sepsis, meningitis or cellulitis) 10.A family history of primary immune deficiency

*The Jeffrey Modell Foundation and the American Red Cross

Characteristics
Humoral defects Onset Infections 5-6 m.o. Respiratory tract Digestive Phagocytic defects Any age Respiratory tract Skin Deep tissues (incl. bones) Etiology Bacteria Enteroviruses Bacteria Fungi SCID 0-1 y.o. Respiratory tract Digestive Sepsis GVHD Bacteria Viruses Mycobact. Oportunistic (CMV, Candida, P.carinii) Lymphoid tissue Normal/absent Normal Absent

*Espanol T, Hernandez M, Giner MT, Casas C, Gurbindo D, Marco T, Larramona H, Garcia JM. Directorio de pruebas diagnsticas de las inmunodeficiencias primarias. Allergologia et immunopathologia. Domingo 1 Mayo 2005. Volumen 33 - Nmero 03 p. 157 - 161

Characteristics of Complement Defects

Late (C5-C9) Neisserial infections: meningitidis, septic arthritis from gonorrhoeae. Early (C1, C4, and C2) autoimmune disease C3 deficiency overwhelming sepsis, especially with gram negative organisms

Physical Exam
physical exam may be normal! Look for:
General appearance, weight, overall health Hair, connective tissue Dysmorphic features Gingivitis, dental erosions, signs of sinusitis Tonsillar tissue, adenopathy, splenomegaly Arthritis, ataxia, neuro deficits

 Eczema and petechiae WAS (Wiskott Aldrich syndrome)

Telangiectasia ATS (Ataxia telangiectasia)

 Oculocutaneous albinism Chediak Higashi Chronic dermatitis HIS (hyper IgE syndrome)

Generalized molluscum, extensive warts, candidiasis T cell defects

Lab tests (1)

Global immunologic screening in all children with recurrent infections: not feasible Starting point: HISTORY + CLINIC EXAM Progressive approach (first things first)
Total WBC, ANC, ALC, AEC (age-appropriate values)
Lymphopenia = < 3,000 in infants, < 1500 in children and adults Persistently high ANC occurs in LAD Hemolytic anemia, thrombocytopenia, leukopenia (B-Cell deficiencies)

Quantification of serum immunoglobulins (Ig main classes)

Lab tests (2)

Lymphocytes phenotyping (flow cytometry) Qualitative Evaluation of Antibodies
Isohaemagglutinins Antibodies to ABO blood-group determinants Antibodies to tetanus and diptheria glycoproteins and pneumococcal polysaccharides.
If low titers, give booster, then repeat titers 4 weeks later. Children younger than 2 can not be tested for polysaccharide antigen antibody (Pneumo, HiB)

Cytokines, cytokines receptors Granulocytes

Adhesion antigens by flow cytometry (CD11/CD18) checks for adhesion defects Chemiluminescence phagocytic killing power

Lab tests (3)

T-Cell Immunity
Delayed-hypersensitivity skin tests
Intradermal injection of antigens: Candida, tetanus, trichophyton. Should produce redness and induration of > 5mm by 4872 hours. Severe illness or steroids can cause diminished responses (anergy)

Mitogen testing
In vitro proliferative responses to concanavalin A, phytohemagglutinin, pokeweed mitogen

Lab tests (4)

Complement function
Total hemolytic complement (CH100/AP100) tests functional integrity of classic complement pathway The most common reason for an abnormal complement assay is improper handling of specimen. MBL deficiency the most freq. but uncertain clinical importance

General Management
Strict hygiene
Prompt recognition of infection and aggressive treatment

Avoidance of crowded spaces and ill persons

Obtain cultures, and initiate early empiric therapy for suspected pathogens

General Management
Prophylactic antibiotics for patients with significant T (cotrimoxazole) or B-cell defects (cotrimoxazole/ azithromycin) Only irradiated, leukocyte reduced, virus-free (CMV) blood products should be given
HIV HVB HVC CMV

Monitor growth and weight gain Live vaccines should not be given to children with T-cell defects

Treatment for Primary Immune Deficiencies

Bone marrow transplantation Immunoglobulin replacement Enzyme replacement Gene therapy

Bone marrow/stem cells transplant

Complete and permanent cure Possible in SCID, WAS, CGD, LAD, HIES, DOCK8, Problems:
Only possible in some PID Compatibility/donor issues Age (the smaller, the better) Infection-free at the moment of BMT GvHD Functional thymus needed

Immunoglobulines replacement therapy

periodic (each 3-4 weeks for i.v./once weekly for s.c.), based on the half-life of the main Ig (IgG) efficiency also depends on the donors immune experience Evaluation criteria:
trough levels Lack of serious infections

Good results in B cell defects, associated or not with antibiotic prophylaxis

Enzyme replacement
in unique enzyme deficiency (ADA, PNP) SCID without a compatible donor periodic infusion of the missing enzyme, linked to a high molecular weight molecule (PEG), in order to increase the half-life in the present only feasible in SCID by ADA deficiency

Citokyne substitution treatment

in CGD (chronic granulomatous disease), with gamma-IFN in neutropenia: GM-SCF, G-CSF problems:
Expensive Associated pathology (lymphohistiocytosis for IFN, leukemia for GM/G-CSF)

 Hx of same kind of problems in maternal uncles, nephews, cousins Well for first 6-9 months Recurrent infections with pneumococcus, H.influenzae, Giardia. Minimal tonsillar tissue, and no palpable lymph nodes. <2SD below normal levels of IgG, IgA, IgM, IgE Low CD19 Defect in Btk gene (Bruton tyrosine kinase)

X-linked Agammaglobulinemia (Bruton disease)

Hx of same kind of problems in maternal uncles, nephews, cousins Well for first 6-9 months Recurrent infections with pneumococcus, H.influenzae, Giardia. Minimal tonsillar tissue, and no palpable lymph nodes. <2SD below normal levels of IgG, IgA, IgM, IgE Low CD19 Defect in Btk gene (Bruton tyrosine kinase)

 Recurrent sinopulmonary infections with usual pathogens. Age of onset 15-35 years. Equal male:female. Low IgG and poor antibody responses to immunizations. Variable levels of IgM and IgA. Increased risk for autoimmune diseases and malignancy. B-Cells phenotypically normal.

 Recurrent sinopulmonary infections with usual pathogens. Age of onset 15-35 years. Equal male:female. Low IgG and poor antibody responses to immunizations. Variable levels of IgM and IgA. Increased risk for autoimmune diseases and malignancy. B-Cells phenotypically normal.

Common Variable Immunodeficiency

 Recurrent sinopulmonary disease. Telangiectasias between 3-6 years. Progressive ataxia soon after learning to walk, in wheelchair by 10-12 years. Often low or absent IgA. Variable depressions of other immunoglobulins. Anergy and depressed mitogen studies. Risk for lymphoreticular malignancy.

Ataxia-Telangiectasia
Recurrent sinopulmonary disease. Telangiectasias between 3-6 years. Progressive ataxia soon after learning to walk, in wheelchair by 10-12 years. Often low or absent IgA. Variable depressions of other immunoglobulins. Anergy and depressed mitogen studies. Risk for lymphoreticular malignancy.

 1:400 to 1:800 Symptoms: GI, GU, RTI infections. Many asymptomatic patients. Normal IgG and IgM response to pathogens and vaccines. Role in diagnosis of Celiac disease. May evolve into CVID.

IgA Deficiency
1:400 to 1:800 Symptoms: GI, GU, RTI infections. Many asymptomatic patients. Normal IgG and IgM response to pathogens and vaccines. Role in diagnosis of Celiac disease. May evolve into CVID.

 Decreased IgG beyond 6 months. Normal IgA, and variable IgM. Able to synthesize antibodies to blood type, diphteria, and tetanus antigens normally. May have increase otitis and sinusitis. Usually resolves by 4 years of age.

Transient Hypogammaglobulinemia of Infancy

Decreased IgG beyond 6 months. Normal IgA, and variable IgM. Able to synthesize antibodies to blood type, diptheria, and tetanus antigens normally. May have increase otitis and sinusitis. Usually resolves by 4 years of age.

 Recurrent infections by three months. Can be life-threatening. Candida, PCP, cryptosporidiosis, HSV, RSV, rotavirus, adeno, entero, EBV, CMV, HHV6. Absence of lyphoid tissue, lymphopenia, no thymic shadow. Anergy, abnormal T-Cell proliferation, +/- Bcell dysfunction. Absence of adaptive immunity.

 Recurrent infections by three months. Can be life-threatening. Candida, PCP, cryptosporidiosis, HSV, RSV, rotavirus, adeno, entero, EBV, CMV, HHV6. Absence of lyphoid tissue, lymphopenia, no thymic shadow. Anergy, abnormal T-Cell proliferation, +/- Bcell dysfunction. Absence of adaptive immunity.

Severe Combined Immunodeficiency

 1:10 million Striking neutrophilia. Recurrent bacterial and fungal infections without pus. Severe gingivitis, periodontitis, alveolar bone loss. Decreased or absent CD18/CD11 by flow. Delayed separation of umbilical cord.

Leukocyte Adhesion Defect

1:10 million Striking neutrophilia. Recurrent bacterial and fungal infections without pus. Severe gingivitis, periodontitis, alveolar bone loss. Decreased or absent CD18/CD11 by flow. Delayed separation of umbilical cord.

Unsure of clinical relevance. May be evolving form of CVID. May be normal variation. Does not need treatment or evaluation unless there is an impaired ability to form antibodies to protein and polysaccharide antigens.

Selective IgG Subclass Deficiencies

Unsure of clinical relevance. May be evolving form of CVID. May be normal variation. Does not need treatment or evaluation unless there is an impaired ability to form antibodies to protein and polysaccharide antigens.

Variable hypoplasia of thymus and parathyroid. Hypocalcemia seizures Susceptibility to fungi, viruses, PCP. T-Cells variable in number, abnormal mitogen studies Normal to increased B-Cells, normal antibody levels. Micro deletion of 22q11.2 Associated heart defects, facial anomalies, esophageal atresia.

DiGeorge Anomaly
Variable hypoplasia of thymus and parathyroid. Hypocalcemia seizures Susceptibility to fungi, viruses, PCP. T-Cells variable in number, abnormal mitogen studies Normal to increased B-Cells, normal antibody levels. Micro deletion of 22q11.2 Associated heart defects, facial anomalies, esophageal atresia.

 Initially asymptomatic. Defective response to EBV. Fulminant often fatal lymphomas, acquired hypogammalobulinemia. 70% of boys die by 10. Impairment of antibody to EBNA Viral capsid antigen antibody titers may be absent to exaggerated.

X-linked Lymphoproliferative Syndrome

Initially asymptomatic. Defective response to EBV. Fulminant often fatal lymphomas, acquired hypogammalobulinemia. 70% of boys die by 10. Impairment of antibody to EBNA Viral capsid antigen antibody titers may be absent to exaggerated.

 Recurrent abscesses, lymphadenitis, or osteomyelitis at multiple sites. Unusual infections with catalase positive organisms: Staph, Serratia, Aspergillus, Candida, Salmonella, gram enteric rods. Defect in NADPH oxidase enzyme leading to the inability to produce H2O2. No problem with streptococci. NBT test Chemiluminescence (DHR test)

Chronic Granulomatous Disease

Recurrent abscesses, lymphadenitis, or osteomyelitis at multiple sites. Unusual infections with catalase positive organisms: Staph, Serratia, Aspergillus, Candida, Salmonella, gram - enterics. Defect in NADPH oxidase enzyme leading to the inability to produce H2O2. No problem with streptococci. NBT test Chemiluminescence (DHR test)

 Regular, periodic oscillation in the number of peripheral neutrophils. Neutropenia every 21+/- 3 days. May develop fever, stomatitis, pharyngitis, pneumonia, occasionally sepsis and death. May spontaneously abate. Cycles become less noticeable with age.

Cyclic Neutropenia
Regular, periodic oscillation in the number of peripheral neutrophils. Neutropenia every 21+/- 3 days. May develop fever, stomatitis, pharyngitis, pneumonia, occasionally sepsis and death. May spontaneously abate. Cycles become less noticeable with age.

 Chronic pruritic dermatitis. Recurrent staph infections of skin, lungs, joints, and dental infections. Lung cavities colonized with Aspergillus, Pseudomonas Course facial features. Markedly elevated IgE and eosinophilia.

Hyper-IgE Syndrome
Chronic pruritic dermatitis. Recurrent staph infections of skin, lungs, joints, and dental infections. Lung cavities colonized with Aspergillus, Pseudomonas Course facial features. Markedly elevated IgE and eosinophilia.

 Atopic dermatitis Microcytic thrombocytopenia bleeding Recurrent infections with encapsulated bacteria (Strep pneum esp.) but also viruses, fungi Variable antibody levels. Often low IgM, high IgA and IgE. Poor antibody function. Low to low-normal T-Cells. boys.

Wiskott-Aldrich Syndrome
Atopic dermatitis Microcytic thrombocytopenia bleeding Recurrent infections with encapsulated bacteria (Strep pneum esp.) but also viruses, fungi Variable antibody levels. Often low IgM, high IgA and IgE. Poor antibody function. Low to low-normal T-Cells. boys.

 Partial oculocutaneous albinism. Frequent infections of skin, mucous membranes, respiratory tract. Gram -, Gram +, and fungi. Large inclusions in all nucleated blood cells. Accelerated lymphoma-like syndrome; nonneoplastic infiltration of liver, spleen, and lymph nodes associated with recurrent infections and death.

Chediak-Higashi Syndrome
Partial oculocutaneous albinism. Frequent infections of skin, mucous membranes, respiratory tract. Gram -, Gram +, and fungi. Large inclusions in all nucleated blood cells. Accelerated lymphoma-like syndrome; nonneoplastic infiltration of liver, spleen, and lymph nodes associated with recurrent infections and death.