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When to Consider, and How to Structure an Immunodeficiency Work-up

Craig Moffat, M.D., FACP September 29, 2006

Objectives:

· To understand:

­ When should I consider immunodeficiency in a patient? ­ What are the most common primary immunodeficiency syndromes in adults ­ their clinical presentation, pathogenesis and laboratory findings? ­ What are the appropriate screening tests in evaluating primary immunodeficiency and how do I interpret them? ­ What treatments are available for common primary immunodeficiency disorders?

· Assumptions:

­ Will focus primarily on primary immunodeficiency disorders seen in adults ­ Will not address secondary immunodeficiencies

Case Report

38 year old Caucasian male

· · 1983-86: 4 episodes lobar pneumonia involving different sites, one culture positive for S. pneumoniae; 3 episodes radiographic sinusitis 1986: Lobar pneumonia complicated by empyema Rx'd chest tube, Rifampin, Ancef ­ Lab: · CBC with diff normal except PC 10,000 which normalized when antibiotics changed · IgG 382 mg/dl (>700 normal), IgA < 1, IgM 85 (>44 normal) · Anti-pneumoccocal, hemophilus antibodies negative; no response to vaccination · CD 4, CD 8 , CD 19 normal · (-) anti-platelet antibodies ­ IVIG q 3 weeks from 1983 to 2001, trough level 800's mg/dL 1990: thrombocytopenia, splenomegaly, (+) platelet antibodies Rx'd steroids; later RML pneumonia leading to RM lobectomy 1993: mixed cell non-Hodgkins lymphoma ­ CHOP chemotherapy failed; subsequently ara-C and cisplatinum with remission 1995-1999: ITP, AHA treated with intermittent corticosteroids; chronic renal failure (Cr 2.05.5 leading to dialysis) 2001: splenectomy 2001: death due to bilateral pneumonia, Legionella sepsis

· · · · ·

Case Report

· Summary:

­ Recurrent sinopulmonary bacterial infections with generalized hypogammaglobulinemia ­ Autoimmune disorder: ITP, AHA ­ Lymphoreticular malignancy, treatment complicated by chronic renal failure ­ Sepsis, death

· Diagnosis:

Common Variable Immune Deficiency

Overview of Normal Immunity

Innate (natural, native)

1. 2. 3. First line of defense; responds to invasion within minutes to hours Phylogenetically primitive Anti-microbial soluble proteins, receptors constitutively "hard-wired" in germline Recognizes pathogenassociated molecular patterns No memory Leads to activation of adaptive immunity

· Adaptive (specific)

4. 5. 6.

Chaplin DD, "Overview of the immune response" in Primer on Allergic and Immunologic Diseases, J All Clin Immun 2003;111 (No.2): S442

Overview of Normal Immunity

Innate Immunity Components:

1. Anatomic Barriers

1. Epithelial and mucosal cell layers 2. Secreted mucus layer in respiratory, GI and GU tracts 3. Epithelial cilia that allows constant refreshment once contaminated

2. Humoral Barriers:

1. Soluble proteins and small molecules constitutively present

1. Complement: bacterial lysis, opsonins, increased vascular permeability 2. Antimicrobial peptides: Cathelicidin, defensins, lysozyme, phospholipase

2. Released upon activation

1. 2. 3. 4. Cytokines ­ regulate the function of other cells (IFN, IL, TNF-) Chemokines ­ attract inflammatory leukocytes Lipid mediators of inflammation Bioactive amines and enzymes

Tosi, MF. Innate Immunity responses to infection JACI 2005; 116: 241

Overview of Normal Immunity

Innate Immunity Components:

3. Cell surface receptors that bind molecular patterns expressed on microbes

1. Toll-like receptors

1. Expressed on broad array of macrophages, dendritic cells, neutrophils, eosinophils, keratinocytes 2. Transmembrane receptors resembling IL-1 receptor 3. Recognize microbial PAMPs: LPS, peptidoglycan, lipoteichoic acid, bacterial flagellin, DNA CpG motifs 4. Primary function is to elicit mediators that program T-helper cells toward a TH1 response

4. Phagocytes

1. PMN, macrophages, monocytes, NK cells, eosinophils 2. Generate interferon, inflammasomes, cationic proteins, defensins, oxidative reactants of oxygen (H2O2, hydroxyl radicals, hypochlorous acid) to destroy organisms

Tosi, MF. Innate Immunity responses to infection JACI 2005; 116: 241

complement

microbes CR Microbe death Toll-like receptors

granulocyte

Partial killing

Innate Immunity

Overview of Normal Immunity

Innate (natural, native)

1. 2. 3. First line of defense; responds to invasion within minutes to hours Phylogenetically primitive Anti-microbial soluble proteins, receptors constituitively "hard-wired" in germline Recognizes pathogenassociated molecular patterns No memory Leads to activation of adaptive immunity

Adaptive (specific)

1. 2. 3. 4. 5. 6. Second line of defense; responds to invasion within hours to days More highly evolved phylogenetically Great specificity, enormously diverse antigen recognition Feedback regulation Sophisticated mechanisms to discriminate between self and non-self Immunologic memory with capacity for rapid clonal expansion

4. 5. 6.

Chaplin DD, "Overview of the immune response" in Primer on Allergic and Immunologic Diseases, J All Clin Immun 2003;111 (No.2): S442

Overview of Normal Immunity

Adaptive Immunity:

1. Exquisite specificity: Able to generate very specific responses to microbial antigens through receptors expressed on surface of T and B (immunoglobulin) lymphocytes 2. Marked diversity: assembles these antigen receptors by rearranging germline-encoded gene elements with capability of forming millions of different receptors (T cells 1 x 1018, B cells 1 x 1015) 3. Produces long-lived cells that persist in a dormant state but rapidly re-express when they encounter their antigen again 4. Greater reactivity upon repeated exposure 5. Components:

1. T cells: CD4 helper, CD8 cytotoxic/suppressor 2. B cells: CD19, CD20

6. Able to differentiate self from non-self by recognition of MHC surface molecules

Adaptive Immunity

Macrophage

Microbes antibody microbe

Thymus

Microbe death

complement

Activated TH -cell TH -cell Bone Marrow Signal Transduction

Memory Clonal Expansion Cytokines IgM

granulocyte

B-cell

IgA IgG

Plasma Cells, Antibody

Macrophage

Immunodeficiency: Classification

Primary

1. 2. Innate Adaptive

1.

1. 2. 3.

Secondary

Infections

HIV EBV Congenital rubella, CMV, Toxoplasma Chemotherapy Neuroleptics Gold Sulfasalazine Chloroquine Malabsorption Malnutrition

1. 2. 3. Protein calorie Zinc deficiency Iron deficiency

5. Chromosomal 1. Trisomy 21 6. Metabolic/endocrine 1. Diabetes mellitus 2. Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked Syndrome (IPEX) 7. Autoimmune 1. Autoimmune lymphoproliferative syndrome (ALPS)

2.

Drugs

1. 2. 3. 4. 5.

3.

Nutritional

1. 2.

4.

Malignancies

1. 2. B cell thymoma

Primary Immunodeficiency

1. Definition: a heterogenous group of primarily single-gene disorders of the immune system leading to impairment of immune responses 2. Inheritance: Inherited as x-linked or autosomal disorders, including dominant and recessive 3. Genetics: Gene defects lead to missing enzymes, developmental arrest in immune differentiation, absent or non-functional proteins, abnormal DNA repair proteins, altered signal transduction molecules, disturbances of intracellular communication

"Immunodeficiencies" in Allergy and Immunology MKSAP, 3rd Edition, 2003, page 289;

Primary Immunodeficiency: Demographics

Incidence and Prevalence:

1. Ranges from 1:300 healthy donors (sIgA deficiency) to 1:100,000 live births (SCID); aggregate 1:10,000 live births 2. Age: 80% of affected persons are <20 years of age at diagnosis; 70% occur among males (5:1 males in children, 1:1 in adults) 3. While over 120 different forms of primary immunodeficiency exists, <20 account for over 90% of cases 4. Prevalence by general category:

1. 2. 3. 4. 5. Humoral (antibody) disorders: 50% Cellular (T-cell) disorders: (10-20%) Combined Humoral and Cellular disorders (10-20%) Phagocytic disorders: (10-20%) Complement disorders (1%)

Applying Public Health Strategies to Primary Immunodeficiency Diseases, MMWR 2004; 53 (No. RR-1): 1-3

When should I suspect immunodeficiency?

· Infections: increased frequency, severity, or unusual pathogen

­ Eight or more episodes of OM/year, especially after early childhood ­ Two or more episodes of consolidative pneumonia in one year; chronic bronchitis without a history of smoking ­ Two or more serious sinus infections in one year ­ Recurrent deep skin or organ abscesses ­ Two or more deep-seated infections such as meningitis, sepsis, osteomyelitis, cellulitis ­ IV antibiotics necessary to clear up infections ­ Antibiotics have little effect even if taken for 2 or more months ­ Persistent oral or skin thrush after age 1 ­ Pneumocystis carinii, Aspergillus infections

Hildebrand et al. J Resp Dis 2001; 22:471; see also Sorensen RU Peds Clin N A 2000;42:1225

When should I suspect immunodeficiency?

· Organ complications from infections:

­ lungs (i.e. bronchiectasis) or sinuses (chronic sinuisitis, mastoiditis, CNS penetration)

· Chronic diarrhea, malabsorption due to recurrent giardiasis, rotavirus, cryptosporidiosis · Chronic GI inflammatory diseases: IBD, gluten enteropathy, atrophic gastritis with pernicious anemia, nodular lymphoid hyperplasia · Autoimmune disorders: autoimmune hemolytic anemia, thrombocytopenia, leukopenia, SLE · Positive family history

Hildebrand et al. J Resp Dis 2001; 22:471

When should I suspect immunodeficiency?

· Other causes for recurrent, severe or opportunistic infections have been carefully evaluated and eliminated:

­ Allergic rhinitis, nasal structural abnormalities (polyps, deviated septum, chronic hyperplastic rhinitis) ­ Adenoidal hypertrophy ­ Cystic fibrosis, ciliary dyskinesia, other lung conditions (COPD, bronochiectasis) ­ Immunosuppressive therapy, malnutrition, infiltrative diseases, malignancies, infectious diseases (HIV/AIDS), protein losing disorders

Hildebrand et al. J Resp Dis 2001; 22:471

General Approach to Immunodeficiency

Practice Parameter for the Dx and Mx of Primary Immunodef Ann All Asth Imm 2005;94:S1

Antibody Deficiency: Clinical Presentation

1. 2. Onset after 6 months of age after loss of maternal antibodies Recurrent or persistent upper and lower respiratory tract infections (OM, sinusitis, bronchitis, pneumonia) due to encapsulated organisms, i.e. S. pneumoniae, H. influenza B, Moraxella sp; less often S. aureus, Neisseria sp, Pseudomonas, Salmonella, Campylobacter, Ureaplasma, Mycoplasma) Organ damage including bronchiectasis, abscess leading to disability or death Most viral infections are controlled, but some may be devastating, i.e. poliomyelitis due to live vaccine, Hepatitis C, enterovirus-induced chronic meningoencephalitis Protozoal infections with Giardia lamblia, Pneumocystis carinii Physical examination: FTT, weight loss, enlargement or absence of lymph nodes, organomegaly, dermatitis, oral candidiasis, short stature, clubbing

3. 4. 5. 6.

Practice Parameter for the Dx and Mx of Primary Immunodef Ann All Asthm Immun 2005; 94:1; "Primary Immunodeficiency Diseases" in Primer on Allergic and Immunologic Diseases, J All Clin Immun 2003; 111: S571

"Immunodeficiencies" in Allergy and Immunology MKSAP, 2003, page 290

Antibody Deficiency: Pathogenesis

"Primary Antibody Deficiencies" in Clinical Immunology: Principles and Practices, 2nd Ed., 2002 pg 34.1 Mosby, London

Antibody Deficiency: Work-up

Practice Parameter for the Dx and Mx of Primary Immunodef Ann All Asth Immun 2005;94:S5

Case Report

12 year old male · 8 months of age: diarrhea for one month, nuchal rigidity. Left facial weakness, left 6th cranial nerve palsy · Negative family history of immunodeficiency · Received childhood immunizations including live polio virus at 2, 4 and 6 months of age · Physical exam:

­ Absent tonsillar tissue, no palpable lymph nodes

·

Lab:

­ CSF fluid: lymphocytic pleocytosis, normal protein and glucose ­ Stool and throat cultures grew vaccine strain poliovirus ­ Immune evaluation:

· · · · · · · · CBC: normal WBC, absolute lymphopenia CH50: mildly elevated NBT: normal QIG: all low; absent isohemagglutinins Antibodies to tetanus, diphtheria very low; pneumococcus antibodies not tested CXR: thymus present; DTH skin tests negative Lymphocyte enumeration: normal T cells, decreased B cells Lymphocyte mitogen response: normal

· · ·

Diagnosis: X-linked agammaglobulinemia Course: presenting neurological symptoms resolved but developed lowerextremity flaccid paralysis Treatment: IVIG

Case Report

26 year old Asian female · History of recurrent OM as a child necessitating PE tubes x 2 at age 2 and 5. · Age 17 onset recurrent "sinus infections" often starting with a typical URI and complicated by prolonged facial pain, discharge, purulent PND lasting weeks ­ 5-6 episodes a year mostly in winter ­ Sinus CT on two occasions abnormal with acute and chronic inflammation without structural abnormalities or polyps ­ Antibiotic therapy generally helpful while on treatment for 10 days, but often symptoms recur when stopped ­ Has undergone endoscopic surgery including repair of a deviated nasal septum, turbinate reduction, and bilateral maxillary and ethmoid antrostomies · No known history of seasonal allergies, eczema; family history negative for immunodeficiency · Physical examination: ­ Normal HEENT except bilateral TM scars; pulmonary examination normal, lymph nodes present · Laboratory ­ Normal CBC with differential, normal CH50 ­ QIG normal, IgG subclasses normal, isohemagglutinin normal ­ Functional antibodies to tetanus, diphtheria protective ­ Non-protective antibody titers to hemophilus and 14/14 strains of pneumococcus ­ 4 week post immunization titers to non-conjugate vaccines: hemophilus 4-fold rise, 3/14 strains of pneumococcus 2-fold rise ­ Lymphocyte enumeration normal · Diagnosis: Specific antibody deficiency syndrome · Treatment: IVIG

Cellular (T cell) or Combined Deficiency: Clinical Presentation

1. 2. Appearance within first few days or weeks; most serious forms die within first year without prompt definitive therapy; improved survival if treatment starts before life-threatening infections Susceptible to serious infections, often opportunistic 1. Fungal, including oral and cutaneous candidiasis, disseminated infections with candida, cryptococcus, histoplasmosis, nocardia 2. Protozoal, including P carinii, toxoplasmosis, cryptosporidiosis 3. Viral, including herpesviruses, respiratory viruses including adenovirus, parainflulenza, RSV 4. Atypical organisms including Mycobacterium tuberculosis or avium complex, listeria Diarrhea, malabsorption, FTT, seizures, cardiac outflow tract disorders Physical examination: FTT, weight loss, enlargement or absence of LN, organomegaly, dermatitis, petechiae, facial abnormalities, cardiac abnormalities, oral candidiasis, dwarfism, short stature, clubbing, ataxia, telangiectasis

3. 4.

Practice Parameter for the Dx and Mx of Primary Immunodef Ann All Asthm Immun 2005; 94:1; "Primary Immunodeficiency Diseases" in Primer on Allergic and Immunologic Diseases, J All Clin Immun 2003; 111: S571

Adaptive Immunity

Macrophage

Microbes antibody microbe

Thymus

Microbe death

complement

Activated TH -cell TH -cell Bone Marrow Signal Transduction

Memory Clonal Expansion Cytokines IgM

granulocyte

B-cell

IgA IgG

Plasma Cells, Antibody

Macrophage

T-cell Immunodeficiencies

<1%

50% 5-10%

20% 20%

Mild, minor

Severe Combined Immunodeficiency (SCID): ·Genetic defects identified in >95% of cases ·10 different molecular defects at key steps in T cell differentiation

"Immunodeficiencies" in Allergy and Immunology MKSAP, 3rd Edition, 2003, page 291

Adaptive Immunity

Macrophage

Microbes antibody microbe

Thymus

Microbe death

complement

Activated TH -cell TH -cell Bone Marrow Signal Transduction

Memory Clonal Expansion Cytokines IgM

granulocyte

B-cell

IgA IgG

Plasma Cells, Antibody

Macrophage

"Immunodeficiencies" in Allergy and Immunology MKSAP 3rd Edition, 2003, page 292

Combined cellular and B-cell deficiency

Practice Parameter for the Dx and Mx of Primary Immunodef Ann All Asth Imm 2005;94:S9

Case Report

6 month old female · 2 weeks of age onset rash, OM · Poor weight gain, frequent spitting up, coughing spells, persistent diarrhea · No parental risk factors for HIV · Physical Examination: ­ Emaciated infant with no palpable lymphoid tissue ­ Oral examination consistent with thrush · Laboratory: ­ Barium swallow: no GERD; Sweat Chloride normal ­ Stool viral cultures persistently positive for rotavirus ­ QIG: below or just above the LLN; Isohemagglutinin not tested ­ Specific antibodies not tested (no immunizations) ­ CBC: absolute lymphopenia and neutropenia (latter resolved) ­ CXR: absent thymic shadow ­ DTH tests: not placed ­ Lymphocyte enumeration: marked low CD4, CD8 and CD19/CD20 ­ Lymphocyte proliferation: no response to PHA ­ Serum adenosine deaminase: low · Diagnosis: SCID secondary to ADA deficiency · Treatment: ADA replacement therapy and IVIG

Phagocyte Deficiency: Clinical Presentation

1. Onset in early to mid-childhood 2. Recurrent infections of skin, deep tissue abscesses; recurrent lung infections, granulomatous changes in liver, skin 3. Organisms: gram positive (staphlococcus), gram negative, fungal (aspergillus, candida) 4. Physical examination

1. Eczema, chronic dermatitis, granulomatous skin lesions, coarse facial features

Practice Parameter for the Dx and Mx of Primary Immunodef Ann All Asthm Immun 2005; 94:1; "Primary Immunodeficiency Diseases" in Primer on Allergic and Immunologic Diseases, J All Clin Immun 2003; 111: S571

"Immunodeficiencies" in Allergy and Immunology MKSAP, 3rd Edition, 2003, page 322

CGD X-linked 65%

CGD AR 35%

Phagocyte Deficiency: Work-up

Practice Parameter for the Dx and Mx of Primary Immunodef Ann All Asth Imm 2005;94:S11

Case Report

15 year old male · 4 months of age presented with 5 week history of OM and pharyngitis with fever leading to pneumonia worsening despite oral antibiotic therapy · Pneumonia complicated by pleural effusion and pneumatoceles · Required 4 weeks of antistaphlococcal IV therapy for resolution · Family history negative for immunodeficiency; mother received blood transfusion as a child · Physical examination age 4 months: ­ Small male with tonsillar tissue present; no lymphadenopathy, hepatosplenomegaly or thrush · Laboratory age 4 months ­ Normal to elevated QIG; CH50 normal; sweat chloride normal ­ WBC elevated with neutrophilia; absolute lymphocyte count normal ­ CXR with positive thymic shadow; DTH to candida positive ­ HIV negative ­ NBT test 0% staining of WBC; mother's NBT test decreased to 87% · Diagnosis: Chronic Granulomatous Disease · Course: subsequent infections have included recurrent pneumonia, liver abscesses due to Serratia marcescens, perirectal abcesses · Treatment: prophylactic antibiotic (TMS) and interferon-Ib

Complement Deficiency: Clinical Presentation

1. Absent early components leads to susceptibility to gram positive bacteria, autoimmune disease (SLE, glomerulonephritis) 2. Absent late components leads to Neisseria infections (meningitis, sepsis)

Practice Parameter for the Dx and Mx of Primary Immunodef Ann All Asthm Immun 2005; 94:1; "Primary Immunodeficiency Diseases" in Primer on Allergic and Immunologic Diseases, J All Clin Immun 2003; 111: S571

"Immunodeficiencies" in Allergy and Immunology MKSAP, 3rd Edition, 2003, page 293

Complement Deficiency Work-up

Practice Parameter for the Dx and Mx of Primary Immunodef Ann All Asth Imm 2005;94:S12

Case Report

18 year old female · Recurrent OM and bronchitis · Hospitalized for pneumonia age 3 · Normal growth and development · Family history: no diagnosed immune deficiency but two siblings with history of recurrent OM and bronchitis · Physical Examination (age 3): ­ Normal tonsillar tissue, small lymph nodes in cervical region · Laboratory (age 3): ­ WBC with differential normal ­ CXR: positive thymic shadow ­ DTH: positive for candida, tetanus and negative for PPD ­ QIG: normal; anti tetanus, diphtheria, pneumococcus antibodies protective; isohemagglutinins normal ­ CH50: undetectable; C3, C4 normal; C2 = 0 ­ Parent: C2 levels ½ normal value · Diagnosis: C2 deficiency · Course: Continued chronic sinusitis, bronchitis; no autoimmune disease

Malignancy Risk: Primary Deficiency

1. Higher risk in patients with T-cell deficiencies, ? Due to failure of immunosurveillance 2. Lymphoreticular malignancies predominate, non-Hodgkins lymphoma the most common followed by adenocarcinoma of the GI tract and epithelial tumors of the skin 3. Risk not necesssarily related to severity of immune defect:

1. Wiskott-Aldrich (16%), Ataxia-telangiectasia (12%), CVID (8.5%)

Primary Immunodeficiency: Laboratory Evaluation

· Use a step-wise approach with screening tests that are relatively inexpensive, performed rapidly, and reasonably sensitive and specific · Select highly reliable laboratory with experience and expertise in tests of immunity

Folds, et al "Clinical and laboratory assessment of immunity" in Primer on Allergic and Immunologic Diseases J All Clin Imm 2003; 111:S702; "Diagnostic Laboratory Immunology: in Allergy and Immunology MKSAP, 3rd Edition, 2003, pg 347; Practice Parameter for the Diagnosis and Management of Primary Immunodeficiency, Ann All Asthma Immun 2005;94:S1

Antibody Deficiency: Laboratory Evaluation

1. 2. B cell enumeration (CD19, CD20) 1. Interpretation: normal = present Quantitative immunoglobulins: IgG, IgA, IgM; possibly IgG subclasses, IgE 1. Interpretation: normal based on age; 1. IgA deficiency requires level < 7 mg/dl; 2. low IgG subclasses of ? significance; must be accompanied by deficiency of antibody response to be clinically meaningful Specific antibody testing: 1. Obtain baseline and if low, immunize with appropriate vaccine and repeat antibody levels in 3-4 weeks 2. Protein (anti-tetanus, anti-diphtheria antibodies) 1. Interpretation: normal = protective value indicated by laboratory 2. Post immunization: 4-fold rise in antibody level; or specific concentration 3. Polysaccharide (anti-hemophilus influenza B, anti-pneumococcus serotypes) 1. Interpretation: normal = protective value indicated by laboratory 2. Post immunization: 4-fold rise in antibody level or > 1.3 mg/ml; children <2 do not respond with rise, children 2-5 should elevate 50% of serotypes, >5 should elevate 70% of serotypes 4. Isohemagglutinins (IgM vs ABO antigens)

3.

Cellular/Combined Deficiency: Laboratory Evaluation

CBC with differential, absolute lymphocyte count, platelet count and morphology 2. CXR: thymic shadow 3. Lymphocyte enumeration by flow cytometry: CD3 (pan T-cell), CD4 (helper T-cell), CD8 (suppressor/cytotoxic T-cell), CD19, CD20 (Bcell), CD 16, 56 (natural killer cell) 1. Interpretation: normal = present 4. Delayed-type hypersensitivity (anergy) skin testing 1. Agents: PPD, candida; mumps and tetanus no longer commerciallly available; histoplasmin and coccidiodomycosis in endemic areas 2. 2-5 mm induration positive at 48-72 hours

1. Interpretation: positive = 1-2 of 4 positive tests

1.

5.

Invitro lymphocyte responses (advanced testing) 1. Mitogens (phytohemagglutinin: T cells; concanavalin A: T cells; pokeweed mitogen: T and B cells) 2. Antigens: Tetanus, candida, mixed lymphocyte reaction

1. Interpretation: positive = >50% counts compared to control

Phagocyte Deficiency: Laboratory Evaluation

1. CBC with manual differential, attention to granules 2. Reduced intracellular killing

1. NBT: abnormal test unable to reduce dye to yellow 2. Dihydrorhodamine chemiluminescence: abnormal test unable to generate chemiluminescence on FACS

3. Reduced engulfment (advanced testing)

1. Latex bead, zymosan: abnormal test unable to engulf

4. Reduced chemotaxis (advanced testing)

1. Boyden chamber: abnormal test no phagocytic cell chemotaxis to chemoattractants 2. Integrin deficiency (CD 11a, 11b, 11c; CD18); abnormal test shows absent markers by flow cytometry 3. Selectin deficiency (CD 62L, CD15sw); abnormal test shows absent markers by flow cytometry

Complement Deficiency: Laboratory Evaluation

1. Classical pathway: CH50

1. Interpretation: concentration of patient serum able to lyse 50% of sheep RBC sensitized by rabbit antibody

2. Alternative pathway: AH50

1. Interpretation: concentration of patient serum able to lyse 50% of unsensitized rabbit RBC

3. Concentration of individual complement components

1. Interpretation: absent levels of specific components

Primary Immunodeficiency: Management

General principles of therapy: 1. Early diagnosis and prompt treatment:

1. >70% of patients are followed by their PCP 2. Enhances survival and improves quality of life

1. Death rate increases to 80% by age 1 in SCIDS if stem cell transplantation does not occur in first 3 months

3. Reduces permanent organ damage or death from overwhelming infection 4. Considerations underway for genetic screening in newborns

Practice Parameter for the Diagnosis and Management of Primary Immunodeficiency, Ann All Asthma Immun 2005;94:S1; Use of Intravenous Immunoglobulin in Human Disease J All Clin Immun 2006; 117 (No. 4): S525-553

Primary Immunodeficiency: Management (continued)

General principles of therapy: 2. Avoid live virus vaccines (MMR, influenza, varicella) 3. Reduce exposure to infectious agents in daycare or with older siblings 4. Aggressive use of antibacterial, antifungal, antiprotozoal and antiviral agents including prophylaxis

1. 2. Consider early combined antimicrobial therapy, prolonged courses May require both IVIG and antibiotic to prevent and treat infections

5. 6. 7.

Replacement of antibody deficiency with infusions of IVIG in patients with reduced IgG antibody responses to antigens Reconstitute immunocompetent tissue in patients with cellular immune defects Genetic counseling

Intravenous Immunoglobulin (IVIG)

1. Indicated for all disorders demonstrating significant infections and impairment of specific IgG antibody production 2. Specific Disorders

1. Clear benefit: agammaglobulinemia, hypogammaglobulinemia with impaired specific antibody production, Hyper-IgM 2. Probable benefit: normogammaglobulinemia with impaired specific antibody production 3. May benefit: Hyper-IgE syndrome, WAS 4. No benefit: IgA deficiency, THI

Intravenous Immunoglobulin

3. Formulations:

1. Prepared by cold ethanol fractionation of plasma pooled from 10,000 to 60,000 donors followed by processes that remove antibody aggregates and inactive potential viral pathogens 2. Differences in product separation, stabilization, purification, virus inactivation, sugar content, sodium content, osmolality, pH, and IgA content 3. Differences in chemical structure, specific antibody concentrations, subclass distribution, level of antibodies to specific antigens, electrophoretic profile 4. 99% is IgG with trace IgA and IgM

Intravenous Immunoglobulin

4. Efficacy:

1. Well-documented reductions in incidence and severity of serious bacterial infections in XLA and CVID 2. May not interrupt the occurrence or progression of permanent lung damage

5. Dosing

1. Proper dosing not determined by controlled trials 2. Current recommendations 200-600 mg/kg/month 3. Target trough levels:

1. Some suggest achieving level 400 mg/dl over baseline 2. 500 mg/dl effectively prevents severe acute bacterial infections, but pulmonary disease and sinusitis still occur (1) 3. Trial comparing double dose of IVIG to 800 mg/kg/month showed significant reduction in the number and duration of pulmonary infections (2)

(1) Quartier et al J Ped 1999; 134: 589; (2)Eijkhout et al. Ann Int Med 2001; 135: 165

Intravenous Immunoglobulin

6. Safety:

1. No cases of HIV/AIDS reported 2. Several isolated cases of Hepatitis C in Europe and Australia in 1980's and in 1993 outbreak in the US and other countries led to further measures to kill these viruses 3. No documented transmission of infection from other viruses or prions (CreutzfeldtJacob disease) but concerns about transmission of other unknown agents exists. Data exists that IVIG isolation process also inactivates prions.

Intravenous Immunoglobulin

7. Adverse effects:

1. Frequency: 2-10% for all infusions, 17% of all patients, but 99.8% able to complete infusions 2. Most common: headache (48%), flushing (25%), chills (24%), nausea, vomiting, myalgias

1. Less often, hives or wheezing which respond to antihistamines 2. Headaches may be severe, especially if history of migraines, and may occur 3-5 days after; some have CSF leukocytes and protein, cause unknown

3. More common with early infusions, less common after normal serum levels of IgG are attained 4. Reactions often relate to rate of infusion and may require build-up; slow rate until reaction subsides

Intravenous Immunoglobulin

7. Adverse effects (continued):

5. Serious AE have been reported:

· · Renal failure if pre-existing abnormalities, 17 fatalities; 88% occurred in preparations stabilized with sucrose, volume depletion, or over age 65 Thrombosis: infrequent, multi-factorial, including platelet activation, pro-coagulants in product, increased sodium; stroke, MI in patients with pre-existing disease; suggest use 5% products, slower rate Aseptic meningitis

·

6. Pretreatment may prevent AE, including 100 mg HC one hour before, ASA 15 mg/kg/dose, acetamenophen 15 mg/kg/dose, diphenhydramine 1 mg/kg/dose, ? H2 blockers if IgE mediated 7. Monitoring: obtain IgG levels, LFT every 3-6 months, HBSAG, HCV PCR and LFTs baseline

Subcutaneous Immunoglobulin

1. An alternative to IVIG 2. Indications:

1. IV access problems 2. Uncorrectable AE to IVIG; anaphylaxis 3. Can't maintain therapeutic concentrations for more than 2 weeks due to reduced Ig half-life 4. Avoid large volumes/ fluid shifts (renal disease, pregnancy 5. Persistent ECHO virus infection 6. Possible improved control of infection

Subcutaneous Immunoglobulin

3. Protocol:

1. Use 10% solutions or newly approved 16% Vivaglobulin 2. Infuse monthly dose divided into weekly or twiceweekly infusions, 4 hours each with a portable pump 3. 20 cc/site, branched tubing with multiple needles, multiple pumps 4. Able to deliver 6 grams in 2-3 hours , or 40 cc over 6-8 hours while sleeping 5. Range in peak/trough only 100 mg/dl vs 900 mg/dl with IVIG 6. AE: local pain or redness (2-20%), systemic reactions (0-3.3%)

Subcutaneous Immunoglobulin

4. Patient preference:

1. 15 children, 32 adults on IVIG switched to SCIG 2. 16% product, same dose, weekly dosages 50-150 mg/kg 3. FU 6 and 10 months 4. Outcome:

1. Children: SCIG gave better health, improved school/social function; reduced emotional distress and limitations on personal time for parents, fewer limitations on family activities (Child Health Questionnaire) 2. Adults: Improvement in treatment satisfaction due to greater independence and convenience (Short Form 36)

Gardult A et al Children and adults with primary antibody deficiencies gain quality of life by subcutaneous IgG self-infusions at home. J All Clin Immun 2004; 114: 936

Subcutaneous Immunoglobulin

5. Efficacy:

1. 40 patients randomized for one year to IVIG or SQIG 2. Primary endpoint: number and severity of infections 3. Secondary endpoint: AE, length of infections, days lost from school or work due to infections and patient acceptability 4. Outcome: No significant differences in efficacy or AE

Chapel et al The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J Clin Immun 2000; 20:94

Immuno-reconstitution by hematopoietic stem cells

1. Use depends on type of defect 2. Early recognition and diagnosis are vital to treatment of patients with cellular defects

1. Most bacterial and protozoal infections can be treated successfully, but viral infections (CMV, EBV) can be fatal 2. Place child in protective isolation when diagnosis suspected, irradiate blood products, use leukocyte depleted, CMV negative donors

Immuno-reconstitution by hematopoietic stem cells

3. Stem cell transplantation is therapy of choice for patients with severe defects

1. Most from bone marrow, but cord blood and peripheral blood stem cells have been used successfully 2. SCID

1. Complete: transplant without cytoreductive or ablative therapy 2. All others: Condition, including busulfan, CTX, ATG

3. HLA-identical sibling clearly preferred source 4. Can use anti-T cell monoclonal antibodies for haploidentical or half-matched parental marrow

Immuno-reconstitution by hematopoietic stem cells

5. T cell function develops rapidly, but B cell function more slowly, some years, and likely require long term IVIG

6. Success affected by:

· · Absence of chronic CMV, EBV Transplantation less than 3 months, HLA matching

7. Successfully applied in virtually all SCIDS and many other combined immunodeficiencies, phagocytic disorders

Other Treatments

1. 2. 3. 4. Partially HLA-matched thymic epithelium with good success in DeGeorge's Thymic hormones with anecdotal success Thymic extracts from lysates of lymphocytes (transfer factors) in CMC Enzyme replacement:

1. ADA deficiency using PEG-ADA with good serum levels, reduction in toxic levels of deoxyadenosine, good clinical improvement, but immune reconstitution variable; weekly infusions, expensive, useful if transplant not an option IL2: some improvement, but trials suspended due to CVA IFN-gamma: helpful in CGD G-CMF: may help in CGD ADA deficiency: insertion occurred but only transient SCID (1): successful but 3 patients died due to leukemia secondary to retroviral-carried gene insertions

5.

Cytokine replacement:

1. 2. 3.

6.

Gene Therapy:

1. 2.

(1) Puck JM et al. Gene therapy for immune disorders: Good news tempered by bad news. J All Clin Immun 1006;117:865

Some days it's hard to make the right decision !

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