Primary Immune Deficiencies (Pid)

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Primary immune deficiencies

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Intrinsic defects in the immune system; some somatic some somatic but mostly genetic; antibody deficiencies most diagnosed

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When does one suspect PID?

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Too many infxns or ones that just won't go away; infxns in weird places; early onset autoimmunity, weird patterns of autoimmunity or immunodysregulation

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Secondary immunodeficiencies

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Infxns (HIV, measles, severe sepsis, miliary tuberculosis), Malnutrition, malignacies (lymphoma), Metabolic (diabetes, liver disease), Loss of lymphocytes or antibodies, Immunosuppressants (corticosteroids, rituximab, and others) collagen vascular disease

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Chronic Granulomatous Disease

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Case: Abscess fluid, always on antibiotics, skin leasions, abdom. pain; Functional absence of respiratory burst in neutrophils and moncytes-impaired bactericidal killing; X-linked (76%) some autosomal recessive (hypermorphic mutation); onset by age 2; Test done with Flow cytometry' with DHR (picks up carriers)

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NADPH oxidase

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essential for respiratory burst. four subunits-defects in any leads to CGD; gp91phox most common

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CGD treatment

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TM-sulfa prophylaxis (staph) Itraconazole prophylaxis; prednisone for granulomas; definitive Rx: bone marrow transplantation

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Leucocyte Adhesion Deficiency-1

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Presentation: recurrent fevers and non-healing skin lesions; multiple episodes of pneumonia, mouth sores, SKIN ULCERS WITHOUT PUS; delayed umbilical cord detachment, leucocytosis, inability to form pus; autosomal recessive deficiency of LFA-1/Mac-1, p150, 95 family of integrins (adhesion molecules)

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LAD-1 treatment

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Aggressive RX infection, BM transplant in severe cases

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LAD-1 diagnosis

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Flow cytometry with CD18 deficiency;

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LAD II diagnosis

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Flow cytometry with Fucosylation deficiency (CD15/16)

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TLR's

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key component of the innate immune system; pattern recognition receptors (PRR); recognize conserved motifs in PAMPs; downstream signaling leads to production of inflammatory cytokines

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MyD88-IRAK

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signaling dependent on all TLRs except 3 and 4 (4 can still use the pathway)

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MyD88-IRAK-4 Deficiency

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Early onset of infections from Strep, Staph, Pseudomonas (this or cystic fibrosis); people rely on TLRs more at a younger age (mortality levels off); no increased susceptibility to virus, fungi other pathogens; may have reduced inflammaotry response to invasive infection; IVIG and ABx improves outcome; mice are different

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Mutations in TLR3 and TLR3-signaling pathway

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Recurrent Herpes Virus encephalitis; no problems with other viruses; unexpected based on mouse models

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Late Complement Deficiency (C5-C9)

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Not until teen years does disease surface; Presents-prior meningitis, CC:scattered petechiae, photophobia and meningismus; Recurrent menigococcal disease; 50-60% of patients; only affects homozygotes

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Early Complement Deficiencies

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C2: most common deficiency; 1:10,000-28,000, autosomal recessive; recurrent bacteremia: pneumococcus, H. Influenzae, enteric bacteria, staph.

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Best screening test for alll classical complement deficiencies

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CH50

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Severe Combined Immunodeficiency

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Profound defect in cellular and humoral immunity; Onset in infancy: Pneumonia, otitis media, thrush, intractable diarrhea, failure to thrive, 100% mortality without bone marrow transplant; early Rx improves survival rates; more common in premature births

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SCID diagnostic tests

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Screening: CBC, lymphopenia; confirmatory test: lymphocyte enumeration (T cells-naive/memory, B cells, NK cells) absent or nonfunctional T-cells; abnormal screen doesnt mean that the infant has SCID

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TRECs

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occur during T-cell receptor chain recombination; they are a surrogate marker of naive T cells; Screening test for SCID: TRECs are low in all forms of SCID; Nonreplicating circular pieces of DNA in naive T cells generated in the process of making a T cell receptor; rtPCR

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DiGeorge Syndrome/22q11.2 deletion syndrome (22qDS)

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Presentation: 3 yo male with recurrent thrush, otitis media and 4 CXR documented pneumonias, trouble swallowing liquids; Field defedt first to sixth pharyngeal pouches; Deletion of TBX1 underlies many of the abnormalities, 1:2,000; many cases undiagnosed until late childhood/adults; Dx) DNA microarray copy # var. (FISH)

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DiGeroge syndrome clinical symptoms

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CATCH22-cardiac defects, abnormal facies, Thymic HYPOplasia, Cleft Palate, Hypocalcemia, 22nd chromosome

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DiGeorge Syndrome testing

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All infants with significant heart defects, Unexplained lymphopenia, or cleft lip; Diagnositic tests: FISH (false neg in 15% of patients); Chromosome microarray/DNA duplication deletion test; RT-QPCR for haploinsufficiency TBX1 (CHW)

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DiGeorge Syndrome Immune Abnormalities

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Up to 30% have low T-cell counts; Antibody deficiency: up to 15% require monthly IVIG; Recommend immune evaluation BEFORE live vaccines; Autoummunity up to 30%-abnormalities in thymic function likely lead to autoimmunity

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X-linked Agammaglobulinemia (XLA)

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Quantitative immunoglobulins-IgG, IgA, IgM: result: severe pan-hypogammaglobulinemia; Normal T-cell numbers, NO B-cells present; Diffuse bronchiectasis; presents with recurrent otitis media, intractable sunusitis; "several" hospitalizations for pneumonia; Encapsulated bacteria (S. pneum, H. Infl and Mycoplasma); severe enteroviral infections: vaccine related polio;

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XLA screening

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IgG, IgA, IgM are the best screening test for ALL Ab deficiencies

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Btk and BLNK

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Help keep B-cells alive

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Bronchiectasis

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Presents: severe "asthma" severe obstruction; recurrent sinusitis/pneumonias over last 10 years; partial lobectomy of RLL; Chronic, productive cough; either IgA or IgM is low with a low IgG

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Bronchiectasis in CVID

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most common lung abnormaility in CVID; low antibodies but normal T and B cell levels; Leads to abnormal function of bronchi/cilia that predisposes to pneumonias

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Bronchiectasis Tx

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Daily chest physiotherapy, hypertonic saline may be useful, hospitalization with IV Abx for acute exacerbations; Role of chronic Abx/azithromycin Rx unclear

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CVID

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decrease in IgG and a low IgA or IgM; onset >4 yo; poor response to vaccines; exclude primary Ab deficiency and secondary Ab deficiency (drugs, lymphomas); also interstitial lung disease; Causes of death: Pulmonary disease, cancer, autoimmune, liver disease, infection

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Dianostics for CVID and XLA

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DONT do serological assays unless patient is receiving IVIG; Infectious disease must be done by culture, PCR or other direct methods to directly test the presence of the pathogen

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Diffuse Parenchymal disease

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Non-infectious Cxns of CVID GLID (reduced survival esp w/o treatment), cryptogenic organizing pneumojnia, lymphoma, hypersensitivity pneumonitis, gastric metastatic carcinoma

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GLID in CVID

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Granulomatous disease, Lymphocytic interstitial pneumonitis, follicular bronchiolitis, frequently large areas of organizing pneumonia, Enlarged spleen and diffuse adenopathy; multisystemic lymphoproliferative disease; tx with rituximab and 6MP