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I & I Part I > Primary and Congenital Immunodeficiency > Flashcards

Primary and Congenital Immunodeficiency Flashcards

1
Q

Primary Immunodeficiency

A
  • : A genetic (congenital; inborn) mutation that manifests as immunodeficiency
  • e.g., IgA deficiency, common variable ID, SCID
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2
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Secondary Immunodeficiency

A
  • An acquired immune deficiency brought on by infection, drug, or environmental exposure.
  • e.g., immunosuppressants (corticosteroids, chemo), radiation, HIV, age, malnutrition
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8
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Antibody Deficiencies

A
  • Antibody deficiencies are the most common of primary immune deficiency diseases (about 50% of all primary immunodeficiencies).
  • Patients usually present with an increased susceptibility to infection; especially encapsulated bacterial organisms (H. influenzae, S. pneumoniae).
  • In patients who are treated with numerous courses of broad-spectrum antibiotics, infection with other GNR (e.g., pseudomonas) may occur.
  • Also, be cognizant of atypical organisms (opportunists): Viruses (e.g. Enteroviruses), Protozoa (Giardia, Cryptosporidium).
  • Clinically, expect recurrent URI and LRI. When you see a patient with >1 pneumonia annually, intractable sinusitis, recurrent otitis media, or unusual GI tract infections, think about a humoral immunodeficiency.
  • Finally, autoimmunity and increased incidence of malignancies are associated with some forms of Ab deficiency.
  • Therapeutic options vary, depending upon the exact condition, and include replacement therapy (IVIG), suppressive antibiotic therapy, and aggressive therapy of existing infections.
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9
Q

Antibody Deficiencies - X-linked (Bruton) agammaglobulinemia (XLA) Presentation

A
  • Well until passive maternal Ab “wears off” at 4-6 mo (may have mucosal infections prior)
  • Recurrent infections w/ encapsulated bugs (pneumococcus, H flu, strep)
  • No fungal infections; some enteroviruses and chronic GI bugs problematic (echo, cocksackie, adeno; giardia, campylobacter)
  • Also meningococcus, pseudomonas—may be systemic
  • No germinal centers (no tonsils, adenoids, nodes); thymus is normal
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10
Q

Antibody Deficiencies - X-linked (Bruton) agammaglobulinemia (XLA) Pathophysiology

A
  • Mutation in Bruton thymidine kinase gene (Btk)
  • Over 500 BTK mutations described
  • Pre-B cells (w/ pre-BCR) require Btk downstream signaling to mature; XLA causes arrest in B cell development in the BM.
  • BTK has role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. Several BTK inhibitors available.
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11
Q

Antibody Deficiencies - X-linked (Bruton) agammaglobulinemia (XLA) Diagnosis

A
  • Quant Igs: Very low/absent Ig levels of all classes
  • Flow cytometry:
  • Few / no circulating B cells
  • Normal circulating T cells and NK cells (T cell functions normal)

• BTK protein expression low/gene sequencing: mutations

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12
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Antibody Deficiencies - X-linked (Bruton) agammaglobulinemia (XLA) Treatment

A

• Immunoglobulin replacement (IVIG/ScIG): maintain trough levels above 700-900 mg/dL

  • 400-600 mg/kg IVIG q 4 wks
  • 100-150 mg/kg ScIG q wk

• Prophylactic antibiotics

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13
Q

Antibody Deficiencies - Selective IgA Deficiency Presentation

A
  • Isolated low/undetectable IgA (<10 mg/dL); Normal IgG, IgM
  • Most common PID in humans (1:400-1:600)
  • 67% of pts are healthy and asymptomatic. Minority have: sinopulmonary infections and pneumonias; GI disorders (giardiasis, celiac, IBD); autoimmune disorders (RA, SLE, etc).
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14
Q

Antibody Deficiencies - Selective IgA Deficiency Pathophysiology

A
  • Defect is unknown!! Even inheritance is unclear. May be present in families with CVID.
  • 45% of patients have anti-IgA antibodies in their serum
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15
Q

Antibody Deficiencies - Selective IgA Deficiency Diagnosis

A
  • Clinical suspicion
  • Quantitative Igs: Low IgA; nl IgM, IgG
  • Nl B cell, T cell numbers
  • IgG = 425 mg/dl (700-1600)
  • IgM = 35 mg/dl (40-280)
  • IgA = 32 mg/dl (70-400)
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16
Q

Antibody Deficiencies - Selective IgA Deficiency Treatment

A
  • Prompt diagnosis and aggressive therapy of active infections
  • Prophylactic antibiotics
  • IVIG not indicated
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17
Q

Antibody Deficiencies - Common Variable Immunodeficiency (CVID) Presentation

A
  • Second most common primary immunodeficiency; seen in 20-40 yo; M=F; May have later onset than other PID (e.g., XLA); most cases are sporadic.
  • Similar range of infections to other agammaglobulinemias (resp/ GI big): sinusitis, pneumonia w/ bronchiectasis.
  • Most lymph organs are WNL (within normal limits; 25% have splenomegaly)
  • Linked to autoimmunity (thyroiditis, hemolytic anemia, thrombocytopenia, pernicious anemia), amyloidosis, sarcoidosis
  • 500-fold increased risk of lymphoma; 50-fold increased risk gastric CA
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18
Q

Antibody Deficiencies - Common Variable Immunodeficiency (CVID) Pathophysiology

A
  • “Catch-all” diagnosis; heterogeneous causes
  • Some described defects in CVID pts: inability to produce memory B cells (CD27+) and mature plasma cells, impaired B-cell survival or activation, T-cell signaling, and cytokine expression.
  • IgA, IgG, and IgM-bearing B-cell precursors: Normal
  • Impaired B cell differentiation and Ig production
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19
Q

Antibody Deficiencies - Common Variable Immunodeficiency (CVID) Diagnosis

A
  • Low total serum IgG concentration (<400); 2 SD below age mean
  • Reduced serum concentrations of 1 or more other Igs (IgA or IgM)
  • Poor IgG responses to immunization (Pneumovax, ΦX174)
  • Absence of other defined immunodeficiencies
  • T cells and subsets usually normal
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20
Q

Antibody Deficiencies - Common Variable Immunodeficiency (CVID) Treatment

A
  • Aggressively treat infections • Consider suppressive antibiotics (H. flu, strep)
  • IVIG / SCIG (300 to 400 mg/kg every 3-4 weeks)*
  • Surveillance: periodic CBC, annual thyroid examination and labs, annual PFTs +/- HRCT of chest every two to three years if lung disease, biopsy of enlarged lymphoid tissue, etc.
  • Clinical surveillance of asymptomatic at-risk individuals may allow timely intervention and improve outcome.
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21
Q

Primary T cell Deficiencies

A
  • Primary T cell deficiencies are less common, and typically are detected early in childhood.
  • Many have associated developmental abnormalities that may be noticed first.
  • These patients usually have increased susceptibility to infections produced by opportunists including CMV, candida species and Pneumocystis jirovecii.
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22
Q

Primary T cell Deficiencies - DiGeorge Syndrome Presentation

A
  • Neonatal hypocalcemic seizures (↓PTH; parathyroid hypoplasia), abnormal facies, cardiac abnormalities (congenital heart and great vessel defects)
  • T cell deficiency due to thymic aplasia (recurrent viral/fungal infections); absent thymic shadow on CXR
  • Partial DiGeorge: cognitive issues and mild “defects”
  • Severe DiGeorge: resembles pts with SCID (opportunist infections); death by age 2 w/o intervention
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23
Q

Primary T cell Deficiencies - DiGeorge Syndrome CATCH - 22

A

An acronym that is commonly used for DiGeorge is: CATCH-22 (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia resulting from 22q11.2 deletion).

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24
Q

Primary T cell Deficiencies - DiGeorge Syndrome Pathophysiology

A
  • 22q11 deletion
  • Dysmorphogenesis of the 3rd and 4th pharyngeal pouch, leading to hypoplasia/aplasia of thymus and parathyroids
  • Mutations also linked to velocardiofacial defects
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25
Q

Primary T cell Deficiencies - DiGeorge Syndrome Diagnosis

A
  • Neonatal seizures; hypocalcemia. Cardiac defect(s)
  • T cell deficiencies (low CD3+); normal CD4/CD8 ratios; may see increases in B cell numbers
  • Ig levels may be normal, but IgA deficiency can be seen
  • T cell mitogen responses depressed
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26
Q

Primary T cell Deficiencies - DiGeorge Syndrome Treatment

A

•Immune reconstitution via transplanatation of of unrelated thymic tissue explants…

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27
Q

Primary T cell Deficiencies - Hyper IgE Syndrome (Job’s Syndrome) - Presentation

A
  • Recurrent staph abscesses from infancy: skin, lungs, joints, etc
  • Severe eczema
  • Recurrent pneumonias w/ pneumatoceles (pseudomonas, aspergillus)
  • Coarse facial features: prominent forehead, broad nasal bridge, prognathism, failure of primary teeth to shed…
  • Increased risk lymphoma
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28
Q

Primary T cell Deficiencies - Hyper IgE Syndrome Pathophysiology

A
  • Most (70%) are autosomal dominant (but there are at least 3 forms)
  • Defect: Impaired differentiation of IL-17 secreting cells (i.e., no Th17 cells) due to a STAT3 mutation (signal transducer and activator of transcription 3) most commonly. Exactly how this mutation causes all of these features is unclear.
  • IL-17 impt in candidal and extracellular bacterial infections.
  • IL-17 signaling is also involved in neutrophil chemotaxis and proliferation. So, impaired neutrophil responses due to impaired IL-17A signaling might account for the recurrent staphylococcal infections in patients with HIES…
29
Q

Primary T cell Deficiencies - Hyper IgE Syndrome Diagnosis

A
  • Clinical Suspicion
  • Markedly elevated IgE (2000-130,000 IU/mL); nl IgG, M, A
  • Pronounced blood and tissue (LN, spleen) eosinophilia
  • Normal CD3, CD4, CD8 populations; decreased CD45RO memory T cells
  • Marked decreased Th17 response
  • Decreased memory B cells (CD45RO)
  • Low anamnestic antibody responses to vaccination
  • STAT3 gene sequencing
30
Q

Primary T cell Deficiencies - Hyper IgE Treatment

A
  • Bleach baths for skin care
  • Chronic prophylactic antibiotics, antifungals
  • Surgery for pneumatoceles
31
Q

Primary T cell Deficiencies - Chronic mucocutaneous candidiasis (CMC)

A
  • Chronic mucocutaneous candidiasis (CMC) is a chronic infection of skin and mucous membranes with Candida; of note, the infections are superficial, and not invasive.
  • There are at least 6 mutations that have been observed: several affect Th17 cells, implying a role of IL-17.
  • These patients fail to respond to Candida skin testing and in vitro Candida T-cell proliferation assays.
  • Treatment is with chronic prophylaxis using topical or oral antifungals.
32
Q

Combined B & T cell disorders

A
  • The organization of these conditions is a bit arbitrary in that the immune system rarely acts in a strict T- or B- cell independent manner. Rather, all of these cells interact and work cooperatively to produce a functional immune system.
  • Defects may arise in one cell lineage or another, but the manifestations may spill over into multiple lineages.
33
Q

Combined B & T cell disorders - Severe Combined Immunodeficiency Disease (SCID) Presentation

A
  • Fatal syndrome of profound B &T cell function deficiencies
  • Appears in 1st few months: D, PNA, otitis, sepsis, FTT
  • Persistent infections: Candida, P. jirovecii, VZV, adeno, EBV, etc
  • V. small thymus, LN, tonsils, adenoids, PP are absent
34
Q

Combined B & T cell disorders - Severe Combined Immunodeficiency Disease (SCID) Pathophysiology

A
  • X-linked is most common form (SCID-Xl); 50% of cases
  • IL-2R gamma chain defective •

Xq13 codes for common gamma chain (yc) shared by IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 receptors.

• Mutations in IL-2R gene causes faulty signaling in several different cell types

35
Q

Combined B & T cell disorders - Severe Combined Immunodeficiency Disease (SCID) Diagnosis

A
  • Clinical Suspicion
  • Profound T-cell lymphopenia (< 500 CD3+/ul), low NK, (B-cell can be WNL, but not functional)
  • Lymphocyte function sucks: neg proliferative responses to ag, mitogens
  • Low/no serum Igs, no vaccine responses
  • TRECs are low or ND
36
Q

Combined B & T cell disorders - Severe Combined Immunodeficiency Disease (SCID) Treatment

A
  • Emergent IVIG/ScIG replacement therapy; prophylactic abx; avoid live vaccines
  • Need HLA-identical / haploidentical BMT needed, or death before 1 yo…BMT by 3.5 mo: 94% survival
  • Gene therapy: lentiviral vectors
37
Q

Combined B & T cell disorders - Severe Combined Immunodeficiency Disease (SCID) Other SCIDs

A
  • Enzyme defects (adenosine deaminase deficiency)
  • HLA expression defect (bare lymphocyte syndrome)
  • Defective VDJ recombination at TCR locus (A-T, WAS)
38
Q

Combined B & T cell disorders - Ataxia Telangiectasia Presentation

A
  • Progressive cerebellar (gait/truncal) ataxia; may begin as toddlers
  • Oculocutaneous telangectasias (scleral)
  • Oculomotor apraxia; choreoathetosis
  • Immune defects 2o to low IgG, IgA (rhinosinusitis)
  • High risk of malignancy (us. lymphoma)
39
Q

Combined B & T cell disorders - Ataxia Telangiectasia Pathophysiology

A
  • Autosomal recessive mutation in ATM gene (serine/ threonine kinase)
  • ATM gene product: tumor supressor/DNA repair enzyme
  • Patient’s cells have chromosomal breakage, are sensitive to radiation, have defective DNArepair
  • Over 50% have x-some breakage in 7 (TCR) or 14 (IgHC)
40
Q

Combined B & T cell disorders - Ataxia Telangiectasia Diagnosis

A
  • Clinical suspicion
  • Immunoglobulin levels (↓ IgA: 50-80%)
  • Elevated serum AFP
  • ATM protein levels (90% have none)
  • Genetic sequencing • DNA repair assay (radiosensitivity assay)
41
Q

Combined B & T cell disorders - Ataxia Telangiectasia Treatment

A
  • None
  • Poor prognosis (lymphoreticular malignancy, progressive neurological disease, infections)
  • Gene therapy?? Not yet…
42
Q

Combined B & T cell disorders - Hyper IgM Syndrome Presentation

A
  • Recurrent encapsulated bacterial infections (like XLA folks). Recurrent pneumonia, otitis, sinusitis, chronic diarrhea; P. jirovecii pneumonia common.
  • Pts have lotsa IgM; little or no IgG, IgA, IgE. Specific vaccineinduced Ab negative.
  • Intermittent neutropenia +/- thrombocytopenia
  • Many forms (X-linked, AR, or AD)
43
Q

Combined B & T cell disorders - Hyper IgM Syndrome Pathophysiology

A
  • Genetically diverse; >6 mutated genes. Originally classified as a B cell defect, because only IgM is produced.
  • Normal numbers of B cells; they can make IgG, IgA, IgM when cocultured with activated T cell line.
  • X-linked is most common type (HIGM1); mutation in CD154 (CD40L): T cell surface molecule that interacts with CD40 on B cells. CD40L is found on activated CD4 T cells.
  • CD40 + CD40L on dendritic cells —> IL-12 secretion—> IFN-g (Th1 cytokines); is this the mechanism for opportunists in these folks?
  • FYI: HIGM3: Autosomal recessive; CD40 deficiency (on B cells)— clinically identical to CD40L deficiency.
44
Q

Combined B & T cell disorders - Hyper IgM Syndrome Diagnosis

A
  • Clinical Suspicion
  • Normal or elevated IgM; low or absent IgG, IgA, IgE
  • Normal B cell numbers (but no CD27+IgM-IgD-)
  • Flow cytometry for CD40L on T cells will be negative; CD40L gene sequencing shows mutation (4-6 wks).
45
Q

Combined B & T cell disorders - Hyper IgM Syndrome Treatment

A
  • Monthly IVIG/ScIG (400-600 mg/kg/month)
  • Abx prophylaxis (e.g., TMP-SMX) for P. jirovecii
  • Treat neutropenia (GCSF)
  • 40% survival beyond 25 yo…but HSCT is curative. 70% survival rate w/ HLA-matched
46
Q

Combined B & T cell disorders - Wiscott-Aldrich Syndrome (WAS) Presentation

A
  • May present in early infancy: bleeding from circ site, bloody diarrhea, bruising
  • TRIAD:
  • Atopic eczema
  • Recurrent infections (pneumococci, P. jirovecii, HSV)
  • Thrombocytopenic pupura / vasculitis

• High risk autoimmunity/cancer

47
Q

Combined B & T cell disorders - Wiscott-Aldrich Syndrome (WAS) Pathophysiology

A
  • X-linked recessive mutation(s) of the WASP gene (expressed in hematopoietic cells)
  • WASP function: actin nucleation factor (adds actin monomer to existing filament); essential for cell motility and shape
  • Normal megakaryocytes; small defective platelets
  • Mutation inhibits T cell activation (TCR conformation depends on actin), and ultimately B cell activity
48
Q

Combined B & T cell disorders - Wiscott-Aldrich Syndrome (WAS) Diagnosis

A
  • Clinical suspicion
  • Platelet count and smear
  • Sequencing of the WAS gene
  • Impaired humoral responses to polysaccharide antigens (low isohemagglutinins). Poor anamnestic responses
  • Usually low IgM, elevated IgA
  • Poor NK function; poor mitogen responses
49
Q

Combined B & T cell disorders - Wiscott-Aldrich Syndrome (WAS) Treatment

A
  • HLA-identical sibling BMT: complete correction
  • In kids <5yo, stem cell transplant efficacious
  • Survival beyond teens is rare w/o BMT
  • Death from infections and bleeding; EBV-induced lymphoreticular malignancy
50
Q

Phagocyte dysfunction

A

Phagocyte dysfunction is rare, but the analysis of these cases helped to define the stages of phagocyte intracellular killing, and show up as frequent Step 1 questions. Know the defect and its intracellular consequence.

51
Q

Phagocyte dysfunction - Chronic Granulomatous Disease (CGD) Presentation

A
  • Defective intracellular killing of bacteria and fungi
  • Infancy: severe infections with catalase positive bugs (Staph, Serratia, Pseudomonas, etc).
  • No problems with catalase neg bugs (Strep, H flu)
  • Abscesses (skin, lungs, nodes); obstructive granulomas (liver, GI)—(bugs ingested but not destroyed)
  • Osteomyelitis common (bacterial and fungal)
  • Most cases X-linked (X-CGD)
52
Q

Phagocyte dysfunction - Chronic Granulomatous Disease (CGD) Pathophysiology

A
  • Defective production of reactive oxygen intermediates by phagocytes
  • Mutation in gp91phox (phagocyte oxidase; heavy chain of b245 heterodimer); >400 mutations identified
  • 65% X-linked; 35% autosomal recessive

CGD is characterized by defective intracellular killing of both bacteria and fungi. The immunological defect is in the NADPH oxidase system that forms reactive oxygen species and leads to a respiratory burst in neutrophils that kills susceptible organisms. CGD presents during infancy: recurrent infections with catalase positive organisms (Staphylococcus, Pseudomonas, and Salmonella). It does not impact catalase negative organisms.

53
Q

Phagocyte dysfunction - Chronic Granulomatous Disease (CGD) Diagnosis

A
  • Only defect is inability of phagocyte to kill ingested bugs
  • Tests rely upon ability of phagocyte to reduce a dye
  • Screen with NBT or DHR; then, sequence phox genes
54
Q

Phagocyte dysfunction - Chronic Granulomatous Disease (CGD) Treatment

A
  • Aggressive prohylactic antibiotics and anti-fungals
  • IFN-gamma (SC 3x/week) reduction in hospitalizations
  • SCT problematic due to chronic indolent infections
  • Gene therapy experimental (malignant transformations)
55
Q

Phagocyte dysfunction - Chediak-Higashi Syndrome Presentation

A
  • is an autosomal recessive disorder due to a mutation in a lysosomal gene that renders the phagosome unable to fuse with the lysosome. As a result, the neutrophils contain giant lysosomal granules. Ingested bacteria cannot be lysed normally due to this inability to fuse. Additionally, there is a nearly complete absence of cytotoxic T lymphocyte and NK cell activity, presumably from abnormal lysosomal granule function in these cells.
  • Immunodeficiency: neutropenia; impaired chemotaxis; granule-mediated intracellular bacterial killing sucks; No T cell or NK cell cytolytic activity (cutaneous abscesses, oral lesions, and gm+ pneumonia)
  • Oculocutaneous albinism (mild —> severe) due to poor melanocyte granule development
  • Progressive neuro issues: peripheral neuropathy, cerebellar ataxia, CN palsies
  • 80% of pts have accelerated phase: Hemophagocytic lymphohistiocytosis (HLH) lymphoproliferative, infiltrative dz
56
Q

Phagocyte dysfunction - Chediak-Higashi Syndrome Pathophysiology

A
  • Autosomal recessive mutation in lysosomal trafficking regulator gene (LYST); faulty microtubule activity and poor fusion of lysosomal granules.
  • Leads to defective exocytosis of intracellular proteins, and giant intracellular granules in neutrophils
57
Q

Phagocyte dysfunction - Chediak-Higashi Syndrome Diagnosis

A
  • Albinism
  • Giant neutrophil cytoplasmic granules on peripheral smear
  • Recurrent pyogenic infections
  • NK cell number wnl; no T cell/NK cell activity
  • LYST gene sequencing
58
Q

Phagocyte dysfunction - Chediak-Higashi Syndrome Treatment

A
  • Lethal condition: from sepsis in first decade, or accelerated phase
  • Aggressive abx therapy (and prophylaxis)
  • HSCT mandatory; 62% 5-year survival (need to do this sooner)
59
Q

Phagocyte dysfunction - Leukocyte adhesion deficiency (type 1) Presentation

A
  • Delayed separation of cord at birth w/ omphalitis
  • Leukocytosis (50,000-100,000/ ul)
  • Recurrent skin, mucus membrane infections (Staph, Pseudomonas, candida); gingivitis
  • No pus (defect in neutrophil adhesion)
60
Q

Phagocyte dysfunction - Leukocyte adhesion deficiency (type 1) Pathophysiology

A
  • Autosomal recessive
  • LAD1: deficiency/ defect in common beta chain of b2 integrin (CD18)
  • impaired neutrophil adhesion and chemotaxis; neutrophils cannot leave the vasculature (no extravasation)
61
Q

Phagocyte dysfunction - Leukocyte adhesion deficiency (type 1) Diagnosis and Treatment

A
  • CBC with elevated neutrophil count (demarginated)
  • Flow cytometry with absent or reduced CD18
  • Can sequence beta integrin gene
  • Tx with SCT
62
Q

Complement deficiencies

A
  • Complement deficiencies have been seen in just about every C’ component.
  • Most of the complement genes are autosomal, so complete deficiency requires homozygous mutations.
  • Patients with deficiencies in either the classical pathway or later components tend to do relatively well, except with severe infections.
  • By contrast, patients with alternative pathway factor deficiencies tend to have more frequent and severe infections, particularly early in life.
  • A high incidence of autoimmune diseases seen in patients with inherited complement deficiencies perhaps because of inadequate removal of immune complexes from the circulation due to a lack of opsonins derived from the complement pathway.
63
Q

Complement deficiencies Presentation

A
  • One of the most common types (real-life and Step 1) is terminal complement component deficiency (C5, C6, C7, or C8)
  • High incidence of disseminated Neisserial infections (meningitis, gonococcal inf). They have normal C3, and can opsonize Neisseria, but cannot lyse them
  • Also see increased incidence of autoimmune disease (SLE, RA)
  • C2 deficiency is most common complement deficiency in Caucasian populations; may be asymptomatic, or recurrent respiratory infections (esp S. pneumoniae). Risk of autoimmunity high (esp SLE).
64
Q

Complement deficiencies Diagnosis

A
  • Suspect with recurrent encapsulated infections (esp neisserial infections)…more than one episode of Neisseria infection = C assays
  • Screen with a CH50 test (will be low or ND in all inherited C’ protein deficiencies.
  • Then add on individual C’ component tests (C3, C4, C5-9)
65
Q

Complement deficiencies Treatment

A
  • Meningococcal and pneumococcal vaccinations. (can receive live vaccines).
  • Prophylactic antibiotics if needed
  • No role for FFP
66
Q

Herditary Angioedema: Clinical

A
  • Recurrent episodes of non-pruritic,nonpitting, subcutaneous or submucosal edema; typically involving the arms, legs, hands, feet, bowels, genitalia,trunk,face,tongue,or larynx.
  • Symptoms typically begin in childhood (2-3 yo), worsen in puberty, and persist throughout life, with unpredictable severity.
  • Untreated patients have attacks every 7 to 14 days on average, with the frequency ranging from virtually never to every 3 days
  • Triggers: minor trauma and stress (many attacks occur w/o trigger)
  • Patients with HAE have an increased frequency of autoimmune diseases, especially glomerulonephritis.
67
Q

Herditary Angioedema: Pathophysiology

A
  • C1 esterase inhibitor deficiency
  • C1-INH is made in the liver; modulatesthe complement, coagulation, and contact (bradykinin) pathways. [offswitch]
  • C1 inhibitor:
  • inhibits the formation of activated C1 and the cleavage of C2 and C4.
  • inhibits the ability to produce bradykinin.
  • In HAE: (1) the formation of bradykinin is increased, and patients experience angioedema; (2) the classical complement pathway is excessively activated (C1 INH protein normally blocks both the spontaneous activation of C1 and the formation of activated C1,therefore not allowing C3 convertase to be created).
  • Screen: C4,then C1-INH
68
Q

Herditary Angioedema: Key Points

A
  • Autosomal dominant inheritance
  • 2 main forms: low C1-INH (80%) and non-functional C1-INH (20%)
  • Mimics acute abdomen
  • Major cause of death: laryngeal edema/suffocation
  • No response to epi, antihistamines,corticosteroids
69
Q

Herditary Angioedema: Treatment

A
  • Acute: up until 3 yrs ago–no agents…now IV Pasteurized C1-INH (2009); Nanofiltered pasteurized (2009) [hard to store; hospital use only]
  • Ecallantide (kallikrein inhibitor–no effect on comp or coag pathway); works well
  • Icatibant (bradykinin receptor antagonist)
  • Chronic: Androgen therapy (Danazol) ?increases hepatic production

I & I Part I (25 decks)

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