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47 Cards in this Set
- Front
- Back
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Primary immune deficiencies vs. Secondary ID
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PID are intrinsic defects in the immune system (usually but not always inherited). Secondary ID are due to extrinsic factors that depress the immune response (HIV-1, immunosuppressive drugs)
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When to suspect PID?
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Too many infections or infections that won't go away, weird infections, Infections in weird places, early onset autoimmunity, weird patterns of autoimmunity or immunodysregulation
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Secondary immune diseases - examples/causes?
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Infections (HIV, measles, mononucleosis, severe sepsis, miliary tuberculosis, leprosy), malnutrition, malignancies (lymphoma, leukemias, myeloma), metabolic (diabetes, liver dz, uremia), loss of lymphocytes or AB (nephrotic syndrome, protein-losing enteropathy, burns), Immunosuppressants (corticosteroids, rituximab, others), Collagen vascular dz
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Neutrophil defects: 1. onset; 2. symptoms; 3. common pathogens; 4. examples
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1. early onset in infancy, childhood; 2. severe bacterial infections, Abscesses (skin, internal organs), Gingival/peridontal dz, Poor wound healing (ex. umbilicus), lack of pus; 3. catalase + organisms = Staphylococcus, Aspergillus, nocardia, Burkholderia; 4. CGD, Congenital/cyclic neutropenia, Leukocyte adhesion deficiency
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Neutrophil defects: workup? (initial & secondary evaluation)
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1. CBC with differential (calculate ANC), Oxidative burst testing (DHR-preferred, NBT-old); 2. Chemotaxis, Anti-neutrophil Abs
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Which defect? - Abscesses (skin, internal organs), poor wound healing
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Neutrophil defects
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Complement Defect: 1. onset; 2. types
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Present at any age. 1. Early (C2, C4) defects - Sinopulmonary infections, increased susceptibility to S. pneumoniae, H. Influenzae, Autoimmune dz (SLE, glomerulonephritis); 2. Late (C5-C9) defect - increased susceptibility to Neisserial infections; 3. C3 defects - severe pyogenic infections
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Complement defect: workup (initial & secondary)
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1. CH50 (test for integrity for all classical components); 2. Individual component testing if CH50 low. If >1 complement protein low/absent --> suspect complement consumption (ex. autoimmune dz), AH50 - useful for rare alternative pathway defects
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B-cell/Antibody defects: 1. commonality; 2. symptoms; 3. examples
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1. AB deficiencies most common PIDs (~50%); 2. Agamma-globulinemias usually present in first year or two of life (CVID at any age), REcurrent sinopulmonary bacterial infection (H. Flu, S. pneumo), Enteroviral mengitis, Chronic GI infections (malabsorption, FTT); 3. XLA, CVID, Specific Ab deficiencies
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B-cell/Antibody Defects: workup
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1. Initial - quantitative immunoglobulins (IgG/A/M/E), Vaccine titers (Diphtheria, tetanus, pneumococcus), measure ability to make specific AB; Consider CH50, sweat chloride, CT sinuses/chest; 2. Secondary - FLow cytometry for lymphocytes subsets/ B-cell subsets
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T-cell or Combined T cell/B cell defects: Characteristics & examples
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1. SCID (first year of life - check FHx); 2. Recurrent severe infections; Viruses (disseminated CMV, EBV, varicella), Fungi (oral Candidiasis/thrush>1year old), Bacteria, Opportunistic pathogens (P. jiroveci, Mycobacteria); 3. Poor growth/FTT/Chronic diarrhea; 4. example: T cell - 22q11.2DS (DGS1), DiGeorge syndrome
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T-cell or Combined T cell/B cell defectts (workup)
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Lymphocyte subset enumeration (flow cytometry): numbers of T/B/NK cells, memory, and naive T cells. Cannot diagnose T-cell deficiency by an ALC alone. Immunoglobulins (quantitative, functional). T-cell proliferative response to mitogens (PHA) (Mitogens/Ag stimulation, DTH)
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In all cases of PID, what is the first screening test to do?
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CBC with differential
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Initial screening test for PMN?
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PMN example is CGD. Dihydrorhodamine (DHR) test preferred or NBT
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Case: 3-month old male with respiratory distress. Brother died at age 4 months. Nasal flaring, retractions, poor aeration. Imaging - Bilateral pneumonia/ARDS. Urgent bronchoscopy -- biopsy reveals no thymic shadow
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Severe combined immunodeficiency (SCID)
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WHat is the most common SCID in US?
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X-linked SCID (46% cases)
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X-linked SCID 1. molecular basis; 2. symptom/mortality; 3. Diagnostic studies
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1. Mutation in the common gamma-chain (gamma-c) of the IL-2 receptor. Gamma-c is a shared component for other interleukin receptors(IL-4, IL-7, IL-15, IL-21) --> lack T cells and NK cells; 2. 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); 3. Screening test (CBC - lymphophenia <1.5k in majority of cases). Confirmatory test (lymphocyte enumeration (T cells-naive/memory, B cells, NK cells). Newborn screening for SCID in several states
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What cell count is used for SCID screening test? (What is the common feature of all SCIDs)
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Absent/Non-functional T cells (Naive T Cells reduced in all forms of SCID)
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Why newborn screening for SCID?
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Universally fatal without treatment. Incidence meets criteria for newborn screening. Asymptomatic at birth. Curative therapy is readily available for most. Early treatment (HSCT before 3 months) improves mortality. Cost efficient.
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Screening Test for SCID
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Count TRECs (T cell Receptor Excision Circles) - Nonreplicating circular pieces of DNA in nairve T cells generated in the process of making a T cell receptor. The numbers of TRECs (measured by real-time quantitative PCR) are a surrogate marker for numbers of normal, naive T cells. T cell numbers and TRECs are low in all forms of SCID and other forms of T cell Lymphopenia
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Case: 3 year old male with recurrent thrush, otitis media and 4 CXR documented pneumonias. Child often has problems swallowing liquids (liquid comes out of the nose). VSD repair in infancy. Dysmorphic on PE (low set ears, small chin)
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DiGeorge syndrome (DGS) / 22q11.2 Deletion Syndrome (22qDS)
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DiGeorge Syndrome/22qDS: 1. cause; 2. symptoms
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1. Microdeletion in chromsome 22q11.2 - field defect of 1st to 6th pharyngeal pouchs. Deletion of TBX1 underlies many of the abnormalities; 2. Common (1:2000 - 4000 live births). Wide clinical spectrum - CATCH22 (Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia, 22nd chromosome)
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DiGeorge syndrome - Dx (testing)?
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ALL infants with significant heart defects or unexplained lymphopenia. Chromosome microarray/DNA duplication deletion test (preferred test) - virtually 100% sensitive and specific. FISH (Fluorescent in situ hybridization) - most commonly used test BUT false negative result up to 15%. RT-QPCR for haploinsufficiency TBX1
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DIGeorge syndrome - abnormalities in 1st through 4th pouch
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1st Arch - Facial anomalies (maxillary and mandible - PRS, DGS, RCS); 1st pouch/cleft - tubotympanic anomalies; 2nd pouch; tonsil/thyroid anomalies; 3rd pouch - inferior parathyroid & thymus deficiencies; 4th pouch - superior parathyroid
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DiGeorge syndrome - major phenotypic features
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Immunodeficient (77%), cardiac defect (77%), palate abnormalities (69%), autoimmune disorders(30%), Craniofacial abnormalities, Motor delay, Psychosocial/cognitive delay
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DIGeorge syndrome -- immune abnormalities
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Recurrent/chronic infection and autoimmunity. T cell abnormalities (up to 30% have low T cell counts). AB deficiency (up to 15% require monthly IVIG - B cell sneed T cells to function properly). Recommen immune evaluation before live vaccines. Autoimmunity up to 30% (abnormalities in thymic function likely lead to autoimmunity)
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Case: 5 year old male, recurrent otitis media (2 set of ear tubes), Intractable sinusitis, several hospitalizations for pneumonia beginning in the first year of life. Now with chronic, productive cough. Maternal uncle died at age 30 from pneumonia. Acute sinusitie, bilateral conjunctivitis, bilateral acute otitis media, no tonsils of LN / Quantitative immunoglobulins (Severe pan-hypogammaglobulinemia). Lymphocyte subsets (Normal T cell numbers, no B cell present). HRCT chest (diffuse bronchiectasis)
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X-linked Agammaglobulinemia (XLA)
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XLA (X-linked agammaglobulinemia) - cause
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Mutations in Bruton's tyrosine kinase gene (Btk) results in failure in the differentiation of B cells. Most mutations result in absence of Btk protein can be diagnosed by flow cytometry.
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XLA (X-linked agammaglobulinemia) - symptoms, screening test
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80% of all forms of inherited aggamaglobulimenia are XLA. 1:100,000 live births. Recurrent otitis, sinusitis, pneumonia. EArly dx/Rx(gamma globulin) to prevent bronchiectasis. Encapsulated bacteria AND mycoplasma sp. Severe enteroviral infections - vaccine related polio. Onset infancy or early childhood in most. IgG, IgA, IgM - best screening test for ALL Ab deficiencies.
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Case: 25 yo female. 10 year history of recurrent sinusitis. 4 CXR proven pneumonias in the last 2 years. Chronic, productive cough. Exam: purulent rhinorrhea, bilateral scarred TMs and diffuse sonorous rhonchi / HRCT chest (Bronchiectasis). Cinus CT (opacification R-maxillary sinus/mucosal thickening). Quantitative IGS: IgG-340 mg/dl; IgA-non detected; IgM-22 mg/dl. Lymphocyte subsets (normal numbers of T and B cells)
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Common VAriable immunodeficiency (CVID)
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CVID: commonality, onset, associated dz, cause of death
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Most common PIDD that required the regular care of clinical immunologist. Onset at any age, clinical course variable, delay in diagnosis common. Infections (RTI/GI common). Pulmonary dz (Bronchiectasis and interstitial lung dz). Autoimmunity (ITP, AHA others) 10-20%. Causes of Death - Pulmonary dz. Cancer (B cell lymphomas > gastric cancter). Autoimmune complications, liver dz infection
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CVID - common non-infectious Cxn
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1. lung: diffuse (restrictive - GLILD, BOOP, malignancy), Obstructive (bronchiectasis, asthma, BO); 2. Neoplasia (lymphoma - B cell, Gastric Carcinoma; 3. Autoimmunity - Cytopenias (ITP, AHA, CD4 lymphopenia); 4. GI dz (IBD, Focal nodular hyperplasia, atrophic gastritis; 5. Liver Dz (granulomatous hepatitis, autoimmune hepatitis
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CVID - diagnosis
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Decrease in IgG (>2 SD below mean) AND a low IgA and/or IgM: onset > 2 yo. Absent isohemagglutinins and poor response to vaccines. Exclude primary AB deficiency (XLA), Exclude secondary AB deficiency (drugs - corticosteroids, rituximab; protein losing enteropathy, B cell lymphomas)
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IgA deficiency
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Most common AB deficiency (1:400 live births). Extremely low IgA (<10mg/dl), normal IgG, IgM. Rarely associated with IgG subclass deficiency (IgG2) and/or CVID (assess AB response to immunization in patients with recurrent infection). Normal T cell function. Many subjects are normal (no phenotype). Some subjects with increased sinopulmonary infections or increased GI infections (Giarda). Increased incidence of atopy and autoimmune disease. DO no Rx with IVIG
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What is the most common AB deficiency?
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IgA deficiency
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Disease? pulmonary disease - bronchiectasis and interstitial lung disease. Most common PIDD
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CVID
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Antibody deficiencies(Lab tests): Serum IgG, IgA, IgM levels - 1. decrease in all isotypes?; 2. decrease in 2 of 3 major isotypes including IgG
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1. XLA; 2. CVID
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How does XLA and CVID respond to serum IgG, IgA, IgM test? response to vaccine?
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1. XLA - low in all isotypes; 2. CVID - low IgG AND low IgA or/and IgM; 3. Both have poor specific Ab response to vaccines
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Case: 3 year-old-male with fever, abdominal pain. History of recurrent, severe skin infections, poor growth, always on antibiotics. Multiple healed skin leasons, lymphadenopathy, abdominal pain. Ultrasound shows rim-enhancing, fluid-filled lesion in liver. Labs - abscess fluid (liver) grows S. Aureaus
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Chronic Granulomatous disease
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CGD - 1. cause; 2. clinical finding
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1. All genetic forms: functional absence of respiratory burst in neutrophils and monocytes- impaired bactericidal killing. NADPH oxidase has four subunits -- defects in any leads to CGD. X-linked (76%). Others are autosomal recessive (have some leftover oxidase); 2. Pneumonia (70%), Adenopathy/adenitis/abscesses (40-50%), sepsis (25%), osteomyelitis (20%), Infection with catalase + bacteria (S. aureus, Serratia, Salmonella, Nocardia, Klebsiella, Burkholderia) and fungi (Aspergillus, Candida)
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CGD - Diagnosis and treatment
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Diagnosis - Dihydrorhodamine test (DHR - preferred) or Nitroblue tetrazolium test (NBT). Treatment - bone marrow transplantation.
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Liver abscess in infant or young child. which dz?
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CGD
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Case: 20 yo male with scattered petechiae, photophobia and meningismus. prior history of meningitis in past. Culture (N. Meningitidis)
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Late Complement Deficiency (C5-C9)
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Late Complement deficiencies
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Patient percentage - healthy (25-40%), Autoimmune disease (<1%), Infection (50-60%). First infection 17 years. Homozygotes ar eat risk. Recurrent meningococcal disease. C5, C6-C9 late components of complement form the membrane attack complex.
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Recurrent Meningococcal disease. Membrane attack complex. Which dz?
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Late Complement Deficiency (C5-C9)
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Early Complement deficiencies
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C2: most common deficiency. AR. Associated with collagen vascular diseases (SLE). Recurrent bacteremia: pneumococcus, H. Influenzae, enteric bacteria, staph.
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Best screening test for ALL classical complement deficiencies?
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CH50
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