Updated: 12/13/2019

Hypersensitivity Reactions

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Overview
  • Auto immune disease or excess response to foreign stimulus
    • categorized by
      • type of effector mechanism
        • Types I, II, and III are all antibody mediated
        • Type IV is TH1 mediated
  • Commonalities between all types
    • requires a sensitizing exposure
    • reactions occur in later exposures
  • Timeline
    • [Fastest] Type I < Type II / III < Type IV [Slowest]
Type I
  • Immune relationship
    • IgE mediated
      • only type
    • fast
      • within minutes of re-exposure
    • protective against parasites
    • atopic or alleric responses
    • effector cells
      • basophil, mast cell
  • Mechanism of tissue injury
    • sensitizing exposure
    • followed by a reaction exposure
  • Presentation
    • vasodilation of post capillary venules
    • inflammation
    • bronchoconstriction
    • intestinal hypermotility
    • tissue damage
  • Disorder
    • anaphylaxis
      • bronchial/trachial constriction
      • systemic vasodilation
      • death
      • e.g. bee sting, some food/drug allergies
      • treat with EpiPen (epinephrine)
    • allergic rhinitis
      • "hay fever"
    • asthma
      • bronchial/trachial constriction
      • inflammation
      • mucus
  • Test
    • scratch test
      • wheal and flare
      • in vivo
      • skin edema, reddening near scratch introduction
    • radioimmunosorbent assay
Type II
  • Immune relationship
    • Antibody mediated
      • IgM, IgG bind to antigen
      • complement activation
      • results in lysis via membrane attack complex or phagocytosis
    • effector cells
      • cytotoxic
        • PMN, macrophages, NK cells
      • non-cytotoxic
        • none
  • Mechanism of tissue injury
    • antibodies lead to disease via three different processes
      • activation of complement or opsonization
      • recruitment of neutrophils and macrophages that incite tissue damage
      • interfere with normal receptor function
  • Presentation
    • disease localized to specific tissues where antibodies are present
  • Disorder
    • cytotoxic
      • autoimmune hemolytic anemia (HDNB)
        • anti-RBC antibodies (other than ABO proetins)
        • destruction of RBC
          • hemolysis, anemia
      • idiopathic thrombocytopenic purpura
        • anti-platelet antibodies
        • destruction of platelet
          • thrombocytopenia, bleeding
      • erythroblastosis fetalis
        • aka Hemolytic disease of the newborn (HDNB)
          • RhD- mother must have had previous RhD+ pregnancy where she was exposed to fetal blood
            • delivery, termination
          • anti-RhD+ IgG that can cross the placenta attack fetus
        • prophylaxis/treatment
          • RhoGAMTM
            • anti-RhD IgG
            • given to Rh- mother at
              • 28 weeks gestation
              • within 72 hours of delivery
            • prevents mother from developing B-cell memory of RhD
      • acute hemolytic transfusion reactions
        • anti-ABO RBC protiens IgM (isohemagglutinins)
          • hemolysis
      • acute rheumatic fever
        • antibody against streptococcal cell wall binds healthy tissue
          • heart and joint inflammation
      • Goodpasture's syndrome 
        • anti-type IV collagen antibody 
          • lung alveoli
            • lung hemmorhage
          • kidney glomeruli
            • nephritis
            • linear deposits
              • unlike post-streptococcal glomerulonephritis
                • lumpy bumpy pattern
      • bullous pemphigoid
        • anti-hemidesmosomes at the dermoepidermal junction
          • separation of epidermis from basement membrane
          • results in formation of tense blisters
      • pemphigus vulgaris
        • autoantibodies against desmoglein 1 and/or 3 in the epidermis
        • results in acantholysis and formation of flaccid blisters 
    • non-cytotoxic
      • Graves' disease
        • anti-TSH receptor antibody
          • stimulates T3/4 release
            • hyperthyroid followed by hypothyroid
      • myasthenia gravis
        • anti-Acetylcholine receptor antibody
          • inhibits muscle stimulation
            • muscle weakness, paralysis
      • pernicious anemia
        • anti-intrinsic factor antibody
          • inhibits binding of IF to receptor
            • decreased vit B12 absorbtion >> macrocytic anemia
      • type II diatbetes
        • anti-Inuslin receptor antibody
          • inhibits binding of insulin
            • hyperglycemia
  • Test
    • direct Coombs test
      • measures IgG/C3b bound to RBCs
        • "direct attachment"
    • indirect Coombs test
      • measures free antibodies in serum
Type III
  • Immune relationship
    • Immune complex mediated
      • antigen-antibody (IgG) complexes form
      • antigens can be self or foreign
    • effector cells
      • PMN, macrophages
  • Mechanism of tissue injury
    • complexes are filtered out of circulation and deposited in healthy tissue
    • neutrophils attracted and complement activated by Ab-Ag complex
    • neutrophils release lysosomal enzymes
    • healthy tissue damaged
  • Presentation
    • widespread mobility of Ab-Ag complexes allows for vasculitis and systemic manifestations
      • compared to type II with generally localized reactions
  • Disease
    • SLE
      • anti-dsDNA, anti-Sm, anti-Rho antibodies in complex with antigen
        • butterfly facial rash, nephritis, arthritis, vasculitis
    • Serum sickness
      • antibodies to the foreign proteins are produced and complex formed
        • takes 5 days
        • e.g., horse antithymocyte globulin antibody in transfused serum
          • now more common from drugs
            • e.g., beta-lactams, sulfa drugs, anti-venin
        • fever, urticaria, arthralgias, proteinuria, lymphadenopathy 
          • 5-10 days after antigen exposure 
        • usually self-limited, and will resolve with withdrawal of the offending agent
          • management may also involve symptomatic treatment 
            • e.g., antihistamines or steroids
    • Arthus reaction
      • antigen-antibody complexes cause the Arthus reaction
      • a local subacute antibody-mediated hypersensitivity (type III) reaction
      • intradermal injection of antigen induces antibodies, which form antigen-antibody complexes in the skin
      • characterized by edema, necrosis, and activation of complement
    • rheumatoid arthritis
      • anti-IgM Fc region antibody complex with antigen
        • joint pain, decrease in range of motion
    • polyarteritis nodosa
      • deposition of complexes in medium sized arteries
    • poststreptococcal glomerulonephritis
      • anti-Streptococcal cell wall antibody with antigen
      • nephritis
        • "lumpy bumpy pattern" on immunofluorescence staining
          • large complexes so they cannot coat the entire membrane like in Goodpasture's (small IgG)
    • hypersensitivity pneumonitis
      • inhaled dust forms an Ab-Ag complex
      • e.g. farmer's lung
  • Test
    • immunofluorescent staining
Type IV
  • Immune relationship
    • senstitizing antigen exposure
      • memory T-lymphocytes generated
    • effector cells
      • CTL, Th1 , macrophages
  • Mechanism of injury
    • sensitized T lymphocytes encounter antigen and then release lymphokines
      • mainly IFN-γ
      • leads to macrophage activation
        • TNF secretion
      • no antibody involved
    • cell-mediated toxicity, therefore not transferable by serum
  • Presentation
    • response is delayed and does NOT involve antibodies (vs. types I, II, and III) or complement
  • Disease 
    • type 1 DM
      • T-cells against islet cells, insulin, glutamic acid decarboxylase
    • multiple sclerosis
      • T-cells against myelin of CNS
    • Guillain-Barré syndrome
      • T-cells against myelin of PNS
    • Hashimoto's thyroiditis
      • T-cells against antigen in thyroid
    • graft-versus-host disease
      • T-cells of transplant origin become activated against MHC of host
    • PPD (test for M. tuberculosis)
      • T-cells of skin against tuberculin/mycolic acid
    • contact dermatitis 
      • e.g. poison ivy, nickel allergy
      • pruritus, rash, skin lesions
  • Test
    • patch test
      • e.g. PPD, patch containing any antigen placed on skin

References

 

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Questions (3)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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(M2.DM.17.4769) A five-year-old boy presents with his mother to your clinic complaining of a fever and rash. His mother says the patient was in his usual state of health until two weeks ago when he developed “strep throat.” He was prescribed a ten day treatment with oral amoxicillin by his primary care physician, which he has since completed. The mother reports that he seemed to feel better until two days ago when he began to complain of joint pain and an itchy rash. His mother notes the patient is on an “alternative vaccine schedule.” She is nervous because her son attends day-care three days a week, and there has been a recent “viral" outbreak. The patient’s temperature is 103°F (39.4°C), blood pressure is 99/59 mmHg, pulse is 110/min, and respirations are 20/min with an oxygen saturation of 99% O2 on room air. On physical exam, you note cervical adenopathy, joint swelling, mild peripheral edema, and a diffuse rash (shown in Figure A). Which of the following is the best treatment for this patient’s condition? Review Topic | Tested Concept

QID: 109136
FIGURES:
1

Penicillin

4%

(1/28)

2

Aspirin and IVIG

18%

(5/28)

3

Rituximab

11%

(3/28)

4

Diphenhydramine

57%

(16/28)

5

Vitamin A

11%

(3/28)

L 3 D

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(M2.DM.14.9) A 14-year-old boy presents to his family physician with a 1-day history of a rash. He denies any history of a similar rash or any dermatologic diagnoses in the past. The mother states that their family was in upstate New York for the past week; however, the child has had no other new events or exposures. His temperature is 98.0°F (36.7°C), blood pressure is 104/74 mmHg, pulse is 87/min, respirations are 12/min, and oxygen saturation is 98% on room air. Physical exam is notable for the finding in Figure A. Which of the following diagnoses shares the same pathophysiology as this patient's diagnosis? Review Topic | Tested Concept

QID: 104220
FIGURES:
1

Anaphylaxis

36%

(4/11)

2

Goodpasture syndrome

36%

(4/11)

3

Hashimoto thyroiditis

0%

(0/11)

4

Serum sickness

0%

(0/11)

5

Urticaria

0%

(0/11)

L 2 E

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