# Clinical Cases: Immunopathology

## Case 1: Anaphylaxis - Type I Hypersensitivity

### Patient Demographics
- **Age:** 28 years
- **Sex:** Female
- **Occupation:** Software engineer

### Chief Complaint
"I can't breathe and my throat is closing up."

### History of Present Illness
A 28-year-old woman is brought to the emergency department by ambulance after developing sudden onset of difficulty breathing, throat tightness, and generalized itching at a restaurant. She was eating dinner when she noticed tingling of her lips about 10 minutes after starting her meal. Within minutes, she developed hives all over her body, swelling of her lips and tongue, throat tightness, difficulty breathing, and lightheadedness. Her meal contained shrimp, which she has eaten many times before without problems. However, she recalls having "mild hives" after eating crab 3 months ago, which resolved on its own. Paramedics administered epinephrine 0.3 mg IM en route, with partial improvement.

### Past Medical History
- Seasonal allergies (allergic rhinitis)
- Mild asthma (uses albuterol PRN, rare)
- Possible shellfish allergy (recent mild reaction to crab)

### Allergies
- Penicillin (childhood rash - unclear details)

### Physical Examination (On ED Arrival)
- **Vital Signs:** BP 88/54 mmHg, HR 122 bpm, RR 28/min, O2 sat 91% on room air
- **General:** Anxious, diaphoretic, using accessory muscles
- **HEENT:** Angioedema of lips and tongue; uvula edematous; stridor audible
- **Skin:** Diffuse urticaria (raised, erythematous, pruritic wheals) over trunk and extremities
- **Respiratory:** Inspiratory stridor, diffuse wheezing bilaterally
- **Cardiovascular:** Tachycardic, weak peripheral pulses

### Immediate Assessment
**Anaphylaxis** - Clinical criteria met:
1. Acute onset involving skin (urticaria) AND
2. Respiratory compromise (stridor, wheezing, hypoxia) AND
3. Hypotension

### Pathophysiology - Type I (IgE-Mediated) Hypersensitivity

**Sensitization Phase (Prior Exposure):**
1. Initial exposure to allergen (shellfish proteins)
2. Allergen processed by APCs, presented to Th2 cells
3. Th2 cells produce IL-4 and IL-13, promoting B cell class switching to IgE
4. Allergen-specific IgE produced and binds to FcepsilonRI receptors on mast cells and basophils (sensitization complete)

**Effector Phase (Current Exposure):**
1. Re-exposure to allergen (shrimp proteins cross-react with crab)
2. Allergen cross-links IgE antibodies on mast cell surface
3. Cross-linking triggers mast cell degranulation within SECONDS
4. Release of preformed mediators:
   - **Histamine:** Vasodilation, increased vascular permeability, bronchoconstriction, pruritus
   - **Tryptase:** Mast cell activation marker (diagnostic)
   - **Heparin, proteases**
5. Synthesis of new mediators (late phase):
   - **Leukotrienes (LTC4, LTD4):** Prolonged bronchoconstriction
   - **Prostaglandins (PGD2):** Vasodilation, bronchoconstriction
   - **Cytokines:** Sustain inflammatory response

**Clinical Manifestations by System:**
| System | Manifestation | Mechanism |
|--------|---------------|-----------|
| Skin | Urticaria, flushing, angioedema | Histamine-mediated vasodilation, increased permeability |
| Respiratory | Bronchospasm, laryngeal edema, stridor | Smooth muscle contraction, mucosal edema |
| Cardiovascular | Hypotension, tachycardia | Vasodilation, fluid shift to extravascular space |
| GI | Nausea, vomiting, cramping, diarrhea | Smooth muscle contraction, increased secretions |

### Treatment

**IMMEDIATE - First-Line Treatment:**

**1. EPINEPHRINE (Most Critical Intervention):**
- **Epinephrine 0.3-0.5 mg IM (1:1000 concentration) into anterolateral thigh**
- Repeat every 5-15 minutes if no improvement
- Patient received one dose en route; give second dose now

**Why Epinephrine Works:**
- Alpha-1 agonism: Vasoconstriction (reverses hypotension, reduces angioedema)
- Beta-1 agonism: Increased cardiac output
- Beta-2 agonism: Bronchodilation, inhibits mast cell mediator release

**2. Positioning:**
- Trendelenburg (legs elevated) if hypotensive
- Sitting up if respiratory distress predominates
- Do not have patient sit or stand suddenly (risk of cardiac arrest)

**3. Airway Management:**
- High-flow oxygen
- Prepare for intubation if worsening stridor/angioedema
- Consider early intubation before complete airway obstruction

**4. IV Access and Fluids:**
- Large-bore IV access
- Normal saline 1-2 L bolus for hypotension (may need several liters)
- Anaphylaxis causes massive third-spacing

**SECOND-LINE Adjunctive Treatments:**

**5. Antihistamines:**
- **H1 blocker:** Diphenhydramine 25-50 mg IV
- **H2 blocker:** Famotidine 20 mg IV
- Help with urticaria and pruritus; do NOT replace epinephrine

**6. Glucocorticoids:**
- **Methylprednisolone 125 mg IV** or hydrocortisone 200 mg IV
- Onset delayed (4-6 hours); used to prevent biphasic reaction
- Does NOT treat acute symptoms

**7. Bronchodilators:**
- **Albuterol nebulizer** for bronchospasm not responding to epinephrine

**8. If Refractory Hypotension:**
- Epinephrine infusion (1-10 mcg/min)
- Vasopressors (norepinephrine) if needed

### Clinical Course
- Second IM epinephrine given with improvement in BP (102/68) and breathing
- Intubation not required; stridor resolved
- Urticaria improved with antihistamines
- Observed for 6 hours for biphasic reaction (occurs in 1-20% of cases)
- Discharged with epinephrine auto-injector prescription and allergy referral

### Discharge Plan

**Prescriptions:**
1. **Epinephrine auto-injector (EpiPen):** Carry at ALL times; prescribe 2 devices
2. **Diphenhydramine 25 mg:** Take every 6 hours for 3 days for residual symptoms
3. **Prednisone 50 mg daily x 3 days:** Prevent biphasic/protracted reaction

**Education:**
1. Strict shellfish avoidance (all crustaceans: shrimp, crab, lobster, crawfish)
2. Cross-reactivity: ~75% cross-react between crustacean species
3. Read all food labels; ask about ingredients at restaurants
4. Know how to use epinephrine auto-injector
5. Seek emergency care immediately after using epinephrine

**Referrals:**
1. Allergist/immunologist for confirmatory testing (skin prick test, specific IgE)
2. Consider evaluation of penicillin allergy (may be outgrown)

### Clinical Pearl
Epinephrine is the ONLY first-line treatment for anaphylaxis - antihistamines and steroids are adjuncts only. Delayed epinephrine administration is associated with increased mortality. Biphasic anaphylaxis (recurrence of symptoms hours after initial resolution) occurs in up to 20% of cases, which is why observation for 4-6 hours and steroid administration are recommended. Serum tryptase, if drawn within 1-2 hours of onset, can help confirm mast cell activation and support the diagnosis. All patients with anaphylaxis should be prescribed epinephrine auto-injectors and referred to an allergist.

### Clinical Image
![Urticaria](case_01_image.jpg)

*Clinical photograph demonstrating urticaria (hives) with characteristic raised, erythematous, pruritic wheals. Urticaria results from histamine-mediated vasodilation and increased vascular permeability in type I hypersensitivity reactions.*

**Image Source:** Wikimedia Commons - "Urticaria"
**License:** CC BY-SA 3.0
**URL:** https://commons.wikimedia.org/wiki/File:Urticaria.jpg

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## Case 2: Systemic Lupus Erythematosus - Type III Hypersensitivity

### Patient Demographics
- **Age:** 24 years
- **Sex:** Female
- **Occupation:** Graduate student

### Chief Complaint
"I have joint pain, a rash on my face, and I've been so tired."

### History of Present Illness
A 24-year-old woman presents with a 3-month history of fatigue, joint pain, and facial rash. She first noticed symmetric pain and swelling in her hands (particularly the small joints of her fingers and wrists) that is worse in the morning and lasts several hours. She developed a rash across her cheeks and nose that worsens with sun exposure. She reports profound fatigue, low-grade fevers, and oral ulcers that come and go. She has lost 10 pounds without trying. She also notes her fingers turn white then blue in cold weather. Over the past week, she has noticed ankle swelling and "foamy urine."

### Past Medical History
- Previously healthy
- History of recurrent pregnancy loss (two first-trimester miscarriages)

### Family History
- Mother with rheumatoid arthritis
- Maternal aunt with "lupus"

### Physical Examination
- **Vital Signs:** BP 148/92 mmHg, HR 88 bpm, T 37.9C
- **General:** Tired-appearing young woman
- **Skin:** Erythematous, slightly raised rash over malar eminences bilaterally, sparing nasolabial folds (malar/butterfly rash); photosensitivity reported
- **HEENT:** Painless oral ulcers on hard palate
- **Musculoskeletal:** Symmetric synovitis of MCPs and wrists; no deformities
- **Cardiovascular:** Regular rhythm, no murmurs, rubs, or gallops
- **Respiratory:** Clear to auscultation
- **Extremities:** 2+ pitting edema bilaterally
- **Neurologic:** Alert, oriented; no focal deficits

### Workup

**Laboratory Studies:**
- **CBC:** WBC 3,200 (leukopenia), Hgb 10.2 g/dL (anemia), Platelets 118,000 (thrombocytopenia)
- **BMP:** Cr 1.4 mg/dL (elevated), BUN 28 mg/dL
- **Urinalysis:** 3+ protein, 2+ blood, RBC casts present
- **24-hour urine protein:** 3.2 g (nephrotic range)
- **Complement levels:** C3 42 mg/dL (low; normal 90-180), C4 8 mg/dL (low; normal 10-40)

**Autoantibodies:**
- **ANA:** Positive, 1:640 titer, homogeneous pattern
- **Anti-dsDNA:** Positive, 185 IU/mL (elevated; correlates with disease activity)
- **Anti-Smith (Anti-Sm):** Positive (highly specific for SLE)
- **Antiphospholipid antibodies:** Positive (lupus anticoagulant, anticardiolipin IgG)
- **Direct Coombs:** Positive (evidence of autoimmune hemolysis)

**Renal Biopsy:**
- Class IV diffuse proliferative lupus nephritis
- "Full house" immunofluorescence: IgG, IgA, IgM, C3, C1q deposits
- Active inflammatory lesions

### Diagnosis
**Systemic Lupus Erythematosus (SLE)** with:
- Class IV lupus nephritis
- Antiphospholipid syndrome (positive aPL antibodies, recurrent pregnancy loss)
- Autoimmune cytopenias (leukopenia, anemia, thrombocytopenia)

**2019 EULAR/ACR Classification Criteria Met:**
- Entry criterion: ANA positive
- Clinical domains: Constitutional, mucocutaneous (malar rash, oral ulcers, photosensitivity), musculoskeletal (synovitis), renal (proteinuria, RBC casts)
- Immunologic domains: Low complement, anti-dsDNA, anti-Sm, antiphospholipid antibodies

### Pathophysiology - Type III Hypersensitivity

**Immune Complex Disease:**
1. **Autoantibody production:** Loss of self-tolerance leads to antibodies against nuclear antigens (DNA, histones, ribonucleoproteins)
2. **Immune complex formation:** Antibodies bind circulating self-antigens, forming antigen-antibody complexes
3. **Immune complex deposition:** Complexes deposit in vessel walls, glomeruli, skin, joints, and other tissues
4. **Complement activation:** Deposited complexes activate complement (classical pathway via C1q binding)
5. **Inflammatory response:** Complement activation generates C3a/C5a (anaphylatoxins), recruits neutrophils, causes tissue damage
6. **Tissue injury:** Neutrophil degranulation, oxidative damage, fibrinoid necrosis

**Why Complement is LOW in Active SLE:**
- Complement is consumed during immune complex clearance
- Low C3 and C4 indicate active complement consumption
- C3/C4 levels and anti-dsDNA titers correlate with disease activity

**Key Autoantibodies in SLE:**
| Antibody | Sensitivity | Specificity | Clinical Correlation |
|----------|-------------|-------------|---------------------|
| ANA | 95-99% | Low | Screening test; not specific |
| Anti-dsDNA | 70% | 95% | Correlates with nephritis activity |
| Anti-Smith | 25% | 99% | Highly specific; does not correlate with activity |
| Anti-histone | 70% | Low | Drug-induced lupus |
| Antiphospholipid | 30-40% | Moderate | Thrombosis, pregnancy loss |

### Treatment Plan

**ACUTE MANAGEMENT OF LUPUS NEPHRITIS (Class IV):**

**1. Induction Therapy:**
- **Mycophenolate mofetil (MMF) 1 g BID** (preferred for many patients)
  - OR Cyclophosphamide IV (Euro-Lupus protocol: 500 mg every 2 weeks x 6 doses)
- **PLUS Glucocorticoids:**
  - Methylprednisolone 500-1000 mg IV daily x 3 days (pulse)
  - Then prednisone 1 mg/kg/day (max 60 mg), taper over months

**2. Maintenance Therapy (after induction):**
- MMF 1-2 g daily or azathioprine 2 mg/kg/day
- Low-dose prednisone (goal <7.5 mg/day)

**3. Adjunctive Therapies:**
- **Hydroxychloroquine 200-400 mg daily** - ALL SLE patients
  - Reduces flares, damage accrual, mortality
  - Mechanism: Inhibits TLR signaling, reduces cytokine production
- **ACE inhibitor** for proteinuria and hypertension

**4. Antiphospholipid Syndrome Management:**
- Aspirin 81 mg daily (primary prevention)
- If thrombosis occurs: Lifelong warfarin anticoagulation
- Discuss pregnancy planning (high risk)

**MONITORING:**
- Renal function and urinalysis regularly
- Anti-dsDNA and complement levels (activity markers)
- CBC for cytopenias
- Hydroxychloroquine: Annual ophthalmologic exam (retinal toxicity)

### Follow-up
- Rheumatology and nephrology co-management
- Repeat renal function in 2-4 weeks
- Assess response to induction therapy at 3-6 months
- Transition to maintenance when remission achieved

### Clinical Pearl
SLE is the prototypical immune complex (Type III hypersensitivity) disease. The "full house" immunofluorescence on renal biopsy (IgG, IgA, IgM, C3, C1q) is characteristic of lupus nephritis and reflects the broad polyclonal autoantibody production. Anti-dsDNA levels and complement consumption (low C3/C4) correlate with disease activity, particularly nephritis - rising anti-dsDNA and falling complement often herald a flare. Hydroxychloroquine is disease-modifying and should be prescribed to ALL SLE patients regardless of disease activity. Class IV (diffuse proliferative) lupus nephritis requires aggressive immunosuppression to prevent progression to ESRD. The combination of SLE with antiphospholipid antibodies significantly increases thromboembolic risk and requires careful management during pregnancy.

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