# Clinical Cases: Innate Immunity

## Case 1: Chronic Granulomatous Disease

### Patient Demographics
- **Age:** 4 years old
- **Sex:** Male
- **Ethnicity:** Caucasian

### Chief Complaint
Recurrent skin abscesses and pneumonia

### History of Present Illness
A 4-year-old boy is brought to the pediatric immunology clinic for evaluation of recurrent infections. Since infancy, he has had multiple skin abscesses requiring surgical drainage, three episodes of pneumonia requiring hospitalization, and one episode of liver abscess. His mother notes that the abscesses often lack significant redness and pus despite being large. He was recently hospitalized for Aspergillus pneumonia requiring antifungal therapy.

### Past Medical History
- Multiple skin abscesses (Staphylococcus aureus cultured from several)
- Pneumonia at ages 1, 2, and 4 years
- Liver abscess at age 3 (Serratia marcescens cultured)
- Perianal abscess at age 2

### Family History
- Maternal uncle died at age 12 from recurrent infections
- Mother has no history of significant infections

### Physical Examination
- **General:** Alert, thin-appearing child, below 10th percentile for weight
- **Vital Signs:** T 37.8C, HR 110, RR 22, BP 95/60
- **HEENT:** Cervical lymphadenopathy
- **Lungs:** Decreased breath sounds at right base, scattered rhonchi
- **Abdomen:** Hepatomegaly palpable 3 cm below costal margin
- **Skin:** Multiple hyperpigmented scars from prior abscesses, one active draining lesion on right thigh

### Laboratory Workup
| Test | Result | Reference Range |
|------|--------|-----------------|
| WBC | 18,500/uL | 5,500-15,500/uL |
| Neutrophils | 72% | 40-70% |
| Immunoglobulins | Normal IgG, IgA, IgM | -- |
| **DHR Flow Cytometry** | **Absent oxidative burst** | Normal burst expected |
| Genetic testing | CYBB mutation | -- |

### Clinical Image
![Chronic Granulomatous Disease - Skin Abscess](https://upload.wikimedia.org/wikipedia/commons/thumb/5/5e/Chronic_Granulomatous_Disease.jpg/220px-Chronic_Granulomatous_Disease.jpg)

*Image source: Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Chronic_Granulomatous_Disease.jpg). Licensed under CC BY-SA 3.0.*

### Diagnosis
**X-linked Chronic Granulomatous Disease (CGD)** due to CYBB mutation affecting the gp91phox component of the NADPH oxidase complex.

### Discussion
CGD results from defects in the phagocyte NADPH oxidase complex, which generates superoxide and other reactive oxygen species essential for intracellular killing. The X-linked form (affecting CYBB/gp91phox) accounts for approximately 65% of cases. Patients characteristically develop infections with catalase-positive organisms (Staphylococcus aureus, Aspergillus, Serratia, Burkholderia cepacia, Nocardia) because these organisms destroy their own hydrogen peroxide, preventing the phagocyte from using this pathogen-derived source for oxidative killing.

### Treatment
1. **Prophylaxis:** Trimethoprim-sulfamethoxazole (TMP-SMX) for bacterial prophylaxis, itraconazole for fungal prophylaxis
2. **Interferon-gamma:** Reduces infection frequency by enhancing residual phagocyte function
3. **Aggressive treatment of infections:** Prompt identification and treatment with appropriate antimicrobials
4. **Definitive therapy:** Hematopoietic stem cell transplantation (curative); gene therapy under investigation

---

## Case 2: Hereditary Angioedema

### Patient Demographics
- **Age:** 28 years old
- **Sex:** Female
- **Ethnicity:** Hispanic

### Chief Complaint
Recurrent episodes of facial swelling and abdominal pain

### History of Present Illness
A 28-year-old woman presents to the emergency department with progressive swelling of her lips and face over the past 6 hours. She has experienced similar episodes multiple times since adolescence, often preceded by stress or minor trauma. She also reports frequent episodes of severe abdominal pain lasting 1-3 days, sometimes associated with vomiting. Notably, antihistamines and corticosteroids have never provided relief during these episodes. Her sister and father have similar symptoms.

### Past Medical History
- Multiple ER visits for facial swelling (10+ episodes)
- One episode of laryngeal swelling requiring intubation at age 22
- Frequent unexplained abdominal pain episodes

### Family History
- Father with similar recurrent swelling episodes
- Sister with recurrent abdominal pain and one episode of laryngeal edema
- Paternal grandmother died of "airway swelling"

### Physical Examination
- **General:** Anxious-appearing woman with visible facial swelling
- **Vital Signs:** T 37.0C, HR 95, RR 18, BP 125/80, SpO2 98% on room air
- **HEENT:** Significant lip edema (especially upper lip), periorbital edema, no urticaria
- **Oropharynx:** Uvula edema, no stridor, able to handle secretions
- **Skin:** No hives or erythema
- **Lungs:** Clear
- **Abdomen:** Soft, mild diffuse tenderness

### Laboratory Workup
| Test | Result | Reference Range |
|------|--------|-----------------|
| C4 level | 3 mg/dL | 14-40 mg/dL |
| C1 inhibitor level | 6 mg/dL | 21-39 mg/dL |
| C1 inhibitor function | 15% | 70-130% |
| C3 level | Normal | -- |
| Tryptase | Normal | -- |

### Clinical Image
![Hereditary Angioedema - Lip Swelling](https://upload.wikimedia.org/wikipedia/commons/thumb/4/4a/Angioedema2010.JPG/220px-Angioedema2010.JPG)

*Image source: Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Angioedema2010.JPG). Licensed under CC BY-SA 3.0.*

### Diagnosis
**Hereditary Angioedema Type 1** due to C1 inhibitor deficiency.

### Discussion
Hereditary angioedema (HAE) results from deficiency or dysfunction of C1 inhibitor (C1-INH), a serine protease inhibitor that regulates the classical complement pathway (inhibiting C1r and C1s) and the contact activation system (inhibiting kallikrein and factor XIIa). When C1-INH is deficient, uncontrolled activation of the contact system leads to excessive bradykinin generation. Bradykinin is the primary mediator of angioedema in HAE, causing increased vascular permeability without mast cell activation - explaining why antihistamines and corticosteroids are ineffective.

Key features:
- Angioedema WITHOUT urticaria (distinguishing it from allergic angioedema)
- Recurrent abdominal attacks from bowel wall edema
- Risk of potentially fatal laryngeal edema
- Low C4 (even between attacks) is a sensitive screening test
- Autosomal dominant inheritance

### Treatment
**Acute attacks:**
- C1 inhibitor concentrate (plasma-derived or recombinant)
- Icatibant (bradykinin B2 receptor antagonist)
- Ecallantide (kallikrein inhibitor)
- Fresh frozen plasma (if specific treatments unavailable)

**Prophylaxis (for frequent attacks):**
- Lanadelumab (anti-kallikrein monoclonal antibody)
- C1 inhibitor concentrate
- Berotralstat (oral kallikrein inhibitor)
- Attenuated androgens (danazol) - less commonly used due to side effects

---

## Case 3: Complement C5 Deficiency

### Patient Demographics
- **Age:** 19 years old
- **Sex:** Male
- **Ethnicity:** African American

### Chief Complaint
Second episode of meningococcal meningitis

### History of Present Illness
A 19-year-old male college student presents with fever, severe headache, neck stiffness, and photophobia for 1 day. Three years ago, he was hospitalized for meningococcal meningitis (Neisseria meningitidis serogroup Y) and made a full recovery. He had received the meningococcal conjugate vaccine before college.

### Past Medical History
- Meningococcal meningitis at age 16
- Otherwise healthy
- Up to date on vaccinations including meningococcal conjugate and serogroup B vaccines

### Family History
- Older brother had gonococcal arthritis at age 25
- No other family history of unusual infections

### Physical Examination
- **General:** Ill-appearing, lethargic
- **Vital Signs:** T 39.5C, HR 120, RR 24, BP 100/65
- **HEENT:** Photophobia, positive Kernig and Brudzinski signs
- **Skin:** Several petechiae on lower extremities
- **Neurological:** GCS 14, neck rigidity

### Laboratory Workup
| Test | Result | Reference Range |
|------|--------|-----------------|
| WBC | 22,000/uL | 4,500-11,000/uL |
| CSF WBC | 2,500/uL (95% PMNs) | 0-5/uL |
| CSF protein | 250 mg/dL | 15-45 mg/dL |
| CSF glucose | 25 mg/dL | 40-70 mg/dL |
| CSF Gram stain | Gram-negative diplococci | -- |
| Blood culture | N. meningitidis serogroup W | -- |
| **CH50** | **<10 U/mL (undetectable)** | 30-75 U/mL |
| AH50 | <10 U/mL (undetectable) | Normal |
| C3 | Normal | -- |
| C5 | Undetectable | -- |

### Clinical Image
![Meningococcal Petechiae](https://upload.wikimedia.org/wikipedia/commons/thumb/b/b5/Meningococcal_disease_-_purpuric_rash.jpg/220px-Meningococcal_disease_-_purpuric_rash.jpg)

*Image source: Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Meningococcal_disease_-_purpuric_rash.jpg). Licensed under CC BY-SA 3.0.*

### Diagnosis
**Terminal Complement (C5) Deficiency** with recurrent Neisseria meningitidis infection.

### Discussion
Terminal complement pathway deficiencies (C5, C6, C7, C8, or C9) cause specific susceptibility to invasive Neisseria infections (meningococcal and gonococcal disease). These patients have up to 1000-fold increased risk of meningococcal disease compared to the general population. The membrane attack complex (MAC), formed by C5b-C9, is essential for complement-mediated lysis of Neisseria species, which are uniquely dependent on this mechanism for immune control.

Key features:
- Recurrent Neisseria infections (meningitis, disseminated gonococcal infection)
- Both CH50 and AH50 are undetectable (all pathways converge at terminal pathway)
- C3 is normal (distinguishing from C3 deficiency)
- Interestingly, mortality from individual episodes may be lower, possibly due to attenuated inflammatory response
- The brother's gonococcal arthritis suggests inherited complement deficiency

### Treatment
1. **Acute management:** Appropriate antibiotics for meningitis (ceftriaxone)
2. **Vaccination:** Quadrivalent meningococcal conjugate vaccine AND serogroup B vaccine (though response may be suboptimal without complement)
3. **Education:** Prompt evaluation for any febrile illness
4. **Family screening:** Test siblings and parents for complement deficiency
5. **Consider prophylactic antibiotics:** Some experts recommend penicillin prophylaxis