# Clinical Cases: Adaptive Immunity Overview

## Case 1: Severe Combined Immunodeficiency (SCID)

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

### Chief Complaint
Failure to thrive and recurrent infections

### History of Present Illness
A 4-month-old male infant is referred to pediatric immunology after being hospitalized for Pneumocystis jirovecii pneumonia (PJP). He has had persistent oral thrush since 2 weeks of age despite multiple courses of nystatin. His mother reports chronic diarrhea and poor weight gain. He was born full-term with no complications. Newborn screening was not available for SCID in his birth state.

### Past Medical History
- Oral thrush since 2 weeks of age
- Chronic diarrhea starting at 2 months
- Admitted twice for respiratory infections
- Pneumocystis jirovecii pneumonia (current)

### Birth History
- Full-term, uncomplicated vaginal delivery
- Birth weight: 3.4 kg (50th percentile)
- No newborn SCID screening performed

### Family History
- Parents are non-consanguineous
- Maternal uncle died at 5 months of age from "lung infection"

### Physical Examination
- **General:** Wasted, ill-appearing infant, visibly malnourished
- **Vital Signs:** T 38.2C, HR 160, RR 55, SpO2 88% on room air
- **Weight:** 4.5 kg (<3rd percentile, was 50th at birth)
- **HEENT:** Oral thrush coating tongue and buccal mucosa, NO visible tonsils
- **Lymphatics:** NO palpable lymph nodes
- **Lungs:** Bilateral crackles, increased work of breathing
- **Abdomen:** No hepatosplenomegaly
- **Skin:** No rashes, no evidence of graft-versus-host disease

### Laboratory Workup
| Test | Result | Reference Range |
|------|--------|-----------------|
| WBC | 3,200/uL | 6,000-17,500/uL |
| Absolute lymphocyte count | 200/uL | 3,000-9,500/uL |
| CD3+ T cells | 15/uL | 2,500-5,600/uL |
| CD4+ T cells | 8/uL | 1,600-4,000/uL |
| CD8+ T cells | 5/uL | 560-1,700/uL |
| CD19+ B cells | 850/uL | 300-2,000/uL |
| CD16+56+ NK cells | 8/uL | 170-1,100/uL |
| IgG | 180 mg/dL (maternal) | 141-930 mg/dL |
| IgA | <5 mg/dL | 8-74 mg/dL |
| IgM | <10 mg/dL | 26-210 mg/dL |
| TREC levels | Undetectable | Present |
| Genetic testing | IL2RG mutation | -- |

### Clinical Image
![Oral Thrush](https://upload.wikimedia.org/wikipedia/commons/thumb/e/e2/Human_tongue_infected_with_oral_candidiasis.jpg/220px-Human_tongue_infected_with_oral_candidiasis.jpg)

*Image source: Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Human_tongue_infected_with_oral_candidiasis.jpg). Public domain.*

### Diagnosis
**X-linked Severe Combined Immunodeficiency (X-SCID)** due to IL2RG (common gamma chain) mutation, presenting with T-B+NK- phenotype.

### Discussion
SCID represents the most severe form of primary immunodeficiency, characterized by profound defects in T cell development. X-linked SCID is caused by mutations in IL2RG, which encodes the common gamma chain shared by receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. IL-7 signaling is essential for T cell development, and IL-15 is required for NK cell development, explaining the T-B+NK- phenotype. B cells develop but cannot function without T cell help.

Key features distinguishing this case:
- Profound lymphopenia with markedly reduced T cells
- Absent T cell and NK cells with preserved B cell numbers (T-B+NK-)
- Opportunistic infection (PJP) indicates severe cellular immunodeficiency
- Maternal uncle's death suggests X-linked inheritance
- Absent lymphoid tissue (tonsils, lymph nodes)

### Treatment
1. **Immediate:** Treat PJP with TMP-SMX, prophylaxis against infections, IVIG replacement
2. **Isolation:** Strict infection precautions, avoid live vaccines
3. **Definitive therapy:** Hematopoietic stem cell transplantation (HSCT) - outcomes are best when performed before 3.5 months of age and before infections develop
4. **Gene therapy:** Now FDA-approved for X-SCID as an alternative to HSCT

**Note:** This case highlights the importance of newborn SCID screening using the TREC assay, now universal in all US states.

---

## Case 2: Common Variable Immunodeficiency (CVID)

### Patient Demographics
- **Age:** 32 years old
- **Sex:** Female
- **Ethnicity:** Caucasian

### Chief Complaint
Recurrent sinusitis and pneumonia

### History of Present Illness
A 32-year-old woman is referred for evaluation of recurrent respiratory infections. Over the past 5 years, she has had 8-10 episodes of sinusitis requiring antibiotics annually and 3 episodes of pneumonia requiring hospitalization. She also reports chronic diarrhea and has been diagnosed with "IBS." She had childhood chickenpox and recovered normally from measles vaccine. Review of records shows progressively worsening pulmonary function tests.

### Past Medical History
- Recurrent sinusitis (8-10 episodes/year for 5 years)
- Three hospitalizations for bacterial pneumonia (Streptococcus pneumoniae, Haemophilus influenzae)
- Chronic diarrhea (5 years)
- Autoimmune thyroiditis (on levothyroxine)
- Idiopathic thrombocytopenic purpura (ITP) at age 28

### Family History
- Brother with "immune problems"
- No consanguinity

### Physical Examination
- **General:** Well-appearing woman
- **Vital Signs:** Normal
- **HEENT:** Mucosal inflammation of nasal turbinates, no tonsillar tissue visible
- **Lungs:** Scattered crackles at bases bilaterally
- **Abdomen:** Mild hepatomegaly, spleen not palpable
- **Extremities:** No clubbing
- **Lymphatics:** Small palpable lymph nodes in cervical chain

### Laboratory Workup
| Test | Result | Reference Range |
|------|--------|-----------------|
| IgG | 180 mg/dL | 700-1600 mg/dL |
| IgA | <5 mg/dL | 70-400 mg/dL |
| IgM | 25 mg/dL | 40-230 mg/dL |
| CD19+ B cells | 8% (normal) | 5-20% |
| CD4+ T cells | Normal | -- |
| CD8+ T cells | Normal | -- |
| Tetanus antibody (post-vaccine) | <0.1 IU/mL | >0.5 IU/mL |
| Pneumococcal antibodies (post-Pneumovax) | 0/14 serotypes protective | >70% protective |
| HIV | Negative | -- |
| CT chest | Bronchiectasis lower lobes | -- |

### Clinical Image
![Bronchiectasis on CT](https://upload.wikimedia.org/wikipedia/commons/thumb/5/5d/Bronchiectasis_HRCT.jpg/220px-Bronchiectasis_HRCT.jpg)

*Image source: Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Bronchiectasis_HRCT.jpg). Licensed under CC BY-SA 4.0.*

### Diagnosis
**Common Variable Immunodeficiency (CVID)** with secondary bronchiectasis and autoimmune complications.

### Discussion
CVID is the most common symptomatic primary immunodeficiency in adults, characterized by hypogammaglobulinemia with impaired vaccine responses but preserved B cell numbers. The pathophysiology is heterogeneous, with identified genetic causes (ICOS, TACI, BAFFR, CD19 mutations) in only 10-15% of patients.

Key diagnostic criteria:
- Low IgG plus low IgA and/or IgM
- Impaired vaccine responses (tested with both protein and polysaccharide antigens)
- Exclusion of other causes (HIV, medications, protein-losing states)
- Age >4 years (to exclude transient hypogammaglobulinemia of infancy)

CVID complications beyond infections:
- **Autoimmunity** (ITP, AIHA, autoimmune thyroiditis) - present in 20-25%
- **Granulomatous disease** (lungs, liver, spleen)
- **GI disease** (IBD-like, nodular lymphoid hyperplasia, malabsorption)
- **Lymphoma** (10-fold increased risk)
- **Bronchiectasis** (from recurrent infections)

### Treatment
1. **Immunoglobulin replacement:** IVIG or subcutaneous Ig (SCIG) - lifelong, targeting trough IgG >500 mg/dL (higher for those with chronic lung disease)
2. **Treat established bronchiectasis:** Airway clearance, surveillance for infections
3. **Monitor for complications:** Annual screening for autoimmunity, lymphoproliferation
4. **Vaccination:** Inactivated vaccines can be given (may have suboptimal response); avoid live vaccines

---

## Case 3: DiGeorge Syndrome (22q11.2 Deletion)

### Patient Demographics
- **Age:** 2 weeks old
- **Sex:** Female
- **Ethnicity:** Asian

### Chief Complaint
Seizures and cardiac murmur

### History of Present Illness
A 2-week-old female infant presents with seizures at home. She was born full-term with prenatal diagnosis of interrupted aortic arch. Echocardiography confirmed interrupted aortic arch type B and ventricular septal defect. Today she developed brief tonic-clonic movements of all extremities. The parents note she has had feeding difficulties.

### Birth History
- Full-term, cesarean delivery due to fetal cardiac anomaly
- Birth weight: 2.8 kg (25th percentile)

### Family History
- No family history of immunodeficiency or congenital anomalies
- Non-consanguineous parents

### Physical Examination
- **General:** Small-for-age infant with subtle dysmorphic features
- **Vital Signs:** T 36.8C, HR 150, RR 45
- **HEENT:** Hypertelorism, short palpebral fissures, small ears with overfolded helices, micrognathia, high-arched palate
- **Cardiac:** Harsh systolic murmur, single S2
- **Lungs:** Clear
- **Neurological:** Post-ictal, mildly hypotonic

### Laboratory Workup
| Test | Result | Reference Range |
|------|--------|-----------------|
| Calcium | 5.8 mg/dL | 8.5-10.5 mg/dL |
| Phosphorus | 8.5 mg/dL | 4.5-6.5 mg/dL |
| PTH | <5 pg/mL | 15-65 pg/mL |
| Absolute lymphocyte count | 1,200/uL | 2,000-11,000/uL |
| CD3+ T cells | 650/uL | 2,500-5,600/uL |
| CD4+ T cells | 350/uL | 1,600-4,000/uL |
| CD8+ T cells | 200/uL | 560-1,700/uL |
| CD19+ B cells | Normal | -- |
| FISH 22q11.2 | **Deletion present** | No deletion |
| Thymic shadow on CXR | Absent | Present |

### Clinical Image
![DiGeorge Syndrome Facies](https://upload.wikimedia.org/wikipedia/commons/thumb/1/1e/DiGeorge_Syndrome.jpg/180px-DiGeorge_Syndrome.jpg)

*Image source: Wikimedia Commons (https://commons.wikimedia.org/wiki/File:DiGeorge_Syndrome.jpg). Public domain.*

### Diagnosis
**DiGeorge Syndrome (22q11.2 Deletion Syndrome)** with partial T cell immunodeficiency, hypoparathyroidism, and conotruncal cardiac defect.

### Discussion
DiGeorge syndrome results from microdeletion at chromosome 22q11.2, affecting development of structures derived from the third and fourth pharyngeal pouches (thymus, parathyroids) and the cardiac outflow tract. The mnemonic CATCH-22 describes the features:
- **C**ardiac defects (conotruncal: interrupted aortic arch, truncus arteriosus, tetralogy of Fallot)
- **A**bnormal facies
- **T**hymic hypoplasia/aplasia
- **C**left palate
- **H**ypocalcemia (from hypoparathyroidism)
- **22**q11.2 deletion

The immunodeficiency spectrum ranges from:
- **Complete DiGeorge** (rare, <1%): Absent thymus, profound T cell deficiency (similar to SCID)
- **Partial DiGeorge** (common): Thymic hypoplasia, reduced but present T cells, often improves with age

This case represents partial DiGeorge syndrome with:
- Moderate T cell lymphopenia (not absent)
- Severe hypocalcemia causing seizures
- Conotruncal cardiac defect
- Characteristic facies

### Treatment
1. **Acute management:** IV calcium gluconate for hypocalcemia, anticonvulsants
2. **Calcium/vitamin D supplementation:** Long-term for hypoparathyroidism
3. **Cardiac surgery:** Repair of interrupted aortic arch and VSD
4. **Immunological management:**
   - Partial DiGeorge: Monitor T cells, which often improve with age; may give live vaccines if T cells adequate
   - Complete DiGeorge: Thymus transplantation or HSCT required
5. **Multidisciplinary care:** Speech therapy, developmental support, cardiology follow-up