# Clinical Cases: Immunodeficiency Disorders

## Case 1: HIV/AIDS with Opportunistic Infections

### Patient Demographics
- **Age:** 34 years old
- **Sex:** Male
- **Ethnicity:** African American

### Chief Complaint
Fever, cough, and shortness of breath for 2 weeks

### History of Present Illness
A 34-year-old man presents with progressive dyspnea on exertion, dry cough, and low-grade fevers for 2 weeks. He has also experienced a 20-pound unintentional weight loss over 3 months and has had white patches in his mouth. He denies any medical history and has not seen a doctor in over 10 years. He reports multiple male sexual partners without consistent condom use.

### Past Medical History
- None known
- No prior HIV testing

### Social History
- Men who have sex with men (MSM)
- Inconsistent condom use
- No IV drug use
- Works as a restaurant manager

### Physical Examination
- **General:** Thin, ill-appearing man in mild respiratory distress
- **Vital Signs:** T 38.5C, HR 105, RR 26, BP 110/70, SpO2 88% on room air
- **HEENT:** Oral thrush coating tongue and palate; hairy leukoplakia on lateral tongue
- **Lymphatics:** Generalized lymphadenopathy (cervical, axillary, inguinal)
- **Lungs:** Bilateral dry crackles; increased work of breathing
- **Skin:** Seborrheic dermatitis; violaceous nodules on lower extremities and hard palate

### Laboratory Workup
| Test | Result | Reference Range |
|------|--------|-----------------|
| WBC | 3,200/uL | 4,500-11,000/uL |
| Absolute lymphocyte count | 450/uL | 1,000-4,800/uL |
| Hemoglobin | 10.5 g/dL | 14-18 g/dL |
| **HIV-1/2 Ag/Ab** | **Reactive** | Non-reactive |
| HIV-1 RNA viral load | 450,000 copies/mL | Undetectable |
| **CD4 count** | **45 cells/uL** | 500-1500 cells/uL |
| CD4 percentage | 4% | 30-60% |
| LDH | 850 U/L | 140-280 U/L |
| Beta-D-glucan | Positive | Negative |
| CXR | Bilateral diffuse interstitial infiltrates | Normal |
| BAL | Pneumocystis jirovecii (DFA positive) | Negative |
| Skin biopsy | Kaposi sarcoma | -- |

### Clinical Image
![PCP Chest X-ray](https://upload.wikimedia.org/wikipedia/commons/thumb/7/7d/Pneumocystis_jiroveci_01.jpg/220px-Pneumocystis_jiroveci_01.jpg)

*Image showing bilateral interstitial infiltrates characteristic of Pneumocystis jirovecii pneumonia in AIDS. Image source: Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Pneumocystis_jiroveci_01.jpg). Public domain.*

### Diagnosis
**AIDS (CD4 <200) with Pneumocystis jirovecii pneumonia (PJP) and Kaposi sarcoma** in a newly diagnosed HIV infection.

### Discussion
HIV infection is the most common cause of secondary (acquired) immunodeficiency worldwide:

**HIV pathogenesis:**
- HIV primarily infects CD4+ T cells via the CD4 receptor and CCR5/CXCR4 coreceptors
- Progressive CD4+ T cell depletion leads to immunodeficiency
- AIDS is defined by CD4 <200 cells/uL OR an AIDS-defining condition

**CD4 count and infection risk:**
| CD4 Count | Opportunistic Infections |
|-----------|-------------------------|
| <500 | Oral candidiasis, herpes zoster, bacterial infections |
| <200 | PJP, toxoplasmosis, cryptococcosis |
| <100 | CMV disease, MAC, CNS lymphoma |
| <50 | Disseminated MAC, CMV retinitis |

**This patient's presentation:**
- **PJP:** Most common AIDS-defining opportunistic infection; presents with subacute dry cough, dyspnea, and bilateral interstitial infiltrates; elevated LDH and positive beta-D-glucan support diagnosis
- **Kaposi sarcoma:** Caused by HHV-8; presents as violaceous nodules on skin and mucous membranes; AIDS-defining
- **Oral thrush and hairy leukoplakia:** Indicate immunosuppression

**Prophylaxis guidelines based on CD4:**
- CD4 <200: PJP prophylaxis (TMP-SMX first-line)
- CD4 <100: Toxoplasma prophylaxis (TMP-SMX covers both)
- CD4 <50: MAC prophylaxis (azithromycin)

### Treatment
1. **PJP treatment:** TMP-SMX high dose for 21 days; add prednisone (PaO2 <70 or A-a gradient >35)
2. **Start ART:** After 2 weeks of PJP treatment to reduce immune reconstitution inflammatory syndrome (IRIS) risk
3. **Kaposi sarcoma:** Will likely improve with ART-induced immune reconstitution; chemotherapy if extensive
4. **OI prophylaxis:** TMP-SMX for PJP and toxoplasmosis prophylaxis
5. **Counseling:** Risk reduction, partner notification

---

## Case 2: Wiskott-Aldrich Syndrome

### Patient Demographics
- **Age:** 3 years old
- **Sex:** Male
- **Ethnicity:** Caucasian

### Chief Complaint
Recurrent infections, bloody diarrhea, and extensive eczema

### History of Present Illness
A 3-year-old boy is referred for evaluation of recurrent infections and unusual bleeding. Since infancy, he has had severe eczema unresponsive to topical treatments. He has experienced multiple ear infections, two episodes of pneumonia, and recurrent skin abscesses. His mother reports he bruises easily and has had several episodes of bloody diarrhea. Neonatal records reveal thrombocytopenia noted on day 2 of life.

### Past Medical History
- Thrombocytopenia since birth
- Severe eczema since 1 month of age
- Recurrent otitis media (10+ episodes)
- Two hospitalizations for pneumonia
- Multiple skin abscesses
- Bloody diarrhea (presumed colitis)

### Family History
- Maternal uncle died at age 5 from "bleeding and infection"
- Mother's brother's son (maternal cousin) also died young

### Physical Examination
- **General:** Small, irritable child with diffuse rash
- **Vital Signs:** T 37.5C, HR 110, RR 24
- **Growth:** Weight 5th percentile, Height 10th percentile
- **Skin:** Diffuse eczematous dermatitis on face, trunk, and extremities; multiple petechiae and ecchymoses
- **HEENT:** Bilateral TM scarring
- **Abdomen:** Mild hepatosplenomegaly

### Laboratory Workup
| Test | Result | Reference Range |
|------|--------|-----------------|
| WBC | 8,500/uL | 6,000-17,500/uL |
| Hemoglobin | 9.5 g/dL | 10-14 g/dL |
| **Platelet count** | **35,000/uL** | 150,000-400,000/uL |
| **Mean platelet volume (MPV)** | **5.5 fL** | 7.5-11.5 fL |
| IgG | 450 mg/dL (low-normal) | 345-1236 mg/dL |
| IgA | 350 mg/dL (elevated) | 14-159 mg/dL |
| IgM | 25 mg/dL (low) | 43-207 mg/dL |
| **IgE** | **1800 IU/mL** | <100 IU/mL |
| Isohemagglutinins | Absent | Present |
| CD4+ T cells | Moderately reduced | -- |
| **WASP protein** | **Absent** (by flow cytometry) | Present |
| WAS gene | Hemizygous mutation | Wild type |

### Clinical Image
![Eczema and Petechiae](https://upload.wikimedia.org/wikipedia/commons/thumb/7/73/Allergischer_Hautausschlag_Arm.jpg/220px-Allergischer_Hautausschlag_Arm.jpg)

*Image showing severe eczematous rash similar to that seen in Wiskott-Aldrich syndrome. Image source: Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Allergischer_Hautausschlag_Arm.jpg). Licensed under CC BY-SA 3.0.*

### Diagnosis
**Wiskott-Aldrich Syndrome (WAS)** due to WAS gene mutation.

### Discussion
WAS is an X-linked combined immunodeficiency caused by mutations in the WAS gene, encoding WASP (Wiskott-Aldrich Syndrome Protein):

**WASP function:**
- Regulates actin cytoskeleton reorganization in hematopoietic cells
- Required for proper immune cell function and platelet production/function

**Classic triad:**
1. **Thrombocytopenia with SMALL platelets** (pathognomonic finding)
2. **Eczema** (severe, refractory)
3. **Immunodeficiency** (progressive, combined)

**Why are platelets small?**
- Unlike ITP (large platelets), WAS platelets are small due to intrinsic defect
- Low MPV (<7 fL) is highly characteristic and helps distinguish from ITP

**Immunological abnormalities:**
- Low IgM, normal/low IgG, elevated IgA and IgE (characteristic pattern)
- Poor antibody responses to polysaccharide antigens
- Absent isohemagglutinins (which are anti-polysaccharide antibodies)
- Progressive T cell lymphopenia and dysfunction

**Complications:**
- Autoimmunity (30%): AIHA, ITP, vasculitis, inflammatory bowel disease
- Malignancy: Markedly increased lymphoma risk
- Life-threatening bleeding
- Severe infections (bacterial, viral, opportunistic)

### Treatment
1. **HSCT:** Curative and recommended for classic WAS; best outcomes with early transplant
2. **Gene therapy:** Emerging option with promising results
3. **Supportive care:**
   - IVIG for antibody replacement
   - Prophylactic antibiotics
   - Aggressive eczema management
   - Platelet transfusion for severe bleeding (avoid if possible due to alloimmunization)
4. **Splenectomy:** Can improve platelet count but increases infection risk; controversial
5. **Avoid live vaccines and aspirin/NSAIDs**

---

## Case 3: Leukocyte Adhesion Deficiency Type 1

### Patient Demographics
- **Age:** 6 weeks old
- **Sex:** Male
- **Ethnicity:** Middle Eastern (Saudi Arabian descent)

### Chief Complaint
Delayed umbilical cord separation and skin infection

### History of Present Illness
A 6-week-old male infant is brought in for evaluation of an infected umbilical stump. The umbilical cord did not separate until 4 weeks of age (normally 1-2 weeks), and since separation, the site has remained red and oozing. He was recently hospitalized for a skin infection on his arm that failed to improve despite IV antibiotics and required extensive debridement. Notably, there was minimal pus despite the severe infection.

### Birth History
- Full-term, vaginal delivery
- Birth weight: 3.5 kg
- Uncomplicated pregnancy
- Parents are first cousins

### Family History
- Parents are first cousins
- Two older siblings died in infancy from "severe infections"

### Physical Examination
- **General:** Alert infant, appears uncomfortable
- **Vital Signs:** T 38.8C, HR 170, RR 45
- **Umbilicus:** Erythematous, indurated, oozing purulent material; extensive surrounding cellulitis
- **Skin:** Healing wound on left arm from recent debridement; minimal surrounding erythema
- **Lungs:** Clear

### Laboratory Workup
| Test | Result | Reference Range |
|------|--------|-----------------|
| **WBC** | **65,000/uL** | 6,000-17,500/uL |
| **Neutrophils** | **85% (ANC 55,000)** | 40-70% |
| Hemoglobin | 10.5 g/dL | 10-14 g/dL |
| Platelets | 450,000/uL | 150,000-400,000/uL |
| Blood culture | Staphylococcus aureus | Negative |
| Wound culture | Staphylococcus aureus | Negative |
| IgG, IgA, IgM | Normal | -- |
| **CD18 expression** | **Absent on neutrophils** | Present |
| **CD11a, CD11b** | **Absent** | Present |

### Clinical Image
![Omphalitis](https://upload.wikimedia.org/wikipedia/commons/thumb/c/c4/Neonatal_omphalitis.png/220px-Neonatal_omphalitis.png)

*Image showing omphalitis (umbilical cord infection), a characteristic presentation of LAD-1. Image source: Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Neonatal_omphalitis.png). Licensed under CC BY-SA 4.0.*

### Diagnosis
**Leukocyte Adhesion Deficiency Type 1 (LAD-1)** due to CD18 (beta-2 integrin) deficiency.

### Discussion
LAD-1 results from mutations in ITGB2 encoding CD18, the beta-2 integrin chain common to:
- LFA-1 (CD11a/CD18): Binds ICAM-1; essential for leukocyte adhesion to endothelium
- Mac-1 (CD11b/CD18): Binds ICAM-1 and iC3b; important for phagocytosis
- CR4 (CD11c/CD18): Complement receptor

**Why can't neutrophils reach infection sites?**
- Normal leukocyte recruitment: Rolling (selectins) → Firm adhesion (integrins) → Transmigration
- Without CD18/integrins, neutrophils can roll but cannot firmly adhere
- Neutrophils are trapped in the bloodstream (marked leukocytosis)
- Sites of infection lack neutrophil infiltration (no pus!)

**Characteristic clinical features:**
- **Delayed umbilical cord separation** (>3 weeks) - highly characteristic
- **Recurrent severe bacterial infections** of skin, soft tissue, respiratory tract
- **Absence of pus** despite high fever and severe infection
- **Marked leukocytosis** (often >25,000, can exceed 100,000)
- **Impaired wound healing**

**Severity correlates with CD18 expression:**
- Severe phenotype (<1% CD18): Often fatal in infancy
- Moderate phenotype (2-10% CD18): Milder disease, may survive to adulthood

**Differential: Other LAD types:**
- LAD-2: Selectin ligand defect (fucose metabolism); mental retardation, short stature
- LAD-3: Kindlin-3 deficiency; LAD-1-like infections PLUS bleeding (platelet dysfunction)

### Treatment
1. **HSCT:** Only curative option; urgently indicated for severe phenotype
2. **Aggressive antibiotic therapy:** Prolonged courses for infections
3. **Surgical debridement:** Often required as neutrophils cannot clear infection
4. **G-CSF:** May help in moderate phenotype by increasing neutrophil numbers
5. **Prophylactic antibiotics:** TMP-SMX
6. **Gene therapy:** Under investigation
7. **Genetic counseling:** Autosomal recessive; family planning discussion

**Prognosis:** Without HSCT, severe LAD-1 is typically fatal in early childhood.