A 20-year-old girl was brought by her mother, herself a medical doctor, with a long history of recurrent severe infections beginning in early childhood.
 

She developed middle lobe collapse in childhood, for which a lobectomy was performed, yet she continued to suffer from recurrent respiratory infections thereafter.

Over the years, the frequency and severity of infections progressively increased; initially occurring every three to six months, then becoming more frequent, and now recurring almost every ten days.

In the past year, she was treated for multidrug-resistant tuberculosis, and her infectious history also includes pulmonary aspergillosis, staphylococcal infections, and Moraxella infections, involving predominantly the respiratory tract.

Despite extensive investigations over the years and management at multiple levels of care, no unifying diagnosis has yet been established, raising strong concern for an underlying, previously unrecognized primary immunodeficiency disorder.

What is Chronic Granulomatous Disease (CGD):

CGD is a rare but life-threatening primary immunodeficiency caused by a defect in the ability of neutrophils to kill certain bacteria and fungi.

Although traditionally considered a childhood disease, many patients—especially females—present in adolescence or adulthood, often after years of recurrent infections.

CGD should be strongly suspected in any young patient with:

• Recurrent lung infections since childhood
• Severe or unusual organisms (e.g., Aspergillus, Staphylococcus, TB)
• Normal immunoglobulin levels
• Poor response to standard treatments

Pathophysiology (What Goes Wrong in CGD?)

In CGD, neutrophils lack a functioning NADPH oxidase enzyme, which is required to produce reactive oxygen species (oxidative burst). Without this burst:

• Phagocytes can ingest pathogens
• ❌ But cannot kill catalase-positive organisms

This leads to:

• Recurrent infections
• Granuloma formation
• Persistent inflammation

Genetics

• X-linked CGD (most common)
• Autosomal recessive CGD
• Females may be symptomatic carriers due to lyonization

Common Organisms Seen in CGD:

CGD patients are particularly susceptible to catalase-positive organisms, including:

• Staphylococcus aureus
• Aspergillus species (hallmark infection)
• Serratia marcescens
• Burkholderia cepacia
• Nocardia
• Mycobacterium tuberculosis and atypical mycobacteria

📌 Aspergillus pneumonia in a young person with normal Ig levels is CGD until proven otherwise.

Clinical Features of CGD:

Recurrent Infections

• Pneumonia
• Lung abscesses
• Skin abscesses
• Osteomyelitis
• Lymphadenitis

Pulmonary Complications of CGD:

• Recurrent pneumonias
• Bronchiectasis
• Cavitary lesions

ENT Involvement:

• Recurrent otitis media
• Chronic sinusitis
• Hearing loss (secondary to chronic ear disease)

How to Diagnose CGD:

🔑 Gold Standard Test

Dihydrorhodamine (DHR) Flow Cytometry

• Measures neutrophil oxidative burst
• Preferred over the older NBT test

DHR Result Patterns:

📌 Routine flow cytometry (CD3/CD4/CD8/CD19) does NOT diagnose CGD.

Additional Investigations

• CBC with differential
• ESR / CRP
• HRCT chest (bronchiectasis, cavities)
• Sputum culture (bacterial, fungal, AFB)
• TB GeneXpert and culture
• ENT assessment + audiometry
• Genetic testing (if available)

Differential Diagnosis: How to Differentiate CGD from Similar Conditions:

📌 Normal immunoglobulin levels strongly argue against CVID.

Management of CGD

1️⃣ Infection Prevention (Cornerstone of Treatment)

Antibacterial Prophylaxis

• Trimethoprim–Sulfamethoxazole (TMP-SMX)
• Reduces serious infections by >70%

Antifungal Prophylaxis

• Itraconazole (mandatory if prior Aspergillus)
• Monitor liver function

Interferon-Gamma (IFN-γ)

(If available)

• Reduces severe infections
• SC injections 3 times weekly

2️⃣ Management of Acute Infections

⚠️ Any fever in CGD is a medical emergency

• Immediate cultures
• Early broad-spectrum IV antibiotics
• Consider antifungal therapy if pulmonary symptoms

3️⃣ TB and Mycobacterial Disease

• Strict adherence to MDR-TB protocols
• Longer treatment courses often required
• Close infectious disease supervision

4️⃣ Pulmonary & ENT Care

• Regular chest physiotherapy
• Early treatment of exacerbations
• ENT follow-up for hearing loss
• Audiometry and hearing rehabilitation if needed

Vaccination Guidelines

✅ Allowed (Non-Live Vaccines)

• Influenza
• Pneumococcal
• COVID-19
• Hepatitis B

❌ Contraindicated (Live Vaccines)

• BCG
• Oral polio
• MMR
• Varicella

Lifestyle & Preventive Advice

Patients should avoid:

• Gardening and soil exposure
• Compost, mulch
• Construction sites
• Mold-rich environments

Seek urgent care for:

• Fever
• Chest pain
• Persistent cough
• Skin swelling or abscess

Definitive Treatment: Hematopoietic Stem Cell Transplant (HSCT)

🔴 HSCT is the only curative treatment for CGD

Best considered when:

• Severe infections
• Aspergillus disease
• MDR-TB
• Young age

Early referral improves outcomes.

Family Screening & Genetic Counseling

• Screen siblings
• Test the mother for carrier status
• Counsel regarding future pregnancies

Key Take-Home Messages

• Normal immunoglobulins do not exclude immunodeficiency
• Aspergillus infection in young patients is a red flag
• DHR flow cytometry is the diagnostic test of choice
• Early prophylaxis saves lives
• HSCT offers a cure in selected patients

Conclusion:

Chronic Granulomatous Disease is often missed for years, leading to preventable complications. Awareness, early diagnosis, and appropriate long-term management can dramatically improve survival and quality of life.