Common variable immunodeficiency

Background

• Characterized by decreased IgG immunoglobulins, with or without decreases in IgA and IgM, and decreased response to vaccination
• Must exclude other causes of hypogammaglobulinemia

Epidemiology

• Affects up to 1 in 25,000 people

Clinical Manifestations

• Wide spectrum of manifestations
• Most common presentation is recurrent sinopulmonary infections
  • Especially Streptococcus pneumoniae and Haemophilus influenzae
  • Severe or chronic Mycoplasma infections
  • Severe or chronic Enterovirus infections, including meningitis
  • Empyema, bacteremia, meningitis, and osteomyelitis
• Can eventually develop chronic lung disease including obstruction, restriction, and bronchiectasis
• Diarrhea is common (21 to 57%)
  • Giardia lamblia is the most common cause of chronic diarrhea
  • Others include Cryptosporidium parvum, CMV, Salmonella, Clostridium difficile, and Campylobacter jejuni
• Can also develop sarcoidosis (8 to 22%), with granulomatous changes occurring years before the hypogammaglobulinemia
  • Mainly in lung, lymph nodes, or liver
  • Portends a higher risk of immune-mediated thrombocytopenia and autoimmune hemolytic anemia
• Autoimmune phenomena include immune-mediated thrombocytopenia, autoimmune hemolytic anemia, Evans syndrome, and autoimmune neutropenia
• Higher rates of malignancies, primarily non-Hodgkin lymphoma and stomach cancer
  • The latter may be related to infection with Helicobacter pylori

Prognosis

• Decreased life expectancy
• Median survival 13.7 years with granulomatous changes or 28.8 years without

Investigations

Serum IgG (mg/dL)	Recommendation
<150	repeat immunoglobulins to confirm
150-250	repeat immunoglobulins to confirm consider tetanus and diphtheria titres consider pneumococcal vaccine titres pre- and post-vaccination
250-450	repeat immunoglobulins to confirm check tetanus and diphtheria titres check pneumococcal vaccine titres pre- and post-vaccination
450-600	repeat immunoglobulins to confirm check tetanus, diphtheria, MMR, and VZV titres check pneumococcal vaccine titres pre- and post-vaccination

Differential Diagnosis

• Primary hypogammaglobulinemia
  • IgG subclass deficiency
  • Hyperimmunoglobulin M syndrome
  • Other combined immunodeficiency
• Secondary hypogammaglobulinemia
  • Drugs, including rituximab, CAR-T, BiTE, long-term corticosteroids, certain antiseizure medications, cytotoxic chemotherapy
  • Malignancy, including CLL, lymphoma, multiple myeloma, and Waldenström macroglobulinemia
  • Thymoma with hypogammaglobulinemia (Good syndrome)

Diagnosis

• Over the age of 4 years
• All of the following:
  • Low IgA and/or IgM
  • Poor or absent response to immunization
  • Absence of other immunodeficiency

Management

Immune Globulin Replacement

• The mainstay of therapy if IVIg 400 to 600 mg/kg IV monthly, usually given every 3 to 4 weeks
  • Can be given subcutaneously, divided every 1 to 2 weeks, if IV access is difficult
• Target trough depends on baseline IgG level
  • <100 mg/dL: target trough 600 mg/dL
  • 300 mg/dl: target trough 900 mg/dL
• Although many are IgA deficient, there are low rates of anti-IgA antibodies in CVID, so IVIg is generally safe

Follow-Up

Patients	Assessment	Interval
all	History and physical	annually
	CBC, liver and renal panel, albumin	annually
	spirometry	annually
	serum trough IgG ± IgA and IgM	6-12 months
	chest x-ray	on referral
lung disease	high-resolution CT chest	3-4 years or after change of therapy
	lung function with DLCO	annually
GI complications	upper and/or lower endoscopy	as required
malabsorption or loss of height	bone density and micronutrient assessment	as required

Further Reading

• How I treat common variable immune deficiency. Blood. 2010;116(1):7-15. doi: 10.1182/blood-2010-01-254417