Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a primary antibody deficiency with markedly low IgG and low IgA and/or IgM, poor vaccine responses and no secondary cause, in a person older than 4 years. Infection is the first problem, and immune dysregulation follows in many.

Pathophysiology. B cells fail to become class switched memory B cells and plasma cells. T cell help and regulatory function are also impaired in many patients.

About 10 to 30% have a single gene cause (for example in NFKB1, NFKB2, CTLA4, LRBA, PIK3CD, ICOS, CD19, STAT3 gain of function). Heterozygous TNFRSF13B variants raise risk but are not sufficient alone.

Prevalence is about 1 in 25,000 to 1 in 50,000. Onset peaks in childhood and again at 20 to 40 years, with a delay of several years before diagnosis.

Non-infectious complications develop in over a quarter and are a major cause of death.

• Recurrent sinusitis, otitis media, bronchitis and pneumonia (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis), bronchiectasis
• Chronic diarrhoea and weight loss: Giardia, Campylobacter, Salmonella, norovirus, or enteropathy
• Autoimmune cytopenias: immune thrombocytopenia, autoimmune haemolytic anaemia, Evans syndrome
• Lymphadenopathy and splenomegaly
• Granulomatous and lymphocytic interstitial lung disease (GLILD): breathlessness, cough, reduced gas transfer
• Nodular regenerative hyperplasia of the liver with portal hypertension
• Other autoimmunity: arthritis, thyroid disease, pernicious anaemia, vitiligo, alopecia
• Malignancy: non-Hodgkin lymphoma (about 10 times population risk or more) and gastric cancer

• Immunoglobulins: IgG under the age adjusted 5th percentile (usually under 4 g/L in adults) with low IgA and/or IgM, confirmed on repeat.
• Specific antibody responses: absent or poor response to tetanus, diphtheria and pneumococcal polysaccharide vaccines. Isohaemagglutinins are absent in non-AB patients.
• Lymphocyte subsets and B cell phenotype: class switched memory B cells under 2% of B cells, raised CD21-low and transitional B cells, and CD4 count to grade T cell involvement.
• Exclusion of secondary causes: drugs (anticonvulsants, rituximab, corticosteroids, sulfasalazine), HIV, lymphoma, myeloma, protein losing enteropathy, nephrotic syndrome.
• Genetic testing with a panel for immune dysregulation, especially with early onset, autoimmunity or family history.
• Baseline workup: full blood count with differential, reticulocytes, direct antiglobulin test, liver enzymes including alkaline phosphatase, creatinine, thyroid function, vitamin B12, hepatitis B and C and HIV serology, faecal calprotectin and stool pathogens.
• Imaging and physiology: high resolution CT of the chest, spirometry with gas transfer (DLCO), ultrasound of the abdomen.
• Endoscopy with biopsy for persistent gastrointestinal symptoms.

Differential diagnosis.

• Secondary hypogammaglobulinaemia (drugs, lymphoproliferative disease, protein loss)
• X-linked agammaglobulinaemia, with absent B cells
• Good syndrome (thymoma)
• Combined immunodeficiency with antibody failure
• Monogenic disorders of immune dysregulation
• Selective IgA deficiency and IgG subclass deficiency
• HIV infection

• Immunoglobulin replacement for life in patients with proven antibody failure and infection:
  • Intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly (or double the dose every 2 weeks).
  • Target trough IgG at least 6 g/L, usually 7 to 9 g/L, higher with bronchiectasis or breakthrough infection. Check the trough before the next dose at 3 to 4 months, then every 3 to 6 months.
  • Start intravenous infusions at the slow rate on the product label and increase stepwise as tolerated. After a reaction, slow the rate and premedicate with paracetamol 15 mg/kg orally (maximum 1 g) and chlorphenamine 4 mg orally in adults.
  • For anaphylaxis, stop the infusion and give adrenaline 0.5 mg intramuscularly (0.01 mg/kg in children, maximum 0.5 mg).
  • Rare adverse effects: aseptic meningitis, haemolysis, thrombosis, renal impairment (avoid sucrose containing products with renal disease; keep well hydrated).
• Antibiotic prophylaxis for adults with bronchiectasis or frequent exacerbations: azithromycin 500 mg orally three times weekly or 250 mg once daily (children 10 mg/kg three times weekly, maximum 500 mg), after ECG shows QTc under 450 ms and sputum is clear of non-tuberculous mycobacteria.
• Acute chest infection: amoxicillin 1 g orally three times daily or doxycycline 200 mg on day 1 then 100 mg daily, for 10 to 14 days, by sputum culture. Add airway clearance with physiotherapy.
• Pneumocystis prophylaxis when T cell numbers are low or with prolonged corticosteroids or rituximab: co-trimoxazole 960 mg orally three times weekly (children trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week).
• Vaccines: inactivated influenza yearly, pneumococcal conjugate vaccine and COVID-19 vaccine, although responses are weak. Avoid live vaccines (BCG, measles-mumps-rubella, varicella, yellow fever, oral typhoid, live attenuated influenza).
• Autoimmune cytopenia: prednisolone 1 mg/kg orally once daily (maximum 60 mg) tapered over 4 to 8 weeks, or intravenous immunoglobulin 1 g/kg as a single dose, repeated the next day if needed. Rituximab 375 mg/m2 intravenously weekly for 4 doses for relapse, after hepatitis B screening.
• GLILD: prednisolone 0.5 to 1 mg/kg daily with taper, with rituximab 375 mg/m2 weekly for 4 doses plus azathioprine 1 to 2 mg/kg daily (after thiopurine methyltransferase activity is checked) or mycophenolate mofetil 1 g orally twice daily.
• Enteropathy: exclude infection first (stool PCR, norovirus), then budesonide 9 mg orally once daily or prednisolone, with nutritional support.
• Targeted treatment of the gene defect when found (for example abatacept for CTLA4 deficiency, leniolisib for PI3K delta syndrome). Haematopoietic stem cell transplantation is considered for severe monogenic disease.
• Cancer surveillance: lymphadenopathy or constitutional symptoms need early biopsy. Gastroscopy for dyspepsia or anaemia.

Special groups.

• Pregnancy: continue replacement and increase the dose to hold the trough, since IgG crosses the placenta. Avoid live vaccines. Review immunosuppressants.
• Children: weight based doses, and adjust with growth.

Monitoring. Trough IgG every 3 to 6 months. Full blood count, liver enzymes including alkaline phosphatase, and creatinine every 6 months. Spirometry with DLCO yearly. High resolution CT every 2 to 3 years with bronchiectasis or GLILD. Ultrasound for spleen and liver yearly. Record infections and antibiotic courses.

Referral and escalation. Care sits with immunology. Urgent for cytopenias, rapidly enlarging nodes, weight loss, new breathlessness, portal hypertension, or invasive infection.