Secondary Hypogammaglobulinaemia

Secondary hypogammaglobulinaemia is a low serum IgG (and often IgA and IgM) caused by a disease or drug that reduces antibody production or increases loss. It is far commoner than primary antibody deficiency and is often missed.

Pathophysiology. Immunoglobulins fall through reduced production (B cell and plasma cell malignancy, drugs, infection) or increased loss (kidney, gut, skin or lymphatic leak). The cause decides whether the defect is reversible.

Common causes of reduced production are chronic lymphocytic leukaemia, myeloma and lymphoma, anti-CD20 therapy (rituximab), BTK inhibitors, CAR-T cell therapy, chemotherapy, long term corticosteroids, anticonvulsants (phenytoin, carbamazepine, valproate), sulfasalazine, penicillamine, and HIV infection.

Common causes of loss are nephrotic syndrome, protein losing enteropathy, intestinal lymphangiectasia, burns and exfoliative dermatitis.

• Recurrent or severe sinopulmonary infection, pneumonia and bronchiectasis
• Recurrent skin and urinary infection, and shingles
• Chronic diarrhoea with Giardia in some
• Features of the underlying disease: oedema and proteinuria, diarrhoea and weight loss, lymphadenopathy, bone pain, cytopenias
• Poor response to vaccines
• Many patients have no symptoms and are found on testing

• Serum IgG, IgA and IgM, repeated, with serum protein electrophoresis and serum free light chains.
• Albumin, urine protein-to-creatinine ratio (nephrotic syndrome), and faecal alpha-1 antitrypsin (protein losing enteropathy).
• Lymphocyte subsets and B cell count: B cells absent after anti-CD20 therapy.
• Full blood count and film; bone marrow or imaging for lymphoproliferative disease and myeloma.
• HIV test.
• Specific antibody responses to tetanus and pneumococcal polysaccharide vaccines.
• Drug history: rituximab and other anti-CD20, BTK inhibitors, CAR-T, anticonvulsants, corticosteroids, sulfasalazine, penicillamine.
• Chest imaging for bronchiectasis with recurrent infection.

Differential diagnosis.

• Common variable immunodeficiency and other primary antibody deficiencies
• Transient hypogammaglobulinaemia of infancy
• Good syndrome (thymoma)
• Multiple myeloma and Waldenström macroglobulinaemia
• Laboratory artefact (haemodilution)
• Specific antibody deficiency with normal immunoglobulins

• Treat or remove the cause: treat the leukaemia or lymphoma, control nephrotic syndrome or enteropathy, stop or substitute offending drugs when possible.
• Antibiotic prophylaxis for patients with recurrent infection: azithromycin 500 mg orally three times weekly or 250 mg once daily in adults (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. Amoxicillin 500 mg orally once daily at night in adults is an alternative.
• Immunoglobulin replacement for IgG under 4 g/L with recurrent or severe infection, or with failure of vaccine responses: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with a trough IgG of at least 6 g/L, usually 7 to 9 g/L. Give it as a time limited course of 6 to 12 months, then stop for 3 to 6 months to judge recovery and continued need. It is of little use in protein losing states, since the infused IgG is lost quickly.
• Pneumocystis prophylaxis with prolonged corticosteroids or anti-CD20 therapy: co-trimoxazole 960 mg orally three times weekly.
• Vaccination: inactivated influenza yearly, pneumococcal conjugate vaccine and COVID-19 vaccine; give vaccines before starting anti-CD20 therapy or chemotherapy if possible. Avoid live vaccines in patients on immunosuppression.
• Treat infections early by culture, with longer courses for chest infection (10 to 14 days).
• Hepatitis B screening (HBsAg and anti-HBc) before anti-CD20 therapy or chemotherapy.

Special groups.

• Chronic lymphocytic leukaemia and myeloma: replacement lowers serious infection when IgG is low and infections recur.
• Children: transient hypogammaglobulinaemia of infancy resolves, so avoid long term replacement without proof of antibody failure.

Monitoring. IgG, IgA and IgM before treatment, at 3 months, and then every 3 to 6 months. Trough IgG every 3 to 6 months on replacement. Full blood count, liver enzymes and creatinine every 6 months. Chest imaging if infections recur.

Referral and escalation. Refer to immunology for recurrent infection with IgG under 4 g/L, or poor vaccine response. Urgent for sepsis or an unexplained monoclonal band or cytopenia.