Selective IgM Deficiency

Selective IgM deficiency is a rare primary antibody deficiency. Serum IgM is markedly low (usually under 0.2 g/L, or more than 2 SD under the age matched mean) with normal IgG and IgA, normal T cell numbers and no secondary cause.

Pathophysiology. IgM memory and marginal zone B cells are reduced, and natural IgM that clears encapsulated bacteria is lost. The genetic basis is unknown in most cases, and a T helper defect is reported in some.

The prevalence is uncertain. It is found in all ages and is sometimes familial.

Serious infection with encapsulated bacteria is the main concern, and the risk resembles that of splenic hypofunction.

• Recurrent sinusitis, otitis media, bronchitis and pneumonia
• Invasive infection with Streptococcus pneumoniae, Neisseria meningitidis or Haemophilus influenzae: sepsis, meningitis, osteomyelitis
• Recurrent skin infection with Staphylococcus aureus, and recurrent diarrhoea
• Atopy: asthma, allergic rhinitis, eczema
• Autoimmune disease: lupus, autoimmune thyroid disease, immune thrombocytopenia
• Splenic hypofunction in some
• Many patients are asymptomatic

• Serum IgM, IgG and IgA, repeated after at least 4 weeks.
• Specific antibody responses: pneumococcal polysaccharide titres before and 4 to 6 weeks after a polysaccharide vaccine, and tetanus titres. Isohaemagglutinins (anti-A and anti-B) are low or absent in people who are not group AB.
• Lymphocyte subsets and B cell phenotype: reduced IgM memory B cells (CD27 positive, IgM positive, IgD positive).
• Exclusion of secondary causes: HIV test, serum protein electrophoresis and free light chains for myeloma and lymphoproliferative disease, urine protein and serum albumin (nephrotic syndrome, protein losing enteropathy), full blood count and blood film, and a drug history (rituximab, phenytoin, corticosteroids).
• Splenic function: blood film for Howell-Jolly bodies and spleen ultrasound.
• Serum complement (CH50) when invasive neisserial disease has occurred.

Differential diagnosis.

• Secondary IgM deficiency (lymphoma, myeloma, nephrotic syndrome, protein losing enteropathy, rituximab)
• Common variable immunodeficiency
• Specific antibody deficiency
• Splenic hypofunction and asplenia
• Complement deficiency
• Hyper IgM syndromes, in which IgM is high
• HIV infection

• Treat the cause when secondary.
• Vaccination: pneumococcal conjugate vaccine, then pneumococcal polysaccharide vaccine at least 8 weeks later, meningococcal ACWY and B vaccines, Haemophilus influenzae type b vaccine and yearly inactivated influenza vaccine. Recheck pneumococcal titres 4 to 6 weeks later.
• Antibiotic prophylaxis after an invasive infection or with recurrent severe infections: phenoxymethylpenicillin 250 mg orally twice daily in adults (children under 6 years 125 mg twice daily; 6 to 11 years 250 mg twice daily). Use azithromycin 500 mg three times weekly in adults (children 10 mg/kg three times weekly, maximum 500 mg) for penicillin allergy, after confirming QTc under 450 ms on ECG. Review at 6 to 12 months.
• Febrile illness: fever over 38.5 degrees Celsius with unwellness needs same day assessment and early parenteral antibiotics, because of the risk of rapid sepsis.
• Immunoglobulin replacement only for confirmed specific antibody failure with serious or recurrent infection despite prophylaxis: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, adjusted to a trough IgG of at least 6 g/L, usually 7 to 9 g/L. Immunoglobulin supplies IgG and not IgM, so benefit comes through IgG. Plan a time limited course of 12 months and then stop for 3 to 6 months to judge continued need.
• Infusion reactions: slow the rate; for repeated reactions premedicate with paracetamol 15 mg/kg orally (maximum 1 g) and chlorphenamine 4 mg orally in adults.
• Treat atopy, chronic sinus disease and autoimmune disease in the usual way.

Special groups.

• Patients with splenic hypofunction are at high risk of overwhelming infection, so keep lifelong prophylaxis under review.

Monitoring. Yearly clinical review. Repeat IgM, IgG and IgA yearly. Recheck serum protein electrophoresis yearly in adults over 40 years. Review vaccine titres every 3 to 5 years. During immunoglobulin replacement: trough IgG every 3 to 6 months, creatinine and liver enzymes every 6 months.

Referral and escalation. Refer to immunology for the diagnosis. Urgent for sepsis or meningitis, and for new cytopenia, lymphadenopathy or a monoclonal band.