CD40 Ligand Deficiency

CD40 ligand deficiency is an X-linked combined immunodeficiency from variants in CD40LG, also called X-linked hyper IgM syndrome. Boys present in infancy or early childhood with low IgG and IgA, normal or high IgM, and opportunistic infections.

Pathophysiology. CD40 ligand on activated CD4 T cells binds CD40 on B cells, macrophages and dendritic cells. Without it, B cells cannot switch class from IgM, germinal centres fail, and macrophage activation against intracellular organisms is weak.

It affects about 1 in a million males. Female carriers are usually well.

Pneumocystis pneumonia is the first manifestation in many infants. Cryptosporidium and liver disease shorten survival without transplant.

• Pneumocystis pneumonia in infancy
• Recurrent sinopulmonary infection and bronchiectasis
• Neutropenia (cyclic or chronic) with mouth ulcers and perianal infection
• Chronic diarrhoea, Cryptosporidium infection and sclerosing cholangitis
• Opportunistic infection: Cryptococcus, Histoplasma, Mycobacterium, CMV
• Autoimmune cytopenias and arthritis
• Liver disease with biliary and hepatocellular carcinoma in adulthood
• Maternal male relatives with early death from infection

• Immunoglobulins: low IgG and IgA, with normal or high IgM.
• CD40 ligand expression on activated CD4 T cells by flow cytometry (absent or reduced), with sequencing of CD40LG for confirmation and carrier testing of the mother.
• Full blood count with differential, repeated, for neutropenia.
• Lymphocyte subsets: normal B cells that are IgM and IgD positive and lack switched memory B cells.
• Pneumocystis PCR on respiratory samples, stool Cryptosporidium PCR, and viral PCR.
• Liver enzymes, ultrasound and cholangiography for sclerosing cholangitis.
• High resolution CT if chronic lung disease is suspected.

Differential diagnosis.

• CD40 deficiency (autosomal recessive)
• Activation induced cytidine deaminase and UNG deficiency (hyper IgM without opportunistic infection)
• Common variable immunodeficiency
• X-linked agammaglobulinaemia
• NEMO deficiency
• Severe combined immunodeficiency
• Secondary neutropenia

• Immunoglobulin replacement: 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. Slow the infusion after a reaction; for anaphylaxis give adrenaline 0.01 mg/kg intramuscularly (maximum 0.5 mg).
• Pneumocystis prophylaxis from diagnosis: co-trimoxazole with trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week (adults 960 mg three times weekly).
• Pneumocystis pneumonia: co-trimoxazole with trimethoprim 15 to 20 mg/kg daily in 3 to 4 divided doses, intravenously or orally, for 21 days (halve at creatinine clearance 15 to 30 mL/min). Add prednisolone for hypoxaemia (PaO2 under 9.3 kPa): 40 mg twice daily for 5 days, then 40 mg daily for 5 days, then 20 mg daily for 11 days (children 1 mg/kg twice daily, then tapered over the same schedule).
• Neutropenia: filgrastim 1 to 5 microgram/kg subcutaneously daily or on alternate days, titrated to keep neutrophils at 1.0 x 109/L or more. Febrile neutropenia needs piperacillin with tazobactam 4.5 g intravenously every 6 hours in adults after blood cultures (adjust to renal function).
• Cryptosporidium prevention and treatment: use boiled or filtered water, and avoid swimming pools and contact with animals. Treat infection with nitazoxanide 500 mg orally twice daily for 3 to 14 days (children aged 12 years and over; younger children by weight under specialist direction).
• Liver disease: ursodeoxycholic acid 15 mg/kg orally daily in divided doses for cholestasis, and ultrasound and liver enzymes every 6 months.
• Haematopoietic stem cell transplantation is the only cure, with best results before age 10 years and before liver disease or chronic lung disease develop.
• Vaccines: inactivated only; avoid live vaccines.

Special groups.

• Female carriers: genetic counselling, with a 50% chance that a son will be affected.
• Infants: start prophylaxis as soon as the diagnosis is made.

Monitoring. Trough IgG every 3 months. Full blood count with differential monthly while neutropenic. Liver enzymes and ultrasound every 6 months. Annual lung imaging or lung function.

Referral and escalation. Refer urgently to immunology and a transplant centre at diagnosis. Emergency for respiratory distress, fever with neutropenia, jaundice or sepsis.