ICOS Deficiency

ICOS deficiency is an autosomal recessive combined immunodeficiency from biallelic loss-of-function variants in ICOS. It looks like common variable immunodeficiency, with low immunoglobulins and recurrent infections, but starts earlier and brings T cell complications.

Pathophysiology. ICOS, a co-stimulatory receptor on activated T cells, is needed for T follicular helper cell development. Without it, germinal centres fail, B cells do not class switch or form memory, and antibody levels fall.

It is very rare. Onset is in childhood or early adulthood.

Some regions have founder variants, including large deletions, so family history and consanguinity help.

• Recurrent sinusitis, otitis media and pneumonia, with bronchiectasis
• Viral infections: CMV, EBV, herpes simplex and zoster, molluscum
• Autoimmune disease: cytopenias, arthritis, inflammatory bowel disease
• Lymphadenopathy and splenomegaly
• Granulomatous disease and interstitial lung disease
• Chronic diarrhoea and enteropathy
• Lymphoma in some

• Immunoglobulins: low IgG, IgA and IgM, with poor vaccine response.
• Lymphocyte subsets: low class switched memory B cells, low circulating T follicular helper cells, normal or raised total B cells, and variable CD4 lymphopenia.
• ICOS expression on activated T cells by flow cytometry (absent), with sequencing of ICOS for confirmation.
• Viral load by PCR for CMV and EBV.
• Autoimmune workup and high resolution CT chest.
• Endoscopy with biopsy for enteropathy.

Differential diagnosis.

• Common variable immunodeficiency
• CD40 ligand and CD40 deficiency
• Activated PI3K delta syndrome
• CTLA-4 haploinsufficiency and LRBA deficiency
• Autoimmune lymphoproliferative syndrome
• Secondary hypogammaglobulinaemia

• 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, and higher with bronchiectasis. Slow the infusion after a reaction; for anaphylaxis give adrenaline 0.5 mg intramuscularly (0.01 mg/kg in children, maximum 0.5 mg).
• Antibiotic prophylaxis: azithromycin 500 mg orally three times weekly 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.
• Pneumocystis prophylaxis: co-trimoxazole 960 mg orally three times weekly in adults (children trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week), especially with T cell lymphopenia or immunosuppression.
• Viral infection: CMV disease with valganciclovir 900 mg orally twice daily for 21 days (reduce at creatinine clearance under 60 mL/min; check blood count weekly), maintenance 900 mg once daily while viraemic.
• Autoimmunity: prednisolone 1 mg/kg orally daily (maximum 60 mg) tapered over 4 to 8 weeks; rituximab 375 mg/m2 intravenously weekly for 4 doses after hepatitis B screening; sirolimus 1 to 2 mg once daily in adults, adjusted to a trough of 5 to 10 microgram/L.
• Vaccines: inactivated only; avoid live vaccines.
• Haematopoietic stem cell transplantation is the definitive treatment and is offered to patients with severe disease or lymphoproliferation.

Special groups.

• Children: weight based doses, and early transplant planning for a matched donor search.

Monitoring. Trough IgG every 3 to 6 months. Full blood count, liver enzymes and creatinine every 3 to 6 months. CMV and EBV PCR with symptoms. CT chest and spirometry yearly.

Referral and escalation. Refer to immunology and a transplant centre. Urgent for opportunistic infection, cytopenia, or rapid lymphadenopathy.