Snapshot A 6-month-old boy presents with a past medical history of skin infections presents with difficulty breathing, high fever, and nonproductive cough. He is immediately started on broad-spectrum antibiotics. On further questioning, his family history includes a maternal uncle dying at age 20 from overwhelming pneumonia. Sputum is induced with hypertonic saline inhalation, and eventual staining shows Pneumocystis. He is immediately started on IVIG. Introduction Inherited primary combined B- and T-cell immunodeficiency characterized by increased levels of IgM Genetics X-linked recessive mutation in gene that codes for CD40 ligand (CD40L) Pathogenesis CD40L is expressed on activated T-helper cells defect in humoral immunity CD40L is necessary to induce B-cells to undergo Ig class-switching from IgM to IgG, IgA, and IgE see illustration above defect cell-mediated immunity CD40L also required for maturation of T-cells, dendritic cells, and macrophages Symptoms onset by 1 year, often with Pneumocystis infections most diagnosed before 4 years Presentation Symptoms severe pyogenic infections early in life chronic diarrhea opportunistic infections pneumonia Pneumocystis Cryptosporidium CMV echovirus encephalitis pancytopenia common fatigue infection pallor bleeding Evaluation Ig levels ↑ IgM ↓ IgA, IgG, and IgE due to defect in class-switching Diagnosis confirmed with flow cytometry deficient expression of CD40L on activated T-helper cells normal T- and B-cells CBC neutropenia thrombocytopenia possible Differential Diagnosis Bruton agammaglobulinemia CVID SCID Treatment Prophylaxis of Pneumocystis Regular IVIG replacement Prognosis, Prevention, and Complications Prognosis 20% survival rate past young adulthood leading cause of death pneumonia encephalitis malignancy Complications increased risk of autoimmunity increased risk of malignancies HCC carcinoid tumor infection bronchiectasis