Primary immunodeficiency in southern Sweden. Strategies for diagnosis and clinical management

Sammanfattning: The overall aim of this PhD project was to gain insight into the incidence of primary immunodeficiency (PID) in southern Sweden and to optimize diagnostic and treatment measures for these patients. We estimated the occurrence rate of PID in the pediatric population of southern Sweden during a period of 4 years and described the demographic, clinical and immunological characteristics of the identified cases. The occurrence rate of PID was about four new cases per year in this population. Several different PID diagnoses were found, and the application of specified criteria to identify PID patients was useful. In children who are prone to infection, the use of a predefined set of immunological laboratory analyses at their first examination was beneficial for early identification of patients with primary immunodeficiency. Complement C2 deficiency (C2D) is associated with immunological diseases and increased susceptibility to invasive infections caused by encapsulated bacteria such as Neisseria (N.) meningitidis. We evaluated the immunogenicity of vaccination against N. meningitidis in C2D patients and healthy controls who received a tetravalent meningococcal vaccine. Response was measured by determining serum bactericidal antibody (SBA) titers against the four meningococcal serogroups A, C, Y and W included in the vaccine. We also investigated other immunological factors that could influence the vaccine responses. In general, vaccination against meningococci gave rise to antibody responses in the C2D patients that equal those of healthy controls. The response rate was lower to serogroup A and among C2D patients with history of invasive infections. The presence of G2M'n/G2M'n genotype was associated with higher SBA titers after immunization. None of the other tested immunological factors influenced the vaccination responses. We described the first Swedish patient with purine nucleoside phosphorylase (PNP) deficiency with novel mutations in the PNP gene. We presented also the results of the hematopoietic stem cell transplantation (HSCT) and evaluated the impact of HSCT on the neurological symptoms. We could conclude that HSCT is curative for the immunological defect caused by PNP deficiency and our case strengthens earlier reports that HSCT is effective as a treatment even for neurological symptoms in PNP deficiency. We presented a novel approach of treating SCID by successfully combining a haploidentical HSCT with a subsequent donor lymphocyte infusion (DLI). No acute or chronic graft-versus-host disease (GvHD) was observed after any of the procedures. The HSCT graft was selectively depleted of potentially GvHD-inducing α/β T-cells while the DLI graft was enriched for memory T-cells for enhanced anti-viral immunity. HSCT engraftment was rapid with complete donor chimerism and after DLI the T-cell levels normalized and all infections were cleared.