Hematopoietik Kök Hücre Nakli Yapıldıktan Sonra En Az İki Yıl İzlenmiş Ağır Kombine İmmün Yetmezlik Olgularının Klinik Özelliklerinin, Laboratuvar Bulgularının ve İmmün Rekonstitüsyonunun Değerlendirilmesi

Abstract

ABSTRACT Guner Demirtas, D. Evaluation of the long-term clinical, laboratory and immune reconstitution of hematopoietic stem cell transplanted severe combined immunodeficiency cases. Hacettepe University Faculty of Medicine, Thesis in Pediatrics, Ankara 2015. Severe combined immunodeficiency (SCID) is a hereditary primary immunodeficiency characterized by deficiency in the development and/or function of T lymphocyte and antibody production and affects both cellular and humoral immunity. The definitive treatment option for all SCID types is hematopoietic stem cell transplantion (HSCT). The study includes a total of 44 patients which includes 25 males (56.8%), 19 females (43.2%) who were followed for two years after receiving HSCT treatment for SCID between June 1994 and May 2013 in Hacettepe University, Ihsan Dogramaci Pediatry Department. The application age for the patients was 5 months (0-25 months), mean age at transplantation was 7.1 months (23 days-32.8 months). The transplantation was done before 6 months of age to 19 patients (%43.2), after 6 months to 25 patients (56.8%). The amount of time passed after HSCT is 8.7 years (2-21 years). The time passed after HSCT is more than 10 years in 19 of the patients (43.2%), 5 to 10 years in 12 of the patients (27.3%) and 2 to 5 years in 13 of the patients (29.5%). The most common complaints in admission were chronic diarrhea (54.5%), oral candidiasis (52.3%) and recurrent lung infection (50%). The parents of 37 patients (84.1%) have consanguinity. When the patients were categorized immunophenotypically; 25 patients (56.8%) were T-B-NK+, 15 patients (34.1%) were T-B+NK-, 3 patients (6.8%) were T-B+NK+ and one patient was (2.3%) T+B-NK+. The genetic defect that causes severe combined immunodeficiency was found in 34 patients (77.3%), Artemis gene defect was found in 8 patients (23.5%), 7 patients (20.6%) had IL2RG deficiency, 7 patients (20.6%) had RAG2 gene defect, 6 patients (17.6%) had RAG1 gene defect, 2 patients (5.9%) had Cernunnos deficiency, 2 patients (5.9%) had JAK3 deficiency, 1 patient (2.9%) had IL7RA deficiency and 1 patient (2.9%) had DNA-PKcs deficiency. The most common genetic deficiency were RAG1/RAG2 gene defects which were found in a total of 13 patients (38%). The source for HSCT was bone marrow in 31 patients (70.4%), peripheral stem cell in 12 patients (27.3%), cord blood in one patient (2.3%). Hematopoietic stem cell transplantation was applied from HLA identical donors to 34 patients (72.3%), from HLA 1-mismatched donors to 4 patients (9.1%), from HLA 2-mismatched donors to 1 patient (2.3%), from haploidentical donors to 5 patients (11.3%). At admission the body weight of 51.2% of the patients, height of 28.2%, head circumference of 34.4% were below the third percentile for age and gender. At admission, 37 patients (84.1%) had low absolute lymphocyte count (ALC) (100-3264/mm³), 6 patients (13.6%) had normal ALC and 1 patient (2.3%) had high ALC. At admission, 42% of the patients had low immunoglobulin (Ig) A, 67.4% had low IgM and 44.4% had low IgG. After transplantation, 14 of 44 patients (31.8%) developed acute graft versus host disease (GVHD), 3 of the patients (6.8%) developed chronic GVHD. It is observed that GVHD has developed less for patients using bone marrow stem cell than those using peripheral stem cell as the source (p=0.024). It is observed that acute GVDH has developed less for patients who were applied HSCT using bone marrow stem cell than using peripheral stem cell as the source for identical donors (p=0.010). In final controls for patients other than the ones with the Cernunnos deficiency, body weight vii of 74.3% of the patients, height of 82.8% and head circumference of 82.8% of the patients were within normal limits. In the final controls, ALC for 90.9%, CD3 count for 95.4%, CD4 count for 88.1% and CD8 count for 97.6% of the patients were found normal. After the transplantation, mitogen response to phytohemagglutinin, to concanavalin A and to ionomisin were found normal respectively in 94.6%, 94.3% and 91.2% of the patients. In final controls it is observed that for 32 of 44 patients (72.7%) monthly intravenous immunoglobulin (IVIG) replacement treatment was discontinued. 54.5% of the patients for whom two years has passed after the HSCT, CD19 count was found low, and for 44.5% of them the count was found normal. The CD19 count was found significantly better for B+ SCID patients than B- SCID (p<0.001). CD19 count was found significantly better for B+ SCID patients who had transplantation from identical donors and who did not receive pretransplantation conditioning than for B- SCID patients (p<0.001). Immunoglobulin A value was found normal/high for 59% of the patients and for 70.6% of patients who had transplantation from identical donors, and the value was found normal for 56.3% of the patients whose IVIG replacement treatment was discontinued. For 53.6% of the patients whose IVIG replacement treatment was discontinued, antiHbs value was found positive, for 77.8% of them isohemoagglutinin titer was found normal and for 50% of them pneumococcus vaccine response was found normal. No difference was found for IVIG discontinuation ratios and antibody responses in B- and B+ immunophenotypes, although B cell counts are significantly better for HSCT patients who have B+ SCID immunophenotype. Key Words: Severe combined immunodeficiency, hematopoietic stem cell transplantation, immune reconstitution