sirolimus and Primary-Immunodeficiency-Diseases

Activated phosphoinositide 3-kinase δ syndrome (APDS), a recently described primary immunodeficiency,is caused by autosomal dominant mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta(PIK3CD) gene encoding the p110δ catalytic subunit of PI3Kδ (APDS1) or the PIK3R1 gene that encodes the p85α regulatory subunit of PI3Kδ (APDS2). Gain-of-function mutation of PIK3CD in APDS1 leads to p110δ hyperactivity, with the result of the hyperphosphorylation of downstream mediators of Akt and mammalian target of rapamycin that cause a series of clinical symptoms. Few cases with APDS were reported in Asia.. We report a 6-year-old patient with a recurrent respiratory infection, cryptosporidium enteritis, lymphoproliferation, high serum immunoglobulin-M level, anemia, and inverted CD4+/CD8+ ratio. The whole exome sequencing confirmed a heterozygous missense mutation c.3061G>A（p.E1021K）in patient and her mother. Her mutant gene is inherited from her mother, but her mother has not any clinical symptoms.. Activated phosphoinositide 3-kinase δ syndrome.. The patient was received immunoglobulin (Ig) replacement therapy, antibiotics, and rapamycin treatment. Through effectively controlling infection and optimal timing of transplantation by adjusting the conditioning regimen, haploidentical Hematopoietic Stem Cell Transplantation(haplo-HSCT) from her brother was successfully performed.. The patient is in good condiion with a good quality of life after 20 months of follow-up.. We reported a rare APDS1 case with PIK3CD E1021K gene mutation, Successfully treated with haplo-HSCT. This case provided a reference for treating APDS with haplo-HSCT.

Topics: Child; Class I Phosphatidylinositol 3-Kinases; Cryptosporidiosis; Cryptosporidium; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Deficiency Syndromes; Male; Mutation; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Primary Immunodeficiency Diseases; Quality of Life; Sirolimus

Topics: Allografts; Class I Phosphatidylinositol 3-Kinases; Class Ia Phosphatidylinositol 3-Kinase; Enzyme Inhibitors; Humans; Immunologic Deficiency Syndromes; Lymphoproliferative Disorders; Mutation; Phosphatidylinositol 3-Kinases; Primary Immunodeficiency Diseases; Respiratory Tract Infections; Sirolimus; Stem Cell Transplantation

Activated phosphoinositide 3-kinase δ syndrome (APDS) is a primary immunodeficiency first described in 2013, which is caused by gain-of-function mutations in PIK3CD or PIK3R1, and characterized by recurrent respiratory tract infections, lymphoproliferation, herpesvirus infection, autoimmunity, and enteropathy. We sought to review the clinical phenotypes, immunological characteristics, treatment, and prognosis of APDS in a large genetically defined Chinese pediatric cohort.. Clinical records, radiology examinations, and laboratory investigations of 40 APDS patients were reviewed. Patients were contacted via phone call to follow up their current situation.. Sinopulmonary infections and lymphoproliferation were the most common complications in this cohort. Three (10.3%) and five (12.5%) patients suffered localized BCG-induced granulomatous inflammation and tuberculosis infection, respectively. Twenty-seven patients (67.5%) were affected by autoimmunity, while malignancy (7.5%) was relatively rare to be seen. Most patients in our cohort took a combined treatment of anti-infection prophylaxis, immunoglobulin replacement, and immunosuppressive therapy such as glucocorticoid or rapamycin administration. Twelve patients underwent hematopoietic stem cell transplantation (HSCT) and had a satisfying prognosis.. Clinical spectrum of APDS is heterogeneous. This cohort's high incidence of localized BCG-induced granulomatous inflammation and tuberculosis indicates Mycobacterial susceptibility in APDS patients. Rapamycin is effective in improving lymphoproliferation and cytopenia. HSCT is an option for those who have severe complications and poor response to other treatments.

Topics: BCG Vaccine; Child; China; Class I Phosphatidylinositol 3-Kinases; Humans; Inflammation; Primary Immunodeficiency Diseases; Sirolimus; Tuberculosis

Cartilage-hair hypoplasia (CHH) is a syndromic immunodeficiency characterized by metaphyseal dysplasia, cancer predisposition, and varying degrees of anemia. It may present as severe combined immunodeficiency in infancy, or slowly progress until fully manifesting in late adolescence/adulthood. No targeted treatment is currently available, and patients are usually managed with supportive measures, or are offered a bone marrow transplant if the clinical phenotype is severe and a suitable donor is available. We report the case of a young girl presenting with transfusion-dependent erythropoietic failure and immunological features resembling autoimmune lymphoproliferative syndrome who responded well to empirical sirolimus. She later developed a marked growth delay, which was ultimately attributed to metaphyseal dysplasia. A diagnosis of CHH was reached through whole-genome sequencing (WGS), after a less sensitive genetic diagnostic strategy failed. The patient eventually underwent a haploidentical bone marrow transplant due to progressive combined immunodeficiency manifested as cryptococcal meningoencephalitis. This case illustrates the potential role of sirolimus in correcting anemia and partially controlling the immune aberrations associated with CHH, and serves as a reminder of the invaluable role of WGS in diagnosing patients with complex and atypical presentations.

Topics: Adult; Anemia; Erythropoiesis; Female; Hair; Hirschsprung Disease; Humans; Osteochondrodysplasias; Primary Immunodeficiency Diseases; Sirolimus

Post hematopoietic cell transplantation (HCT) autoimmune cytopenia (AIC) is a potentially life-threatening complication, but studies focusing on large cohorts of patients transplanted for primary immunodeficiency are lacking.. This study sought to determine the incidence, risk factors, and outcomes of post-HCT AIC and B-lymphocyte function following rituximab.. We retrospectively studied 502 children with primary immunodeficiency who were transplanted at our center between 1987 and 2018.. Thirty-six patients (9%) developed post-HCT AIC, with a median onset of 6.5 months post-HCT. On univariate analysis, pre-HCT AIC, mismatched donor, alemtuzumab, anti-thymocyte antiglobulin, and acute and chronic graft versus host disease were significantly associated with post-HCT AIC. After multivariate analysis, alemtuzumab (subdistribution hazard ratio, 9.0; 95% CI, 1.50-54.0; P = .02) was independently associated with post-HCT AIC. Corticosteroid and high-dose intravenous immunoglobulin achieved remission in 50% (n = 18), additional rituximab led to remission in 25% (n = 9), and the remaining 25% were treated with a combination of various modalities including sirolimus (n = 5), bortezomib (n = 3), mycophenolate mofetil (n = 2), splenectomy (n = 2), and second HCT (n = 3). The mortality of post-HCT AIC reduced from 25% (4 of 16) prior to 2011 to 5% (1 of 20) after 2011. The median follow-up of 5.8 years (range, 0.4 to 29.1 years) showed that 26 of 30 survivors (87%) were in complete remission, and 4 were in remission with ongoing sirolimus and low-dose steroids. Of the 17 who received rituximab, 7 had B-lymphocyte recovery, 5 had persistent low B-lymphocyte count and remained on intravenous immunoglobulin replacement, 2 had second HCT, and 3 died.. The frequency of post HCT AIC in our cohort was 9%, and the most significant risk factors for its occurrence were the presence of graft versus host disease and the use of alemtuzumab.

Topics: Antibodies, Monoclonal, Humanized; B-Lymphocytes; Child; Combined Modality Therapy; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Incidence; Male; Postoperative Complications; Primary Immunodeficiency Diseases; Retrospective Studies; Rituximab; Sirolimus; Transplantation Conditioning; Treatment Outcome; United Kingdom

Topics: Adolescent; Adult; Child; Child, Preschool; Class I Phosphatidylinositol 3-Kinases; Europe; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Middle Aged; Primary Immunodeficiency Diseases; Registries; Sirolimus; Societies, Medical; Young Adult

Premature T-cell immunosenescence with CD57

Topics: CD57 Antigens; Cell Differentiation; Cellular Senescence; Class I Phosphatidylinositol 3-Kinases; Cytokines; Humans; Immunologic Deficiency Syndromes; Immunophenotyping; Lymphocyte Count; Phosphatidylinositol 3-Kinases; Primary Immunodeficiency Diseases; Sirolimus; T-Lymphocyte Subsets; Telomere Shortening

Activated phosphoinositide 3-kinase δ (PI3Kδ) syndrome is a newly defined and relatively common primary immunodeficiency, which is caused by heterozygous gain-of-function (GOF) mutations in PIK3CD or PIK3R1. Here, we report a novel de novo GOF mutation (c.1570 T > A, p.Y524N) in PIK3CD in a 6-year-old Chinese girl. The patient suffered recurrent sinopulmonary infection, bronchiectasis, lymphoproliferation, herpesvirus infection, and distinctive nodular lymphoid hyperplasia of mucosal surfaces. Immunological analysis revealed increased CD4+ T cell senescence and B cell immaturity. Further analysis revealed an increase in almost all CD4+ T cell subsets to varying degrees, including effector T cells and Treg cells. Increased levels of plasma T cell-related cytokines corroborated these results. Hyperactivation of the PI3Kδ-Akt-mTOR signaling pathway was also confirmed. Treatment with rapamycin ameliorated the lymphoproliferative immunodeficiency caused by hyperactivation of mTOR. These results expand genetic spectrum of APDS and will facilitate further study of the genotype-phenotype correlation in those with PIK3CD mutations.

Topics: Adolescent; Case-Control Studies; CD4-Positive T-Lymphocytes; Cellular Senescence; Child; Child, Preschool; Class I Phosphatidylinositol 3-Kinases; Female; Gain of Function Mutation; Genotype; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Infant; Infant, Newborn; Phenotype; Primary Immunodeficiency Diseases; Sequence Analysis, DNA; Signal Transduction; Sirolimus; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory

We aimed to report the clinical manifestations and immunological features of activated phosphatidylinositol 3-kinase δ syndrome 1 (APDS1) in a Chinese cohort. Moreover, we investigated the efficacy and safety of rapamycin therapy for Chinese patients with APDS1.. Fifteen Chinese patients with APDS1 from 14 unrelated families were enrolled in this study. These patients were diagnosed based on clinical features, immunological phenotype, and whole-exome sequencing. Four patients were treated with rapamycin, and the clinical efficacy and safety of rapamycin were observed. The changes of phosphorylation of Akt and mammalian target of rapamycin (mTOR) signaling pathway after rapamycin treatment were detected by flow cytometry and real-time PCR.. The common clinical manifestations of the patients included lymphadenopathy (93%), recurrent sinopulmonary infections (93%), hepatosplenomegaly (93%), and diarrhea (78%). Epstein-Barr virus (EBV) (80%) and fungus (Aspergillus) (47%) were the most common pathogens. Immunological phenotype included elevated Immunoglobulin (Ig) M levels (100%), decreased naive T cells, increased senescent T cells, and expanded transitional B cells. Whole-exome sequencing indicated that 13 patients had heterogeneous PIK3CD E1021K mutations, 1 patient had heterogeneous E1025G mutation and 1 patient had heterogeneous Y524N mutation. Gain-of-function (GOF) PIK3CD mutations increased the phosphorylation of the Akt-mTOR signaling pathway. Four patients underwent rapamycin therapy, experiencing substantial improvement in clinical symptoms and immunological phenotype. Rapamycin inhibited the activated Akt-mTOR signaling pathway.. We described 15 Chinese patients with APDS1. Treatment with the mTOR inhibitor rapamycin improved patient outcomes.

Topics: Adolescent; Child; Child, Preschool; Class I Phosphatidylinositol 3-Kinases; Class Ia Phosphatidylinositol 3-Kinase; Cohort Studies; Female; Hepatomegaly; Humans; Immunoglobulin M; Immunologic Deficiency Syndromes; Infant; Lymphadenopathy; Male; Mutation; Oncogene Protein v-akt; Phosphorylation; Precursor Cells, B-Lymphoid; Primary Immunodeficiency Diseases; Respiratory Tract Infections; Signal Transduction; Sirolimus; T-Lymphocytes; TOR Serine-Threonine Kinases

Topics: Child, Preschool; Class I Phosphatidylinositol 3-Kinases; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Male; Prednisolone; Primary Immunodeficiency Diseases; Rituximab; Sirolimus; T-Lymphocytes

Heterozygous gain of function mutations in the gene encoding p110δ subunit of PI3K have been recently associated with activated PI3K-δ syndrome (APDS), a novel combined immune deficiency characterized by recurrent sinopulmonary infections, lymphopenia, reduced class-switched memory B cells, lymphadenopathy, CMV and/or EBV viremia and EBV-related lymphoma. Here we report a dominant gain of function PIK3CD mutation (E1021K) in a patient presenting with recurrent otitis media, massive splenomegaly, and persistent EBV-viraemia. The immunological studies showed low IgA level, but normal IgM, IgG, and normal antibody response to diphtheria and tetanus toxoid vaccination. Analysis of B lymphocyte subsets revealed abnormal expansion of transitional B cells, and low percentage of switched CD27

Topics: B-Lymphocyte Subsets; Child, Preschool; Class I Phosphatidylinositol 3-Kinases; Early Diagnosis; Female; Humans; Immunologic Deficiency Syndromes; Lymphopenia; Mutation; Otitis; Phosphatidylinositol 3-Kinases; Primary Immunodeficiency Diseases; Respiratory Tract Infections; Sirolimus; Spleen; Splenomegaly; T-Lymphocyte Subsets

Topics: Child, Preschool; Class I Phosphatidylinositol 3-Kinases; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Male; Primary Immunodeficiency Diseases; Sirolimus