Hematopoietic Cell Transplantation for Adenosine Deaminase Severe Combined Immunodeficiency-Improved Outcomes in the Modern Era.

Current treatment for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) includes enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplant (HSCT), or ex vivo corrected autologous hematopoietic stem cell gene therapy. Historic data show HSCT survival is superior using unconditioned matched sibling and family compared to matched unrelated and haploidentical donors. Recent improvement in HSCT outcomes prompted us to retrospectively examine HSCT survival and long-term graft function in ADA-SCID transplanted at our center. Thirty-three ADA-deficient patients received HSCT between 1989 and 2020, with follow-up data to January 2021. Chemotherapy conditioning regimens were defined as myeloablative (MAC-busulfan/cyclophosphamide), reduced-toxicity myeloablative (RT-MAC-treosulfan-based, since 2007), or no conditioning. Serotherapy used included alemtuzumab (with or without other conditioning agents) or antithymocyte globulin (ATG). ERT was introduced routinely in 2010 until commencement of conditioning. Median age at HSCT was 3.2 (0.8-99.8) months. Twenty-one (63.6%) received stem cells from unrelated or haploidentical donors. Seventeen (51.5%) received chemotherapy conditioning and 16 (48.5%) received alemtuzumab. Median follow-up was 7.5 (0.8-25.0) years. Overall survival (OS) and event-free survival (EFS) at 8 years were 90.9% (95% CI: 79.7-100.0%) and 79% (55-91%), respectively. OS after 2007 (n = 21) was 100% vs 75% before 2007 (n = 12) (p = 0.02). Three (9.1%) died after HSCT: two from multiorgan failure and one from unexplained encephalopathy. There were no deaths after 2007, among those who received ERT and treosulfan-based conditioning pre-HSCT. Ten (30.3%) developed acute GvDH (3 grade II, 2 grade III); no chronic GvHD was observed. In the modern era, conditioned HSCT with MUD has a favorable outcome for ADA-deficient patients.

Multisystem inflammatory syndrome in the context of paediatric COVID-19 infection in the Republic of Ireland April 2020 to April 2021.

AIM: Our aim was to describe the epidemiology of multisystem inflammatory syndrome in children (MIS-C) in the Republic of Ireland, in the context of all cases of COVID-19 in children, during the first year of the SARS-CoV-2 pandemic. METHODS: Cases of MIS-C were identified by prospective surveillance in Irish hospitals from April 2020 to April 2021. Paediatric COVID-19 cases and outbreaks in schools or childcare facilities were notified to and routinely investigated by Public Health. Univariate and bivariate analyses were carried out in Excel, Stata and JMP statistical package. RESULTS: Fifty-four MIS-C cases (median age 7.58 years; males 57%) were identified over the study period. MIS-C incidence was higher in certain ethnicities ('black' 21.3/100,000 [95% CI 4.3-38.4]; and 'Irish Traveller' 14.7/100,000 [95% CI -5.7-35.1]) than those of 'white' ethnicity (3.4 /100,000). MIS-C cases occurred in three temporal clusters, which followed three distinct waves of community COVID-19 infection, irrespective of school closures. Formal contact tracing identified an epidemiological link with a COVID-19-infected family member in the majority of MIS-C cases (77%). In contrast, investigation of COVID-19 school outbreaks demonstrated no epidemiological link with MIS-C cases during the study period. CONCLUSION: Efforts at controlling SARS-CoV-2 transmission in the community may be a more effective means to reduce MIS-C incidence than school closures. Establishing a mandatory reporting structure for MIS-C will help delineate the role of risk factors such as ethnicity and obesity and the effect of vaccination on MIS-C incidence.

Novel Gain-of-Function Mutation in Stat1 Sumoylation Site Leads to CMC/CID Phenotype Responsive to Ruxolitinib.

Mutations in the coiled-coil and DNA-binding domains of STAT1 lead to delayed STAT1 dephosphorylation and subsequently gain-of-function. The associated clinical phenotype is broad and can include chronic mucocutaneous candidiasis (CMC) and/or combined immunodeficiency (CID). We report a case of CMC/CID in a 10-year-old boy due to a novel mutation in the small ubiquitin molecule (SUMO) consensus site at the C-terminal region of STAT1 leading to gain-of-function by impaired sumoylation. Immunodysregulatory features of disease improved after Janus kinase inhibitor (jakinib) treatment. Functional testing after treatment confirmed reversal of the STAT1 hyper-phosphorylation and downstream transcriptional activity. IL-17 and IL-22 production was, however, not restored with jakinib therapy (ruxolitinib), and the patient remained susceptible to opportunistic infection. In conclusion, a mutation in the SUMO consensus site of STAT1 can lead to gain-of-function that is reversible with jakinib treatment. However, full immunocompetence was not restored, suggesting that this treatment strategy might serve well as a bridge to definitive therapy such as hematopoietic stem cell transplant rather than a long-term treatment option.

HIV virological suppression influences response to the AS03-adjuvanted monovalent pandemic influenza A H1N1 vaccine in HIV-infected children.

DESIGN: Children with HIV are especially susceptible to complications from influenza infection, and effective vaccines are central to reducing disease burden in this population. We undertook a prospective, observational study to investigate the safety and immunogenicity of the inactivated split-virion AS03-adjuvanted pandemic H1N1(2009) vaccine in children with HIV. SETTING: National referral centre for Paediatric HIV in Ireland. SAMPLE: Twenty four children with HIV were recruited consecutively and received two doses of the vaccine. The serological response was measured before each vaccine dose (Day 0 and Day 28) and 2 months after the booster dose. Antibody titres were measured using a haemagglutination inhibition (HAI) assay. Seroprotection was defined as a HAI titre ≥ 1:40; seroconversion was defined as a ≥ fourfold increase in antibody titre and a postvaccination titre ≥ 1:40. MAIN OUTCOME MEASURES: The seroconversion rates after prime and booster doses were 75% and 71%, respectively. HIV virological suppression at the time of immunization was associated with a significantly increased seroconversion rate (P = 0·009), magnitude of serological response (P = 0·02) and presence of seroprotective HAI titres (P = 0·017) two months after the booster dose. No other factor was significantly associated with the seroconversion/seroprotection rate. No serious adverse effects were reported. Vaccination had no impact on HIV disease progression. The AS03-adjuvanted pandemic H1N1 vaccine appears to be safe and immunogenic among HIV-infected children. A robust serological response appears to be optimized by adherence to a HAART regimen delivering virological suppression.

Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage.

Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-δ syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110δ. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110δ inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.

Idiopathic suppurative pylephlebitis: interventional radiological diagnosis and management.

We report the imaging findings and management of a case of suppurative pylephlebitis of unknown cause in a 10-year-old girl. Percutaneous aspiration of frank pus from the portal vein confirmed the diagnosis and contributed to therapy. Percutaneous transhepatic thrombolysis was attempted but was unsuccessful. Because of the nonspecific presentation of this condition and the lack of familiarity of physicians with this entity, the diagnosis is often delayed. Our aim is to increase the awareness of this entity and stress the importance of early diagnosis and appropriate therapy.