Introduction
Since the first description of gain of function (GOF) mutations in signal transducer and activator of transcription (STAT) 1, more than 300 patients have been described with a broad ...clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, their indications, dosing, and monitoring remain to be established.
Methods
A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature.
Results
Ten children (median age 8.5 years (3–18), receiving JAKinibs (ruxolitinib (
n
= 9) and baricitinib (
n
= 1)) with a median follow-up of 18 months (2–42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune deficiency and dysregulation activity scores were 15.99 (5.2–40) pre and 7.55 (3–14.1) under therapy (
p
= 0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response.
Conclusions
Our study supports the potentially beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.
Abstract
Background
Currently, data on treatment, outcome, and prognostic factors in children with tuberculous meningitis (TBM) in Europe are limited. To date, most existing data on TBM originate ...from adult studies, or studies conducted in low-resource settings.
Methods
We designed a multicenter, retrospective study involving 27 pediatric healthcare institutions in 9 European countries via an established pediatric TB research network, before and after the 2014 revision of World Health Organization (WHO) dosing recommendations.
Results
Of 118 children, 39 (33.1%) had TBM grade 1, 68 (57.6%) grade 2, and 11 (9.3%) grade 3. Fifty-eight (49.1%) children received a standard 4-drug treatment regimen; other commonly used drugs included streptomycin, prothionamide, and amikacin. Almost half of the patients (48.3%; 56/116) were admitted to intensive care unit, with a median stay of 10 (interquartile range IQR 4.5–21.0) days. Of 104 children with complete outcome data, 9.6% (10/104) died, and only 47.1% (49/104) recovered fully. Main long-term sequelae included spasticity of 1 or more limbs and developmental delay both in 19.2% (20/104), and seizure disorder in 17.3% (18/104). Multivariate regression analyses identified microbiological confirmation of TBM, the need for neurosurgical intervention, and mechanical ventilation as risk factors for unfavorable outcome.
Conclusions
There was considerable heterogeneity in the use of TB drugs in this cohort. Despite few children presenting with advanced disease and the study being conducted in a high-resource setting, morbidity and mortality were high. Several risk factors for poor outcome were identified, which may aid prognostic predictions in children with TBM in the future.
To analyze host and pathogen factors related to disease severity of community-acquired bone and joint infections in children, a cohort of pediatric patients was prospectively recruited from 13 ...centers in 7 European countries. A total of 85 children were included, 11 (13%) had a severe infection. Panton-Valentine leukocidin–positive isolates were 17%, and 6% of the isolates were methicillin-resistant Staphylococcus aureus. Multivariate analysis identified Panton-Valentine leukocidin presence (adjusted odds ratio, 12.6; P = 0.01) as the only factor independently associated with severe outcome, regardless of methicillin resistance.
A unified surveillance mechanism for hand hygiene and hospital-acquired infections for pediatric wards is lacking in Europe. We managed to setup such a mechanism in 9 pediatric intensive care units ...in 7 European countries, using World Health Organization's definitions and common methodology which allows for benchmarking among units and countries. Median hand hygiene compliance was found high 82.3% (interquartile range 71.6-94.5%), but gaps in practices were identified.
Erythropoiesis involves significant changes in the cells, which are mediated by the plasma membrane and the actin cytoskeleton. The composition of the actin cytoskeleton and the interaction between ...its components are dynamically modified during erythropoiesis, however the precise role that different actin regulators play during erythroid differentiation is poorly understood. The dedicator of cytokinesis (DOCK) family member DOCK11 regulates actin cytoskeleton dynamics via its guanine nucleotide exchange factor (GEF) activity, resulting in activation of the small Rho GTPase CDC42. CDC42 has been implicated in regulating the early stages of erythroid development, as well as the terminal maturation steps involving enucleation. However, the role of human DOCK11 in hematopoietic cell function and human disease had not been defined. We analyzed a cohort of four patients from four unrelated families presenting with recurrent infections, early-onset severe immune dysregulation, systemic inflammation, as well as normocytic anemia and anisocytosis of unknown origin. Using whole-exome sequencing, we identified rare, hemizygous germline mutations in DOCK11 in these patients. Two mutations - an early stop-gain mutation and a To study the role of DOCK11 during erythropoiesis, we generated a dock11-knockout zebrafish model. We found that the dock11-knockout zebrafish embryos recapitulated the anemia and aberrant erythrocyte morphology observed in human DOCK11 deficiency. The anemia was amenable to rescue with constitutively active CDC42, suggesting that DOCK11 regulates erythrocyte numbers in a CDC42-dependent manner. As a next step we modeled human erythroid differentiation in vitro using an erythroid liquid culture system starting from purified CD34+ cells. ShRNA-mediated knockdown of DOCK11 in CD34 + cells revealed impairment of cell growth and differentiation during erythroid development. In line with moderate erythroid hypoplasia observed in the bone marrow of one of the patients, these data suggest an erythroid-intrinsic role of DOCK11 during erythropoiesis. As the patients with germline DOCK11 defects also presented with recurrent infections and systemic inflammation, we further assessed the role of DOCK11 in immune cells. In line with its role in actin dynamics, we found that human DOCK11 regulates T-cell morphology and migration, suggesting that defects in DOCK11 might impact the T cells' capability to fight infections. We further uncovered that the immune dysregulation observed in the patients involved aberrant T-cell activation and cytokine production. Mechanistically, using cells from DOCK11-deficient patients and Dock11-knockout mice, we were able to show that Dock11 regulates cytokine production at the transcriptional level by modulating the nuclear translocation of the T-cell transcription factor NFATc1, known to regulate the production of several cytokines. Collectively, we identified germline loss-of-function mutations affecting the actin regulator DOCK11 in a previously unknown disorder associating anemia and systematic inflammation. This work earmarks the DOCK11-CDC42 axis as an attractive future target for the treatment of a broader range of immune and hematological diseases
In this study, DOCK11 was shown to regulate T-cell shape and migration and erythroid development. Inherited loss-of-function variants in
DOCK11
led to early-onset severe immune dysregulation and ...normocytic anemia.
Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is ...potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited.
We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers.
We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months.
Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function GOF, 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 aka SOCS1 loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival.
Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.
