ABSTRACT
BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Subject(s)
Immunologic Deficiency Syndromes , Janus Kinase Inhibitors , Child , Humans , Janus Kinase Inhibitors/therapeutic use , Retrospective Studies , Prospective Studies , Immunologic Deficiency Syndromes/therapy , Treatment OutcomeABSTRACT
OBJECTIVES: To investigate neurocognitive, psychosocial, and quality of life (QoL) outcomes in children with Multisystem Inflammatory Syndrome in Children (MIS-C) seen 3-6 months after PICU admission. DESIGN: National prospective cohort study March 2020 to November 2021. SETTING: Seven PICUs in the Netherlands. PATIENTS: Children with MIS-C (0-17 yr) admitted to a PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children and/or parents were seen median (interquartile range [IQR] 4 mo [3-5 mo]) after PICU admission. Testing included assessment of neurocognitive, psychosocial, and QoL outcomes with reference to Dutch pre-COVID-19 general population norms. Effect sizes (Hedges' g ) were used to indicate the strengths and clinical relevance of differences: 0.2 small, 0.5 medium, and 0.8 and above large. Of 69 children with MIS-C, 49 (median age 11.6 yr [IQR 9.3-15.6 yr]) attended follow-up. General intelligence and verbal memory scores were normal compared with population norms. Twenty-nine of the 49 followed-up (59%) underwent extensive testing with worse function in domains such as visual memory, g = 1.0 (95% CI, 0.6-1.4), sustained attention, g = 2.0 (95% CI 1.4-2.4), and planning, g = 0.5 (95% CI, 0.1-0.9). The children also had more emotional and behavioral problems, g = 0.4 (95% CI 0.1-0.7), and had lower QoL scores in domains such as physical functioning g = 1.3 (95% CI 0.9-1.6), school functioning g = 1.1 (95% CI 0.7-1.4), and increased fatigue g = 0.5 (95% CI 0.1-0.9) compared with population norms. Elevated risk for posttraumatic stress disorder (PTSD) was seen in 10 of 30 children (33%) with MIS-C. Last, in the 32 parents, no elevated risk for PTSD was found. CONCLUSIONS: Children with MIS-C requiring PICU admission had normal overall intelligence 4 months after PICU discharge. Nevertheless, these children reported more emotional and behavioral problems, more PTSD, and worse QoL compared with general population norms. In a subset undergoing more extensive testing, we also identified irregularities in neurocognitive functions. Whether these impairments are caused by the viral or inflammatory response, the PICU admission, or COVID-19 restrictions remains to be investigated.
Subject(s)
COVID-19 , Child , Humans , COVID-19/epidemiology , Quality of Life , Prospective Studies , Intensive Care Units, PediatricABSTRACT
The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS.
Subject(s)
Bone Neoplasms , Osteosarcoma , Acetylmuramyl-Alanyl-Isoglutamine/analogs & derivatives , Bayes Theorem , Biomarkers , Bone Neoplasms/pathology , Humans , Liposomes , Neoplasm Recurrence, Local/drug therapy , Osteosarcoma/pathology , PhosphatidylethanolaminesABSTRACT
OBJECTIVES: We report on the therapeutic management of early-onset severe neurologic symptoms in cytotoxic T lymphocyte antigen-4 haploinsufficiency (CTLA-4h) and the presence of antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) as an important finding. METHODS: This is a case report from a Dutch academic hospital. Repeated clinical examinations, repeated brain MRI and extended diagnostics on serum and CSF were performed. We used the CARE checklist. RESULTS: A 7-year-old boy was diagnosed with CTLA-4h based on family screening. On diagnosis, he had mild chronic diarrhea and autism spectrum disorder, but no abnormalities in extensive laboratory screening. Six months later, he presented with sudden-onset autoimmune encephalitis. Repeated brain MRI revealed no abnormalities, but immunohistochemistry analysis on serum and CSF showed the presence of AMPAR antibodies. Treatment was initially focused on immunomodulation and targeted CTLA-4 replacement therapy. Because of the persistent fluctuating cerebellar and neuropsychiatric symptoms and the potential clinical significance of the AMPAR antibodies, treatment was intensified with repetition of first-line immunomodulation and rituximab. This combined therapy resulted in sustained clinical improvement and served as a bridge to curative hematopoietic stem cell transplantation. DISCUSSION: This case illustrates the rare early onset of autoimmune encephalitis and presence of AMPAR antibodies in CTLA-4h. Targeted CTLA-4 replacement therapy resulted in a partial response. However, awaiting its optimal therapeutic effect, refractory CNS symptoms required intensification of immunomodulation. The identification of AMPAR antibodies guided our treatment decisions. CLASSIFICATION OF EVIDENCE: This provides Class IV evidence. It is a single observational study without controls.
Subject(s)
Autoantibodies , CTLA-4 Antigen , Encephalitis , Haploinsufficiency , Hashimoto Disease , Receptors, AMPA , Humans , Male , Child , Encephalitis/diagnosis , Encephalitis/drug therapy , Encephalitis/immunology , Hashimoto Disease/diagnosis , Hashimoto Disease/drug therapy , Autoantibodies/blood , Autoantibodies/cerebrospinal fluid , Receptors, AMPA/immunology , Rituximab/administration & dosage , Rituximab/therapeutic use , Immunologic FactorsABSTRACT
BACKGROUND: An umbilical infection (omphalitis) is frequent in de neonatal period. The infection usually presents as a relatively mild cellulitis. However, in rare cases omphalitis has a complicated course. CASE DESCRIPTION: A 20-day-old infant was referred to our Emergency Department with a fever and red umbilicus. Our diagnosis was "omphalitis" and after taking cultures we started with flucloxacillin and gentamicin intravenously. Upon clinical deterioration, we added ceftazidime and performed an ultrasound of the abdomen. A urachal remnant was found. The umbilical swab was positive for Staphylococcus aureus, which we treated with flucloxacillin monotherapy until the infiltrate disappeared on ultrasound. CONCLUSION: A patient with an omphalitis should be referred to the pediatrician. Clinical admission, obtaining cultures and starting antibiotic treatment is necessary. A large number of health care providers are involved in the care during the neonatal period. Therefore, broad knowledge about prevention and early identification of this disease is important.
Subject(s)
Infant, Newborn, Diseases , Skin Diseases , Soft Tissue Infections , Staphylococcal Infections , Cellulitis/diagnosis , Floxacillin , Humans , Infant , Infant, Newborn , Inflammation/diagnosis , UmbilicusABSTRACT
A 4-month-old female infant presented with a vesicular lesion on her left hand present since 1 day. A few days prior to presentation, she had a similar lesion on the lower lip. Two days after presentation, she returned with new lesions on her thorax and upper eyelid. PCR of the vesicle was positive for herpes simplex virus type 1. The transmission to her chest and face probably resulted from autoinoculation, caused by rubbing of the hand on other parts of the body. Transmission of herpes simplex through skin-to-skin contact is a common route of infection in people engaging in contact sports. Antiviral therapy was started because of the extensiveness and expansion of lesions and risk of developing herpetic keratitis. The patient completely recovered. This case shows that in an otherwise healthy infant, multiple herpetic skin lesions were not due to disseminated infection, but through autoinoculation.