Patient-Reported Outcomes and Medical Provider Satisfaction Among Adult and Pediatric Ataxia-Telangiectasia Patients.

PURPOSE: Ataxia-telangiectasia (A-T) is a rare genetic condition with malfunctioning DNA repair processes resulting in significant clinical findings, including progressive neurologic decline, elevated malignancy risk, immunodeficiency, oculocutaneous telangiectasias, and severe pulmonary disease. Research has been limited into the quality of life of such patients and yet to be completed are studies quantitatively analyzing psychosocial, physical, and cognitive patient-reported outcomes (PROs) within the A-T population. METHODS: PRO evaluations of 90 international adult and pediatric A-T patients and their caregivers were completed via secure online administration of Patient-Reported Outcomes Measurement Information System (PROMIS) short forms evaluating anger, cognition, mood, social health, fatigue, pain, anxiety, and upper extremity function. The impact of age, gender, race/ethnicity, prior malignancy diagnosis, and current supportive treatment interventions on such PROs was additionally assessed. Finally, given the importance of medical providers in the care of A-T patients and the impact of patient satisfaction on healthcare outcomes, we further analyzed, via a novel survey, how patients and caregivers perceived their primary A-T healthcare provider's A-T expertise, trustworthiness, accessibility, and level of compassion. RESULTS/CONCLUSION: It was found that a diagnosis of A-T complexly impacts patient PROs, but such data offers the potential for preventative and therapeutic interventions to improve the care of such patients. While most A-T patients and their caregivers feel their primary A-T medical provider has expertise and compassion in addition to being accessible and trustworthy, a significant percentage of study subjects did not agree that their provider was an expert in A-T or overall trustworthy.

In cis "benign" SOCS1 variants linked to enhanced interferon signaling and autoimmunity.

We aimed to characterize the genetic basis of disease in a family with multiple autoimmune manifestations, including systemic lupus erythematosus (SLE), immune thrombocytopenia, and autoimmune thyroiditis. Whole exome sequencing (WES) was conducted to identify candidate variants, which were analyzed by flow cytometry, immunoblotting, immunoprecipitation, and luciferase reporter assay in transfected 293T cells. Gene expression in peripheral blood mononuclear cells (PBMC) was profiled by bulk RNA sequencing and plasma cytokines were measured by proximity extension assay. In two siblings with early-onset SLE and immune thrombocytopenia, WES identified two maternally inherited in cis variants (p. Pro50Leu and p.Ala76Gly) in Suppressor of cytokine signaling 1 (SOCS1), flanking the kinase inhibitory domain that interacts with Janus kinases (JAK). Both variants were predicted to be benign by most in silico algorithms and neither alone affected the ability of SOCS1 to inhibit JAK-STAT1 signaling by functional studies. When both variants were expressed in cis, the mutant SOCS1 protein displayed decreased binding to JAK1 and reduced capacity to inhibit type I interferon (IFN-I) signaling by ∼20-30% compared to the wildtype protein. PBMC from the probands and their mother showed increased expression of interferon-inducible genes compared to healthy controls, supporting defective regulation of IFN-I signaling. Cells from all three subjects displayed heightened sensitivity to IFN-I stimulation, while response to IFN-γ, IL-4, and IL-6 was comparable to healthy controls. Our work illustrates the critical fine-tuning of IFN-I signaling by SOCS1 to prevent autoimmunity. We show that a combination of genetic variants that are individually benign may have deleterious consequences.

NF-κB and Related Autoimmune and Autoinflammatory Diseases.

The NF-κB pathway is a cardinal signaling pathway that has been implicated in the development of a diverse range of clinical diseases. Numerous cellular processes converge on this pathway, which results in cell proliferation and survival. Defects in this pathway and in its upstream regulators have been described as causing immunodeficiency. However, there is a growing body of literature connecting autoimmune and autoinflammatory conditions to NF-κB pathway dysfunction. This review serves as a current appraisal of the literature of these disorders.

SOCS1 Haploinsufficiency Presenting as Severe Enthesitis, Bone Marrow Hypocellularity, and Refractory Thrombocytopenia in a Pediatric Patient with Subsequent Response to JAK Inhibition.

Haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1) is a recently discovered autoinflammatory disorder with significant rheumatologic, immunologic, and hematologic manifestations. Here we report a case of SOCS1 haploinsufficiency in a 5-year-old child with profound arthralgias and immune-mediated thrombocytopenia unmasked by SARS-CoV-2 infection. Her clinical manifestations were accompanied by excessive B cell activity, eosinophilia, and elevated IgE levels. Uniquely, this is the first report of SOCS1 haploinsufficiency in the setting of a chromosomal deletion resulting in complete loss of a single SOCS1 gene with additional clinical findings of bone marrow hypocellularity and radiologic evidence of severe enthesitis. Immunologic profiling showed a prominent interferon signature in the patient's peripheral blood mononuclear cells, which were also hypersensitive to stimulation by type I and type II interferons. The patient showed excellent clinical and functional laboratory response to tofacitinib, a Janus kinase inhibitor that disrupts interferon signaling. Our case highlights the need to utilize a multidisciplinary diagnostic approach and consider a comprehensive genetic evaluation for inborn errors of immunity in patients with an atypical immune-mediated thrombocytopenia phenotype.

Case Report: Use of Obinutuzumab as an Alternative Monoclonal Anti-CD20 Antibody in a Patient With Refractory Immune Thrombocytopenia Complicated by Rituximab-Induced Serum Sickness and Anti-Rituximab Antibodies.

Management of refractory immune thrombocytopenia frequently involves rituximab, a chimeric anti-CD20 monoclonal antibody, to target B cells and induce remission in most patients. However, neutralizing antibodies to rituximab that nullify therapeutic response and may lead to serum sickness have been rarely reported. Here, we present a case of a young adult woman with Evans syndrome treated with rituximab, complicated by the development of serum sickness, acute respiratory distress syndrome, and platelet refractoriness presumed secondary to neutralizing antibodies to rituximab. She was successfully treated with the humanized anti-CD20 monoclonal antibody, obinutuzumab, with subsequent symptom resolution. Additionally, a review of 10 previously published cases of serum-sickness associated with the use of rituximab for idiopathic thrombocytopenic purpura (ITP) is summarized. This case highlights that recognition of more subtle or rare symptoms of rituximab-induced serum sickness is important to facilitate rapid intervention.

Immune Suppression in Allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for high-risk hematologic disorders. There are multiple immune-mediated complications following allo-HSCT that are prevented and/or treated by immunosuppressive agents. Principal among these immune-mediated complications is acute graft-versus-host disease (aGVHD), which occurs when the new donor immune system targets host tissue antigens. The immunobiology of aGVHD is complex and involves all aspects of the immune system. Due to the risk of aGVHD, immunosuppressive aGVHD prophylaxis is required for nearly all allogeneic HSCT recipients. Despite prophylaxis, aGVHD remains a major cause of nonrelapse mortality. Here, we discuss the clinical features of aGVHD, the immunobiology of aGVHD, the immunosuppressive therapies used to prevent and treat aGVHD, how to mitigate the side effects of these immunosuppressive therapies, and what additional immune-mediated post-allo-HSCT complications are also treated with immunosuppression.

Elevated inflammatory responses and targeted therapeutic intervention in a preclinical mouse model of ataxia-telangiectasia lung disease.

Ataxia-telangiectasia (A-T) is an autosomal recessive, multisystem disorder characterized by cerebellar degeneration, cancer predisposition, and immune system defects. A major cause of mortality in A-T patients is severe pulmonary disease; however, the underlying causes of the lung complications are poorly understood, and there are currently no curative therapeutic interventions. In this study, we examined the lung phenotypes caused by ATM-deficient immune cells using a mouse model of A-T pulmonary disease. In response to acute lung injury, ATM-deficiency causes decreased survival, reduced blood oxygen saturation, elevated neutrophil recruitment, exaggerated and prolonged inflammatory responses and excessive lung injury compared to controls. We found that ATM null bone marrow adoptively transferred to WT recipients induces similar phenotypes that culminate in impaired lung function. Moreover, we demonstrated that activated ATM-deficient macrophages exhibit significantly elevated production of harmful reactive oxygen and nitrogen species and pro-inflammatory cytokines. These findings indicate that ATM-deficient immune cells play major roles in causing the lung pathologies in A-T. Based on these results, we examined the impact of inhibiting the aberrant inflammatory responses caused by ATM-deficiency with reparixin, a CXCR1/CXCR2 chemokine receptor antagonist. We demonstrated that reparixin treatment reduces neutrophil recruitment, edema and tissue damage in ATM mutant lungs. Thus, our findings indicate that targeted inhibition of CXCR1/CXCR2 attenuates pulmonary phenotypes caused by ATM-deficiency and suggest that this treatment approach represents a viable therapeutic strategy for A-T lung disease.

Quality of life and patient-reported outcomes in chronic severe neutropenia conditions.

Quality of life (QOL) and patient-reported outcomes (PROs) assessments in immunodeficiency patients, including those with chronic severe neutropenia conditions, are imperative to determining modifiable health-related features to optimize care. We present the largest study to date of QOL in those with chronic severe neutropenia conditions with further evaluation of patient provider satisfaction and patient-reported outcome measures. Subjects completed electronic surveys assessing QOL, PROs, and patient provider satisfaction. There is a significantly negative impact of a chronic severe neutropenia disorder on QOL, fatigue, physical function, cognitive function and pain in adult patients when compared to controls. Children with a chronic neutropenia condition had comparable QOL to controls, but reported fewer depressive symptoms, improved mobility, and stronger self-reported peer relationships. Adults had worse scores for QOL, depression and fatigue when compared to children. Adult and pediatric chronic severe neutropenia patients or their caregivers felt that their medical provider was compassionate, trustworthy, and accessible. However, less than 50% of adult patients agreed their clinician had excellent expertise in white blood cell disorders. Chronic neutropenia complexly affect QOL and PROs. An analysis of these parameters allows for targeted interventions to improve patient psychosocial, physical and neurocognitive health.

Line Associated Thrombosis in Pediatric Patients With NF-κB Pathway Variants.

Our report explores the complex role that nuclear factor-kappa B (NF-κB) plays in thrombosis formation, inflammation, and immunity; while additionally demonstrating that patients with NF-κB pathway pathogenic variants appear to carry a substantial thrombotic risk, particularly when secondary thrombotic risk factors are present. We propose that prophylactic anticoagulation should be strongly considered in such patients during high-risk situations and provide additional hematologic management strategies for those with NF-κB pathway alterations. We hope our work also calls to attention the potential need for a broader assessment of venous thromboembolism risk in patients with immune dysregulation to better delineate which patient populations may benefit from anticoagulation prophylaxis.

Neutropenia Is an Underrecognized Finding in Pediatric Primary Immunodeficiency Diseases: An Analysis of the United States Immunodeficiency Network Registry.

BACKGROUND: The frequency of neutropenia in pediatric primary immunodeficiency disorders (PIDDs) is unknown and potentially underappreciated. Our study aimed to determine the overall frequency and severity of neutropenia in children diagnosed with a PIDD entered in the United States Immunodeficiency Network (USIDNET) patient registry. PROCEDURE: Neutropenia data and demographic/clinical information from 1145 patients younger than 21 years of age was obtained from the USIDNET registry. RESULTS: Neutropenia is more common in PIDD patients entered within the USIDNET registry than previously appreciated. There was a >10% occurrence rate of neutropenia in all broad primary immunodeficiency categories as well as in nearly all individual PIDDs. Neutropenia frequency was greater in African American pediatric PIDD patients than in white or Asian patients. The degree of neutropenia did not associate with mortality in pediatric patients with a PIDD. CONCLUSION: Although our study did not assess the frequency of PIDD in patients presenting with neutropenia, the possibility of a primary immune disorder should be considered in patients with idiopathic neutropenia.

Provider Perceptions of Quality of Life, Neurocognition, Physical Well-being, and Psychosocial Health in Patients with Primary Immunodeficiency/Immune Dysregulation Conditions.

PURPOSE: Both pediatric and adult patients with a primary immunodeficiency/immune dysregulation (PID/PIDR) diagnosis report inferior quality of life (QOL) and patient-reported outcomes (PROs) as compared with their healthy peers. Recognition of the negative impact on QOL and PROs provides an opportunity for clinicians to intervene with supportive measures. However, provider perceptions of PID/PIDR patients' quality of life, physical well-being, psychosocial health and neurocognition, and access to supportive resources have yet to be systematically evaluated. METHODS: We report specialty providers' perception of the QOL and psychosocial and physical well-being of their pediatric and adult patients with PID/PIDR through the utilization of an online survey assessing QOL and the impact of disease or its associated treatment on their physical well-being, mental health, social relationships, neurocognition, and work/school performance. RESULTS: Clinicians trended towards believing adult PID/PIDR patients had worse overall QOL than children with PID/PIDR. Providers additionally identified their adult patients' QOL to be more deleteriously affected by co-morbidities than their pediatric patients. Clinicians distinguished anxiety and social relationships as the psychosocial aspects most often affected by a complex immunological diagnosis in all patients. Of physical health considerations, energy, rather than mobility or pain, was perceived to be more negatively influenced by PID/PIDR in both adult and pediatric patients. CONCLUSIONS: Knowledge of these clinician perceptions can affect communication of findings with patients, as well as ongoing management, and thus, it is important to understand these fully to improve healthcare delivery to, and clinical management of, these patients.

Immune-Mediated Cytopenias After Hematopoietic Cell Transplantation: Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment Strategies.

PURPOSE OF REVIEW: Discuss the pathophysiology, clinical presentation, diagnosis, and treatment of immune-mediated cytopenias (IMC) after hematopoietic cell transplantation (HCT). RECENT FINDINGS: Key risk factors for post-HCT IMC include younger age, non-malignant disease, and umbilical cord blood stem cell source. While anemia predominates, any or all three hematopoietic cell lines can be affected. In rare cases, IMC can cause graft failure or death. IMC is hypothesized to result from immune dysregulation upon reconstitution of donor hematopoietic cells (i.e., dysfunctional regulatory T cells). Aside from blood product transfusions, IMC treatment includes immune-suppressive or ablative agents. First-line therapies, including corticosteroids and intravenous immunoglobulin, are often inadequate, prompting use of additional agents aimed at antibody production/T cell dysfunction or direct antibody removal via plasmapheresis. IMC occurs in up to 20% of high-risk HCT populations. Morbidity and mortality from IMC post-HCT have been reduced by improved recognition and aggressive early interventions.

Severe Combined Immunodeficiency: A Review for Neonatal Clinicians.

The proper development and function of T cells is imperative in the creation of adequate cell-mediated and humoral immunity. Healthy term newborns have baseline immune immaturity, increasing their risk of infections, but significant immunologic consequences can occur, because of abnormal T-cell maturation. Combined immunodeficiencies can result, because B cells and natural killer cells rely on successful interactions with T cells to ensure their proper performance and survival. Severe combined immunodeficiency (SCID) is the most noteworthy of these conditions, leading to considerable early morbidity and often death by the age of 1 year if left untreated. Newborn screening for SCID is effective and allows for early implementation of lifesaving supportive measures, including protective isolation, initiation of prophylactic antimicrobials, caution with blood product transfusions, and avoidance of live vaccinations. Once a definitive diagnosis of SCID has been established, treatment frequently involves bone marrow or stem cell transplantation; however, enzyme replacement and gene therapy are also becoming options in those with SCID due to adenosine deaminase deficiency and other forms of SCID. Neonatal clinicians should understand the screening and diagnostic approach to SCID along with the initial management approaches for these extremely high-risk patients.

KRAS mutant tenosynovial giant cell tumor in a pediatric patient: a case report.

Tenosynovial giant cell tumors (TSGCT) are a group of rare, benign soft tissue tumors with common histologic and cytogenetic features, with a median age of diagnosis being 47 years. Generally divided into localized and diffuse subtypes, TSGCTs are typically driven by overexpression of macrophage colony stimulating factor receptor-1 (CSF1R). Treatment of TSGCT is tumor resection, followed by radiation therapy in cases of incomplete resection. Even when the tumor is completely removed, recurrence rates can be as high as 30% in some anatomical locations. Here we report the identification of a previously undescribed KRAS p.G12D activating mutation within a pediatric TSGCT patient, who clinically presented with an enlarging right lower extremity mass pathologically consistent with TSGCT. The patient continues to be in remission three years after complete surgical removal. KRAS mutations are usually found in adult cancers, such as lung and pancreatic, as well as giant cell lesion of the jaw. This case demonstrates the utility of integrative clinical sequencing in identifying lesions with aggressive potential and aiding in complex diagnoses.