Natural history study of patients with familial platelet disorder with associated myeloid malignancy.

ABSTRACT: Deleterious germ line RUNX1 variants cause the autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematologic malignancies (HMs). We launched a FPDMM natural history study and, from January 2019 to December 2021, enrolled 214 participants, including 111 patients with 39 different RUNX1 variants from 45 unrelated families. Seventy of 77 patients had thrombocytopenia, 18 of 18 had abnormal platelet aggregometry, 16 of 35 had decreased platelet dense granules, and 28 of 55 had abnormal bleeding scores. Nonmalignant bone marrows showed increased numbers of megakaryocytes in 12 of 55 patients, dysmegakaryopoiesis in 42 of 55, and reduced cellularity for age in 30 of 55 adult and 17 of 21 pediatric cases. Of 111 patients, 19 were diagnosed with HMs, including myelodysplastic syndrome, acute myeloid leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia, and smoldering myeloma. Of those 19, 18 were relapsed or refractory to upfront therapy and referred for stem cell transplantation. In addition, 28 of 45 families had at least 1 member with HM. Moreover, 42 of 45 patients had allergic symptoms, and 24 of 30 had gastrointestinal (GI) symptoms. Our results highlight the importance of a multidisciplinary approach, early malignancy detection, and wider awareness of inherited disorders. This actively accruing, longitudinal study will genotype and phenotype more patients with FPDMM, which may lead to a better understanding of the disease pathogenesis and clinical course, which may then inform preventive and therapeutic interventions. This trial was registered at www.clinicaltrials.gov as #NCT03854318.

Incidence of and risk factors for paediatric perioperative anaphylaxis in the USA.

BACKGROUND: Perioperative anaphylaxis is a serious and often life-threatening immediate hypersensitivity reaction. There are few published data on paediatric perioperative anaphylaxis (pPOA). We evaluated the incidence of and risk factors involved in the occurrence of pPOA within a large US national database. METHODS: Deidentified data from the US Nationwide Inpatient Sample from 2005 to 2014 were used to identify pPOA cases and to conduct a retrospective multivariate analysis of preselected independent variables. RESULTS: Among 3,601,180 surgeries and procedures in children aged 0-18 yr, 297 pPOA cases were identified for an incidence of one in 12,125 surgeries and procedures. Compared with controls, pPOA cases had an increased median length of stay (6 vs 2 days; P<0.001) and median hospital cost ($54 719 vs $5109; P<0.0001). The age groups between 6 and 12 yr (odds ratio [OR] 7.1; 95% confidence interval [CI] 3.9-12.9; P<0.001) and 13 and 17 yr (OR 8.5; 95% CI 4.7-15.2; P<0.001) were associated with increased odds of pPOA. Transplant (OR 46.3; 95% CI 20.8-102.9; P<0.001), cardiac (OR 16.4; 95% CI 7.5-35.9; P<0.001), and vascular (OR 15.2; 95% CI 7.5-30.7; P<0.001) procedures posed the highest risk for pPOA. Chronic pulmonary disease, coagulopathy, and fluid and electrolyte disorders were also associated with pPOA (OR 2.2; 95% CI 1.5-3.3; P<0.001). CONCLUSIONS: The incidence of pPOA was one in 12,125 cases. Risk factors included age, procedure type, and comorbidities.

Severe eczema in Wiskott-Aldrich syndrome-related disorder successfully treated with dupilumab.

Treatment of severe eczema in patients with primary immunodeficiencies can be particularly challenging as there are no guidelines with regards to these conditions. Dupilumab is an interleukin (IL)-4Rα antagonist that inhibits both IL-4 and IL-13 and is approved for the treatment of atopic dermatitis in pediatric patients. In this report, we describe a patient with a case of severe eczema in the context of Wiskott-Aldrich syndrome-related disorder, who was successfully treated with dupilumab.

A Heterozygous Gain-of-Function Variant in IKBKB Associated with Autoimmunity and Autoinflammation.

PURPOSE: Biallelic loss-of-function variants in IKBKB cause severe combined immunodeficiency. We describe a case of autoimmunity and autoinflammation in a male infant with a heterozygous gain-of-function (GOF) IKBKB variant. METHODS: Case report and review of the literature. We performed in silico variant analysis, measurement of plasma soluble biomarkers associated with immune activation, functional stimulation of patient peripheral blood mononuclear cells, and functional validation of variants transduced in Jurkat cells. RESULTS: A patient with two heterozygous IKBKB variants (E518K and T559M) presents with previously undescribed autoimmune cytopenias and autoinflammation. He had decreased TNF-α-induced IkBα degradation in vitro, and had increased serum biomarkers associated with macrophage recruitment and activation. Jurkat cells transduced with the IKKb T559M variant showed increased basal levels of phosphorylation of IKKα/b and p65, and higher degradation of IkBα suggesting a GOF mechanism. No significant changes were observed in Jurkat cells transduced with the E518K variant. CONCLUSIONS: A GOF variant in IKBKB may associate with autoinflammation and autoimmunity highlighting a novel clinical phenotype.

Nodular regenerative hyperplasia in X-linked agammaglobulinemia: An underestimated and severe complication.

BACKGROUND: Late-onset complications in X-linked agammaglobulinemia (XLA) are increasingly recognized. Nodular regenerative hyperplasia (NRH) has been reported in primary immunodeficiency but data in XLA are limited. OBJECTIVES: This study sought to describe NRH prevalence, associated features, and impact in patients with XLA. METHODS: Medical records of all patients with XLA referred to the National Institutes of Health between October 1994 and June 2019 were reviewed. Liver biopsies were performed when clinically indicated. Patients were stratified into NRH+ or NRH- groups, according to their NRH biopsy status. Fisher exact test and Mann-Whitney test were used for statistical comparisons. RESULTS: Records of 21 patients with XLA were reviewed, with a cumulative follow-up of 129 patient-years. Eight patients underwent ≥1 liver biopsy of whom 6 (29% of the National Institutes of Health XLA cohort) were NRH+. The median age at NRH diagnosis was 20 years (range, 17-31). Among patients who had liver biopsies, alkaline phosphatase levels were only increased in patients who were NRH+ (P = .04). Persistently low platelet count (<100,000 per µL for >6 months), mildly to highly elevated hepatic venous pressure gradient and either hepatomegaly and/or splenomegaly were present in all patients who were NRH+. In opposition, persistently low platelet counts were not seen in patients who were NRH-, and hepatosplenomegaly was observed in only 1 patient who was NRH-. Hepatic venous pressure gradient was normal in the only patient tested who was NRH-. All-cause mortality was higher among patients who were NRH+ (5 of 6, 83%) than in the rest of the cohort (1 of 15, 7% among patients who were NRH- and who were classified as unknown; P = .002). CONCLUSIONS: NRH is an underreported, frequent, and severe complication in XLA, which is associated with increased morbidity and mortality.

Interpretation of Dihydrorhodamine-1,2,3 Flow Cytometry in Chronic Granulomatous Disease: an Atypical Exemplar.

PURPOSE: This is a functional characterization of a novel CYBA variant associated with normal DHR flow cytometry. Chronic granulomatous disease (CGD) is an inborn error of immunity characterized by recurrent bacterial and fungal infections and dysregulated inflammatory responses due to defective phagocytic cell function leading to the formation of granulomas. CGD patients have pathogenic variants in any of the five components of the phagocytic NADPH oxidase, which transfers electrons through the phagosomal membrane and produces superoxide upon bacterial uptake. Here, we report a pediatric female patient with a novel homozygous missense variant (c.293C > T, p.(Ser98Leu)) in CYBA, encoding the p22phox protein, associated with autosomal recessive CGD. METHODS AND RESULTS: The patient presented with severe recurrent pneumonia. Specific pathogens identified included Burkholderia and Serratia species suggesting neutrophil functional abnormalities; however, the dihydrorhodamine-1,2,3 (DHR) flow cytometric and cytochrome c reduction assays for neutrophil respiratory burst fell within the low side of the normal range. Western blot and flow cytometric analysis of individual NADPH oxidase components revealed reduced levels of p22phox and gp91phoxphox proteins. The pathological consequence of the p.Ser98Leu variant was further evaluated in heterologous expression systems, which confirmed reduced p22phox protein stability and oxidase activity. CONCLUSIONS: Although this patient did not exhibit all the classic features of CGD, such as granulomas and skin infections, she had recurrent pneumonias with oxidant-sensitive pathognomonic organisms, resulting in appropriate targeted CGD testing. This case emphasizes the need to contextually interpret laboratory data, especially using clinical findings to direct additional assessments including genetic analysis.

Targeted pharmacologic immunomodulation for inborn errors of immunity.

Inborn errors of immunity consist of over 400 known single gene disorders that may manifest with infection susceptibility, autoimmunity, autoinflammation, hypersensitivity and cancer predisposition. Most patients are treated symptomatically with immunoglobulin replacement, prophylactic antimicrobials or broad immunosuppression pertaining to their disease phenotype. Other than haematopoietic stem cell transplantation, the aforementioned treatments do little to alter disease morbidity or mortality. Further, many patients may not be transplant candidates. In this review, we describe monogenic disorders affecting leucocyte migration, disorders of immune synapse formation and dysregulation of immune cell signal transduction. We highlight the use of off-label small molecules and biologics mechanistically targeted to altered disease pathophysiology of such diseases.

BTK inhibitors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): A systematic review.

INTRODUCTION: The Bruton tyrosine kinase (BTK) regulates B cell and macrophage signaling, development, survival, and activation. Inhibiting BTK has been hypothesized to ameliorate lung injury in patients with severe COVID-19, however clinical outcome data is inconclusive. OBJECTIVE: To evaluate the clinical outcomes of BTK inhibitors (BTKinibs) in patients with COVID-19. EVIDENCE REVIEW: We searched PubMed, Embase, and Web of Science:Core on December 30, 2020. Clinical studies with at least 5 COVID-19 patients treated with BTKinibs were included. Case reports and reviews were excluded. FINDINGS: 125 articles were identified, 6 of which met inclusion criteria. The most common clinical outcomes measured were oxygen requirements (4/6) and hospitalization rate or duration (3/6). Three studies showed decreased oxygen requirements in patients who started or continued BTKinibs. All three studies that evaluated hospitalization rate or duration found favorable outcomes in those on BTKinibs. CONCLUSIONS AND RELEVANCE: BTKinib use was associated with decreased oxygen requirements and decreased hospitalization rates and duration.

Infectious Complications Predict Premature CD8+ T-cell Senescence in CD40 Ligand-Deficient Patients.

PURPOSE: CD40 ligand (CD40L)-deficient patients display increased susceptibilities to infections that can be mitigated with effective prophylactic strategies including immunoglobulin G (IgG) replacement and prophylactic antibiotics. CD8+ T-cell senescence has been described in CD40L deficiency, but it is unclear if this is an intrinsic feature of the disease or secondary to infectious exposures. To address this question, we assessed CD8+ T-cell senescence and its relationship to clinical histories, including prophylaxis adherence and infections, in CD40L-deficient patients. METHODS: Peripheral CD8+ T-cells from seven CD40L-deficient patients and healthy controls (HCs) were assessed for senescent features using T-cell receptor excision circle (TREC) analysis, flow cytometry, cytometry by time of flight (CyTOF) and in vitro functional determinations including CMV-specific proliferation and cytokine release assays. RESULTS: Three patients (5, 28, and 34 years old) who were poorly adherent to immunoglobulin G replacement and Pneumocystis jirovecii pneumonia (PJP) prophylaxis and/or experienced multiple childhood pneumonias (patient group 1) had an expansion of effector memory CD8+ T-cells with the senescent phenotype when compared to HCs. Such changes were not observed in the patient group 2 (four patients, 16, 22, 24, and 33 years old) who were life-long adherents to prophylaxis and experienced few infectious complications. CyTOF analysis of CD8+ T-cells from the 5-year-old patient and older adult HCs showed similar expression patterns of senescence-associated molecules. CONCLUSIONS: Our findings support that recurrent infections and non-adherence to prophylaxis promote early CD8+ T-cell senescence in CD40L deficiency. Premature senescence may increase malignant susceptibilities and further exacerbate infectious risk in CD40L-deficient patients.

NAPDH Oxidase-Specific Flow Cytometry Allows for Rapid Genetic Triage and Classification of Novel Variants in Chronic Granulomatous Disease.

PURPOSE: Chronic granulomatous disease (CGD) is an innate immune deficiency, primarily affecting the phagocytic compartment, and presenting with a diverse phenotypic spectrum ranging from severe childhood infections to monogenic inflammatory bowel disease. Dihydrorhodamine (DHR) flow cytometry is the standard diagnostic test for CGD, and correlates with NADPH oxidase activity. While there may be genotype correlation with the DHR flow pattern in some patients, in several others, there is no correlation. In such patients, assessment by flow cytometric evaluation of NADPH oxidase-specific (NOX) proteins provides a convenient and rapid means of genetic triage, though immunoblotting has long been used for this purpose. METHODS AND RESULTS: We describe the clinical utility of the NOX flow cytometry assay through assessment of X-linked and autosomal recessive CGD patients and their first-degree relatives. The assessment of specific NOX proteins was correlated with overall NADPH oxidase function (DHR flow), clinical phenotype and genotype. NOX-specific protein assessment is a valuable adjunct to DHR assessment and genotyping to classify and characterize CGD patients. CONCLUSIONS: The atypical clinical presentation of some CGD patients can make genotype-phenotype correlation with DHR flow data challenging. Genetic testing, while useful for confirmation of diagnosis, can take several weeks, and in some patients does not provide a conclusive answer. However, NADPH-oxidase-specific protein flow assessment offers a rapid alternative to identification of the underlying genetic defect in cellular subsets, and can be utilized as a reflex test to an abnormal DHR flow. Further, it can provide insight into correlation between oxidative burst relative to protein expression in granulocytes and monocytes.

Inpatient ß-lactam test-dose protocol and antimicrobial stewardship in patients with a history of penicillin allergy.

BACKGROUND: Penicillin allergy is the most commonly reported drug allergy in hospitalized patients, resulting in increased second-line antibiotic use, nosocomial infections, and health care use. Given that most patients are not truly allergic, a safe strategy that empowers the admitting physician is needed. OBJECTIVE: To assess the effect on antibiotic prescribing practices for hospitalized patients with penicillin allergy using a validated intervention. METHODS: An intervention was implemented to educate health care professionals on management of patients with penicillin allergy using a validated risk stratification algorithm to guide testing and antibiotic use. Thirty days of control data using current standard of care was compared with 60 days of postintervention data measuring documentation of penicillin allergy history and antibiotic selection. RESULTS: The relative use of cephalosporin and penicillin antibiotics increased by 121.2% (P = .03) and 256% (P = .04), respectively, without an increase in adverse drug reactions. There was a decrease in the use of broad-spectrum antibiotics: vancomycin, 67.2% (P = .04); quinolones, 33.3% (P = .31); carbapenems, 81.9% (P = .08); and aztreonam, 73.8% (P = .18). CONCLUSION: The antibiotic choice in patients admitted to the hospital with a reported penicillin allergy can be improved by better evaluation of the allergy history and the use of a risk stratification guideline.

Utilization and timeliness of an inpatient penicillin allergy evaluation.

BACKGROUND: A history of penicillin allergy is associated with an increased risk of nosocomial infections because patients are exposed to non-beta lactam antibiotics. Ruling out inaccurate penicillin allergy during hospitalization decreases prescription of beta lactam antibiotics. However, the utilization of penicillin allergy testing and timeliness in relation to initiation of antibiotics is not known. OBJECTIVE: Our aim was to describe the proportion and characteristics of patients who underwent inpatient penicillin allergy testing in a hospital without a guideline or infrastructure for inpatient penicillin allergy testing. METHODS: We performed a retrospective chart review of patients admitted to our institution between January 1, 2008, and December 31, 2015, who underwent penicillin allergy testing. RESULTS: Forty-nine patients were identified; 27 (55.1%) were women. The median age was 61.5 years (interquartile range [IQR], 48.5-71 years). The median Charlson-Comorbidity index score was 4 (IQR, 2-5.5). Of these patients, 42.86% (21) were admitted to the intensive care unit, 79.6% of allergy consults were requested by infectious disease physicians, and 87.8% of patients were receiving non-beta lactam antibiotics at the time of testing. The patients received a median of 5 days of antibiotics before testing (range, 0-16 days; IQR, 3-7 days). Antimicrobial therapy was changed in 78.0% of the patients (32), of whom 68.3% (21/32) was attributable to penicillin allergy testing. CONCLUSION: Inpatient penicillin allergy testing is a critical component of antibiotic stewardship; however, an adequate infrastructure is essential for timely evaluation. Inpatient penicillin allergy evaluation requires a multidisciplinary approach focused on patient selection; risk stratification; and optimization of a timely, safe, and cost-effective approach to optimize patient outcomes.

CLINICAL UTILITY OF INTERLEUKIN-1 INHIBITORS IN PEDIATRIC SEPSIS.

ABSTRACT: The pathophysiology of pediatric sepsis is characterized by increased innate immune activation earlier in life. Interleukin-1 is a proinflammatory cytokine implicated in the pathophysiology of sepsis, and ferritin is a stable surrogate biomarker for elevated IL-1 levels. Data in adult sepsis have shown that use of anakinra, an anti-IL-1 receptor antagonist, led to improved clinical outcomes in patients with features of macrophage activation and hyperferritinemia. However, data in pediatric sepsis are lacking. Our narrative review sought to highlight the current understanding of using IL-1 inhibitors in pediatric sepsis. We identified five studies including one case report and four retrospective case series that described clinical outcomes in relation to use of anakinra for secondary hemophagocytic lymphohistiocytosis (HLH). A few patients in this pooled heterogenous cohort of 72 patients had concomitant infection meeting the criteria for sepsis. All studies measured ferritin levels and reported a decrease in ferritin after initiating anakinra. Twelve patients died after treatment initiation. There was no clear comparison in clinical outcomes between infected and noninfected patients. The pathophysiology of pediatric sepsis suggests that there is a need for blinded clinical trials using targeted immunomodulation such as IL-1 inhibitors in pediatric sepsis cohort with an immunophenotype suggesting increased innate immune activation.