Airway Injury Caused by Aspiration of Iron Sulfate Pills: A Series of 11 Cases.

It is not widely recognized that iron (ferrous sulfate) pill aspiration causes airway damage. Clinical diagnosis is challenging because patients are often unaware that they have aspirated a pill. The literature on this entity consists mainly of case reports. The aim of this study is to describe the clinical and pathologic features of iron pill aspiration in a series of 11 patients. A retrospective review of our pathology archives was performed to identify cases of iron pill aspiration (2013-2023). All available histologic and cytologic material was rereviewed. Clinical information was collected from the electronic medical record, and imaging studies were rereviewed. Eighteen endobronchial biopsies were identified from 11 patients (7 women and 4 men; mean age, 70 years; range, 44-82 years). Eight patients had corresponding cytology (20 specimens). Medication history was available in 9 of 11 patients, all of whom were taking iron sulfate pills. Two patients reported possible aspiration episodes; 4 had risk factors for aspiration. The diagnosis of iron pill aspiration was suspected prior to biopsy in only 1 case. Histologically, iron pill particles were yellow, golden brown, or gray, were elongated and crystal or fiber like, and stained strongly with an iron stain. Common histologic findings included mucosal ulceration, acute and/or chronic inflammation, fibrosis, and squamous metaplasia. Iron pill particles were also identified in 11 cytology specimens from 6 patients. On Papanicolaou staining, iron pill particles were yellow to golden, fiber like, refractile, and crystalline. Reactive epithelial cells, squamous metaplasia, and acute inflammation were common. The combination of iron pill intake and discolored mucosa on bronchoscopy is a potential clue to the diagnosis of iron pill aspiration. Pathologists should familiarize themselves with the appearance of iron pill particles in endobronchial biopsies and cytology specimens from the respiratory tract as this diagnosis is seldom suspected on clinical grounds, and most patients lack a history of aspiration.

Infection control in the bronchoscopy suite: effective reprocessing and disinfection of reusable bronchoscopes.

PURPOSE OF REVIEW: With advancements in technology, flexible bronchoscopes have become thinner in diameter and in need of more thorough reprocessing to prevent infection transmission than ever before. Many experienced bronchoscopists are not aware of the critical steps involved in effective bronchoscope reprocessing and we hope to bridge this gap by describing this process in detail. RECENT FINDINGS: Bronchoscope reprocessing includes several distinct steps (precleaning, leak testing, manual cleaning, visual inspection, terminal reprocessing, rinsing and drying). Each step is comprehensive and needs to be carried out systematically by trained personnel. Failure of any step can lead to serious downstream events such as outbreaks and pseudo-outbreaks. Some experts now recommend sterilization when feasible, although high-level disinfection remains the minimum standard. We also will review some literature on the utility of borescopes, automated endoscope reprocessors and disposable bronchoscopes. SUMMARY: Our article will focus on the most recent recommendations for effective reprocessing and disinfection of reusable bronchoscopes.

Lung Ultrasonographic Signs in Pulmonary Disease - A Video Review.

Lung ultrasound (US) is a well-established imaging tool in the inpatient and critical care setting. It has proven its worth in the rapid bedside diagnosis of a variety of conditions pertaining to the lungs and the thorax. Lung US was initially introduced as a bedside imaging tool to evaluate the size and characteristics of pleural effusion. Over the years, the field of lung ultrasonography has rapidly expanded introducing nuances in image interpretation. Numerous primary and secondary signs have been described in the literature to identify both normal and abnormal findings. The primary signs can help narrow the list of differential diagnoses, whereas the addition of secondary signs help create an imaging pattern facilitating the confirmation of diagnosis or recognition of the underlying disease process. These wide variety of signs and patterns can present a challenge to the learning of lung ultrasonography, particularly to a novice user. We sought to compile a comprehensive list of these findings to serve as a useful resource to aid effortless adoption of lung ultrasonography in clinical practice. In this review, we narrate the evolution of lung US, describe common protocols applied in performance of the lung US, and illustrate a comprehensive list of common lung US signs and patterns along with their differential diagnosis and clinical utility.

Prospective cohort of cryobiopsy in interstitial lung diseases: a single center experience.

RATIONALE: Transbronchial cryobiopsy has been increasingly used to diagnose interstitial lung diseases. However, there is uncertainty regarding its accuracy and risks, mainly due to a paucity of prospective or randomized trials comparing cryobiopsy to surgical biopsy. OBJECTIVES: To evaluate the diagnostic yield and complications of cryobiopsy in patients selected by multidisciplinary discussion. METHODS: This was a prospective cohort from 2017 to 2019. We included consecutive patients with suspected interstitial lung diseases being considered for lung biopsy presented at our multidisciplinary meeting. MEASUREMENTS AND MAIN RESULTS: Of 112 patients, we recommended no biopsy in 31, transbronchial forceps biopsy in 16, cryobiopsy in 54 and surgical biopsy in 11. By the end of the study, 34 patients had had cryobiopsy and 24 patients, surgical biopsy. Overall pathologic and multidisciplinary diagnostic yield of cryobiopsy was 47.1% and 61.8%, respectively. The yield increased over time for both pathologic (year 1: 28.6%, year 2: 54.5%, year 3: 66.7%, p = 0.161) and multidisciplinary (year 1: 50%, year 2: 63.6%, year 3: 77.8%, p = 0.412) diagnosis. Overall rate of grade 4 bleeding after cryobiopsy was 11.8%. Cryobiopsy required less chest tube placement (11.8% vs 100%, p < 0.001) and less hospitalizations compared to surgical biopsy (26.5% vs 95.7%, p < 0.001), but hospitalized patients had a longer median hospital stay (2 days vs 1 day, p = 0.004). CONCLUSIONS: Diagnostic yield of cryobiopsy increased over time but the overall grade 4 bleeding rate was 11.8%.

Assessment of plasma lyso-Gb3 for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease.

PURPOSE: To assess the utility of globotriaosylsphingosine (lyso-Gb3) for clinical monitoring of treatment response in patients with Fabry disease receiving migalastat. METHODS: A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)-experienced patients with migalastat-amenable GLA variants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb3 and measures of Fabry disease progression (left ventricular mass index [LVMi], estimated glomerular filtration rate [eGFR], and pain) and the relationship between lyso-Gb3 and incidence of Fabry-associated clinical events (FACEs) were assessed in both groups. The relationship between changes in lyso-Gb3 and kidney interstitial capillary (KIC) globotriaosylceramide (Gb3) inclusions was assessed in treatment-naive patients. RESULTS: No significant correlations were identified between changes in lyso-Gb3 and changes in LVMi, eGFR, or pain. Neither baseline lyso-Gb3 levels nor the rate of change in lyso-Gb3 levels during treatment predicted FACE occurrences in all patients or those receiving migalastat for ≥24 months. Changes in lyso-Gb3 correlated with changes in KIC Gb3 inclusions in treatment-naive patients. CONCLUSIONS: Although used as a pharmacodynamic biomarker in research and clinical studies, plasma lyso-Gb3 may not be a suitable biomarker for monitoring treatment response in migalastat-treated patients.

Brain Microglial Activation Increased in Glucocerebrosidase (GBA) Mutation Carriers without Parkinson's disease.

BACKGROUND: Glucocerebrosidase gene mutations are a common genetic risk factor for Parkinson's disease. They exhibit incomplete penetrance. The objective of the present study was to measure microglial activation and dopamine integrity in glucocerebrosidase gene mutation carriers without Parkinson's disease compared to controls. METHODS: We performed PET scans on 9 glucocerebrosidase gene mutation carriers without Parkinson's disease and 29 age-matched controls. We measured microglial activation as 11 C-(R)-PK11195 binding potentials, and dopamine terminal integrity with 18 F-dopa influx constants. RESULTS: The 11 C-(R)-PK11195 binding potential was increased in the substantia nigra of glucocerebrosidase gene carriers compared with controls (Student t test; right, t = -4.45, P = 0.0001). Statistical parametric mapping also localized significantly increased 11 C-(R)-PK11195 binding potential in the occipital and temporal lobes, cerebellum, hippocampus, and mesencephalon. The degree of hyposmia correlated with nigral 11 C-(R)-PK11195 regional binding potentials (Spearman's rank, P = 0.0066). Mean striatal 18 F-dopa uptake was similar to healthy controls. CONCLUSIONS: In vivo 11 C-(R)-PK11195 PET imaging detects neuroinflammation in brain regions susceptible to Lewy pathology in glucocerebrosidase gene mutation carriers without Parkinson's. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Clinical outcomes after 4.5 years of eliglustat therapy for Gaucher disease type 1: Phase 3 ENGAGE trial final results.

Eliglustat, an oral substrate reduction therapy, is approved for eligible adults with Gaucher disease type 1. In the Phase 3 ENGAGE trial of previously untreated adults with Gaucher disease type 1, eliglustat-treated patients had statistically significant improvements in organ volumes and hematologic parameters compared with placebo in the 9-month primary analysis. We report final outcomes by time on eliglustat among all patients who participated in the ENGAGE trial and extension. No patient deteriorated clinically or withdrew due to adverse events; 39/40 patients entered the open-label extension period and 34/40 (85%) remained in the trial until completion or switching to commercial eliglustat after its approval (2.3-6 years). Clinically meaningful improvements in Gaucher disease manifestations were seen in all patients concomitant with reductions in pathological lipid substrate levels (glucosylceramide and glucosylsphingosine). Among patients with 4.5 years of eliglustat exposure, mean spleen volume decreased by 66% (from 17.1 to 5.8 multiples of normal [MN], n = 13), mean liver volume decreased by 23% (from 1.5 to 1.1 MN, n = 13), mean hemoglobin increased 1.4 g/dl (from 11.9 to 13.4 g/dl, n = 12), mean platelet count increased by 87% (from 67.6 to 122.6 × 109 /L, n = 12), median chitotriosidase decreased by 82% (from 13 394 to 2312 nmol/h/ml, n = 11), median glucosylceramide decreased by 79% (from 11.5 to 2.4 µg/ml, n = 11), median glucosylsphingosine decreased by 84% (from 518.5 to 72.1 ng/ml, n = 10), and mean spine T-score increased from -1.07 (osteopenia) to -0.53 (normal) (n = 9). The magnitude of improvement in Gaucher disease manifestations and biomarkers over time was similar among the full trial cohort. Eliglustat was well-tolerated and led to clinically significant improvements in previously untreated patients with Gaucher disease type 1 during 4.5 years of treatment.

Life-Threatening Hemoptysis.

Life-threatening hemoptysis (LTH) is any amount of hemoptysis that causes significant hemodynamic decompensation or respiratory distress which may lead to death if left untreated. While the amount of hemoptysis that qualifies as massive hemoptysis has continued to be debated, any amount between 100 to 1,000 mL/day is considered significant. Up to 15% cases of hemoptysis are LTH and need urgent life-saving intervention. Understanding of pulmonary vascular anatomy is of paramount importance to manage LTH. The goal of treatment lies in airway protection, appropriate oxygenation, and prevention of exsanguination. Once the airway is stabilized, a quick diagnosis and control of bleeding site is targeted. This chapter highlights current practices and approach to LTH including medical management, bronchoscopic approach, and advanced therapies such as bronchial artery embolization and surgical resection. We review situations, such as bronchiectasis, vascular malformation, diffuse alveolar hemorrhage, and tracheostomy bleed and specific approach to management of these conditions in a systematic and evidence-based manner.

Sans Standardization: Effective Endoscope Reprocessing.

Bronchoscopy is a commonly performed procedure within thoracic and critical care medicine. Modern bronchoscopes are technologically advanced tools made of fragile electronic components. Their design is catered to allow maximum maneuverability within the semi-rigid tracheobronchial tree. Effective cleaning and reprocessing of these tools can be a challenge. Although highly functional, the design poses several challenges when it comes to reprocessing. It is a very important step, and lapses in the procedure have been tied to nosocomial infections. The process lacks universal standardization; several organizations have developed their own recommendations. Data have shown that key stakeholders are not fully versed in the essentials of endoscope reprocessing. A significant knowledge gap exists between those performing bronchoscopy and those who are stewards of effective endoscope reprocessing. To service as a resource for bronchoscopists, this study summarizes the steps of effective reprocessing, details the important elements within a health-care facility that houses this process, and reviews some of the current data regarding the use of disposable endoscopes.

Argon Plasma Coagulation: Elucidation of the Mechanism of Gas Embolism.

BACKGROUND: Argon plasma coagulation (APC) is a tool used in the management of tracheobronchial obstruction or bleeding. Complications include gas embolism which can cause devastating effects including hemodynamic instability, cardiac arrest, and stroke. Multiple theories as to how gas embolism occurs with APC have been postulated; however, none have identified the exact mechanism. OBJECTIVES: To identify the mechanism by which APC causes gas embolism in the tracheobronchial tree. METHODS: Using an explanted porcine tracheobronchial tree with lung parenchyma, the APC catheter was applied through noncontact and direct contact to the endobronchial airway mucosa via flexible bronchoscopy. This was done at multiple gas flow settings and pulse durations. Visual changes in the mucosa were photographed, videoed, and described. RESULTS: Gross evidence of submucosal gas transfer occurred when the APC catheter was in direct contact with the mucosa at all gas flow settings in all applications, despite using shorter pulse durations. Whenever the catheter was not in contact with the mucosa, there was no transfer of gas at any gas flow setting or pulse duration. CONCLUSIONS: Direct mucosal contact with the APC probe leads to submucosal gas deposition and is a likely mechanism for gas entry into the intravascular space. In reported cases of APC-associated gas embolism, presence of a vascularized endobronchial tumor may have increased the risk of gas tracking into the intravascular space. Care should be taken when applying APC during brisk bleeding or limited vision, as inadvertent mucosal contact may occur and could increase the risk of gas embolism.

Safety of Laser and Thermal Therapy During Rigid Bronchoscopy Using Manual Hand Jet Ventilation.

INTRODUCTION: Thermal ablative therapies (laser, radiofrequency ablation, electrocautery, argon plasma coagulation) are often used during rigid bronchoscopy for the treatment of central airway obstructions (CAO). An airway fire is a feared complication that can occur during endobronchial thermal ablation. MATERIALS AND METHODS: This was a single-center, retrospective, observational study. A total of 175 patients were reviewed undergoing rigid bronchoscopy in the operating room and bronchoscopy suite requiring manual hand jet ventilation and thermal therapy between September 2014 and September 2018. The study objective was to determine the safety of manual hand jet ventilation during endobronchial thermal therapies with rigid bronchoscopy. RESULTS: Over a five-year period, 175 patients underwent endobronchial thermal therapy during rigid bronchoscopy with manual hand jet ventilation for the treatment CAOs. Immediately prior to thermal therapy activation, jet ventilation was paused. No incidences (0/175) of airway fires occurred despite immediate delivery of thermal energy following a jet ventilation hold. CONCLUSIONS: Results of our study show that performing thermal ablative therapy during rigid bronchoscopy with jet ventilation using a breath-hold technique is safe.

Fatigue, quality of life and physical fitness following an exercise intervention in multiple myeloma survivors (MASCOT): an exploratory randomised Phase 2 trial utilising a modified Zelen design.

BACKGROUND: Exercise may improve fatigue in multiple myeloma survivors, but trial evidence is limited, and exercise may be perceived as risky in this older patient group with osteolytic bone destruction. METHODS: In this Phase 2 Zelen trial, multiple myeloma survivors who had completed treatment at least 6 weeks ago, or were on maintenance only, were enrolled in a cohort study and randomly assigned to usual care or a 6-month exercise programme of tailored aerobic and resistance training. Outcome assessors and usual care participants were masked. The primary outcome was the FACIT-F fatigue score with higher scores denoting less fatigue. RESULTS: During 2014-2016, 131 participants were randomised 3:1 to intervention (n = 89) or usual care (n = 42) to allow for patients declining allocation to the exercise arm. There was no difference between groups in fatigue at 3 months (between-group mean difference: 1.6 [95% CI: -1.1-4.3]) or 6 months (0.3 [95% CI: -2.6-3.1]). Muscle strength improved at 3 months (8.4 kg [95% CI: 0.5-16.3]) and 6 months (10.8 kg [95% CI: 1.2-20.5]). Using per-protocol analysis, cardiovascular fitness improved at 3 months (+1.2 ml/kg/min [95% CI: 0.3-3.7]). In participants with clinical fatigue (n = 17), there was a trend towards less fatigue with exercise over 6 months (6.3 [95% CI: -0.6-13.3]). There were no serious adverse events. CONCLUSIONS: Exercise appeared safe and improved muscle strength and cardiovascular fitness, but benefits in fatigue appeared limited to participants with clinical fatigue at baseline. Future studies should focus on patients with clinical fatigue. CLINICAL TRIAL REGISTRATION: The study was registered with ISRCTN (38480455) and is completed.

Cytomegalovirus reactivation after bortezomib treatment for multiple myeloma and light chain amyloidosis.

OBJECTIVE: Cytomegalovirus (CMV) is an opportunistic herpesvirus, and reactivation of infection is possible in immunocompromised patients. Historically, the risk for haematology patients is restricted to those treated with an allogeneic transplant or T-cell depleting agents. Bortezomib is a highly efficacious proteasome inhibitor widely used to treat multiple myeloma and light chain (AL) amyloidosis patients. The objective of this small prospective study was to quantify the risk of CMV reactivation associated with bortezomib treatment. METHODS: Fifty-seven consecutive multiple myeloma or AL amyloidosis patients commencing bortezomib-based therapy were included. Viral copy numbers were established at baseline and then at fortnightly intervals during treatment. Pre-emptive anti-viral treatment was initiated in patients with a viral load >7500 copies/mL. RESULTS: Reactivation of CMV was detected in 39% (n = 12/31) of seropositive bortezomib treated patients compared with 0% of CMV seronegative patients. Detectable DNAemia developed during the first two cycles of treatment in 83% (n = 10/12) patients. Anti-viral treatment was initiated in 42% (n = 5/12), but no cases of active CMV disease were seen. CONCLUSION: This study suggests that there is a substantial risk of CMV reactivation in CMV-seropositive plasma cell dyscrasia patients treated with bortezomib.

A review of endovascular stenting for superior vena cava syndrome in fibrosing mediastinitis.

Fibrosing mediastinitis (FM) is a rare disorder of inflammation and fibrosis involving the mediastinum. The formation of fibroinflammatory mass in the mediastinum can lead to obstruction of mediastinal structures and cause severe debilitating and life-threatening symptoms. Superior vena cava syndrome (SVCS) is a dreaded complication of FM with no medical therapy proven to be efficacious. Spiral vein grafting has long been utilized as first-line therapy for SVC syndrome due to FM. Endovascular repair with stents and angioplasty for malignant causes of SVC syndrome is well established. However, there are limited data on their utility in SVC syndrome due to FM. We present two cases of SVC syndrome due to FM treated with endovascular stenting and a detailed review of current literature on its utility in SVCS due to benign causes.

Scoring system to facilitate diagnosis of Gaucher disease.

BACKGROUND: Gaucher disease (GD) manifests heterogeneously and other conditions are often misdiagnosed in its place, leading to diagnostic delays. The Gaucher Earlier Diagnosis Consensus (GED-C) initiative proposed a point-scoring system (PSS) based on the signs and covariables that are most indicative of GD to help clinicians identify which individuals to test for GD. AIMS: To validate the PSS retrospectively in a test population including patients with GD and other conditions with overlapping manifestations. METHODS: Four cohorts of adults with GD, liver disease, haematological malignancy or immune thrombocytopenia were identified from hospital records. Clinical data were audited for GED-C factors identified as potentially indicative of GD and aggregate scores calculated (sum of scores/number of factors) based on published PSS weightings. Threshold discriminatory PSS scores, sensitivity and specificity were determined by receiver-operating characteristic analysis. RESULTS: Among 100 patients (GD, n = 25; non-GD, n = 75), analyses based on 11 possible factors estimated group mean (standard deviation) PSS scores of: GD (n = 14), 1.08 (0.25); non-GD (n = 38), 0.58 (0.31). Mean between-group difference (95% confidence interval) was -0.49 (-0.68, -0.31) and area under the receiver-operating characteristic analysis curve (95% confidence interval) was 0.88 (0.78, 0.97). A threshold PSS score of 0.82 identified all 14 patients with GD in the analysis set (100% sensitivity) and 27 of 38 patients in the non-GD group (71% specificity). Patients with liver disease and haematological malignancy were most likely to have manifestations overlapping GD. CONCLUSIONS: Preliminary validation of the GED-C PSS discriminated effectively between patients with GD and those with overlapping signs.

Evolution and clustering of prodromal parkinsonian features in GBA1 carriers.

BACKGROUND: Five to 25% of patients with PD carry glucocerebrosidase gene mutations, and 10% to 30% of glucocerebrosidase carriers will develop PD by age 80. Stratification of PD risk in glucocerebrosidase carriers provides an opportunity to target disease-modifying therapies. OBJECTIVE: Cross-sectional and longitudinal survey of prodromal PD signs among glucocerebrosidase carriers. DESIGN: Prospective assessment of 82 glucocerebrosidase mutation carriers and 35 controls over 4 to 5 years for prodromal clinical PD features. RESULTS: At all time points, olfactory (measured using University of Pennsylvania Smell Identification Test) and cognitive (Montreal Cognitive Assessment) function and the International Parkinson and Movement Disorder Society UPDRS parts II and III scores were significantly worse amongst glucocerebrosidase mutation carriers. Progression to microsmia (odds ratio: 8.5; 95% confidence interval: 2.6-28.2; P < 0.05) and mild cognitive impairment (odds ratio: 4.2; 95% confidence interval: 1.1-16.6; P < 0.05) were more rapid compared to controls. Those with worse olfaction also had worse cognition (OR, 1.5; 95% CI: 0.0-2.8; P < 0.05) and depression (OR, 1.3; 95% CI: 0.6-2.8; P < 0.05). No participants reached the MDS prodromal PD diagnostic criteria before PD diagnosis. One participant developed PD. He did not fulfill the International Parkinson and Movement Disorder Society prodromal PD criteria before diagnosis. CONCLUSION: Assessment of individual and clustered PD prodromal features may serve as a useful tool to identify high-risk subjects for conversion to PD. As a result of the low conversion rate in our glucocerebrosidase mutation carriers to date, prospective validation is needed in larger cohorts to establish the profile of these features in PD convertors. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Effect of bilateral lung transplantation on excessive dynamic airway collapse.

INTRODUCTION: Excessive dynamic airway collapse (EDAC) is associated with significant respiratory morbidity. It has been hypothesized that EDAC may limit the benefits of lung transplantation in chronic obstructive pulmonary disease (COPD) patients. We aim to find the effect of bilateral lung transplantation on EDAC in COPD patients. METHODS: Retrospective chart review was performed to identify patients with concomitant presence of COPD and EDAC before undergoing bilateral lung transplantation from December 2011 to December 2014. Pre- and post-transplant pulmonary function tests, flow-volume (FV) loops, computed tomography (CT) of the chest, and flexible bronchoscopies were studied. RESULTS: A total of 165 patients underwent bilateral lung transplantation during the study period. Eight patients had COPD and EDAC prior to the transplant. Post-transplantation, 7 out of 8 patients showed resolution of EDAC on expiratory CT chest and 1 patient did not have post-transplant CT chest. All eight showed no EDAC on post-transplant surveillance bronchoscopy. Post-transplant, mean predicted FEV1/FVC increased from 37% to 117% and mean predicted FEV1 increased from 20% to 61%. CONCLUSIONS: There is resolution of EDAC post-bilateral lung transplantation in this retrospective COPD patient population. EDAC should not be considered as a benefit-limiting factor to bilateral lung transplantation. However, prospective studies are required to explore potential indication.

Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study.

BACKGROUND: Two recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes. METHODS: In this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with agalsidase alfa and beta at their registered dose after correction for phenotype and sex. RESULTS: 387 patients (192 women) were included, 248 patients received agalsidase alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with agalsidase beta, specifically in men with classical FD (ß: -18 nmol/L, P<0.001), persisting in the presence of antibodies. The risk to develop antibodies was higher for patients treated with agalsidase beta (OR 2.8, P=0.04). LVMI decreased in a higher proportion following the first year of agalsidase beta treatment (OR 2.27, P=0.03), while eGFR slopes were similar. CONCLUSIONS: Treatment with agalsidase beta at higher dose compared with agalsidase alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with agalsidase beta.

Presenting signs and patient co-variables in Gaucher disease: outcome of the Gaucher Earlier Diagnosis Consensus (GED-C) Delphi initiative.

BACKGROUND: Gaucher disease (GD) presents with a range of signs and symptoms. Physicians can fail to recognise the early stages of GD owing to a lack of disease awareness, which can lead to significant diagnostic delays and sometimes irreversible but avoidable morbidities. AIM: The Gaucher Earlier Diagnosis Consensus (GED-C) initiative aimed to identify signs and co-variables considered most indicative of early type 1 and type 3 GD, to help non-specialists identify 'at-risk' patients who may benefit from diagnostic testing. METHODS: An anonymous, three-round Delphi consensus process was deployed among a global panel of 22 specialists in GD (median experience 17.5 years, collectively managing almost 3000 patients). The rounds entailed data gathering, then importance ranking and establishment of consensus, using 5-point Likert scales and scoring thresholds defined a priori. RESULTS: For type 1 disease, seven major signs (splenomegaly, thrombocytopenia, bone-related manifestations, anaemia, hyperferritinaemia, hepatomegaly and gammopathy) and two major co-variables (family history of GD and Ashkenazi-Jewish ancestry) were identified. For type 3 disease, nine major signs (splenomegaly, oculomotor disturbances, thrombocytopenia, epilepsy, anaemia, hepatomegaly, bone pain, motor disturbances and kyphosis) and one major co-variable (family history of GD) were identified. Lack of disease awareness, overlooking mild early signs and failure to consider GD as a diagnostic differential were considered major barriers to early diagnosis. CONCLUSION: The signs and co-variables identified in the GED-C initiative as potentially indicative of early GD will help to guide non-specialists and raise their index of suspicion in identifying patients potentially suitable for diagnostic testing for GD.

How we manage Gaucher Disease in the era of choices.

Treatment of Gaucher Disease (GD) is now beset with the abundance of therapeutic options for an individual patient, making the choice of therapy complex for both expert and non-expert clinicians. The pathogenesis of all disease manifestations is a gene mutation-driven deficiency of glucocerebrosidase, but the clinical expression and response of each of the clinical manifestations to different therapies can be difficult to predict. Enzyme replacement therapy has been available since 1991 and is well-established, with known efficacy and minimal toxicity. Of interest, the three available enzymes are distinct molecules and were registered as new products, not biosimilars. Oral substrate reduction therapy has undergone a revitalisation with a newly approved agent in this class for which some efficacy and toxicity questions have been raised. Herein we present our approach to the management of GD in the era of choices, including a new algorithm for how to manage a newly diagnosed patient.