Unusual Cause of Hemoptysis in a Woman With Cystic Fibrosis.

CASE PRESENTATION: A 20-year-old patient with cystic fibrosis (CF) complicated by pansinusitis, pancreatic insufficiency, and diabetes presented to the local ED after an episode of large-volume hemoptysis at home. At baseline, she had advanced lung disease (FEV1, 0.97 L; 31% predicted) and upper lobe-predominant fibrocavitary changes. She was intermittently followed at a regional lung transplant center. She was previously evaluated for transplant but was not listed at the time of this presentation because of nontuberculous mycobacteria infection. She had never used tobacco, without reports of recreational inhaled drug use. Her mother had CF, and one of her brothers died in 2018 at age 24 of respiratory failure resulting from the disease.

Inhaled mRNA therapy for treatment of cystic fibrosis: Interim results of a randomized, double-blind, placebo-controlled phase 1/2 clinical study.

BACKGROUND: MRT5005, a codon-optimized CFTR mRNA, delivered by aerosol in lipid nanoparticles, was designed as a genotype-agnostic treatment for CF lung disease. METHODS: This was a randomized, double-blind, placebo-controlled Phase 1/2 study performed in the US. Adults with 2 severe class I and/or II CFTR mutations and baseline ppFEV1 values between 50 and 90% were randomized 3:1 (MRT5005: placebo). Six dose levels of MRT5005 (4, 8, 12, 16, 20, and 24 mg) or placebo (0.9% Sodium Chloride) were administered by nebulization. The single ascending dose cohort was treated over a range from 8 to 24 mg; the multiple ascending dose cohort received five weekly doses (range 8-20 mg); and the daily dosing cohort received five daily doses (4 mg). RESULTS: A total of 42 subjects were assigned to MRT5005 [31] or placebo [11]. A total of 14 febrile reactions were observed in 10 MRT5005-treated participants, which were mild [3] or moderate [11] in severity; two subjects discontinued related to these events. Additionally, two MRT5005-treated patients experienced hypersensitivity reactions, which were managed conservatively. The most common treatment emergent adverse events were cough and headache. No consistent effects on FEV1 were noted. CONCLUSIONS: MRT5005 was generally safe and well tolerated through 28 days of follow-up after the last dose, though febrile and hypersensitivity reactions were noted. The majority of these reactions resolved within 1-2 days with supportive care allowing continued treatment with MRT5005 and careful monitoring. In this small first-in-human study, FEV1 remained stable after treatment, but no beneficial effects on FEV1 were observed.

Acromial and Scapular Fractures After Reverse Total Shoulder Arthroplasty with a Medialized Glenoid and Lateralized Humeral Implant: An Analysis of Outcomes and Risk Factors.

This article was updated on TK because of a previous error, which was discovered after the preliminary version of the article was posted online. In Table VII, the fracture rate in the study by Walch et al. that had read "4.6% (21 of 457)" now reads "0.9% (4 of 457)." BACKGROUND: Acromial and scapular fractures after reverse total shoulder arthroplasty (rTSA) are rare and challenging complications, and little information is available in the literature to identify patients who are at risk. This study analyzes risk factors for, and compares the outcomes of patients with and without, acromial and scapular fractures after rTSA with a medialized glenoid/lateralized humeral implant. METHODS: Four thousand one hundred and twenty-five shoulders in 3,995 patients were treated with primary rTSA with 1 design of reverse shoulder prosthesis by 23 orthopaedic surgeons. Sixty-one of the 4,125 shoulders had radiographically identified acromial and scapular fractures. Demographic characteristics, comorbidities, implant-related data, and clinical outcomes were compared between patients with and without fractures to identify risk factors. A multivariate logistic regression, 2-tailed unpaired t test, and chi-square test or Fisher exact test identified significant differences (p < 0.05). RESULTS: After a minimum duration of follow-up of 2 years, the rate of acromial and scapular fractures was 1.77%, with the fractures occurring at a mean (and standard deviation) of 17.7 ± 21.1 months after surgery. Ten patients had a Levy Type-1 fracture, 32 had a Type-2 fracture, 18 had a Type-3 fracture, and 1 fracture could not be classified. Patients with acromial and scapular fractures were more likely to be female (84.0% versus 64.5% [p = 0.004]; odds ratio [OR] = 2.75 [95% confidence interval (CI) = 1.45 to 5.78]), to have rheumatoid arthritis (9.8% versus 3.3% [p = 0.010]; OR = 3.14 [95% CI = 1.18 to 6.95]), to have rotator cuff tear arthropathy (54.1% versus 37.8% [p = 0.005]; OR = 2.07 [95% CI = 1.24 to 3.47]), and to have more baseplate screws (4.1 versus 3.8 screws [p = 0.017]; OR = 1.53 [95% CI = 1.08 to 2.17]) than those without fractures. No other implant-related differences were observed in the multivariate analysis. Patients with fractures had significantly worse outcomes than patients without fractures, and the difference in mean improvement between these 2 cohorts exceeded the minimum clinically important difference for the majority of measures. CONCLUSIONS: Acromial and scapular fractures after rTSA are uncommon, and patients with these fractures have significantly worse clinical outcomes. Risk factors, including female sex, rheumatoid arthritis, cuff tear arthropathy, and usage of more baseplate screws were identified on multivariate logistic regression analysis. Consideration of these findings and patient-specific risk factors may help the orthopaedic surgeon (1) to better inform patients about this rare complication preoperatively and (2) to be more vigilant for this complication when evaluating patients postoperatively. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

2019 Frank Stinchfield Award: A comparison of prosthetic joint infection rates between direct anterior and non-anterior approach total hip arthroplasty.

AIMS: We studied the impact of direct anterior (DA) versus non-anterior (NA) surgical approaches on prosthetic joint infection (PJI), and examined the impact of new perioperative protocols on PJI rates following all surgical approaches at a single institution. PATIENTS AND METHODS: A total of 6086 consecutive patients undergoing primary total hip arthroplasty (THA) at a single institution between 2013 and 2016 were retrospectively evaluated. Data obtained from electronic patient medical records included age, sex, body mass index (BMI), medical comorbidities, surgical approach, and presence of deep PJI. There were 3053 male patients (50.1%) and 3033 female patients (49.9%). The mean age and BMI of the entire cohort was 62.7 years (18 to 102, sd 12.3) and 28.8 kg/m2 (13.3 to 57.6, sd 6.1), respectively. Infection rates were calculated yearly for the DA and NA approach groups. Covariates were assessed and used in multivariate analysis to calculate adjusted odds ratios (ORs) for risk of development of PJI with DA compared with NA approaches. In order to determine the effect of adopting a set of infection prevention protocols on PJI, we calculated ORs for PJI comparing patients undergoing THA for two distinct time periods: 2013 to 2014 and 2015 to 2016. These periods corresponded to before and after we implemented a set of perioperative infection protocols. RESULTS: There were 1985 patients in the DA group and 4101 patients in the NA group. The overall rate of PJI at our institution during the study period was 0.82% (50/6086) and decreased from 0.96% (12/1245) in 2013 to 0.53% (10/1870) in 2016. There were 24 deep PJIs in the DA group (1.22%) and 26 deep PJIs in the NA group (0.63%; p = 0.023). After multivariate analysis, the DA approach was 2.2 times more likely to result in PJI than the NA approach (OR 2.2 (95% confidence interval 1.1 to 3.9); p = 0.006) for the overall study period. CONCLUSION: We found a higher rate of PJI in DA versus NA approaches. Infection prevention protocols such as use of aspirin, dilute povidone-iodine lavage, vancomycin powder, and Gram-negative coverage may have been positively associated with diminished PJI rates observed for all approaches over time. Cite this article: Bone Joint J 2019;101-B(6 Supple B):2-8.

Preoperative bisphosphonate treatment may adversely affect the outcome after shoulder arthroplasty.

AIMS: The aim of this study was to investigate the effects of preoperative bisphosphonate treatment on the intra- and postoperative outcomes of arthroplasty of the shoulder. The hypothesis was that previous bisphosphonate treatment would adversely affect both intra- and postoperative outcomes. PATIENTS AND METHODS: A retrospective cohort study was conducted involving patients undergoing arthroplasty of the shoulder, at a single institution. Two patients with no previous bisphosphonate treatment were matched to each patient who had received this treatment preoperatively by gender, age, race, ethnicity, body mass index (BMI), and type of arthroplasty. Previous bisphosphonate treatment was defined as treatment occurring during the three-year period before the arthroplasty. The primary outcome measure was the incidence of intraoperative complications and those occurring at one and two years postoperatively. A total of 87 patients were included: 29 in the bisphosphonates-exposed (BP+) group and 58 in the non-exposed (BP-) group. In the BP+ group, there were 26 female and three male patients, with a mean age of 71.4 years (51 to 87). In the BP- group, there were 52 female and six male patients, with a mean age of 72.1 years (53 to 88). RESULTS: Previous treatment with bisphosphonates was positively associated with intraoperative complications (fracture; odds ratio (OR) 39.40, 95% confidence interval (CI) 2.42 to 6305.70) and one-year postoperative complications (OR 7.83, 95% CI 1.11 to 128.82), but did not achieve statistical significance for complications two years postoperatively (OR 3.45, 95% CI 0.65 to 25.28). The power was 63% for complications at one year. CONCLUSION: Patients who are treated with bisphosphonates during the three-year period before shoulder arthroplasty have a greater risk of intraoperative and one-year postoperative complications compared with those without this previous treatment.

Risk factors for recurrent instability or revision surgery following arthroscopic Bankart repair.

Aims: The factors that predispose to recurrent instability and revision stabilization procedures after arthroscopic Bankart repair for anterior glenohumeral instability remain unclear. We sought to determine the rate and risk factors associated with ongoing instability in patients undergoing arthroscopic Bankart repair for instability of the shoulder. Materials and Methods: We used the Statewide Planning and Research Cooperative System (SPARCS) database to identify patients with a diagnosis of anterior instability of the shoulder undergoing arthroscopic Bankart repair between 2003 and 2011. Patients were followed for a minimum of three years. Baseline demographics and subsequent further surgery to the ipsilateral shoulder were analyzed. Multivariate analysis was used to identify independent risk factors for recurrent instability. Results: A total of 5719 patients were analyzed. Their mean age was 24.9 years (sd 9.3); 4013 (70.2%) were male. A total of 461 (8.1%) underwent a further procedure involving the ipsilateral shoulder at a mean of 31.5 months (sd 23.8) postoperatively; 117 (2.1%) had a closed reduction and 344 (6.0%) had further surgery. Revision arthroscopic Bankart repair was the most common subsequent surgical procedure (223; 65.4%). Independent risk factors for recurrent instability were: age < 19 years (odds ratio 1.86), Caucasian ethnicity (hazard ratio 1.42), bilateral instability of the shoulder (hazard ratio 2.17), and a history of closed reduction(s) prior to the initial repair (hazard ratio 2.45). Revision arthroscopic Bankart repair was associated with significantly higher rates of ongoing persistent instability than revision open stabilization (12.4% vs 5.1%, p = 0.041). Conclusion: The incidence of a further procedure being required in patients undergoing arthroscopic Bankart repair for anterior glenohumeral instability was 8.1%. Younger age, Caucasian race, bilateral instability, and closed reduction prior to the initial repair were independent risk factors for recurrent instability, while subsequent revision arthroscopic Bankart repair had significantly higher rates of persistent instability than subsequent open revision procedures. Cite this article: Bone Joint J 2018;100-B:324-30.

Psoas Muscle Area Predicts All-Cause Mortality After Endovascular and Open Aortic Aneurysm Repair.

OBJECTIVE: Psoas muscle area (PMA) is a validated surrogate for muscle mass that can be easily measured from a clinical CT scan. This study sought to determine whether PMA was associated with post-operative mortality after endovascular or open aortic aneurysm repair. METHODS: A retrospective review was undertaken of patients who underwent elective endovascular or open aortic aneurysm repair between 2010 and 2015 at a tertiary vascular center in Montreal, Quebec, Canada. Pre-operative CT scan images were analyzed with the CoreSlicer.com software tool to measure PMA at the axial level of the L4 vertebrae. Measurements were made by two independent observers blinded to clinical data. The primary endpoint was all-cause mortality. RESULTS: The cohort consisted of 149 patients with a mean age of 75.6 ± 8.8 years. The mean PMA was 24.0 ± 5.8 cm2 in males, and 14.3 ± 3.1 cm2 in females. There were 31 deaths over a mean follow-up of 22.4 months. After adjusting for age, sex, revised cardiac risk index, and surgical approach, Cox regression revealed a graded association between PMA and all-cause mortality with a hazard ratio of 0.86 per cm2 (95% CI 0.79-0.93). Addition of PMA to the model with the clinical covariates resulted in an improvement in C-statistic from 0.57 to 0.67, and BIC from 307 to 301 (with lower BIC values preferred). CONCLUSIONS: PMA is independently associated with all-cause mortality after elective endovascular and open aortic aneurysm repair, and may be integrated into the pre-operative risk assessment to optimize care in high-risk frail patients.

Change in Driving Performance following Arthroscopic Shoulder Surgery.

The current study aimed to measure perioperative changes in driving performance following arthroscopic shoulder surgery using a validated driving simulator.21 patients who underwent arthroscopic surgery for rotator cuff or labral pathology were tested on a driving simulator preoperatively, and 6 and 12 weeks postoperatively. An additional 21 subjects were tested to establish driving data in a control cohort. The number of collisions, centerline crossings, and off-road excursions were recorded for each trial. VAS and SPADI scores were obtained at each visit.The mean number of collisions in the study group significantly increased from 2.05 preoperatively to 3.75 at 6 weeks (p<0.001), and significantly decreased to 1.95 at 12 weeks (p<0.001). Centerline crossings and off-road excursions did not significantly change from preoperative through 12 weeks, although centerline crossings were statistically different from the controls at each time point (p<0.001). Surgery on the dominant driving arm resulted in greater collisions at 6 weeks than surgery on the non-dominant driving arm (p<0.001).Preliminary data shows that driving performance is impaired for at least 6 weeks postoperatively, with a return to normal driving by 12 weeks. Driving is more profoundly affected in conditions that require avoiding a collision and when the dominant driving arm is involved.

The influence of a history of clinical depression on peri-operative outcomes in elective total shoulder arthroplasty: a ten-year national analysis.

AIMS: Depression can significantly affect quality of life and is associated with higher rates of medical comorbidities and increased mortality following surgery. Although depression has been linked to poorer outcomes following orthopaedic trauma, total joint arthroplasty and spinal surgery, we wished to examine the impact of depression in elective total shoulder arthroplasty (TSA) as this has not been previously explored. PATIENTS AND METHODS: The United States Nationwide Inpatient Sample (NIS) was used to identify patients undergoing elective TSA over a ten-year period. Between 2002 and 2012, 224 060 patients underwent elective TSA. RESULTS: Among the identified patients who had undergone TSA, 12.4% had a diagnosis of a history of depression. A diagnosis of depression was twice as common in women compared with men (16.0% vs 8.0%, p < 0.001), and more frequent in those with low income and Medicaid insurance (p < 0.001). A diagnosis of depression was an independent risk factor for post-operative delirium (odds ratio (OR) 2.29, p < 0.001), anaemia (OR 1.65, p < 0.001), infection (2.09, p = 0.045) and hospital discharge to a placement other than home (OR 1.52, p < 0.001) CONCLUSION: A history of clinical depression is present in 12.4% of patients undergoing elective TSA and the disease burden is projected to increase further in the future. Depression is often underdiagnosed and pre-operative screening and appropriate peri-operative management of patients is encouraged. TAKE HOME MESSAGE: The awareness that clinical depression is associated with increased complications following total shoulder arthroplasty provides physicians an opportunity for early intervention in this at-risk population. Cite this article: Bone Joint J 2016;98-B:818-24.

Beating the Odds: Successful Establishment of a Phase II/III Clinical Research Trial in Resource-Poor Liberia during the Largest-Ever Ebola Outbreak.

It has been argued that a country such as Liberia, not fully recovered from the devastation of decades of civil unrest, lacked the appropriate ethical and regulatory framework, basic human and health care services, and infrastructure to carry out clinical trials according to international standards of quality during a public health emergency. However, as Liberia, Sierra Leone, and Guinea were being ravaged by the largest and most devastating Ebola Virus Disease (EVD) outbreak ever recorded, the topic of conducting clinical trials of experimental vaccine and treatment candidates in these resource-poor countries generated the keen interest and concern of scientists, researchers, physicians, bioethicists, philanthropists, and even politicians. Decisive action on behalf of the Liberian government, and a timely positive and supportive response from the United States (U.S.) government, led to the formation of PREVAIL (Partnership for Research on Ebola Vaccines in Liberia) - a clinical research partnership between the two governments. Within a span of 12 weeks, this partnership accomplished the unimaginable: the successful initiation of a Phase II/III vaccine clinical trial for EVD in Liberia. This paper will discuss the dynamics of the research collaboration, barriers encountered, breakthroughs realized, key elements of success, and lessons learned in the process.

Decreasing spine implant costs and inter-physician cost variation: the impact of programme of cost containment on implant expenditure in spinal surgery.

The demand for spinal surgery and its costs have both risen over the past decade. In 2008 the aggregate hospital bill for surgical care of all spinal procedures was reported to be $33.9 billion. One key driver of rising costs is spinal implants. In 2011 our institution implemented a cost containment programme for spinal implants which was designed to reduce the prices of individual spinal implants and to reduce the inter-surgeon variation in implant costs. Between February 2012 and January 2013, our spinal surgeons performed 1493 spinal procedures using implants from eight different vendors. By applying market analysis and implant cost data from the previous year, we established references prices for each individual type of spinal implant, regardless of vendor, who were required to meet these unit prices. We found that despite the complexity of spinal surgery and the initial reluctance of vendors to reduce prices, significant savings were made to the medical centre.

Identifying a standard set of outcome parameters for the evaluation of orthogeriatric co-management for hip fractures.

BACKGROUND AND PURPOSE: Osteoporotic fractures are an increasing problem in the world due to the ageing of the population. Different models of orthogeriatric co-management are currently in use worldwide. These models differ for instance by the health-care professional who has the responsibility for care in the acute and early rehabilitation phases. There is no international consensus regarding the best model of care and which outcome parameters should be used to evaluate these models. The goal of this project was to identify which outcome parameters and assessment tools should be used to measure and compare outcome changes that can be made by the implementation of orthogeriatric co-management models and to develop recommendations about how and when these outcome parameters should be measured. It was not the purpose of this study to describe items that might have an impact on the outcome but cannot be influenced such as age, co-morbidities and cognitive impairment at admission. METHODS: Based on a review of the literature on existing orthogeriatric co-management evaluation studies, 14 outcome parameters were evaluated and discussed in a 2-day meeting with panellists. These panellists were selected based on research and/or clinical expertise in hip fracture management and a common interest in measuring outcome in hip fracture care. RESULTS: We defined 12 objective and subjective outcome parameters and how they should be measured: mortality, length of stay, time to surgery, complications, re-admission rate, mobility, quality of life, pain, activities of daily living, medication use, place of residence and costs. We could not recommend an appropriate tool to measure patients' satisfaction and falls. We defined the time points at which these outcome parameters should be collected to be at admission and discharge, 30 days, 90 days and 1 year after admission. CONCLUSION: Twelve objective and patient-reported outcome parameters were selected to form a standard set for the measurement of influenceable outcome of patients treated in different models of orthogeriatric co-managed care.

Scapular notching and osteophyte formation after reverse shoulder replacement: Radiological analysis of implant position in male and female patients.

This study provides recommendations on the position of the implant in reverse shoulder replacement in order to minimise scapular notching and osteophyte formation. Radiographs from 151 patients who underwent primary reverse shoulder replacement with a single prosthesis were analysed at a mean follow-up of 28.3 months (24 to 44) for notching, osteophytes, the position of the glenoid baseplate, the overhang of the glenosphere, and the prosthesis scapular neck angle (PSNA). A total of 20 patients (13.2%) had a notch (16 Grade 1 and four Grade 2) and 47 (31.1%) had an osteophyte. In patients without either notching or an osteophyte the baseplate was found to be positioned lower on the glenoid, with greater overhang of the glenosphere and a lower PSNA than those with notching and an osteophyte. Female patients had a higher rate of notching than males (13.3% vs 13.0%) but a lower rate of osteophyte formation (22.9% vs 50.0%), even though the baseplate was positioned significantly lower on the glenoid in females (p = 0.009) and each had a similar mean overhang of the glenosphere. Based on these findings we make recommendations on the placement of the implant in both male and female patients to avoid notching and osteophyte formation.

Effects of enzyme replacement therapy on the cardiomyopathy of Anderson-Fabry disease: a randomised, double-blind, placebo-controlled clinical trial of agalsidase alfa.

BACKGROUND: Anderson-Fabry disease is an X-linked glycosphingolipid storage disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. This leads to a progressive accumulation of globotriaosylceramide (Gb(3)) in the lysosomes of cells throughout the body that ultimately results in premature death from renal, cardiac or cerebrovascular complications. Until recently, there was no effective therapy available for this disease. The present study was designed to assess the safety and efficacy of enzyme replacement therapy with agalsidase alfa on the cardiac manifestations of Anderson-Fabry disease. METHOD: The effects of therapy with agalsidase alfa on cardiac structure and function were assessed in a randomised, double-blind, placebo-controlled study of 15 adult male patients with Anderson-Fabry disease. The following parameters were measured at baseline and 6 months: left ventricular mass, QRS duration and levels of Gb(3) in cardiac tissue, urine sediment and plasma. After 6 months of the randomised trial patients were enrolled in a 2-year open-label extension study. RESULTS: Left ventricular mass, as measured by MRI, was significantly reduced following 6 months of treatment with agalsidase alfa compared with placebo (p = 0.041). A mean 20% reduction in myocardial Gb(3) content as assessed by serial transvenous endomyocardial biopsies was demonstrated over the 6 months of enzyme replacement compared to a mean 10% increase in patients receiving placebo (p = 0.42) CONCLUSION: Enzyme replacement therapy with agalsidase alfa resulted in regression of the hypertrophic cardiomyopathy associated with Anderson-Fabry disease.

Review: hepatitis B immune globulin for prevention of hepatitis B infection.

Specific hepatitis B immune globulin (HBIG) contains a high titer of antibody to hepatitis B surface antigens and provides immediate passive protection against infection with hepatitis B virus, after acute exposure to infection. It is now generally combined with active immunization with hepatitis B vaccine. The principal indications for administration of HBIG are: a single acute percutaneous exposure to hepatitis B virus (HBV); mucocutaneous exposure; unprotected sexual exposure; mother-to-infant transmission; prevention of re-infection after liver transplantation; non-responders to hepatitis B vaccine and immunosuppressed patients.

Safety and immunogenicity profile of an experimental hepatitis B vaccine adjuvanted with AS04.

The reactogenicity and safety of an experimental hepatitis B (HB) vaccine containing adjuvant system (AS04) was compared with a licensed vaccine in a phase III, single-blind, randomised study in healthy volunteers >or=15 years of age. A total of 1303 subjects were enrolled to receive either two doses of HB-AS04 (0, 6 months) or three doses of the comparator vaccine (0, 1, 6 months). Two doses of HB-AS04 elicited seroprotection rates close to 100% and two-fold higher GMTs than the comparator vaccine. Results showed that both vaccines were well tolerated and the general safety profile of HB-AS04 was similar to that of the comparator vaccine.

Differential injury responses in oral mucosal and cutaneous wounds.

Oral mucosa heals faster than does skin, yet few studies have compared the repair at oral mucosal and cutaneous sites. To determine whether the privileged healing of oral injuries involves a differential inflammatory phase, we compared the inflammatory cell infiltrate and cytokine production in wounds of equivalent size in oral mucosa and skin. Significantly lower levels of macrophage, neutrophil, and T-cell infiltration were observed in oral vs. dermal wounds. RT-PCR analysis of inflammatory cytokine production demonstrated that oral wounds contained significantly less IL-6 and KC than did skin wounds. Similarly, the level of the pro-fibrotic cytokine TGF-b1 was lower in mucosal than in skin wounds. No significant differences between skin and mucosal wounds were observed for the expression of the anti-inflammatory cytokine IL-10 and the TGF-beta1 modulators, fibromodulin and LTBP-1. These findings demonstrate that diminished inflammation is a key feature of the privileged repair of oral mucosa.

Hearing loss in Fabry disease: the effect of agalsidase alfa replacement therapy.

The aim of this study was to describe the nature and prevalence of hearing loss in Fabry disease (McKusick 301500), a rare X-linked lysosomal storage disorder, and its response to enzyme replacement therapy with agalsidase alfa. Fifteen hemizygous male Fabry patients (aged 25-49 years) were randomized to receive placebo or enzyme replacement therapy for 6 months; all have received open-label enzyme replacement therapy for an additional 24 months thus far. Pure-tone audiometry, impedance audiometry and otoacoustic emission testing were performed at 0 (baseline), 6, 18 and 30 months. Four patients (27%) had bilateral and 7 (47%) had unilateral high-frequency sensorineural hearing loss (SNHL). Two (13%) had unilateral middle ear effusions with conductive losses persisting beyond 6 months. Only 3 (20%) had normal hearing. High-frequency SNHL deteriorated over the first 6 months in both placebo and active treatment groups by a median 4.3 dB ( p =0.002, Wilcoxon matched pairs). This hearing loss subsequently improved above baseline by 2.1 dB at 18 months ( p =0.02) and by 4.9 dB at 30 months ( p =0.004). In conclusion, significant hearing loss, usually high-frequency SNHL, is a common manifestation of Fabry disease in adults. alpha-Galactosidase A replacement therapy with agalsidase alfa appears to reverse the hearing deterioration in these patients. This improvement is gradual, however, suggesting the need for long-term enzyme replacement therapy.

Hearing improvement in patients with Fabry disease treated with agalsidase alfa.

AIM: To describe the nature and prevalence of hearing loss in Fabry disease, and its response to enzyme replacement therapy (ERT) with agalsidase alfa. METHODS: Fifteen male patients with Fabry disease were enrolled in a randomized, double-blind study and received placebo (n = 8) or ERT (n = 7) with agalsidase alfa for 6 months. This was followed by an open-label extension of 36 months thus far. Alongside this trial, an additional eight men and two women have so far received open-label ERT for between 6 and 30 months. Pure-tone audiometry, impedance audiometry and otoacoustic emission testing were performed at 0 (baseline), 6, 18, 30 and 42 months. RESULTS: Nine patients (36%) had bilateral and ten (40%) had unilateral high-frequency sensorineural hearing loss (SNHL). Three (12%) had unilateral middle ear effusions with conductive losses persisting beyond 6 months. Only five patients (20%) had normal hearing. The high-frequency SNHL deteriorated over the first 6 months in both placebo and active treatment groups by a median 6.3 dB (p < 0.0001, Wilcoxon matched-pairs). This hearing loss subsequently improved above baseline by 1.5 dB at 18 months (p = 0.07), by 5.0 dB at 30 months (p = 0.006) and by 4.0 dB at 42 months (p = 0.01). CONCLUSION: Significant hearing loss, usually high-frequency SNHL, is a common manifestation of Fabry disease in adults. Alpha-galactosidase A replacement therapy with agalsidase alfa appears to reverse the hearing deterioration in these patients. This improvement, however, is gradual, suggesting the need for long-term ERT.