Eradication of Mycobacterium abscessus infection in cystic fibrosis with initiation of Elexacaftor/Tezacaftor/Ivacaftor.

Mycobacterium abscessus is a nontuberculous mycobacterium that is often multi-drug resistant, difficult to eradicate and associated with a rapid decline in lung function in cystic fibrosis (CF). Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a combination CFTR modulator that improves lung function and decreases exacerbations, but limited data exists about its impact on respiratory infections. A 23-year-old male with CF (F508del, unknown) was diagnosed with Mycobacterium abscessus subspecies abscessus infection. He completed 12-weeks of intensive therapy, followed by oral continuation therapy. Antimicrobials were later discontinued for optic neuritis secondary to linezolid. He remained off antimicrobials with persistently positive sputum cultures. He then initiated ETI, and bronchoscopy eight months later suggested eradication of M. abscessus. By modulating CFTR protein function, ETI may improve innate airway defence mechanisms, facilitating the clearance of infections such as M. abscessus. This case highlights the potential positive implications of ETI on the challenging treatment of M. abscessus infections in CF.

External Validation of the BACES Score in Canadian Patients With Nontuberculous Mycobacterial Pulmonary Disease.

BACKGROUND: The clinical course of nontuberculous mycobacterial pulmonary disease (NTM-PD) can be variable and difficult to predict. Recently, the BACES score was developed as a tool to predict all-cause mortality in patients with NTM-PD. This score is calculated based on five patient characteristics (BMI, age, cavity, erythrocyte sedimentation rate, and sex), and higher scores portend worse prognosis. Although the BACES score has been validated in a cohort of South Korean patients, it has not yet been validated in other settings or ethnic groups. RESEARCH QUESTION: How well does the BACES mortality score perform in a cohort of Canadian patients with NTM-PD? STUDY DESIGN AND METHODS: We performed a single-center retrospective chart review. Patients who were seen between July 2003 and June 2021 were eligible for inclusion if they met guideline-based diagnostic criteria for NTM-PD and were excluded if any component of the BACES score was missing. To assess the model's discriminatory performance, we compared Kaplan-Meier curves between risk groups and calculated Harrell's C index. To assess calibration, we used a graphical calibration curve. RESULTS: The cohort included 435 patients with a median follow-up of 5.8 years. The median age was 64 years and 74% were female. Based on the BACES scores, patients were classified into three risk groups: low, moderate, or high. Survival curves showed clear separation of the risk groups. Harrell's C index was 0.733 in the study cohort, indicating moderate to good discriminatory performance, although this was lower than the value reported in the derivation cohort (0.812). The graphical calibration curve showed a tendency of the BACES model to underpredict mortality. INTERPRETATION: The BACES model was evaluated in a multicultural cohort of Canadian patients and demonstrated good discriminatory performance but suboptimal calibration, which may be due to population differences, the use of dichotomized variables in model construction, or both.

Tolerability Outcomes of American Thoracic Society/Infectious Diseases Society of America Guideline-Recommended Multidrug Antibiotic Treatment for Mycobacterium avium Complex Pulmonary Disease in US Medicare Beneficiaries With Bronchiectasis.

BACKGROUND: Nontuberculous mycobacteria are environmental organisms that are increasingly causing chronic and debilitating pulmonary infections, of which Mycobacterium avium complex (MAC) is the most common pathogen. MAC pulmonary disease (MAC-PD) is often difficult to treat, often requiring long-term multidrug antibiotic therapy. RESEARCH QUESTION: Is there an association between various guideline-based three-drug therapy (GBT) regimens and (1) therapy-associated adverse events or (2) regimen change/discontinuation, within 12 months of therapy initiation? STUDY DESIGN AND METHODS: In a retrospective cohort study, we examined tolerability outcomes of GBT regimens for MAC-PD in 4,626 US Medicare beneficiaries with bronchiectasis, who were prescribed a GBT as initial antibiotic treatment for presumed MAC-PD during 2006 to 2014. Using multivariable Cox proportional hazard regression, we estimated adjusted hazard ratios (aHRs) to compare the risk of adverse events and regimen change/discontinuations within 12 months of therapy initiation in various GBT regimens. RESULTS: The cohort had a mean age ± SD of 77.9 ± 6.1 years at treatment start, were mostly female (77.7%), and were mostly non-Hispanic White (87.2%). The risk of regimen change/discontinuation within 12 months of therapy was higher for clarithromycin-based regimens than azithromycin-based regimens (aHR, 1.12; 95% CI, 1.04-1.20 with rifampin; aHR, 1.11; 95% CI, 0.93-1.32 with rifabutin as the companion rifamycin), and for rifabutin-containing regimens than rifampin-containing regimens (aHR, 1.49; 95% CI, 1.33-1.68 with azithromycin; aHR, 1.47; 95% CI, 1.27-1.70 with clarithromycin as the companion macrolide). The aHR comparing regimen change/discontinuation with clarithromycin-ethambutol-rifabutin and azithromycin-ethambutol-rifampin was 1.64 (95% CI, 1.43-1.64). INTERPRETATION: Overall, an azithromycin-based regimen was less likely to be changed or discontinued than a clarithromycin-based regimen, and a rifampin-containing regimen was less likely to be changed or discontinued than a rifabutin-containing regimen within 12 months of therapy start. Our work provides a population-based assessment on the tolerability of multidrug antibiotic regimens used for the treatment of MAC-PD.

Incremental mortality associated with nontuberculous mycobacterial lung disease among US Medicare beneficiaries with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients with nontuberculous mycobacterial lung disease (NTMLD). Both conditions are associated with increased morbidity and mortality, but data are lacking on the additional burden associated with NTMLD among patients with COPD. Thus, the goal of this study was to assess the incremental mortality risk associated with NTMLD among older adults with COPD. METHODS: A retrospective cohort study was conducted using the US Medicare claims database (2010-2017). Patients with preexisting COPD and NTMLD (cases) were matched 1:3 by age and sex with patients with COPD without NTMLD (control patients). Patients were followed up until death or data cutoff (December 31, 2017). Incremental risk of mortality was evaluated by comparing the proportions of death, annualized mortality rate, and mortality hazard rate between cases and control patients using both univariate and multivariate analyses adjusting for age, sex, comorbidities, and COPD severity. RESULTS: A total of 4,926 cases were matched with 14,778 control patients. In univariate analyses, a higher proportion of cases (vs. control patients) died (41.5% vs. 26.7%; P < 0.0001), unadjusted annual mortality rates were higher among cases (158.5 vs. 86.0 deaths/1000 person-years; P < 0.0001), and time to death was shorter for cases. This increased mortality risk was also reflected in subsequent multivariate analyses. Patients with COPD and NTMLD were more likely to die (odds ratio [95% CI], 1.39 [1.27-1.51]), had higher mortality rates (rate ratio [95% CI], 1.36 [1.28-1.45]), and had higher hazard of death (hazard ratio [95% CI], 1.37 [1.28-1.46]) than control patients. CONCLUSIONS: The substantial incremental mortality burden associated with NTMLD in patients with COPD highlights the importance of developing interventions targeting this high-risk group and may indicate an unmet need for timely and appropriate management of NTMLD.

Treatment of the Less Common Nontuberculous Mycobacterial Pulmonary Disease.

Nontuberculous mycobacterial pulmonary disease caused by the less common nontuberculous mycobacteria have distinct features depending on the species. Diagnostic evaluation follows the established criteria for all nontuberculous mycobacteria, but with certain qualifications given species-specific and regional differences in pathogenicity. Clinicians should first institute nonpharmacologic management and evaluate clinical, radiologic, and microbiologic factors in the decision regarding antimycobacterial therapy. Treatment is challenging, and evidence-based recommendations are limited for most species. Drug susceptibility testing is used to help with regimen selection; however, this approach is imperfect given the uncertain correlation between in vitro activity and clinical response for most drugs.

Prognostic implication of pre-transplant FEV1 on long-term outcomes following allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Pre-transplant pulmonary function testing (PFT) is essential before allogeneic hematopoietic stem cell transplant (HCT), yet the optimal cutoff value for affecting transplant outcomes remains poorly defined. STUDY DESIGN: Retrospective analysis of pre-HCT PFT data from 605 consecutive patients at the Princess Margaret Cancer Centre between January 1, 2004 and December 31, 2013 used binary recursive partitioning to identify cutoff values for overall survival (OS) as an endpoint of transplant outcomes. These values were compared to HCT comorbidity index (HCT-CI) FEV1 cutoffs for OS, cumulative incidence of relapse and non-relapse mortality. RESULTS: FEV1 ≥ 81% was the identified cutoff point. The OS rate at 3 years showed 49.8% (FEV1 ≥ 81%) vs. 36.6% (<81%, p < .001). For HCT-CI cutoffs, the OS rate at 3 years for FEV1 ≥ 80%, 66%-80% and ≤65% were 49.0%, 38.1% and 37.6% (p = .011), respectively. Multivariate analysis confirmed that FEV1 ≥ 81% predicted reduced mortality (HR 0.682, p = .001). Subgroup analysis showed both FEV1 ≥ 81% and FEV1 by HCT-CI cutoffs may stratify patients according to OS and NRM risk in subgroups receiving myeloablative, but not reduced intensity conditioning. CONCLUSION: FEV1 ≥ 81% can predict OS and NRM in our cohort and is potentially simpler when risk stratifying patients undergoing allogeneic HCT, particularly those receiving myeloablative conditioning.

Pulmonary Nontuberculous Mycobacteria, Ontario, Canada, 2020.

We measured annual prevalence of microbiologically defined nontuberculous mycobacterial lung disease in Ontario, Canada. Mycobacterium avium prevalence was 13 cases/100,000 persons in 2020, a 2.5-fold increase from 2010, indicating a large increase in true M. avium lung disease. During the same period, M. xenopi decreased nearly 50%, to 0.84 cases/100,000 persons.

Identifying potentially undiagnosed nontuberculous mycobacterial lung disease among patients with chronic obstructive pulmonary disease: Development of a predictive algorithm using claims data.

BACKGROUND: Nontuberculous mycobacterial lung disease (NTMLD) is a debilitating disease. Chronic obstructive pulmonary disease (COPD) is the leading comorbidity associated with NTMLD in the United States. Their similarities in symptoms and overlapping radiological findings may delay NTMLD diagnosis in patients with COPD. OBJECTIVE: To develop a predictive model that identifies potentially undiagnosed NTMLD among patients with COPD. METHODS: This retrospective cohort study developed a predictive model of NTMLD using US Medicare beneficiary claims data (2006 - 2017). Patients with COPD with NTMLD were matched 1:3 to patients with COPD without NTMLD by age, sex, and year of COPD diagnosis. The predictive model was developed using logistic regression modeling risk factors such as pulmonary symptoms, comorbidities, and health care resource utilization. The final model was based on model fit statistics and clinical inputs. Model performance was evaluated for both discrimination and generalizability with c-statistics and receiver operating characteristic curves. RESULTS: There were 3,756 patients with COPD with NTMLD identified and matched to 11,268 patients with COPD without NTMLD. A higher proportion of patients with COPD with NTMLD, compared with those with COPD without NTMLD, had claims for pulmonary symptoms and conditions, including hemoptysis (12.6% vs 1.4%), cough (63.4% vs 24.7%), dyspnea (72.5% vs 38.2%), pneumonia (59.2% vs 13.4%), chronic bronchitis (40.5% vs 16.3%), emphysema, (36.7% vs 11.1%), and lung cancer (15.7% vs 3.5%). A higher proportion of patients with COPD with NTMLD had pulmonologist and infectious disease (ID) specialist visits than patients with COPD without NTMLD (≥ 1 pulmonologist visit: 81.3% vs 23.6%, respectively; ≥ 1 ID visit: 28.3% vs 4.1%, respectively, P < 0.0001). The final model consists of 10 risk factors (≥ 2 ID specialist visits; ≥ 4 pulmonologist visits; the presence of hemoptysis, cough, emphysema, pneumonia, tuberculosis, lung cancer, or idiopathic interstitial lung disease; and being underweight during a 1-year pre-NTMLD period) predicting NTMLD with high sensitivity and specificity (c-statistic, 0.9). The validation of the model on new testing data demonstrated similar discrimination and showed the model was able to predict NTMLD earlier than the receipt of the first diagnostic claim for NTMLD. CONCLUSIONS: This predictive algorithm uses a set of criteria comprising patterns of health care use, respiratory symptoms, and comorbidities to identify patients with COPD and possibly undiagnosed NTMLD with high sensitivity and specificity. It has potential application in raising timely clinical suspicion of patients with possibly undiagnosed NTMLD, thereby reducing the period of undiagnosed NTMLD. DISCLOSURES: Dr Wang and Dr Hassan are employees of Insmed, Inc. Dr Chatterjee was an employee of Insmed, Inc, at the time of this study. Dr Marras is participating in multicenter clinical trials sponsored by Insmed, Inc, has consulted for RedHill Biopharma, and has received a speaker's honorarium from AstraZeneca. Dr Allison is an employee of Statistical Horizons, LLC. This study was funded by Insmed Inc.

Management of nontuberculous mycobacteria in lung transplant cases: an international Delphi study.

Rationale: Nontuberculous mycobacterial (NTM) diseases are difficult-to-treat infections, especially in lung transplant (LTx) candidates. Currently, there is a paucity of recommendations on the management of NTM infections in LTx, focusing on Mycobacterium avium complex (MAC), M. abscessus and M. kansasii. Methods: Pulmonologists, infectious disease specialists, LTx surgeons and Delphi experts with expertise in NTM were recruited. A patient representative was also invited. Three questionnaires comprising questions with multiple response statements were distributed to panellists. Delphi methodology with a Likert scale of 11 points (5 to -5) was applied to define the agreement between experts. Responses from the first two questionnaires were collated to develop a final questionnaire. The consensus was described as a median rating >4 or <-4 indicating for or against the given statement. After the last round of questionnaires, a cumulative report was generated. Results: Panellists recommend performing sputum cultures and a chest computed tomography scan for NTM screening in LTx candidates. Panellists recommend against absolute contraindication to LTx even with multiple positive sputum cultures for MAC, M. abscessus or M. kansasii. Panellists recommend MAC patients on antimicrobial treatment and culture negative can be listed for LTx without further delay. Panellists recommend 6 months of culture-negative for M. kansasii, but 12 months of further treatment from the time of culture-negative for M. abscessus before listing for LTx. Conclusion: This NTM LTx study consensus statement provides essential recommendations for NTM management in LTx and can be utilised as an expert opinion while awaiting evidence-based contributions.

Environmental risk of nontuberculous mycobacterial infection: Strategies for advancing methodology.

The National Institute of Allergy and Infectious Diseases organized a symposium in June 2022, to facilitate discussion of the environmental risks for nontuberculous mycobacteria exposure and disease. The expert researchers presented recent studies and identified numerous research gaps. This report summarizes the discussion and identifies six major areas of future research related to culture-based and culture independent laboratory methods, alternate culture media and culturing conditions, frameworks for standardized laboratory methods, improved environmental sampling strategies, validation of exposure measures, and availability of high-quality spatiotemporal data.

Evaluation of Mycobacterium Avium Complex Pulmonary Disease Treatment Completion and Adherence to ATS/IDSA Guidelines.

BACKGROUND: Nontuberculous mycobacteria are environmental organisms that cause infections leading to chronic, debilitating pulmonary disease, among which Mycobacterium avium complex (MAC) is the most common species. METHODS: We described patterns of macrolide-based multidrug antibiotic therapies for MAC pulmonary disease (MAC-PD) in US Medicare beneficiaries with bronchiectasis between January 2006 and December 2014. MAC therapy was defined as a multidrug regimen containing a macrolide plus ≥1 other drug targeting MAC-PD (rifamycin, ethambutol, fluoroquinolone, or amikacin) prescribed concomitantly for >28 days. RESULTS: We identified 9189 new MAC therapy users, with a mean age (standard deviation) of 74 (6 years) at the start of therapy; 75% female and 87% non-Hispanic white. A guideline-based regimen (a macrolide, ethambutol, and rifamycin, with or without amikacin) was prescribed for 51% of new MAC therapy users at treatment start, of whom 41% were continuing guideline-based therapy at 6 months, and only 18% at 12 months. Of all new MAC therapy users, by 18 months only 11% were still receiving MAC treatment, 55% had discontinued therapy, and 34% were censored owing to death or the end of the study period. CONCLUSIONS: Overall, nearly half of new MAC therapy users were prescribed a non-guideline-recommended macrolide-based therapy, including regimens commonly associated with promoting macrolide resistance. Treatment discontinuation was common, and once discontinued, only a few beneficiaries resumed therapy at a later time. Our study adds important data to the current literature on treatment patterns for MAC-PD among older US populations. Future research should examine treatment patterns using more contemporary data sources.

The Other Nontuberculous Mycobacteria: Clinical Aspects of Lung Disease Caused by Less Common Slowly Growing Nontuberculous Mycobacteria Species.

Slowly growing nontuberculous mycobacteria (NTM) comprise a diverse group of environmental organisms, many of which are important human pathogens. The most common and well-known member of this group is Mycobacterium avium, the leading cause of nontuberculous mycobacterial pulmonary disease (NTM-PD) globally. This review focuses on the less common, but notable, species of slowly growing NTM with respect to lung disease. To prepare this article, literature searches were performed using each species name as the key word. Society guidelines were consulted, and relevant articles also were identified through the reference lists of key articles. The specific organisms highlighted include Mycobacterium kansasii, Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium simiae, and Mycobacterium szulgai. Although these organisms are closely related, they have distinct epidemiologic features and behavior as pathogens. Therefore, the diagnosis and management of NTM-PD require a nuanced approach that takes into consideration the unique characteristics of each species. There is limited evidence to inform the optimal treatment of NTM-PD. Antimicrobial therapy is often challenging because of the presence of drug resistance and few antibiotic options. Regimen selection should generally be guided by drug susceptibility testing, although the correlation between clinical outcomes and in vitro susceptibility thresholds has not been defined for most species.

Amikacin liposome inhalation suspension clinical benefit-risk assessment for refractory Mycobacterium avium complex lung disease.

Marraset al. report a low number needed to treat and high number needed to harm supporting addition of amikacin liposome inhalation suspension to guideline-based treatments in patients with treatment-refractory Mycobacterium avium complex lung disease https://bit.ly/3tPFW7D.

Increasing and More Commonly Refractory Mycobacterium avium Pulmonary Disease, Toronto, Ontario, Canada.

In mid-2014, Public Health Ontario Laboratories identified coincident increasing Mycobacterium avium isolation and falling M. xenopi isolation in the Toronto, Ontario, Canada, area. We performed a retrospective cohort of all patients in a Toronto clinic who began treatment for either M. avium or M. xenopi pulmonary disease during 2009-2012 (early period) or 2015-2018 (late period), studying their relative proportions and sputum culture conversion. We conducted a subgroup analysis among patients who lived in the Toronto-York region. The proportion of patients with M. avium was higher in the late period (138/146 [94.5%] vs. 82/106 [77.4%]; p<0.001). Among M. avium patients, conversion was lower in the late period (26.1% vs. 39.0%; p = 0.05). The increase in the proportion of patients with M. avium pulmonary disease and the reduction in the frequency of sputum culture conversion is unexplained but could suggest an increase in environmental M. avium exposure.

Consensus management recommendations for less common non-tuberculous mycobacterial pulmonary diseases.

The 2020 clinical practice guideline for the treatment of non-tuberculous mycobacterial pulmonary disease (NTM-PD) by the American Thoracic Society, European Respiratory Society, European Society of Clinical Microbiology and Infectious Diseases, and Infectious Diseases Society of America; and the 2017 management guideline by the British Thoracic Society covered pulmonary diseases in adults caused by Mycobacterium avium complex, Mycobacterium kansasii, Mycobacterium xenopi, and Mycobacterium abscessus. In order to provide evidence-based recommendations for the treatment of less common non-tuberculous mycobacterial (NTM) species in adult patients without cystic fibrosis or HIV infection, our expert panel group performed systematic literature searches to provide management guidance for pulmonary diseases caused by seven additional organisms: Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium genavense, Mycobacterium gordonae, Mycobacterium malmoense, Mycobacterium simiae, and Mycobacterium szulgai. Treatment recommendations were developed by a structured consensus process. The evidence from the scientific literature published in English for treatment recommendations for pulmonary diseases caused by other NTM species was of very low quality, with the exception of M malmoense, and based on the evaluation of case reports and case series. For M malmoense, results from two randomised controlled trials and three retrospective cohort studies provided a better evidence base for treatment recommendations, although the evidence was still of low quality.

Time to Positive Culture Detection Predicts Mycobacterium avium Pulmonary Disease Severity and Treatment Initiation.

Rationale: Additional biomarkers are needed to guide initiation of treatment for Mycobacterium avium pulmonary disease (Mav-PD). Time to positive sputum culture detection (TTP) may offer potential prognostic and monitoring value. Objectives: To determine whether TTP is associated with infection severity and early treatment response in Mav-PD. Methods: We undertook a retrospective cohort study of patients with two or more sputum cultures positive for M. avium, an "index" sputum M. avium isolate during 2015-2019, a computed tomographic scan within 6 months, and no treatment for at least 6 months before index sputum. TTP was estimated from the date of laboratory receipt of the specimen to the date of culture positivity confirmation. TTP was tested for association with markers of infection severity (Mav-PD, bronchiectasis, cavitary disease, treatment initiation by 3 and 6 months, and acid fast bacilli [AFB] smear) and treatment response using Mann-Whitney U, Spearman's correlation coefficient, and Wilcoxon signed-rank tests. We explored a threshold TTP that could identify significant M. avium disease. Results: We included 125 patients with mean (standard deviation) age 68.5 (12.5) years and 65% fulfilled disease criteria. Median TTP was 12 (interquartile range 10-15; range 6-44) days. TTP and AFB smear grade were negatively correlated (ρ -0.58; P < 0.001). TTP was associated with nontuberculous mycobacteria (NTM) disease (P = 0.03), AFB smear positivity (P < 0.001), and treatment initiation by 3 (P = 0.01) and 6 (P = 0.03) months. A threshold TTP of 10 days or less was associated with Mav-PD (80.6% vs. 58.4%; ð [95% confidence interval (CI)] 22.1% [5.6-38.6%]; P = 0.02), AFB smear positivity (83.3% vs. 20.2%, ð [95% CI] 63.1% [48.3-77.9%]; P < 0.001), treatment by 3 (38.9% vs. 13.5%; ð [95% CI] 25.4% [8.0-42.8%]; P = 0.003) and 6 (47.2% vs. 19.1%; ð [95% CI] 28.1% [9.9-46.4%]; P = 0.003) months. After 3 and 6 months of treatment, the median (interquartile range) change in TTP was 8 (1 undefined; P < 0.001) and 7 (0 undefined; P = 0.001) days, respectively. Conclusions: TTP is associated with bacterial burden and infection severity and increases in response to treatment. A threshold of 10 days or less may be useful in predicting significant Mav-PD. As a readily available biomarker, further exploration of TTP is imperative.

Clinical Considerations for Routine Auditory and Vestibular Monitoring in Patients With Cystic Fibrosis.

Purpose Specific classes of antibiotics, such as aminoglycosides, have well-established adverse events producing permanent hearing loss, tinnitus, and balance and/or vestibular problems (i.e., ototoxicity). Although these antibiotics are frequently used to treat pseudomonas and other bacterial infections in patients with cystic fibrosis (CF), there are no formalized recommendations describing approaches to implementation of guideline adherent ototoxicity monitoring as part of CF clinical care. Method This consensus statement was developed by the International Ototoxicity Management Working Group (IOMG) Ad Hoc Committee on Aminoglycoside Antibiotics to address the clinical need for ototoxicity management in CF patients treated with known ototoxic medications. These clinical protocol considerations were created using consensus opinion from a community of international experts and available evidence specific to patients with CF, as well as published national and international guidelines on ototoxicity monitoring. Results The IOMG advocates four clinical recommendations for implementing routine and guideline adherent ototoxicity management in patients with CF. These are (a) including questions about hearing, tinnitus, and balance/vestibular problems as part of the routine CF case history for all patients; (b) utilizing timely point-of-care measures; (c) establishing a baseline and conducting posttreatment evaluations for each course of intravenous ototoxic drug treatment; and (d) repeating annual hearing and vestibular evaluations for all patients with a history of ototoxic antibiotic exposure. Conclusion Increased efforts for implementation of an ototoxicity management program in the CF care team model will improve identification of ototoxicity signs and symptoms, allow for timely therapeutic follow-up, and provide the clinician and patient an opportunity to make an informed decision about potential treatment modifications to minimize adverse events. Supplemental Material https://doi.org/10.23641/asha.16624366.