Publications by authors named "Theodore K Marras"

82 Publications

Aspergillus isolation in nontuberculous mycobacterial pulmonary disease: Associated with antimycobacterial treatment initiation but not response.

Respir Med 2021 Apr 12;179:106338. Epub 2021 Feb 12.

Toronto Western Hospital, University Health Network, Department of Medicine, Division of Respirology, Toronto, Ontario, Canada; West Park Healthcare Centre, Department of Respiratory Medicine, Toronto, Ontario, Canada; University of Toronto, Department of Medicine, Division of Respirology, Toronto, Ontario, Canada. Electronic address:

Purpose: Chronic pulmonary aspergillosis is a serious complication of nontuberculous mycobacterial pulmonary disease (NTM-PD), and diagnosis remains challenging. The present study examined associations between the respiratory isolation of Aspergillus and the clinical characteristics and treatment outcomes of patients with NTM-PD.

Methods: All patients meeting NTM-PD criteria as defined by the ATS/IDSA statement, with at least one respiratory sample cultured for fungi, were included in this retrospective cohort analysis. Patients with at least one respiratory sample isolating Aspergillus were compared to patients who did not isolate Aspergillus. The primary outcomes were culture conversion and radiologic evolution 12 months after NTM-PD treatment initiation.

Results: During a 12 year period, 497 patients meeting the inclusion criteria were seen in our tertiary care center, of whom 130 grew Aspergillus. Median follow up after NTM-PD diagnosis was 46 months. Inhaled corticosteroid use, a nodular-bronchiectatic CT pattern and NTM-PD treatment initiation were more frequent in patients who isolated Aspergillus compared to those who did not (p-value respectively 0.01, 0.03 and < 0.001). Rates of culture conversion (63.0% vs. 62.2%, respectively; p-value 1) and radiologic evolution (improvement or stability in 69.7% vs. 77.2%, respectively; p-value 0.25) were not significantly different between treatment groups. Likewise, culture reversion rate and 5-year mortality were not significantly different. Additionally, A. fumigatus and repeated detection of Aspergillus were not associated with treatment outcomes.

Conclusion: There was no association between respiratory isolation of Aspergillus and NTM-PD treatment outcomes in this cohort. However, treatment for NTM-PD was initiated more frequently in patients who isolated Aspergillus.
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http://dx.doi.org/10.1016/j.rmed.2021.106338DOI Listing
April 2021

Amikacin Liposome Inhalation Suspension for MAC Lung Disease: A 12-Month Open-Label Extension Study.

Ann Am Thorac Soc 2020 Dec 16. Epub 2020 Dec 16.

The University of Texas Health Science Center at Tyler, 12341, Medicine, Tyler, Texas, United States.

Rationale: Patients with refractory Mycobacterium avium complex (MAC) lung disease have limited treatment options. In the CONVERT study, amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) increased culture conversion rates vs GBT alone by Month 6. Limited data are available regarding >6-month treatment in a refractory population.

Objectives: Evaluate 12-month safety, tolerability, and efficacy of ALIS+GBT.

Methods: Adults with refractory MAC lung disease not achieving culture conversion by CONVERT Month 6 could enroll in this open-label extension (INS-312) to receive 590 mg once-daily ALIS+GBT for 12 months. Two cohorts enrolled: the "ALIS-naive" cohort included patients randomized to GBT alone in CONVERT, and the "prior-ALIS" cohort included those randomized to ALIS+GBT in CONVERT. Safety and tolerability of ALIS over 12 months (primary endpoint) and culture conversion by Months 6 and 12 were assessed.

Results: In the ALIS-naive cohort, 83.3% of patients (n=75/90) experienced respiratory treatment-emergent adverse events (TEAEs), and 35.6% (n=32) had serious TEAEs; 26.7% (n=24) achieved culture conversion by Month 6 and 33.3% (n=30) by Month 12. In the prior-ALIS cohort, 46.6% of patients (n=34/73) experienced respiratory TEAEs, and 27.4% (n=20) had serious TEAEs; 9.6% (n=7) achieved culture conversion by Month 6 (≤14 months ALIS exposure) and 13.7% (n=10) by Month 12 (≤20 months ALIS exposure). Nephrotoxicity-related TEAEs and measured hearing decline were infrequent in both cohorts.

Conclusions: In up to 20 months of ALIS use, respiratory TEAEs were common, nephrotoxicity and hearing decline were infrequent, and culture conversion continued beyond 6 months of therapy. Clinical trial registered with www.clinicaltrials.gov (NCT02628600).
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http://dx.doi.org/10.1513/AnnalsATS.202008-925OCDOI Listing
December 2020

Management of drug toxicity in M. avium complex pulmonary disease - an expert panel survey.

Clin Infect Dis 2020 Sep 10. Epub 2020 Sep 10.

Division of Pulmonary and Critical Care Medicine, Seoul National University College of Medicine, Seoul, South Korea.

Adverse events are frequent in NTM pulmonary disease treatment, but evidence to support their management is scarce. An expert panel survey on management of adverse events shows consistent opinions on management of hepatoxicity, ocular toxicity, ototoxicity, tinnitus and GI upset. These opinions can provide assistance in individual patient management decisions.
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http://dx.doi.org/10.1093/cid/ciaa1361DOI Listing
September 2020

Costs Associated with Nontuberculous Mycobacteria Infection, Ontario, Canada, 2001-2012.

Emerg Infect Dis 2020 09;26(9):2097-2107

To determine incidence-based healthcare costs attributable to nontuberculous mycobacterial (NTM) pulmonary disease (PD) and NTM pulmonary isolation (PI), from the healthcare payer perspective, we conducted a population-based matched cohort study in Ontario, Canada. We established cohorts of patients with incident NTM-PD and NTM-PI during 2001-2012 by using individually linked laboratory data and health administrative data, matched to unexposed persons from the general population. To estimate attributable costs for acute and long-term illness, we used a phase-of-care approach. Costs were stratified by age, sex, and healthcare resource, and reported in 2018 Canadian dollars (CAD) and US dollars (USD), standardized to 10 days. Costs were highest during the before-death phase (NTM-PD CAD $1,352 [USD $1,044]; NTM-PI CAD $731 [USD $565]). The cumulative mean attributable 1-year costs were CAD $14,953 (USD $11,541) for NTM-PD and CAD $8,729 (USD $6,737) for NTM-PI. Costs for patients with NTM-PD and NTM-PI were higher than those for unexposed persons.
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http://dx.doi.org/10.3201/eid2609.190524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454113PMC
September 2020

Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline.

Clin Infect Dis 2020 Aug;71(4):905-913

Divisions of Infectious Diseases, Schools of Public Health and Medicine, Oregon Health and Science University, Portland, Oregon, USA.

Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.
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http://dx.doi.org/10.1093/cid/ciaa1125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768745PMC
August 2020

Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline.

Eur Respir J 2020 07 7;56(1). Epub 2020 Jul 7.

Divisions of Infectious Diseases, Schools of Public Health and Medicine, Oregon Health and Science University, Portland, OR, USA.

Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as complex, , and among the slowly growing NTM and among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.
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http://dx.doi.org/10.1183/13993003.00535-2020DOI Listing
July 2020

Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline: Executive Summary.

Clin Infect Dis 2020 Aug;71(4):e1-e36

Divisions of Infectious Diseases, Schools of Public Health and Medicine, Oregon Health and Science University, Portland, Oregon, USA.

Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.
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http://dx.doi.org/10.1093/cid/ciaa241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768748PMC
August 2020

Clinical outcomes in Mycobacterium xenopi versus Mycobacterium avium complex pulmonary disease: A retrospective matched cohort study.

Respir Med 2020 06 15;167:105967. Epub 2020 Apr 15.

Division of Respirology, Department of Medicine, University of Toronto, Toronto, Canada; Division of Respirology, Department of Medicine, Toronto Western Hospital, Toronto, Canada.

Mycobacterium xenopi is associated with the highest mortality among pulmonary nontuberculous mycobacterial (NTM) infections, but whether this is due to the infection or other factors is unclear. There is little information regarding outcomes among patients infected with M. xenopi versus other NTM species. We conducted a retrospective matched cohort study comparing M. xenopi pulmonary disease (Mx-PD) to M. avium complex (MAC)-PD. Patients were matched by sex, age, radiologic subtype, and presence of cavitation. Baseline clinical characteristics, treatment, and outcomes were compared using matched analyses. We identified 70 Mx-PD cases: 29 fibrocavitary-type, 28 nodular-bronchiectatic-type, and 13 unclassifiable-type CT patterns, mean (SD) age 63 (13) years, and 54.3% (n = 38) female. Median follow-up duration was longer in the Mx-PD cohort (1552 days versus 1035 days, p = 0.01). Symptoms, radiologic phenotype, and pulmonary function were similar between groups although the Charlson Comorbidity Index was numerically higher in Mx-PD patients (3.6 versus 3.2, p = 0.08). Rifamycins were used less frequently in Mx-PD (59.5% versus 85.7%, p = 0.02). Although combined clinical and radiologic improvement was similar between the groups, successful treatment was more common with Mx-PD (40.5% versus 16.7%, p = 0.02) owing to superior culture conversion (70.8% versus 33.3%, p = 0.0001). Mortality 24 months after initiation of treatment was numerically but not statistically greater in the Mx-PD cohort (20.4% versus 10.3%, p = 0.32). Among matched Mx-PD and MAC-PD patients, standard anti-mycobacterial treatment was significantly more likely to achieve culture conversion and successful treatment for Mx-PD patients. Mortality among Mx-PD patients was numerically, but not statistically higher, possibly explained by increased comorbidity burden.
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http://dx.doi.org/10.1016/j.rmed.2020.105967DOI Listing
June 2020

Outcomes of a Peri- and Postoperative Management Protocol for Non-TB Mycobacteria in Lung Transplant Recipients.

Chest 2020 Aug 2;158(2):523-528. Epub 2020 Apr 2.

Department of Medicine, University of Toronto, Toronto, ON, Canada; Infectious Diseases, Toronto General Hospital, Toronto, ON, Canada.

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http://dx.doi.org/10.1016/j.chest.2020.01.056DOI Listing
August 2020

Clinical efficacy and safety of fluoroquinolone containing regimens in patients with complex pulmonary disease.

Eur Respir J 2020 04 23;55(4). Epub 2020 Apr 23.

Dept of Medicine, University of Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.1183/13993003.01240-2019DOI Listing
April 2020

Incidence and Prevalence of Nontuberculous Mycobacterial Lung Disease in a Large U.S. Managed Care Health Plan, 2008-2015.

Ann Am Thorac Soc 2020 02;17(2):178-185

Insmed Incorporated, Bridgewater, New Jersey.

Estimating the annual incidence and prevalence of nontuberculous mycobacterial (NTM) lung disease may assist in improving understanding of the public health and economic impacts of this disease and its treatment. To estimate the yearly incidence and prevalence of administrative claims-based NTM lung disease between 2008 and 2015 in a U.S. managed care claims database. We used a national managed care claims database (Optum Clinformatics Data Mart) representing a geographically diverse population of approximately 27 million members annually. All medical claims from January 1, 2007, to June 30, 2016, were scanned for diagnosis codes for NTM lung disease ( [ICD-9-CM] code 031.0 or ICD-10-CM code A31.0). We defined a case of NTM lung disease as having at least two medical claims with a code of 031.0 or A31.0 that were dated at least 30 days apart. Annual incidence and prevalence were estimated for each calendar year from 2008 to 2015. From 2008 to 2015, the annual incidence of NTM lung disease increased from 3.13 (95% confidence interval [CI], 2.88-3.40) to 4.73 (95% CI, 4.43-5.05) per 100,000 person-years, and the annual prevalence increased from 6.78 (95% CI, 6.45-7.14) to 11.70 (95% CI, 11.26-12.16) per 100,000 persons. The average annual changes in incidence and prevalence were +5.2% (95% CI, 4.0-6.4%;  < 0.01) and +7.5% (95% CI, 6.7-8.2%;  < 0.01), respectively. For women, the annual incidence increased from 4.16 (95% CI, 3.76-4.60) to 6.69 (95% CI, 6.19-7.22) per 100,000 person-years, and the annual prevalence increased from 9.63 (95% CI, 9.08-10.22) to 16.78 (95% CI, 16.04-17.55) per 100,000 persons. For individuals aged 65 years or older, the annual incidence increased from 12.70 (95% CI, 11.46-14.07) to 18.37 (95% CI, 16.98-19.87) per 100,000 person-years, and the annual prevalence increased from 30.27 (95% CI, 28.41-32.24) to 47.48 (95% CI, 45.37-49.67) per 100,000 persons. The incidence and prevalence of NTM lung disease increased in most U.S. states and overall at the national level. The incidence and prevalence of NTM lung disease appears to be increasing in the United States, particularly among women and older age groups.
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http://dx.doi.org/10.1513/AnnalsATS.201804-236OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993793PMC
February 2020

Prescribing Patterns for Treatment of Mycobacterium avium Complex and M. xenopi Pulmonary Disease in Ontario, Canada, 2001-2013.

Emerg Infect Dis 2019 07;25(7)

Surveys suggest that clinicians diverge from guidelines when treating Mycobacterium avium complex (MAC) pulmonary disease (PD). To determine prescribing patterns, we conducted a cohort study of adults >66 years of age in Ontario, Canada, with MAC or Mycobacterium xenopi PD during 2001-2013. Using linked laboratory and health administrative databases, we studied the first treatment episode (>60 continuous days of >1 of a macrolide, ethambutol, rifamycin, fluoroquinolone, linezolid, inhaled amikacin, or, for M. xenopi, isoniazid). Treatment was prescribed for 24% MAC and 15% of M. xenopi PD patients. Most commonly prescribed was the recommended combination of macrolide, ethambutol, and rifamycin, for 47% of MAC and 36% of M. xenopi PD patients. Among MAC PD patients, 20% received macrolide monotherapy and 33% received regimens associated with emergent macrolide resistance. Although the most commonly prescribed regimen was guidelines-recommended, many regimens prescribed for MAC PD were associated with emergent macrolide resistance.
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http://dx.doi.org/10.3201/eid2507.181817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590764PMC
July 2019

Safety and effectiveness of low-dose amikacin in nontuberculous mycobacterial pulmonary disease treated in Toronto, Canada.

BMC Pharmacol Toxicol 2019 06 3;20(1):37. Epub 2019 Jun 3.

Joint Division of Respirology, Department of Medicine, University Health Network and Sinai Health System, 399 Bathurst Street, Toronto, M5T 2S8, ON, Canada.

Background: Treatment guidelines suggest either a low-dose or high-dose approach when prescribing amikacin for nontuberculous mycobacterial pulmonary disease (NTM PD), but data supporting the low-dose approach are limited. The purpose of this study was to describe the safety and efficacy of the use of a low-dose of intravenous amikacin in a cohort of patients with NTM PD.

Methods: We retrospectively reviewed all patients with NTM PD who received amikacin at our institution between July 1, 2003 and February 28, 2017. Demographics, clinical, microbiological and radiological data, indication and dose of amikacin, and adverse drug effects were recorded.

Results: A total of 107 patients received a regimen containing amikacin for a median (IQR) of 7 (4-11) months. Seventy (65.4%) were female and the mean age (SD) was 58.3 (14.9) years. Amikacin was started at a median dose of 9.9 (2.5) mg/kg/day. Ototoxicity was observed in 30/77 (39%) patients and it was related to female sex (OR 4.96, 95%CI 1.24-19.87), and total dose of amikacin per bodyweight (OR 1.62, 95%CI 1.08-2.43). Patients of East Asian ethnicity were less likely to develop ototoxicity (0.24, 95%CI 0.06-0.95). Out of 96 patients who received amikacin for more than 3 months, 65 (67.7%) experienced symptom improvement and 30/62 (49.2%) converted their sputum to culture negative within a year.

Conclusions: Patients with NTM PD treated with low-dose intravenous amikacin frequently developed ototoxicity, which was associated with female sex, and total dose of amikacin per bodyweight. Physicians should carefully consider dose, treatment duration, and long term prognosis in balancing risks and benefits of intravenous amikacin in NTM PD.
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http://dx.doi.org/10.1186/s40360-019-0302-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547538PMC
June 2019

Guidelines-based treatment associated with improved economic outcomes in nontuberculous mycobacterial lung disease.

J Med Econ 2019 Nov 10;22(11):1126-1133. Epub 2019 Jun 10.

Insmed Incorporated , Bridgewater , NJ , USA.

The prevalence of nontuberculous mycobacterial lung disease (NTMLD) in the US has increased; however, data characterizing the associated healthcare utilization and expenditure at the national level are limited. To examine associations between economic outcomes and the use of anti- complex (MAC) guidelines-based treatment (GBT) for newly-diagnosed NTMLD in a US national managed care claims database (Optum Clinformatics Data Mart). NTMLD was defined as having ≥2 claims for NTMLD (ICD-9 031.0; ICD-10 A31.0) on separate occasions ≥30 days apart (between 2007 and 2016). The cohort included patients insured continuously over a period of at least 36 months (12 months before initial NTMLD diagnostic claim and for the subsequent 24 months). Treatment was classified as GBT (consistent with American Thoracic Society/Infectious Diseases Society of America guidelines), non-GBT, or untreated. All-cause hospitalization rates and total healthcare expenditures at Year 2 were assessed as outcomes of the treatment prescribed in Year 1 after NTMLD diagnosis. A total of 1,039 patients met study criteria for NTMLD (GBT,  = 294; non-GBT,  = 298; untreated,  = 447). After adjustment for baseline characteristics, GBT was associated with a significantly lower all-cause hospitalization risk vs non-GBT (odds ratio [OR] = 0.53; 95% CI = 0.33-0.85,  = 0.008), and vs being untreated (OR = 0.57; 95% CI = 0.35-0.91,  = 0.020). Adjusted total healthcare expenditure in Year 2 with GBT ($69,691) was lower than that with non-GBT ($77,624) with a difference of -$7,933 (95% CI = -$14,968 to -$899;  = 0.03). Patients with NTMLD in a US managed care claims database who were prescribed GBT had lower hospitalization risk than those who were prescribed non-GBT or were untreated. GBT was associated with lower total healthcare expenditure compared with non-GBT.
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http://dx.doi.org/10.1080/13696998.2019.1620243DOI Listing
November 2019

Radiologic types of Mycobacterium xenopi pulmonary disease: different patients with similar short-term outcomes.

Eur J Clin Microbiol Infect Dis 2019 Feb 14;38(2):373-381. Epub 2018 Dec 14.

Division of Respirology, Department of Medicine, University of Toronto, Toronto, ON, Canada.

Mycobacterium xenopi pulmonary disease (Mxe-PD) is common among nontuberculous mycobacterial infections in Europe and Canada. Associations between radiological pattern and clinical features and outcomes are inadequately studied in Mxe-PD. We sought to investigate clinical characteristics and outcomes according to the dominant radiological pattern among patients with Mxe-PD. We retrospectively studied patients with Mxe-PD seen in our clinic, categorizing their predominant CT pattern as nodular bronchiectasis, fibrocavitary, or unclassifiable, and compared clinical characteristics, treatment, and outcomes between radiologic groups. Of 94 patients with Mxe-PD, CT patterns comprised nodular bronchiectasis (40/94, 42.6%), fibrocavitary (37/94, 39.4%), and unclassifiable (17/94, 18.1%). Compared with fibrocavitation, patients with nodular bronchiectasis were female dominant, less often had COPD, less often had AFB smear-positive sputum, and more frequently had co-isolation of Pseudomonas. Patients with nodular bronchiectasis were less often treated (65% versus 91.9%) and when treated, they received fewer anti-mycobacterial drugs (on average 3 versus 4). Outcomes did not differ significantly by radiological pattern. Nodular bronchiectasis was common among Mxe-PD patients in our clinic. Compared with fibrocavitary disease, patients with nodular bronchiectasis had features suggestive of milder disease and were less often treated. Among treated patients, outcomes did not differ by radiologic pattern.
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http://dx.doi.org/10.1007/s10096-018-3437-xDOI Listing
February 2019

Relative risk of all-cause mortality in patients with nontuberculous mycobacterial lung disease in a US managed care population.

Respir Med 2018 12 22;145:80-88. Epub 2018 Oct 22.

Pulmonary Branch/NHLBI, National Institutes of Health, Bethesda, MD, USA.

Rationale: The risk of all-cause mortality of nontuberculous mycobacterial lung disease (NTMLD) in the United States (US) population is not well established.

Objectives: This study aims to assess the public health burden of NTMLD in the US by comparing the relative risk of all-cause mortality in the NTMLD population with an age- and sex-matched cohort from the general population.

Methods: Patients with physician claims for NTMLD (ICD-9 0.031; ICD-10 A31.0) were identified between 2007 and 2016 from a large US national managed care insurance plan covering approximately 15-18 million members annually. A control group with no NTMLD ICD-9 or 10 codes was randomly selected from the general population and matched 3:1 to the NTMLD sample according to birth year, gender, and insurance benefit coverage. The date of first NTMLD diagnosis of each patient was assigned to the matched controls as the index date. The Cox proportional hazard method compared survival between cohorts, adjusting for demographic factors and baseline comorbidities.

Results: A total of 2005 patients with NTMLD and 6014 controls were identified, with a mean follow-up duration of 3.4 years and 3.7 years, respectively. The NTMLD group had substantially higher proportions of patients with asthma (23.3% versus 3.5%), bronchiectasis (36.5% versus 0.1%), COPD (52.0% versus 5.9%), arrhythmia (22.6% versus 6.5%), coronary artery disease (18.5% versus 6.6%), heart failure (11.9% versus 4.1%), and cancer (18.5% versus 5.0%). The unadjusted rate of all-cause mortality from the index date was 20.7 per 1000 person-years in the NTMLD group vs 5.6 per 1000 person-years in the control group (rate ratio = 3.73; 95% CI: 2.93-4.75). Multivariable Cox regression, adjusted for the above variables as well as all other important baseline covariates, showed a doubling risk of all-cause mortality (hazard ratio [HR] = 2.06; CI: 1.52-2.79; P < 0.001) in the NTMLD vs control group.

Conclusions: All-cause mortality, adjusted for other factors, more than doubled with NTMLD compared with an age-sex-matched control group in a large US national managed care insurance plan.
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http://dx.doi.org/10.1016/j.rmed.2018.10.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283283PMC
December 2018

Procedure volume and mortality after surgical lung biopsy in interstitial lung disease.

Eur Respir J 2019 02 21;53(2). Epub 2019 Feb 21.

Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, ON, Canada.

Surgical volume-outcome relationships are well established but have not been studied in patients with interstitial lung disease (ILD) undergoing surgical lung biopsy (SLB). Our study objective was to determine if hospital SLB volume is associated with post-operative mortality in patients with ILD.A cohort study using administrative, population-based data from Ontario, Canada was performed in adults with ILD who underwent a SLB between 2001 and 2014. The association between yearly hospital SLB volume and 30-day post-operative mortality was assessed using multilevel logistic regression modelling.3057 surgical lung biopsies for ILD were performed during the study period with a median (interquartile range) yearly hospital volume of 73 (34-143) procedures. 30-day mortality was 7.1%, 20.2% and 1.9% in overall, nonelective and elective patients, respectively. Higher yearly hospital SLB volume was associated with lower odds of 30-day post-operative mortality after adjusting for patient characteristics (OR 0.84, 95% CI 0.73-0.97; p=0.02), with the association appearing stronger for nonelective elective procedures (OR 0.84, 95% CI 0.69-1.02; p=0.08 OR 0.94, 95% CI 0.74-1.18; p=0.57).Higher yearly hospital SLB volume was associated with lower post-operative mortality in patients with ILD, with the association appearing to be mainly driven by nonelective cases. SLB mortality was significantly higher for nonelective cases.
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http://dx.doi.org/10.1183/13993003.01164-2018DOI Listing
February 2019

Amikacin Liposome Inhalation Suspension for Treatment-Refractory Lung Disease Caused by Complex (CONVERT). A Prospective, Open-Label, Randomized Study.

Am J Respir Crit Care Med 2018 12;198(12):1559-1569

21 OHSU-PSU School of Public Health, Portland, Oregon.

Improved therapeutic options are needed for patients with treatment-refractory nontuberculous mycobacterial lung disease caused by complex (MAC). To evaluate the efficacy and safety of daily amikacin liposome inhalation suspension (ALIS) added to standard guideline-based therapy (GBT) in patients with refractory MAC lung disease. Adults with amikacin-susceptible MAC lung disease and MAC-positive sputum cultures despite at least 6 months of stable GBT were randomly assigned (2:1) to receive ALIS with GBT (ALIS + GBT) or GBT alone. Once-daily ALIS was supplied in single-use vials delivering 590 mg amikacin to the nebulizer. The primary endpoint was culture conversion, defined as three consecutive monthly MAC-negative sputum cultures by Month 6. Enrolled patients (ALIS + GBT,  = 224; GBT-alone,  = 112) were a mean 64.7 years old and 69.3% female. Most had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%), or both (11.9%). Culture conversion was achieved by 65 of 224 patients (29.0%) with ALIS + GBT and 10 of 112 (8.9%) with GBT alone (odds ratio, 4.22; 95% confidence interval, 2.08-8.57;  < 0.001). Patients in the ALIS + GBT arm versus GBT alone were more likely to achieve conversion (hazard ratio, 3.90; 95% confidence interval, 2.00-7.60). Respiratory adverse events (primarily dysphonia, cough, and dyspnea) were reported in 87.4% of patients receiving ALIS + GBT and 50.0% receiving GBT alone; serious treatment-emergent adverse events occurred in 20.2% and 17.9% of patients, respectively. Addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion by Month 6 than GBT alone, with comparable rates of serious adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT02344004).
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http://dx.doi.org/10.1164/rccm.201807-1318OCDOI Listing
December 2018

Health Care Utilization and Expenditures Following Diagnosis of Nontuberculous Mycobacterial Lung Disease in the United States.

J Manag Care Spec Pharm 2018 Oct 20;24(10):964-974. Epub 2018 Jul 20.

3 Insmed, Bridgewater, New Jersey.

Background: Nontuberculous mycobacterial lung disease (NTMLD) is an important public health concern that has been increasing in prevalence.

Objectives: To (a) describe hospitalizations and health care expenditures among patients with newly diagnosed NTMLD and (b) estimate attributable hospitalizations and expenditures to NTMLD in the United States.

Methods: In this matched cohort study, patients and controls were identified from a large U.S. national managed care insurance database containing aggregated health claims of up to 18 million fully covered members annually. NTMLD was defined based on diagnostic claims for NTMLD on ≥ 2 separate occasions ≥ 30 days apart between 2007 and 2016. Thirty-six months of continuous enrollment (12 months before and 24 months after the first diagnostic claim) was required. Health care utilization and standardized health care expenditures were summarized over 12 months before NTMLD diagnosis and for 2 subsequent years. The percentage of patients that were hospitalized in years 1 and 2 was evaluated using a generalized mixed effects model with adjustment for baseline hospitalizations, Charlson Comorbidity Index, and baseline diseases. A general estimating equation model was used to evaluate health care expenditures.

Results: There were 1,039 patients in the NTMLD cohort and 2,078 in the control cohort. NTMLD patients had a 55.0% risk of hospitalization in year 1 (95% CI = 45.4-64.3) and a 38.8% risk in year 2 (95% CI = 30.0-48.4). The adjusted risk of hospitalization was significantly higher in the NTMLD group compared with the control group in year 1 (OR = 4.64; 95% CI = 3.74-5.76; P < 0.001) and year 2 (OR = 2.26; 95% CI = 1.78-2.87; P < 0.001). Year 1 adjusted mean health care expenditures for the total NTMLD patient population were $72,475 (95% CI = $58,510-$86,440) and for the matched control population were $28,405 (95% CI = $8,859-$47,950), with a difference of $44,070 (95% CI = $27,132-$61,008; P < 0.001). Year 2 adjusted mean expenditures for the overall NTMLD patient group were $48,114 (95% CI = $31,722-$64,507) and for the matched control group were $28,990 (95% CI = $9,429-$48,552), with a difference of $19,124 (95% CI = $7,865-$30,383; P < 0.001).

Conclusions: Patients with NTMLD have a significantly greater risk of hospitalization and higher total health care expenditures than matched control patients without NTMLD.

Disclosures: This study was financially sponsored by Insmed. Marras reports fees from Insmed, Astra Zeneca, RedHill, and Horizon, all outside the current work. Mirsaeidi has nothing to disclose. Eagle, Q. Zhang, Chou, and Leuchars are employees of Insmed. R. Zhang is a contracted consultant at Insmed. The views expressed here are those of the authors and are not to be attributed to their respective affiliations.
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http://dx.doi.org/10.18553/jmcp.2018.18122DOI Listing
October 2018

Mycobacterium xenopi Genotype Associated with Clinical Phenotype in Lung Disease.

Lung 2018 04 18;196(2):213-217. Epub 2018 Jan 18.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.

Mycobacterium xenopi is responsible for pulmonary disease (PD) in Europe and Canada. Despite its high prevalence and increasing clinical importance, little is known about the genetic diversity of M. xenopi. Through a prospective study for M. xenopi strain type and the relation to clinical phenotype, 39 patients with M. xenopi PD were analyzed. Our study demonstrated that sequence type (ST) 5 was dominant in Ontario among 15 distinct STs and caused PD in people even without underlying lung disease, whereas disease due to non-ST5 was found almost exclusively in patients with underlying lung disease.
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http://dx.doi.org/10.1007/s00408-018-0087-9DOI Listing
April 2018

Pulmonary versus Nonpulmonary Nontuberculous Mycobacteria, Ontario, Canada.

Emerg Infect Dis 2017 11;23(11):1898-1901

In Ontario, Canada, during 1998-2010, nontuberculous mycobacteria (NTM) from pulmonary sites comprised 96% of species/patient combinations isolated; annual rates of isolation and cases increased steadily. NTM isolates from nonpulmonary sites comprised 4% of species/patient combinations; annual rates and cases were temporally stable. NTM increases were driven exclusively by pulmonary isolates and disease.
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http://dx.doi.org/10.3201/eid2311.170959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652412PMC
November 2017

Incidence and Risk Factors for Nontuberculous Mycobacterial Infection after Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2018 02 3;24(2):366-372. Epub 2017 Oct 3.

Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Allogenic hematopoietic stem cell transplant (HCT) recipients are at risk of many infections. Nontuberculous mycobacteria (NTM) are increasingly recognized as clinically significant pathogens in this population. We investigated the incidence and risk factors for NTM infection after allogeneic HCT. This retrospective cohort study included all patients with allogeneic HCT at our institution during 2001 to 2013. Patients who developed significant NTM infection (NTM disease) were identified. Multivariable modeling was used to identify risk factors for NTM disease, and a risk score model was constructed to identify high-risk patients. Of 1097 allogeneic HCT patients, 45 (4.1%) had NTM isolated and 30 (2.7%) had NTM disease (28 [93.3%] exclusively pulmonary, 2 [6.7%] pulmonary plus another site). Incidence of NTM infection by competing risk analysis was 2.8% at 5 years (95% CI, 1.9% to 4.0%). The median time to diagnosis was 343 days (range, 19 to 1967). In Fine-Gray proportional hazards modeling, only global severity of chronic graft-versus-host disease (cGVHD) (HR, 1.99; 95% CI, 1.12 to 3.53; P = .019,) and cytomegalovirus (CMV) viremia (HR, 5.77; 95% CI, 1.71 to 19.45; P = .004) were significantly associated with NTM disease. Using these variables a risk score was calculated: 1 point for CMV viremia or moderate cGVHD and 2 points for severe cGVHD. The score divided patients into low risk (0 to 1 points, n = 820 [77.3%], 3-year NTM risk 1.2%), intermediate risk (2 points, n = 161 [15.4%], 3-year NTM risk 7.1%), and high risk (3 points, n = 56 [5.4%], 3-year NTM risk 14.3%). NTM disease after allogeneic HCT is common. Severe cGVHD and CMV viremia are associated with increased risk, permitting risk stratification.
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http://dx.doi.org/10.1016/j.bbmt.2017.09.015DOI Listing
February 2018

The risk of mycobacterial infections associated with inhaled corticosteroid use.

Eur Respir J 2017 09 20;50(3). Epub 2017 Sep 20.

Division of Respirology, Dept of Medicine, University of Toronto, Toronto, ON, Canada.

Inhaled corticosteroid (ICS) use is associated with an increased risk of pneumonia. This study was performed to determine if ICS use is associated with an increased risk of nontuberculous mycobacterial pulmonary disease (NTM-PD) or tuberculosis (TB).We conducted a population-based nested case-control study using linked laboratory and health administrative databases in Ontario, Canada, including adults aged ≥66 years with treated obstructive lung disease ( asthma, chronic obstructive pulmonary disease (COPD) or asthma-COPD overlap syndrome) between 2001 and 2013. We estimated odds ratios comparing ICS use with nonuse among NTM-PD and TB cases and controls using conditional logistic regression.Among 417 494 older adults with treated obstructive lung disease, we identified 2966 cases of NTM-PD and 327 cases of TB. Current ICS use was associated with NTM-PD compared with nonuse (adjusted OR (aOR) 1.86, 95% CI 1.60-2.15) and was statistically significant for fluticasone (aOR 2.09, 95% CI 1.80-2.43), but not for budesonide (aOR 1.19, 95% CI 0.97-1.45). There was a strong dose-response relationship between incident NTM-PD and cumulative ICS dose over 1 year. There was no significant association between current ICS use and TB (aOR 1.43, 95% CI 0.95-2.16).This study suggests that ICS use is associated with an increased risk of NTM-PD, but not TB.
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http://dx.doi.org/10.1183/13993003.00037-2017DOI Listing
September 2017

Bleomycin pulmonary toxicity does not adversely affect the outcome of patients with Hodgkin lymphoma.

Leuk Lymphoma 2017 11 15;58(11):2607-2614. Epub 2017 May 15.

d Medical Oncology and Hematology , Princess Margaret Cancer Centre , Toronto , Canada.

Bleomycin pulmonary toxicity (BPT) is a well-described complication of bleomycin-containing regimens. Previous data on risk factors and the impact of BPT on survival in Hodgkin lymphoma (HL) were conflicting. We reviewed 253 HL patients treated with adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) at the Princess Margaret Hospital from 1999 to 2009 to examine the incidence and risk factors for BPT, and the effect of BPT on survival. BPT was defined by pulmonary symptoms, bilateral interstitial infiltrates on computed tomography, and the absence of infection. Kaplan-Meier estimates were used to compare overall survival (OS) and progression-free survival (PFS) between groups. The incidence of BPT was low (11%). Age ≥45 (OR = 2.5) and granulocyte colony-stimulating factor use (OR = 3.6) were identified as predictors of BPT on multivariable logistic models. At a follow-up of 5 years, OS and PFS were 88% and 82%, respectively. Neither BPT nor bleomycin discontinuation had significant impact on survival outcomes.
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http://dx.doi.org/10.1080/10428194.2017.1307980DOI Listing
November 2017

Long-Term Outcomes in a Population-based Cohort with Respiratory Nontuberculous Mycobacteria Isolation.

Ann Am Thorac Soc 2017 07;14(7):1120-1128

1 OHSU-PSU School of Public Health, Oregon Health & Science University, Portland, Oregon.

Rationale: The natural history of nontuberculous mycobacteria (NTM) respiratory infection in the general population is poorly understood.

Objectives: To describe the long-term clinical, microbiologic, and radiographic outcomes of patients with respiratory NTM isolates.

Methods: We previously identified a population-based cohort of patients with respiratory NTM isolation during 2005-2006 and categorized patients as cases or noncases using the American Thoracic Society/Infectious Diseases Society of America pulmonary NTM disease criteria at that time. During 2014-2015, we reviewed medical charts of patients alive on January 1, 2007. Outcomes of interest were the proportion of baseline noncases who later met case criteria and the proportions of patients with culture conversion or findings consistent with persistent disease at least 2-5 years and at least 5 years after first isolation. We defined disease persistence radiographically as infiltrate, nodules, or cavities and microbiologically as a positive respiratory mycobacterial culture. We used logistic regression to evaluate factors associated with evidence of persistence.

Results: The study included 172 patients (62% of 278 eligible); those not included either refused consent (n = 47) or were not located (n = 56). One hundred two (59%) included patients met case criteria at baseline. Mycobacterium avium complex was commonly isolated among baseline cases (n = 91 [89%]) and noncases (n = 52 [74%]). Overall, 57 (55%) baseline cases had died, as compared with 43 (61%) noncases (P = 0.47). Among baseline noncases, only four (5.7%) later met case criteria. Overall, 55 (54%) baseline cases and 6 (9%) noncases initiated NTM treatment. Among cases, cultures were converted in 25 (64.1%) treated versus 4 (40%) untreated patients (P = 0.04). Of 89 cases alive 2 years after isolation, 61 (69%) had additional radiography, and 35 (39%) had respiratory cultures. Of these individuals, 54 (89%) had radiographic evidence and 17 (49%) had microbiologic evidence of disease persistence. At 5 years after first isolation these figures were 36 (82%) and 13 (54%), respectively. Women were more likely to have persistent radiographic findings and microbiologic persistence, and patients with chronic obstructive pulmonary disease were less likely to have microbiologic persistence.

Conclusions: In the general population, follow-up beyond 2 years of patients with respiratory NTM isolation is limited. Among those with additional evaluations, at least half of individuals have persistent positive cultures or radiographic findings consistent with NTM at least 2 years after isolation.
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http://dx.doi.org/10.1513/AnnalsATS.201610-801OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566291PMC
July 2017

Pulmonary Nontuberculous Mycobacteria-Associated Deaths, Ontario, Canada, 2001-2013.

Emerg Infect Dis 2017 03;23(3):468-476

Survival implications of nontuberculous mycobacterial pulmonary disease (NTM-PD) and NTM pulmonary isolation without disease (NTM-PI) are unclear. To study deaths associated with NTM-PD and NTM-PI and differences in survival between them, we conducted a population-based cohort study of persons with microbiologically defined NTM-PD or NTM-PI diagnosed during 2001-2013 in Ontario, Canada. We used propensity score matching and Cox proportional hazards models to compare survival. Among 9,681 NTM-PD patients and 10,936 NTM-PI patients, 87% and 91%, respectively, were successfully matched with unexposed controls. Both NTM-PD and NTM-PI were associated with higher rates of death for all species combined and for most individual species. Compared with NTM-PI, NTM-PD was associated with higher death rates for all species combined, Mycobacterium avium complex, and M. xenopi. NTM-PD and NTM-PI were significantly associated with death, NTM-PD more so than NTM-PI.
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http://dx.doi.org/10.3201/eid2303.161927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382758PMC
March 2017

Patient-Centered Research Priorities for Pulmonary Nontuberculous Mycobacteria (NTM) Infection. An NTM Research Consortium Workshop Report.

Ann Am Thorac Soc 2016 09;13(9):S379-84

13 Division of Infectious Diseases, Public Health, and Preventive Medicine, Oregon Health & Science University, Portland, Oregon.

Nontuberculous mycobacteria (NTM) cause an increasingly important chronic and debilitating lung disease in older adults. Diagnosis is often delayed, although awareness among clinicians and patients is increasing. When necessary, treatment often lasts 18-24 months and consists of three or four antibiotics that can have serious side effects. Relapses are common and commonly require resumption of prolonged therapy. Given the need for improved diagnostic techniques and clinical trials to identify new therapies or to improve existing therapies, a group of North American clinicians and researchers formed the NTM Research Consortium (NTMRC) in 2014. The NTMRC recognized the importance of including the patient voice in determining research priorities for NTM. In November 2015, patients, caregivers, patient advocates, clinical experts, and researchers gathered for a 1-day meeting in Portland, Oregon funded by the Patient-Centered Outcomes Research Institute. The meeting goal was to define patient-centered research priorities for NTM lung infections. Patients expressed frustration with the number of people who have endured years of missed diagnoses or inadequate treatment of NTM. Participants identified as top research priorities the prevention of NTM infection; approval of more effective treatments with fewer side effects and easier administration; understanding the best chest physiotherapy methods; validating and using tools to measure quality of life; and developing a disease-specific activity and severity assessment tool. Workshop participants agreed that two complementary objectives are critical to ensure the best achievable outcomes for patients: (1) additional clinician education to improve screening and diagnosis of NTM infections; and (2) development of a geographically distributed network of experts in NTM disease to offer consultation or direct therapy after a diagnosis is made.
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http://dx.doi.org/10.1513/AnnalsATS.201605-387WSDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461946PMC
September 2016