Julie V. Philley

Semiquantitative Culture Analysis during Therapy for Mycobacterium avium Complex Lung Disease

RATIONALE Microbiologically based criteria such as sputum culture conversion to negative have traditionally been used to define treatment success for mycobacterial diseases. There are, however, limited data regarding whether nontuberculous mycobacterial sputum culture conversion or semiquantitative culture analysis correlates with subjective or nonmicrobiologic objective indices of treatment response. OBJECTIVES To determine whether a semiquantitative mycobacterial culture scale correlated with clinical disease status and was predictive of long-term sputum mycobacterial culture conversion to negative in a cohort of patients with nodular/bronchiectatic Mycobacterium avium complex lung disease undergoing therapy. METHODS One hundred and eighty patients undergoing standard macrolide-based therapy for M. avium complex lung disease were monitored at standard frequent intervals with symptomatic, radiographic, and microbiologic data collected, including semiquantitative mycobacterial culture analysis. Analyses were used to evaluate clinical and microbiologic predictors of long-term sputum conversion to culture negative. MEASUREMENTS AND MAIN RESULTS After 12 months of therapy, 148 (82%) patients had sputum conversion to culture negative. Baseline semiquantitative sputum culture scores did not differ between patients with sputum conversion and those without. The change in sputum culture semiquantitative score from baseline to Month 3 was highly predictive of subsequent sputum long-term conversion status indicative of treatment success, as was improvement in cough, and especially early radiographic improvement. CONCLUSIONS Early semiquantitative sputum agar plate culture results can be used to predict symptomatic and radiographic improvement as well as long-term sputum culture conversion to negative in this population. We suggest that semiquantitative sputum culture scores can be a useful tool for evaluating new nontuberculous mycobacterial lung disease therapies.

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

Rationale: Improved therapeutic options are needed for patients with treatment‐refractory nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex (MAC). Objectives: 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. Methods: 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. Measurements and Main Results: Enrolled patients (ALIS + GBT, n = 224; GBT‐alone, n = 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; P < 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. Conclusions: 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).

Exosome secretome and mediated signaling in breast cancer patients with nontuberculous mycobacterial disease

Bronchiectasis Nontuberculous mycobacterium (NTMnb) infection is an emerging health problem in breast cancer (BCa) patients. We measured sera exosome proteome in BCa-NTMnb subjects and controls by Mass Spectroscopy. Extracellular matrix protein 1 (ECM1) was detected exclusively in the circulating exosomes of 82% of the BCa-NTMnb cases. Co-culture of ECM1+ exosomes with normal human mammary epithelial cells induced epithelial to mesenchymal transition accompanied by increased Vimentin/CDH1 expression ratio and Glutamate production. Co-culture of the ECM1+ exosomes with normal human T cells modulated their cytokine production. The ECM1+ exosomes were markedly higher in sera obtained from BCa-NTMnb subjects. Exclusive expression of APN, APOC4 and AZGP1 was evident in the circulating exosomes of these BCa-NTMnb cases, which predicts disease prevalence independent of the body max index in concert with ECM1. Monitoring ECM1, APN, APOC4 and AZGP1 in the circulating exosomes could be beneficial for risk assessment, monitoring and surveillance of BCa-NTMnb.

Impulse Oscillometry and Bronchiectasis. We Still Haven’t Found What We’re Looking For?

When we ask patients whether they have ever heard the term “bronchiectasis,” the typical response is “Yes, but I don’t know what it is,” unfailingly followed by, “Can you spell it for me?” After intense and animated explanation, the next questions that inevitably follow are, “How did I get this, and how long have I had it?” The answer to the first question is all too often not forthcoming. We confidently answer the second question for most patients with, “a long time,” but we really cannot know that with certainty for individual patients because there is no mechanism for identifying early bronchiectasis before it is symptomatically and radiographically manifest. Bronchiectasis is the final common pathway of multiple pathophysiologic processes, all of which are associated with intense and/or chronic bronchial inflammation (1, 2). Some patients have identifiable predisposing factors. We are, however, unable to identify the underlying cause of the bronchiectasis in approximately half of our patients with adult non-cystic fibrosis bronchiectasis presumably because of our ignorance of where and how to look for that underlying cause. For the majority, we cannot determine when anatomic changes began or when in their course they progressed sufficiently to be radiographically detectable or cause symptoms, although it is axiomatic that this process takes a very long time. Bronchiectasis was historically not widely recognized because there were few diagnostic options for identifying it. Performing bronchography entailed dumping barium into a patient’s lungs, which quite understandably explains clinicians’ hesitation to use this thankfully forgotten procedure. The emergence of bronchiectasis from the shadows parallels the development of chest computed tomography scanning, which facilitated the recognition of bronchiectasis in association with multiple processes, from mycobacterial infections to chronic obstructive and interstitial lung diseases (3–6). The overall understanding of bronchiectasis has unfortunately not kept pace with our improved ability to identify it. Although, by necessity, we have focused attention on therapeutic considerations, our treatment strategies remain rudimentary. Even as inadequate as our treatment efforts are, they are still far beyond our ability to describe fundamental aspects of bronchiectasis epidemiology, pathophysiology, and natural history (1, 2, 7, 8). The major impediment to progress in these areas is the lack of an inexpensive, noninvasive diagnostic tool with adequate sensitivity to detect early bronchial changes that could be used to screen large populations. In this month’s issue of AnnalsATS, Guan and colleagues (pp. 657–665) report their findings comparing impulse oscillometry (IOS) values with clinical parameters in 100 patients with bronchiectasis compared with 28 healthy subjects (9). The IOS apparatus generates pressure oscillations at the mouth that propagate via movement of the air column in the conducting airways, which is followed by distension and recoil of the elastic components of lung tissues and creation of backpressure. Low-frequency signals (5 Hz) penetrate to the lung periphery, whereas high-frequency signals (20 Hz) only reach the proximal airways. When distal airway obstruction occurs, R5 (resistance measured at 5 Hz) and X5 (reactance measured at 5 Hz) may be increased. Higher-frequency oscillations, such as 20 Hz, transmit signals proximally to identify central airways obstruction, whereas disease isolated to the distal airways will increase R5 to a greater extent than the R20. IOS is almost independent of patient effort and cooperation, and therefore can be applied to a larger age range than spirometry. In the study by Guan and colleagues, IOS parameters readily discriminated bronchiectasis patients from healthy subjects but were not superior to the diagnostic performance of spirometry. In steady-state bronchiectasis, but not with bronchiectasis exacerbations, IOS parameters were also stratified by clinical indices and significantly correlated with clinical parameters including computed tomography scan and spirometric findings. The authors noted that any single IOS parameter being abnormal was a more sensitive marker for mild bronchiectasis than FEV1, likely because IOS parameters, but not FEV1, reflected preferentially on peripheral airway abnormalities. All patients in this study had symptoms and radiographic abnormalities consistent with bronchiectasis. IOS did not provide additional diagnostic sensitivity to the constellation of tests already available, and specifically was not superior to spirometry. What is needed is a technique more sensitive than spirometry for detecting early bronchiectasis-related changes, which presumably are heralded by peripheral

Reply: Cure Not Possible, by Definition

1. Griffith DE, Adjemian J, Brown-Elliott BA, Philley JV, Prevots DR, Gaston C, Olivier KN, Wallace RJ Jr. Semiquantitative culture analysis during therapy for Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2015:192:754–760. 2. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, et al.; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367–416. 3. Olaru ID, Heyckendorf J, Grossmann S, Lange C. Time to culture positivity and sputum smear microscopy during tuberculosis therapy. PLoS One 2014;9:e106075. 4. Lee BY, Kim S, Hong Y, Lee SD, Kim WS, Kim DS, Shim TS, Jo KW. Risk factors for recurrence after successful treatment of Mycobacterium avium complex lung disease. Antimicrob Agents Chemother 2015;59:2972–2977. 5. Boyle DP, Zembower TR, Reddy S, Qi C. Comparison of clinical features, virulence, and relapse amongMycobacterium avium complex species. Am J Respir Crit Care Med 2015;191:1310–1317. 6. Wallace RJ Jr, Brown-Elliott BA, McNulty S, Philley JV, Killingley J, Wilson RW, York DS, Shepherd S, Griffith DE. Macrolide/azalide therapy for nodular/bronchiectatic Mycobacterium avium complex lung disease. Chest 2014;146:276–282.

Disease Caused by Mycobacterium Abscessus and Other Rapidly Growing Mycobacteria (RGM)

Rapidly growing mycobacteria (RGM) are divided into six major groups including the two clinically most important groups, M. chelonae/M. abscessus complex and Mycobacterium fortuitum group. This chapter discusses infections associated with these groups with an emphasis on pulmonary disease. Phenotypic and molecular laboratory identification methods are reviewed as accurate organism identification is necessary for optimal RGM lung disease patient management. Antimicrobial susceptibility patterns for the most common pathogenic RGM species are discussed with an emphasis on the impact of inducible macrolide resistance found in many RGM species and subspecies. Because of antibiotic resistance, the RGM are frequently difficult to treat successfully. Current therapeutic approaches are reviewed with an emphasis on antibiotic options in the context of both innate and acquired antibiotic resistance.