Microbiological outcome of interventions against pulmonary MAC disease: A systematic review

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1 Accepted Manuscript Microbiological outcome of interventions against pulmonary MAC disease: A systematic review R. Diel, A. Nienhaus, F. Ringshausen, E. Richter, T. Welte, K.F. Rabe, R. Loddenkemper PII: S (18) DOI: /j.chest Reference: CHEST 1537 To appear in: CHEST Received Date: 18 October 2017 Revised Date: 20 December 2017 Accepted Date: 12 January 2018 Please cite this article as: Diel R, Nienhaus A, Ringshausen F, Richter E, Welte T, Rabe K, Loddenkemper R, Microbiological outcome of interventions against pulmonary MAC disease: A systematic review, CHEST (2018), doi: /j.chest This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Microbiological outcome of interventions against pulmonary MAC disease: A systematic review Diel R 1,2, Nienhaus A 3,4, Ringshausen F 5, Richter E 6, Welte T 5, Rabe KF 2, Loddenkemper R 7 1 Institute for Epidemiology, University Medical Hospital Schleswig-Holstein, Kiel, Germany. 2 LungClinic Grosshansdorf, Germany. Airway Research Center North (ARCN), German Center for Lung Research (DZL) 3 Institute for Health Service Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 4 Institution for Statutory Accident Insurance and Prevention in the Health and Welfare Services (BGW), Hamburg, Germany Start, Germany 5 Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany. German Center for Lung Research (BREATH) 6 MVZ Labor Dr. Limbach, TB Laboratory, Heidelberg, Germany 7 German Central Committee Against Tuberculosis, Berlin, Germany Address for correspondence: Roland Diel, MD, MPH, Institute for Epidemiology, University Medical Hospital Schleswig-Holstein, Niemannsweg 11, Kiel, Germany. Mail: roland.diel@epi.uni-kiel.de Running Head: Microbiological outcome of interventions against MAC-PD Figures: 4 Tables: 6 Word count: Abstract: 249 Main text: 4159 Potential conflicts of interest: R.D. has received fees for lectures and/or consultancy 1

3 from Insmed, Bayer Healthcare and Riemser. F.R. reports grants, personal fees and other from Bayer Healthcare, Grifols Germany, Insmed and InfectoPharm. T.W. reports fees for lectures from Bayer, Basilea, Boehringer, GSK, Novartis and Pfizer. E. R. reports personal fees from Insmed. All other authors have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

4 Abstract Objective Pulmonary disease (PD) caused by Mycobacterium avium complex (MAC) is increasing worldwide. We conducted a systematic review of studies that include microbiological outcomes to evaluate current macrolide-based treatment regimens. Methods We searched literature published before April 2017 using MEDLINE, Cochrane, and EMBASE databases. Risk of bias in randomized trials was assessed using the Cochrane tool. Results 333 citations were retrieved and 42 studies including 2748 patients evaluated. 18 studies were retrospective chart reviews, 18 were prospective and 6 randomized. The weighted average proportion of sputum culture conversions in macrolidecontaining regimens after subtracting posttreatment microbiological recurrences was 52.3% (95% CI 44.7%-59.9%). Following ATS-recommended triple drug regimens achieved treatment success in 61.4% (95% CI 49.7%-72.5%). It further increased to 65.7% (95% CI 53.3%-77.4%) when drugs were taken for at least one year by macrolide susceptible and previousy untreated MAC-patients. The overall risk of bias was low in 5 of the 6 randomized trials. However, selective outcome reporting due to a posteriori exclusion of initially included patients (14.0%), uncompleted treatment (17.6%) and inconsistent use of outcome parameters (17 definitions of treatment success ) hampered the comparison of non-randomized trials. Conclusion To date, randomized studies on treatment outcome in MAC-PD patients are scarce. Long-term treatment of macrolide-susceptible patients with ATS-recommended regimens are superior to other macrolide-based therapies. A standardized definition of treatment success and genotypical distinction between reinfection and relapse by pre- and post-treatment identification of MAC-species in case of microbiological recurrences may help to optimize evaluation of treatment regimens in the future. 3

5 Abbreviations AE: Adverse events ATS: American Thoracic Society AMX: Amikacin AZT: Azithromycin BID: Two times daily BIW: Two times per week BN: Bronchiectatic nodules BR: Bronchiectasis CF: Cystis fibrosis CFX: Cefoxitin Cipro: Ciprofloxacin CLARI: Clarithromycin CFZ: Clofazimine CT: Computed tomography CXR: Chest x-ray examination EMB (E): Ethambutol EQ: EuroQOL Questionnaire FQ: Fluoroquinolones GFLX: Gatifloxacin GI: Gastrointestinal IV: Intravenously IQR: Interquartile range IM: Intramuscularly KM: Kanamycin LAI: Liposomal amikacin for inhalation LVFX: Levofloxacin LY: Life year LYG: Life year gained MAC: Mycobacterium avium complex MAC-PD: Pulmonary disease due to MAC MDR: Multi-drug resistant MAB: Mycobacterium abscessus

6 NB: Nodular Bronchiectasis NQ: New quinolones NTM: Nontuberculous mycobacteria PTS: Patients PZA: Pyrazinamide QOL: Quality of life PD: Pulmonary disease RIF (R): Rifampicin RBT: Rifabutin RCT: Randomized controlled trials SCC: Sputum Culture Conversion SF: Short Form Health Survey SM: Streptomycin SMX: Sulfamethoxazole SGRQ: St. George Respiratory Questionnaire TB: Tuberculosis TIW: Three times per week UTHTC: University of Texas Health Center at Tyler VNTR: Variable Number Tandem Repeat WHO: World Health Organization Introduction Non-tuberculous mycobacteria (NTM) have been isolated worldwide and comprise more than 160 validly described species, partly divided into several subspecies [1]. The frequency of pulmonary disease caused by NTM has been recognized as steadily increasing globally [2], [3], [4]. Apart from underlying genetic factors [5], preexisting lung diseases favor the development from inapparent infection to clinical disease [2]. In particular, cystic fibrosis (CF), bronchiectasis and chronic obstructive pulmonary disease are to blame [6], [7]. Of the NTM species commonly associated with pulmonary disease (PD), M. avium complex (MAC) that encompasses several subspecies including M. avium, M. intracellulare and M. chimaera is by far the most frequent [8], [9]. If left untreated, 5

7 MAC pulmonary disease (MAC-PD) can be progressive, especially in fibrocavitary forms which mostly involve the upper lobes [10] and result in extensive lung destruction and respiratory failure [2]. In untreated patients with chronic MAC-PD, a mortality rate of 33.3% was found, while the treated MAC patients demonstrated a 5- year mortality rate of 22.2% [11]. Although guidelines for management and treatment of NTM are available, including the ATS/IDSA guidelines [2] of 2007 or the older BTS guidelines [12], with an update of the latter expected before the end of 2017, the impact of MAC-PD still seems to be broadly underestimated. In Adjemian s recent representative survey [6] on 349 US physicians treating 915 patients with MAC or Mycobacterium abscessus (MAB), reported antibiotic regimens were consistent with the ATS/IDSA guidelines in only 15% of institutions. The gaping lack of compliance to guidelines may reveal not only frustration, as Adjemian herself suspected, but also uncertainty as to the effectiveness of the currently recommended regimens. To date, much work has been published on NTM epidemiology and on laboratory and clinical diagnostics. Our Medline search, however, revealed only three reviews reporting treatment outcome of pre-defined treatment regimens of pulmonary MAC patients. These included only 12 studies on macrolide-based treatment up to 2002 [13], 10 studies up to 2008 [14] and 16 studies up to 2016 [15], which, however, represent only a fraction of the studies on MAC-PD published in peer-reviewed journals. Thus, with the goal of providing more comprehensive evidence, we conducted an upto-date systematic review that includes the most recently published studies on microbiological outcome of MAC-PD without restriction to any intervention type, taking a qualitative approach. As the only drugs in which the in vitro susceptibility of isolates of Mycobacterium avium correlates with a clinical response are macrolides [16] (and amikacin) [17], only studies using macrolide-based regimens were considered in our review. Treatment outcome of studies using a combined therapy with macrolides (clarithomycin or azithromycin), ethambutol and a rifamycin as recommended by the ATS [2], was assessed separately. Methods Study search

8 We searched studies published in English, French, Italian, or Spanish through 31 March 2017 (see Supplement for details). Initially, all NTM species were included in our search criteria; our final selection, however, included only articles concerning individual MAC species for which a microbiological treatment outcome was reported. Assessment of study quality The systematic review was conducted according to the PRISMA guidelines [18]. Risk of bias in randomized studies was assessed using the Cochrane risk of bias tool [19]. Asessement of treatment outcome As to date there is no consistent definition of sputum culture conversion (SCC), we only considered conversion of sputum cultures under medication from positive to negative where the previously positive patient turned negative and remained negative throughout the course of follow-up in the respective study. Folllowing the approach of Field et al. [13] for achieving comparability between studies, we calculated average effects sizes by addressing the proportion of SCC and then subtracted subsequent microbiological recurrences, wherever sustained conversion was not explicitly stated by the authors. Results Figure 1 presents a flow-diagram of the literature search results. In the selection process, 333 journal abstracts were identified, of which 104 abstracts indicated eligibility for analysis and were read in full text. Finally, 42 studies published in peerreview journals were included for in-depth analysis and were deemed to be eligible to be included into the review (references 20-61). No unpublished studies showing outcome data were found in trial registers. Nine studies also included at least one patient infected with species other than MAC ([22], [33], [45], [47], [48], [49], [52], [61]). In Milanés-Virelles s study [45] the outcome of the two non-mac patients was not reported separately and transferred to the MAC infections. The excluded 291 studies are shown in the Annex together with the respective reasons for exclusion. 7

9 Origin of studies The therapy studies came from a total of 9 countries. Most were from the USA (15/41, 36.6%) 8 of which came from the University of Texas Health Center at Tyler (UTHCT) and Japan (15/41, 36.3%). Further source countries were South Korea (3), the UK (2), France (2), Canada (2), Taiwan (1), Cuba (1), and Australia (1) (see also the comprehensive Tables 1 and 2). Study participants A total of 2376 study participants with MAC-PD (mean 56.6 participants per study, IQR 45.5) established the final body of evaluation of the 42 included studies (see Table 1). However, 372 participants in total (13.5% of initially included 2748 participants) were excluded a posteriori by the authors from a total of 20 studies, due to a variety of reasons, prior to the establishment of final groups. The most common reasons were non-completion of treatment or non-compliance as reported in 11 studies, lost to follow-up (4 studies), and unavailability for follow-up visits (3 studies). Twenty-three of the 42 studies reported failure in 469 MAC participants (19.7%) to complete treatment after final inclusion as study members, predominantly due to adverse drug effects. In the overwhelming majority of the studies, known HIV infection was excluded a priori; only in the study of Wallace et al. (1994) [57], and Ye et al. [60], a small number of patients who tested HIV-positive received treatment (8 and 1 patients, respectively). Only in 15 of the 42 studies, or 35,7% [25, 29-31, 33, 34, 38-40, 46, 47, 52-55], comprising a total of 1004 patients, an ATS recommended therapy including at least a macrolide, ethambutol and a rifamycin [2] was administered from the start. Study design Eigthteen out of the total of 42 evaluated studies (42.9%) were retrospective chart reviews and 18 studies (42.9%) were prospective, but not randomized: [21], [23], [24], [26], [27] [29], [36], [37]) [39], [43], [47], [44], [49], [55], [50], [57-59]. Only 6 studies were randomized ([25], [33], [38], [45], [46] and [61]). Of these, 3 studies were double-blinded controlled studies: Kobashi et al. [38], Milanés-Virelles et al. [45] and Olivier et al. [61].

10 Duration of treatment The duration of treatment of MAC-PD patients varied greatly, from 3 months, e.g., in Leventhal s study [44], up to at least 24 months in the studies of Kobashi et al. [39], Murray et al. [47] and Jenkins et al. (2008) [33]. In 9 studies, treatment duration was reported to be 6 months [22, 26-28, 45] or less [23, 44, 57, 61]; in 16 studies overall (or at least for a separately notified proportion of patients) treatment duration was at least 12 months ([25], [29], [30], [33], [34], [37-40], [46], [47], [50], [52], [54], [55] and [68]. Prior treatment and drug susceptibility 611 patients with prior NTM treatment out of the total of 2376 MAC patients (25.7%) were identified in 24 of the 42 included studies (57.1%). In 3 studies a prior treatment was reported, but the number of those patients was not provided [57, 29, 33] and in 5 studies, information on whether MAC patients had ever been treated was not specified [31, 45, 47, 50, 53]. Only in seven studies [25, 30, 34, 40, 46, 54] were all patients previously untreated, their MAC isolates determined to be macrolide-susceptible prior to initiation of treatment and their outcome monitored through to the end of the respective studies. In Tanaka s study [55] 27 out of 33 fully or intermediately susceptible patients converted, but it remained unclear which of these remained culture negative. In Kobashi s study [39] the MIC was only measured in 48 out of 65 patients, of whom 3 patients were clarithromycin-resistant. Identification of subspecies In only 9 of 45 studies ([2024], [ ], [41 42], [55 54], [58 57]) were subspecies of the MAC complex determined to be present (M. intracellulare and/or M. avium). Subspecies M. chimaera was not identified in any of these therapeutic studies. Potential bias in randomized trials Jenkins et al. (2008) [33] compared clarithromycin (Clari) and ciprofloxacin (Cipro) as a third drug added to rifampicin (R) and ethambutol (E) using an open-label multicenter approach. Permuted blocks were used for randomization of patients 9

11 whose pulmonary disease was associated with one of the three species (MAC, Mycobacterium xenopi (MX) and M. malmoense) and no differences were observed in outcome between the REClari and the RECipro groups. Fujita s [25] open-label, randomized trial with full intention-to-treat analysis uses centralized service with sealed envelopes, thus minimizing risk of bias. In contrast, Miwa et al. [46] only stratified according to the presence of cavitation to gain balance between the two-drug and three-drug group, but did not provide any information on allocation schedule or concealment. Although an intention-to-treat analysis was performed, study results may be biased by the high proportion of non-compliers, especially due to adverse events (27 out of 59 patients, or 46.8%, and 20 out of 60 patients, or 33.3%, respectively, in both treatment arms), in terms of attrition bias, which could have influenced the lack of statistical significance with respect to treatment outcome. In the two double-blinded trials of Kobashi et al. [38] and Milanés-Virelles et al. [45] block-randomization with sealed envelopes or by creating a computer-generated random number list was performed. While there were no withdrawals in Kobashi s study, the proportion of 4 drop-outs among the 14 participants in the placebo group (29%) in Milanés-Virelles s study was clearly higher than the only two drop-outs among the 18 participants in the IFN-gamma group (11%). In intention-to-treat analysis, however, there was no impact in favor of the IFN-gamma group. Olivier et al. [61] in their phase II randomized, placebo-controlled trial evaluated a liposomal amikacin for inhalation (LAI). There, LAI or placebo had been administered once daily by an eflow nebulizer to a total of 57 treatment-refractory MAC patients. The technique of randomization used in the trial, however, and the number of patients who finally competed their LAI treatment, is not fully described and thus a potential bias cannot be judged at present. Thus, as shown in Table 3, the risk of bias among the few randomized studies was considered low or unclear in 5 and estimated as high in only one [46] of the studies. Definitions of treatment outcome Treatment success rather than cure was the most frequently used expression of a favorable study outcome. In fact, 17 mostly slightly, but also substantially different definitions were found which were used in 22 studies (see Table 4). According to the definition of some studies, microbiological recurrences have again to be subtracted

12 from the final number of patients gaining success, while according to other studies treatment success could already be considered if a small treatment period in which SCC could be gained was fulfilled. Only in 6 of the 22 studies where definitions could be retrieved ([29], [34], [41], [42], [47] and [59]), the ATS success criterion of 12 months of sputum culture negativity while on therapy [2] was fully met. Although in 22 of the 42 studies relapses were reported (Table 2), it remains unclear for the most part whether these newly appearing isolates represented true relapses or new infections. Only in the studies of Wallace et al. [57, 59] and Olivier et al. [61] were MAC species before SCC and newly appearing isolates after SCC compared by DNA genotyoping. There, the emergence of a newly positive culture was considered as a relapse if the results of pulsed-field gel electrophoresis [57, 59] or of variablenumber of tandem repeat (VNTR) analysis [61] between pre- and posttreatment strains were identical. To render comparable the results of all the studies, including those in which no genotyping was performed, we considered recurrent isolates as relapses wherever they were declared to be relapses by the authors themselves. Quality of life Only two studies reporting both microbiological outcomes of intervention and QOL could be retrieved for MAC-PD: Leventhal et al. [44] demonstrated that in a shortcourse of clarithromycin-containing three-drug therapy, the symptom scores on the SGRQ improved after three-month treatment completion in 10 of the 12 patients (80%) compared with baseline. There was also an improvement on the mental subscale score, but not on the physical subscale score of the SF-12 questionnaire at 6 months. Olivier et al. [61] summarized changes in QOL at each visit (day 1, 28, 56 and 84), by treatment arm, in non-cf subjects and assessed post-hoc correlations between the change from baseline in the St. George Respiratory Questionnaire (SGRQ) and a QOL-Bronchiectasis-NTM Module at day 84. However, no significant difference between patients of the LAI and of the placebo group could be found. Surgery The outcome of local surgical resection of lung regions destroyed by MAC-PD was evaluated in 8 studies. The impact of that procedure is generally promising, but the reported number of patients who underwent surgery is quite low and appears to be significant only in three studies: Shiraishi et al. (2002) [51], Shiraishi et al. (2013) 11

13 [52], and Watanabe et al. [56] achieved 100% sputum-negativity by surgery with or without adjunctive postoperative therapy in 21, 55 and 22 MAC patients, respectively. In contrast, in Wallace s study (1996) [58] only three patients who remained sputumpositive in long-term treatment received surgery, of those one died in the intermediate postoperative period and two converted. In Griffith s study (1998) [27] all 4 surgical patients converted. In Sim s study [54] surgical resection was performed in 8 (8%) out of a total of 96 patients, and of those, culture conversion was achieved in six. In Koh s study [42], three out of four persistently culture-positive patients who underwent resection achieved cure and in Jarand s study [32] three patients underwent resection and converted to negative after surgery, but one had a relapse one year later. Radiological manifestations MAC-PD generally shows upper lobe cavities (fibrocavitary form) or multiple small nodules in patients with multifocal nodular bronchiectasis (nodular-bronchiectatic form). Three studies (Griffith et al. (1998) [27], Field et al. [24], and Shimomura et al. [53]) did not describe radiological manifestations, in the remaining 39 studies there were in total 983 cavities reported and 1184 nodular bronchiectasis (NB). However, treatment success in these studies was difficult to compare with respect to radiologicial features, as in 25 studies nodular-bronchiectatic and fibrocavitary disease were analyzed together. Of note, only in 19 studies the radiological manifestations were assessed by computed tomography (see table 1), thus probably resulting in an underestimation of nodular-bronchiectatic lesions. Only 8 studies compared treatment success or mortality with respect to radiological manifestations: Wallace et al. [57], Roussel et al. [50] and Koh et al. [41] found no statistical difference between macrolide responders and non-responders with respect to cavitation; in Tanaka et al. [55], Ye et al. [60], Sim et al. [54] and Ellender et al. [22], no difference in sustained SCC was shown with respect to presence or nonpresence of NB or cavities. In contrast, Lam et al. [43] demonstrated that having noncavitary disease increased conversion rate by four times. Reported deaths The number of patients who died specifically as result of their underlying pulmonary MAC disease was surpringly low, with a total of 58 reported deaths, or 2.4%, among

14 the 2376 finally evaluated MAC patients. A total of 60 patients, or 2.5%, died from unrelated diseases throughout the considerably varying treatment durations and/or follow-up periods of the respective studies. Weighted treatment outcome Across all studies, in MAC-PD patients treated with a macrolide-containing regimen the pooled rate of SCC without relapse as a surrogate of treatment success was 52.8% (95% CI; 45.5% to 60.1%, see Figure 2). However, there was considerable heterogeneity between the studies (I² [inconsistency] 92.3% [95% CI; 90.8% to 93.4%]). When the average effect size of those 15 studies in which all patients were treated with an ATS recommended regimen was calculated, pooled treatment success clearly increased to 61.4% (95% CI; 49.7% to 72.5%, see Figure 3). Further modifying the analysis of ATS recommended regimens for at least 12 months including macrolide susceptible patients who had not been treated previously gained pooled treatment success in even 65.7% (95% CI 53.3% to 77.4%, see Figure 4). However, only seven studies including 494 patients provided that information and could be included, and in Kobashi s study [40] all patients were clarithromycin susceptible but resistant to ethambutol (and streptomycin). New treatment perspectives Davis et al. [20], Olivier et al. [48] and Philley et al. [49] used inhalational (but not liposomal) AMX in off-label use, in the latter study together with azithromycin (AZT) and bedaquiline, if systemic application of amikacin was not tolerated. However, the number of MAC patients receiving aerosolized AMX regimens was not shown in Philley s study and was very small in the studies of Davies et al. [20] and Oliver et al. [48], comprising only 6 and 5 patients, respectively. In view of this insufficient number of participants, Olivier et al. [61] described promising results in a larger series of 57 MAC-PD patients as members of a randomized, placebo-controlled phase II trial evaluating liposomal amikacin for inhalation. There, 11 of 29 (37.9%) patients with liposomal amikacin achieved SCC at day 84, i.e, at the end of the double-blind treatment period, versus 3 of 28 patients (10.7%) on placebo. Of note, nine of those 11 patients in the LAI arm who had SCC 13

15 at day 84, remained also converted 12 months later versus 2 out of the 3 patients with placebo in an intention-to-treat approach. Discussion A steady rise in the prevalence of pulmonary disease caused by NTM, especially by MAC, is being noted worldwide and thus deserves increasing awareness. An epidemiological analysis on NTM in England, Wales and Northern Ireland demonstrated a doubling of the incidence of MAC-PD among men and women in 2012 compared to 2007 [62], continuing the previously reported trend [63]. Diel et al., in their recent burden- of- illness study, found that NTM-PD patients in Germany had a 3.6-fold increased risk of death during the 3-year follow up period relative to matched controls [64]. The introduction of macrolides (clarithromycin or AZT) in 1994 as components of multi-drug regimens has markedly improved the treatment outcome of MAC-PD, but sustained microbiological sputum conversion is often elusive. In our actual analysis based on 42 studies with macrolide-containing regimen overall treatment success in a total of finally evaluated 2376 MAC-PD did not exceed 52.3% (95% CI 44.7% to 59.9%), indicating that any macrolide-containing regimen is not sufficient, especially if patients are kept on drugs for less than 12 months, as it was the case in the majority of the presented studies. In contrast, treatment success clearly increased when macrolide-based drug-intake was part of the triple therapy administered together with ethambutol and a rifamycin according to the current ATS guidelines [2]. There, the average treatment success increased by nearly ten percent to 61.4% (95% CI 49.7%-72.5%). Modifying the analysis to include only macrolide susceptible and previously untreated patients reveiving those regimens for at least 12 months would theoretically provide the most accurate data on MAC treatment response. Doing so, a five points better success rate of 65.7% (95% CI 53.3% to 77.4%) could be shown. Thus, although there is highly statistical heterogeneity between the analysed studies (as represented by an I 2 of 84.6% [95% CI; 67.5% to 90.8%]), treatment duration and pre-treatment susceptibility appear to be the key parameter in the complex efforts to fight MAC-PD. Importantly, these precious few seven studies [25, 30, 34, 40, 46, 54] that followed the ATS guidelines and explicitly determined pre-treatment macrolide susceptibility

16 may well underestimate the chances of favourable microbioogical outcome in this group of patients. Of note, most of the 42 studies included in our review are relatively small represented by a mean value of only 57 participants (IQR 45.5) and of the 6 available randomized trials addressing treatment of MAC-PD, only two studies (Jenkins et al. [33] and Kobashi et al. [38]) indeed included 170 and 146 patients, respectively. Therefore, it is difficult to make definitive statements about the superiority of one combination of drugs over the other for producing longterm sputum conversion. While the risk of bias was low in 5 of the 6 randomized studies, there was a considerable risk of sampling bias by a posteriori exclusion of potential study participants in many non-randomized studies: Selective outcome reporting due to a posteriori exclusion of initially included patients (14.0%) and uncompleted treatment of participants (17.6%) hampered the comparison of individual trials. Another variable complicating the interpretation of microbiologic outcome and recurrences in the various studies is the lack of agreed-upon definitions of outcome parameters. As described above, seventeen different definitions of treatment success were found in the 42 studies included, and in only 6 of these the ATS definition of treatment success was fulfilled ([29], [34], [41], [42], [47] and [59]). New drugs or new pharmaceutical formulations of old drugs, such as the evaluation of liposomal amikacin for inhalation described by Olivier et al. [61] in a series of 57 MAC-PD patients, may be of increasing importance in improving treatment of problematic or drug-resistant species. In this regard, researchers would benefit greatly from the long-overdue establishment of formulated requirements for study design on MAC treatment that in particular include uniform definitions of treatment success and cure. When substracting microbiological recurrences after treatment from SCC results as a proxy for treatment success it must be kept in mind that the authors assessment of relapse does not provide a clear distinction from reinfection as, with the exceptions of Wallace s [59] and Olivier s publications [61], no confirmation was attempted by genotyping. It is quite possible that without that distinction some patients may have been successfully treated, only then to become reinfected with different strains of MAC. This hampers considerably the comparison 15

17 of treatment outcome between studies. More importantly, that distinction may have an impact on future treatment decisions as patients with multiple true relapse MAC isolates are considered treatment failures and usually require treatment intensification [59]. Consequently, to avoid an underestimation of the impact of current MAC therapy and a widely held nihilism about MAC lung disease therapy in general [65], this type of analysis will likely be important in the future for comparing MAC treatment study results. Less clear than the impact of optimized medical regimens on microbiological outcome is that of pulmonary patterns: Only 8 studies compared treatment success with respect to the presence of fibrocavitary or nodular-bronchiectatic lesions as distinct radiological types but only in Lam s study [43] cavities were reported to have a negative influence on treatment response. Any asociations between pulmonary patterns and mortality as it has been observed for cavitary disease in the retrospective analyses of Hayashi et al. [62] and Gochi et al. [63] were not reported. Nevertheless, adequate treatment of underlying diseases, e.g., consistent therapy of COPD and stop of smoking, as requested by the ATS [2] and also by the German guideline [64] plays an important role, as it may improve the prognosis by achieving a better response to NTM treatment. This aspect was, however, only been indirectly mentioned in a few studies (e.g. [38], [40], [54]). Given the low number of six randomized studies in our review, further studies for assessing the treatment outcome of macrolide-based regimens are needed. These should preferably have a RCT design with a defined allocation procedure. In any case, studies have to be at least prospective in order to reduce bias, and must include a clear baseline definition of criteria for justifiable later exclusion of patients. To make study results comparable, the included patients (or at least a separated subgroup of those) should be treatment-naive and macrolid-susceptible. As the reponse to a specific therapy may differ between MAC subspecies, authors must characterize the subspecies and include genotyping of the cultured strains prior to and at the end of treatment. This will preclude subjective judgement on relapses. Duration of treatment should follow the ATS criteria (12 months after sputum negativity) and quality of life should be assessed through a respiratory illness

18 questionnaire, e.g. St George s Respiratory Questionnaire (SGRQ), at baseline and subsequently at each visit. Conclusion Long-term treatment of macrolide-susceptible patients with ATS-recommended regimens are superior to other macrolide-based therapies. A standardized definition of treatment success and genotypical distinction between reinfection and relapse by pre- and post-treatment identification of MAC-species in case of microbiological recurrences may help to optimize evaluation of treatment regimens in the future. To overcome treatment refractory MAC-PD, further research on new drugs is needed, but also on the best possible combination of already established drugs, especially where new applications are available. Particular attention should be given to proper and sufficiently powered study designs. Acknowledgments Author contributions: Dr Diel guarantees the integrity of the work. Dr Diel: contributed to study selection and review, conducted the statistical analysis, and wrote the manuscript. Dr. Loddenkemper, Dr. Rabe, Dr. Richter. Dr. Ringshausen and Dr. Welte: reviewed and amended the manuscript and approved the final decision for submission. Dr Nienhaus: contributed to study selection and review and approved the final decision for submission. 17

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