Treatment outcome definitions in nontuberculous mycobacterial pulmonary disease: an NTM-NET consensus statement

Discussion

To improve the quality in reporting and enable meta-analyses of clinical studies, we are now proposing consensus definitions for key outcome parameters to be used in the treatment of NTM-PD. These definitions can also aid in the design of future clinical trials for new treatment regimens.

Consensus on the definition for cure proved hardest to obtain due to the risk of reinfection in patients with NTM-PD. For other diseases, including tuberculosis (TB), the term “cure” is reserved for patients remaining disease-free for a specified period after the end of treatment [6, 7]. For NTM this is more complicated; (clinical) cure is based on a decrease in, rather than full resolution of, symptoms, because of underlying lung diseases and exposure to the causative agents is likely commonplace owing to their ubiquity in the environment [1, 2]. Typing tools to distinguish relapses from reinfections and thus to offer feedback on treatment effect are not widely available yet and have not been standardised and validated [8]. Hence, for now, adding a disease-free period after treatment cessation to define cure did not obtain a majority of expert votes. Aware of this limitation, we propose to use the end of treatment as the moment to define cure. In the future, with validated biomarkers of disease and tools for strain typing, the definition of cure may include a period of disease-free survival with negative cultures.

There was very high agreement for definitions other than for cure, although the vote in step 3 did not always yield a clear favourite. Some draft definitions varied only in details (e.g. one or two positive cultures; table 1); in absence of any evidence in favour of either option, having agreed-upon definitions was perhaps considered as important as their exact details.

Applying these definitions, a single positive culture after culture conversion does not yet mean treatment failure. This stresses the importance of requesting repeated follow-up cultures after culture conversion and end of treatment. Sputum induction or bronchoscopy, perhaps with computed tomography imaging for guidance, may be required to obtain good quality respiratory specimens to determine treatment outcome. Essentially, a single positive culture after culture conversion equals that of a single positive culture at the time of first diagnosis [2].

The next challenge is how to convert these definitions into uniform clinical practice. A pressing issue is what to do when patients meet the definition for failure. Is that the point when a switch to a second-line regimen is warranted? The timing set out in the current definition, after 12 months of treatment, may be regarded by some to be too conservative. One may question whether it is ethical to wait that long in patients still culture positive after 6 months of guideline-compliant NTM-PD treatment. In addition, this timing aspect may be different for disease caused by different NTM species or for different disease manifestations, i.e. fibro-cavitary disease versus nodular-bronchiectatic disease. In multidrug-resistant TB, a manifestation of TB that shares similar features to NTM-PD in respect to management, adverse events of therapy, prognosis and costs, a positive culture status at 6 months of therapy has recently been suggested to define failure [9]. The recent study on semi-quantitative cultures to monitor treatment effect suggests that a lack of microbiological response after 6 months of treatment is a very accurate predictor of treatment failure (non-response) at 12 months and beyond [10], and this time point has thus been chosen in ongoing clinical trials in failing patients [4]; on the other hand, culture conversion after month 6 certainly does occur [11, 12].

Proper use of these outcome definitions does set requirements for standards of care for NTM-PD patients. For example, to effectively monitor culture conversion and (microbiological) cure requires submission of multiple good-quality sputum samples, but may also require computed tomography (CT) imaging and guided bronchoscopy for bronchoalveolar lavage (BAL) specimens, at set times during and after the entire course of treatment. Also, monitoring improvement in symptoms and signs to establish clinical cure requires the use of validated instruments to measure these. The recent recommendations on diagnosis and treatment of NTM-PD in cystic fibrosis patients provide pragmatic schemes to set these standards [3]. Nonetheless, standards of care specific to NTM-PD and relevant to all patients would still be helpful.

These definitions and the process by which they were set have some important limitations. First, these definitions result from a debate that included expert pulmonologists, infectious disease physicians, microbiologists and a patient representative. Thus, the process and its outcomes are based on expert opinion rather than a systematic review of the literature, a shortcoming also noted for the TB-NET document [4] from which the methodology was derived [13]. This methodology was chosen for its pragmatism, in a field devoid of data to support weighing of relevance of outcomes based on systematic review. This method also introduces selection bias as most members of this NTM-NET committee are in frequent contact and this may have already introduced uniformity in the definition and use of outcome parameters; also, four panel members joined after the initial drafting, hence could only vote, not draft. Second, these outcome definitions reflect the outcomes of current treatment regimens. With the advent of new treatment modalities for NTM-PD, including new antibiotics, time to sputum culture conversion may be shortened and this could affect the definition of treatment failure. Third, in the absence of other validated biomarkers for treatment response, these definitions rely heavily on culture of respiratory specimens. This is problematic in patients who do not produce sputum and may require CT imaging, guided bronchoscopy and the acquisition of BAL fluid specimens to determine culture conversion and cure, as stated in the recent British Thoracic Society guidelines on NTM-PD management [14]. Non-culture-based biomarkers for diagnosis and treatment response remain urgently needed. Radiological improvement as a marker is helpful but does not, by definition, follow the clinical and microbiological response to treatment [15, 16]. Fourth, molecular detection of NTM directly in clinical specimens is still not commonplace, but is likely to become routine in the upcoming years [17]. The interpretation of its results and how these affect current outcome definitions should be subject of future studies. Last, for many (especially retrospective) studies, the data gathered will not allow use of all outcomes defined here. For example, the distinction of recurrences into relapses and reinfections requires molecular typing data.

In summary, we have achieved international expert consensus on treatment outcome definitions for NTM-PD, using a five-round drafting and voting process. There was very high agreement among experts for all outcome definitions with the exception of the definition for cure. Definitions will need to be re-evaluated when more longitudinal clinical data on NTM-PD become available. We encourage the application of these definitions in both clinical management and in future studies and their design. Uniform outcome measures and reports will facilitate meta-analyses of trials and case series, which in turn will increase the quality of evidence available to support treatment regimens for these difficult-to-treat infections.