Abstract
Treatment of Mycobacterium abscessus pulmonary disease (MAB-PD), caused by M. abscessus subsp. abscessus, M. abscessus subsp. massiliense or M. abscessus subsp. bolletii, is challenging.
We conducted an individual patient data meta-analysis based on studies reporting treatment outcomes for MAB-PD to clarify treatment outcomes for MAB-PD and the impact of each drug on treatment outcomes. Treatment success was defined as culture conversion for ≥12 months while on treatment or sustained culture conversion without relapse until the end of treatment.
Among 14 eligible studies, datasets from eight studies were provided and a total of 303 patients with MAB-PD were included in the analysis. The treatment success rate across all patients with MAB-PD was 45.6%. The specific treatment success rates were 33.0% for M. abscessus subsp. abscessus and 56.7% for M. abscessus subsp. massiliense. For MAB-PD overall, the use of imipenem was associated with treatment success (adjusted odds ratio (aOR) 2.65, 95% CI 1.36–5.10). For patients with M. abscessus subsp. abscessus, the use of azithromycin (aOR 3.29, 95% CI 1.26–8.62), parenteral amikacin (aOR 1.44, 95% CI 1.05–1.99) or imipenem (aOR 7.96, 95% CI 1.52–41.6) was related to treatment success. For patients with M. abscessus subsp. massiliense, the choice among these drugs was not associated with treatment outcomes.
Treatment outcomes for MAB-PD are unsatisfactory. The use of azithromycin, amikacin or imipenem was associated with better outcomes for patients with M. abscessus subsp. abscessus.
Abstract
For Mycobacterium abscessus pulmonary disease in general, imipenem use is associated with improved outcome. For M. abscessus subsp. abscessus, the use of either azithromycin, amikacin or imipenem increases the likelihood of treatment success. http://ow.ly/w24n30nSakf
Introduction
The incidence and prevalence of pulmonary disease caused by nontuberculous mycobacteria (NTM) are increasing globally [1–4]. Mycobacterium abscessus, comprising of three subspecies, i.e. M. abscessus subsp. abscessus, M. abscessus subsp. massiliense and M. abscessus subsp. bolletii, is the second most common NTM causing pulmonary disease, following Mycobacterium avium complex, in East Asia and the USA [2, 5–8].
Treatment for M. abscessus pulmonary disease (MAB-PD) is challenging because of the high frequency of mutational and acquired resistance to commonly used antibiotics [9]. Although macrolides are recommended as a cornerstone of chemotherapy [10, 11], mutations in the rrl gene of M. abscessus, which encodes 23S rRNA, lead to the acquisition of clarithromycin resistance [12, 13]. Moreover, the erm(41) gene, which encodes a ribosomal methylase, confers inducible resistance to macrolide antibiotics [14]. M. abscessus subsp. abscessus and M. abscessus subsp. bolletii typically express a functional erm(41) gene, and hence demonstrate inducible resistance to macrolide antibiotics. Most M. abscessus subsp. massiliense harbours a mutation in the erm(41) gene that renders it nonfunctional, hence M. abscessus subsp. massiliense isolates are intrinsically susceptible to clarithromycin [12, 15].
For the treatment of MAB-PD, the American Thoracic Society (ATS)/Infectious Disease Society of America (IDSA) recommends multidrug therapy that includes a macrolide and one or more parenteral drugs (amikacin plus cefoxitin or imipenem) [10]. The British Thoracic Society (BTS) guidelines recommend an antibiotic regimen comprised of intravenous amikacin, tigecycline and imipenem with a macrolide for the initial treatment phase, followed by a continuation phase comprised of nebulised amikacin and a macrolide in combination with additional oral antibiotics [11].
However, the effectiveness of these treatment approaches has not yet been precisely determined, because different studies have adopted different definitions of treatment success [16, 17]. Some researchers defined sputum culture conversion and maintenance of conversion as treatment success [16], while others reported treatment outcomes based on clinical improvement in addition to sputum culture conversion [17]. Furthermore, the effect of individual drugs has not been elucidated.
Recently, two meta-analyses reporting treatment outcomes for MAB-PD were published [18, 19]. According to these analyses, the treatment success rates for M. abscessus subsp. abscessus and M. abscessus subsp. massiliense were 34.0–41.2% and 54.0–69.8%, respectively. However, accurate measurement of the outcomes and role of each drug in MAB-PD treatment could not be determined because these analyses were based on aggregated data provided in published articles.
In this study, we performed a meta-analysis based on individual patient data to clarify treatment outcomes of MAB-PD as well as the impact of each drug on these outcomes.
Methods
This study was performed in accordance with the PRISMA individual participant data statement [20]. The study protocol was registered with the PROSPERO database (identifier CRD42017070348). Exemption from ethical approval was confirmed by the Institutional Review Board of Seoul National University Hospital (Seoul, South Korea) (1707-007-864).
Search strategy and selection criteria
We conducted a literature search of the MEDLINE, Embase and Cochrane databases using Medical Subject Heading (MeSH) terms and text words associated with MAB-PD and its treatment. The search query was [(Mycobacterium abscessus) OR (Mycobacterium massiliense) OR (Mycobacterium bolletii)] AND [(Treat*) OR (Therapy)]. The literature search was restricted to articles published between January 1, 1987 and July 31, 2017. The abstracts were independently reviewed by two investigators (N.K. and J.P.). Randomised controlled studies and observational studies reporting treatment outcomes for MAB-PD were selected for a full-text review. The discrepancies were resolved by reaching a consensus with a third investigator (J-J.Y.).
We selected all studies of patients who were diagnosed as MAB-PD according to the criteria suggested by the ATS/IDSA or BTS [10, 11], who underwent chemotherapy, and for whom microbiological and clinical outcomes were reported. We excluded studies with case reports, with patients <15 years old and with insufficient reporting of treatment outcomes. Studies mainly comprising patients refractory to previous chemotherapy or patients with acquired mutational macrolide resistance were also excluded.
Data collection and quality assessment
The corresponding authors of eligible studies were contacted by e-mail and requested to provide the raw data. The following variables were collected: age, sex, body mass index (BMI), past medical history (previous NTM/tuberculosis (TB) treatment, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis (CF), bronchiectasis, malignancy or HIV infection), subspecies identification results, radiographic features (nodular bronchiectatic, fibrocavitary or indeterminate), detailed medical treatment history, duration of parenteral drug(s) use, duration of total treatment, details of adjunctive surgery and treatment outcomes (microbiological, radiographic and symptomatic). If the reply from these authors could not be obtained, repeated contacts were attempted two times more.
The de-identified data provided by the corresponding authors were reviewed by two investigators. All data were merged and transformed into one common dataset. Methodological quality of the studies was evaluated with the Newcastle–Ottawa Scale [21]. The scale was modified with reference to previous reports that described treatment outcomes of single-arm studies [22, 23].
Definitions
Treatment success was defined as culture conversion for ≥12 months while on treatment or sustained culture conversion without relapse until the end of treatment [10, 11, 23, 24]. Culture conversion was defined as three or more consecutive negative mycobacterial cultures of sputum. Symptomatic and radiographic improvements were decided based on evaluations by the treating physician at the completion of treatment.
Statistical analysis
Descriptive variables were summarised with median, interquartile ranges and proportions. These variables were compared between subspecies using Fisher's exact test and the Wilcoxon rank-sum test.
For the analysis of treatment outcomes, the proportions of patients with treatment success, symptomatic and radiographic improvement were calculated. The 95% confidence intervals for each proportion were obtained with the DerSimonian–Laird random effects model [25]. I2 statistics were used to estimate heterogeneity across the studies [26]. The effect of excluded studies on treatment success rates was measured with meta-regression. The potential source of heterogeneity was also assessed with meta-regression [27]. Potential for publication bias was measured using the funnel plot and the Egger test [28].
As a small number of studies and small sample sizes were expected, the one-stage approach was adopted [29]. We used multilevel mixed effects logistic regression with a random intercepts model, and used the random effect parameter for each study and the fixed effect parameter for each intervention to estimate the adjusted odds ratios (aOR) and 95% confidence intervals of treatment outcomes. Estimates were adjusted for five covariates: age, sex, BMI, radiographic features and presence of respiratory comorbidity [30, 31]. Stata version 14.2 (StataCorp, College Station, TX, USA) was used for all statistical analyses.
Results
Study selection
We identified a total of 1600 records with our key word-directed literature search, and the titles and abstracts of 1529 articles remained after the removal of duplicates. Of these, 187 articles were selected for full-text review based on the criteria described in the Methods. Full-text reviews narrowed this number down to 14 and the authors were contacted for study participation (Cohen's κ for interrater agreement 0.76). The data could not be obtained from six studies [17, 32–36] owing to inaccessibility of the data from four studies, refusal from one study and absence of a response from the authors of one study. Finally, eight studies were the subject of the final analysis: one from Brazil [37], one from Australia [38], one from the USA [39], one from Japan [40], one from the Netherlands [41] and three from South Korea [42–44] (figure 1). Six [37–41, 44] out of the eight were retrospective observational studies, while the other two [42, 43] were prospective observational studies (table 1). Two studies [42, 43] were published by the same institution and the data from these studies were merged into a combined dataset. Requested and retrieved items from the authors are described in supplementary table E1. The updated data were collected from one study [41]. Four studies [37, 41–43] had a low risk of bias in all aspects, while the others had a risk of bias in terms of representativeness of MAB-PD patients [40], subspecies identification [39] and adequacy of follow-up after treatment [38, 40, 44] (supplementary table E2). The characteristics of the excluded studies are described in supplementary table E3.
Characteristics of study population
A total of 303 patients with MAB-PD were included: 126 patients with M. abscessus subsp. abscessus, 95 with M. abscessus subsp. massiliense, one with M. abscessus subsp. bolletii and 81 without subspecies identification. The subspecies identification was determined based on sequencing of rpoB [38, 40, 42–44], hsp65 [38–43], erm(41) [39, 41], secA [38] and the internal transcribed spacer region [40] or hsp65 PCR restriction enzyme analysis [37].
The median age of the patients was 59 years, 78.6% were female, 141 (46.5%) had a previous treatment history for NTM or TB and 12 (4.0%) had CF. Nodular bronchiectatic features were more prevalent among patients with M. abscessus subsp. massiliense (74.7%) than patients with M. abscessus subsp. abscessus (63.5%; p=0.023) (table 2). Detailed characteristics of the included patients are provided in supplementary table E4.
Treatment outcomes and modalities
Among the 303 patients with MAB-PD, 164 patients met the criteria for treatment success. The weighted proportion of treatment success for MAB-PD overall was 45.6% (95% CI 26.7–64.4%), while the specific treatment success rates were 33.0% (95% CI 16.1–49.8%) for M. abscessus subsp. abscessus and 56.7% (95% CI 9.9–97.8%) for M. abscessus subsp. massiliense (figure 2). If we excluded studies comprising MAB-PD patients where subspeciation was not performed, the treatment success rates for M. abscessus subsp. abscessus and M. abscessus subsp. massiliense pulmonary disease were 27.2% (95% CI 10.8–43.5%) and 57.2% (95% CI 10.9–97.5%), respectively. For M. abscessus subsp. abscessus pulmonary disease, the patients with treatment success received azithromycin (p=0.037), parenteral amikacin (p=0.008) or imipenem (p=0.034) more frequently than patients without treatment success, but not cefoxitin (p=0.444). Among patients with MAB-PD as well as patients with M. abscessus subsp. abscessus, durations of total treatment were longer in the treatment failure group than in the success group (p<0.001 and p=0.044, respectively). Duration of parenteral drug(s) use was also longer in the treatment failure group among patients with MAB-PD (p<0.001) (table 3).
The weighted proportion of symptomatic improvement after treatment was 64.2% (95% CI 51.6–76.7%) among MAB-PD patients overall: 63.4% (95% CI 43.9–81.1%) for patients with M. abscessus subsp. abscessus and 63.6% (95% CI 15.9–99.6%) for patients with M. abscessus subsp. massiliense (supplementary figure E1). Parenteral amikacin was more frequently prescribed to patients with M. abscessus subsp. abscessus or M. abscessus subsp. massiliense who experienced symptomatic improvement (p=0.008 and p=0.001, respectively) (supplementary table E5).
The weighted proportion of radiographic improvement was 46.8% (95% CI 36.8–56.8%) among MAB-PD patients. Radiographic improvement was attained for 35.7% (95% CI 27.2–44.8%) of patients with M. abscessus subsp. abscessus and 70.5% (95% CI 33.6–98.0%) of patients with M. abscessus subsp. massiliense (supplementary figure E2). For M. abscessus subsp. abscessus pulmonary disease, azithromycin rather than clarithromycin was used more commonly in patients with radiographic improvement (p=0.006) (supplementary table E6).
Treatment outcomes according to age, sex, BMI, respiratory comorbidities and radiographic features are provided in supplementary table E7.
Meta-regression and publication bias
The concordance of treatment outcomes between included and excluded studies was confirmed with meta-regression (coefficient −0.04, p=0.765). The ethnicity of the population (Asian versus non-Asian) (coefficient 0.31, p=0.052), design of studies (prospective versus retrospective) (coefficient 0.28, p=0.137) and study quality (low risk of bias versus medium to high risk of bias) (coefficient −0.02, p=0.922) did not contribute to the heterogeneity. The funnel plot showed asymmetry (supplementary figure E3), while the Egger test proved no evidence of publication bias (p=0.073).
Effect of individual drugs on treatment success
For patients with MAB-PD, the use of imipenem (aOR 2.65, 95% CI 1.36–5.10) was associated with treatment success, while the other drugs did not show any significant impact on treatment outcomes. For patients with M. abscessus subsp. abscessus specifically, the use of azithromycin (aOR 3.29, 95% CI 1.26–8.62), parenteral amikacin (aOR 1.44, 95% CI 1.05–1.99) or imipenem (aOR 7.96, 95% CI 1.52–41.6) was associated with higher treatment success, while the use of cefoxitin (aOR 1.22, 95% CI 0.53–2.86) was not. For patients with M. abscessus subsp. massiliense, the choice among these drugs and treatment outcomes did not show significant correlation (table 4).
Effect of individual drugs on symptomatic improvement
Among the 303 patients with MAB-PD, parenteral amikacin was associated with symptomatic improvement (aOR 2.95, 95% CI 1.26–6.91). For patients with M. abscessus subsp. abscessus, the use of azithromycin (aOR 4.58, 95% CI 1.48–14.2) or amikacin (aOR 19.5, 95% CI 2.01–189.7) was related to symptomatic improvement, while the use of clarithromycin (aOR 0.20, 95% CI 0.07–0.62) was not. For patients with M. abscessus subsp. massiliense, amikacin was associated with symptomatic improvement (aOR 31.7, 95% CI 3.70–271.6) (supplementary table E8).
Effect of individual drugs on radiographic improvement
For patients with MAB-PD overall, none of the individual drugs was related to radiographic improvement. However, the use of azithromycin (aOR 5.66, 95% CI 1.86–17.2) rather than clarithromycin (aOR 0.16, 95% CI 0.06–0.49) was related to the radiographic response for M. abscessus subsp. abscessus. Among patients with M. abscessus subsp. massiliense, no drugs showed significant correlation to radiographic improvement (supplementary table E9).
Discussion
We analysed treatment outcomes for MAB-PD and the predictors thereof based on the individual data of 303 patients from seven institutions across six countries. The two main findings of this analysis were: 1) the overall treatment outcomes for MAB-PD, irrespective of subspecies, were unsatisfactory, and 2) the use of azithromycin, amikacin and imipenem was associated with better treatment outcomes among patients with M. abscessus subsp. abscessus pulmonary disease. Previous studies have also reported poor treatment outcomes for MAB-PD, especially for M. abscessus subsp. abscessus [18, 19, 45]. According to a recent meta-analysis, the rates of sputum culture conversion were 54% for MAB-PD altogether, 35% for M. abscessus subsp. abscessus and 79% for M. abscessus subsp. massiliense [18]. Our study showed similar findings to these reports: the overall treatment success rate of MAB-PD was 45.6%. Specifically, 33.0% of patients with M. abscessus subsp. abscessus and 56.7% with M. abscessus subsp. massiliense achieved treatment success. Longer treatment duration in patients with MAB-PD, as well as patients with M. abscessus subsp. abscessus in whom treatments failed, might reflect the difficulties of treatment.
Which macrolide (clarithromycin or azithromycin) is better for the treatment of MAB-PD has not yet been proven and the results of in vitro studies on this issue have been mixed; these mixed results apply both to efficacy and to the differential ability to induce erm(41)-mediated macrolide resistance [38, 39]. One study that was included in the present meta-analysis reported a higher treatment success rate with azithromycin than clarithromycin for patients with MAB-PD [44]. This finding also emerged in our study. The use of azithromycin, rather than clarithromycin, was associated with better outcomes in terms of treatment success as well as the symptomatic and radiographic improvement of patients with M. abscessus subsp. abscessus.
Most clinical isolates of M. abscessus are susceptible to amikacin [46, 47]. In addition, imipenem has the highest in vitro activity among the carbapenems [48] and is preferred over meropenem or ertapenem for the treatment of MAB-PD [10]. In our analysis, the use of amikacin (aOR 1.44, 95% CI 1.05–1.99) or imipenem (aOR 7.96, 95% CI 1.52–41.6), but not cefoxitin (aOR 1.22, 95% CI 0.53–2.86), was associated with treatment success among patients with M. abscessus subsp. abscessus. The importance of the β-lactam antibiotics is supported by hollow fibre model simulations, which applied cefoxitin because imipenem is too unstable, in which the β-lactam antibiotic proved to be the main driver of the efficacy of the cefoxitin–amikacin–clarithromycin regimen [49]. The lower effectiveness of cefoxitin in clinical practice can be explained in two ways. First, cefoxitin has lower bactericidal and intracellular activity towards M. abscessus subsp. abscessus than imipenem [50]. Second, cefoxitin frequently causes adverse drug events, including leukopenia, thrombocytopenia or drug-induced hepatotoxicity. According to a previous report, 60% of patients cannot tolerate cefoxitin because of these adverse events [51]. Given the ineffectiveness observed in the current study, frequent adverse events and unavailability of the drug in some regions [11, 33], the use of imipenem rather than cefoxitin for the treatment of MAB-PD may be a reasonable approach.
As it is difficult to achieve long-term sputum culture conversion for MAB-PD, radiographic or symptomatic improvements are suggested as alternative goals of treatment [10]. Quality of life after treatment has also been suggested as a treatment measure [52]. In our study, treatment outcomes in terms of radiographic and symptomatic improvement were included in the analysis. Again, the use of azithromycin rather than clarithromycin was associated with radiographic and symptomatic improvement in M. abscessus subsp. abscessus pulmonary disease, although the two macrolides were comparable in M. abscessus subsp. massiliense pulmonary disease.
While azithromycin, amikacin and imipenem were associated with better treatment outcomes in M. abscessus subsp. abscessus pulmonary disease in our study, only amikacin was associated with improvement in symptoms of patients with M. abscessus subsp. massiliense. As most M. abscessus subsp. massiliense has intrinsic susceptibility towards clarithromycin [12], treatment outcomes of patients with M. abscessus subsp. massiliense are better than those with M. abscessus subsp. abscessus when using this drug [42, 44]. In our study, treatment success rates for M. abscessus subsp. abscessus and M. abscessus subsp. massiliense pulmonary disease were 27.2% and 57.2%, respectively, after the exclusion of studies including MAB-PD patients without subspeciation. The higher success rate of M. abscessus subsp. massiliense pulmonary disease treatment in general may have otherwise masked the superiority of azithromycin over clarithromycin and the effectiveness of imipenem and amikacin.
Our study has several limitations. First, drug susceptibility test results were not available from some institutions and the impact of constitutive clarithromycin resistance could not be adjusted for in the analysis [13]. Second, individual patient data from only eight out of the 14 eligible studies could be obtained. This could limit the generalisability of our results. Third, the asymmetry of the funnel plot and the result of the Egger test suggested the possibility of publication bias, although the Egger test provided a nonsignificant p-value. Fourth, multiple comparisons resulting from the analysis of subspecies and a diverse range of drugs might lead to the risk of type I errors [53]. Fifth, the role of newly adopted drugs, such as tigecycline or the inhaled amikacin, could not be elucidated in our analysis because the numbers of patients using these drugs were too small. Finally, the causality between some drugs and outcomes may not have been fully elucidated because salvage regimens might be associated with poor outcomes regardless of their effectiveness. Despite these limitations, this study has several strengths. This is the first individual patient data meta-analysis of not only patients with MAB-PD but of patients across the whole NTM pulmonary disease spectrum. With the data of individual patients, we were able to evaluate treatment outcomes and the impact of each drug more accurately.
In conclusion, treatment outcomes for MAB-PD are unsatisfactory. For patients with M. abscessus subsp. abscessus, the use of azithromycin, imipenem and amikacin was associated with better treatment outcomes. For patients with M. abscessus subsp. massiliense, the choice among these drugs was not related to treatment outcomes. These findings may prove helpful to clinicians in the design of treatment regimens for patients with MAB-PD.
Supplementary material
Supplementary Material
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Supplementary tables. ERJ-01991-2018.Supplement
Supplementary figure E1. Weighted proportion of symptomatic improvement after treatment for selected studies. a) Mycobacterium abscessus, b) Mycobacterium abscessus subspecies abscessus, c) Mycobacterium abscessus subspecies massiliense. ERJ-01991-2018.Figure_E1
Supplementary figure E2. Weighted proportion of radiographic improvement after treatment for selected studies. a) Mycobacterium abscessus, b) Mycobacterium abscessus subspecies abscessus, c) Mycobacterium abscessus subspecies massiliense. ERJ-01991-2018.Figure_E2
Supplementary figure E3. Funnel plot assessing symmetry of effect estimates for included studies. ERJ-01991-2018.Figure_E3
Footnotes
This article has supplementary material available from erj.ersjournals.com
This study is registered at PROSPERO with identifier number CRD42017070348.
Author contributions: The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors, were fully responsible for all content and were involved at all stages of manuscript development. Study conception and design: N. Kwak and J-J. Yim; data collection: N. Kwak, M.P. Dalcolmo, C.L. Daley, G. Eather, R. Gayoso, N. Hasegawa, B.W. Jhun, W-J. Koh, H. Namkoong, J. Park, J. van Ingen, S.M.H. Zweijpfenning and J-J. Yim; and data interpretation: N. Kwak, M.P. Dalcolmo, C.L. Daley, G. Eather, R. Gayoso, N. Hasegawa, B.W. Jhun, W-J. Koh, H. Namkoong, J. Park, J. van Ingen, S.M.H. Zweijpfenning and J-J. Yim.
Conflict of interest: N. Kwak has nothing to disclose.
Conflict of interest: M.P. Dalcolmo has nothing to disclose.
Conflict of interest: C.L. Daley reports grants and personal fees from Insmed, and personal fees from Horizon, Spero and Johnson and Johnson, outside the submitted work.
Conflict of interest: G. Eather has nothing to disclose.
Conflict of interest: R. Gayoso has nothing to disclose.
Conflict of interest: N. Hasegawa reports grants and personal fees from Insmed Inc., during the conduct of the study; grants from Nikon Corporation, Taisho-Toyama Pharmaceutical Co., Ltd, Eisai Co., Ltd, Daiichi Sankyo Co., Ltd, MSD KK a subsidiary of Merck & Co. Inc., Sumitomo Dainippon Pharma Co., Ltd, Pfizer Inc., Astellas Pharma Inc., Cepheid Inc., Precision System Science Co., Ltd, and Medical and Biological Laboratories Co., Ltd, outside the submitted work.
Conflict of interest: B.W. Jhun has nothing to disclose.
Conflict of interest: W-J. Koh has received a consultation fee from Insmed Inc. for the Insmed advisory board meeting, not associated with the submitted work.
Conflict of interest: H. Namkoong has nothing to disclose.
Conflict of interest: J. Park has nothing to disclose.
Conflict of interest: R. Thomson reports personal fees for advisory board work from Insmed and Savara, and personal fees for CME talks from Menarini and AstraZeneca, outside the submitted work.
Conflict of interest: J. van Ingen reports personal fees for advisory board membership from Insmed, Spero Therapeutics and Johnson & Johnson, during the conduct of the study.
Conflict of interest: S.M.H. Zweijpfenning reports personal fees and nonfinancial support from Insmed and Novartis outside the submitted work.
Conflict of interest: J-J. Yim has nothing to disclose.
Support statement: This work was supported by the Seoul National University College of Medicine Research Fund (grant 2320170050). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received October 17, 2018.
- Accepted February 20, 2019.
- Copyright ©ERS 2019