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Epidemiology and management of nontuberculous mycobacterial disease in people with cystic fibrosis, the Netherlands

Open AccessPublished:November 05, 2022DOI:https://doi.org/10.1016/j.jcf.2022.10.009

      Highlights

      • Nontuberculous mycobacteria (NTM) prevalence increased in people with CF in the Netherlands.
      • M. abscessus is the most frequent variant.
      • More than half of NTM isolations seem to be singletons.
      • Lower lung function and more infections in children prior to NTM isolation.
      • Treatment efficacy is less than 50%, independent of type of treatment.

      Abstract

      Background

      Nontuberculous mycobacteria (NTM) are opportunistic, difficult to treat pathogens. With increasing prevalence of NTM infections in people with cystic fibrosis (pwCF) and the improved life expectancy, the burden is expected to grow.

      Methods

      We assessed the epidemiology and management of NTM isolation and disease in pwCF in the Netherlands using a survey and retrospective, case-controlled data from the Dutch CF Registry. We determined the isolation prevalence, treatment and outcomes from 2013-2019.

      Results

      NTM isolation prevalence increased from 1.0% to 3.6% (2013-2019). This was a single NTM isolation in 53.7% of the adults and 60.0% of the children. M. abscessus and M. avium complex (MAC) were most frequent (47.1 and 30.9%). Of the treated pwCF, 48.5% attained culture conversion of M. abscessus; 54.5% for MAC. Children with an NTM isolation showed more infections with S. maltophilia and/or A. fumigatus (p < 0.001) compared to controls. In the year prior to NTM isolation, children in the NTM group had a lower mean FEV1% predicted (81.5 ± 16.7 vs. 88.6 ± 15.3, p = 0.024), while adults in the NTM group had more IV antibiotic days compared to controls (60 vs. 17, p = 0.047). In the following years, FEV1% predicted declined faster in pwCF with NTM than the control group (children: -3.8% vs. -1.6%, p = 0.023; adults: -0.7% and 0.4%, ns).

      Conclusions

      The isolation prevalence of 3.6%, poor treatment outcomes and associated lung function decline emphasize that NTM pulmonary disease (NTM-PD) is a significant health issue among pwCF in the Netherlands. Its prevention and treatment require increased attention.

      Keywords

      1. Background

      Nontuberculous mycobacterial pulmonary disease (NTM-PD) is a notorious opportunistic infection of people with cystic fibrosis (pwCF). The Mycobacterium avium complex (MAC) and M. abscessus bacteria are the most frequent causative agents, but the species distribution differs between geographical areas and age groups. The prevalence of these infections also differs between geographical areas, with an isolation prevalence of 3.7% in France [

      Vaincre la Mucoviscidose (2021) Registre français de la mucoviscidose – Bilan des données 2019.

      ] to 13.9% in the United States [

      Cystic Fibrosis Foundation. (2020) Cystic Fibrosis Foundation Patient Registry 2019 Annual Data Report. Bethesda, Maryland.

      ].
      Treatment of NTM-PD in pwCF is difficult and its outcomes, particularly for M. abscessus-PD, are poor, even with the use of guideline-compliant antibiotic regimens [
      • Floto R.A.
      • et al.
      US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis.
      ]. With increasing life expectancy, increasing isolation prevalence and cure rates as low as 40-50% for M. abscessus [
      • Chacko A.
      • et al.
      Improved clinical outcome after treatment of Mycobacterium abscessus complex pulmonary disease in children with cystic fibrosis.
      ,
      • DaCosta A.
      • et al.
      Outcomes associated with antibiotic regimens for treatment of Mycobacterium abscessus in cystic fibrosis patients.
      ,
      • Floto R.A.
      • et al.
      US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis.
      ], the total burden of NTM-PD in the CF community could rapidly increase.
      Recent studies have focused on the possibility of human carriage and (indirect) human transmission of M. abscessus and increased virulence and drug resistance acquired during human passage [
      • Bryant J.M.
      • et al.
      Emergence and spread of a human-transmissible multidrug-resistant nontuberculous mycobacterium.
      ,
      • Bryant J.M.
      • et al.
      Stepwise pathogenic evolution of Mycobacterium abscessus.
      ,
      • Ruis C.
      • et al.
      Dissemination of Mycobacterium abscessus via global transmission networks.
      ]. The prospect of more virulent, more drug-resistant and more transmissible M. abscessus -or NTM in the broader sense- strains is very alarming.
      To evaluate the current burden of NTM isolation and disease in pwCF, we have set up a nationwide survey in all CF centers in the Netherlands. We used the survey to query diagnostic practices, isolation prevalence as well as antibiotic treatment and outcomes from 2013-2019. We combined the results with retrospective, case-controlled data from the Dutch CF Registry to determine differences [

      Dutch CF Registry (no date) Dutch CF Registry 2013-2019.

      ].

      2. Methods

      From the Dutch CF Registry, with a coverage of 95%, data were extracted from all people with CF with new NTM isolations from 2013-2019.

      2.1 Survey

      With a survey among all CF centers in the Netherlands, the number of NTM isolations between 2013-2019 were evaluated. The NTM species isolated were queried, along with the type of treatment and outcome, the type of residence (urban/rural) and province.
      In the Dutch CF Registry, NTM isolation was annually registered as positive when at least one positive sputum sample was detected. It cannot be concluded from the Registry whether the diagnostic criteria for NTM-PD were met or whether screening guidelines were fully adhered to [
      • Floto R.A.
      • et al.
      US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis.
      ].

      2.2 Analyses

      From the Dutch CF registry, we selected all pwCF with a first M. abscessus or MAC isolation and a matched control group with no record of NTM isolation, with two controls per NTM case. We matched for gender, age (maximal one year difference) and mutation or, if needed, type/class of mutation. Registry data were used from both groups the year before the first NTM isolation (T-1), the year of first NTM isolation (T0) and two years after (T1 and T2). The NTM group was the same for all years of analysis, regardless of eradication of NTM after T0.
      Characteristics studied were best annual FEV1% predicted and FVC% predicted for people age six years and older [
      • Quanjer P.H.
      • et al.
      Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations.
      ], (sds)BMI, use of inhaled antibiotics for at least three months, azithromycin, oral and inhaled corticosteroids, IV antibiotic treatment, CF-related diabetes, allergic bronchopulmonary Aspergillosis (ABPA), chronic infection with Pseudomonas aeruginosa, chronic infection with Staphylococcus aureus, infection with Stenotrophomonas maltophilia and infection with Aspergillus fumigatus. Normality of the data was tested using the Shapiro-Wilk test, which showed that data on FEV1% predicted, FVC% predicted and sdsBMI were normally distributed. Statistical analyses were done with independent sample t-tests, chi-squared tests, mixed-effects analyses and Mann-Whitney U tests when applicable.

      2.3 Software

      Graphs were generated using GraphPad Prism 9. Statistical analyses were done using IBM SPSS Statistics 25.

      3. Results

      3.1 Characteristics

      All seven CF centers participated in the study, covering 95% of all people with CF in the Netherlands (1,353-1,516 from 2013 to 2019). In this period, 136 NTM isolations were detected in 102 people with CF.
      Annually, the prevalence of NTM increased from 1% in 2013 to 3.6% in 2019 (Fig. 1A). The increase was mostly due to an increased incidence of NTM in the pediatric population (Fig. 1B). Between 2015 and 2017 the increase is the biggest.
      Fig 1
      Fig. 1NTM prevalence, incidence and detection. Prevalence (A), incidence (B), years of continuous detection (C) and relative isolation percentage per CF center (D) of NTM in people with CF in the Netherlands from 2013-2019. CF: cystic fibrosis; NTM: nontuberculous mycobacteria.
      More than half of all NTM isolations were a single episode of NTM isolation (i.e. single years in which NTM isolation was reported) with negative follow-up cultures in both pediatric (60.0%) and adult (53.7%) populations (Fig. 1C). Isolation of NTM for four years or more was more frequent in the adult population. Some adults had NTM in their sputum samples during the complete study period of 2013-2019.
      The highest mean annual NTM isolation prevalence amounted to 17.5%, with the lowest at 0.0% (Fig. 1D).
      M. abscessus and MAC made up 47.1% and 30.9% of all NTM isolations. Both were slightly less prevalent in the pediatric population than in adults (45.5 vs. 48.1% for M. abscessus and 29.1 vs. 30.9% for MAC). In total 17.6% of the isolations were of other NTM species. In 58.3% of those isolations, the NTM species were specified (Supplementary table S1). For 4.4% of the isolations the species of NTM could not be determined or data was missing.
      We found no differences in the NTM species distribution in pwCF living in urban vs. rural areas, nor between the different provinces within the Netherlands (data not shown).

      3.2 Management after an NTM isolation

      In total 40 people were treated for NTM, with in total 48 treatments (due to multiple NTM species from 2013-2019). Eradication was the goal for 62.5% of the treatments, suppression for 12.5%, first eradication and then suppression for 12.5%. For the remaining 12.5% data on the treatment goal was missing. 39.3% of all treatments was done with antibiotic regimens that were in accordance with current guidelines.
      Treatment was started in the minority of people with NTM (35.3% of all NTM isolations). In the following years, NTM were not detected upon treatment in 54.2% of isolations (Table 1), but were still present in sputum samples in the remaining 45.8%. This rate of culture conversion did not differ between treatments according to the guidelines and other treatments (data not shown). The remaining people with NTM was not (yet) treated for NTM, 63.2% of isolations, still 58.1% of those isolations was not detected in the following year.
      Table 1Outcomes of NTM treatment. NTM: nontuberculous mycobacteria.
      Total, N (%)Culture conversion, N (%)No or unknown culture conversion, N (%)
      SumMABMACOtherSumMABMACOther
      Treated48 (35.3)26 (54.2)166422 (45.8)1750
      1 year13 (50.0)6430 (0.0)000
      >1 year13 (50.0)102122 (100.0)1750
      Not treated86 (63.2)50 (58.1)15112436 (41.9)15192
      1 year found38 (76.0)99200 (0.0)000
      >1 year12 (24.0)63336 (100.0)1592
      Unknown2 (1.5)1 (50.0)11 (50.0)1
      Sum136773117295933242
      The reasons for not starting treatment for NTM were: stable symptoms, stable situation, not officially classified as NTM-PD, necessity to treat other infections first, or single positive culture only.
      People with M. abscessus isolations were more often treated (51.6% of isolations) than people with MAC (26.8% of isolations) or other NTM species (16.0% of isolations, Table 1). Culture conversion was achieved for 48.4% of M. abscessus isolations and for 41.5% of MAC isolations. Of the other NTM species isolated, culture conversion was achieved for 93.5%.
      The majority of culture conversions of M. abscessus upon treatment showed a durability longer than one year (62.5%), while for MAC and other NTM species the percentages were lower (33.3% and 25.0%, respectively, Table 1). 58.1% of pwCF who showed NTM culture conversion without antimycobacterial treatment has a single positive culture only.

      3.3 Characteristics prior to NTM isolation

      In children, occurrences of a bacterial infection with S. maltophilia or fungal infection with A. fumigatus were higher in the NTM group (p < 0.001, supplementary table S2). In addition, a lower FEV1% predicted was measured in the year before first NTM isolation, compared to the control group (81.5 ± 16.7 vs. 88.6 ± 15.3, p = 0.024, supplementary table S2).
      The adult NTM group was longer on IV antibiotic treatment in the year prior to and the first year of NTM isolation, compared to the control group (60 vs. 17 days, p = 0.047 and 52.5 vs. 21 days, p = 0.037, supplementary tables S3 and S7).

      3.4 Pulmonary function & other outcomes of treatment

      3.4.1 Children

      In the year after the first NTM isolation, the FEV1% predicted and the FVC% predicted decreased in children with more than 10% (absolute %, p = 0.002 and 0.018, respectively; Fig. 2A and B; supplementary table S4). After two years (T2), the FEV1% predicted was significantly lower compared to children without an NTM isolation (p = 0.01; see Supplementary Table S5).
      Fig 2
      Fig. 2Pulmonary function of and co-infections in children. FEV1% predicted (A, mean±SD) and FVC% predicted (B, mean±SD) and infection with S. maltophilia (C) and A. fumigatus (D) in children with CF, with an NTM isolation of M. abscessus or M. avium complex (NTM group) or without (control group). * means a significant difference (p < 0.05) between both groups within a year. CF: cystic fibrosis; NTM: nontuberculous mycobacteria.
      The FEV1% predicted declined faster in the NTM group during the study period compared to the controls (-3.8% vs. -1.6%, p = 0.023).
      The percentages of children with a co-infection with S. maltophilia or A. fumigatus were 2-2.5 times higher in the NTM group compared to the control group in the year of first NTM isolation and the years after (p < 0.001, Fig. 2C and D, supplementary tables S4-6). An infection with both S. maltophilia and A. fumigatus occurred in 20% of children with an NTM isolation compared to 2.5% of the controls.
      Use of medication increased significantly in the children in the years after first NTM isolation, compared to controls (Fig.3). This was observed for the prescription of azithromycin (T1: p = 0.004, T2: p = 0.011, Fig. 3A, supplementary tables S5-6) and the use of inhaled antibiotics (T2: p < 0.001, Fig. 3B, supplementary table S6). The prescription of oral corticosteroids was temporarily increased in the year after first NTM isolation (T1: p = 0.025, Fig. 3C, supplementary table S5).
      Fig 3
      Fig. 3Other outcomes of NTM isolation in children with CF. Prescription of medication (%, A-D), days on IV antibiotic treatment (median and 25th-75th percentile, E) and prevalence of ABPA (%, F) in children with CF, with an NTM isolation of M. abscessus or M. avium complex (NTM group) or without (control group). * means a significant difference between both groups within a year. CF: cystic fibrosis; NTM: nontuberculous mycobacteria.
      In the year of first NTM isolation (T0), the percentage of children receiving IV antibiotic treatment was significantly higher in the NTM group (p < 0.001, Fig. 3D, supplementary table S4). The number of IV treatment days increased in both years after first NTM isolation with no significant difference (Fig. 3E, supplementary tables S5-6).
      Two years after first NTM isolation, the percentage of children with an ABPA was higher in the NTM group compared to the controls (p = 0.007, Fig. 3F, supplementary table S6).

      3.4.2 Adults

      In the adult NTM group, no significant difference in lung function was observed compared to the control group (Fig. 4A). However, FEV1% predicted declined in the NTM group (-0.7% average per year), but not in the control group (0.4% increase average per year).
      Fig 4
      Fig. 4Outcomes of NTM isolation in adults with CF. FEV1% predicted (A, mean±SD), percentages with prescribed inhaled corticosteroids (B) or CF-related diabetes (C) in adults with CF, and days on IV treatment for adults with at least 1 IV day (D, median and 25th-75th percentile), with an NTM isolation of M. abscessus or M. avium complex (NTM group) or without (control group). * means a significant difference between both groups within a year. CF: cystic fibrosis; NTM: nontuberculous mycobacteria.
      No increase in medication prescription was observed in the adult NTM group. In fact, two years after the first NTM isolation, inhaled corticosteroids were significantly more prescribed in the control group (p = 0.013, Fig.4B, supplementary table S9).
      No differences were observed in frequency of infections with microorganisms or ABPA in adults with an NTM. CF-related diabetes, with the need for daily insulin, was less frequent in adults with an NTM isolation in the complete study period (T-1: p = 0.044, T1: p = 0.037, T2: p = 0.013,
      Fig. 4C, supplementary tables S6, S8-9).

      4. Conclusions

      We recorded an NTM isolation prevalence of 3.6% among pwCF in the Netherlands in 2019; this is in line with the 3.7% observed in France [

      Vaincre la Mucoviscidose (2021) Registre français de la mucoviscidose – Bilan des données 2019.

      ]. The distribution of NTM species, with a predominance of M. abscessus (47.1%), is similar to data from neighboring countries including the UK (56.7%) [

      UK Cystic Fibrosis Trust (2020) UK Cystic Fibrosis Registry Annual Data Report 2019.

      ]; it differs from a previous report from the CF Foundation Patient Registry from the USA where MAC was overall more frequent [

      Cystic Fibrosis Foundation. (2020) Cystic Fibrosis Foundation Patient Registry 2019 Annual Data Report. Bethesda, Maryland.

      ].
      S. maltophilia and A. fumigatus were more frequent among children with CF prior to NTM isolation and/or disease (p < 0.001), in line with previous observations in a smaller Dutch pwCF cohort [
      • Verregghen M.
      • et al.
      Risk factors for Mycobacterium abscessus infection in cystic fibrosis patients; a case–control study.
      ]. A recent meta-analysis showed an increased risk of NTM positivity with older age, use of oral corticosteroids and chronic colonization with Staphylococcus aureus, Stenotrophomonas maltophilia and Aspergillus fumigatus [
      • Reynaud Q.
      • et al.
      Risk factors for nontuberculous mycobacterial isolation in patients with cystic fibrosis: a meta-analysis.
      ].
      In the years after NTM isolation, the frequencies of S. maltophilia and A. fumigatus were still significantly higher compared to the control group (p < 0.001). These findings suggest a causal relationship or a shared cause. The frequent co-occurrence of aspergillosis and NTM-PD has also been observed in non-CF patients in the Netherlands [
      • Geurts K.
      • et al.
      Nontuberculous mycobacterial pulmonary disease and Aspergillus co-infection: Bonnie and Clyde?.
      ] and may be linked to either antibiotic use or severe destruction of the airways creating a permissive niche or to immunodeficiences [
      • Becker K.L.
      • et al.
      Deficient interleukin-17 production in response to Mycobacterium abscessus in cystic fibrosis.
      ,
      • Geurts K.
      • et al.
      Nontuberculous mycobacterial pulmonary disease and Aspergillus co-infection: Bonnie and Clyde?.
      ].
      Pulmonary function declined faster in children with NTM (-3.8% FEV1% predicted, versus -1.6% in the control group, p = 0.023). The decline is mainly observed in pwCF with isolates of M. abscessus, of which less single isolates are found compared to the other NTM species. Pulmonary function did decline in adults with NTM but not in the control group (-0.7% vs. 0.4%, respectively). These findings echo the landmark study by Esther et al., who documented accelerated lung function decline (-2.5% predicted FEV(1)/years, compared to -1.6% in controls) in pwCF with M. abscessus [
      • Esther C.R.
      • et al.
      Chronic Mycobacterium abscessus infection and lung function decline in cystic fibrosis.
      ].
      It was surprising to find that more than 50% of the NTM isolates found in pwCF were single isolations, including M. abscessus – this phenomenon and its frequency have only been described by Martiniano et al., who reported similar similar percentages [
      • Martiniano S.L.
      • et al.
      Clinical significance of a first positive nontuberculous mycobacteria culture in cystic fibrosis.
      ]. Typing studies are necessary to understand whether these are true singletons with a likely environmental source or whether these are part of possible transmission chains. Similarly, the importance of host immunological factors in the development of NTM disease after proven exposure / a first positive culture is an important subject for study. Both bacterial [
      • Bryant J.M.
      • et al.
      Emergence and spread of a human-transmissible multidrug-resistant nontuberculous mycobacterium.
      ,
      • Bryant J.M.
      • et al.
      Stepwise pathogenic evolution of Mycobacterium abscessus.
      ,
      • Ruis C.
      • et al.
      Dissemination of Mycobacterium abscessus via global transmission networks.
      ] and host factors [
      • Becker K.L.
      • et al.
      Deficient interleukin-17 production in response to Mycobacterium abscessus in cystic fibrosis.
      ] may determine whether exposure leads to infection and disease.
      The increase in NTM isolation prevalence is predominantly caused by an increased incidence in the pediatric CF population in the Netherlands. We also observed substantial variation between individual CF centers regarding mean annual NTM prevalence (0.0% to 17.5%). Geographical differences do not seem to play a role. Prevention and screening are key, given the poor outcome of NTM isolation and NTM-PD. Segregation is a relevant factor in infection prevention. Whole genome sequencing and other methods have to be performed to learn how to implement prevention and segregation [
      • Bryant J.M.
      • et al.
      Stepwise pathogenic evolution of Mycobacterium abscessus.
      ].
      At group level, macrolide maintenance therapy appeared not to protect nor to trigger NTM. This suggests that azithromycin maintenance therapy did not prevent NTM isolation in our retrospective study. Many adults were already on azithromycin which might suggest a protecting effect but could also imply false-negative cultures for NTM. CFTR-modulators might be more promising, and also host-directed immunomodulatory therapies might be more important [
      • Becker K.L.
      • et al.
      Deficient interleukin-17 production in response to Mycobacterium abscessus in cystic fibrosis.
      ]. The effect of CFTR-modulators on NTM, especially M. abscessus, needs to be evaluated in the future.
      For the 32 pwCF treated for M. abscessus disease, with eradication as the goal of treatment, 15 (46.9%) achieved culture conversion. This outcome is similar to the control group as well as previous reports from others [
      • Bryant J.M.
      • et al.
      Emergence and spread of a human-transmissible multidrug-resistant nontuberculous mycobacterium.
      ,
      • DaCosta A.
      • et al.
      Outcomes associated with antibiotic regimens for treatment of Mycobacterium abscessus in cystic fibrosis patients.
      ,
      • Tippett E.
      • et al.
      Mycobacterium abscessus complex: Natural history and treatment outcomes at a tertiary adult cystic fibrosis center.
      ].
      In the pediatric NTM group, we observed a significantly higher rate of prescribed oral corticosteroids in the first year after NTM isolation, compared to the control group (p = 0.025). In adults, less inhaled corticosteroids were prescribed in the NTM group, compared to controls. This might be due to the known risk of developing NTM-PD with such treatments [
      • Andréjak C.
      • et al.
      Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis.
      ].
      A limitation of this study is the retrospective design. Prospective studies are needed to confirm our findings. In our analyses, we grouped the pwCF with M. abscessus and MAC isolates into a single group; as a result, we may have missed phenomena that are relevant to M. abscessus but not to MAC or vice versa. Finally, the increase in NTM isolation frequency might be caused by an increase in the culture frequency and/or the quality of the cultures.
      In summary, with an isolation prevalence of 3.6% in 2019, varying treatment practices, poor treatment outcomes and significant long-term effects on pulmonary function of children with CF, NTM and NTM-PD are an important health burden among pwCF in the Netherlands. The predominance of M. abscessus is worrying, but in line with observations in nearby countries. Prevention, screening and segregation are important to control the emergence of these opportunistic pathogens, but require more study.

      CRediT authorship contribution statement

      Domenique Zomer: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing. Jakko van Ingen: Conceptualization, Data curation, Formal analysis, Visualization, Writing – original draft, Writing – review & editing. Regina Hofland: Conceptualization, Data curation, Formal analysis, Supervision, Writing – review & editing. O.W. Akkerman: Data curation, Writing – review & editing. J. Altenburg: Data curation, Writing – review & editing. M. Bakker: Data curation, Writing – review & editing. M.A.G.E. Bannier: Data curation, Writing – review & editing. L.H. Conemans: Data curation, Writing – review & editing. V.A.M. Gulmans: Data curation, Resources, Software, Writing – review & editing. H.G.M. Heijerman: Data curation, Writing – review & editing. R.A.S. Hoek: Data curation, Writing – review & editing. H.M. Janssens: Data curation, Writing – review & editing. R. van der Meer: Data curation, Writing – review & editing. P.J.F.M. Merkus: Data curation, Writing – review & editing. J.J. Noordhoek: Data curation, Resources, Writing – review & editing. M. Nuijsink: Data curation, Writing – review & editing. S.W.J. Terheggen-Lagro: Data curation, Writing – review & editing. H. van der Vaart: Data curation, Writing – review & editing. K.M. de Winter-de Groot: Data curation, Writing – review & editing.

      Declaration of Competing Interest

      None of the authors report any conflicts of interest broadly relevant to the work presented herein.

      Acknowledgements

      We thank all people with CF who consented to the Dutch CF Registry. We also thank all CF centers for participating in this project, with special thanks to the people who filled in the survey and/or imported the data for the Dutch CF Registry.
      No external funding was received for this study.

      Appendix. Supplementary materials

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