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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Non-tuberculous mycobacteria &#40;NTM&#41; comprise all mycobacteria other than those that cause tuberculosis or leprosy&#46; While several NTM species may cause significant disease&#44; those comprising the <span class="elsevierStyleItalic">Mycobacterium</span><span class="elsevierStyleItalic">avium</span> complex &#40;MAC&#41; and the subspecies of <span class="elsevierStyleItalic">Mycobacterium</span><span class="elsevierStyleItalic">abscessus</span> &#40;MAB&#41; are among the most common encountered clinically&#46; The lungs are the commonest site of NTM infection&#46; There remains a poor evidence base in NTM pulmonary disease &#40;NTM-PD&#41; with knowledge gaps in relation to epidemiology&#44; infection control&#44; pathogenesis heterogeneity and optimal treatment regimens&#46; Interest is however increasing among academics&#44; clinicians and industry alike&#44; with an increase in publications and clinical trial development&#46; In this editorial&#44; we consider some of the latest data pertaining to the epidemiology&#44; diagnosis and management of NTM-PD&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The number of NTM infection cases continues to rise globally&#46; In a systematic review and meta-analysis of 47 studies from over 18 countries encompassing 285&#44;681 positive NTM isolates&#44; 81&#37; of the studies identified increasing trends&#44; with a &#43;4&#46;0&#37; annual rate of change for NTM infection and disease per 100&#44;000 persons&#47;year&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> Increasing prevalence and incidence have been reported in studies from Africa&#44; Asia&#44; Europe&#44; North America&#44; South America and Oceania&#44; with variation depending on the NTM species and MAC being the most common species in most regions&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> It should however be noted that NTM infections are not notifiable in most countries and the annual prevalence of NTM-PD may be stable in some areas&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">While several studies have investigated putative transmission of MAB clones between cohorts with cystic fibrosis &#40;CF&#41;&#44; less has been published on the potential transmission of other NTM species between individuals with CF&#44; non-CF bronchiectasis or other chronic respiratory disease&#46; Through whole genome sequencing of longitudinal sputum MAC isolates collected from a cohort in a tertiary NTM treatment centre in London&#44; van Tonder et al&#46; demonstrated the presence of putative transmission clusters for <span class="elsevierStyleItalic">M&#46; avium</span> subsp&#46; <span class="elsevierStyleItalic">avium</span>&#44; <span class="elsevierStyleItalic">M&#46;</span><span class="elsevierStyleItalic">avium</span> subsp&#46; <span class="elsevierStyleItalic">hominissuis</span>&#44; <span class="elsevierStyleItalic">Mycobacterium</span><span class="elsevierStyleItalic">intracellulare</span> and <span class="elsevierStyleItalic">Mycobacterium</span><span class="elsevierStyleItalic">chimaera</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a> Epidemiological links however were not identified for most individuals within the clusters and the absence of environmental sampling meant that transmission dynamics could not be fully elucidated&#46; In another study investigating the potential transmission of MAC in a CF centre in Vermont&#44; Gross et al&#46; found that there was no significant genetic similarity between environmental and respiratory MAC isolates&#59; but there was some similarity between respiratory <span class="elsevierStyleItalic">M</span>&#46; <span class="elsevierStyleItalic">chimaera</span> isolates and those found in a hospital water biofilm sample&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">5</span></a> This reinforces the notion that healthcare settings may possibly provide a reservoir for environmental acquisition of NTM&#59; but direct human-to-human transmission has not been unequivocally proven&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Diagnosing NTM-PD is contingent upon microbiological&#44; radiological and clinical criteria being satisfied&#46; Danho et al&#46; found that time-to-positivity &#40;TTP&#41; in Mycobacterium Growth Indicator Tube automated broth culture may predict culture conversion&#46; A TTP of &#62;7 days at baseline and &#62;15 days at 3 months was predictive of culture conversion at 6 months in a cohort treated for MAC-PD&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">6</span></a> Culture-based techniques for mycobacteria can be slow in providing final results&#44; causing delays in clinical decision-making&#46; To address this&#44; Ellis et al&#46; developed molecular assays to quantify the burden of six NTM species&#46; They demonstrated that a custom qPCR assay for <span class="elsevierStyleItalic">M&#46;</span><span class="elsevierStyleItalic">abscessus</span> in particular had a high sensitivity and specificity when applied to NTM DNA extracted from longitudinally acquired sputum samples from individuals with NTM-PD&#59; and that there was a significant decrease in mycobacterial burden associated with the use of NTM-PD treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">7</span></a> Such molecular tests may hold potential utility in monitoring response to treatment in future&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Treatment regimens for NTM-PD are complex due to the use of multiple drugs&#44; medication interactions&#44; side effects and <span class="elsevierStyleItalic">in vitro</span> drug susceptibility testing results for NTM isolates not necessarily correlating with <span class="elsevierStyleItalic">in vivo</span> effectiveness&#46; The use of amikacin liposome inhalation suspension &#40;ALIS&#41; has been extensively investigated in treatment-refractory MAC pulmonary disease &#40;MAC-PD&#41;&#46; In the CONVERT study&#44; Griffith et al&#46; demonstrated that adding ALIS to guideline-based therapy &#40;GBT&#41; for refractory MAC-PD resulted in improved rates of culture conversion at six months&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a> Winthrop et al&#46; subsequently showed that culture conversion continued beyond six months when using ALIS with GBT and that the most frequent adverse effects associated with treatment were respiratory in nature&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">9</span></a> Additionally&#44; culture conversion is sustained when using ALIS with GBT for 12 months following initial conversion&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">10</span></a> More recently&#44; Siegel et al&#46; have investigated the utility of adding ALIS to multidrug regimens used in MAB pulmonary disease &#40;MAB-PD&#41;&#46; In a MAB-PD cohort in which all pretreatment isolates were susceptible to amikacin but most were macrolide-resistant&#44; 6&#47;33 individuals developed amikacin resistance following the addition of ALIS&#44; potentially due to insufficient companion drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a> Among the 15 participants for whom longitudinal culture data demonstrated culture conversion&#44; 10 individuals had sustained culture conversion at 12 months&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a> In view of the generally poor clinical outcomes associated with MAB-PD&#44; these findings are noteworthy and suggest that larger scale prospective trials are warranted&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Various novel treatments have been under evaluation for the treatment of NTM-PD&#46; Omadacycline&#44; an aminomethylcycline&#44; has shown potential efficacy when used in multidrug treatment regimens for MAB&#46; In a retrospective analysis of 117 patients treated with omadacycline for MAB infections&#44; Mingora et al&#46; found that 44&#47;95 &#40;46&#37;&#41; of the cohort with MAB-PD had at least one negative culture at the end of the period of microbiological assessment&#59; 17&#47;95 &#40;18&#37;&#41; met the definition for culture conversion&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">12</span></a> Furthermore&#44; among those with refractory MAB-PD&#44; 7&#47;31 &#40;23&#37;&#41; culture converted at the end of the assessment period&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">12</span></a> Notable side effects that limited the duration of treatment included the development of haematological abnormalities &#40;anaemia&#44; thrombocytopaenia&#44; leukopaenia&#44; eosinophilia&#41; or liver function test derangement &#40;transaminitis&#44; hyperbilirubinaemia&#41;&#44; although none of these were deemed to be life-threatening&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">12</span></a> Additionally&#44; the potential utility of clofazimine in treating MAC-PD is increasingly recognised&#46; Zweijpfenning et al&#46; recently demonstrated that using clofazimine in place of rifampicin alongside ethambutol and a macrolide in MAC-PD resulted in similar degrees of sputum culture conversion&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">13</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Furthermore&#44; inhaled granulocyte&#8211;macrophage colony stimulating factor has been evaluated in 24 individuals with refractory MAC-PD and 8 individuals with MAB-PD&#46; Thomson et al&#46; found that inhaled molgramostim in addition to GBT was associated with culture conversion in 7&#47;24 &#40;29&#46;2&#37;&#41; MAC-PD cases and 1&#47;8 &#40;12&#46;5&#37;&#41; MAB-PD cases with no significant safety signal&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">14</span></a> Inhaled nitric oxide &#40;iNO&#41; therapy may also show some promise&#46; In a study of adults with NTM-PD&#44; 4&#47;10 &#40;40&#37;&#41; of participants had negative mycobacterial sputum cultures after addition of iNO treatment&#59; of these&#44; three participants reverted to culture positivity three months following iNO cessation&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">15</span></a> Another emerging therapeutic option for NTM-PD is the use of bacteriophage therapy&#46; In a study of 20 individuals with treatment-refractory pulmonary&#44; extrapulmonary or disseminated mycobacterial infections who were treated with phages on compassionate grounds&#44; at least half of the cohort subsequently had positive clinical outcomes and no adverse reactions were reported&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">16</span></a> Other agents under investigation in phase 1&#8211;3 trials include epetraborole and SPR720 &#40;a novel bacterial DNA gyrase inhibitor&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">17</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">There remain a number of unanswered questions with respect to the long-term clinical trajectories of individuals who have been treated for NTM-PD&#46; Factors predisposing individuals to relapse or reinfection require further exploration&#46; This should be with a view to elucidating biomarkers that can be used clinically to identify those at greatest risk of future NTM infection recurrence&#46; Furthermore&#44; the association between NTM and other infections should be evaluated&#46; There is known to be a link between NTM and concomitant or sequential fungal pulmonary infection&#44; but the mechanisms underlying this association and the appropriate strategies for monitoring and treatment are still to be determined&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">18</span></a> The value of multidisciplinary clinical management&#44; particularly in relation to airway clearance&#44; pulmonary rehabilitation and nutritional support&#44; must also be remembered&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">19</span></a> Additionally&#44; long-term morbidity associated with treated NTM-PD&#44; such as the lasting impact on lung function&#44; psychological outcomes and quality of life&#44; merit study&#46; The creation of validated patient-reported outcome measures is vital if this is to be achieved&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0045" class="elsevierStylePara elsevierViewall">None&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Authors&#8217; contributions</span><p id="par0050" class="elsevierStylePara elsevierViewall">KK prepared the original draft&#46; MRL critically revised the manuscript for content&#46; Both authors approved the version of the article that was submitted for publication&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflict of interests</span><p id="par0055" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">KK&#58;</span> None declared in relation to this article&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">MRL&#58;</span> MRL has received honoraria for consultancy or lectures not related to this article from Insmed&#44; Armata&#44; 30T&#44; Astra Zeneca&#44; Parion&#44; Chiesi&#44; Zambon&#44; Electromed&#44; Recode&#44; Boehringer Ingelheim&#44; Ethris&#44; Mannkind&#44; AN2 Therapeutics and Cepheid&#46;</p></span></span>"
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Journal Information
Vol. 60. Issue 10.
Pages 609-611 (October 2024)
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Vol. 60. Issue 10.
Pages 609-611 (October 2024)
Editorial
Non-Tuberculous Mycobacterial Pulmonary Disease—Where are we Now?
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Kartik Kumara,b, Michael R. Loebingera,b,
Corresponding author
m.loebinger@rbht.nhs.uk

Corresponding author.
a Host Defence Unit, Department of Respiratory Medicine, Royal Brompton Hospital, Guy's and St Thomas’ NHS Foundation Trust, London, UK
b National Heart and Lung Institute, Imperial College London, London, UK
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