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Surgery in nontuberculous mycobacteria pulmonary disease

Medical treatment of pulmonary nontuberculous mycobacteria (NTM) disease has highly variable outcomes. Despite the use of multiple antibiotics, sputum clearance is often difficult to achieve, especially in cases with macrolide resistant NTM infection. Immunocompromised patients and those with structural lung disease are at increased risk, although occurrence in immunocompetent patients without structural lung disease is well recognised. Most pulmonary NTM disease involves Mycobacterium avium complex (MAC), but with enhanced identification multiple species have now been recognised as opportunistic pathogens. The observed increase in NTM disease, especially infection with multidrug-resistant Mycobacterium abscessus complex, is probably multifactorial. Surgery has been used as adjuvant treatment in patients with 1) focal disease that can be removed or 2) bothersome symptoms despite medical treatment that can be ameliorated. Early post-surgical mortality is low, but long-term morbidity and mortality are highly dependent on the degree of lung involvement and the residual lung function, the potency of medical treatment and the type of surgical intervention. In conjunction with antibiotic therapy, reported post-surgical sputum clearance was excellent, although publication bias should be considered. Bronchopleural fistulae were problematic, especially in pneumonectomy cases. Study results support the use of minimal resection surgery, in a carefully selected subgroup of patients with focal disease or persistent symptoms. Educational aims To critically review the literature describing the use of surgery in the treatment of pulmonary disease caused by nontuberculous mycobacteria (NTM). To assess the outcomes and complications observed with different surgical approaches used in the treatment of pulmonary NTM disease.


Educational aims • •
To critically review the literature describing the use of surgery in the treatment of pulmonary disease caused by nontuberculous mycobacteria (NTM).

• •
To assess the outcomes and complications observed with different surgical approaches used in the treatment of pulmonary NTM disease.

Introduction
NTM are ubiquitous organisms, commonly found in soil and water, that rarely cause human disease. However, in people with underlying structural lung disease such as bronchiectasis, poor sputum clearance as found in cystic fibrosis (CF), or underlying immunodeficiency they do have pathogenic potential. In some instances, lung disease occurs without identifiable underlying "risk factors". Concern has been expressed that the incidence of pulmonary NTM disease is on the rise globally, with Japan having one of the highest incidence rates [1][2][3][4][5][6][7][8]. This is probably multifactorial, especially in patients with CF, with contributions from better diagnostics, increased surveillance sampling and a dramatic increase in life expectancy [9][10][11].
Despite optimised antibiotic treatment, sputum clearance is difficult to achieve and highly variable in patients with pulmonary NTM disease. Based on current American Thoracic Society (ATS)/ Infectious Disease Society of America (IDSA) recommendations, multidrug treatment regimens Medical treatment of pulmonary nontuberculous mycobacteria (NTM) disease has highly variable outcomes. Despite the use of multiple antibiotics, sputum clearance is often difficult to achieve, especially in cases with macrolide resistant NTM infection. Immunocompromised patients and those with structural lung disease are at increased risk, although occurrence in immunocompetent patients without structural lung disease is well recognised. Most pulmonary NTM disease involves Mycobacterium avium complex (MAC), but with enhanced identification multiple species have now been recognised as opportunistic pathogens. The observed increase in NTM disease, especially infection with multidrug-resistant Mycobacterium abscessus complex, is probably multifactorial. Surgery has been used as adjuvant treatment in patients with 1) focal disease that can be removed or 2) bothersome symptoms despite medical treatment that can be ameliorated. Early post-surgical mortality is low, but long-term morbidity and mortality are highly dependent on the degree of lung involvement and the residual lung function, the potency of medical treatment and the type of surgical intervention. In conjunction with antibiotic therapy, reported post-surgical sputum clearance was excellent, although publication bias should be considered. Bronchopleural fistulae were problematic, especially in pneumonectomy cases. Study results support the use of minimal resection surgery, in a carefully selected subgroup of patients with focal disease or persistent symptoms. of 1-2-years duration yield sputum conversion rates of 54-87% [12][13][14][15][16][17]. Sputum conversion rates are lower in those previously treated or in patients infected with macrolide-resistant species [14,18]. The recurrence rate after successful treatment with clarithromycin-containing regimens ranges between 20% and 44% [14][15][16][17]19]. Many antibiotics used in the treatment of pulmonary NTM disease may have severe adverse effects (table 1) [10], resulting in frequent treatment interruptions and a high cost from additional investigations and the management of side-effects. [20]. Surgery has been used as adjuvant therapy in the treatment of NTM pulmonary disease [12,21], to effect higher rates of cure in patients with focal lung involvement. Increased cure and reduced relapse rates have been demonstrated with the use of lung surgery in the treatment of multidrugresistant tuberculosis (MDR-TB). A recent metaanalysis of the role of surgery as an adjuvant therapy demonstrated that partial lung resections, but not pneumonectomy, were associated with improved treatment success (cure and completion) (OR 3.0; 95% CI 1.5-5.9; I 2 R 11.8%), and that a good outcome was more likely when surgery was performed after initial culture conversion [22]. We critically reviewed the treatment outcomes achieved with surgical management of pulmonary NTM disease.

Studies undertaken in the pre-and post-clarithromycin era
Studies showed that combined medical and surgical management of NTM had low mortality with high rates of sputum conversion [23][24][25][26][27], which was often difficult to achieve with antibiotic treatment alone. With the addition of clarithromycin (in the late 1990s) the success rate from antibiotic treatment increased [12][13][14][15][16][17]; however, treatment failure rates with clarithromycin-resistant species or with acquired-clarithromycin resistance during treatment remained high. Studies undertaken after the clarithromycin era demonstrated benefit from lung surgery in select patient groups only [19,[28][29][30][31]. Table 2 presents an overview of identified studies where surgical intervention was performed and describes the characteristics of the patient cohorts selected for surgery. Other studies where surgery was performed in a small number of the overall cohort did not have sufficiently detailed information about the surgery cases to be included in the table [32,33]. None of the studies included children and there was a female predominance. Most patients had bronchiectasis and/or lung cavities visible on a chest radiograph or computed tomography scan. A history of cigarette smoking (range 18-97%) or previous pulmonary TB (range 8-26%) was common in the studies where this was mentioned [30,31,[34][35][36][37]. Underlying immunodeficiency was uncommon and absent in six studies where this was mentioned [19,28,29,[38][39][40]. Low body mass index (BMI) was common in studies where immunodeficiency was reported [29-31, 37, 40, 41], and was identified as a predictor of poor prognosis in one study [37]. Most studies included patients with MAC disease and were performed in the USA and Japan. None of the studies included patients with CF.

Indications for surgery
According to ATS/IDSA guidelines, surgery should only be considered in select patients who meet the diagnostic criteria for pulmonary NTM disease [12]. Specifically, they need to have localised disease deemed amenable to resection and be judged to have adequate pulmonary reserve [12]. Generally, the indications for surgery fall into three categories: 1) removing a disease focus to optimise the chances of cure; 2) removing a destroyed part of the lung for symptomatic relief or prevention of a catastrophic bleed; and 3) limiting the rate of disease progression in cases with a poor response to medical treatment.
Nelson et al. [38] indicated that in the preclarithromycin era, most of the surgical treatments were used at an earlier stage of infection in conjunction with medical therapy to try and cure the NTM disease. However, since newer generation macrolides (specifically clarithromycin) became available, surgery has predominantly been used in the setting of treatment failure (71% of cases) [38]. Poor response to antibiotic treatment has been defined as the lack of sputum clearance and/or ongoing features of active disease and progressive lung destruction on imaging. Clarithromycin susceptibility is an important factor when considering surgical resection, given that clarithromycin-resistant strains have significantly reduced sputum conversion rates (∼25%) with antibiotic therapy compared with susceptible strains (∼85%) [14].
Excessive haemoptysis can be lethal and is the most common symptom leading to surgical resection. Intractable cough is another symptomatic indication for surgery if this has a major negative impact on a patient's quality of life. In these instances, surgical intervention seeks to provide symptom relief or prevent a life-threatening complication, irrespective of clinical cure. The third indication is to use surgery to protect the unaffected or residual lung by removal of an intractable disease focus that remains a source of infected secretions with risk of intrapulmonary spread [42].

Surgical options
All the surgical interventions were conducted under general anaesthesia with frequent use of a double lumen endobronchial tube. Surgery duration ranged from 1 h to 8 h and blood loss from 10 mL to more than 3 litres, depending on the types of surgical resections performed and the complications encountered [28,29,35,37,38,40]. Either a postero-or antero-lateral thoracotomy approach was used, depending on anticipated pleural adhesions. Conversion from thoracoscopic to open surgery occurred when extrapleural dissection was required or because of concerns regarding underlying vital structures. Pre-operative Continued Surgery in NTM pulmonary disease airway toilet using bronchoscopy was selectively used to reduce the infected secretion burden in the airways and surgeons needed to be vigilant to avoid spillage of infected debris within the pleural space or around the wound site. This type of surgery is best carried out in specialist centres with considerable experience in infectious lung surgery [42]. Some centres involved multidisciplinary teams consisting of surgeons, dieticians, respiratory and infectious diseases physicians specialising in NTM infections in decision making [43]. Table 3 summarises the indication for and type of surgery performed for pulmonary NTM disease. Lobectomies and segmentectomies were the most common procedures performed. Table 4 summarises the outcomes following surgical intervention.

Surgical outcomes Mortality
Most studies reported no early post-operative deaths [23, 28-31, 34, 35, 39, 40]. Nelson et al. [38] reported two (7%) deaths out of 28 patients; one died of a myocardial infarction and the second due to acute respiratory failure. Mitchell et al. [43] also reported two early post-operative deaths (out of 236 patients; <1%) with one death secondary to ARDS and another due to bronchopleural fistula with MI.
Long-term mortality varied between 3% and 21% and was mostly due to respiratory failure. Most studies followed patients for 6-8 years, but two studies followed patients for nearly 20 years post-surgery [34,37]. Two case series conducted in the pre-clarithromycin era demonstrated reduced mortality (0% versus 10%) in patients managed more aggressively with earlier surgery [23,44]. However, these finding are less relevant today, given that the overall mortality rates associated with surgical treatment of pulmonary NTM disease declined from 7% in the 1980s to <1% today [43].

Common complications
In the studies evaluated, post-operative complication rates averaged 28%, but varied widely across the studies (range 0-63%) and most complications occurred post-pneumonectomy. Asakura et al. [37] found that pneumonectomy, when compared to other resections, was associated with higher rates of post-operative complications with an odds ratio of 4.1 (95% CI 1.6-10.3; p=0.005). Pneumonectomy was generally associated with higher rates of bronchopleural fistula; up to 27% of cases in one series [29]. Bronchial stumps were often reinforced with muscle flaps (latissimus dorsi, serratus anterior or intercostal) and occasionally omental flaps to try to reduce this risk, but its effectiveness is uncertain, and Mitchell et al. [43] found that the risk of bronchopleural fistula was associated with positive sputum at the time of surgery. Other complications included lobar atelectasis requiring bronchoscopy, wound infection, wound dehiscence and haemorrhage (table 3).

Risk factors for poor prognosis
Asakura et al. [37] found that, in addition to pneumonectomy, older age, low BMI and remnant cavitary lesions were predictors of poor prognosis. Sputum clearance was higher after pneumonectomy, but with increased morbidity and unfortunately the characteristics of those who may benefit from a pneumonectomy were not identified [37]. Limited resection was generally associated with better outcome [35,39].
Pomerantz et al. [36] compared outcomes of pulmonary resections in those with TB and NTM subjects. Their group found that those infected with    NTM had poorer results with higher incidences of complications compared with the TB group. They proposed that this might be due to the older age group of those with NTM disease and the indolent nature of disease resulting in more extensive parenchymal involvement at the time of surgery, resulting in more extensive surgical resections [36]. Low BMI (≤18.5 kg·m −2 ) was associated with worse outcomes (OR 1.91, 95% CI 1.11-3.29) in patients undergoing lung surgery for MDR-TB [45] and pulmonary NTM disease [37].

Sputum clearance
The sputum clearance rates reported across studies ranged from 84% to 100%; with better conversion rates if antibiotics were continued post-operatively [38]. Excellent long-term clearance rates of 95% at 1 year and 87% at 3 years after surgery have been reported in some recent studies [28]. Relapses may be due to occult bilateral disease or infection of the healthy lung around the time of surgical resection; one patient with initial post-surgery sputum conversion required a second lobectomy in the contralateral lung [28]. Relapse rates of 0-20% have been reported with concomitant antibiotic therapy and follow-up periods of 9 months to 19 years. Asakura et al. [37] showed that the presence of persisting cavitary lesions after surgery is a significant predictor of microbiological recurrence with an adjusted hazard ratio of 6.73 (CI 1.68-22.7; p=0.0095). Jarand et al. [41] compared patients with combined antibiotic and surgical therapy compared with antibiotic therapy alone and showed that the surgical group had a significantly higher rates of culture conversion and remained culture negative at 1 year (57% versus 28%; p=0.022).

Lung function
Only one study reported results of lung function after surgery [39]. It showed that vital capacity and forced expiratory volume in 1 s were at 89% and 84% of the pre-operative values, respectively. The study did not assess for ongoing decline after surgery.

Pre-operative
Despite the introduction of clarithromycin, surgery still assists culture conversion in those who fail medical treatment [28]. Most patients were treated for 6-18 months with multiple antibiotics prior to surgery with some patients on treatment for up to 6 years. Across the studies, sputum conversion with antibiotics alone prior to surgery ranged between 12% and 80% (table 4). Elkadi et al. [23] found that patients on the longest treatment course of antibiotics prior to surgery took longer to achieve sputum clearance post-operatively; which may suggest increased acquisition of drug resistance if surgery is delayed for too long, or simply reflect selection bias. On average, studies reported a delay of ∼14 months from diagnosis before surgery was performed.

Post-operative
Hattler et al. [25] showed that the sputum conversion rate after operative management was 91% compared to 27% with medical treatment Self-evaluation questions 1. What is the role of surgery in the treatment of pulmonary NTM disease? a) Surgery is the main treatment for localised pulmonary NTM disease b) Surgery has no role in the treatment of pulmonary NTM disease c) Surgery should be considered as an adjuvant treatment in selected patients with localised pulmonary NTM disease d) Surgery should be only considered in the treatment of pulmonary NTM disease if antibiotic treatments have failed 2. What initial factors are important to consider when evaluating the role of surgery for the treatment of NTM pulmonary disease? a) Age, sex and BMI b) Localised disease that is amenable to resection in a patient with adequate underlying pulmonary reserve c) Localised disease due to Mycobacterium avium complex (MAC) d) Irretraceable coughing and recurrent haemoptysis 3. Which of the statements around the indication for surgery in the treatment of pulmonary NTM disease is false? a) In the post-macrolide era, most surgical treatment of pulmonary NTM disease was due to medical treatment failure b) Surgery might be indicated to prevent further spread NTM pulmonary infection c) Haemoptysis is the most frequent indication for surgery d) At times, surgery might be indicated early to optimise chances of cure 4. Which of the following statements is true? a) Pneumonectomy is the most common type of surgical procedure used b) Bronchopulmonary fistulae are the most common major postoperative complication and occur most often after lobectomy c) Post-operative mortality rates are high d) Bronchopulmonary fistulae occur more commonly after pneumonectomy 5. With regards to post-operative outcomes, which of the following statements is false? a) Sputum clearance is high post-operatively b) Sputum clearance improves with pre-and post-operative antibiotic treatment c) Persisting cavitary lesions after surgery is a significant predictor of microbiological recurrence of disease d) Antibiotics can be reassuringly ceased after sputum clearance post-pneumonectomy alone, while Corpe [24] found that bacteriological cure was 2-3 times greater with combined surgical and medical treatment; however, both studies were conducted in the pre-clarithromycin era.
Most studies continued antibiotic treatment after surgery, which was associated with greater sputum clearance [39,40]. The duration of antibiotic treatment ranged from a few months to several years. Current ATS/IDSA guidelines advocate treatment for 12 months after culture conversion [12], which was mostly achieved following surgery. Some centres recommended treatment for 2 years after pneumonectomy, since stump breakdown or infection of the remaining lung can be fatal [29].

Limitations and future directions
It is challenging to accurately assess the impact of surgical interventions, since no randomised controlled trials (RCT) have compared the benefits of surgery to antibiotic therapy alone [46]. RCTs are required to draw firm conclusions about the role of surgery in this setting but are problematic due to low patient numbers and variability in the mycobacterial species and drug susceptibility patterns of individual patients. No studies have been performed in children or in patients with CF. Specific to CF, the United States CF Foundation and European CF society urge caution when considering surgical treatment for CF pulmonary NTM disease as localised disease is rare and it is difficult to differentiate NTM changes from the underlying disease process [46]. The studies performed to date have largely focused on subjects with MAC disease and the impact of NTM species on outcomes remains unclear. Hopefully improved standardisation of NTM treatment and identification of candidates for surgery following the publication of consensus guidelines from the ATS/IDSA will facilitate easier comparison of future surgical case series.

Conclusion
The results of studies to date suggest that lung surgery may have value in the management of NTM pulmonary disease. However, its role requires further clarification and there must be careful consideration of the risks and benefits. While surgery is associated with low rates of post-operative mortality the longterm mortality and morbidity is highly variable. The value of surgery in children and patients with CF with pulmonary NTM disease remains unclear, but should be considered with caution.