Surgery in nontuberculous mycobacteria pulmonary disease

Mimi Lu; Dominic Fitzgerald; Jonathan Karpelowsky; Hiran Selvadurai; Chetan Pandit; Paul Robinson; Ben J. Marais

doi:10.1183/20734735.027218

Tables

Table 1

Common adverse effects of antibiotics used to treat NTM infections in patients with CF^#

Antibiotic (delivery route)	Common adverse effects	Suggested monitoring
Amikacin (intravenous; intramuscular)^¶	Nephrotoxicity Auditory-vestibular toxicity (tinnitus, high-frequency hearing loss)	Trough levels Serum creatinine
Amikacin (nebulisation)^¶	None described
Azithromycin (oral)⁺	Nausea, vomiting, diarrhoea Auditory-vestibular toxicity Prolonged QTc	Symptoms Audiology ECG
Bedaquiline (oral)^¶	Headaches, dizziness, joint aches Prolonged QTc Liver enzyme derangement	Symptoms ECG LFT
Cefoxitin (intravenous)^¶	Fever, rash Eosinophilia, anaemia, leukopenia, thrombocytopenia Interference with serum creatinine measurement	Symptoms FBC
Clofazimine (oral)^¶	Discoloration of skin or sclera Enteropathy (can mimic pancreatic insufficiency), nausea and vomiting	Symptoms
Ethambutol (oral)⁺	Optic neuritis	Symptoms, colour vision and acuity
Imipenem (intravenous)^¶	Nausea, vomiting, diarrhoea Hepatitis	Symptoms LFT
Linezolid (oral)^¶	Anaemia, leukopenia, thrombocytopenia Peripheral neuropathy, optic neuritis	FBC Symptoms/clinical
Minocycline (oral)^¶	Photosensitivity, skin discolouration Nausea, vomiting, diarrhoea Vertigo	Symptoms
Moxifloxacin (oral)^¶	Nausea, vomiting, diarrhoea Insomnia, agitation, anxiety Tendonitis Photosensitivity Prolonged QTc	Symptoms ECG
Rifabutin (oral)⁺	Leukopenia, anterior uveitis (when combined with clarithromycin), flu-like symptoms (polyarthralgia or myalgia)	Symptoms FBC
Rifampicin (oral)⁺	Orange discolouration of bodily fluids, fever, chills, nausea, vomiting, diarrhoea Hepatitis Thrombocytopenia Renal failure Increased drug metabolism	Symptoms LFT FBC EUC
Streptomycin (intravenous, intramuscular)^¶	Nephrotoxicity	Trough levels, serum creatinine
Tigecycline (intravenous)^¶	Nausea, vomiting, diarrhoea Pancreatitis Hypoproteinaemia, bilirubinaemia	Symptoms Serum amylase, lipase LFT plus albumin

LFT: liver function test; FBC: full blood count; EUC: electrolytes, urea and creatinine; QTc: corrected QT interval. ^#: based on United States CF Foundation (USCF) and European CF society (ECFS) consensus recommendations [46]; ^¶: primarily used for Mycobacterium abscessus complex; ⁺: primarily used for MAC. Reproduced from [10] with permission.

Table 2

Overview of patient characteristics in NTM lung surgery studies performed to date

First author  [ref.]	Study year(s),  location	Patients  n	Median (range)  age years	Females %	NTM species	Lung involvement and/or comorbidities
Studies without clarithromycin
Elkadi [23]	1962–1973 Missouri, USA	48	48 (20–72)	33%	M. kansasii 54% M. intracellulare 42% Rapid grower 2%	Lung cavities 77%
Pomerantz [36]	1983–1990 Colorado, USA	38	50 (33–39)	68%	MAC 87% M. kansaii 3% M. chelonae 3% M. xenopi 3%	Previous lobectomy 18% Previous TB 8% Bronchopleural fistula 8% Chest radiation 8%
Ono [35]	1991–1996 Wakayama, Japan	8	50 (36–72)	50%	MAC 100%	Cigarette smoker 25% Bronchiectasis, 25% Previous TB 25% Sjögren's syndrome 13%
Nelson [38]	1989–1997 Texas, USA	28	Mean±sd 50±11	25%	MAC 100%	Almost all were smokers 67% >20% below weight standard No immunocompromised
Shiraishi [34]	1979–1996 Tokyo, Japan	33	50 (30–69)	48%	MAC 100%	Cigarette smoker 97% Bronchiectasis 21% Cavity 64%; nodule 3% Previous TB 9% Pneumonia 9%
Studies incorporating clarithromycin
Shiraishi [28]	1993–2001 Kyoto, Japan	21	56 (27–67)	48%	MAC 100%	Bronchiectasis 10% Cavity 76%; nodule 10% Destroyed lung 5% No immunocompromised
Shiraishi [29]	1983–2002 Tokyo, Japan	11	57 (43–69)	73%	MAC 91% M. abscessus 9%	Multiple cavities 55% Destroyed lung 46% Bilateral disease 36% No immunocompromised
Watanabe [39]	1990–2005 Tokyo, Japan	22	54 (30–77)	68%	MAC 100%	Bronchiectasis predominant 64% Cavitary predominant 36% No immunocompromised
Mitchell [43]	1983–2006 Colorado, USA	236	54 (23–77)	83%	MAC 80% M. abscessus 14%	Focal bronchiectasis 55% Cavitary lung disease 29% Mixed pattern 9% Prior thoracic surgery 20%
Koh [40]	2002–2007 Seoul, Korea	23	45 (24–66)	70%	MAC 43% M. abscessus 52% M. xenopi 4%	Cavities 70% Bronchiectasis 30% No immunocompromised
van Ingen [19]	2000–2009 Holland	8	52 (41–59)	25%	MAC 88% M. xenopi 12%	Cavitary 62% Mixed pattern 25% Bronchiectasis 13% No immunocompromised
Yu [30]	2004–2009 Colorado, USA	128	59 (34–81)	96%	MAC 88% M. abscessus or chelonae 10%	Bronchiectasis 95% Cigarette smoker 16% Cavitary disease 3% Mixed pattern 2% Prior thoracic procedure 10%
Jarand [41]^#	2001–2008 Alberta, Canada	24	Mean±sd 57.7±11.1	83%	M. abscessus 100%	Localised bronchiectasis 86% Coexisting/previous MAC 54.2% Cavitary disease 37% Previous smokers 23% Previous TB 8.3%
Shiraishi [31]	2007–2011 Tokyo, Japan	60	50 (20–72)	68%	MAC 92% M. abscessus 5% M. gordonae 2% M. xenopi 2%	Bronchiectasis 48% Cavities 42% Cigarette smoker 18% Mixed pattern 7% Diabetes mellitus 6.7%
Asakura [37]	1994–2015 Yokohama, Japan	125	60 (IQR 49–66)	53%	MAC 80% M. intracellulare 8% M. abscessus 5% M. kansasii 3% Others 5%	Cavities 70%; nodules 98% Bronchiectasis 89% Cigarette smoker 29% Old TB 26%, COPD 10% Diabetes mellitus 10%

M. kansasii: Mycobacterium kansasii; M. intracellulare: Mycobacterium intracellulare; M. chelonae: Mycobacterium chelonae; M. xenopi: Mycobacterium xenopi; M. abscessus: Mycobacterium abscessus; M. gordonae: Mycobacterium gordonae; IQR: interquartile range; COPD: chronic obstructive pulmonary disease. ^#: compared combined antibiotic and surgical treatment with antibiotic treatment alone.

Table 3

Indication, type and complications of surgery performed for pulmonary NTM disease

First author [ref.]	Patients n	Surgical indications	Type of surgery	Hospital stay	Complications
Studies without clarithromycin
Elkadi [23]	48	Medical treatment failure	Lobectomy 67% Segmentectomy 21% Pneumonectomy 6% Wedge resection 4% Extrapleural plombage 2%	2.4–4 months^#	Total=13% Bronchopleural fistula 4% Wound dehiscence 4% Infection 2% Haemorrhage 2%
Pomerantz [36]	38	Localised disease with complications	Lobectomy 59% Pneumonectomy 41% Both (7%)	Not reported	Total=50% Bronchopleural fistula 21%^¶ Prolonged air leak 11% Respiratory failure 5% Wound dehiscence 3% Pericardial effusion 3% Horner's syndrome 3%
Ono [35]	8	Medical treatment failure Persistent symptoms	Lobectomy 75% +partial resection 25%	Not reported	None reported
Nelson [38]	28	Medical treatment failure Significantly destroyed lung Severe haemoptysis	Partial resection 71% Pneumonectomy 29%	Not reported	Total=32% Bronchopleural fistula 4% Prolonged air leak 14% Atelectasis requiring bronchoscopy 4% Severe post-thoracotomy pain 4% Death due to post-operative MI 4%
Shiraishi [34]	33	Symptomatic localised disease	Lobectomy 79% Segmentectomy 15% Pneumonectomy 3% Wedge resection 3%	Not reported	Total=18% Bronchopleural fistula 3% Residual pleural space 15%
Studies incorporating clarithromycin
Shiraishi [28]	21	Medical treatment failure or drug intolerance	Lobectomy 76% Two lobes 5% Pneumonectomy 14% (90% right sided)	Not reported	Total=29% Bronchopleural fistula 10% Prolonged air leak 4% Residual pleural space 10% Pneumonia 4%
Shiraishi [29]	11	Multiple cavities or total lung destruction	Pneumonectomy 100%	Not reported	Total=45% Bronchopleural fistula 27% Empyema 9% ARDS 9%
Watanabe [39]	22	Medical treatment failure Persistent symptoms	Lobectomy 64% ⁺ Two lobes 5%⁺ Partial lung resection 27%⁺ Segmentectomy 18%⁺ Wedge resection 27%⁺ Multiple resections 45%	Not reported	Total=9% Residual pleural space 5% Home oxygen for 2 months 5%
Mitchell [43]	236	Medical treatment failure Focal persistent lung damage	Lobectomy 48% Segmentectomy 21% Pneumonectomy 17% Mixed procedures 15%	Not reported	Total=19% Bronchopleural fistula 4% Prolonged air leak 4% Respiratory failure/pneumonia 3% Post-operative bleeding 2% Wound dehiscence 1% ARDS 1% Atrial fibrillation 4%
Koh [40]	23	Medical treatment failure 48% Remaining cavity relapse risk 35% Persistent symptoms 17%	Lobectomy 70% Two lobes 9% Two sides 13% Segmentectomy 13% Pneumonectomy 17%	9 days (IQR 6–15 days)	Total=35% Bronchopleural fistula 9% Prolonged air leak 9% Pneumonia 13% Wound dehiscence 4% Pneumonectomy syndrome 4%
van Ingen [19]	8	Treatment failure Infected destroyed lung	Lobectomy 63% Two lobes 13% Wedge resection 13% Pneumonectomy 25%	Not reported	Total=63% Pneumothorax 38% Atelectasis requiring bronchoscopy 13% Respiratory distress 13% Pneumonia 13%
Yu [30]	134	Localised disease ±cavitation Medical treatment failure Persistent symptoms	Lobectomy 100% Middle 59% Lingulectomy 41%	3 days (1–15 days)	Total=8% Prolonged air leak 4% Wound infection 1% Atelectasis 1% Pleural effusion 1% Atrial fibrillation 1%
Jarand [41]	24	Localised bronchiectasis 86% Cavitary disease 37% Haeptysis 11%	Lobectomy 83% Pneumonectomy 21% Segmentectomy 10% Wedge resection 3%	Not reported	Total=25% Haemorrhage 4% Bronchopleural fistulae 4% Wound infection 4% Brachial plexus injury 4% Frozen shoulder 4% Respiratory failure/death 4%
Shiraishi [31]	60	Medical treatment failure 87% Persistent symptoms 10% Secondary infection 3%	Lobectomy 90% Two lobes 5% Segmentectomy 7% Pneumonectomy 2% Wedge resections 3%	Not reported	Total=12% Prolonged air leak 6% Atelectasis 3% Respiratory failure 1% Haemorrhage 1% Atrial fibrillation 1%
Asakura [37]	125	Medical treatment failure 56% Cavities; severe bronchiectasis 29% Persistent symptoms 15%	Lobectomy 88% Two lobes 10% Pneumonectomy 25% Segmentectomy 11% Wedge resection 2%	Not reported	Total=22% Bronchopulmonary fistula 6% Bronchopleural fistula 2% Prolonged air leak 1% Wound dehiscence 1% Pneumonia or empyema 7% Bronchial stenosis 1% Diaphragmatic hernia 1% Left atrial rupture 1%

MI: myocardial infarction; ARDS: acute respiratory distress syndrome. ^#: patients were kept in hospital until sputum conversion; ^¶: 15% of bronchopleural fistula occurred post-right pneumonectomy; ⁺: primarily as 45% of this cohort had multiple resections.

Table 4

Pre- and post-surgical treatment with sputum clearance, relapse and mortality (early and total)

First author [ref.]	Patients n	NTM species	Pre-surgery antibiotics % on antibiotics; duration; macrolide; % sputum clearance	Post-surgery antibiotics % on antibiotics; duration	Follow up duration^#,^¶	Sputum conversion immediately post-surgery	Relapse	Mortality early and total
Studies without clarithromycin
Elkadi [23]	48	M. kansasii 54% M. intracellulare 42% Rapid grower 2%	100%; 1–22 months; no clarithromycin; 54%	Up to 9 months or until sputum conversion	Not reported	85.4% With additional antibiotics 100%	Not reported	None and None
Pomerantz [36]	38	MAC 87% M. kansaii 2.6% M. chelonae 2.6% M. xenopi 2.6%	100%; 3 months; no clarithromycin; 32%	Not reported	Not reported	Not reported	Not reported	2.6% and 21%
Ono [35]	8	MAC 100%	62.5%; 8.1 months (1–30 months); no clarithromycin; 12.5%	Nil treatment post-operatively	20 months^# (4–56)	100%	13% 6 months	None and None
Nelson [38]	28	MAC 100%	100%; 1 year (1–6 years); 61% had clarithromycin; 50%	100%; up to 12 months	39 months^#	>90% 3 months after surgery: 93% (of those alive)	4% 2 years	7% and 14%⁺
Shiraishi [34]	33	MAC 100%	85%; 8 months (1–64 months);  4% had clarithromycin; 35%	91%; 13 months (1–96 months)	(1–18 years)	94%	3% 5 years 12% 10 years	None and 6%
Studies incorporating clarithromycin
Shiraishi [28]	21	MAC 100%	100%; 11 months (2.2–29.1); 100% on clarithromycin; 38%	90%; 6–12 months	35 months^¶ (6–99)	100%	10% 2 years	None and None
Shiraishi [29]	11	MAC 91% M. abscessus 9%	100%; 57 months  (13–109 months); 100% had clarithromycin; Not reported	64%; 6–24 months	2 years^¶ (0.6–17)	100%	9% 2 years	None and 18%
Watanabe [39]	22	MAC 100%	100%; 17 months (2–37 months); 82% on clarithromycin; 80%^§	100%; 6–35 months	46 months^¶ (6–164)	90% 100% after antimicrobials	Not reported	None and None
Mitchell [43]	236	MAC 80% M. abscessus 14%	100%; 2–6 months; 57% negative sputum prior surgery	Not reported	Not reported	100%	Not reported	2.6% and 2.6%
Koh [40]	23	MAC 43% M. abscessus 52% M. xenopi 4%	87%; 7.5 months (5–17 months);100% on clarithromycin; 26%	97%; 12 months (6–26 months)	14 months^¶ (IQR 6–11)	100% (in 1–2 months)	Not reported	None and 9%
van Ingen [19]	8	MAC 87.5% M. xenopi 12.5%	100%; 22 months; Not reported	50%; 9 months	19 months^#	88%	0% 19 months	12.5% and 12.5%
Yu [30]	128	MAC 88% M. abscessus or chelonae 10%	100%; at least 2–3 months; Not reported	100%; duration not reported	23 months^# (0–70)	84% 97% sputum negative at final follow up at 34 months	7% 17 months	None and None
Jarand [41]	24	M. abscessus 100%	100%; uncertain; % macrolide uncertain; 71%	100%; duration not separately reported for surgery group	34 months (2–82)^#	Uncertain Overall 65%	Never converted or relapsed 35%	Uncertain and 17%
Shiraishi [31]	60	MAC 92% M. abscessus 5% M. gordonae 1.6% M. xenopi 1.6%	100%; 14.2 months (3.3–75.2); 100% clarithromycin; Not reported	100%; at least 12 months post-surgery or post-sputum conversion	34 months^¶ (13–70)	100%	3% 34 months	None and None
Asakura [37]	125	MAC 80% M. Intracellulare 8% M. abscessus 5% M. kansasi 3% Others 5%	94% treatment before and after surgery; 7 months (IQR 6–18 months); 82% clarithromycin; Not reported	94% (before and after); 7 months (IQR 6–18 months)	7.1 years^¶ (IQR 3.5–10.3)	91%	5% 1 year 10% 3 years 15% 5 years 20% 19 years	4% and 4%

^#: mean; ^¶: median (range); ⁺: 2 patients (7%) suffered late deaths due to unrelated causes; ^§: only those (5 out of 25) who did not sputum convert were referred on for surgical treatment and joined 17 other patients from another hospital to make up to 22 patients in the cohort.