- Email: [email protected]
Pulmonary resection for Mycobacterium xenopi pulmonary infection
Pulmonary Resection for Mycobacterium xenopi Pulmonary Infection Loı¨c Lang-Lazdunski, MD, PhD, Catherine Offredo, MD, Franc¸oise Le Pimpec-Barthes, MD, Claire Danel, MD, Antoine Dujon, MD, and Marc Riquet, MD, PhD Departments of Thoracic Surgery and Pathology, Hoˆpital Europe´en Georges Pompidou, Paris, and Department of Bacteriology, Hoˆpital Necker, Paris, France
Background. Results of medical therapy for Mycobacterium xenopi pulmonary infection remain unreliable. Pulmonary resection may be beneficial to patients whose disease is localized and who can tolerate a resectional operation. Methods. Eighteen patients underwent pulmonary resection between 1991 and 2000: 14 men and 4 women, with a mean age of 50 ⴞ 12 years (range 27 to 68 years). Indications for operation were either therapeutic (n ⴝ 9) or diagnostic (n ⴝ 9). Four patients received antimycobacterial chemotherapy before their operation and 2 patients were HIV positive. Results. Therapeutic procedures included completion pneumonectomy (n ⴝ 1), lobectomy (n ⴝ 6), segmentectomy (n ⴝ 1), and bilateral wedge resection (n ⴝ 1). Diagnostic procedures included lobectomy (n ⴝ 1) and wedge resection (n ⴝ 8). Complete resection could be achieved in 15 patients (83%). There was no in-hospital mortality. Postoperative complications included prolonged air leak (5 of 18 patients, 27.7%) and pleural
effusion requiring insertion of a new chest tube (3 of 18 patients, 16.6%). Mean hospital stay was 14 ⴞ 8 days. Follow-up was 100% complete. Eleven patients received antimycobacterial chemotherapy for 4 to 24 months, postoperatively. Late mortality was 11% and was unrelated to progression of mycobacterial disease. After the operation, the sputum remained positive in only 2 patients (11%) with incomplete resections. Fourteen patients were asymptomatic with no relapse at a mean follow-up of 38 ⴞ 22 months (range 85 to 13 months). Conclusions. Resection represents an important adjunct to chemotherapy for the treatment of M xenopi pulmonary disease. In the setting of localized nodular or cavitary disease, failure to respond to medical therapy, relapse after treatment discontinuation, coexistent aspergilloma or polymicrobial contamination, or patient intolerance of medical therapy, pulmonary resection can be undertaken with acceptable morbidity and mortality. (Ann Thorac Surg 2001;72:1877– 82) © 2001 by The Society of Thoracic Surgeons
D
clarify the operative indications and the results of surgical treatment.
uring the past 10 years effective chemotherapy has drastically reduced the need for surgical treatment for some atypical mycobacterial diseases [1– 4]. However, results of medical therapy remain unpredictable for other nontuberculous mycobacteria (NTM) such as Mycobacterium xenopi [5–7], with the condition not responding to initial chemotherapy or some patients deteriorating while receiving chemotherapy or relapsing several years after cessation of treatment [5]. Thus, M xenopi pulmonary disease mostly occurs in patients with chronic pulmonary disease and represents a problem because of the variable in vitro susceptibility of M xenopi to antimycobacterial drugs [5–7]. Therefore, surgical therapy has frequently been advocated as part of first-line treatment for M xenopi pulmonary disease [1, 5]. Because reports of surgical therapy for M xenopi have often been sparse and obtained from small series [5, 8 –11], we decided to review our 10-year experience obtained at a single institution to Accepted for publication Aug 17, 2001. Address reprint requests to Dr Riquet, Service de Chirurgie Thoracique, Hoˆpital Europe´en Georges Pompidou 20 rue Leblanc, 75015 Paris, France; e-mail: [email protected].
© 2001 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
Material and Methods Surgical and medical records of the Lae¨nnec hospital were screened retrospectively for all patients who had undergone thoracic operation for M xenopi pulmonary infection between January 1, 1991, and December 31, 2000. In addition, we undertook a chart review of all patients who had M xenopi isolated from surgical specimens by the bacteriology laboratory during the same period. Clinical and microbiologic data of the identified patients were reviewed carefully. Patients were included if they met the American Thoracic Society criteria for lung disease due to NTM: 1. If three sputum/bronchial wash results were available from the previous 12 months: three positive cultures with negative acid fast bacilli (AFB) smear results or two positive cultures and one positive AFB smear. 2. If only one bronchial wash was available, positive 0003-4975/01/$20.00 PII S0003-4975(01)03245-3
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Table 1. Numbers of Nontuberculous Mycobacteria Isolated From Surgical Specimens, 1991–2000 Microorganisms Mycobacterium Mycobacterium Mycobacterium Mycobacterium Mycobacterium
xenopi avium kansasii gordonae szulgai
AIDS Patients 2 1 0 0 0
Table 2. Comorbid Conditions in 18 Patients With Mycobacterium xenopi Pulmonary Disease
Non-AIDS Patients 16 3 2 1 1
culture with a 2⫹, 3⫹, or 4⫹ AFB smear, or 2⫹, 3⫹, or 4⫹ growth on solid media. 3. Transbronchial or lung biopsy yielding a NTM or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) and one or more sputums or bronchial washings positive for a NTM even in low numbers [1]. All patients had close clinical follow-up and news on recent medical conditions was obtained from the referring physicians or pulmonologists. All patients had postoperative evaluation including chest roentgenogram, chest computed tomography, pulmonary function tests, arterial blood gas analysis, bronchoscopy, and smear and culture of sputum. Microbiologic relapse was defined as two or more positive cultures with one or more cultures being positive for M xenopi or three or more positive cultures, which were all M xenopi smear negative after being culture negative a minimum of 4 months [1]. At our institution, between 1991 and 1996, LowensteinJensen medium (37°C) was used exclusively and examined weekly for 100 days, for the diagnosis of NTM disease. From November 1996, the Bacteriology Laboratory used both the Lowenstein-Jensen medium and the mycobacteria growth indicator tube (MGIT, BectonDickinson; BACTEC MGIT 960). The culture time in the MGIT system was reduced to 8 weeks. Identification of M xenopi was performed by standard biochemical testing and confirmed by molecular biology techniques (PCR, Innolipa). The Middlebrook 7H11 medium was used to determine minimal inhibitory concentration to the different antimycobacterial drugs. During the same period our pathologist used the Ziehl staining to detect AFB on surgical specimens.
Results Patients Between January 1, 1991, and December 31, 2000, 189 patients with pulmonary tuberculosis had pulmonary resection at our institution. During the same period, 26 patients with proven NTM disease, including 18 patients with M xenopi pulmonary infection, underwent pulmonary resection (Table 1). Patients (14 men and 4 women) ranged in age from 27 to 68 years (mean 50 ⫾ 12 years). Eleven patients smoked and 3 had a history of alcohol abuse. Comorbid conditions of the patients are reported in Table 2. The nutri-
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Conditions
Group 1 (No.)
Group 2 (No.)
3 2 2 1 1 1 1 0 1 0 0 0 1
5 1 0 1 1 1 0 1 0 1 1 1 0
COPD/emphysema Previous pulmonary tuberculosis Pulmonary aspergillosis AIDS Lung cancer Gastroduodenal ulcer (gastrectomy) Pneumothorax Larynx cancer Bronchiectasis Hodgkin lymphoma Hepatitis B and C Aortoiliac bypass Splenectomy COPD ⫽ chronic obstructive pulmonary disease.
tional status was generally poor in all but 5 patients. Factors contributing to weight loss and malnutrition were usually underlying chronic pulmonary disease or antimycobacterial therapy itself. Cough was the next most common symptom (9 of 18 patients), followed by expectoration (8 of 18), fever (3 of 18), hemoptysis (3 of 18), and chest pain (2 of 18). Two patients were HIV positive with CD4 cell counts being 40/mm3 and 70/mm3, respectively. Patients were separated into two groups according to operative indications (Table 3): group 1 (n ⫽ 9) consisted of patients operated on with a therapeutic intent, and group 2 (n ⫽ 9) included patients operated on with a diagnostic intent. Mean ages at operation were 50 ⫾ 11 and 51 ⫾ 13 years in groups 1 and 2, respectively. Seven men and 2 women were in each group.
Table 3. Indications for Operation in 18 Patients With Mycobacterium xenopi Pulmonary Disease Indications Group 1. Patients operated on with a therapeutic intent Excavated pulmonary nodule(s) associated with hemoptysis Destroyed pulmonary lobe or segment or disease progression under treatment Nonregressive pulmonary infiltrates associated with bilateral pneumothorax Group 2. Patients operated on with a diagnostic intent Large bulla(e) requiring resection and nodule(s) on the same lung Solitary pulmonary nodulea Multiple pulmonary nodulesb
No. 9 3 5 1 9 3 3 3
Operation was performed to rule out lung cancer (n ⫽ 1), larynx b Operation was carcinoma metastasis (n ⫽ 1), and lymphoma (n ⫽ 1). performed to rule out lymphoma in an HIV-positive patient (n ⫽ 1), tuberculosis (n ⫽ 1), or lung cancer (n ⫽ 1). a
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Radiologic Findings Ten patients had cavitary disease, 3 of whom had a completely destroyed pulmonary lobe with consolidation and multiple cavities. Four patients had multiple pulmonary nodules. Three patients had infected bullae associated with nodules. One patient had nonregressive right upper lobe and left upper lobe infiltrates. Four patients had mediastinal adenopathies diagnosed on chest computed tomography.
Bacteriologic Findings Four patients in group 1 had M xenopi found in the preoperative sputum on more than three successive samples. Those patients received antimycobacterial chemotherapy preoperatively, including clarithromycin, ofloxacin, ethambutol, and rifabutin for 4 to 8 months. All other patients had sputum cultures that were negative for M xenopi and no other mycobacterium could be isolated from sputum cultures preoperatively. Two patients in group 1 had coexistent aspergilloma diagnosed preoperatively. One patient in group 1 had polymicrobial infection (Enterobacter cloacae ⫹ Klebsiella pneumoniae) diagnosed preoperatively.
Surgical Procedures Indications for operation are reported in Table 3. Nine patients were operated on with a therapeutic intent and nine with a diagnostic intent. Four patients had a destroyed pulmonary lobe (n ⫽ 3) or segment (n ⫽ 1) with positive sputum persisting after 4 to 8 months of chemotherapy. In those patients, resectional surgical procedures were used to facilitate cure of the M xenopi infection. Three patients were operated on for resection of bullae with hydroaeric level and coexisting pulmonary nodule. Patients were operated on using double-lumen endotracheal tubes. Rib blocks and patient-controlled analgesia were used routinely. Nineteen operations were performed in 18 patients. In group 1, 1 patient had a completion right pneumonectomy performed 11 years after bilobectomy (upper and middle lobectomy) for lung cancer. Six patients had right upper lobectomy and 1 patient had a right apicodorsal segmentectomy. One patient had a bilateral apical wedge resection performed by video-assisted thoracic surgery. Those resections were associated with a pleural decortication in seven cases because of tight pleural adhesions. No muscle flap was used to improve healing of the bronchial stumps, even in patients who had positive sputum at the time of operation. However, every attempt was made to cover the bronchial stump in those patients with either a pleural or pericardial flap. In group 2, 1 patient had a right upper lobectomy and 8 patients had a wedge resection involving the left upper lobe (n ⫽ 2), left lower lobe (n ⫽ 2), both left upper and lower lobes (n ⫽ 2), right upper lobe (n ⫽ 1), and both right middle and lower lobes (n ⫽ 1). Two patients had their wedge resection performed by videothoracoscopy. Complete resection was achieved in
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15 patients (8 patients in group 1 and 7 patients in group 2). Surgical specimens demonstrated granulomatous inflammation in all patients. Direct microscopic examination (Ziehl staining) was AFB positive in five cases. All patients had M xenopi isolated from surgical specimens within 20 to 100 days, either with the Lowenstein-Jensen medium or the MGIT, or both. Mean time for isolation of M xenopi was 60 ⫾ 23 days (median 54 days) with the Lowenstein-Jensen medium and 40 ⫾ 15 days (median 35 days) with the MGIT. Only 2 patients had M xenopi infection that was resistant to rifampin. All other patients had M xenopi infection that responded to clarithromycin, ofloxacin/ciprofloxacin/sparfloxacin, ethambutol, rifampin, and rifabutin.
Postoperative Course and Follow-up In-hospital mortality was 0%. The average time to removal of all chest tubes was 11 ⫾ 9 days (range 4 to 26 days, median 6 days) in group 1, and 7 ⫾ 7 days (1 to 23 days, median 4.5 days) in group 2. Mean hospital stay was 16 ⫾ 7 days (range 7 to 26 days, median 13 days) in group 1, and 12.5 ⫾ 8.5 days (range 4 to 29 days, median 9.5 days) in group 2. Postoperative complications in group 1 patients included prolonged air leak (longer than 7 days) in 2 (22%) and pleural effusion requiring insertion of a new chest tube in 2 (22%). In group 2, 3 patients (33%) had prolonged air leak and 1 patient (11%) had pleural effusion requiring chest tube drainage. Follow-up was 100% complete. Mean follow-up was 36 ⫾ 21 months (range 13 to 85 months, median 30.5 months). Mean follow-up for group 1 patients was 36 ⫾ 21 months (range 18 to 85 months, median 34 months) and mean follow-up for group 2 patients was 36 ⫾ 23 months (range 13 to 76 months, median 27 months). There were 2 late deaths, one in group 1 resulting from a ruptured aortic aneurysm at 48 months, and the other in group 2 because of AIDS progression 8 months postoperatively. One patient in group 1 with severe emphysema was on a wait list for a pulmonary transplantation. Most patients were given antituberculous chemotherapy, postoperatively, based on pathologic examination, except patients with a preoperative diagnosis of M xenopi pulmonary disease (n ⫽ 4), who received a drug regimen adapted to the preoperative antibiogram. Two of those patients were given treatment for 12 months postoperatively. Considering that the diseased pulmonary lobe or segment had been resected, and that further treatment was not needed, the 2 other patients did not receive any postoperative chemotherapy. Most of the other patients were initially put on a regimen associating izoniazid, rifampicin, and ethambutol, before the results of specimen cultures revealed M xenopi. Then treatment was adapted to the antibiogram in each patient (Table 4). Only 2 patients, one in each group, had postoperative smears or cultures of sputum repeatedly positive for M xenopi. Those 2 patients had had incomplete resection. The first patient had a bilateral wedge resection performed in the upper left and upper right lobes. She returned to Japan and stopped chemotherapy after 4
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Table 4. Postoperative Chemotherapy, Results of Postoperative Smear or Culture of Sputum, and Follow-Up Patient No. Group 1 1 2 3 4 5 6 7 8 9 Group 2 10 11 12 13 14 15 16 17 18
Postoperative Chemotherapy
Duration (Months)
None None CLARI/ETHAM/OFLO None None CLARI/RIFAB/INH/ETHAM CLARI/RIFAB/ETHAM/OFLO CLARI/RIFAB/ETHAM CLARI/RIFAB/ETHAM/OFLO
Follow-up (Months)
⫺ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
48 (deceased) 85 37 34 34 23 23 22 18
⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺
76 8 (deceased) 54 53 49 27 22 20 13
4
6 12 6 12
INH/RIFAM/ETHAM/PZN None None CLARI/RIFAB/ETHAM/OFLO None INH/RIFAB/ETHAM INH/RIFAM/CIPRO CLARI/RIFAB/ETHAM/OFLO CLARI/ETHAM/OFLO
CIPRO ⫽ ciprofloxacin; CLARI ⫽ clarithromycin; RIFAB ⫽ rifabutin; RIFAM ⫽ rifampin.
Result of Cultures
6
24 4 5 12 6 ETHAM ⫽ ethambutol;
months. The second patient had chronic obstructive pulmonary disease and multiple bilateral nodules. He had a wedge resection and was given chemotherapy for 12 months postoperatively. These 2 patients were well postoperatively and were working and living normally. They have undergone regular evaluation in our outpatient clinic. The first patient has had no evidence of new pulmonary infiltrates or nodules. The second patient has had stable bilateral nodules on chest roentgenogram. All other patients (n ⫽ 16) had repeatedly negative sputum after their operations and have been well, except the 2 patients who died. They also have undergone regular evaluations in our outpatient clinic. Thirteen patients have been well and living normally, with chest roentgenogram and pulmonary function tests being satisfactory. One patient with severe emphysema was put on a wait list for a pulmonary transplantation.
Comment Mycobacterium xenopi is an atypical mycobacterium that was first isolated in 1959 [12] and first reported in the sputum of a patients with chronic obstructive pulmonary disease in 1965 [13]. It is a slow-growing scotochromogen producing a characteristic yellow pigment that has been reported to contaminate hot-water systems and to grow at increased temperature (42°C) [14]. This mycobacterium is generally considered a nonpathogenic colonizer of airways in nonimmunocompromised patients or in patients without chronic lung disease, but may become pathogenic in patients with immunologic compromise or in patients with chronic pulmonary disease (especially chronic obstructive pulmonary disease, emphysema, and cavitary disease) [14 –16].
INH ⫽ isoniazid;
OFLO ⫽ ofloxacin;
PZN ⫽ pyrazinamide;
In the United States, M avium-intracellulare and M kansasii are the most frequent NTM pathogens causing lung disease [1, 14]. In Europe and some parts of Canada (Ontario), M xenopi ranks second overall to M aviumintracellulare [14]. Recent publications have reported a dramatic rise in number of M xenopi isolates, probably because of the use of more sensitive laboratory isolation techniques (MGIT systems), rather than a true increase in clinical disease [14]. Although clinical M xenopi lung disease is still considered unusual even in HIV-positive patients, recent reports have indicated a dramatic rise in NTM disease due to M xenopi among AIDS patients [14 –17]. It is of interest to mention that no patient with M xenopi pulmonary disease has been operated on in our department from 1981 through 1990. All cases reported in the present series have been treated since 1994, attesting to better isolation techniques for the past 6 years. Treatment for M xenopi lung disease before the 1990s had represented a problem because of the variable in vitro susceptibility of this NTM to the common antimycobacterial drugs [6, 7]. Moreover, the results of susceptibility tests performed by the modal resistance method do not correlate with the clinical response to chemotherapy in most patients [18]. However, the addition of clarithromycin, rifabutin, and fluorinated quinolones to the available treatment regimens has improved the results of medical therapy, although these results have been barely reported in recent literature [3, 4, 19]. Most patients in our series were immunocompetent and demonstrated upper lobe cavitary disease, as reported by others [20]. Of the 2 HIV-positive patients, 1 had an excavated nodule in the right upper lobe and the other had multiple bilateral nodules. Those results are in accordance with the current literature [17, 20]. Of impor-
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tance, 7 patients in our series required decortication because of adjacent pleural disease. This feature should be kept in mind when planning a pulmonary resection in patients with M xenopi lung disease. Because of the poor response to medical therapy and the high prevalence of relapse after treatment discontinuation, some researchers have recommended early pulmonary resection in patients who can tolerate it [5, 11]. Banks and colleagues [5] reported a series of 47 patients treated between 1970 and 1979: 23% of patients were cured with chemotherapy alone and 26% eventually relapsed. Resection was performed in 5 patients with resultant cure in 4 and postoperative death in 1 [5]. These investigators stated that “earlier intervention while the disease remains limited is likely to carry a better chance of success” and that “resection might be part of first-line treatment and should usually be performed if patients fail to respond to initial chemotherapy or if they relapse” [5]. Bellamy and colleagues [8] reported 4 patients with bullous emphysema and clinical M xenopi lung disease. All patients had resectional operation with resultant cure in 3 [8]. Parrot and Grosset [11] reported a multiinstitutional series of 57 patients with M xenopi pulmonary infection who underwent operations in France between 1964 and 1985. In that series, 50% of patients were cured, but 13% had relapses [11]. Recently, Froidure and colleagues [2] reported 8 HIV-negative patients treated for M xenopi lung disease between 1994 and 1999: 2 were operated on with resultant cure, although they did not receive postoperative chemotherapy. In the present study, more than 85% of patients who had had surgical resection combined or not with chemotherapy have been cured. Only 2 patients have had repeated positive cultures of sputum, although their pulmonary disease has remain stable clinically and radiologically. Indications and timing for operation remain controversial and no clear recommendation has been published for the treatment of M xenopi pulmonary disease [1]. Most patients having pneumonectomy or lobectomy in our series, as in others, had been followed up for months or years before undergoing operation. It should be stressed that entire lobar or segmental destruction has occurred in most of these patients with localized and apparently indolent NTM disease. Four drugs regimens associating clarithromycin, rifabutin, and ethambutol with another antibiotic have demonstrated good results in AIDS patients with NTM disease [3, 4]. In the present series, all patients with cavitary disease who did receive this type of regimen preoperatively had pulmonary disease progression under treatment. Moreover, all patients in our series had surgical specimens that were positive for M xenopi, whether or not they received preoperative chemotherapy. Therefore, resection seems necessary to obtain reliable cure and prevent relapse in patients with M xenopi pulmonary disease who can tolerate resection, especially those with cavitary disease. Other arguments support early operation in patients with M xenopi pulmonary disease: more than 70% of such patients subsequently develop aspergilloma, a proportion much higher than in other NTM diseases [21]. Moreover, unsuspected lung
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cancer was diagnosed on surgical specimens in 2 patients in our series operated on with a therapeutic intent [22]. Based on other experiences, we elected to operate on patients with positive smears and cultures after at least 3 months of appropriate chemotherapy [10]. Thus, increased mortality and morbidity have been reported in patients with positive sputum at the time of operation [10, 23]. Considering the high rate of bronchopleural fistulas occurring in those patients, liberal use of muscle flaps have been recommended by other researchers [10]. We agree that in case of anticipated space problem in those patients, muscle flaps or thoracoplasty may be useful [10, 24]. In agreement with other researchers, we recommend operation in patients with localized disease before entire lobe or entire lung destruction [23–25]. Operation should also be considered an absolute indication in patients with massive hemoptysis, fungal balls, or polymicrobial infection. Careful preoperative evaluation with chest roentgenogram, chest computed tomography, pulmonary function tests, bronchoscopy, and quantitative ventilation/perfusion scans should be performed to determine which type of resection the patient can tolerate. Whenever possible, all diseased lung tissue should be resected to achieve a low reactivation rate. Lobectomy, segmentectomy, or wedge resection can be performed, depending on the patient’s functional status and on the lesion. Pneumonectomy should be considered only in patients with a destroyed lung and unilateral disease. Postoperative chemotherapy should be maintained in patients with incomplete resection for at least 12 months, depending on whether the smear and culture of sputum are negative. Based on our experience, postoperative chemotherapy is not mandatory in patients with complete resection. Whether postoperative chemotherapy should be maintained preventively in patients with AIDS or immunocompromise remains to be established. Patients whose condition does not respond to medical therapy or who cannot tolerate resection because of poor functional status or disseminated infectious process might benefit from collapse therapy with plombage [26]. Resectional surgical procedures can be performed in patients with M xenopi with low mortality and morbidity and resultant cure in more than 85%. Surgical procedures should be considered as part of first-line therapy for patients with localized disease, cavitary disease, persistent sputum positivity, intolerance to chemotherapy or prolonged chemotherapy, coexistent Aspergillus infection, polymicrobial contamination, and hemoptysis. When M xenopi is discovered incidentally on surgical specimens, postoperative chemotherapy seems appropriate in patients with AIDS, immunosuppression, or those with incomplete resection.
References 1. Wallace RJ Jr, Glassroth J, Griffith DE, et al. American Thoracic Society: diagnosis and treatment of disease caused by nontuberculous mycobacteria. Chest 1997;156 (Suppl):S1– 25. 2. Froidure M, Massin F, Duez JM, et al. Mycobacterium xenopi
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lung infection in HIV-negative patients: a propos of 8 cases (in French). Rev Mal Respir 2000;17:481–7. Dautzenberg B, Piperno D, Truffot-Pernot C, Chauvin JP. Clarithromycin in the treatment of Mycobacterium avium lung infections in patients without AIDS: Clarithromycin Study Group of France. Chest 1995;107:1035– 40. Dautzenberg B. The use of rifabutin in Europe for the treatment of mycobacterial infection in AIDS patients. Infection 1997;25:63– 6. Banks J, Hunter AM, Campbell IA, Jenkins PA, Smith AP. Pulmonary infection with Mycobacterium xenopi: review of treatment and response. Thorax 1984;39:376– 82. Baugnee PE, Pouthier F, Delaunois L. Pulmonary mycobacteriosis due to Mycobacterium xenopi: in-vitro sensitivity to classical antitubercular agents and clinical development. Acta Clin Belg 1996;51:19–27. Tortoli E, Simonetti MT. Radiometric susceptibility testing of Mycobacterium xenopi. J Chemother 1995;7:114–7. Bellamy J, Leroy-Terquem E, Duhamel JP, et al. An infection by Mycobacterium xenopi in bullous emphysema: a report of four operated cases (in French). Rev Mal Respir 1987;4:261– 4. Moran JF, Alexander LG, Staub EW, Young WG Jr, Sealy WC. Long-term results of pulmonary resection for atypical mycobacterial disease. Ann Thorac Surg 1983;35:597– 604. Pomerantz M, Madsen L, Goble M, Iseman M. Surgical management of resistant mycobacterial tuberculosis and other mycobacterial pulmonary infections. Ann Thorac Surg 1991;52:1108–12. Parrot RG, Grosset JH. Post-surgical outcome of 57 patients with Mycobacterium xenopi pulmonary infection. Tubercle 1988;69:47–55. Schwabacher H. A strain of mycobacterium isolated from skin lesions of a cold-blooded animal, Xenopus laevis, and its relation to atypical acid-fast bacilli. J Hyg (London) 1959;57: 57– 67. Marks J, Schwabacher H. Infection due to Mycobacterium xenopi. BMJ 1965;1:32–3. Donnabella V, Salazar-Schicchi J, Bonk S, Hanna B, Rom WN. Increasing incidence of Mycobacterium xenopi at Bellevue Hospital. An emerging pathogen or a product of improved laboratory methods? Chest 2000;118:1365–70. El-Solh AA, Nopper J, Abul Khoudoud MR, et al. Clinical and radiographic manifestations of uncommon pulmonary
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Background. Results of medical therapy for Mycobacterium xenopi pulmonary infection remain unreliable. Pulmonary resection may be beneficial to patients whose disease is localized and who can tolerate a resectional operation. Methods. Eighteen patients underwent pulmonary resection between 1991 and 2000: 14 men and 4 women, with a mean age of 50 ⴞ 12 years (range 27 to 68 years). Indications for operation were either therapeutic (n ⴝ 9) or diagnostic (n ⴝ 9). Four patients received antimycobacterial chemotherapy before their operation and 2 patients were HIV positive. Results. Therapeutic procedures included completion pneumonectomy (n ⴝ 1), lobectomy (n ⴝ 6), segmentectomy (n ⴝ 1), and bilateral wedge resection (n ⴝ 1). Diagnostic procedures included lobectomy (n ⴝ 1) and wedge resection (n ⴝ 8). Complete resection could be achieved in 15 patients (83%). There was no in-hospital mortality. Postoperative complications included prolonged air leak (5 of 18 patients, 27.7%) and pleural
effusion requiring insertion of a new chest tube (3 of 18 patients, 16.6%). Mean hospital stay was 14 ⴞ 8 days. Follow-up was 100% complete. Eleven patients received antimycobacterial chemotherapy for 4 to 24 months, postoperatively. Late mortality was 11% and was unrelated to progression of mycobacterial disease. After the operation, the sputum remained positive in only 2 patients (11%) with incomplete resections. Fourteen patients were asymptomatic with no relapse at a mean follow-up of 38 ⴞ 22 months (range 85 to 13 months). Conclusions. Resection represents an important adjunct to chemotherapy for the treatment of M xenopi pulmonary disease. In the setting of localized nodular or cavitary disease, failure to respond to medical therapy, relapse after treatment discontinuation, coexistent aspergilloma or polymicrobial contamination, or patient intolerance of medical therapy, pulmonary resection can be undertaken with acceptable morbidity and mortality. (Ann Thorac Surg 2001;72:1877– 82) © 2001 by The Society of Thoracic Surgeons
D
clarify the operative indications and the results of surgical treatment.
uring the past 10 years effective chemotherapy has drastically reduced the need for surgical treatment for some atypical mycobacterial diseases [1– 4]. However, results of medical therapy remain unpredictable for other nontuberculous mycobacteria (NTM) such as Mycobacterium xenopi [5–7], with the condition not responding to initial chemotherapy or some patients deteriorating while receiving chemotherapy or relapsing several years after cessation of treatment [5]. Thus, M xenopi pulmonary disease mostly occurs in patients with chronic pulmonary disease and represents a problem because of the variable in vitro susceptibility of M xenopi to antimycobacterial drugs [5–7]. Therefore, surgical therapy has frequently been advocated as part of first-line treatment for M xenopi pulmonary disease [1, 5]. Because reports of surgical therapy for M xenopi have often been sparse and obtained from small series [5, 8 –11], we decided to review our 10-year experience obtained at a single institution to Accepted for publication Aug 17, 2001. Address reprint requests to Dr Riquet, Service de Chirurgie Thoracique, Hoˆpital Europe´en Georges Pompidou 20 rue Leblanc, 75015 Paris, France; e-mail: [email protected].
© 2001 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
Material and Methods Surgical and medical records of the Lae¨nnec hospital were screened retrospectively for all patients who had undergone thoracic operation for M xenopi pulmonary infection between January 1, 1991, and December 31, 2000. In addition, we undertook a chart review of all patients who had M xenopi isolated from surgical specimens by the bacteriology laboratory during the same period. Clinical and microbiologic data of the identified patients were reviewed carefully. Patients were included if they met the American Thoracic Society criteria for lung disease due to NTM: 1. If three sputum/bronchial wash results were available from the previous 12 months: three positive cultures with negative acid fast bacilli (AFB) smear results or two positive cultures and one positive AFB smear. 2. If only one bronchial wash was available, positive 0003-4975/01/$20.00 PII S0003-4975(01)03245-3
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Table 1. Numbers of Nontuberculous Mycobacteria Isolated From Surgical Specimens, 1991–2000 Microorganisms Mycobacterium Mycobacterium Mycobacterium Mycobacterium Mycobacterium
xenopi avium kansasii gordonae szulgai
AIDS Patients 2 1 0 0 0
Table 2. Comorbid Conditions in 18 Patients With Mycobacterium xenopi Pulmonary Disease
Non-AIDS Patients 16 3 2 1 1
culture with a 2⫹, 3⫹, or 4⫹ AFB smear, or 2⫹, 3⫹, or 4⫹ growth on solid media. 3. Transbronchial or lung biopsy yielding a NTM or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) and one or more sputums or bronchial washings positive for a NTM even in low numbers [1]. All patients had close clinical follow-up and news on recent medical conditions was obtained from the referring physicians or pulmonologists. All patients had postoperative evaluation including chest roentgenogram, chest computed tomography, pulmonary function tests, arterial blood gas analysis, bronchoscopy, and smear and culture of sputum. Microbiologic relapse was defined as two or more positive cultures with one or more cultures being positive for M xenopi or three or more positive cultures, which were all M xenopi smear negative after being culture negative a minimum of 4 months [1]. At our institution, between 1991 and 1996, LowensteinJensen medium (37°C) was used exclusively and examined weekly for 100 days, for the diagnosis of NTM disease. From November 1996, the Bacteriology Laboratory used both the Lowenstein-Jensen medium and the mycobacteria growth indicator tube (MGIT, BectonDickinson; BACTEC MGIT 960). The culture time in the MGIT system was reduced to 8 weeks. Identification of M xenopi was performed by standard biochemical testing and confirmed by molecular biology techniques (PCR, Innolipa). The Middlebrook 7H11 medium was used to determine minimal inhibitory concentration to the different antimycobacterial drugs. During the same period our pathologist used the Ziehl staining to detect AFB on surgical specimens.
Results Patients Between January 1, 1991, and December 31, 2000, 189 patients with pulmonary tuberculosis had pulmonary resection at our institution. During the same period, 26 patients with proven NTM disease, including 18 patients with M xenopi pulmonary infection, underwent pulmonary resection (Table 1). Patients (14 men and 4 women) ranged in age from 27 to 68 years (mean 50 ⫾ 12 years). Eleven patients smoked and 3 had a history of alcohol abuse. Comorbid conditions of the patients are reported in Table 2. The nutri-
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Conditions
Group 1 (No.)
Group 2 (No.)
3 2 2 1 1 1 1 0 1 0 0 0 1
5 1 0 1 1 1 0 1 0 1 1 1 0
COPD/emphysema Previous pulmonary tuberculosis Pulmonary aspergillosis AIDS Lung cancer Gastroduodenal ulcer (gastrectomy) Pneumothorax Larynx cancer Bronchiectasis Hodgkin lymphoma Hepatitis B and C Aortoiliac bypass Splenectomy COPD ⫽ chronic obstructive pulmonary disease.
tional status was generally poor in all but 5 patients. Factors contributing to weight loss and malnutrition were usually underlying chronic pulmonary disease or antimycobacterial therapy itself. Cough was the next most common symptom (9 of 18 patients), followed by expectoration (8 of 18), fever (3 of 18), hemoptysis (3 of 18), and chest pain (2 of 18). Two patients were HIV positive with CD4 cell counts being 40/mm3 and 70/mm3, respectively. Patients were separated into two groups according to operative indications (Table 3): group 1 (n ⫽ 9) consisted of patients operated on with a therapeutic intent, and group 2 (n ⫽ 9) included patients operated on with a diagnostic intent. Mean ages at operation were 50 ⫾ 11 and 51 ⫾ 13 years in groups 1 and 2, respectively. Seven men and 2 women were in each group.
Table 3. Indications for Operation in 18 Patients With Mycobacterium xenopi Pulmonary Disease Indications Group 1. Patients operated on with a therapeutic intent Excavated pulmonary nodule(s) associated with hemoptysis Destroyed pulmonary lobe or segment or disease progression under treatment Nonregressive pulmonary infiltrates associated with bilateral pneumothorax Group 2. Patients operated on with a diagnostic intent Large bulla(e) requiring resection and nodule(s) on the same lung Solitary pulmonary nodulea Multiple pulmonary nodulesb
No. 9 3 5 1 9 3 3 3
Operation was performed to rule out lung cancer (n ⫽ 1), larynx b Operation was carcinoma metastasis (n ⫽ 1), and lymphoma (n ⫽ 1). performed to rule out lymphoma in an HIV-positive patient (n ⫽ 1), tuberculosis (n ⫽ 1), or lung cancer (n ⫽ 1). a
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Radiologic Findings Ten patients had cavitary disease, 3 of whom had a completely destroyed pulmonary lobe with consolidation and multiple cavities. Four patients had multiple pulmonary nodules. Three patients had infected bullae associated with nodules. One patient had nonregressive right upper lobe and left upper lobe infiltrates. Four patients had mediastinal adenopathies diagnosed on chest computed tomography.
Bacteriologic Findings Four patients in group 1 had M xenopi found in the preoperative sputum on more than three successive samples. Those patients received antimycobacterial chemotherapy preoperatively, including clarithromycin, ofloxacin, ethambutol, and rifabutin for 4 to 8 months. All other patients had sputum cultures that were negative for M xenopi and no other mycobacterium could be isolated from sputum cultures preoperatively. Two patients in group 1 had coexistent aspergilloma diagnosed preoperatively. One patient in group 1 had polymicrobial infection (Enterobacter cloacae ⫹ Klebsiella pneumoniae) diagnosed preoperatively.
Surgical Procedures Indications for operation are reported in Table 3. Nine patients were operated on with a therapeutic intent and nine with a diagnostic intent. Four patients had a destroyed pulmonary lobe (n ⫽ 3) or segment (n ⫽ 1) with positive sputum persisting after 4 to 8 months of chemotherapy. In those patients, resectional surgical procedures were used to facilitate cure of the M xenopi infection. Three patients were operated on for resection of bullae with hydroaeric level and coexisting pulmonary nodule. Patients were operated on using double-lumen endotracheal tubes. Rib blocks and patient-controlled analgesia were used routinely. Nineteen operations were performed in 18 patients. In group 1, 1 patient had a completion right pneumonectomy performed 11 years after bilobectomy (upper and middle lobectomy) for lung cancer. Six patients had right upper lobectomy and 1 patient had a right apicodorsal segmentectomy. One patient had a bilateral apical wedge resection performed by video-assisted thoracic surgery. Those resections were associated with a pleural decortication in seven cases because of tight pleural adhesions. No muscle flap was used to improve healing of the bronchial stumps, even in patients who had positive sputum at the time of operation. However, every attempt was made to cover the bronchial stump in those patients with either a pleural or pericardial flap. In group 2, 1 patient had a right upper lobectomy and 8 patients had a wedge resection involving the left upper lobe (n ⫽ 2), left lower lobe (n ⫽ 2), both left upper and lower lobes (n ⫽ 2), right upper lobe (n ⫽ 1), and both right middle and lower lobes (n ⫽ 1). Two patients had their wedge resection performed by videothoracoscopy. Complete resection was achieved in
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15 patients (8 patients in group 1 and 7 patients in group 2). Surgical specimens demonstrated granulomatous inflammation in all patients. Direct microscopic examination (Ziehl staining) was AFB positive in five cases. All patients had M xenopi isolated from surgical specimens within 20 to 100 days, either with the Lowenstein-Jensen medium or the MGIT, or both. Mean time for isolation of M xenopi was 60 ⫾ 23 days (median 54 days) with the Lowenstein-Jensen medium and 40 ⫾ 15 days (median 35 days) with the MGIT. Only 2 patients had M xenopi infection that was resistant to rifampin. All other patients had M xenopi infection that responded to clarithromycin, ofloxacin/ciprofloxacin/sparfloxacin, ethambutol, rifampin, and rifabutin.
Postoperative Course and Follow-up In-hospital mortality was 0%. The average time to removal of all chest tubes was 11 ⫾ 9 days (range 4 to 26 days, median 6 days) in group 1, and 7 ⫾ 7 days (1 to 23 days, median 4.5 days) in group 2. Mean hospital stay was 16 ⫾ 7 days (range 7 to 26 days, median 13 days) in group 1, and 12.5 ⫾ 8.5 days (range 4 to 29 days, median 9.5 days) in group 2. Postoperative complications in group 1 patients included prolonged air leak (longer than 7 days) in 2 (22%) and pleural effusion requiring insertion of a new chest tube in 2 (22%). In group 2, 3 patients (33%) had prolonged air leak and 1 patient (11%) had pleural effusion requiring chest tube drainage. Follow-up was 100% complete. Mean follow-up was 36 ⫾ 21 months (range 13 to 85 months, median 30.5 months). Mean follow-up for group 1 patients was 36 ⫾ 21 months (range 18 to 85 months, median 34 months) and mean follow-up for group 2 patients was 36 ⫾ 23 months (range 13 to 76 months, median 27 months). There were 2 late deaths, one in group 1 resulting from a ruptured aortic aneurysm at 48 months, and the other in group 2 because of AIDS progression 8 months postoperatively. One patient in group 1 with severe emphysema was on a wait list for a pulmonary transplantation. Most patients were given antituberculous chemotherapy, postoperatively, based on pathologic examination, except patients with a preoperative diagnosis of M xenopi pulmonary disease (n ⫽ 4), who received a drug regimen adapted to the preoperative antibiogram. Two of those patients were given treatment for 12 months postoperatively. Considering that the diseased pulmonary lobe or segment had been resected, and that further treatment was not needed, the 2 other patients did not receive any postoperative chemotherapy. Most of the other patients were initially put on a regimen associating izoniazid, rifampicin, and ethambutol, before the results of specimen cultures revealed M xenopi. Then treatment was adapted to the antibiogram in each patient (Table 4). Only 2 patients, one in each group, had postoperative smears or cultures of sputum repeatedly positive for M xenopi. Those 2 patients had had incomplete resection. The first patient had a bilateral wedge resection performed in the upper left and upper right lobes. She returned to Japan and stopped chemotherapy after 4
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Table 4. Postoperative Chemotherapy, Results of Postoperative Smear or Culture of Sputum, and Follow-Up Patient No. Group 1 1 2 3 4 5 6 7 8 9 Group 2 10 11 12 13 14 15 16 17 18
Postoperative Chemotherapy
Duration (Months)
None None CLARI/ETHAM/OFLO None None CLARI/RIFAB/INH/ETHAM CLARI/RIFAB/ETHAM/OFLO CLARI/RIFAB/ETHAM CLARI/RIFAB/ETHAM/OFLO
Follow-up (Months)
⫺ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
48 (deceased) 85 37 34 34 23 23 22 18
⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺
76 8 (deceased) 54 53 49 27 22 20 13
4
6 12 6 12
INH/RIFAM/ETHAM/PZN None None CLARI/RIFAB/ETHAM/OFLO None INH/RIFAB/ETHAM INH/RIFAM/CIPRO CLARI/RIFAB/ETHAM/OFLO CLARI/ETHAM/OFLO
CIPRO ⫽ ciprofloxacin; CLARI ⫽ clarithromycin; RIFAB ⫽ rifabutin; RIFAM ⫽ rifampin.
Result of Cultures
6
24 4 5 12 6 ETHAM ⫽ ethambutol;
months. The second patient had chronic obstructive pulmonary disease and multiple bilateral nodules. He had a wedge resection and was given chemotherapy for 12 months postoperatively. These 2 patients were well postoperatively and were working and living normally. They have undergone regular evaluation in our outpatient clinic. The first patient has had no evidence of new pulmonary infiltrates or nodules. The second patient has had stable bilateral nodules on chest roentgenogram. All other patients (n ⫽ 16) had repeatedly negative sputum after their operations and have been well, except the 2 patients who died. They also have undergone regular evaluations in our outpatient clinic. Thirteen patients have been well and living normally, with chest roentgenogram and pulmonary function tests being satisfactory. One patient with severe emphysema was put on a wait list for a pulmonary transplantation.
Comment Mycobacterium xenopi is an atypical mycobacterium that was first isolated in 1959 [12] and first reported in the sputum of a patients with chronic obstructive pulmonary disease in 1965 [13]. It is a slow-growing scotochromogen producing a characteristic yellow pigment that has been reported to contaminate hot-water systems and to grow at increased temperature (42°C) [14]. This mycobacterium is generally considered a nonpathogenic colonizer of airways in nonimmunocompromised patients or in patients without chronic lung disease, but may become pathogenic in patients with immunologic compromise or in patients with chronic pulmonary disease (especially chronic obstructive pulmonary disease, emphysema, and cavitary disease) [14 –16].
INH ⫽ isoniazid;
OFLO ⫽ ofloxacin;
PZN ⫽ pyrazinamide;
In the United States, M avium-intracellulare and M kansasii are the most frequent NTM pathogens causing lung disease [1, 14]. In Europe and some parts of Canada (Ontario), M xenopi ranks second overall to M aviumintracellulare [14]. Recent publications have reported a dramatic rise in number of M xenopi isolates, probably because of the use of more sensitive laboratory isolation techniques (MGIT systems), rather than a true increase in clinical disease [14]. Although clinical M xenopi lung disease is still considered unusual even in HIV-positive patients, recent reports have indicated a dramatic rise in NTM disease due to M xenopi among AIDS patients [14 –17]. It is of interest to mention that no patient with M xenopi pulmonary disease has been operated on in our department from 1981 through 1990. All cases reported in the present series have been treated since 1994, attesting to better isolation techniques for the past 6 years. Treatment for M xenopi lung disease before the 1990s had represented a problem because of the variable in vitro susceptibility of this NTM to the common antimycobacterial drugs [6, 7]. Moreover, the results of susceptibility tests performed by the modal resistance method do not correlate with the clinical response to chemotherapy in most patients [18]. However, the addition of clarithromycin, rifabutin, and fluorinated quinolones to the available treatment regimens has improved the results of medical therapy, although these results have been barely reported in recent literature [3, 4, 19]. Most patients in our series were immunocompetent and demonstrated upper lobe cavitary disease, as reported by others [20]. Of the 2 HIV-positive patients, 1 had an excavated nodule in the right upper lobe and the other had multiple bilateral nodules. Those results are in accordance with the current literature [17, 20]. Of impor-
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tance, 7 patients in our series required decortication because of adjacent pleural disease. This feature should be kept in mind when planning a pulmonary resection in patients with M xenopi lung disease. Because of the poor response to medical therapy and the high prevalence of relapse after treatment discontinuation, some researchers have recommended early pulmonary resection in patients who can tolerate it [5, 11]. Banks and colleagues [5] reported a series of 47 patients treated between 1970 and 1979: 23% of patients were cured with chemotherapy alone and 26% eventually relapsed. Resection was performed in 5 patients with resultant cure in 4 and postoperative death in 1 [5]. These investigators stated that “earlier intervention while the disease remains limited is likely to carry a better chance of success” and that “resection might be part of first-line treatment and should usually be performed if patients fail to respond to initial chemotherapy or if they relapse” [5]. Bellamy and colleagues [8] reported 4 patients with bullous emphysema and clinical M xenopi lung disease. All patients had resectional operation with resultant cure in 3 [8]. Parrot and Grosset [11] reported a multiinstitutional series of 57 patients with M xenopi pulmonary infection who underwent operations in France between 1964 and 1985. In that series, 50% of patients were cured, but 13% had relapses [11]. Recently, Froidure and colleagues [2] reported 8 HIV-negative patients treated for M xenopi lung disease between 1994 and 1999: 2 were operated on with resultant cure, although they did not receive postoperative chemotherapy. In the present study, more than 85% of patients who had had surgical resection combined or not with chemotherapy have been cured. Only 2 patients have had repeated positive cultures of sputum, although their pulmonary disease has remain stable clinically and radiologically. Indications and timing for operation remain controversial and no clear recommendation has been published for the treatment of M xenopi pulmonary disease [1]. Most patients having pneumonectomy or lobectomy in our series, as in others, had been followed up for months or years before undergoing operation. It should be stressed that entire lobar or segmental destruction has occurred in most of these patients with localized and apparently indolent NTM disease. Four drugs regimens associating clarithromycin, rifabutin, and ethambutol with another antibiotic have demonstrated good results in AIDS patients with NTM disease [3, 4]. In the present series, all patients with cavitary disease who did receive this type of regimen preoperatively had pulmonary disease progression under treatment. Moreover, all patients in our series had surgical specimens that were positive for M xenopi, whether or not they received preoperative chemotherapy. Therefore, resection seems necessary to obtain reliable cure and prevent relapse in patients with M xenopi pulmonary disease who can tolerate resection, especially those with cavitary disease. Other arguments support early operation in patients with M xenopi pulmonary disease: more than 70% of such patients subsequently develop aspergilloma, a proportion much higher than in other NTM diseases [21]. Moreover, unsuspected lung
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cancer was diagnosed on surgical specimens in 2 patients in our series operated on with a therapeutic intent [22]. Based on other experiences, we elected to operate on patients with positive smears and cultures after at least 3 months of appropriate chemotherapy [10]. Thus, increased mortality and morbidity have been reported in patients with positive sputum at the time of operation [10, 23]. Considering the high rate of bronchopleural fistulas occurring in those patients, liberal use of muscle flaps have been recommended by other researchers [10]. We agree that in case of anticipated space problem in those patients, muscle flaps or thoracoplasty may be useful [10, 24]. In agreement with other researchers, we recommend operation in patients with localized disease before entire lobe or entire lung destruction [23–25]. Operation should also be considered an absolute indication in patients with massive hemoptysis, fungal balls, or polymicrobial infection. Careful preoperative evaluation with chest roentgenogram, chest computed tomography, pulmonary function tests, bronchoscopy, and quantitative ventilation/perfusion scans should be performed to determine which type of resection the patient can tolerate. Whenever possible, all diseased lung tissue should be resected to achieve a low reactivation rate. Lobectomy, segmentectomy, or wedge resection can be performed, depending on the patient’s functional status and on the lesion. Pneumonectomy should be considered only in patients with a destroyed lung and unilateral disease. Postoperative chemotherapy should be maintained in patients with incomplete resection for at least 12 months, depending on whether the smear and culture of sputum are negative. Based on our experience, postoperative chemotherapy is not mandatory in patients with complete resection. Whether postoperative chemotherapy should be maintained preventively in patients with AIDS or immunocompromise remains to be established. Patients whose condition does not respond to medical therapy or who cannot tolerate resection because of poor functional status or disseminated infectious process might benefit from collapse therapy with plombage [26]. Resectional surgical procedures can be performed in patients with M xenopi with low mortality and morbidity and resultant cure in more than 85%. Surgical procedures should be considered as part of first-line therapy for patients with localized disease, cavitary disease, persistent sputum positivity, intolerance to chemotherapy or prolonged chemotherapy, coexistent Aspergillus infection, polymicrobial contamination, and hemoptysis. When M xenopi is discovered incidentally on surgical specimens, postoperative chemotherapy seems appropriate in patients with AIDS, immunosuppression, or those with incomplete resection.
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