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Ann Thorac Surg 1999;68:321-325
© 1999 The Society of Thoracic Surgeons

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Original Articles

Surgical aspects of resection for suspected invasive pulmonary fungal infection in neutropenic patients

^a Clinic for Cardiothoracic Surgery, Department of Surgery, University Hospital, Basel, Switzerland
^b Divisions of Pneumology and Hematology, Department of Internal Medicine, University Hospital, Basel, Switzerland

Address reprint requests to Dr Habicht, Clinic for Cardiothoracic Surgery, University Hospital Basel, CH-4031 Basel, Switzerland

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. Morbidity and mortality of early resection of invasive pulmonary fungal disease in neutropenic patients are still considered prohibitive for surgical treatment.

Methods. We retrospectively analyzed results of 28 (16 men, 12 women; mean age, 38.9 years) consecutive neutropenic hematologic patients who had lung resections for suspicion of invasive pulmonary fungal disease.

Results. We did 28 lung resections (19 lobectomies, one bilobectomy, eight single or multiple wedge resections including three video-assisted wedge resections). The disease was proved histologically in 22 (78.6%) cases. Intraoperative difficulties, such as diffuse oozing or mycotic infiltration, and solid postinflammatory adhesions were encountered in 5 (17.8%) and 6 (21.4%) patients respectively. In one case (3.6%) it lead to a major intraoperative hemorrhage. There were no intraoperative deaths, overall 30-day mortality rate was two of 28 (7.1%), overall 90-day mortality rate was seven of 28 (25%), with one death (3.6%) possibly related to surgery. Minor surgery-related complications were seen in ten (35.7%) cases, major surgery-related complications occurred in three (10.7%) cases. Twelve of 22 patients (54.5%) with proven invasive fungal infection are currently alive (mean follow-up, 32.3 months).

Conclusions. Surgery-related complications and mortality are acceptable for this high risk group of patients. Resection should be carried out early for diagnostic as well as therapeutic reasons.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
During the past decade, surgical therapy has been advocated as an adjunct to standard medical treatment of localized invasive pulmonary fungal disease, with Aspergillus being the most common cause [1–5]. When pulmonary Aspergillus infection occurs, patients with hematologic neutropenia fare worse than other immunodeficient patients, ie, patients with human immunodeficiency virus infection or solid organ transplants. Invasive disease occurs more often and results in a high mortality rate [6]. In a rabbit model [7], there was more extensive infiltration and angioinvasion as well as predominant intraalveolar hemorrhage after chemotherapy-induced profound neutropenia in comparison with a group of animals receiving cyclosporine plus corticoids for prevention of organ transplant rejection. Another argument supporting resection is that definite diagnosis of invasive pulmonary aspergillosis is difficult to obtain without tissue resection, as sputum and bronchoalveolar lavage often give negative results for fungal growth [3, 8].

An important complication of conservative treatment of invasive fungal disease is hemoptysis and pulmonary hemorrhage. The incidence of lethal bronchial hemorrhage in patients with hematologic disorders is not stated in the surgical literature, but there are some reports of successful emergency operations and embolization techniques. However, the importance of this lethal complication can be derived from the fact that it is often addressed incidentally in reports of successful elective operations [1, 2, 4, 5]. Unfortunately, the risk of hemoptysis also seems higher in the phase of granulocyte recovery [1, 9]. Neutrophils are important in clearing the disease; however, they are believed to cause an influx of proteolytic enzymes and destruction of vascular structures [1, 10].

Early lung resection during agranulocytosis might still be rejected in these patients because of uncertain prognosis of the underlying hematologic disease and because of fear of hemorrhage caused by thrombopenia. Therefore we addressed in detail the intraoperative difficulties, bleeding problems, and perioperative complications in this study.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
Between January 1983 and December 1997, 28 consecutive patients (16 men and 12 women; mean age, 38.9 years; range, 9 to 68 years) had pulmonary resection for suspicion of invasive pulmonary aspergillosis. The underlying disease was leukemia (mainly acute and chronic myeloid) in 19 cases, severe aplastic anemia in 7 cases, and myelodysplastic syndrome and Non-Hodgkin’s lymphoma in 1 case each. Treatment before clinical development of pulmonary disease had been high-dose chemotherapy in 18 patients and bone-marrow or peripheral blood stem cell transplantation in 4 patients. Six patients with idiopathic severe aplastic anemia had received anti-lymphocyte-globulin.

In 22 patients (78.6%) the diagnosis of fungal disease was subsequently proven histologically in the tissue from the resected lung. The fungi were invasive aspergillosis in 20 cases (90.9%) and invasive mucormycosis in 2 (9.1%). Histologically, angioinvasiveness could be documented in all but one case (95.4%). In 6 patients (21.4%) no fungal infection was detectable in the resected lung specimen and histology showed bacterial abscess, lung infarction, scar tissue, or circumscribed intraalveolar fibrosing alveolitis.

All patients had been neutropenic (neutrophil count < 0.5 x 10⁹/L) before the operation and 22 (78.6%) were neutropenic at the day of resection (median neutrophil count, 0.05 x 10⁹/L; range, 0.002 to 7.46 x 10⁹/L). On the day of operation, median hemoglobin was 10.3 g/dL (range, 7.3 to 12.2 g/dL), and median platelet-count was 35 x 10⁹/L (range, 5 to 354 x 10⁹/L). Diagnostic radiology showed localized infiltrates in all patients, with solitary lesions in 22 and multiple (focal) lesions in 6. Sputum was positive for fungal infection preoperatively in only 1 case (4.5%), and preoperative bronchoalveolar lavage was negative in all 15 cases in which it was done.

Nineteen patients had lobectomies, 1 had a bilobectomy, 5 had single or multiple wedge resections, and 3 had wedge resections by video-assisted thoracic operations. Duration of the operation ranged from 40 to 210 minutes (median, 120 minutes). Median intraoperative blood loss was 300 mL (range, < 50 to 1,000 mL). Intraoperatively, a median of 0.9 packs (range, 0 to 2) of erythrocytes were given, and a median of 2.0 packs (range, 0 to 4) were given additionally until postoperative day 2. Perioperatively at least two platelet concentrates were transfused, with a goal of 40 to 50 x 10⁹/L, beginning immediately before and continuing throughout the operation. A median of 2.2 (range, 0 to 5) platelet concentrates were administered within the first postoperative week. Median drainage time was 2 days (range, 1 to 27 days). All patients except 1 were extubated immediately postoperatively, and median length of intensive care stay was 1 day (range, 0 to 10 days). Almost all patients (27 of 28, 96.4%) were treated with broad-spectrum antibiotics, and 22 patients (78.6%) had received antifungal treatment with amphotericine B for a median duration of 11 days (range, 1 to 39 days) preoperatively. Antifungal treatment with amphotericine B was continued postoperatively in cases with proven mycotic disease.

The patients were treated by the hemato-oncologic isolation unit under prospectively recorded standardized conditions according to defined protocols for hematologic malignant diseases or severe idiopathic aplastic anemia [11, 12]. Patients who had solid organ transplantation or human immunodeficiency virus infection were not included in this study. Detailed review of all hospital records was done, with focus on operation protocols and data concerning perioperative morbidity and death. Detailed results of preoperative diagnostic procedures (computed tomography, fungal culture of sputum and tracheal secretions, bronchoscopy, and bronchoalveolar lavage) have been reported by us previously [8, 13].

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Intraoperative difficulties and complications
No anesthesiologic complications were observed, ie, no major bleeding episodes from invasive monitoring, central venous and arterial catheters, or from single- or double-lumen intubation. During operation, conspicuous diffuse oozing leading to prolonged hemostasis was noted in 5 cases (17.8%), rendering dissection difficult when combined with inflammatory adhesions and scar tissue adjacent to mycotic lesions. Adhesions and inflammatory tissue near hilar structures and fissures were a major hindrance in 3 cases (10.7%). Mycotic invasion and solid postinflammatory ingrowth of scar tissue into important structures were present in 3 cases (10.7%). In 1 patient mycotic infiltration of the left upper lung vein was noted, but it did not delay the operative procedure. In another case there was a solid connection of tissue to the distal aortic arch which could be divided only by sharp dissection. Intraoperatively, the findings had strongly suggested mycotic infiltration, but it could not be confirmed by histologic analysis, which found only dense scar tissue. In the third case, there was mycotic infiltration of invasive aspergillosis into the pericardium. In this case en bloc resection with pericardium was not possible, as the phrenic nerve passed through the center of an ulceration (Fig 1) and was anatomically and functionally intact. Also, the pericardium could not be detached from the cardiac surface, suggesting infiltration into the epicardium. Extensive resection was not justified because of likely loss of pulmonary function, questionable radicality, and intraoperative risk. Therefore, after lobectomy a collagen sponge impregnated with an antifungal agent was applied to the pericardium with fibrin glue, and the patient recovered without further events or recurrent fungal infection (follow-up, 22 months). The preceding difficulties led to a major intraoperative complication (hemorrhage, 1,000 mL) in only one case (3.6%), which could be controlled without evident hemodynamic compromise.

View larger version (74K): [in this window] [in a new window]   Fig 1. (A) Computed tomographic scan of a typical solitary lesion in a neutropenic 45-year-old man with early B-cell acute lymphatic leukemia. The lesion is in the left superior lobe. Note that it is adjacent to the pericardium. (B) Infiltration of pericardium by invasive aspergillosis, with the phrenic nerve passing through the center of infiltration. Inflammatory thickening of surrounding pericardium. Same patient as in A.

Major complications occurred in 3 patients (10.7%). One patient needed reoperation for a bronchial stump dehiscence several weeks after right upper lobectomy. In this case, dissection of the lobar hilus had been difficult because of adhesions and scar tissue. The postoperative course had been uneventful during the first 2 weeks; however, fever developed and a peribronchial pocket was visible on chest roentgenogram and computed tomographic scan. During reoperation the stump was resutured using pericardial flap reinforcement. There was no fungal growth in fluid and tissue specimens taken during reoperation, and the postoperative course was uneventful except for the need of chest tube drainage for several days after a pneumothorax reoccurred. The patient was discharged on postoperative day 29. The second major complication that might be attributed to the surgical procedure was persistent air leak after lobectomy (without stump dehiscence). Later, pleural aspergillosis occurred and the patient died of septicemia in persisting aplasia on postoperative day 56. Another major complication was a life-threatening bleeding episode into the abdomen resulting from computed tomography-guided marking of a peripheral lesion in the right lower lobe which was done a few hours preoperatively. The video-assisted resection itself was uneventful; however, the patient required emergency laparatomy after severe hemodynamic deterioration during the first postoperative night as a result of bleeding (3,000 mL) into the right upper abdomen through a 5-mm tear of the liver capsule caused by a tangential lesion of the liver with the 21-gauge marking needle. The patient’s initial recovery was uneventful; however, the patient died 6 weeks postoperatively of leukemic recurrence with intracerebral hemorrhage caused by Aspergillus.

There were no deep wound infections or empyemas necessitating an operation or drainage and no postoperative pneumonias or episodes of pulmonary embolism.

The overall outcome was determined by the underlying disease or fungal recurrence. The 30-day mortality rate was 7.1% (2 of 28 patients). One patient died of necrotizing cholecystitis and bacterial septicemia on day 10 after lobectomy and the other died of relapsing Non-Hodgkin’s lymphoma and orbital aspergilloma on day 21. The overall 90-day mortality rate was 25% (7 of 28 patients). Causes included severe graft versus host disease, cerebral bleeding, pleural and cerebral aspergillosis, and relapsing acute myeloic leukemia. Only one death (3.6%) (pleural aspergillosis) might be attributed to the surgical procedure, as the mycotic lesion had been inside the lung, without any sign of pleural contact, at the time of lobectomy and the patient developed pleural dissemination afterwards.

Recurrent fungal infection developed in three cases (13.6%)—orbital and cerebral aspergilloma both resulting in death, and renal aspergilloma successfully treated by nephrectomy. Nineteen of 22 patients (86.4%) with proven pulmonary mycotic disease cleared their fungal infection. Fifteen of 28 patients (53.6%) were operated on and 12 of 22 patients (54.5%) with proven fungal infection are currently alive (mean follow-up, 32.3 months; range, 0.3 to 168 months).

	Comment

Top Abstract Introduction Patients and methods Results Comment References

 
Pulmonary aspergillosis is classified into allergic, invasive, and saprophytic infections [14]. Most authors who surgically treated pulmonary aspergillosis in the 1970s and 1980s [15–17] reported on the saprophytic forms colonizing preexisting lung cavities. Whereas the perioperative mortality rate was low in simple aspergilloma, the mortality rate in complex saprophytic forms was as high as 34%, and complications occurred in up to 78% of these cases, including empyema, prolonged air leak and bronchopleural fistula, respiratory insufficiency, pleural space hemorrhage, and wound infection [17]. At that time invasive aspergillosis was not regarded as an indication for surgical treatment in hematologic patients because the general opinion was that most of those patients would die of their underlying disease [18]. Since then several reports on surgical treatment of invasive pulmonary fungal disease in immunocompromized patients have shown increasing interest in surgical procedures as a diagnostic and therapeutic tool in this form of mycotic disease [1, 3, 5, 8, 13, 19, 20]. Because surgical treatment of complex saprophytic aspergillomas has created a grim image of surgical mortality and morbidity, we wish to renew the discussion on morbidity and mortality of surgical treatment of invasive pulmonary aspergillosis in neutropenic patients with hematologic disorders.

In contrast to complex saprophytic aspergilloma, localized invasive aspergillosis is an acute disease without thick-walled cavities and often without adhesions. It usually occurs in younger patients with superior cardiopulmonary prerequisites. Whereas Daly and colleagues [17] reported that preexisting cystic lesions were present in 23 of 53 (43.4%) patients and mycobacteria or other chronic infections were found in 14 of 53 (26.4%) as well as bronchial carcinoma in two patients, we found that in patients with hematologic disease who have focal pulmonary lesions the lung is usually healthy and does not show those underlying disorders. In addition, the mean age was approximately 35 years, in contrast to nearly 60 years in the series of Daly and colleagues, and the overall condition of most patients was usually described as being surprisingly good [3]. Furthermore, extensive procedures such as pneumonectomy, cavernostomy, thoracoplasty, muscle-flap transposition, and open pleural windows were generally not necessary because of the different patient population and early intervention. For the reasons just mentioned, we consider it important to distinguish between classic operations for aspergilloma and operations for invasive aspergillosis in severely immunocompromised patients.

Complications and deaths in the above-mentioned studies are compiled in Table 1. In contrast to most other series, in our series all patients with the suspicion of pulmonary aspergillosis, not only on those in whom the diagnosis was eventually proven in the operative specimens, were operated on. Diagnosis cannot be proven preoperatively in many cases and the perioperative risk of surgical complications is equal even if the disease cannot be proven histologically. In our experience there is a 70% to 80% chance that focal lesions of the kind described are fungal in a neutropenic hematological patient population, even if sputum and bronchoalveolor lavage (BAL) cultures are negative. Although strict criteria were chosen (all reported postoperative bleeding episodes stated in the literature, not only those operated on) there was a low incidence (6%) of reported postoperative bleeding in the studies in Table 1 and a 5% incidence of major intraoperative hemorrhage caused by adhesions and difficult dissection rather than low platelet count. Perioperative bleeding complications therefore should be a reason to deny surgical treatment as long as platelets are administered. However any kind of thoracic puncture for diagnostic or therapeutic reasons, even with thin needles, is dangerous in thrombopenic patients, as we observed in the reported series. It should be considered an operative procedure and be done by experienced physicians after application of platelets.

Wong and associates [1] stated that the death of neutropenic patients from massive hemoptysis after invasive mycotic disease incited them to adopt an early and aggressive surgical policy in cases with focal lesions. Similarly, other authors [2, 4, 5] have observed deaths resulting from hemoptysis occurring up to 6 weeks after commencing amphotericin B [4] in patients who had not been operated on. In our view this policy should be supported, taking into account the acceptable surgery-related mortality and morbidity rates found in the present surgical series.

	References

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