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Ann Thorac Surg 1997;64:1441-1447
© 1997 The Society of Thoracic Surgeons
Departments of Surgery, Clinical Hematology, and Radiology, University of Burgundy, Dijon, France
Accepted for publication May 21, 1997.
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentReferences |
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Methods. Nineteen patients with hematologic malignancy, in whom invasive pulmonary aspergillosis developed during the course of neutropenia, had operations. Neutropenia lasted 28 days (range, 15 to 45 days). The preoperative diagnosis of invasive pulmonary aspergillosis was based on computed tomographic scan findings (halo or air crescent signs).
Results. Eight patients underwent emergency operations, before marrow recovery, for prevention of massive hemoptysis. The criterion for operation was an aspergillosis lesion that contacted the pulmonary artery on computed tomography. A lobectomy was performed in all cases. A sleeve resection of the pulmonary artery was necessary on two occasions. There was one postoperative death due to extensive aspergillosis. The length of hospitalization after operation was 13 days (range, 6 to 18 days). Seven patients were treated by elective resection of a residual mass (before hematologic therapy in 6 cases). The types of resection performed were lobectomy (n = 4), lingulectomy (n = 1), and wedge resection (n = 2). There were no postoperative deaths. The average length of stay before discharge from the hospital was 11 days (range, 7 to 20 days). The surgical resection was performed as a diagnostic procedure in the 4 remaining patients after an allotted time of 14 days (range, 4 to 24 days) from initiation of antifungal therapy.
Conclusions. The combination of antifungal agents and surgical resection is an efficient strategy for the treatment of invasive pulmonary aspergillosis in patients with hematologic malignancy.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Aspergillus has an important tropism for the vascular wall. During the marrow recovery phase, the white blood cells accelerate the process of necrosis increase the risk of hemorrhage by arterial perforation [5]. Therefore, an operation could be recommended in the setting of IPA located near a pulmonary artery (or its dividing branches). When the patient has recovered from neutropenia, a residual mass persists that will require medical treatment for several weeks before it disappears. Surgical resection of this residual mass may be necessary if treatment of the hematologic disease requires another chemotherapeutic regimen rapidly, with or without bone marrow transplantation. Finally, a surgical procedure can be used to confirm the diagnosis of aspergillosis when a pulmonary nodule persists despite antifungal treatment.
Here, we analyze the different surgical procedures used for the treatment of IPA their postoperative morbidity mortality rates.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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The clinical signs that clearly revealed IPA were hemoptysis in 8 cases, thoracic pain in 13 cases, and temperature above 39°C for 1 to 7 days in 14 patients. The neutropenia lasted on average for 16 days (range, 8 to 29 days) when the first symptoms occurred. Before operation, direct examination and cultures of bronchoalveolar lavage fluid were positive in 4 patients (Table 1
), Aspergillus antibody test was positive in 3 patients, Aspergillus antigenemia was positive in 1 patient, and Aspergillus antigen test was identified as positive in bronchoalveolar lavage fluid from 10 to 13 examined cases. The identification of an infiltrate on chest roentgenogram during a febrile episode in a neutropenic or bone marrow transplant patient resulted in a systematic search for invasive aspergillosis (Fig 1).
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) and the air crescent sign [7] (Fig 3). The halo sign is described as a mass-like infiltrate with a surrounding halo of ground-glass attenuation [6]. This sign is highly suggestive of IPA during neutropenia [6, 8]. The air crescent sign, which is described as a pulmonary cavitation, appears later at the time of bone marrow recovery [7]. The air crescent sign is not pathognomonic of aspergillosis, but in patients with hematologic malignancies and especially in leukemic patients, it is highly evocative of filamentous fungal disease [7]. The halo sign was present in 17 patients and the air crescent sign was observed in 2 patients. Overall, the diagnosis of IPA before operation was suspected because of positive cultures of bronchoalveolar lavage fluid and CT findings in 4 cases, and CT findings alone in the remaining 15 cases (see Table 1
). The time between the first clinical warning sign and the start of antifungal treatment was 2.6 days (range, 0 to 17 days). The patients received either amphotericin B combined with itraconazole (n = 8), itraconazole alone (n = 7), or a new antifungal compound, voriconazole (n = 4) (see Table 1).
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The indications for the surgical procedure were classified into two groups (Fig 4): emergency and elective. Prevention of massive hemoptysis was an emergency procedure performed before marrow recovery. The need for surgical intervention was based on the observation of repeated chest CT scans showing pulmonary aspergillosis that came into contact with the pulmonary artery or its dividing branches, with a risk of massive hemorrhage. An emergency surgical intervention was performed because the recovery of granulocyte count was a critical period. In the setting of invasive pulmonary aspergillosis located near a pulmonary artery, massive hemoptysis may result from arterial perforation due to an angioinvasive fungal process.
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We calculated the median survival and the probability of survival at 3, 6, and 12 months by the Kaplan-Meier method after IPA diagnosis.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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). The average ANC at the time of operation was 296 cells/µL (range, 0 to 1,000 cells/µL). The average platelet count before operation was 124,000 cells/µL (range, 75,000 to 199,000 cells/µL). Seven patients received 5 to 11 platelet packs preoperatively (see Table 2).
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). We resected only the aspergillosis lesion that threatened the pulmonary artery.
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). On the left side, we performed a sleeve resection of the pulmonary artery in 2 cases because the aspergillosis lesion had already infiltrated the vessel wall. In the first patient, after mobilization of the left upper lobe, we found that the pulmonary artery was ruptured at the ostium level of the upper pulmonary artery. This wall was totally destroyed by the aspergillosis lesion. In this patient, who had an ANC of 1,000 cells/µL at the time of operation, a pulmonary cavitation had been observed on the last CT scan (see Table 3). In another patient, the part of the left upper pulmonary artery that was infiltrated by the aspergillosis lesion was removed by segmental resection. Before segmental resection, the main pulmonary artery had to be occluded in its intrapericardial course and peripherally in the lobar fissure. The vascular anastomosis was done with an end to end technique. In a third patient, we wrapped the left pulmonary artery with a flap of pericardium because the aspergillosis lesion had injured the adventitia (see Table 4). We used the ultrasound dissector to facilitate the procedure. Altogether, we performed eight lobectomies, associated with a segmentectomy in 2 patients (Fowler and paracardial segmental) (see Table 4). We performed no pneumonectomies.
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). One patient had a pleural effusion, which required a new chest tube. One patient with chronic obstructive pulmonary disease died on postoperative day 6 of respiratory failure from progression of IPA despite antifungal treatment. For other patients, the mean duration was 10 days (range, 3 to 20 days) for temperature normalization and 13 days (range, 6 to 18 days) for discharge from the hospital. The patients were treated for several weeks with antifungal therapy. The pathologic examination showed lesions of hemorrhagic necrosis of the parenchyma in 4 patients. Microscopic examination confirmed the vessel invasion and thrombosis by abundant septate hyphae in all cases. Culture from the resected lung tissue was positive in 7 patients: A fumigatus in 5 patients, A nidulans in 1 patient, and A flavus in 1 patient.
Elective Operations
In 7 patients, resection of a residual mass was performed because an important aspergillosis lesion persisted after antifungal treatment for a mean duration of 35 days (range, 21 to 180 days) (see Table 2). At the time of operation, the mean ANC was 2,520 cells/µL (range, 0 to 5,200 cells/µL) and the mean platelet count was 202,000 cells/µL (range, 105,000 to 440,000 cells/µL) (see Table 2). The first patient, a 48-year-old man, had a voluminous cavity and a necrotic mass in the left upper lobe. An operation was scheduled because of repeated severe hemoptysis and infection. We performed a lobectomy with pleurectomy. Postoperative bleeding required a second thoracotomy, but the patient was discharged from the hospital on postoperative day 20. In 2 other patients (respectively, 5 and 40 years of age), an operation was indicated because an allogenic bone marrow transplantation was necessary in the succeeding weeks. We performed a right upper lobectomy in the 40-year-old woman and a wedge resection of the right upper lobe in the 5-year-old child. In these 2 patients, no postoperative complications were observed, and they were discharged from the hospital at 7 and 12 days after operation, respectively. Both received allogenic bone marrow transplantation in the succeeding 2 months without any subsequent fungal infection. We opted for operation in the 4 other patients to allow complementary high-dose chemotherapy. We performed a lingulectomy in a 55-year-old man, a wedge resection of the right upper lobe in a 61-year-old man, a right upper lobectomy in a 60-year-old man, and a left upper lobectomy in a 63-year-old man. There were no postoperative complications. These 4 patients were discharged from the hospital 8 days after the procedure. Pathologic examination showed the typical histologic features of abundant septate hyphae with 45-degree dichotomous branching in all patients. Culture of the resected lung tissue was performed in 6 cases and was positive in 4. Aspergillus fumigatus was isolated in 4 cases.
A surgical procedure was used to make a diagnosis in 4 patients with a persisting peripheral nodule despite antifungal therapy for a mean duration of 14 days (range, 4 to 24 days) (see Table 2). We performed a wedge resection using video-assisted thoracic surgery, without any postoperative complications. The average length of stay in the hospital was 6 days (range, 2 to 8 days). Culture of the resected lung tissue isolated A fumigatus in 3 cases, and pathologic examination confirmed the invasive fungal disease.
Long-Term Follow-up
The mean follow-up period was 17 months (range, 1 to 67 months). Sixteen patients (84%) were considered cured of their aspergillosis (Table 5). In 3 patients, IPA progressed until death occurred (see Table 5). One patient died on day 6 after operation, and the 2 remaining patients died on days 90 and 60, respectively, of progression of both IPA and hematologic disease. None of them died of massive hemoptysis. Twelve patients received myeloablative therapy (chemotherapy in 8 and bone marrow transplantation in 4) (see Table 5). The main reason for late death was relapse of the hematologic malignancy. The median duration of survival after diagnosis of IPA was 15.5 ± 4 months. The probability of survival at 3 months was 0.88 ± 0.07, at 6 months 0.70 ± 0.1, and at 1 year 0.56 ± 0.13.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Since 1991, we have modified our strategy of IPA diagnosis in febrile neutropenic patients, with systematic use of thoracic CT to identify the early halo sign [8]. The systematic use of CT scan was combined with frequent use of surgical resection for aspergillosis lesions [8]. Since then, the rate of deaths from IPA has decreased from 41% to 14% [8].
The operation for IPA in neutropenic patients must be distinguished from operations for aspergilloma that has developed in a preexisting cavity [13, 14]. Most previous studies [11, 15–17] reported surgical management of IPA (occurring after high-dose chemotherapy) but involved operations after bone marrow recovery. Hemoptysis is a severe complication of IPA in neutropenic patients and occurs when the aspergillosis lesion comes into contact with the pulmonary artery or its dividing branches. Marrow recovery induces cavitation, which creates a major risk of massive hemorrhage when the aspergillosis lesion is located near a pulmonary artery or its dividing branches [5, 18]. In the study of Albeda and colleagues [5], the percentage of massive hemoptysis (>150 mL of blood per episode) was 27% in patients with bone marrow recovery and no hemoptysis in patients with no bone marrow recovery. Pagano and associates [2] demonstrated that the principal cause of death in patients with acute leukemia was massive hemoptysis. In this study [2], autopsy was performed in 11 of 12 patients who died of massive hemoptysis and documented a fungal infection.
The angiotropism of Aspergillus could explain the mechanism of hemoptysis. During the neutropenic period following chemotherapy, the hyphae colonize the bronchi and arteries and cause a local infarction [19]. When marrow recovery occurs, the granulocyte count increases and proteolytic enzymes are released from leukocytes at the site of aspergillosis infection; this might cause a destruction of lung tissue [20]. In the setting of invasive pulmonary aspergillosis located near a pulmonary artery (or its dividing branches), it might cause massive hemoptysis by arterial perforation. Therefore, recovery of the granulocyte count is a critical period [2, 5, 18]. In agreement with this hypothesis, the first reported patient in our series had recovered from aplasia, as the ANC was 1,000 cells/µL at the time of surgical intervention; the CT scan showed the air crescent sign; and his pulmonary artery was destroyed by an aspergillosis lesion.
Our criteria for operation were based on analysis of the CT scan, looking for (1) the halo sign or the air crescent sign, (2) localization of the aspergillosis lesion near a pulmonary artery, and (3) disappearance of the fatty border between the vessel wall and the aspergillosis lesion or increase in the aspergillosis lesion size. The CT images were viewed at lung and mediastinal windows. An enhanced CT scan was performed systematically to define whether the aspergillosis mass threatened the integrity of the vessel. In cases of uncertainty, CT was repeated 24 hours later. The CT images were discussed among the thoracic surgeon, radiologists, and clinical hematologists. As soon as we considered that there was a risk of arterial perforation by the angioinvasive fungal process, we initiated an emergency surgical procedure. At an emergency operation, one should resect only the aspergillosis lesion located near the pulmonary artery or its dividing branches. This operation should be as conservative as possible, being limited to a lobectomy, associated, when necessary, with a segmentectomy and a sleeve-resection pulmonary artery. Pneumonectomy should be avoided. This conservative attitude could explain the low rate of postoperative complications observed in our series of patients.
Surgical resection of a residual IPA mass, combined with antifungal therapy, achieved local control of the infection in those patients who needed additional chemotherapy, with or without bone marrow transplantation [10, 15, 16]. Antifungal therapy alone will not be sufficient to cure such an important mass in a few weeks. In this setting, the operation can be a lobectomy, a segmentectomy, or a wedge resection, depending on the location and the size of the aspergillosis lesion. An operation also can be necessary when the residual mass is responsible for mild hemoptysis or lung abscess [11, 15, 16]. This surgical procedure can be difficult when the lesion also involves the chest wall [12, 15, 16, 17].
Finally, an operation can be used for the diagnosis of IPA, especially in patients who received antifungal therapy for more than 2 or 3 weeks and in whom a lesion persists. In this setting, an operation is able to confirm aspergillosis and indicates which treatment is needed. This indication has been described already in the literature [17]. The postoperative mortality rate was 0% to 31%, depending on the series [10–12, 15–17]. The main reason for death was acute respiratory failure from either progression of IPA or pneumonia [12, 16]. In the series reported by Robinson and coworkers [12], the death rate reached 31%, possibly as a consequence of major lung resection (bilobectomy, multiple wedge resection, pneumonectomy) [12, 17]. The death rate was lower in other series, ranging from 0% to 6% [10, 11, 15, 16]. In our series, the only observed death was related to the progression of aspergillosis in the contralateral lung despite antifungal therapy. This patient demonstrated a tobacco-induced chronic obstructive pulmonary disease. Neutropenia at the time of operation was not a negative prognostic factor in the study of Robinson and coworkers [12], the only study reporting operations in patients with ANC less than 500 cells/µL. In this group of patients, the operation must be as conservative as possible to avoid pneumonectomy.
The follow-up results of our patients are comparable to those in the literature [11, 12, 16]. The main reason for death after 6 months was relapse of the hematologic malignancy [11, 12, 16]. No patient died of massive hemoptysis, as reported previously [11, 12, 16]. The only 2 patients who died of IPA, on days 60 and 90, had progressive hematologic disease with persistent neutropenia. The median survival rates range from 11 to 18 months [11, 16]. The decrease in survival of our patients at the end of the first year was related to a relapse of the hematologic malignancy.
We conclude that the combination of antifungal agents and surgical resection is an efficient strategy for the treatment of IPA in patients with hematologic malignancy. An operation is indicated emergently (before marrow recovery) for the prevention of massive hemoptysis or for elective resection of a residual mass (most often after recovery from neutropenia).
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References |
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