Surgical Therapy for Pulmonary Aspergillosis in Immunocompromised Patients

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1 Surgical Therapy for Pulmonary Aspergillosis in Immunocompromised Patients Christopher T. Salerno, MD, David W. Ouyang, BS, Timothy S. Pederson, BA, David M. Larson, MD, Jay P. Shake, MD, Eric M. Johnson, MD, and Michael A. Maddaus, MD Section of Thoracic Surgery, Department of Surgery, University of Minnesota, Minneapolis, Minnesota Background. Medical management for invasive pulmonary aspergillosis (IPA) is often unsatisfactory. Antifungal therapy may be unable to eradicate IPA in the immunocompromised or neutropenic patient. Methods. We retrospectively reviewed the surgical management of IPA in 13 immunocompromised patients at our institution. Twelve patients underwent perioperative bone marrow transplantation (4 autologous, 8 allogenic). All 13 patients received antifungal therapy. Eleven patients were neutropenic at the time of operation. Results. The mean interval from diagnosis of aspergillosis to operation was 42 days (range, 3 to 135 days). Eighteen operations were performed on the 13 patients. Seven patients had resections from multiple pulmonary sites, whereas 6 had a single lesion resected. The average lesion resected was 3.7 cm in greatest diameter (range, 1 to 9 cm). After a mean follow-up of 21 months (range, 0 to 9 years), 3 patients (23%) are alive with no evidence of aspergillosis, 6 patients (46%) died without evidence of aspergillosis, and 4 patients (31%) died secondary to aspergillus infection. All 4 patients who died of aspergillus infection received an allogenic bone marrow transplantation. Two patients with direct extrapulmonic extension of IPA at time of operation died of recurrent aspergillus infections. Three of 4 patients who died of aspergillus infection had an absolute neutrophil count less than 1,300 cells/ L at time of operation. The mean absolute neutrophil count of the patients who cleared the aspergillus infection was 5,538 cells/ L. The mean survival of allogenic bone marrow transplant recipients was 5.2 months, and for recipients of autografts was 51.4 months. Conclusions. In this series, surgical resection of IPA cleared the aspergillus infection in 69% of the patients. Neutropenia, extrapulmonic extension of IPA, and allogenic bone marrow transplantation may predict a worse prognosis. Surgical resection of IPA in immunocompromised patients is an effective form of therapy in a properly selected patient population. (Ann Thorac Surg 1998;65:1415 9) 1998 by The Society of Thoracic Surgeons Accepted for publication Nov 13, Address reprint requests to Dr Salerno, Section of Thoracic Surgery, Department of Surgery, Box 207 UMHC, 420 Delaware St. SE, Minneapolis, MN ( saler002@maroon.tc.umn.edu). Pulmonary infection with aspergillus can lead to three different syndromes: bronchopulmonary aspergillosis (allergic), aspergillomas (proliferating fungus in an existing cavity), and invasive pulmonary aspergillosis (occurring almost exclusively in immunocompromised patients). Invasive pulmonary aspergillosis (IPA) produces a necrotizing bronchopneumonia with invasion of pulmonary parenchyma and blood vessels leading to thrombosis, hemorrhage, and eventual dissemination. In neutropenic patients the risk of acquiring IPA increases progressively with the number of granulocytopenic days, with a 70% incidence after neutropenia exceeding 34 days [1]. Invasive pulmonary aspergillosis develops in 4.5% of all bone marrow transplant (BMT) patients and in 20% of allogenic BMT patients [2, 3]. Medical therapy for IPA in immunocompromised patients is often associated with poor outcomes. Denning [4] reported that BMT patients with IPA had only a 5% to 10% response rate to medical therapy alone (amphotericin B). In addition to the poor prognosis, there is also a substantial risk of reactivation during subsequent druginduced granulocytopenia [5]. Recently several groups have advocated early surgical therapy for immunocompromised patients with IPA [5 8]. Surgical intervention potentially reduces the risk of hemorrhage, may achieve local control of the infection, and diminishes the risk of reactivation. This report details our experience with surgical resection of IPA in 13 immunocompromised patients. Patients and Methods Between January 1986 and December 1996, 13 immunocompromised patients underwent operations for IPA at the University of Minnesota (Table 1). There were 8 men and 5 women with a mean age of 23.8 years (range, 3 to 49 years). All 13 patients had an underlying hematologic disease: acute leukemia, 9 (acute myelogenous leukemia, 6; acute lymphoblastic leukemia, 3); myelodysplastic syndrome, 1; Hodgkin s lymphoma, 1; multiple myeloma, 1; and aplastic anemia, 1. Twelve of the 13 patients underwent BMT. Four patients received an autologous trans by The Society of Thoracic Surgeons /98/$19.00 Published by Elsevier Science Inc PII S (98)

2 1416 SALERNO ET AL Ann Thorac Surg INVASIVE PULMONARY ASPERGILLOSIS 1998;65: Table 1. Summary of Patient Data Patient No. Age (y) Sex Primary Illness Type of BMT Resection Before/ After BMT Days from Diagnosis to Operation Days of Neutropenia ANC at Operation (cells/ L) Initial Surgical Procedure Outcome Follow-up Period 1 9 M AML Allogenic Before lobectomy Died Asper 6 mo 2 3 M MDS Allogenic Before ,300 wedge Died Asper 1.5 mo 3 11 M ALL Allogenic After multiple wedge a Died Asper 2 days 4 33 F AML Allogenic After ,600 multiple wedge, Died Asper 3 mo chest wall resection 5 9 M ALL Autogenic After lobectomy Died no Asper 8.5 mo 6 34 F AML Allogenic After ,600 wedge Died no Asper 42 days 7 7 F HL Autogenic After ,500 wedge b Died no Asper 108 mo 8 49 F ALL Allogenic Before ,100 multiple wedge Died no Asper 4 mo 9 40 M AML Allogenic After 6 4 2,700 wedge Died no Asper 2 mo M AML Allogenic Before ,800 lobectomy, wedge Died no Asper 1 mo M MM Autogenic Before WNL wedge A/W no Asper 5 mo F AML Autogenic After ,600 multiple wedge a A/W no Asper 84 mo M AA Refused Before multiple wedge A/W no Asper 3 mo a Patient underwent two surgical procedures. b Patient underwent three surgical procedures. AA aplastic anemia; ALL acute lymphoblastic leukemia; AML acute myelogenous leukemia; Asper aspergillus infection; A/W alive and well; HL Hodgkin s lymphoma; MDS myelodysplastic syndrome; MM multiple myeloma; WNL within normal limits. plant and 8 had allogenic transplants. The diagnosis of aspergillus infection was initially suspected in all patients by chest roentgenogram (Fig 1). The diagnostic methods used included chest computed tomography (CT), 6; bronchoscopy with bronchoalveolar lavage (BAL), 6; and pleural aspiration, 1. The average platelet count at the time of the operation was /L. The average absolute neutrophil count at the time of the operation was 4,600 cells/ L (range 50 to 11,600 cells/ L). Five BMT patients had surgical resection of their IPA before transplantation and 7 had an operation after their BMT. The operative procedures performed are listed in Table 1. In all cases, surgical resection was performed to achieve local control of the infection. All palpable foci of IPA were resected, most frequently by wedge resection. Lobectomy was performed for large or central lesions technically not amenable to wedge excision or when multiple lesions were within the same lobe. All surgical specimens were cultured and examined postoperatively by standard pathologic techniques. Results Thirteen immunocompromised patients underwent 18 operations (Table 1). Six patients had resections from multiple pulmonary sites. Two patients had direct extrapulmonic extension of their aspergillus infection before the operation (chest wall and pleural fluid). One patient underwent en bloc chest wall resection with a wedge resection for direct extension of IPA. The remaining patients had IPA confined to the periphery of the lung. Three patients required a second procedure for persistent aspergillus infection an average of 57 days after the initial resection (range, 25 to 78 days). One underwent a third procedure to remove two persistent nodules by wedge resection, 30 days after the second operation. The average lesion resected was 3.7 cm in greatest diameter (range, 1 to 9 cm). Two patients were noted to have excessive blood loss (1,200 and 300 ml) and required transfusion. The remaining 11 patients had a mean blood loss of 82 ml (range, 10 to 250 ml). The volume of blood loss did not appear to correlate with the preoperative platelet count. The mean duration of chest tube drainage was 4 days (range, 2 to 10 days). Twelve of the 13 patients survived hospitalization. The only perioperative death occurred in the patient who preoperatively had aspergillus identified in the pleural fluid. Subsequently, this patient had an empyema and died despite further surgical debridement. One patient s surgery was complicated by a postoperative hemothorax, which was successfully treated with thoracostomy tube drainage. There were no other surgical complications. Four patients died secondary to aspergillus infection an average of 79 days after resection (range, 2 to 180 days). Three patients are alive with a mean survival of 30 months (range, 3 to 84 months). Six patients died of their primary hematologic disease with mean survival of 24 months (range, 1 to 108 months). These patients had no evidence of aspergillus infection at time of death. All four deaths caused by aspergillus infection occurred in patients who received an allogenic BMT. Three of these 4 patients had an absolute neutrophil count less than 1,300 cells/ L at time of the operation. The mean absolute neutrophil count of the patients who cleared the aspergillus infection was 5,538 cells/ L. Both patients who had direct extrapulmonic extension of the aspergillus infection eventually died secondary to the fungus.

3 Ann Thorac Surg SALERNO ET AL 1998;65: INVASIVE PULMONARY ASPERGILLOSIS 1417 Fig 1. Posteroanterior (A) and lateral (B) chest films showing an isolated invasive pulmonary aspergillus lesion in the right upper lobe. This finding, the air crescent sign, suggests the presence of necrotic fungus-invaded lung parenchyma, which has separated from the surrounding tissue. Two of the 6 patients who had their IPA resected before BMT died of a recurrence of the disease. Comment Aspergillus infections are caused by a ubiquitous fungus commonly found in soil, decaying vegetation, and dust. There are more than 1,000 species of Aspergillus organisms; however, human disease is primarily caused by only a few: Aspergillus niger, Aspergillus fumigatus, and Aspergillus flavus. Aspergillus spores are easily transported in the air and are frequently inhaled. These spores are of low virulence in an immunocompetent host but can be a source of significant morbidity and mortality in the immunocompromised patient. Pulmonary aspergillosis presents as three different syndromes [8]. The allergic form, bronchopulmonary aspergillosis, results from intrabronchial immunologic reactions to the fungus. The classic aspergilloma, or saprophytic form, results from colonization of an existing cavity. Invasive pulmonary aspergillosis is found almost exclusively in immunocompromised patients. In this setting an aspergillus infection can lead to a necrotizing bronchopneumonia. Further invasion of lung parenchyma and pulmonary vessels produces thrombosis, hemorrhagic infarction, and dissemination. The lesion in IPA is best described as a mycotic lung sequestrum, as it consists of fungusinvaded necrotic lung, separated from the surrounding normal lung [9]. The risk of developing IPA progressively increases with the duration of neutropenia. Gerson and coworkers [1] reported a 70% incidence after 34 days of granulocytopenia. The degree and duration of granulocytopenia appears to be an important prognostic factor in IPA. Albeda and associates [10] reported the mortality to be essentially 100% without normalization of the granulocyte count and approximately 40% with normalization. In immunocompetent individuals pulmonary macrophages consume inhaled aspergillus spores, and neutrophils destroy the hyphae that escape the macrophages. With absence or malfunction of these cell types, aspergillus can proliferate freely [11, 12]. The clinical presentation of IPA is varied. Patients may present with a persistent fever, dyspnea, or nonproductive cough. Although not seen in our series, hemoptysis is an important cause of morbidity and mortality in patients with IPA [2]. In these patients, hemoptysis is often massive and the first episode can be fatal [2, 13]. Early diagnosis and treatment of IPA is crucial. The diagnosis of IPA is difficult without histologic identification of the organism. Bronchoalveolar lavage has been reported to be approximately 20% successful in diagnosing IPA [3, 14]. Chest roentgenographic findings resemble that of an aspergilloma, displaying the air crescent sign, as shown in Figure 1. Computed tomographic scans of early lesions may show segmental infarcts before the lesion progresses to a masslike infiltrate with a surrounding halo of low attenuation, the halo sign, as seen in Figure 2 [15 17]. However, the gold standard for diagnosis still remains histologic evaluation of the lung specimen [9]. Delay in treatment of IPA in an immunocompromised patient can be uniformly fatal [18]. Therefore, given the difficulty of establishing the diagnosis of IPA, it is appropriate to initiate antifungal therapy when IPA is clinically suspected [19]. The mortality in BMT recipients treated with medical therapy alone has been reported to be as high as 100% [20, 21]. Amphotericin B remains the primary agent used for the medical treatment of IPA.

4 1418 SALERNO ET AL Ann Thorac Surg INVASIVE PULMONARY ASPERGILLOSIS 1998;65: Fig 2. Soft-tissue window (A) and lung window (B) chest computed tomographic scans at the level of the carina demonstrating a 3.5-cm discretely marginated opacity in the right upper lobe with hyperlucent areas in the periphery of the lesion that are classic of the air crescent sign. These findings are consistent with cavitation caused by invasive pulmonary aspergillosis. However, amphotericin B administered intravenously is not well distributed in the sputum, which may in part explain the poor outcomes associated with medical therapy alone [22]. Oral itraconazole may be effective in the treatment of IPA, although there are no data to support its efficacy in preventing IPA recurrence [23]. There have been no clinical trials comparing the efficacy of surgical therapy with medical therapy for the treatment of IPA. Recently multiple groups have reported their experience with surgical resection of IPA in immunocompromised patients [5 7, 9, 18, 24]. Robinson and colleagues [6] reported a 64% cure rate with early surgical therapy in 14 patients with hematologic malignancies. Lupinetti and associates [18] reported surgical cures in 3 of 6 pediatric BMT patients with IPA. Young and coinvestigators [7] reported 100% hospital survival in 8 patients with hematologic malignancies who underwent pulmonary resection for IPA. Four of the 8 patients in the latter series underwent BMT for acute leukemia. Moreau and coworkers [5] reported 6 patients with IPA diagnosed during chemotherapy-induced aplasia. All 6 patients underwent a lobectomy, despite lesion size, after hematologic recovery. No patient in this series had reactivation of IPA during subsequent chemotherapy. All patients with additional neutropenias after operation received prophylactic amphotericin B during the neutropenia [5]. Wong and associates [9] reported a series of 16 patients with neutropenia (14 chemotherapy-induced, 2 BMT) who underwent pulmonary resection for IPA. No patients in this series died of recurrent aspergillosis [9]. McWhinney and colleagues [24] reported 16 cases of IPA in 446 BMT patients. Six of these 16 patients underwent surgical resection as part of their treatment for IPA, and none of these patients developed a recurrent infection [24]. Our data are consistent with the previously published reports. Surgical resection of the IPA focus, in conjunction with appropriate antifungal therapy, cleared the infection in 69% of our patients. All of these patients acquired IPA during a period of neutropenia associated with their underlying hematologic disease. Peripheral lesions were easily removed by wedge resection, whereas larger or more central lesions were removed by lobectomy. For example, the peripheral lesion depicted in Figures 1 and 2 was resected with a wedge resection. Patients with multiple lesions in close proximity within the same lobe also underwent lobectomy. We believe that in most cases wedge excision should represent adequate surgical therapy, recognizing that, similar to wedge resections of non small cell lung cancer, residual microscopic fungal elements may be left behind in the lymphatics or lung parenchyma. The role of surgery in this disease is not to eradicate all disease but instead to resect lesions, which because of diminished host defenses cannot be eradicated and can serve as a continued source of infection. Only 2 patients had a blood loss large enough to warrant a transfusion, and both of these patients had multiple foci of IPA resected. The duration of chest tube drainage (mean, 4 days) was similar to that reported by other authors [9]. Twelve of the 13 patients were discharged from the hospital. Of the four aspergillus-related deaths in our series, 3 of 4 patients had an absolute neutrophil count less than 1,300 cells/ L at the time of operation and 2 of these patients had an absolute neutrophil count less than 500 cells/ L at the time of operation. Two of the 4 deaths occurred in patients with extrapulmonic extension at the time of operation (pleural fluid and chest wall). All four deaths occurred in patients who underwent allogenic transplantation. Two of the 5 patients who had an IPA resection before BMT did have a reactivation during subsequent periods of neutropenia. Six patients had multiple sites of IPA resected at the time of operation and 3 patients required multiple operations to control their infection. We did not find a significant correlation between the type or number of resections and patient outcome. Presently it is not clear what is the most effective strategy for treating IPA in immunocompromised patients. Given the extremely high mortality rate associated with medical therapy alone, we advocate an aggressive

5 Ann Thorac Surg SALERNO ET AL 1998;65: INVASIVE PULMONARY ASPERGILLOSIS 1419 surgical approach as described in previous reports [5 7, 9, 18, 21, 24, 25]. As shown in our series surgical resection of IPA can be performed safely. All patients should be treated with antifungal agents before resection and during any subsequent periods of neutropenia. The dose and duration of therapy should be individualized based on the extent of disease and severity of neutropenia. If possible, operations should be performed when the patient is not neutropenic. The surgical resection should include all foci of IPA. Resection of IPA in preparation for BMT can be performed safely but may be associated with recurrence during subsequent episodes of neutropenia. The exact timing for a pre-bmt resection cannot be determined from our data; however other authors have suggested that 2 months before BMT may be an appropriate time [18, 24]. The consideration for the timing of BMT in these patients is a multifactorial decision that should take into account the patient s host defenses and clinical need for a transplant. In conclusion, we found that IPA in immunocompromised patients, when anatomically favorable, can be safely resected even with thrombocytopenia. Factors that appear to correlate with a poor outcome include (1) allogenic BMT, (2) neutropenia at the time of operation, and (3) extrapulmonic spread of IPA to the chest wall or pleural fluid. Finally, preemptive resection of IPA in patients who will become neutropenic secondary to subsequent immunosuppression may be of benefit. References 1. Gerson SI, Talbot GH, Hurwitz S, Strom BL, Lusk EJ, Casileth PA. Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann Intern Med 1984;100: Meyers JD. Fungal infections in bone marrow transplant patients. 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