CLINICAL PATTERNS AMONG INVASIVE PULMONARY ASPERGILLOSIS PATIENTS WITH AND WITHOUT RECENT INTENSIVE IMMUNOSUPPRESSIVE THERAPY

CLINICAL PATTERNS AMONG INVASIVE PULMONARY ASPERGILLOSIS PATIENTS WITH AND WITHOUT RECENT INTENSIVE IMMUNOSUPPRESSIVE THERAPY Gee-Chen Chang, 1,2 Kai-Ming Chang, 1,2 Chieh-Liang Wu, 1 and Chi-Der Chiang 1 Background and Purpose: Invasive pulmonary aspergillosis (IPA) is usually an acute life-threatening infection in cancer patients receiving chemotherapy and in organ transplant recipients receiving immunosuppressive therapy. In some immunocompetent patients, IPA has a chronic and indolent clinical course. We compared the clinical patterns among IPA patients who had received recent intensive immunosuppressive therapy (RIIT) and those who had not (N-RIIT). Methods: We reviewed the medical records of patients with a diagnosis of IPA made between 1992 and 1999. RIIT was defined as chemotherapy or high-dose corticosteroid therapy (at least 500 mg/d methylprednisolone, or equivalent, for at least 3 d) within 2 weeks before the onset of symptoms. RIIT patients were divided into those with and without malignancy. We compared clinical characteristics including age, sex, chest image patterns, diagnostic methods, culture results, treatment conditions, mortality, and recurrence rate in IPA patients: RIIT versus N-RIIT, and RIIT with and without malignancy. Results: A total of 24 patients with IPA, 17 patients who had received RIIT and seven patients who had not (N-RIIT), were included. In the RIIT group, 11 patients had malignancy and six did not. No significant differences in gender, chest image patterns, diagnostic methods, and culture results were found between the RIIT and N-RIIT groups. The N-RIIT group was older and was treated significantly later after the onset of symptoms than the RIIT group (mean ± standard deviation, SD, 89.43 ± 129.47 vs 9.70 ± 9.33 d, p = 0.018). Only one of the seven N-RIIT patients died, while nine of the 17 RIIT patients died (p = 0.08). Among the RIIT patients, five of the six without malignancy died, while four of the 11 patients with malignancy died. IPA recurred in seven of the eight RIIT patients, all of whom had malignancy, but in none of the six N-RIIT patients during a similar follow-up period (mean ± SD, 16.3 ± 18.9 vs 27.0 ± 54.5 mo, p = 0.505). Conclusions: No differences were noted in image and culture studies between RIIT and N-RIIT IPA patients. RIIT IPA patients had acute and fulminant clinical courses, especially patients without malignancy, even though they received treatment with a mean duration of about 10 days starting from the onset of symptoms. All patients with malignancy undergoing further chemotherapy had recurrence of IPA. N-RIIT IPA patients had chronic clinical courses, a trend of lower mortality rate even with delayed diagnosis, and no recurrence. (J Formos Med Assoc 2001;100:762 6) Key words: invasive pulmonary aspergillosis immunosuppressive therapy Aspergillus-related pulmonary disorders may be classified into allergic reactions, colonization, or invasive types. The types of disease caused by Aspergillus species are determined by the host immune activity and struc- tural abnormalities of the lung [1 3]. Invasive pulmonary aspergillosis (IPA) has become an increasingly important cause of morbidity and mortality in immunocompromised patients [1]. IPA is character- 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, and 2 Chung Shan Medical University, Taichung. Received: 28 December 2000. Revised: 29 January 2001. Accepted: 4 September 2001. Reprint requests and correspondence to: Dr. Gee-Chen Chang, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, 160 Chung-Kang Road, Section 3, Taichung, Taiwan. 762

Clinical Patterns of Invasive Pulmonary Aspergillosis ized by a proliferation of fungal hyphae in the lung parenchyma. Major factors predisposing to the development of IPA are neutropenia of any cause, and immunosuppression by corticosteroids or other immunosuppressive agents [2, 3]. Invasive fungal infections are an acute life-threatening illness in cancer patients and are usually treated empirically. Some invasive fungal infections are diagnosed by lung resection when the disease becomes localized after treatment. However, recurrence of the disease is frequent during neutropenic periods in further courses of chemotherapy in cancer patients. IPA interferes with the treatment of the underlying diseases and may cause morbidity and mortality. IPA has been reported in patients without malignancy but taking corticosteroids [4], diabetes mellitus (DM), influenza, alcoholism [5], underlying chest diseases, and organ transplantation [6]. Some patients with IPA have acute clinical courses, especially organ transplant patients receiving intensive immunosuppressive agents. Others, such as DM or asthma patients, have chronic and indolent clinical courses. The purpose of this study was to compare the clinical patterns of IPA between patients who had received recent intensive immunosuppressive therapy (RIIT) and those who had not (N-RIIT). Patients and Methods The CxRs and CT scans were read independently by one pulmonologist and one radiologist. We divided the findings of the CxRs and CT scans into four patterns: multiple bilateral pulmonary nodules, broncho-pneumonia, bronchopneumonia with pleural effusion, and bronchopneumonia with halo signs. A halo sign was defined as the appearance of groundglass attenuation surrounding the nodule. Patients with bronchopneumonia-type IPA showed an acute onset of an alveolar patch on CxR. RIIT was defined as administration of chemotherapy or high-dose corticosteroid therapy (at least 500 mg/d methylprednisolone, or equivalent, for at least 3 d) within 2 weeks before the onset of pulmonary symptoms. Recurrence of IPA was defined as development of IPA after resolution of the first episode by an anti-fungus regimen and/or surgical resection. Statistical analysis Statistical analysis was performed using the Statistical Package for Social Sciences statistical software (SPSS standard version 8.0, SPSS, Inc., Chicago, IL, USA). We compared characteristics, including sex, CxR, CT scans, diagnostic methods, culture results, and mortality rate, between the RIIT and N-RIIT groups with Fisher s exact test. The differences in age and the interval from the onset of pulmonary symptoms to the start of antifungal therapy were determined by Mann-Whitney U test. A p value of less than 0.05 was considered statistically significant. We reviewed the medical records of patients with the diagnosis of IPA who were admitted to Taichung Veterans General Hospital from January 1992 through December 1999. All patients had a positive culture of Aspergillus spp. from open lung biopsy transbronchosc-opic lung biopsy, necropsy, percutaneous transthoracic needle lung aspiration, or pleural effusion aspiration. The surgical specimens and the lung aspiration samples were cultured on Sabouraud s agar and species were identified by their morphology under microscopic examination. Patients were excluded if they: had previous pulmonary mycetoma suggested by chest roentgenogram (CxR) or computerized tomography (CT) scan of the chest; only had compatible tissue morphology without positive fungus culture; or only had positive sputum Aspergillus cultures. We collected clinical data including sex, age, underlying diseases, the number of days of neutropenia (absolute neutrophil count < 500 x 10 6 /L), corticosteroid use, the interval from the onset of pulmonary symptoms to the administration of antifungal treatment, mortality attributed to IPA, and recurrence after resolution of IPA. The diagnostic methods were also recorded. Results The medical records of 31 patients with IPA were studied. Seven of these patients without a positive culture were excluded although they had compatible histopathologic findings. A total of 24 patients were included. There were 17 patients in the RIIT group, 11 of whom had malignancy. Ten of the 11 patients with malignancy had leukemia and one had breast cancer. Two patients without malignancy who had received RIIT had systemic lupus erythematosus (SLE) and four were renal transplant patients. The seven patients in the N-RIIT group had the following underlying diseases: DM (n = 4), asthma (n = 1), osteoarthritis (n = 1), and none (n = 1). The clinical, radiologic, and microbiologic characteristics of patients are listed in the Table. The radiographic patterns in 17 patients revealed bronchopneumonia with or without pleural effusion. Seven cases showed an angioinvasive IPA with bilateral multiple pulmonary nodules (Figure). No significant differences were found between the RIIT and N-RIIT 763

Table. Clinical, radiologic, and microbiologic characteristics of patients with invasive pulmonary aspergillosis (IPA) Variable Malignancy with RIIT Non-malignancy with RIIT N-RIIT p value* (n = 11) (n = 6) (n = 7) Sex (M/F) 5/6 3/3 5/2 0.27 Age (yr) 37.5 39.0 59.6 0.03 Chest roentgenogram pattern 0.96 Bronchopneumonia ± pleural effusion 9 3 5 Bilateral pulmonary nodules 2 3 2 Computerized tomography scan 0.77 Bronchopneumonia ± pleural effusion 7 3 Bilateral pulmonary nodules 1 1 1 Bronchopneumonia + halo sign 2 2 Diagnostic method 0.23 Open lung biopsy or wedge resection 3 1 4 Transthoracic needle lung aspiration 7 4 2 Transbronchoscopic biopsy 1 1 1 Culture results 0.63 Aspergillus fumigatus 9 6 7 Aspergillus versicolor 1 Aspergillus flavus 1 S-Tx (d) 7.55 ± 5.30 14.50 ± 13.43 89.43 ± 129.47 0.018 Mortality 4/11 5/6 1/7 0.08 Recurrence 7/7 0/1 0/6 RIIT = recent intensive immunosuppressive therapy; N-RIIT = non-riit; S-Tx = time from symptom onset to treatment. *RIIT group (± malignancy) vs N-RIIT group; mean ± standard deviation. groups in radiographic patterns, diagnostic methods or microbiologic data. IPA was diagnosed by transthoracic needle aspiration in 13 cases and by transbronchoscopic biopsy in three cases. Eight patients underwent open lung biopsy for diagnosis or curative treatment. All patients with malignancy received chemotherapy and developed neutropenia. The median duration of neutropenia was 15 days (range 11 19 d). There was a significant difference in the time from the onset of symptoms to treatment between RIIT and N-RIIT groups (mean ± standard deviation, SD, 9.70 ± 9.33 vs 89.43 ± 129.47 d, Figure. Angioinvasive invasive pulmonary aspergillosis. Bilateral pulmonary nodules are seen on computerized tomography scan of the chest. Several nodules show signs of cavitation with air-crescence. 764 p = 0.018). The difference in time from the onset of symptoms to the initiation of treatment between RIIT patients with and without malignancy, even though longer in patients without malignancy, was not significant (mean ± SD, 7.55 ± 5.30 vs 14.50 ± 13.43 d, p = 0.26). The amount of amphotericin B (AmB) administered ranged from 1,680 to 2,550 mg in the surviving patients and from 5 to 1,280 mg in patients who died during treatment. The AmB was given at a daily dose of 1 mg/kg after a test dose of 1 mg for most patients. Overall, nine of the 17 RIIT patients died and only one of the seven N-RIIT patients died (p = 0.08). Five of six patients without malignancy died, and four of 11 with malignancy who received RIIT died. Sputum cultures were positive for Aspergillus in eight patients in the RIIT group, but six were positive after the definite diagnosis of IPA had been made. In the N-RIIT group, two patients had positive sputum cultures obtained before diagnosis of IPA and those were considered to indicate colonization. After resolution of IPA, seven of the eight RIIT patients and none of the six N-RIIT patients had recurrence of IPA with similar follow-up periods (mean ± SD, 16.3 ± 18.9 vs 27.0 ± 54.5 mo, p = 0.505). All recurrence was in patients with malignancy. Five of these seven patients underwent percutaneous transthoracic needle lung aspiration and two underwent bronchoalveolar

Clinical Patterns of Invasive Pulmonary Aspergillosis lavage (BAL) by fiberoptic bronchoscopy with positive Aspergillus cultures. One of the leukemia patients had recurrence, but was treated and survived. She did not have another recurrence during 3 years follow-up after successful bone marrow transplantation. Three RIIT patients had histologic evidence of extrapulmonary involvement including the brain, maxillary sinus, and liver. Discussion Chemotherapeutic agents and corticosteroids have a major impact on the immune system s defense against fungal infection. The first immunologic line of defense against Aspergillus in the lungs is the macrophages, which are capable of ingesting and killing spores [7]. The second line of defense is the neutrophils, which primarily kill the hyphae [8]. Corticosteroids substantially impair the ability of macrophages to kill Aspergillus spores and the ability of neutrophils and mononuclear cells to kill Aspergillus hyphae [9, 10]. In this series, the clinical courses were mainly determined by the immune status of the patients. The most immunocompromised patients had the fastest progression (7 14 d from onset to death). This finding is in agreement with previous studies, which have found that immunocompetent and less immunocompromised patients, such as those with DM, usually have indolent symptoms and slow progression (2 3 mo) [11, 12]. IPA is a life-threatening infection occurring mainly in cancer patients and is associated with a mortality rate of 40 to 80% [13]. In many instances, mortality is traceable to a delay in the diagnosis. However, our patients with malignancy were treated empirically with AmB when febrile neutropenia persisted for more than 1 week in spite of broad-spectrum antibiotic therapy. IPA was seldom suspected in RIIT patients without malignancy. All six such patients presented with acute illness, and five died. Only one patient, with SLE, survived after early empirical antifungal treatment, because pulmonary nodules with a halo sign were noted on the CT scan of the chest. In RIIT patients without malignancy, treatment was initiated later and the mortality rate was higher, though not significantly compared with RIIT patients with malignancy. However, these findings might have been due to small patient numbers. Seven N-RIIT patients had subacute or chronic courses with mild fever, cough, or generalized malaise. Underlying conditions reported in patients with IPA have included chronic granulomatous disease [14], DM, alcoholism [5], and patients receiving corticosteroid therapy for chronic pulmonary disease, such as sarcoidosis and chronic obstructive pulmonary disease [4]. In vitro studies in patients with DM have shown decreased leukocyte bactericidal activity and impaired macrophage mobility and phagocytic capacity [15]. However, some patients with IPA did not have any immunocompromising factors [16, 17]. IPA is divided into six distinct clinicopathologic forms of disease, which include acute bronchopneumonia, angioinvasive aspergillosis, acute tracheobronchitis, miliary aspergillosis, pleural aspergillosis, and chronic necrotizing aspergillosis. The first two forms are the most common [11]. The bronchopneumonia form presents a clinical picture that resembles bacterial pneumonia. The lung lesion begins with a patchy infiltration, and then progresses to dense consolidation involving one or both lungs. Angioinvasive aspergillosis often presents with bilateral pulmonary nodules and usually spreads by vascular dissemination to cause thrombosis and necrosis. About one-third of patients initially have normal CxRs at the onset of fever, and later quickly progress to bilateral multiple pulmonary septic emboli lesions [11]. Angioinvasive aspergillosis is usually mistreated as bacterial infection and the mortality rate is very high. Previous studies have shown that CT scans are helpful in detecting early changes in IPA which are not visible on CxRs [18 20]. The pulmonary lesion appears early in the course of IPA infection. Primack et al reported that CT halo signs could indicate an infectious process, including invasive aspergillosis, candidiasis, cytomegalovirus, herpes simplex virus, and coccidioidomycosis, and could also indicate a noninfectious cause including Wegener s granulomatosis, metastatic angiosarcoma, and Kaposi s sarcoma [20]. Thus, CT halo signs can only be used as evidence of pulmonary nodules. A diagnosis of IPA requires the demonstration of septated mycelia, morphologically consistent with aspergillosis, invading the lung parenchyma, in addition to a positive fungal culture. Invasive procedures are often impractical in patients with acute leukemia or in cancer patients undergoing chemotherapy, owing to borderline respiratory status and thrombocytopenia. Empirical treatment should never be withheld in an immunocompromised patient in whom IPA is suspected. BAL could be performed in these patients, but its sensitivity has been reported to be very low in immunocompromised patients [21]. The initial treatment results in RIIT patients with malignancy were much better than in those without malignancy because of early empirical treatment with AmB. However, a previous study reported that the long-term results in RIIT patients with malignancy were not good because of a substantial risk of recur- 765

rence during subsequent drug-induced granulocytopenia [22]. Surgical management of IPA can be diagnostic or curative in patients with localized disease. Robinson et al performed pulmonary resection in 16 immunocompromised patients with IPA when localized disease developed after systemic antifungal therapy. At a median of 8 months follow-up, 11 of the 16 patients had survived without evidence of recurrence [23]. The clinical patterns among patients with IPA are determined by the immune status of the patient. In RIIT patients without malignancy, the diagnosis of IPA is seldom considered, which leads to high mortality. A high index of suspicion, early invasive diagnostic procedures, and early empirical AmB treatment after the failure of broad-spectrum antibiotic therapy, as in RIIT patients with malignancy, might rescue these patients. In RIIT patients with malignancy, recurrence of IPA should be suspected in further courses of chemotherapy. However, in N-RIIT IPA patients, chronic IPA can be cured by AmB after diagnosis with little risk of recurrence. References 1. Aslam PA, Eastridge CE, Huges FA Jr: Aspergillosis of the lung an eighteen-year experience. Chest 1971;59:28 32. 2. Greene R: The pulmonary aspergillosis: three distinct entities or spectrum of disease. Radiology 1981;140:527 30. 3. Turner-Warwick M: Aspergillus fumigatus and lung disease. Postgrad Med 1979;55:642 4. 4. Palmer LB, Greenberg HE, Schiff MJ: Corticosteroid treatment as a risk factor for invasive aspergillosis in patients with lung disease. Thorax 1991;46:15 20. 5. Denning DW, Stevens DA: Antifungal and surgical treatment of invasive aspergillosis: review of 2121 published cases. Rev Infect Dis 1990;12:1147 201. 6. Gustafson TL, Schaffner W, Lavely GB, et al: Invasive aspergillosis in renal transplant recipients: correlation with corticosteroid therapy. J Infect Dis 1983;148:230 8. 7. Schaffner A, Douglas H, Braude A: Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus. Observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes. J Clin Invest 1982;69:617 31. 8. Diamond RD, Krzesicki R, Epstein B, et al: Damage to hyphal forms of fungi by human leukocytes in vitro: a possible host defense mechanism in aspergillosis and mucormycosis. Am J Pathol 1978;91:313 28. 9. Roilides E, Unlig K, Venzon D, et al: Prevention of corticosteroid-induced suppression of human polymorphonuclear leukocyte-induced damage of Aspergillus fumigatus hyphae by granulocyte colony-stimulating factor and gamma interferon. Infect Immun 1993;61:4870 7. 10. Roilides E, Blake C, Holmes A, et al: Granulocyte-macrophage colony-stimulating factor and interferon-gamma prevent dexamethasone-induced immunosuppression of antifungal monocyte activity against Aspergillus fumigatus hyphae. J Med Vet Mycol 1996;34:63 9. 11. Young RC, Bennett JE, Vogel CL, et al: Aspergillosis; the spectrum of the disease in 98 patients. Medicine (Baltimore) 1970;49:147 73. 12. Degregorio MW, Lee WMF, Linkera CA, et al: Fungal infections in patients with acute leukemia. Am J Med 1982; 73:543 8. 13. Denning DW: Therapeutic outcome in invasive aspergillosis. Clin Infect Dis 1996;23:608 15. 14. Mouty R, Fischer A, Vilmer E, et al: Incidence, severity, and prevention of infections in chronic granulomatous disease. J Pediatr 1989;114:555 60. 15. D Silva H, Burtle JF, Cho SY: Disseminated aspergillosis in an apparently immunocompetent host. JAMA 1982; 248:1495 7. 16. Karam GH, Griffin FM Jr: Invasive pulmonary aspergillosis in nonimmunocompromised, nonneutropenic hosts. Rev Infect Dis 1986;8:357 63. 17. Karim M, Alam M, Shah AA, et al: Chronic invasive aspergillosis in apparently immunocompetent hosts. Clin Infect Dis 1997;24:723 33. 18. Kuhlman JE, Fishman EK, Siegelman SS: Invasive pulmonary aspergillosis in acute leukemia: characteristic findings on CT, the CT halo sign, and the role of CT in early diagnosis. Radiology 1985;157:611 4. 19. Blum U, Windfuhr M, Buitrago-Tellez C, et al: Invasive pulmonary aspergillosis. MRI, CT, and plain radiographic findings and their contribution for early diagnosis. Chest 1994;106:1156 67. 20. Primack SL, Hartman TE, Lee KS, et al: Pulmonary nodules and the CT halo sign. Radiology 1994;190:513 5. 21. Kahn FW, Jones JM, England DM: The role of bronchoalveolar lavage in the diagnosis of invasive pulmonary aspergillosis. Am J Clin Pathol 1986;86:518 23. 22. Moreau P, Zahar JR, Milpied N, et al: Localized invasive pulmonary aspergillosis in patients with neutropenia. Effectiveness of surgical resection. Cancer 1993; 72:3223 6. 23. Robinson LA, Reed EC, Galbraith TA, et al: Pulmonary resection for invasive Aspergillus infections in immunocompromised patients. J Thorac Cardiovasc Surg 1995; 109:1182 96. 766