Pulmonary Aspergillosis: An Analysis of 41 Patients

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1 THE ANNALS OF THORACIC SURGERY Vol22 No 1 July 1976 Pulmonary Aspergillosis: An Analysis of 41 Patients Avraam Karas, M.D., John R. Hankins, M.D., Safuh Attar, M.D., John E. Miller, M.D., and Joseph S. McLaughlin, M.D. ABSTRACT During the period 1969 to 1974,41 patients having cultures positive for aspergillus were seen on the thoracic surgical services of the University of Maryland and Mt. Wilson State Hospitals. Intracavitary mycetoma was present in 36 patients. In 32 the underlying disease was chronic cavitary tuberculosis, 5 had decreased immunity due to other diseases, and in 3 no underlying disease was noted. One final patient developed a mycetoma following repair of tetralogy of Fallot. Hemoptysis, the predominant symptom, occurred in 23 patients, all of whom were from the group with intracavitary mycetoma. Hemoptysis was lifethreatening in 8 patients, severe but not lifethreatening in 12, and minimal in 3. Fifteen patients underwent pulmonary resection with 2 deaths. Both patients who died had undergone emergency resection for life-threatening hemoptysis; the fungus ball had developed following a previous resection for tuberculosis, and both had poor pulmonary reserve. Of 10 patients with hemoptysis who were not treated surgically, chiefly because they were poor operative risks, 4 died. This study suggests that pulmonary aspergillosis, particularly of the intracavitary type, is a potentially life-threatening disease. Because of the suddenness with which massive hemoptysis may occur, pulmonary resection is recommended for all patients with intracavitary mycetoma who do not constitute prohibitive operative risks. Pulmonary aspergillosis is being recognized with increasing frequency. In its invasive form it is usually encountered in patients with lowered defense mechanisms due to malignant disease such as leukemia or lymphoma or to therapeutic agents such as steroids, antimetabo- From the Division of Thoracic and Cardiovascular Surgery, University of Maryland School of Medicine, Baltimore, MD. Presented at the Twenty-second Annual Meeting of the Southern Thoracic Surgical Association, Nov 6-8,1976, New Orleans, LA. Address reprint requests to Dr. Hankins, University of Maryland Hospital, Baltimore, MD lites, cytotoxic drugs, antibiotics, or other drugs causing bone marrow depression [6, 201. More frequently it occurs in chronic lung disease as a saprophytic colonizer of preexisting cavities [3, 13, 161. A number of species have been recognized, but Aspergillus fumigatus is the variety most commonly isolated from the sputum in such patients [16,24]. The purpose of this paper is to report our experience with 41 patients who had pulmonary aspergillosis and to review the results of their management. Clinical Material Forty-one patients with pulmonary aspergillosis were treated at the University of Maryland Hospital and the Mt. Wilson State Hospital for Pulmonary Disease during the five-year period 1969 to In 32 patients the underlying disease was chronic cavitary tuberculosis (Table 1). An invasive form was identified in 5 patients with reduced immunity: 3 were receiving steroid treatment for sarcoidosis, 1 had leukemia and was being treated by antimetabolites, and 1 had undergone renal transplantation and immunosuppressive therapy. In 3 additional patients invasive aspergillosis not associated with another disease state was verified. One final patient was diagnosed as having a fungus ball following an open-heart operation and probable pulmonary infarction. Pulmonary cavitation was present in 40 patients, including 2 of the 3 with primary invasive disease. The cavities usually were present in the upper lobes, but in 2 the disease involved the right superior basilar segment, in 3 the middle lobe, and in 1 the right lower lobe. Cavities were present bilaterally in 4 patients. Fungus balls were identified in 36 patients, including all those with primary or invasive disease except the single patient without cavitation. The other 4 patients without fungus balls were being treated for cavitary tuberculosis and had repeated cultures positive for aspergillosis, which

2 2 The AnnaIs of Thoracic Surgery Vol 22 NO 1 July 1976 Table 1. Underlying Disease or Condition Associated with Pulmonary Aspergillosis Disorder No. of Patients Tuberculosis 32 No underlying disease (primary invasive) 3 Invasive with underlying disease 5 Sarcoidosis 3 Leukemia 1 Renal transplant 1 Tetralogy of Fallot repair 1 with pulmonary infarction Table 2. Symptoms in 41 Patients with Pulmonary Aspergillosis Symptom No. of Patients Hemoptysis 23 > 300 ml (massive) ml (severe) 12 < 150 ml (mild) 3 Pulmonary infiltration & fever 2 Cough & fever 15 Asymptomatic 1 represents a saprophytic form without fungus ball formation. Hemoptysis, the most frequent presenting symptom, occurred in 23 patients, all of whom had fungus balls (Table 2). The degree of hemoptysis was arbitrarily categorized according to the amount of blood lost in 24 hours and was considered massive if the amount was more than 300 ml, severe if it was 150 to 300 ml, and mild if less than 150 ml. On this basis hemoptysis was massive in 8, severe in 12, and mild in 3. Fifteen patients were hospitalized because of productive cough, weight loss, and fever. Two patients had fever and roentgenographic evidence of pulmonary infiltration when they were first seen. The ages varied from 19 to 84 years (median age, 51). There were 28 men and 13 women. Thus, the disease was more than twice as frequent in men, but the entire patient population in the hospitals in which these patients were treated comprises approximately two men to one woman. Therapy and Results The 41 patients were divided into three groups for purposes of retrospective study: nonspecific therapy, specific antifungal therapy, and surgical therapy. Nonspecific Therapy Sputum cultures positive for aspergillus were identified in 21 patients admitted for cavitary tuberculosis and being treated by antimicrobial therapy. An intracavitary mycetoma was identified in 17 of this group, in most instances by laminagraphy. Eight of these patients experienced significant hemoptysis. Sixteen patients were discharged from the hospital improved, "improvement" being based upon loss of cough and fever and clearing of the lung fields on roentgenographic examination. Repeat laminagrams were not obtained, and the fate of the fungus balls is unknown. Two patients aged 44 and 84, respectively, died as a result of severe pulmonary insufficiency and bronchopneumonia. Three others died from massive hemoptysis; all 3 had diffuse disease with severe pulmonary insufficiency and were not considered candidates for operation. An asymptomatic patient who had a fungus ball in the left upper lobe following complete correction of tetralogy of Fallot received no treatment and has remained asymptomatic for the past four and one-half years. An t ifu nga I Therapy Specific antifungal treatment with amphotericin B or sodium iodide was utilized in 6 patients, 5 of whom had fungus balls (Table 3). Two patients underwent operation after antifungal treatment failed and are included in the surgical group. Of the 4 patients who received specific antifungal treatment alone, 3 improved and were discharged from the hospital. One of these continues to have intermittent hemoptysis. The fourth, who had leukemia, died from massive hemoptysis (Fig 1). Operative Therapy Fifteen of the 41 patients were treated surgically with 18 procedures being carried out. The un-

3 ~~ ~ 3 Karas et al: Pulmonary Aspergillosis Table 3. Results of Antifungal Therapy in 6 Patients Underlying Fungus Disease Ball Hemoptysis Treatment Result Sarcoidosis RLL Severe Amphotericin B Improved Sarcoidosis RUL None Amphotericin B Improved Leukemia RML Severe Amphotericin B Massive hemoptysis (died) Primary invasive None None Amphotericin B Improved Primary invasive LUL Severe Sodium iodide Continued to bleed; (emphysema) well after LU lobectomy Endocavitary in RUL Massive Cavernostomy, Continued to bleed; tuberculosis amphotericin B died after bilobectomy RLL = right lower lobe; RUL = right upper lobe; RML = right middle lobe; LUL = left upper lobe. derlying disease and results are given in Table4. The indications for operation were the presence of a mycetoma in association with lifeendangering hemoptysis in 13 patients and advanced cavitary tuberculosis with mycetoma formation but without hemoptysis in 2 patients. Three patients were treated by pneumonectomy and 10 by lobectomy. One patient required bilobectomy after cavernostomy failed. A final patient underwent right middle lobectomy and superior segmentectomy followed by thoracoplasty and, when this failed to control the disease, pneumonectomy. The 2 patients in this group who underwent multiple procedures died. Both had undergone pulmonary resection in the past, and both had emergency operations because of massive hemoptysis. The first had undergone a left upper lobectomy for tuberculosis nineteen years previously and had extensive pulmonary fibrosis. He developed bleeding from an intracavitary fungus ball in the right upper lobe. A caver- Table 4. Results of Surgical Resection in 15 Patients Underlying No. with Disease or No. of Fungus No. of Condition Patients Balls Hemoptvsis Deaths Tuberculosis (3 massive, 2 6 severe) Primary invasive (severe) 0 Sarcoidosis (massive) 0 Renal (severe) 0 transplantation nostomy followed by intracavitary instillation of amphotericin B failed, and life-threatening hemoptysis developed. A right upper and middle lobectomy was performed. The patient died postoperatively from pulmonary insufficiency. The other death occurred in a patient with severe hemorrhage in association with a fungus ball in a postresection space following right upper lobectomy performed elsewhere for tuberculosis. The middle lobe and the superior segment of the lower lobe were resected. Thoracoplasty was necessary for a postresection space. Hemorrhage again developed, and a completion pneumonectomy was required. Postoperatively a bronchopleural fistula and empyema developed and the patient died. In the 13 surviving patients there was one significant postoperative complication: a bronchopleural fistula, which closed with tube drainage. Comment Virchow [22] described the presence of aspergilli in human pulmonary disease in 1856, and four major forms of aspergillosis are currently recognized [2,20]: (1) bronchial, with orwithout manifestations attributed to allergic sensitization; (2) intracavitary mycetoma; (3) pneumonic or invasive; and (4) disseminated. The two most frequent clinical forms are the intracavitary and the pneumonic or invasive. The pneumonic form usually occurs in patients in whom preexisting disease depresses

4 4 The Annals of Thoracic Surgery Vol 22 No 1 July 1976 Fig I. Chest roentgenograms ofa 37-year-old woman who underwent chemotherapy for acute myeloblastic leukemia. (A) Lung fields are clear. (B) Nineteen days later pneumonic aspergillosis is demonstratedin the right middle lobe. Three weeks later, despite amphotericin B therapy, posteroanterior (C) and lateral (D) projections show a fungus ball in the area ofprevious infiltration. the antibody and cellular defense mechanisms [2,4]. Examples are generalized debilitating disease, malignant lymphoma, leukemia, and aplastic anemia. Certain therapeutic measures used in the treatment of these diseases may further depress the defense mechanisms, for D example, radiotherapy, immunosuppressive drugs, and steroids [9]. An increase in surface proliferation of the fungi may be precipitated by prolonged use of antibiotics, especially when combined with steroids [211. In the intracavitary form the fungi colonize in preexisting cavities [161 or areas of infection or necrosis. This type has been reported in association with a wide variety of lung disease, principally tuberculosis but also bronchiectasis, histoplasmosis, sarcoidosis, bronchogenic carcinoma, bronchogenic cyst, pulmonary infarction [7, 111, and pyogenic lung abscess [l, 2, 61. Deve [51 in 1938 described the roentgenographic

5 5 Karas et al: Pulmonary Aspergillosis findings. Characteristically, mycetomas appear as intracavitary masses [18] separated from the surrounding cavitary wall by a crescent of air at the upper three-quarters of the cavity. The position of the ball varies with changes in the patient's position. The ball is formed by condensed masses of septate hyphae. Laminagrams may demonstrate a mass when plain chest films are not diagnostic. Symptoms are not distinctive, but hemoptysis occurs in 50 to 80% of the patients so affected [l, 6,12,171 and is associated with a mortality rate of approximately 25% [19] (Table 5). Of the 8 patients who suffered massive hemoptysis in this series, 4 of whom died, 7 had at least one episode of premonitory bleeding prior to the massive episode, and usually there were two to three. The exact etiology of the hemorrhage is unknown. In this series of patients vascular granulation tissue lined the walls of the cavities, and a Rasmussen aneurysm was clearly identified in 1 patient. Why a supposedly saprophytic infestation should produce such a reaction is a point for speculation, but endotoxins have been identified in the aspergillus and possibly account for the marked inflammatory reaction. Diagnosis is made by repeated isolation of the fungus from the sputum or by roentgenographic identification of a mycetoma. Differential diagnosis includes intracavitary blood clots and liquefying pulmonary infarctions [ll]. Isolation of the fungus may be difficult if the cavity does not communicate with the bronchus [2,12]. Precipitin and complement-fixation reactions are likely to be positive during the course of the infection, and they remain so for a period following its eradication [19,23]. If there is coexist- ing allergic hypersensitivity, the skin test may be positive [2, 14, 161. Treatment with antifungal drugs-notably amphotericin B and sodium iodide, and more recently natamycin (Pimaricin)-is an effective modality in invasive aspergillosis [6, 10, 151. Four of our patients with invasive pneumonic aspergillosis were treated systemically with amphotericin B, and 3 improved; 1 received sodium iodide without effect. Intracavitary instillation of amphotericin B and sodium iodide, described by Ramirez [15], has been suggested as primary therapy and as an alternative to operation in patients whose general medical status or poor pulmonary reserve makes the operative risk prohibitive. Eastridge and co-workers [6] utilized intracavitary instillation successfully in 2 patients and emphasized the advantages of an ionic solution of sodium iodide over amphotericin B. In 1 of our patients this type of treatment failed, and emergency resection was undertaken 48 hours later because of massive hemoptysis. One can speculate that although the fungi may be eradicated by such treatment, the basic conditions are not altered, and the possibility of reinfestation and fatal hemorrhage continues to exist. Gerstl and associates [8] in 1948 reported a successful lobectomy for pulmonary aspergillosis. Since then, surgical resection has become widely accepted as the treatment of choice for intracavitary mycetoma. Lobectomy is the preferred procedure, but pulmonary aspergillomas have been removed by segmentectomy, and pneumonectomy has been performed successfully in widespread disease [6,12,171. Antifungal chemotherapy has not been found necessary Table 5. Hemoptysis in 23 Patients with Mycetoma Surgical Management Medical Management No. of No. of No. of No. of No. of Bleeding Patients Patients Deaths Patients Deaths Massive 8 Severe 12 Mild a Total (15%) 10 4 (40%) "Prohibitive operative risk.

6 6 The Annals of Thoracic Surgery Vol 22 No 1 July 1976 as an adjunct to resection in the saprophytic type of infestation. Surgical mortality was less than 7% in the collected series of 84 resections reported by Kilman and his colleagues [12]. Solit [19] and Eastridge [6] and their associates as well as Saab and Fig 2. Chest roentgenogram (A) and laminagram (B) of a 34-year-old man with sputum-positive cavitary tuberculosis. Antit~iberculosis drugs brought about conversion of thesputum to negative within three inonths. Three years later, however, the roentgenogram (C) and laminagram (D) shozu that a inycetama has developed in the "open-negative" right upper lobe cavity. Almond [17] have reported a total of 56 patients undergoing resection without mortality. Two of the 15 patients operated upon in the present series died, a mortality of 13%, but there were no deaths among the 13 patients who had not undergone previous resection. Thus resection of mycetomas, particularly if elective, is a very safe and highly effective means of treatment. Further, the danger of antifungal chemotherapy is obviated. Evidence is accumulating that secondary infestation with aspergillus is an increasingly frequent occurrence [131 (Fig 2). One notes the C D

7 7 Karas et al: Pulmonary Aspergillosis British Tuberculosis Association report [16] that aspergillomas occur in 15% of open negative cavities larger than 2.5 cm, with the highest incidence in cavities of seven to eleven years duration. Further, once hemoptysis occurs, the potential for fatal hemoptysis exists. Therefore it is logical to recommend operative resection of the involved areas since the surgical mortality is exceedingly low and the potential for cure is excellent. References 1. Aslam PA, Eastridge CE, Hughes FA: Aspergillosis of the lung: an eighteen year experience. Chest 59:28, Campbell MJ, Clayton YM: Bronchopulmonary aspergillosis. Am Rev Resp Dis 89:186, Carbone PP, Seymour MS, Sidransky H, et al: Secondary aspergillosis. Ann Intern Med 60:556, Conen PE, Walker GR, Turner JA, et al: Invasive primary aspergillosis of the lung with cerebral metastasis and complete recovery. Chest 42938, Deve F: Une nouvelle forme anatomoradiologique de mycose pulmonaire primitive: le megamycetome intra bronchiectatique. Arch Med Chir Appar Resp 13:337, Eastridge CE, Young JM, Cole F, et al: Pulmonary aspergillosis. Ann Thorac Surg 13:397, Flye MW, Sealy WC: Pulmonary aspergilloma. Ann Thorac Surg 20:196, Gerstl B, Weidman WH, Newmann AV: Pulmonary aspergillosis: report of two cases. Ann Intern Med 28:662, Gowing NF, Hamlin IM: Tissue reactions to aspergillus in case of Hodgkin s disease and leukemia. J Clin Pathol 13:396, Henderson AH, Pearson JE: Treatment of bronchopulmonary aspergillosis with observations on the use of natamycin. Thorax 23:519, Irwin A: Radiology of the aspergilloma. Clin Radio1 18:432, Kilman JW, Ahn C, Andrews NC, et al: Surgery for pulmonary aspergillosis. J Thorac Cardiovasc Surg 57:642, Parker JD, Sarosi GA, Doto IL, et al: Pulmonary aspergillosis in sanatoriums in the South Central United States: a National Communicable Disease Center Cooperative Mycoses Study. Am Rev Resp Dis 101:551, Pepys J, Riddell RW, Citron KM, et al: Clinical and immunologic significance of Aspergillus furnigatus in the sputum. Am Rev Resp Dis 80:167, Ramirez J: Pulmonary aspergilloma: endobronchial treatment. N Engl J Med 271:1281, The Research Committee of the British Tuberculosis Association. Aspergillus in persistent lung cavities after tuberculosis. Tubercle 49:1, Saab SB, Almond C: Surgical aspects of pulmonary aspergillosis. J Thorac Cardiovasc Surg 68:455, Segretain G: Pulmonary aspergillosis. Lab Invest 11:1047, Solit RW, McKeown JJ, Smullens S, et al: The surgical implications of intracavitary mycetomas (fungus balls). J Thorac Cardiovasc Surg 62:411, Symmers WS: Histopathologic aspects of the pathogenesis of some opportunistic fungal infections, as exemplified in the pathology of aspergillosis and the phycomycetoses. Lab Invest 11:1073, Torack RM: Fungus infection associated with antibiotics and steroid therapy. Am J Med 22372, Virchow R: Beitrage zur Lehre von den beim Menschen vorkommenden pflanzlichen Parasiten. Virchows Arch [Pathol Anat] 9:557, Walter JE, Jones RD: Serologic tests in diagnosis of aspergillosis. Dis Chest 53:729, Wilhite JL, Cole FH: Invasion of pulmonary cavities by Nocardia asteroides: report of five cases. Am Surg 32:107, 1966