and Cardiac Presentations of Histoplasmosis

Transcription

1 Pulmonary, Mediastinal, and Cardiac Presentations of Histoplasmosis Richard L. Prager, M.D., D. Patrick Burney, M.D., George Waterhouse, M.D., and Harvey W. Bender, Jr., M.D. ABSTRACT Sixty-one patients with histoplasmosis were identified. They ranged from 14 months to 67 years old. There were 56 male and 5 female patients. Disease presentations were categorized into pulmonary (47), mediastinal (111, pericardial (2), and cardiac (1). Twenty of the patients with pulmonary involvement had histoplasmomas treated by wedge resection (18) or lobectomy (2). Twenty-two of the 27 cavitary lesions were treated by lobectomy and 4 by segmental resection, and 1 required pneumonectomy. The patients with mediastinal granulomas or fibrosis underwent exploration for diagnosis and curative or palliative procedures. Two patients with pericardial histoplasmosis required pericardial windows to relieve acute tamponade. One patient with disseminated histoplasmosis required aortic valve replacement for histoplasmosis valvulitis with severe regurgitation. The 1 operative death was a patient requiring pneumonectomy for mediastinal histoplasmosis. Indications for operative intervention in pulmonary histoplasmosis included resection of a new or enlarging pulmonary nodule to provide a definite pathological diagnosis and resection of persistent thick-walled pulmonary cavities. Mediastinal granuloma with or without fibrosis required exploration for diagnosis, palliation, or cure. Fungal endocarditis necessitated treatment with amphotericin B and valve replacement to stabilize the patient s hemodynamic status and prevent embolization of large fungal vegetations. Pericardial effusion, a rare manifestation of histoplasmosis, was seen as acute tamponade requiring emergency intervention. From the Section of Surgical Sciences, Department of Cardiac and Thoracic Surgery, Vanderbilt University Medical Center, Nashville, TN. Presented at the Twenty-sixth Annual Meeting of the Southern Thoracic Surgical Association, Nov 1-3,1979, San Antonio, TX. Address reprint requests to Dr. Prager, Department of Cardiac and Thoracic Surgery, Vanderbilt University Medical Center, Nashville, TN Vanderbilt Medical Center has played a major role in the diagnosis and delineation of the natural history of histoplasmosis. DeMonbreun, Christie, Diveley, McCracken, and Goodwin have all helped to outline the approach to this disease. In this update of Vanderbilt s clinical and pathological experience, we have viewed histoplasmosis infection in terms of a unified concept because we believe infection in endemic areas is universal and usually asymptomatic. The manifestations represented in this paper are the abnormal host responses to this endemic fungus with a variety of organ systems affected. They are examples of the structural defect present in chronic pulmonary histoplasmosis, the immune defect of disseminated histoplasmosis, and the unique host response occasionally seen to healed primary infections such as mediastinal fibrosis or an enlarging histoplasmoma [9]. Materials and Methods The charts of all patients requiring operation for bacteriologically or pathologically confirmed histoplasmosis at Vanderbilt University Affiliated Hospitals between 1960 and 1978 were reviewed. Only those patients whose bacteriological specimens revealed Histoplasma capsdatum or whose pathological specimen confirmed the organisms were included in the study. Sixty-one such patients were identified. The age of the patients ranged between 14 months and 67 years; there were 56 male and 5 female patients. Disease presentations were divided into the anatomical area affected, and symptoms were dependent on the area involved. Of the 61 patients, 47 had pulmonary involvement. Mediastinal histoplasmosis was found in 11 of the 61 patients. Pericardial histoplasmosis was diagnosed in 2, and 1 patient had aortic valvulitis secondary to disseminated histoplasmosis by The Society of Thoracic Surgeons

2 386 The Annals of Thoracic Surgery Vol 30 No 4 October 1980 Symptoms in 47 Patients with Pulmonary Histoplasmosis Cavitary Pulmonary Lesions Nodule Symptoms (27 Patients) (20 Patients) Pneumonia 6 Malaise 6 Night sweats 3 1 Sputum production 3 1 Dyspnea 3 Fever 6 2 Hemoptysis 5 1 Cough 12 8 Weight loss 7 2 Asymptomatic 5 10 Of the 47 patients with pulmonary involvement, 27 were operated on because of cavitary lesions secondary to chronic pulmonary histoplasmosis. Symptoms in these patients included chronic cough, chronic bronchitis, weight loss, fatigue, and hemoptysis (Table). The other 20 patients underwent exploration for a solitary pulmonary nodule which, on pathological examination, proved to be a histoplasmoma. These patients were explored because of a new nodule on chest roentgenogram or an obviously enlarging one. Half of these patients were asymptomatic. Mediastinal histoplasmosis was diagnosed in 11 patients. This group was seen with atelectasis, pneumonia, and respiratory symptoms in the face of an abnormal chest roentgenogram. Two patients were found to have histoplasmosis pericarditis and underwent pericardial resection for signs of congestive heart failure with elevated central venous pressure and pericardial effusion. Both of the patients were febrile, appeared systemically ill, and had chest pain. One patient with previously diagnosed aortic valve insufficiency had disseminated histoplasmosis, histoplasmosis endocarditis, and aortic valvulitis. Florid congestive heart failure requiring vigorous therapy rapidly developed. Following 2 gm of a 4 gm course of amphotericin B, the patient underwent aortic valve replacement. Results Pulmonary Histoplasmosis Twenty-seven patients with cavitary histoplasmosis underwent operation. Twenty-two were treated by lobectomy and 4 by segmental resection, and 1 required pneumonectomy. Three patients required thoracoplasty because of an empyema following lobectomy. The pneumonectomy was necessary because of extensive mediastinal inflammatory disease as well as cavitary upper lobe disease in a patient with massive hemoptysis. There were no operative deaths in this group. Follow-up has been obtained in 23 of the 27 patients with follow-up ranging from one year to fourteen years. Recurrent cavitary disease developed in 5 patients, 2 of whom were treated with a 2 gm course of amphotericin B. No patient in this group underwent a second operative procedure because of concurrent chronic obstructive pulmonary disease and marginal respiratory reserve. Ten patients in this group had signs and symptoms of obstructive pulmonary disease which compromised their activity level. There was no documented recurrent disease in this group, and the majority of the patients had severe chronic obstructive pulmonary disease. Bronchogenic carcinoma developed in 1 patient who was then lost to follow-up, as were 4 other patients. There were 2 deaths during the follow-up period; one was due to a myocardial infarction and the other, to progressive respiratory insufficiency. Five patients with cavitary histoplasmosis were found to be doing well and were essentially asymptomatic. Twenty patients underwent exploratory thoracotomy for a solitary pulmonary nodule. Eighteen were treated by wedge excision; and 2 underwent lobectomy. Three of these patients have been lost to follow-up during the eighteen-year period. No cavitary pulmonary disease developed in the other 17 patients. Mediastinal Histoplasmosis Eleven patients were found to have mediastinal histoplasmosis. Seven had mediastinal fibrosis, and 4 underwent exploration for noncalcified enlarging mediastinal nodes that proved to have Histoplasma capsulatum present. All of the

3 387 Prager et al: Histoplasmosis patients with mediastinal fibrosis had pathological evidence of Histoplasma organisms. In the group of 7 patients with mediastinal fibrosis, 4 required pneumonectomy for massive hilar fibrosis with atelectasis and pneumonia, and 1 underwent two attempts at superior vena cava enlargement. Two patients underwent diagnostic exploration without mediastinal or pulmonary resection. There was 1 death in the group having pneumonectomy. The patient who died was a 57-year-old man in whom an empyema and bronchopleural fistula developed after pneumonectomy. The 3 remaining patients were doing well at two to seven years postoperatively. One patient had two attempts at superior vena cava enlargement-replacement over a seven-year period and was lost to follow-up two years after the second operation. Two patients were explored for diagnosis and found to have fibrotic masses. One was placed on a regimen of amphotericin B for an unknown time for extrinsic compression of the left main bronchus and was asymptomatic five years later. The other patient was found to have fibrosis surrounding the superior vena cava and azygos vein and was asymptomatic without treatment two years later. Four patients underwent exploration for enlarging noncalcified mediastinal nodes. One patient in this group underwent a right middle lobectomy for persistent pneumonia and atelectasis secondary to enlarging mediastinal nodes laden with Histoplasma capsulatum. The remaining 3 underwent diagnostic exploration for granulomas. All of these patients were asymptomatic without obvious recurrence or signs of fibrosis at one to four years. Pericardial Histoplasmosis Two patients underwent left thoracotomy, lymph node biopsies, and pericardial drainage procedures for acute fibrinous pericarditis and pericardial effusion. On pathological examination, both were found to have Histoplasma capsulatum in the pericardium and surrounding hilar lymph nodes. One patient was lost to follow-up, and the second is doing well without pericardial calcification one year postoperatively. The second patient was treated with amphotericin B. Valvular Histoplasmosis One patient, a 55-year-old man with preexisting aortic regurgitation, was seen with disseminated histoplasmosis and histoplasma endocarditis. Because of refractory congestive heart failure secondary to progressive aortic insufficiency, and a large valvular vegetation, the patient underwent valve replacement with a size 25 Bjork-Shiley valve. Postoperatively the patient completed his 4 gm course of amphotericin B and was doing well, without valve dysfunction or evidence of histoplasmosis, one year postoperatively. Comment Vanderbilt University Medical Center has been intimately involved in deciphering the manifestations of infection with the soil fungus, Histoplasma capsulatum. Following Samuel T. Darling s [5] initial description of this fungus in 1905, W. A. DeMonbreun [61, a pathologist at Vanderbilt, extensively reviewed the available information on Histoplasma capsulatum. He proved, following his isolation of the organism, that the etiological agent in the infections noted by Dr. Darling and others was a fungus. In the 1960s and 1970s, Drs. Goodwin, Snell, and Des- Prez [lo-121 of the Department of Medicine at Vanderbilt compiled several reviews on mediastinal and pulmonary aspects of the disease as well as a collective review of histoplasmosis seen at Vanderbilt. From Vanderbilt s surgical sphere, Drs. Diveley and McCracken [8] in 1966 presented a review of the operative resection of 29 cases of cavitary pulmonary histoplasmosis seen at Middle Tennessee Chest Disease Hospital. The present review of eighteen years of clinical, pathological, and roentgenographic experience with histoplasmosis is built on the information acquired by many of these people Infection with the dimorphic fungus Histoplasma capsulatum as demonstrated by histoplasmin skin reactivity is virtually endemic in the middle parts of Kentucky and Tennessee [41. Human infection is initiated by inhalation of the airborne spores, and the lung is the site of primary infections as well as reinfections [91. Infection in normal populations is usually asymptomatic. However, Goodwin and co-

4 388 The Annals of Thoracic Surgery Vol 30 No 4 October 1980 workers [ll] believe that the patient with pulmonary histoplasmosis is unique because of the conspicuous presence of emphysematous and bullous spaces. It is thought that in cavitary disease there initially has been an inflammatory response to soluble antigenic substances followed by eventual tissue necrosis occasionally accompanied by fibrosis. Twenty percent of patients in whom pulmonary histoplasmosis develops follow this route [ll]. In our series, as in other reports of cavitary pulmonary histoplasmosis, cavitary lesions were seen in older individuals; 24 of the 27 patients were older than 40. The cavities, as noted by Levene [131, Saab [151, and their co-workers, were usually located in the upper lobes, which lends support to the premise that the disease occurs in emphysematous lung tissue. The majority of symptoms in cavitary disease were related to the respiratory tract and infection. Operative intervention is indicated in those patients who have large, thick-walled cavities (3 to 4 mm thick), relentless respiratory symptoms, and no improvement after one or two courses of amphotericin B, 1 to 2 gm each [31. Many of these thick-walled cavities, if unoperated on, progress 1 to 2 cm a year and are a source of persistent infection. These patients are subject to fibrosis secondary to episodic aspiration of cavity contents and eventual progressive respiratory insufficiency [ll]. Those cavities that are thin-walled (< 2 mm) are less likely to harbor persistent infection or to lead to fibrosis secondary to aspiration and therefore are usually treated with amphotericin B alone. In this series of 27 patients with cavitary disease there was no operative mortality and minimal morbidity, results justifying an aggressive operative approach to patients with thick-walled cavitary disease who are unimproved by therapy with amphotericin B. Twenty patients in this series underwent exploration for a solitary pulmonary nodule. Indication for exploration was the necessity to establish a definitive diagnosis, and the explorations were carried out without mortality or significant morbidity. Eighteen of the 20 patients underwent wedge excision only, and 2 required lobectomy. Careful roentgenographic evaluation was carried out in all patients in an attempt to avoid unnecessary thoracotomy. Goodwin and Snell s [12] concept that histoplasmomas continue to elaborate collagen at the periphery of the nodule appears valid since several of these patients that were followed preoperatively had enlarging nodules that were histoplasmomas. None of these patients, however, demonstrated concentric calcium laminations [16]. The 17 patients who were followed have shown no evidence of further pulmonary histoplasmosis, nodular or cavitary. The patients with mediastinal histoplasmosis had signs and symptoms of disease at an earlier age than the pulmonary group. Ten of the 11 patients in this group were less than 30 years old, and all 4 of the patients explored for mediastinal mass lesions without fibrosis were less than 10 years old. These 4 patients are all asymptomatic at follow-up to four years. Mediastinal lesions, either in an encapsulated mass or noncalcified nodes, require tissue diagnosis whether or not they initiate symptoms [71. In this small group of patients with granulomatous nonfibrosing mediastinal histoplasmosis, all patients were seen initially with pneumonia or bronchitis or both. Although no patient received postoperative antifungal therapy, 3 of the 4 were asymptomatic from excisional biopsy and the fourth was cured following middle lobectomy. The single death in this series of 61 patients occurred in the group with fibrous mediastinitis. Five of the 7 patients in this group underwent resectional procedures, and 2 were biopsied only. Obviously, exuberant mediastinal fibrous proliferation represents a malignant reaction to histoplasmosis that occurs in a small percentage of patients with mediastinal granulomas. This either can occur as an immunological reaction to fungal antigen that is released when granulomas rupture or demonstrates the inability of the host to cease collagen formation around a central focus of infection. No specific time can be predicted when this might occur or which individuals are more likely to have mediastinal fibrosis secondary to histoplasmosis. Four of the 7 patients were less than 20 years old and the patient who died was a 57-year-old man who had had a left extrapleural pneumonectomy for recurrent pneu-

5 389 Prager et al: Histoplasmosis monia and necrosis secondary to mediastinal fibrosis. Although involvement of the superior vena cava developed in only 1 of our patients, this is probably a more common occurrence than our series demonstrates. Since the sequelae of mediastinal fibrosis may be severe, total excisional biopsies of undiagnosed mediastinal granulomas should be undertaken if technically feasible, with the aim of diminishing the likelihood of fibrosis developing. The role of amphotericin B in granulomas and fibrosis has yet to be determined; only 1 of our 11 patients received it postoperatively, and there was no documented therapeutic effect. It may be as Williams and Burford [201 suggested and Zajtchuk and colleagues [211 reiterated that an aggressive operative approach to mediastinal granulomas may prevent severe sequelae of fibrosis. Interestingly, two cases in this series demonstrated Histoplasma capsulatum pericarditis. Although this is a rare cause of pericarditis with approximately forty cases described in the literature, it is one that occurs more frequently than thought and carries a good prognosis [141. Both of our patients were acutely ill with febrile illness and large pericardial effusions necessitating drainage. Following pericardial window procedures, both improved dramatically. The pathogenesis of this granulomatous fibrinopurulent pericarditis is thought to be related either to direct extension from mediastinal nodes or pulmonary foci of histoplasmosis, or a hypersensitivity phenomenon. One of our patients demonstrated Histoplasma capsulatum in the hilar nodes as well as the pericardium, which lends credence to the direct extension theory. Follow-up in this group is only one year, and there is no evidence of constriction or calcification, which also confirms the findings of Picardi and colleagues that this type of pericarditis may carry a good prognosis [14]. Since the pericarditis was not a manifestation of disseminated disease nor were the conditions recurrent, amphotericin probably has little effect on the eventual outcome. Although fungal endocarditis is rare, 1 patient in our series with long-standing aortic regurgitation required valve replacement for valvulitis secondary to disseminated histoplas- mosis. Previous papers have supported the concept of secondary infection by Histoplasma capsulatum of a diseased valve, and our patient represents one of the earliest published accounts of valve replacement for histoplasma endocarditis [l, 2, 18, 191. Because of his disseminated process, he was treated aggressively with 2 gm of amphotericin B preoperatively and received 2 additional gm postoperatively. His valve demonstrated Histoplasma organisms and showed the classic large vegetations of fungal endocarditis [17]. Although a rare cause of endocarditis, histoplasmosis must be considered an etiological agent in patients with signs of fungal endocarditis. All of these patients require aggressive antifungal treatment, and some may require valve replacement to improve valve function, remove a source of emboli, and excise lesions of low curability with drugs alone [171. In summary, symptomatic histoplasmosis often is seen as a thoracic diagnostic and therapeutic problem. The natural history of pulmonary histoplasmosis is clear, and the aggressive nature of mediastinal histoplasmosis is. becoming apparent. With more awareness on the part of surgeons, pericardial and cardiac disease caused by histoplasmosis will be more frequently recognized and treated. Finally, therapy with amphotericin B is indicated in cardiac histoplasmosis as well as cavitary pulmonary disease. The place of antifungal therapy in mediastinal and pericardial disease, although individualized, needs further data for definitive clarification. References 1. Akbarion M, Salfelder K, Schwarz J: Experimental histoplasma endocarditis. Arch Intern Med 114:789, Andriole VT, Kravetz HM, Roberts WC, et al: Candida endocarditis: clinical and pathologic studies. Am J Med 12:251, Beatty 0, Levene N, Saliba A, et al: Surgical therapy of chronic pulmonary histoplasmosis with and without amphotericin B. J Thorac Cardiovasc Surg 44:228, Christie A, Peterson JC: Pulmonary calcification in negative reactors to tuberculin. Am J Public Health 38:1131, Darling S: A protozoon general infection producing pseudotubercles in the lungs and focal

6 390 The Annals of Thoracic Surgery Vol 30 No 4 October 1980 necroses in the liver, spleen and lymph nodes. JAMA 46:1283, DeMonbreun WA: The cultivation and cultural characteristics of Darling s Histoplasma capsulatum. Am J Trop Med Hyg 14:93, Dines D, Payne WS, Bernatz P, et al: Mediastinal granuloma and fibrosing mediastinitis. Chest 75:320, Diveley W, McCracken R: The cavitary pulmonary histoplasmosis treated by pulmonary resection. Ann Surg 163:921, Goodwin R, DesPrez R: Histoplasmosis. Am Rev Respir Dis 117:929, Goodwin RA, Nickel1 JA, DesPrez RM: Mediastinal fibrosis complicating heated primary histoplasmosis and tuberculosis. Medicine 51:227, Goodwin R, Owens R, Snell J, et al: Chronic pulmonary histoplasmosis. Medicine 55:413, Goodwin R, Snell J: The enlarging histoplasmoma. Am Rev Respir Dis 100:1, Levene N, Slesh MZ, Torres J, Saliba NA: Surgical aspects of chronic progressive cavitary pulmonary histoplasmosis. Ann Thorac Surg 5:23, Picardi J, Kauffman C, Schwarz J, et al: Pericarditis caused by Histoplasma capsulatum. Am J Cardiol37:82, 1976 Saab S, Ungaro R, Almond C: The role and results of surgery in the management of chronic pulmonary histoplasmosis. J Thorac Cardiovasc Surg 68:159, 1974 Sutaria M, Polk J, Reddy P: Focalized pulmonary histoplasmosis (coin lesion): a report of 58 cases. Chest 61:361, 1972 Utley J, Mills J, Roe B: The role of valve replacement in the treatment of fungal endocarditis. J Thorac Cardiovasc Surg 69:255, 1975 Waterhouse G, Bumey DP, Prager R: Histoplasma capsulatum endocarditis requiring aortic valve replacement for aortic insufficiency. South Med J 73:683, 1980 Weaver DK, Batsakis JG, Nishiyama R: Histoplasma endocarditis. Arch Surg 96:158, 1968 Williams KR, Burford TH: Surgical treatment of granulomatous paratracheal lymphadenopathy. J Thorac Cardiovasc Surg 48:13, 1964 Zajtchuk R, Strevey T, Heydorn W, et al: Mediastinal histoplasmosis. J Thorac Cardiovasc Surg 66:300, 1973