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Ann Thorac Surg 2009;88:399-403. doi:10.1016/j.athoracsur.2009.04.041
© 2009 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

Surgical Management of Pulmonary and Mediastinal Sequelae of Histoplasmosis: A Challenging Spectrum

Zane T. Hammoud, MDa,*, Anthony S. Rose, MDb, Chadi A. Hage, MDb, Kenneth S. Knox, MDb, Karen Rieger, MDc, Kenneth A. Kesler, MDc

a Department of Surgery, Division of Cardiothoracic Surgery, Henry Ford Hospital, Detroit, Michigan
b Department of Medicine, Division of Pulmonary Medicine, Indiana University School of Medicine, Indianapolis, Indiana
c Department of Surgery, Cardiothoracic Division, Indiana University School of Medicine, Indianapolis, Indiana

Accepted for publication April 13, 2009.

* Address correspondence to Dr Hammoud, Division of Cardiothoracic Surgery, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202 (Email: zhammou1{at}hfhs.org).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: Histoplasmosis may result in a spectrum of complications that require thoracic surgical intervention. We reviewed our 17-year experience in the management of histoplasmosis to determine outcomes as well as gain insight into the distribution of complications requiring surgical intervention.

Methods: The hospital records of patients who underwent surgical treatment for complications related to histoplasmosis from 1991 to 2008 were reviewed. Based on the predominant presentation, patients were categorized with complications secondary to broncholithiasis, granulomatous disease, or fibrosing mediastinitis. Patients who underwent diagnostic surgery and were found to have histoplasmosis were excluded.

Results: Of the 49 patients who underwent surgery for histoplasmosis-related complications, 27 (55%) had granulomatous disease, 13 (27%) had broncholithiasis, and 9 (18%) had fibrosing mediastinitis. The most common clinical presentations were recurrent pneumonia (n = 16) and hemoptysis (n = 13); less common presentations included dysphagia (n = 3) and superior vena cava syndrome (n = 1). Two patients required cardiopulmonary bypass for resection; 1 of these died postoperatively (series mortality 2%). Seven patients (14%) had complications. Relief of symptoms was achieved in all surviving patients.

Conclusions: Complications of histoplasmosis requiring thoracic surgical intervention are diverse with pulmonary complications predominating. Although surgically challenging, excellent short- and long-term outcomes may be expected.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Histoplasma capsulatum is the most prevalent endemic mycosis in North America. Infection with the organism most commonly manifests as a benign, self-limited respiratory illness, and many adults living in endemic areas have immunologic (skin test or serology) or radiographic (calcified lung or splenic granulomas) evidence of previous infection. The most common sequelae of histoplasmosis are asymptomatic pulmonary calcifications and calcified mediastinal and peribronchial lymph nodes for which no intervention is warranted. However, progressive complications such as pulmonary and mediastinal granulomatous disease (GD), fibrosing mediastinitis (FM), and broncholithiasis (BL) can occur.

Most patients with GD are asymptomatic. However, GD can occasionally cause constitutional symptoms such as fever and night sweats that may require treatment with antifungal therapies [1]. In general, treatment consists of itraconazole 200 mg three times daily for 3 days and then once or twice daily for 6 to 12 weeks. The decision to treat postoperatively is usually based on the finding of caseous material and the recovery of Histoplasma organisms from the surgical specimen; if such findings exist, additional treatment for 6 to 12 weeks may be warranted. In some instances, GD may lead to the formation of large inflammatory lymph nodes that compress and possibly erode the airways or esophagus, potentially leading to fistula formation. Granulomatous disease may at times coexist with calcified mediastinal nodes or even some elements of fibrosis. Fibrosing mediastinitis is the most severe chronic complication of histoplasmosis in which pulmonary vessels and airways can be compressed with no proven medical therapeutic options. Concomitant perihilar lymph node calcification has been considered a characteristic feature of post–histoplasmosis FM [2]. Broncholithiasis occurs when a calcified mediastinal lymph node erodes into an airway, causing obstruction or hemoptysis. Therefore, GD, FM, and BL all have the potential to compromise pulmonary and mediastinal structures and to lead to a variety of complications that require surgical intervention.

Surgical intervention with these patients is often technically challenging and potentially hazardous because the normal tissue planes are often obliterated. Thus, experience with and knowledge of the surgical options available are valuable when surgeons undertake intervention. Our institution's location in an endemic area allows us to see many patients with complications of histoplasmosis, many of whom do not require intervention. However, some of these patients require surgical intervention for a variety of symptoms for which no medical therapy is effective. We reviewed our experience in the surgical management of histoplasmosis to determine outcomes as well as the spectrum of complications that require surgical intervention.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Patient Population
The study was approved by the Indiana University Institutional Review Board. A retrospective database review was used to identify all patients who underwent surgical intervention for complications of H capsulatum infection or mediastinal fibrosis, or both, from 1991 to 2008. Patients who underwent diagnostic surgery and were found to have histoplasmosis were excluded.

Data Collection
A detailed chart review of all patients identified was performed. Patient demographics, pertinent clinical history (including preoperative radiographs), details of the surgical procedures, pathology, and microbiology results were collected. In addition, inpatient length of stay, postoperative complications, and subsequent follow-up were obtained. Based on the predominant presentation, patients were categorized with complications secondary to one of three groups: (1) FM, defined as progressive proliferation of fibroinflammatory material in the mediastinum encompassing major structures, such as the esophagus, pulmonary vasculature, proximal airways, or heart; (2) GD, defined as focal areas of lymphadenitis impinging upon or eroding into surrounding structures including the airways, local vasculature, or esophagus; or (3) BL, defined as discrete calcified lymph nodes locally eroding into the airways or pulmonary vasculature.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
A total of 49 patients underwent surgery for complications of histoplasmosis: 27 (55%) with GD, 13 (27%) with BL, and 9 (18%) with FM. Patients ranged in age from 14 to 66 years, and 27 were male. Radiographic studies were performed based on patient symptoms. The most common symptoms leading to surgical intervention were recurrent pulmonary infection (n = 17) and hemoptysis (n = 14). Three patients presented with dysphagia, and 1 had superior vena cava (SVC) syndrome. Pathologic evidence of granulomatous inflammation was observed to some degree in all patients with either FM or GD. GMS staining revealed Histoplasma yeast in the biopsy material of 13 patients (27%).

Of the 13 patients in the BL group, 7 underwent lobectomy, 5 bilobectomy, and 1 had transbronchial excision of a broncholith (in a patient with a previous right upper lobectomy). These patients presented with recurrent pneumonia (n = 8) or hemoptysis (n = 5). Among the 27 GD patients, the most common procedure performed was resection of a mediastinal mass (n = 9) and lobectomy (n = 7). Eight GD patients had concomitant or isolated esophageal repairs, and 1 underwent a bronchoplastic procedure. The most common presenting symptoms in the GD patients were hemoptysis (n = 7), recurrent pneumonia (n = 5), and dysphagia (n = 3). Among the 9 FM patients, the most common procedure performed was pneumonectomy (n = 3). Presenting symptoms in this group included 4 patients with recurrent pneumonia, 2 with hemoptysis, 2 with dyspnea, and 1 with SVC syndrome.

Table 1 provides a summary of all patients who underwent surgical intervention. Follow-up ranged from 1 to 29 months, and 3 patients were lost to follow-up. The average length of inpatient hospitalization was 8.2 days (range, 3 to 17). A total of 7 complications occurred, with the majority seen in patients with pathologically confirmed FM. One patient had a small bronchoesophageal fistula that resolved without subsequent intervention. One patient was ventilator-dependent postoperatively, and subsequent workup revealed left diaphragm paralysis, presumably due to injury to the phrenic nerve at the time of surgery. One patient had an empyema 2 weeks after surgery that required decortication. Two patients had major vascular injuries during surgical procedures for FM, requiring cardiopulmonary bypass for repair (both approached by posterolateral thoracotomy). One of these patients required repair of an aortic injury during pulmonary artery dissection; this patient recovered without sequelae. The other patient required repair of an injury to the right main pulmonary artery during right pneumonectomy for fibrotic occlusion of the carina; this patient died postoperatively (the only death in this series).


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  		Table 1 Summary of Three Categories of Sequelae of Histoplasmosis
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
Indiana is a well-identified endemic area for H capsulatum. Thus, the location of our institution allows us to see the full spectrum of complications that may result from infection with histoplasmosis. Our experience with this group of patients offers insight into the varied presentations as well as the surgical and nonsurgical options available for management. We grouped our patients into three distinct categories: mediastinal granulomatous disease, fibrosing mediastinitis, and broncholithiasis. Although the clinical presentation may be similar among the three categories, each presents different goals and challenges with respect to surgical intervention, thereby necessitating an individualized approach to surgical management. All patients were clinically suspected to have histoplasmosis infection as the etiology of their disease, with a definitive histologic diagnosis made in 13 patients (27%). This result is similar to that reported by other institutions located in endemic areas [3–7]. We excluded patients in whom resection was performed primarily to establish diagnosis and who were found to have evidence of histoplasmosis, for example, solitary pulmonary nodules resected to rule out carcinoma. In such patients, histoplasmosis and its sequelae were not suspected preoperatively and thus did not serve as the major indication for surgery.

Broncholithiasis generally involves calcification of tissues related to previous granulomatous inflammation. These lesions can erode into airways and produce intrinsic or extrinsic luminal airway occlusion (Fig 1). This process is generally regarded as a late complication of tuberculosis or histoplasmosis infection, but other etiologies have been described, including foreign body aspiration, primary endobronchial infection, and calcified endobronchial tumors such as carcinoid [8]. Surgical intervention was warranted in the majority of our patients with BL because of hemoptysis or recurrent pulmonary infections secondary to airways obstruction. Thus, the primary goal of surgical intervention is usually relief of obstruction. While lobectomy was the most commonly performed procedure for these cases, some required more extensive resection. Patients with BL generally require anatomic resection such as lobectomy due to chronic lobar or segmental obstruction with resultant dense fibrosis and distal bronchiectasis. At surgery, adhesions and fibrosis are frequently encountered and require pulmonary artery exposure in the fissure and the hilum; at times, it may be advisable to obtain control of the main pulmonary artery, sometimes intrapericardially, before undertaking further dissection.


Figure 1
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  		Fig 1. Computed tomography showing a typical broncholith.

 
Bronchoscopy is essential in the workup of BL to confirm computed tomography findings and intraluminal involvement, as well as to exclude other etiologies such as endobronchial malignancy [9]. Flexible bronchoscopy with forceps extraction can also be therapeutic [10, 11]. Potaris and colleagues [12] reported their experience with 47 patients with BL requiring surgical resection. The majority of patients in their series had right-sided lesions. Their major complication rate was 12.8% (which included 4 major pulmonary artery tears and 1 perioperative death). Interestingly, the authors observed recurrence of BL in 6 patients. None of the patients with BL in our series had disease that was thought to be amenable to bronchoscopic intervention (although 1 patient did undergo transbronchial extraction of a broncholith because of previous contralateral lung resection). Moreover, there were no intraoperative major vascular injuries or deaths for patients with BL in our series. Although rare, bilateral involvement may occur. These cases pose a particular challenge and management is highly individualized (for example, transbronchial or open extraction on one side with possible resection on the other); every effort should be made to preserve enough pulmonary parenchyma to allow adequate recovery and function.

Many patients are referred to our institution for a variety of conditions attributable to complications of histoplasmosis for which surgical intervention is unwarranted or unwise. Patients with partial or total occlusion of the SVC due to FM are often minimally symptomatic owing to the development of rich venous collaterals, making surgical intervention unnecessary. Unlike malignant occlusion, the chronic nature of occlusion secondary to histoplasmosis results in robust venous collaterals. When warranted, however, we have found reconstruction of the SVC with an externally stented polytetrafluoroethylene graft to be optimal. Although only 1 of our patients in this series required SVC reconstruction, our experience with other diseases that require SVC reconstruction, such as mediastinal germ cell tumors, has allowed us to gain some insight into such reconstruction. When symptoms of brachiocephalic venous insufficiency are significant and do not improve over time, SVC reconstruction using an externally stented polytetrafluoroethylene vascular prosthesis through a sternotomy approach is reasonable.

These cases are technically challenging as the dense fibrosis usually involves the brachiocephalic venous confluence. The venous collateral vessels are large, and bleeding should be controlled in a stepwise fashion. We prefer to reconstruct the right brachiocephalic vein to the SVC only, leaving the left brachiocephalic vein occluded. That provides high blood flow through the venous prosthesis and may decrease the risk of thrombosis. Similarly, patients with isolated pulmonary artery occlusion usually are minimally symptomatic, and we have expectantly observed the vast majority of these patients. Airway occlusion tends to result in more symptomatology secondary to shortness of breath and post–obstructive pneumonia, thereby necessitating intervention. In such cases, extensive involvement of either mainstem bronchus may necessitate pneumonectomy. When the central airways are involved, often in patients with FM, these cases pose a particular challenge, and we routinely have cardiopulmonary bypass at the ready should the need arise (Fig 2). Bronchoesophageal fistulas are usually due to GD and most commonly occur in the subcarinal space between the esophagus and the right mainstem bronchus (Fig 3). They are often small and involve the submucosal layer of the esophagus only. After identification and division of the fistulous tract, repair is undertaken by closure of the esophagus in two layers (inner layer of absorbable suture and outer layer of nonabsorbable), the airway in one layer (absorbable suture), and interposition of viable tissue (for example, pericardium or pericardial fat) between the two structures.


Figure 2
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  		Fig 2. Computed tomography showing extensive fibrosing mediastinitis.

 

Figure 3
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  		Fig 3. Barium esophagram showing bronchoesophageal fistula secondary to granulomatous disease.

 
Although a controversial debate, GD and FM are two complications of histoplasmosis that could be temporally related. Schowengardt and colleagues [13] reviewed 180 cases, including 103 GD and 77 FM cases, and concluded that one disease process could account for both manifestations. Their conclusion was based on similar patterns of inflammation, site of involvement (usually superior mediastinal near the carina), and relationship to prior pulmonary infection. Histoplasma capsulatum yeast forms were found in only 16 pathology specimens, and the majority (64%) of patients with FM demonstrated SVC obstruction. This observation contrasts with our experience as SVC obstruction occurred in only 1 of our patients.

To date, no case has documented progression of GD to FM [14]. Investigators in the 1970s advocated the use of "prophylactic" surgical excision of mediastinal granulomas (even asymptomatic lesions) to prevent progression to FM [4, 15–17]. Today, surgery is reserved only for symptomatic disease, especially when vital mediastinal structures are compromised. Unlike BL and FM, a clear role exists for antifungal therapy for patients with GD [18]. Four of our GD patients presented with fevers and constitutional symptoms and were treated with itraconazole. However, failure to improve on medical therapy led to eventual surgical intervention. Concomitant anti-inflammatory therapy can also be considered, especially when airway obstruction is involved [1, 19].

Fibrosing mediastinitis is a late and serious complication of histoplasmosis infection. As a general rule, the diagnosis of FM in endemic areas should rely upon clinical suspicion and not routinely require surgical biopsy because of its unique radiographic features [2, 9, 20, 21]. Previous experience by other investigators has shown that many patients with unilateral disease can be observed without detriment for long periods of time [20]. Mathisen and Grillo [22] reported 4 of 18 deaths in patients undergoing surgery for FM, 3 of whom underwent carinal pneumonectomy. Operative mortality has been notably high in the reported literature [16, 19, 23], albeit with small numbers of patients. Bilateral pulmonary vessel involvement or tracheal involvement portends an unfavorable prognosis [14, 20]. Surgical intervention for symptoms related to FM should be considered palliative in nature, as complete debridement is not technically feasible. Despite the risk, several surgical series [19, 22, 24] have shown that palliation is possible with reasonable outcomes. Percutaneous intravascular stenting is emerging as an alternative to surgery for vascular involvement caused by FM [25] in select patients. Interventional bronchoscopy has been utilized in patients with FM for palliation of airway stenoses [26] and treatment of hemoptysis [27]. Medical therapies, such as steroids and antifungal agents, have no proven role in the treatment of post–histoplasmosis FM [1, 4, 18].

In summary, surgical intervention for mediastinal complications of histoplasmosis is feasible and should be performed by experienced surgeons. Thoracic surgeons must be aware of the pitfalls of surgical intervention and of the surgical options available. Bronchoscopy, endovascular stenting, and antifungal therapy are other therapeutic options that should be carefully considered in patients with complications of histoplasmosis.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

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