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(Chest. 2000;117:279-282.)
© 2000 American College of Chest Physicians

The Role of BAL in the Diagnosis of Pulmonary Mucormycosis*

Mendel Glazer, MD; Samir Nusair, MD; Raphael Breuer, MD; Joel Lafair, MD; Yoav Sherman, MD and Neville Berkman, MBBCh

* From the Institute of Pulmonology (Drs. Glazer, Nusair, Breuer, Lafair, and Berkman) and the Department of Pathology (Dr. Sherman), Hadassah University Hospital, Jerusalem, Israel.

Correspondence to: Neville Berkman, MBBCh, Institute of Pulmonology, Hadassah University Hospital, PO Box 12000, Jerusalem, Israel, 91120.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Five patients with pulmonary mucormycosis diagnosed during life are described. All had underlying predisposing conditions: either posttransplant or hematologic malignancies. In all cases, the diagnosis was made using fiberoptic bronchoscopy. In three patients, BAL was diagnostic. In two of these patients, the diagnosis was made by identifying the typical hyphae of mucormycosis in the BAL fluid alone. Transbronchial biopsy was diagnostic in three patients. Treatment was based on IV antifungal chemotherapy together with surgical removal of involved lung tissue whenever feasible. The clinical outcome of these patients was dismal and was determined primarily by the underlying condition.

Key Words: BAL • immunocompromised • mucormycosis • neutropenia


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Mucor, a fungus from the class of Zygomycetes, is a ubiquitous saprophyte that resides in soil and decaying organic matter. Humans may be infected with Mucor after inhalation of airborne fungal spores. However, normal macrophage and neutrophil function provides immune protection against Mucor. Therefore, patients with neutrophil dysfunction, such as occurs in diabetes, renal failure, or prolonged steroid therapy, are particularly vulnerable to infections with Mucor. Additionally, neutropenic patients may also develop invasive mucormycosis.

The most frequently observed manifestation of mucormycosis is the characteristic rhinocerebral infection, which may initially mimic bacterial sinusitis, and later extend to involve and destroy the hard palate and the orbit, and further invade the carotid artery. The GI tract and the brain may be involved in disseminated mucormycosis. The lung is more rarely involved by infection with this fungus. Such pulmonary involvement may progress and include invasion of blood vessels.

In reported series of invasive pulmonary mucormycosis, the diagnosis is often made at postmortem or premortem examination by using transbronchial biopsy (TBB) or open lung biopsy. However, many patients at risk for this infection are thrombocytopenic, which precludes the performance of invasive diagnostic procedures. BAL has not been evaluated for the diagnosis of this infection.

We present five patients with pulmonary mucormycosis that was diagnosed during life in our institution; three of the five patients had a diagnostic BAL.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
We searched the medical records of patients hospitalized in our institution between the years 1992 and 1997 and identified five patients in whom the diagnosis of pulmonary mucormycosis was made during life. Details regarding the underlying condition, clinical and radiologic presentation, methods of diagnosis, treatment, and clinical outcome were documented in each case.

The definitive diagnosis was made in all patients by fiberoptic bronchoscopy. BAL was performed in all patients, and TBB was performed whenever there was no coagulopathy and the thrombocyte count was > 50,000 cells/µL.

Material from TBB is embedded in paraffin blocks, and sections of 5 µm are stained with hematoxylin-eosin. BAL fluid is routinely cytocentrifuged and stained with Papanicolaou stain, Gomori methenamine silver stain. BAL fluid is also sent for bacterial, fungal, viral, and mycobacterial cultures.

A diagnosis of pulmonary mucormycosis was considered definite in the presence of histologic evidence of invasive fungal infection. For BAL, the finding of typical morphologic features of Mucor on direct staining or culture in the presence of compatible clinical presentation as well as favorable response to antifungal therapy was also considered diagnostic.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
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Clinical Findings
The clinical details of the patients are summarized in Table 1 . All patients were males, with a mean ± SD age at diagnosis of 40 ± 8.3 years. Four patients had an underlying hematopoietic malignancy; two of the four patients had undergone bone marrow transplantation (BMT). The fifth patient was a kidney transplant patient. Diabetes mellitus (DM) secondary to corticosteroid (CSE) therapy, a well-known risk factor for rhinocerebral mucormycosis, was present in two cases. Four patients were receiving CSEs, and one patient (patient 1) was receiving cyclosporine A at the time of infection. Patient 5 had undergone autologous BMT, followed by administration of allogeneic stem cell transfusion. Two patients were neutropenic during the onset of infection with mucormycosis.


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  		Table 1.. Demographic Data of the Patients*

 
The radiologic and bronchoscopic findings in our patients are outlined in Table 2 . Four of the patients had unilateral lung involvement, and only one patient had bilateral lung disease. Three patients had cavitary lesions on chest plain radiography and CT. Other radiographic findings included a single mass in the right upper lobe and an additional nodule in the left lower lobe in one patient, and a right lower lobe (RLL) infiltrate in another patient.


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  		Table 2.. Diagnostic Modalities*

 
In our five patients with pulmonary mucormycosis, TBB was performed in three patients and was diagnostic in all. Of the five patients in whom BAL was performed, three patients had positive findings on direct microscopy. Only one of five patients had a positive finding on BAL culture (Table 2) . In two cases, TBB findings were positive while BAL findings were negative for mucormycosis. In the two patients in whom TBB was not performed, BAL alone was diagnostic. Thus overall, BAL was diagnostic in three of the five patients (60%; Fig 1 ). Culture yielded mucormycosis in only one of five cases, and this patient had positive findings on both BAL and TBB. In one patient only (patient 1), an initial transthoracic needle aspiration of a lung cavity was performed, but was not diagnostic.



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  		Figure 1.. Mucormycosis in BAL. Top, a: Characteristic, right angle branching (long arrows), ribbon-like hyphal fragments without obvious septa. Bottom, b: Note the typical cellular bronchial background of columnar ciliated cells (arrowheads) and macrophages (short arrows; Papanicolaou stain, original magnification x 400).

 
Treatment
All patients were treated with high-dose amphotericin B (AMB); total dose was 1.5 g. In two patients, surgical resection of the involved lung was also performed.

Outcome
The mean survival was 3.6 weeks. None of our patients survived beyond 3 months; however, the two patients who underwent lung resection did not have evidence of recurrence of mucormycosis up until their death. Patient 2 died of ventilator-associated pneumonia in the remaining lung, and patient 1 died 2 months after surgery because of progressive hepatic failure secondary to severe chronic graft-vs-host disease. Patient 3 survived at least 1 month past surgery but later died due to acute myeloblastic leukemia relapse in his home country.


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Mucor belongs to a unique group of fungi within the class Zygomycetes and is generally a noninvasive saprophyte in the normal host. Mucor infection invariably occurs in the presence of underlying disease, most commonly seen as an infectious complication of DM, and typically manifests as a rhinocerebral infection. In contrast, pulmonary mucormycosis is seen infrequently in diabetic patients.1

Besides DM, other well-recognized risk factors for invasive mucormycosis include neutropenia,2 hematopoietic malignancies, and CSE therapy.3 Among solid-organ transplants, patients undergoing renal transplantation (renal-Tx) for end-stage diabetic nephropathy, who are more likely to develop metabolic acidosis, may be more susceptible to mucormycosis.4 Two of our patients had CSE-induced DM, of which one had undergone renal-Tx. Neither patient had metabolic acidosis as a primary event during presentation with pulmonary mucormycosis.

The most common radiographic manifestation in our patients was the presence of cavitary lesions. In a recent review of imaging findings in 32 cases of mucormycosis, two thirds of the patients had consolidation as a main finding.5 Forty-one percent of the patients had cavitation within pulmonary consolidation or masses. Other radiographic manifestations include multifocal consolidation, on "air crescent sign" whenever a pulmonary infarct results from vascular invasion, and rarely pleural effusion.6

The antemortem diagnosis of pulmonary mucormycosis is often missed because the diagnosis is not suspected or pursued thoroughly enough. Because postmortem examinations are rarely performed in our country, this series includes only diseases diagnosed antemortem. It is thus possible that the number of cases of pulmonary mucormycosis in our institution is much higher than that reported here.

According to published studies, the diagnosis of pulmonary mucormycosis requires the demonstration of the typical nonseptated right angle branching-shaped hyphae within the lung tissue.3 A positive finding from BAL culture is suggestive but not considered definitive.6 However, since hematologic patients are frequently thrombocytopenic, obtaining TBB is frequently not feasible. In such cases, BAL may be the only diagnostic modality available.

Of our five cases, the BAL finding was positive in three (60%). Of these, two patients were unable to undergo TBB; in these cases, the diagnosis was made by BAL alone. In all three cases with a positive finding on BAL, mucormycosis proved to indeed be a true pathogen and not merely a coincidental finding; in one case, this was confirmed by surgery (thoracotomy), and in the second by a positive finding on TBB. In the third patient, the clinical response after the initiation of antifungal therapy, together with failure to respond to broad-spectrum antibacterial therapy or to identify another pathogen despite extensive evaluation, led us to believe that mucormycosis was a true pathogen in this patient (patient 3).

There is little available literature that describes the diagnosis of mucormycosis by using BAL.7 8 A recent report described a diabetic patient in whom a diagnosis of pulmonary mucormycosis was made by BAL.9 Conventional recommendations in the literature require demonstration of Mucor hyphae within the pulmonary parenchyma in order to make the diagnosis of pulmonary mucormycosis.6 Our findings suggest otherwise. We believe that whenever mucormycosis is found in BAL cultures from a neutropenic or immunocompromised patient, the diagnosis of invasive mucormycosis is extremely likely and should be assumed until proven otherwise.

The diagnostic yield of fungal culture was poor (20%; one of five cases). The culture finding was negative even in cases in which findings from direct microscopy of BAL or lung tissue were positive. Similar results of culture have been reported by others.5 This yield may be dependent on the specific laboratory performing these cultures, but in our hands, culture adds little to the histopathologic tests. Our data suggest that BAL could be a useful diagnostic procedure for pulmonary mucormycosis, with an acceptable risk for thrombocytopenic and critically ill patients in whom TBB is contraindicated.

From our data, it is not possible to comment on the negative predictive value of BAL for excluding the diagnosis of pulmonary mucormycosis. Conclusions regarding this issue would require the performance of open lung biopsy or postmortem examination in all patients in whom BAL is analyzed.

The recommended treatment for pulmonary mucormycosis includes treatment of the underlying condition, surgical removal of the devitalized tissue, and IV administration of AMB. According to recent reports, early surgical treatment may substantially reduce mortality (45% with surgery vs 70 to 80% with medical management only).5 7 Although surgical resection of pulmonary parenchyma involved with mucormycosis seems to have eradicated mucormycosis in our patients, the underlying condition was the main factor that determined their outcome and survival. Consequently, overall survival in our group was dismal regardless of surgical intervention.

In conclusion, pulmonary mucormycosis should be suspected in patients with a high risk for invasive fungal pulmonary infections, particularly when they present with single or multifocal pulmonary infiltrates with cavitation. The diagnosis of fungal pneumonia requires the demonstration of fungi within the pulmonary parenchyma on lung biopsy; however, BAL, a relatively safe diagnostic tool, may allow the diagnosis of mucormycosis in cases where lung biopsy is contraindicated. Our findings strongly imply that the presence of mucormycosis within the BAL fluid is diagnostic of pulmonary mucormycosis in patients who are prone to such an infection. Although surgical resection of pulmonary parenchyma involved with mucormycosis may have eradicated the infection, the underlying condition was the main factor that determined outcome and mortality.


   Footnotes
 
Abbreviations: AMB = amphotericin B; BMT = bone marrow transplantation; CSE = corticosteroid; DM = diabetes mellitis; renal-Tx = renal transplantation; RLL = right lower lobe; TBB = transbronchial biopsy

Received for publication April 15, 1999. Accepted for publication July 23, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Hansen, LA, Prakash, UBS, Colby, TV (1989) Pulmonary complications in diabetes mellitus. Mayo Clin Proc 64,791-799[ISI][Medline]
  2. Baker, RD (1962) Leukopenia and therapy in leukemia as factors predisposing to fatal mycosis. Am J Clin Pathol 37,358-373
  3. Lehrer, RI, Howard, DH, Sypherd, PS, et al (1980) Mucormycosis. Ann Intern Med 93,93-108
  4. Latif, S, Saffarian, N, Bellovich, K, et al (1997) Pulmonary mucormycosis in diabetic renal allograft recipients. Am J Kidney Dis 29,461-464[ISI][Medline]
  5. McAdams, HP, de Christenson, MR, Strollo, DC, et al (1997) Pulmonary mucormycosis: radiologic findings in 32 cases. AJR Am J Roentgenol 168,1541-1548[Abstract/Free Full Text]
  6. Murphy, RA, Miller, WT, Jr (1996) Pulmonary mucormycosis. Semin Roentgenol 31,83-87[CrossRef][ISI][Medline]
  7. Tedder, M, Spratt, JA, Anstadt, MP, et al (1994) Pulmonary mucormycosis: results of medical and surgical therapy. Ann Thorac Surg 57,1044-1050[Abstract]
  8. Williams, D, Yungbluth, M, Adams, G, et al (1985) The role of fiberoptic bronchoscopy in the evaluation of immunocompromised hosts with diffuse pulmonary infiltrates. Am Rev Respir Dis 131,880-885[ISI][Medline]
  9. Al-Abbadi, MA, Russo, K, Wilkinson, EJ (1997) Pulmonary mucormycosis diagnosed by bronchoalveolar lavage: a case report and review of the literature. Pediatr Pulmonol 23,222-225[CrossRef][ISI][Medline]



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