Mycetoma

Study objectives: Although pulmonary mycetoma has been well-described in immunocompetent hosts, the only description in HIV-infected patients has been of 10 patients from our institution, from 1992 to 1995. To further investigate the impact of HIV status on the presentation and course of pulmonary mycetoma, we conducted a follow-up study.

Design: Retrospective review of all cases of pulmonary mycetoma at Bellevue Hospital from 1992 to 1999.

Setting: Patients were evaluated on the inpatient chest service and in the outpatient chest and HIV clinics of Bellevue Hospital in New York City.

Patients: We identified 74 patients with pulmonary mycetoma; 20 of them were HIV-infected (27%).

Interventions: The 20 HIV-infected patients were treated with antiretroviral and/or antifungal therapy.

Measurements and results: Predisposing diseases were pulmonary tuberculosis (TB), Pneumocystis carinii pneumonia (PCP), or both TB and PCP. Seventeen patients had a CD4+ cell count of < 100 cells/[micro]L at presentation. Hemoptysis was present in 13 patients, but was massive in only 1 patient. Cough was common. Of the 18 patients for whom follow-up was available, 11 received antifungal treatment and 7 were observed without therapy. Six patients received both antiretroviral and antifungal therapy. Disease progression occurred in 50%. Only five patients exhibited radiographic or clinical improvement. All five were treated with both antiretroviral and antifungal therapy.

Conclusions: PCP is a risk factor for pulmonary mycetoma in the HIV-infected individual. HIV-infected patients with mycetomas have a significant rate of disease progression, although they rarely have life-threatening hemoptysis. A combination of antifungal and antiretroviral therapy may improve the clinical outcome in HIV-infected patients with pulmonary mycetoma.

Key words: aspergilloma; Aspergillus fumigatus; HIV; mycetoma

Abbreviations: PCP = Pneumocystis carinii pneumonia; TB = tuberculosis

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A pulmonary mycetoma consists of a dense ball of fungal filaments and amorphous material containing cells and fibrin which fill a preexisting pulmonary cavity. Aspergillus, a fungus present in soil water and decaying vegetation, is one of the more common fungi that can cause this condition and various other diseases in the human host. In the lung, Aspergillus infection can cause obstructive bronchopulmonary aspergillosis, mucoid impaction of the airways, tracheobronchitis, ulcerative bronchitis, pseudomembranous tracheobronchitis, invasive aspergillosis, or aspergilloma. An aspergilloma is defined as Aspergillus infection of a preexisting pulmonary cavity without tissue invasion. Pulmonary mycetomas, and particularly aspergillomas, in the immunocompetent patient have been well-described in the literature, (1-6) but little has been published on the presentation and clinical course of the disease in the HIV-infected patient.

In the immunocompetent population, mycetoma occurs in 10 to 15% of patients with cavitating lung diseases. (7,8) These patients are often asymptomatic, but up to 25% may have massive hemoptysis. (3) The course of disease is variable, and patients are often observed without therapy unless they develop hemoptysis. HIV infection may change the presentation and course of mycetoma in several important ways. HIV-infected patients are particularly susceptible to cavitary lung disease, including Pneumocystis carinii pneumonia (PCP) and tuberculosis (TB), as well as necrotizing bacterial pneumonias. Immunocompromised patients are susceptible to more invasive forms of fungal infection, so it is possible that colonization of a cavity in HIV-infected patients may predispose them to the development of more invasive disease.

There have been several case reports of mycetomas in HIV-infected individuals, (9-13) but, to our knowledge, the only case series of mycetomas in HIV-infected patients to date is a previous study from our institution (14); in that study the clinical presentation, progression of disease, treatment, and outcome of pulmonary aspergilloma were compared in 10 HIV-infected patients and 15 HIV-negative patients. The major findings of that study were the following: (1) although tuberculosis and sarcoidosis were the most prevalent predisposing diseases, a history of PCP was a risk factor for pulmonary aspergilloma in the HIV-infected individual; (2) HIV-infected individuals with a CD4+ count of < 100 cells/[micro]L were more likely to have disease progression despite treatment; and (3) HIV-infected patients were less likely than HIV-negative patients to have hemoptysis requiring intervention.

Since that study was completed, significant strides have been made in the treatment of HIV infection. With the advent of highly effective antiretroviral therapy, patients with HIV are living longer with improved immunologic profiles. In addition, the widespread use of PCP prophylaxis has greatly reduced the incidence of PCP. To further investigate the impact of HIV status on the presentation and course of pulmonary mycetoma in this changing environment and to see whether these patients are at risk, in the long term, for the development of more invasive disease, we conducted a follow-up study in which we reviewed the subsequent clinical course of the original 10 patients and identified an additional 10 cases of pulmonary mycetoma in HIV-infected individuals.

MATERIALS AND METHODS

To identify cases of possible mycetomas, we retrospectively reviewed all Bellevue Hospital Chest Service admissions and consultations recorded in the pulmonary service ledgers, as well as all chest CT scan reports in the Bellevue Hospital chest radiology ledgers, from June 1995 to August 1999. Charts, chest radiographs, and CT scans were selected for further review for all patients who reported a history of a mycetoma or had a chest radiograph or CT scan reading suggestive of a mycetoma. A suggestive chest radiograph was defined as demonstrating either the classic finding of an intracavitary mass with a crescent sign or a filling defect in an upper lobe cavitary infiltrate. CT scan evidence of a mycetoma was defined as demonstration of a solid mass partially surrounded by air or an irregular sponge-like network filling the cavity. (15) Data from mycology cultures, serum immunoprecipitins, bronchoscopic and surgical specimens, HIV testing, viral loads, and CD4+ levels were also evaluated. In addition, we reviewed the subsequent clinical course of the original 10 patients, who had been identified by similar methods in the previous study. (14)

Patients were excluded if charts and/or radiographs could not be obtained, the chest radiograph did not meet the above criteria on reinterpretation, or the chest CT scan did not show evidence of a mycetoma. Patients were also excluded if they were HIV-negative, as determined by enzyme-linked immunosorbent assay, or if no HIV test had been performed and the patients had no history of opportunistic infections. Patients were included if they: (1) had a chest radiograph suggestive of mycetoma and evidence from culture, immunoprecipitins, or a pathologic specimen of an Aspergillus sp, or if they had CT scan evidence of a mycetoma, and (2) were HIV-infected based on a positive enzyme-linked immunosorbent assay result that was confirmed by Western blot, a polymerase chain reaction that was positive for HIV, or a documented opportunistic infection along with known risk factors for HIV infection. Using the above criteria, mycetoma was diagnosed in some patients based on radiographic evidence alone. Mycetomas can be mimicked by other pathologic entities, including carcinoma or hematoma. However, for the purpose of this study, the patients in whom mycetoma had been diagnosed by radiographic evidence alone were included in all analyses because their clinical course and radiographic findings were consistent with mycetomas. Aspergillus is the most common cause of mycetoma formation in preexisting lung cavities.

Clinical presentation, including cough, fever, and amount of hemoptysis, was recorded in each case. Hemoptysis was classified as blood-streaked sputum, mild-to-moderate (< 100 mL/24 h) hemoptysis, or massive hemoptysis (> 100 mL/24 h). When follow-up was available, the patients' subsequent treatment, symptoms, radiographs, laboratory results, and clinical findings were recorded. Disease progression or improvement was defined radiographically (change in size of the mycetoma cavity and/or surrounding infiltrate) or clinically (change in symptoms of cough and/or hemoptysis).

RESULTS

Diagnosis of Pulmonary Mycetoma

We identified 49 new cases of pulmonary mycetoma. Added to the original series of 25 cases, this yielded a total of 74 patients with pulmonary mycetoma who had been diagnosed at Bellevue Hospital from January 1992 to August 1999. Twenty of these patients (27%)--10 from the original series and 10 identified in the subsequent review--were documented as HIV-infected and were included in the current study. Table 1 summarizes these 20 cases. Aspergillus infection was documented in eight patients by fungal culture, pathologic examination, and/or positive immunoprecipitin findings. The remaining patients received diagnoses that were based on radiographic criteria and clinical presentation. All 20 patients had CT scan evidence of mycetoma (as defined above). Fiberoptic bronchoscopy was performed in nine patients for evaluation either of recurrent hemoptysis or a persistent or worsening infiltrate. Aspergillus infection was documented in five of the nine patients who had undergone flexible bronchoscopic procedures.

Demographic and Clinical Features at Presentation

The patients included 14 men and 6 women, whose ages ranged from 31 to 64 years (mean age, 44 years) at presentation. All patients had a history of cavitary lung disease. Twelve patients had a history of pulmonary TB, six had a history of PCP, and two had a history of both pulmonary TB and PCP. Seventeen patients (85%) had a CD4+ cell count of < 100 cells/[micro]L at presentation. Hemoptysis was present in 13 of 20 patients (65%), but was massive in only 1 patient. Cough was a common symptom, present in 17 of 20 patients (85%). Fever was also a prominent symptom, reported by five patients (25%). Only three patients were asymptomatic at presentation (Fig 1).

[FIGURE 1 OMITTED]

Radiographic Findings

All patients had evidence of pulmonary mycetoma on chest CT scans, as previously described. A solitary fungus ball was present in 18 of 20 patients. All had upper lobe disease. Two patients had multiple mycetomas. One (patient 1) had a history of PCP and right upper lobe and left lower lobe aspergillomas at presentation. Another (patient 10), who also had a history of PCP, had a single right upper lobe mycetoma at presentation, but subsequently developed at least two additional mycetomas in other cavities. Seven patients either had an infiltrate surrounding the cavity containing the mycetoma at presentation, or subsequently developed such an infiltrate.

Treatment and Outcome

Two patients were unavailable for follow-up after the initial presentation. For the remaining 18 patients, the follow-up periods ranged from 1 month to 4.8 years (mean, 25.7 months). Case descriptions are summarized in Table 1. Eleven patients received long-term antifungal treatment (oral itraconazole). Two patients received IV amphotericin B, and one was treated with intracavitary amphotericin, in addition to the oral itraconazole. Seven patients were observed without antifungal therapy. Eight patients received and were compliant with antiretroviral therapy, and seven of them experienced improvements in either CD4+ cell counts or viral loads. Six patients received both antifungal and antiretroviral therapy. One patient received concomitant antimycobacterial therapy. No other patients received medications for PCP or TB during the follow-up period.

Disease progression occurred in 9 of 18 patients (50%) in whom follow-up was available. In four patients, infiltrates developed surrounding their mycetoma cavities; in five, enlarging mycetoma cavities developed. Two patients died of causes related to their mycetoma (massive hemoptysis and respiratory failure). All except one of the patients with disease progression had a CD4+ cell count of < 100 cells/[micro]L. Five of the patients with disease progression received long-term antifungal therapy (including the two who died of their infection), one received antiviral therapy, and only one received both antifungal and antiretroviral treatment (Fig 2). Four patients remained stable throughout the follow-up period. One of these patients died of a cause unrelated to the mycetoma (pneumothorax of the uninvolved lung). Two received no treatment for fungal or HIV infection, and one received itraconazole alone (Fig 2).

[FIGURE 2 OMITTED]

Only 5 of 18 patients (28%) had improvement during the follow-up period. In four patients, the improvement was seen radiographically, with reduction in the size of the mycetoma and cavity, and resolution of surrounding infiltrates. In one patient, the improvement was only clinical, with resolution of his cough. All five patients who improved received both antifungal and antiretroviral therapy (Fig 2). One of these five patients was also treated for mycobacterial infection. This patient, described in the original series, was treated for active Mycobacterium xenopi infection with isoniazid, rifampin, pyrazinamide, and ethambutol, as well as itraconazole. He had symptomatic improvement and radiographic resolution of the upper lobe infiltrate. It is likely that his improvement represented a response to antimycobacterial therapy, as the mycetoma was without change, and his itraconazole levels were likely subtherapeutic, given the concomitant use of rifampin. Of the other four patients who improved, two had PCP and two had TB as predisposing conditions, two had Aspergillus spp documented, and all had initial CD4 + counts of < 100 cells/[micro]L at presentation. Two had possible semi-invasive disease, with infiltrates around the mycetoma cavity. Two of the four patients were from the original group and had been categorized in the first article as progressing, despite therapy, but when antiretroviral therapy was added to their regimen they improved both radiologically and clinically. A chest radiograph and CT scans for one such patient are shown in Figure 3.

DISCUSSION

Pulmonary mycetomas occur most commonly in preexisting tuberculous cavities, but they have also been described in lungs that have been destroyed by sarcoidosis, (16) bronchiectasis, (17) lung abscess, (17) neoplasms, (18) pulmonary infarcts, (19) nontuberculous mycobacteria, (20) various mycoses, (21,22) and PCP. (10,13) HIV-infected patients are at increased risk for several of these conditions (TB, bacterial and fungal infections, and PCP). In our previous series, we showed that PCP was a relatively common predisposing condition in HIV-infected patients; the current series has confirmed that finding, with five patients having only a history of PCP as an underlying condition. Pulmonary cysts have been reported in 10% of patients with a history of PCP. (23) Among all the patients with pulmonary mycetomas, the prevalence of HIV infection was high (27%). This may reflect the high risk of infectious cavitary lung disease, such as TB and PCP, in the HIV-infected population.

The clinical presentation of mycetoma in HIV-infected patients is somewhat different from that in the non-HIV-infected population. In immunocompetent patients, mycetomas are often found on routine chest radiographs in asymptomatic patients with prior cavitary lung disease. In contrast, only three patients in our group were asymptomatic at diagnosis. In those immunocompetent patients with mycetomas who are symptomatic, the most common presenting symptoms and signs include cough and hemoptysis. Up to 71% of patients will experience at least one episode of significant hemoptysis during their clinical course. (2,4,5) In our HIV-infected group, cough was common, but significant hemoptysis was rare. On the other hand, fever, generally not a common feature of mycetoma, was a relatively prominent sign in our HIV-infected group. Other infectious etiologies, pulmonary infection related to underlying lung disease, or a transformation to an early form of invasive disease such as chronic necrotizing or semi-invasive aspergillosis, are possible causes.

The clinical course of patients with pulmonary mycetoma can vary widely. Patients usually remain stable over long periods of time, although a slow increase in size or spontaneous resolution of the mycetoma has been reported. Generally, no treatment is necessary unless hemoptysis occurs. Hemoptysis may be severe in up to one third of cases. (24) Massive hemoptysis necessitates surgical intervention with resection of the affected lung in the patient who is a candidate for surgery, or arterial embolization in the patient who is not a candidate for surgery. Mortality from massive hemoptysis varies widely, with differences in underlying lung disease or treatment accounting for the wide range of mortality rates. However, in our study, we found that significant hemoptysis was rare in the HIV-infected group, with only 1 of 20 patients experiencing massive hemoptysis. Possibly, this difference is related to the underlying cavitary lung disease. In the HIV-negative mycetoma population, patients with sarcoidosis have an extremely high rate of hemoptysis, up to 90% in one study. (16) There were no patients with sarcoidosis in our group.

Pulmonary mycetoma is defined as fungal colonization of a preexisting cavity, without invasion into the surrounding structures. Aspergillus sp is one of the more common fungi to cause this condition. Invasive pulmonary aspergillosis usually presents with multiple infiltrates, and pathologic study reveals fungal invasion into adjacent blood vessels causing hemorrhagic pulmonary infarction. It is found almost exclusively in patients who are severely immunosuppressed. (25) Semi-invasive aspergillosis has also been described in patients with immunosuppression (eg, diabetic patients or those receiving long-term, low-dose steroid therapy). Although progression to, or overlap with, more invasive forms of Aspergillus infection has been reported to occur in pulmonary aspergilloma, (26) it is extremely uncommon in the immunocompetent host. Our study indicates that in the HIV-infected patient, this progression may occur more frequently. Seven of our patients developed infiltrates adjacent to their mycetomas at some point during follow-up. Overall, disease progression (consisting of enlarging cavities or development of surrounding infiltrates) occurred in a significant number of patients (50%) with HIV infection and mycetoma.

Because our data show that HIV-infected patients with pulmonary mycetomas are at high risk of disease progression, even if they do not develop hemoptysis, it may not be appropriate to reserve treatment for those who develop hemoptysis, as is often done in the non-HIV-infected population. Invasive Aspergillus infection in patients with HIV infection carries a very poor prognosis. (12,27) A review (28) of 342 cases of invasive pulmonary Aspergillus infection in patients with AIDS described an overall mortality rate at 6 months of 79%. Among the 33 patients in this review who received antifungal treatment for > 7 days, the response rate was 18%. However, it is not clear whether these patients relapsed or survived to 6 months. In our previous study, therapy with oral itraconazole and/or IV amphotericin was apparently ineffective in preventing disease progression. In the current series, we show that only patients who received both antifungal and antiretroviral therapy experienced improvement in both their radiographic and clinical appearance.

As a retrospective review, this study has its limitations. Although the majority of the patients likely had Aspergillus spp as the cause of their mycetomas, we were able to document this fact in only eight patients. In addition, the numbers in each of the treatment groups are small, and patients were not randomized. Nevertheless, the difference in the course of disease between this group and immunocompetent patients with mycetomas was striking and has important implications for treatment.

In conclusion, the presentation and clinical course of pulmonary mycetoma in the HIV-infected patient differs in several ways from those in the immunocompetent patient. These patients are less likely to experience significant hemoptysis, but they have a high risk of disease progression, including the development of possible semi-invasive disease. Invasive fungal infection is associated with an extremely high mortality rate. Early intervention may prevent this progression. Treatment with a combination of antiretroviral and antifungal therapy appears to be effective in improving the clinical and radiographic outcomes of patients with HIV infection and pulmonary mycetoma.

[FIGURE 3 OMITTED]

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* From the Departments of Medicine (Drs. Greenberg, Knapp, Rom, and Addrizzo-Harris) and Environmental Medicine (Dr. Rom), Bellevue Chest Service and the Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, NY.

Manuscript received July 18, 2001; revision accepted February 18, 2002.

Correspondence to: Doreen J. Addrizzo-Harris, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Department Medicine, New York University School of Medicine, 550 First Ave, New York, NY 10016; e-mail: addrid01@gcrc.med.nyu.edu

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