Disseminated Zygomycosis in a Neutropenic Patient: Successful ...

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Disseminated Zygomycosis in a Neutropenic Patient: Successful Treatment with Amphotericin B Lipid Complex and Granulocyte Colony—Stimulating Factor Corina E. Gonzalez, Daniel R. Couriel, and Thomas J. Walsh

From the Infectious Diseases Section, Pediatric Branch, National Cancer Institute, and the National Heart, Lung and Blood Institute, Bethesda, Maryland

Disseminated zygomycosis in persistently neutropenic patients has been almost uniformly fatal despite aggressive surgical and medical management. We describe a neutropenic patient with disseminated zygomycosis that involved the lungs and kidneys and was successfully treated with amphotericin B lipid complex and granulocyte colony — stimulating factor, followed by suppressive therapy with amphotericin B for 1 year. This approach preserved the patient's renal function and restored systemic host defenses. The single pulmonary lesion was resected, but no resection of renal tissue was attempted because of the bilateral extension of the renal lesions. After a 1-year period of followup without antifungal therapy, the patient's condition remains stable, and there has been no relapse of the infection.

Zygomycosis is a rare opportunistic infection that complicates the clinical course of susceptible patients [1-3]. The increasing incidence of this infection in recent years has been attributed to several predisposing conditions including profound neutropenia, therapy with corticosteroids and deferoxamine, hyperglycemia, acidosis, and malnutrition [4-5]. Zygomycosis has been only rarely reported in patients without risk factors. The major clinical presentations are rhinocerebral involvement, pulmonary involvement, cutaneous infection, gastrointestinal involvement, and disseminated infection. Disseminated zygomycosis is associated with an exceedingly high mortality rate and generally occurs in severely immunocompromised patients. Of the 26 patients with documented disseminated zygomycosis and neutropenia who have been described in the literature, only one partially responded to treatment [1, 6-23]. Improved outcome in cases of disseminated zygomycosis has been attributed to timely diagnosis in conjunction with surgical and medical therapy. In three of the reported cases, the patients received empirical WBC transfusions with or without antifungal therapy; the outcome was similarly ominous for all of them. Clearly, new therapies for disseminated zygomycosis are needed. We report the case of a patient with aplastic anemia and disseminated zygomycosis that was successfully treated with a combination of surgical resection, high-dose amphotericin B lipid complex (ABLC; Abelcet, Liposome Co., Princeton, NJ), and granulocyte colony—stimulating factor (G-CSF, Amgen, Thousand Oaks, CA). This case illustrates that the recent introduction of recombinant cytokines and lipid formulations of

Received 30 May 1996; revised 30 July 1996. Reprints or correspondence: Dr. Thomas J. Walsh, Infectious Diseases Section, National Cancer Institute, Building 10, Room 13N-240, Bethesda, Maryland 20892. Clinical Infectious Diseases 1997; 24:192-6 This article is in the public domain.

amphotericin B expands our therapeutic armamentarium against disseminated zygomycosis in neutropenic patients. Case Report A 59-year-old male was found to have aplastic anemia in December 1992. He was initially treated with methylprednisolone (125 mg/d) and transfusions of RBCs and platelets. In March 1993 he was referred to the Warren Grant Magnuson Clinical Center at the National Institutes of Health (Bethesda, MD) to be enrolled in a treatment protocol for aplastic anemia; this protocol consisted of cyclosporin A (300 mg b.i.d. given orally for 6 months) and antithymocyte globulin (40 mg/[kg • d] given every other day for 4 days). A central venous catheter was inserted, and the dose of methylprednisolone was gradually decreased until therapy with this drug was discontinued 1 month later. The patient tolerated this therapy well; secondary hypertension was the only adverse effect detected. In April 1993 he was discharged from the hospital to continue follow-up as an outpatient. At the time, his absolute neutrophil counts (ANCs) ranged from 200/mm 3 to 1,500/mm 3 . Three days after he was discharged, he developed high-grade fevers, cough, lightheadedness, dizziness, and diffuse myalgias. On physical examination, he was febrile (temperature, 39°C) but in no acute distress, and there were no focal findings of infection. A chest radiograph showed a right-upper-lobe infiltrate. A chest CT scan showed a spiculated mass in the right upper lobe. Cultures of bronchoalveolar lavage fluid, blood, and urine were negative. Empirical therapy with iv ceftazidime (2 g q8h) was initiated. After 4 days of persistent fever, needle aspiration of the pulmonary lesion was performed. Broad aseptate hyphae, consistent with a zygomycete, were observed on direct smears of the aspirate and confirmed in culture to be Rhizomucor pusillus. The lesion was resected. Biopsy of the lung revealed hemorrhagic infarction and broad, sparsely septated pleomorphic hyphae invading blood vessels. Therapy with amphotericin B (1.5

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Treatment of Disseminated Zygomycosis with ABLC

mg/[kg • d]) was started, and therapy with cyclosporin A was discontinued in an attempt to restore host defenses. Daily therapy with G-CSF (350 tug/d) was also initiated because of persistent neutropenia. Findings on cerebral and abdominal MRIs and on sinus CT scans were normal. Amphotericin B therapy was complicated by nephrotoxicity (the patient's serum creatinine level increased to 334 Amon from a baseline level of 106 //mon) and by seizures secondary to hypomagnesemia (magnesium level, 0.55 mmol/L). These adverse events prompted a change to therapy with ABLC (4 mg/[kg • d]) after 9 days. The patient's renal function gradually returned to normal, and his ANCs were effectively maintained above 500/mm 3 by treatment with G-CSF. He completed a 1-month course of ABLC in combination with G-CSF. No evidence of progression of the infection was detected on serial chest radiographs and CT scans. At the time of the discharge, he had a central venous catheter in place and remained dependent on transfusions of RBCs and platelets. His medications included cyclosporin A (200 mg/d) and multivitamins. No further therapy with antifungals or G-CSF was recommended. In August 1993 the patient was readmitted to the hospital because of a 3-week history of fever and right-upper-quadrant pain. On physical examination he appeared pale and was febrile. The breath sounds were normal; the abdomen was soft and nontender, with no organomegaly. There was questionable flank tenderness. At this time a complete blood count showed pancytopenia, with an ANC of 66/mm 3 . Urinalysis revealed microhematuria. An abdominal ultrasonogram showed bilateral, hypoechoic, solid renal masses (2-3 cm in diameter); one arose from the interpolar area of the left kidney, and the other arose from the lower pole of the right kidney. A contrast-enhanced MRI of the abdomen confirmed the latter findings (figure 1). Chest radiographs revealed no new pulmonary lesions. Fine needle aspiration of the right renal mass yielded necrotic debris and hyphal elements compatible with a zygomycete. Culture of the renal aspirate and several urine cultures were positive for R. pusillus. Therapy with iv ABLC (4 mg/[kg • d]) and sc G-CSF (300 lig three times a week) was initiated. Surgical resection was not considered to be an alternative because of the bilateral extension of the renal lesions. After 1 month of treatment with ABLC and G-CSF, the patient's fever and right-upper-quadrant pain resolved, but the microhematuria - peisisted. An abdominal MRI initially showed stabilization of the renal lesions; subtle regression of the lesions was observed 2 months after antifungal therapy was started. Because intermittent periods of neutropenia occurred that were related to the underlying aplastic anemia, the patient was discharged and continued to receive suppressive amphotericin B therapy (1 mg/[kg • d], three times per week) for zygomycosis (ABLC was not available in Pakistan, the patient's native country, at that time). As examination of a bone marrow biopsy specimen again showed marked hypocellularity, the patient was considered refractory to treatment with cyclosporin A, and

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Figure 1. Abdominal contrast-enhanced T 1-weighted MRIs dem-

onstrating bilateral renal involvement in a patient with disseminated Rhizomucor pusillus infection. The kidneys are moderately enlarged (arrows); contrast medium is absent in the interpolar area of the left kidney (A) and in the lower pole of the right kidney (B).

therapy with antithymocyte globulin and oxymetholone was instituted. After discharge, he was closely observed by his local physician. Six months later, in May 1994, the patient was seen for follow-up at the National Institutes of Health. He remained asymptomatic but had renal impairment (serum creatinine level, 185 /mon) associated with the prolonged administration of amphotericin B. His ANC was 2,184/mm 3 . An abdominal MRI showed a nonenhancing filling defect in the upper pole of the left kidney and a partially enhanced mass in the lower pole of the right kidney (figure 1). Urine cultures were negative. Given the stability of the lesions, the sustained resolution of fever, the negative urine cultures, and the fact that the ANCs had remained consistently > 1,000 cells/mm 3 for the last 6 months in the absence of G-SCF therapy, treatment with

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Table 1. Summary of data from cases of disseminated zygomycosis in neutropenic patients. Predisposing factors

Year [reference]

Patient no.

Age (y)/ sex

Underlying condition

Corticosteroid therapy

Diabetes mellitus

62/M 20/M 58/M 62/F 51/M 28/F 63/M 58/M 20/F 19/M

Leukemia Leukemia Leukemia Aplastic anemia Leukemia Leukemia Leukemia Leukemia Leukemia Leukemia

Yes Yes Yes Yes Yes Yes Yes Yes Yes NA

No No No No No No No No No No

1 2

69/M 64/M 66/F 0.66/NA 68/F 64/M 44/M 60/M 68/M 42/M 38/M 18/M

Leukemia Leukemia Leukemia Aplastic anemia Leukemia Multiple myeloma Leukemia Lymphoma Leukemia Leukemia Leukemia Leukemia

Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes

Yes No No No No No No No Yes No No No

1994421] 1994422]

1 1

53/F 54/F 32/F

Leukemia Leukemia Lymphoma

Yes Yes Yes

No No No

1994/[23]

1

66/M

Leukemia

Yes

No

19591[6] 1962/[7]

1 2

19671[8]

4

19731[9] 1977410] 1979411]

1 1 1

1979/[12] 1980/[13] 1985414] 1985/[15] 1986416] 1986417] 198941]

1 1 1 1 1 1 2

1992418]

2

19911[19] 1993/[20]

Fungus isolated Zygomycete Zygomycete Zygomycete Zygomycete Zygomycete Zygomycete Zygomycete Rhizomucor pusillus R. pusillus Aspergillus fumigatus, Rhizopus species

Zygomycete Zygomycete Rhizopus oryzae

Zygomycete Zygomycete Zygomycete Zygomycete Zhyomycete Mucor species Zygomycete R. pusillus R. pusillus R. pusillus

Zygomycete Conidiobolus incongruus Cunninghamella bertholletiae

Diagnostic procedure

Antifungal treatment

Outcome

Autopsy Autopsy Autopsy Autopsy Autopsy Autopsy Autopsy Autopsy Autopsy Autopsy

None None None None None None None None WBCs* AmBt

Died Died Died Died Died Died Died Died Died Died

Autopsy Autopsy Autopsy Autopsy Autopsy Autopsy Autopsy Autopsy Autopsy Blood culture, autopsy Lung biopsy, autopsy Lung biopsy, BAL, autopsy Autopsy Skin biopsy, autopsy Lung biopsy, autopsy

None None WBCs* None None None None None None AmB None AmB/AmB i some, pneumonectomy AmBt AmB t AmB; RM, RL lobectomy None

Died Died Died Died Died Died Died Died Died Died Died Died

Autopsy

Died Died Died Died

NOTE. AmB = amphotericin B; BAL = bronchoalveolar lavage; NA = not available; RL = right-lower; RM = right-middle. * Empirical WBC transfusions. t Empirical AmB therapy. I Died of bacterial sepsis.

amphotericin B was discontinued. A repeated renal biopsy was not performed. At follow-up 1 year later, it was noted that the patient's condition had remained stable since discontinuation of the antifungal therapy. Discussion

The first well-documented report- of disseminated zygomycosis was published in 1885 [24]. The clinical aspects, pathogenesis, and putative risk factors for disseminated infection were not characterized until several decades later. Experimental and clinical findings have _consistently underscored the fact that immunosuppression of the host is a critical factor associated with disseminated disease. A review of the medical literature that included reports from 1959 through 1994 revealed 26 cases of disseminated zygomycosis in neutropenic patients (table 1). All cases were well documented, with histopathologic evidence of infection due to Zygomycetes in at least two noncontiguous organs. We included only patients with confirmed neutropenia, defined as

.-.500 cells/mm', which restricted the underlying conditions primarily to leukemia (80% of patients), lymphoma (8%), aplastic anemia (8%), and multiple myeloma (4%). Regardless of the year of the report, the outcome of the cases was uniformly fatal because of the rapid progression of the infection, which, in addition to a lack of diagnosis and adequate therapy, was the clear cause of death for all patients except one. Because disseminated zygomycosis has protean clinical manifestations and requires examination of a tissue specimen for diagnosis, it has been infrequently diagnosed before death. A premortem diagnosis was made for only four patients, and three of them received antifungal therapy. Seven patients received amphotericin B: it was administered empirically to three of these patients; one had a diagnosis of presumed pulmonary aspergillosis; and the last three were being treated for documented invasive zygomycosis. One of these latter patients with disseminated infection underwent pneumonectomy, was treated with a liposomal formulation of amphotericin B (AmBisome; Vestar, San Dimas, CA) and survived longer than any other patient in the series. This patient appeared to initially respond

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Treatment of Disseminated Zygomycosis with ABLC

to therapy but died of bacterial sepsis after 1 month. Autopsy revealed R. pusillus hyphae in his kidneys. Two patients received empirical WBC transfusions during the course of their infections; one of these patients also received low doses of empirical amphotericin B. Surgical resection of the foci of infection was attempted in only a few of the most recent reports. Thus, an aggressive approach combining extensive surgical debridement, high doses of amphotericin B, and reversal of the underlying condition was seldom undertaken for patients in the analyzed cohort. In addition, data on innovative therapeutic approaches such as the use of Ambisome and WBC transfusions are limited. Our patient was successfully treated with a combination of partial surgical resection of the lesions, high doses of ABLC, and restoration of host defenses by decreasing cyclosporin A doses and administering G-CSF therapy. In addition, there was long-term follow-up in this case, which has rarely been reported for patients with disseminated zygomycosis. The evolution of the disease in our patient suggests the development of a primary infection in the lungs, with hematogenous dissemination to both kidneys. Therefore, given the different times at which the pulmonary and renal involvement occurred, the therapeutic approach may have not been effective in preventing dissemination but may have limited the seeding of multiple organs. G-CSF therapy resulted in the effective maintainance of ANCs above neutropenic levels during the treatment of the infection. The results of in vitro studies have indicated that neutrophils play a major role in host defense against Zygomycetes. The role of oxidative mechanisms in neutrophil-mediated damage to hyphae of Rhizopus oryzae is well documented [25]. In addition, nonoxidative mechanisms in the form of cationic peptides produced by neutrophils and other phagocytic cells have also been shown to exert fungicidal activity against hyphae and activated spores of R. oryzae [26]. In light of these studies and the few individual reports of invasive opportunistic fungal infections in cancer patients that were successfully treated with antifungal agents in combination with cytokines [27-30], we elected to add G-CSF to our patient's antifungal regimen. G-CSF therapy ameliorates neutropenia and enhances neutrophil function, particularly phagocytic activity and oxidative metabolism [31]. The fact that our patient did not receive antineoplastic chemotherapy and therefore had fully active neutrophils may have also contributed to the clearance of the infection. It has been reported that cytotoxic drugs impair neutrophil reactive oxidant production and compromise the beneficial effects of colony-stimulating factors on mature neutrophils [32]. The use of ABLC permitted us to maintain effective antifungal activity with minimal renal toxicity. The significantly lower nephrotoxicity associated with lipid formulations of amphotericin B was particularly important for our patient, who developed severe renal impairment due to therapy with the conventional formulation of amphotericin B and who had extensive bilateral

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renal infarction due to R. pusillus. The efficacy of lipid formulations of amphotericin B against invasive opportunistic fungal infections appears to be similar to that of conventional amphotericin B at equivalent doses [33, 34]. There have also been reports in the literature that address the efficacy of these lipid formulations against zygomycete infections. Lipid formulations of amphotericin B along with surgical debridement have been particularly successful against rhinocerebral zygomycosis, as reviewed by Strasser et al. [35]. A case of extensive posttraumatic soft-tissue and renal infections due to Apophysomyces elegans that responded to a multidisciplinary approach including liposomal amphotericin B has also been reported [36]. Given the high mortality rate associated with disseminated zygomycosis despite aggressive treatment, the fact that our patient developed renal zygomycosis after the first course of ABLC may be more related to an insufficient course of therapy than to inefficacy of the drug. After a single dose of amphotericin B is administered, concentrations in renal tissue are below the MICs for most of the filamentous fungi but increase gradually during therapy. Renal concentrations of ABLC follow a similar pattern [34 —37] . In addition, amphotericin B concentrations in the focus of infection can be even lower if tissue infarction is present. StGermain et al. [20] described a patient with R. pusillus infection of the lungs and kidneys who also responded to treatment of the pulmonary lesions; however, the fungus persisted in the kidneys after 1 month of AmBisome therapy [20]. These observations suggest that antifungal therapy for renal zygomycosis in granulocytopenic patients should be prolonged to achieve cure, particularly when the infected tissue cannot be resected. The infected renal tissue could not be resected in our patient because of the bilateral, extensive involvement of the lesions. The patient received a 1-year course of suppressive amphotericin B therapy and did not have neutropenia when the antifungal treatment was discontinued. No relapse of the infection has yet been detected. To our knowledge, this is the first report of a case of disseminated zygomycosis in a neutropenic host in which the outcome was successful, and follow-up was prolonged. The use of ABLC and G-CSF, two novel therapeutic approaches, may have strongly contributed to the survival of our patient. To improve the grave prognosis of invasive zygomycosis, future studies on its treatment should focus on the mechanisms of host resistance and the activities of newer antifungal agents that are more efficacious and less toxic.

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