P has been described in patients with underlying

Transcription

1 SUCCESSFUL CONTROL OF SYSTEMIC ASPERGILLUS NIGER INFECTIONS IN TWO PATIENTS WITH ACUTE LEUKEMIA FELIPE G. GERCOVICH, MD,* STEPHEN P. RICHMAN, MD,+ VICTORIO RODRIGUEZ, MARIO LUNA, MD,~ KENNETH B. MCCREDIE, MD,~ AND GERALD P. BODEY, MD" MD,~ The diagnosis and successful control of systemic Aspergzllus niger infection in 2 adult patients with acute leukemia is reported. During ifiduction therapy, the first patient developed pulmonary infiltrates, skin lesions and abnormal liver function tests. Aspergillus niger was found on skin, and liver biopsy. This patient was successfully treated with Amphotericin B and granulocyte transfusions and he remains in remission. The second patient developed a pneumonitis and adynamic ileus with positive sputum and stool cultures for Aspergillus ntger. The infection only responded to Amphotericin B and granulocyte transfusions and the leukemia to cytoreductive chemotherapy. The patient later relapsed and died after a febrile illness. Fungi morphologically consistent with Aspergillus were found in the liver at autopsy. Infection with A. ntger is rare even in this patient population; however fungal infections have become an increasing problem. The need for a high index of suspicion, especially when an infection is unresponsive to antibacterial antibiotics, the various diagnostic tools, and the need for aggressive therapy are stressed. Amphotericin B is the chemotherapy of choice but may be insufficient in a severely neutropenic host where the simultaneous use of granulocyte transfusions might be lifesaving. Ch~~36: , ULMONARY AND SYSTEMIC ASPERGILLOSIS P has been described in patients with underlying malignant disease, and in immunosuppressed renal transplant recipients. 1*11*16 This infection is rarely diagnosed clinically because the causative organism is seldom isolated. Consequently, the diagnosis has generally been established at autopsy examination. In recent years, there has been an increasing frequency of fungal infections in patients with leukemia. This increase has been related to the impaired host defenses resulting from the underlying disease and its therapy.2.9,6.6,12,18 Because aspergillosis is diagnosed infrequently antemortem, little experience has been obtained with therapy of this infection. Generally, Amphotericin B has not been effective. However, recent advances in the management of patients with acute leukemia have resulted in improved prognosis in aspergillosis. From the Section of Immunology, Department of Developmental Therapeutics, The University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, Houston, TX Supported by Grant No. N01-CB-33888, National Cancer Institute, National Institutes of Health. Address for reprints: Dr. Felipe G. Gercovich, Department of Developmental Therapeutics, The University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, 6723 Bertner St., Houston, TX *Senior Fellow, Department of Developmental Therapeutics, The Universily of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, Houston, Texas 'Advanced Senior Fellow, Department of Developmental Therapeutics, The University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, Houston, TX Chief-Center Pavilion Service, Assistant Professor of Medicine, Department of Developmental Therapeutics, The University of Texas System Cancer Center, M.D. Anderson *Associate Pathologist, Department of Pathology, The University of Texas System Cancer Center, M.D. Anderson Whief-Leukemia Service, Associate Professor of Medicine, Department of Developmental Therapeutics, The University of Texas System Cancer Center, M.D. Anderson "Chief-Section of Infectious Diseases, Associate Professor of Medicine, Scholar of the Leukemia Society of America, Inc., Department of Developmental Therapeutics, The University of Texas System Cancer Center, M.D. Anderson Received for publication October 4, 1974.

2 2272 CANCER December 1975 \ol 76 This report is unique in that 2 patients with acute leukemia were successfully treated for systemic A. niger infections which developed during chemotherapy. Both patients received granulocyte transfusions and Amphotericin B as treatment for their fungal infections. Case 1. A 31-year-old man was admitted with the diagnosis of acute progranulocytic leukemia. He was found to have a white blood count of 40,000 with 96% blasts. The patient was started on chemotherapy with adriarnycin, vincristine, cytosine arabinoside and prednisone. Concomitant irnmunotherapy was given with BCG by scarification. The clinical course was complicated with disseminated intravascular coagulation which responded to heparin therapy. He was febrile on admission and failed to respond to cephalothin, carbenicillin and gentamicin. He was found to have "bilateral patchy densities" in both upper lobes on X- ray examination of the lungs (Figs. 1. 2). Simultaneously, he developed a necrotic lesion in the right leg and a biopsy revealed the presence of Aspergillus (Fig. 3).,4.\fiugi/lu.r niger was later cultured from a liver biopsy performed because of abnormal liver function studies. 'I'he patient was severely neutropenic when Amphotericin H therapy was begun. Therefore, he was given qranulocyte transfusions* from a histocompatible donor daily for 3 weeks. Ile achieved complete remission of his acute leukemia and the fungal infection gradually responded (Fig. 4). Amphotericin H was discontinued when a total dose of 1600 mg was reached and no signs of fungal disease were present 1 b. months after discharge from the hospital. He is currently asymptomatic, with a normal chest x-ray and liver function tests as well. lie remains in complete remission for his leukemia and no signs of Aspergillus infection are present 10 months later (Fig. 5). Fi(; I (:hest X-ray taken two wreks alrcr c hcrnotherapy was started. Hi-lateral patchy densities in the upper Iotlcs were present.

3 CONTHOI. OP A. NI(;EH INYE(:TIONS Geicouzch el al Fit;. 2 Four werks aftrr. cavitation devrloped Case 2. A 33-year-old woman was admitted for chemotherapy of acute myelogenous leukemia. Two months later the patient developed a right lower lobe pneumonitis which did not respond to antibacterial therapy.,4spergzllus nzger was cultured from two sputum specimens. She developed abdominal pain and adynamic ileus was diagnosed on X-ray examination of the abdomen. A. nzger was cultured from a stool specimen at this time. With a diagnosis strongly suggestive of disseminated aspergillus infection, she was started on Amphotericin B (0.5 mg/kg/day), intravenously. However because of progressive azotemia only a total dose of 110 mg was given during a 2-week period. She also received 9 granulocyte transfusions during this time because she had neutropenia. After 4 courses of vincristine-ara-c-prednisone chemotherapy she achieved a complete remission. All symptoms and signs of aspergillosis resolved. One year later, her leukemia recurred. Her course was complicated by multipje infections. Amphotericin B was instituted whefi she failed to respond to antibacterial antibiotics and developed signs of liver impairment. On: week later, the patient expired. At autopsy, multiple healing granulomas were found in the liver, and fungi with the appearance of Aspergillus 1:1(;. 3. L'lrerated necrotic lesion in the lateral aspect of the were identified in the granulomas. riqht Icq

4 2274 CANCER December 1975 \ )I 30 PI(; 5 Xo evidericc of active funsal itlfrction was seen 10 months later

5 No. 6 CONTROL OF A. NIGER INFECTIONS Gercovich et al DISCUSSION Aspergillosis is one of the fungal infections that occurs as a complication in patients with impaired host defense mechanisms. It is most common in patients receiving anti-leukemic therapy or immunosuppressive therapy following renal transplantation. Although there are approximately 350 species of this fungus, Aspergillus fumigatus causes the majority of human infections. Other strains such as A. niger, A. clavatus, A. versicolor, A. nidulans, A. ferreus and A. jlavus, occasionally are pathogenic. However, A. niger rarely causes systemic infection in man. Infection usually originates in the lungs, either as a primary or secondary infection and may spread by the hematogenous route. The most common organs involved in disseminated infection are the gastrointestinal tract, liver, spleen, kidneys and brain, although any organ may be involved. The symptoms and signs of aspergillosis are non-specific and overlap with the other infectious and non-infectious processes. However, the presence of cough, scant sputum, hemoptysis, pleuritic chest pain, bronchospasm and fever, in an immunodepressed host should make the physician suspect the possibility of fungal infection. Skin lesions or lesions of the soft palate and nasal sinuses are two other clues that suggest the diagnosis of aspergillosis. Severe neutropenia is associated with the onset of many fatal mycotic infections and may be responsible for the lack of diagnostic features clinically.' However this is now being modified with the use of granulocytic transfusions which appear to have efficacy in some fungal infections.' The radiological picture is not diagnostic and consists of infiltrating lesions with and without cavitation. Skin test for A. fumigatus does exist, but its diagnostic value has not been well established. Skin tests may show a dual-type reaction consisting of an immediate wheal and erythema reaction and a late Arthus type of reaction." Serological tests are unreliable for some authors and are often falsely negative in patients with invasive aspergillosis. l6 Longbottom and Pepys' reported positive precipitin reactions by double diffusion agar gel in 56 of 57 patients with pulmonary mycetomas. Sputum is the logical specimen for examination to establish the diagnosis, and the isolation of Aspergillus from an immunosuppressed patient is usually meaningful. However, colonization may occur without invasion and Asper- gillus could be found in a sputum specimen as a contaminant. Certainly, the diagnosis cannot be made from a single culture alone, but in a predisposed patient population, the presence of Aspergillus on culture should alert the physician to the possibility of aspergillosis. Otherwise, if one waits for multiple positive cultures for aspergillosis, diagnosis may not be made nor patients treated. The cultures of bronchial secretions, pleural aspirations, and gastric washings are more reliable than cultures of sputa. Collection of tissue by percutaneous needle biopsy or by open thoractomy could be done to confirm diagnosis, but neither one of the methods is completely safe, especially in the "selected" population of immunosuppressed patients. Surgery (in patients who are surgical candidates) appears to be the treatment of choice for single pulmonary lesions. Amphotericin B is the most effective antibiotic available for invasive aspergillosis. The dosage and frequency of administration varies in order to infuse amounts just below systemic toxicity. The duration of therapy is thought to be as important as the above mentioned factors. However, it may produce secondary effects such as: phlebitis, fever, chills, hypersensitivity reactions. The major limitation is the impairment of renal function."." Recently, a number of techniques are available which may decrease the incidence and severity of Aspergillus infections. Improved chemotherapy especially for leukemia and lymphoma, is increasing the number of remissions. Non-specific immunotherapy ( BCG)'v8 may help in immunosuppressed hosts. Supportive care, including sterile environments, prophylactic and specific antibiotic therapy and granulocyte transfusions is now available. The value of all these new techniques is being investigated. However, the early diagnosis of Aspergillus infections is still difficult, and it is in this area where the need should be emphasized. In our experience, Amphotericin B appears to be ineffective in the absence of adequate granulocytes. If a patient with bone marrow invasion fails on chemotherapy, the chances of response to infection are poor. In patients achieving remission, an adequate granulocyte count is the sine qua non of successful therapy with Amphotericin B. It is in these patients that temporary restoration of adequate granulocyte counts with transfusion can be lifesaving when given in conjunction with antibiotics, as suggested in our present case reports.

6 2276 CANCER December 1975 Vol. 36 REFERENCES 1. Bodey, G. P.: Fungal infections complicating acute leukemia. 3. Chron. Dis. 19: , Bodey, G. P., Middleman, E., and Umsawadi, T.: Infection in cancer patients. Results with gentamicin sulfate therapy. Cancer 29: , Burke, P. S., and Coltman, C. A., Jr.: Multiple pulmonary aspergilloma in acute leukemia. Cancer. 28: , Gutterman, J. U., McBride, C., Freireich, E. J, et al.: Active immunotherapy with BCG for recurrent malignant melanoma, Lancet 1: , Hutter, R.V.P., and Collins, H. S.: The occurrence of opportunistic infections in a cancer hospital. Lab. Invest. 11: , Keye, J. D., Jr., and Magee, W. E.: Fungal diseases in a general hospital. Am. 3. Clin. Pathol. 26:1235, Longbottom, J. L., and Pepys, J. : Pulmonary aspergillosis. 3. Pathol. Bact. 88: , Mathe, G., Amiel, J. L., Schwarzenberg, L., et al.: Active Immunotherapy for acute lymphoblastic leukemia. Lancet , McCredie, K. B., Freireich, E. J, and Hester, J. P.: Leucocyte transfusion therapy for patients with host-defense failure. Transplant Proc. 5: , Paterson, R., Fink, J. N., Pruzansky, J. J., et al.: Serum immunoglobulin levels on pulmoanry allergic aspergillosis. Am. J. Med. 54:16-32, Rikind, D., Marchioro, T. L., Schneck, S. A. et al.: Systemic fungal infections complicating renal transplantation and immunosuppressive therapy. Am. 3. Med. 43:28-38, Sidransky, H., and Pearl, M. A,: Pulmonary fungus infections associated with steroids and antibiotic therapy. Dis. Chest. 39: , Utz, J. P.: Recognition and current managment of the systemic mycoses. Med. Clin. N. Amer. 51: , Utz, J. P.: Amphotericin B toxicity. Am. Int. Med. 61: , Young, R. C., and Bennet, J. E.: lnvasive aspergillosis Absence of detectable antibody response. Am. Rev. Resp. Dis. 104: , Young, R. C., Bennett, J. E., Vogel, C. L., P., et al.: Aspergillosis: Spectrum of the disease in 98 patients. Medicine 49: , 1971.