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Mucormycosis in Hematologic Patients Mucormycosis in hematologic patients [haematologica] 2004;89:207-214 LIVIO PAGANO ABSTRACT MASSIMO OFFIDANI LUANA FIANCHI Background and Objectives . To evaluate the clinical characteristics of patients affected ANNAMARIA NOSARI by hematologic malignancies who developed mucormycosis and to ascertain the factors ANNA CANDONI which influenced the outcome following mycotic infection. MARCO PICARDI Design and Methods . This was a retrospective study conducted over a 15-year period LAURA CORVATTA (1987-2001). The study included 59 patients with hematologic malignancies with a proven DOMENICO D’A NTONIO or probable mucormycosis admitted in 18 Hematology Divisions in tertiary care or univer - CORRADO GIRMENIA sity hospitals. PIETRO MARTINO Results . The most frequent sites of infection were lung (64%) and orbito-sinus-facial ALBANO DEL FAVERO (24%); cerebral involvement observed in 19% of cases was always associated with other FOR THE GIMEMA sites of infection. Antifungal treatment was empirically administered in 49 patients (83%); (G RUPPO ITALIANO 7 patients underwent radical surgical debridement (12%). Therapy was successful for only MALATTIE EM ATOLOGICHE DELL 'A DULTO ) 18 patients (37%). Forty-seven patients died within 3 months of the diagnosis of fungal INFECTION PROGRAM infection: the cause of death was mucormycosis in 41 patients (87%) and progression of hematologic disease in 6 patients (13%). At univariate analysis, the factors that correlat - ed with a positive outcome from infection were the following: male sex, amphotericin B treatment, neutrophil recovery from post-chemotherapy aplasia. At multivariate analysis, the only factor that significantly correlated with recovery from infection was the liposo - mal amphotericin B treatment. Interpretation and Conclusions . Mucormycosis is a rare filamentous fungal infection that occurs most frequently in neutropenic patients with acute leukemia. It does not seem to have increased in recent years. Although a reduction of mortality has been observed recently, the mortality rate still remains high. Extensive and aggressive diagnostic and ther - apeutic procedures are essential in order to improve the prognosis in these patients. Key words: mucormycosis, leukemia, lymphoma. From the Istituto di Ematologia, Università Cattolica S. Cuore, ucormycosis is an invasive fungal mucormycosis. In fact dissemination occurs Roma (LP, LF); Clinica di infection caused by various mem - in up to 40% of mucormycosis in patients Ematologia, Università di Ancona (MO, LC); Divisione Talamona, Mbers of the class Phycomycetes , with hematologic malignancies 2,9,10-12 and all Ospedale Niguarda Cà Granda, especially Mucoraceae , subdivided into the of these manifestations are characterized by Milan (AN); Cattedra di Ematolo - gia, Università di Udine (AC); genera Absidia , Rhizopus and Mucor . After a high rate of mortality. 2,13 Dipartimento di Medicina Clinica- aspergillosis, mucormycosis is the second We have already analyzed the epidemio - Azienda Ospedaliera Universi - taria Federico II - Napoli (MP); most common mycosis caused by filamen - logical characteristics of mucor mycosis in Unità di Microbiologia, Divisione tous fungi. Overall, genera of the order patients with hematologic disorders. 2 This di Ematologia, Ospedale Civile Spirito Santo, Pescara (DD); Mucorales represent the third leading cause new analysis is an update of the previous Dipartimento di Biotecnologie of invasive fungal infections following study and a re-evaluation of some of its Cellulari ed Ematologia, Univer - sità «La Sapienza», Roma (CG, Aspergillus and Candida species. 1-5 Among aspects; in fact the recent availability of more PM); Istituto di Clinica Medica 1, patients with hematologic disorders, mucor - effective diagnostic tools and new antifungal Università di Perugia (ADF), Italy mycosis most commonly occurs in those with drugs, together with a larger series of Correspondence: Dr. Livio acute leukemia or lymphoma who have patients, could provide interesting new con - Pagano, Istituto di Ematologia Università Cattolica del S.Cuore developed neutropenia due to malignancy or siderations. We reviewed the clinical features largo A. Gemelli 8, 00168 Rome, to chemo therapy, and in transplanted of 59 patients with a hematologic malignan - Italy. E-mail: [email protected] patients receiving immunosuppressive treat - cy who developed mucormycosis in order to 2,6-8 ©2004, Ferrata Storti Foundatio n ment. Rhino-cerebral, maxillo-facial and evaluate the clinical spectrum of the disease, pulmonary infections are the most frequent its diagnosis and its treatment. Factors that clinical forms, but neutropenic patients are may have influenced the outcome of this at a high risk of developing a disseminated infectious complication were also considered. haematologica 2004; 89(2):February 2004 207 L. Pagano et al. Table 1. Demographic and clinical characteristics of Design and Methods patients with mucormycosis. Eighteen Hematology Departments took part in this Patients, n. 59 study. The clinical records of patients affected by a Age in years: mean (range) 48 (13-80) hematologic malignancy with a diagnosis of mucormy- Sex: M/F 30/29 cosis in the period between January 1987 and Decem- Underlying disease: n. (%) ber 2001 were reviewed. • Acute myeloid leukemia 30 (51%) The diagnosis of mucormycosis was made in vivo and • Acute lymphoblastic leukemia 16 (27%) at autopsy by demonstrating the organism in the tissue • Non Hodgkin’s lymphoma 6 (10%) • of a biopsy specimen, according to previously reported Hairy cell leukemia 2 (3%) • Myelodyspalstic syndromes 2 (3%) criteria.2 • Multiple myeloma 1 (2%) The following information was extracted from the • Chronic myeloid leukemia 1 (2%) clinical records of these patients: demographic charac- • Hodgkin’s disease 1 (3%) teristics; type and stage of hematologic malignancy; clinical symptoms and signs of infection; radiological Primary site of infection: findings; site of infection; laboratory findings (e.g. neu- • Lung 38 (64%) trophil count, microbiological isolates); treatments Alone 28 received; cause of death; autopsy findings. Plus other sites [involving CNS] 10 [7] • Sinus 12 (20%) • Systemic 5 (8%) Statistical methods • Eye 3 (5%) Definitions and end-points of the study were agreed • Other* 3 (5%) upon prior to data retrieval from the clinical records. Success was defined as the disappearance of all signs CNS: central enrvous system. *Heart: 1 case, Oral cavity: 1 case; Bowel: 1 case. and symptoms of the treated fungal infection or con- tinuous improvement and clinical evolution compatible with responding disease Failure was defined as death attributed to the fungal infection as a primary or con- tributing cause, or progressive infection while on ther- patients (10%), myelodysplastic syndrome and hairy cell apy or within 1 month of last therapy. leukemia in 2 patients each (3%) and multiple myelo- Data were analyzed by descriptive statistical methods ma (MM), Hodgkin’s disease, and chronic myeloid and differences between groups were calculated using leukemia in 1 patient each. the χ2 test or Fisher's exact test when appropriate. All but two patients had been previously treated with Factors affecting infection outcome (death vs no aggressive chemotherapy regimens. In particular 5 death) were investigated using a stepwise backward patients (9%) developed the infection during trans- method and were also excluded from the model when plantation procedures (4 autologous and 1 allogeneic the probability was higher than 0.1. Results are pre- bone marrow transplantation). Twenty-nine patients sented as odds ratios (with the 95% confidence inter- received 6-methyl-prednisolone (median total dose of val). The best cut-off of continuous variables was ascer- 500 mg [range 8-5000] over a median time of 22 days, tained empirically using correlation coefficients. [range 2-180]). In all these cases glucocorticoids were Statistical significance was established at p <0.05 administered for the treatment of the hematologic dis- (two sides). Data were analyzed using an SPSS statisti- ease. Only 10 of the patients (17%) had concomitant cal package (SPSS, Chicago, IL, USA). diabetes mellitus. None of the patients had a history of previous mycotic infection. Five patients (8.5%) devel- oped mucormycosis despite protective isolation in a Results laminar airflow room. When the clinical diagnosis of fungal infection was Clinical and laboratory features of the patients made, 47 patients were neutropenic and, in particular, During the study period (1987-2001) 59 episodes of 43 of them had a neutrophil count below 0.5×109/L; the mucormycosis were documented in patients with median duration of neutropenia prior to the diagnosis hematologic malignancies. These patients’ characteris- of mucormycosis was 12 days (range 1-60). Thirty-three tics are summarized in Table 1. The great majority (78%) of these 47 patients (70%) recovered from neutropenia of patients had acute leukemia: acute myeloid leukemia (neutrophil count >1×109/L) in a median time of 7 days (AML) in 30 patients (51%) and acute lymphoblastic after the clinical diagnosis of infection (range 4-30) leukemia (ALL) in 16 patients (27%). Non-Hodgkin's and 18 of them received granulocyte colony-stimulat- lymphoma (NHL) was the underlying malignancy in 6 ing factor (rhG-CSF). 208 haematologica 2004; 89(2):February 2004 Mucormycosis in hematologic patients Diagnosis Table 2. Results of main diagnostic procedures performed According to the criteria of the European
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