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Mucormycosis in Haematological Patients: Case Report and Results of Prospective Study in Saint Petersburg, Russia

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Mucormycosis in Haematological Patients: Case Report and Results of Prospective Study in Saint Petersburg, Russia mycoses Diagnosis,Therapy and Prophylaxis of Fungal Diseases Supplement article Mucormycosis in haematological patients: case report and results of prospective study in Saint Petersburg, Russia Nikolay N. Klimko,1 Sofya N. Khostelidi,1 Alisya G. Volkova,2 Marina O. Popova,2 Tatyana S. Bogomolova,1 Ludmila S. Zuborovskaya,2 Aleksey S. Kolbin,3 Nadezhda V. Medvedeva,4 Ilya S. Zuzgin,5 Sergey M. Simkin,5 Nataliya V. Vasilyeva1 and Boris V. Afanasiev2 1I. Metchnikov North-Western State Medical University, St. Petersburg, Russia, 2I. Pavlov Saint Petersburg State Medical University, St. Petersburg, Russia, 3Pediatric City Hospital No 1, St. Petersburg, Russia, 4City Hospital No 31, St. Petersburg, Russia and 5Leningrad Regional Clinical Hospital, St. Petersburg, Russia Summary We prospectively observed 36 haematological patients with mucormycosis from nine hospitals of St. Petersburg during 2004–2013. The most frequent underlying dis- eases were acute leukaemia (64%), and main risk factors were prolonged neutrope- nia (92%) and lymphocytopenia (86%). In 50% of the patients, mucormycosis was diagnosed 1–65 days after invasive aspergillosis. Main clinical form of mucormycosis was pulmonary (64%), while two or more organ involvement was noted in 50% of the cases. The most frequent aetiological agents of mucormycosis were Rhizopus spp. (48%). Twelve-week survival rate was 50%. Combination therapy (echinocan- dins + amphotericin B forms) and recovery from the underlying disease significantly improved the survival rate. Key words: Mucormycosis, haematological malignancy, acute leukaemia, Lichtheimia corymbifera, skin and soft tis- sue, mucormycosis, pulmonary mucormycosis. The range of underlying conditions in mucormyco- Introduction sis has changed. In the period 1980–1990, mucormy- Mucormycosis (zygomycosis) is a severe opportunistic cosis predominantly had developed in patients with infection. At present, an increased frequency of muco- decompensated diabetes mellitus. Over the last years, rmycosis is noted worldwide, particularly in patients mucormycosis most frequently has been diagnosed in with haematological malignancies. This is not only patients with haematological malignancies.1,2 We rep- due to improvement of diagnostic methods for fungal resent a clinical case of successful treatment of muco- infections, but rather because of more aggressive rmycosis in a patient with acute myeloid leukaemia schemes of cytostatic therapy and more extensive use (AML), along with results of a prospective study of of haematopoietic stem cell transplantation. mucormycosis in haematological patients in St. Peters- burg, Russia during the period (2004–2013). Correspondence: Prof. N. Klimko, I. Metchnikov North-Western State Case report Medical University, Department of Clinical Mycology, Allergology and Immunology str. Santiago-de-Cuba, 1/28; St.-Petersburg 194291, Russia. A 53-year-old woman was admitted to Leningrad Tel.: +7812 3035146. Fax: +7812 5106277. Regional Clinical Hospital in September 2010. She E-mail: [email protected] was in severe condition, conscious but retarded. She had general weakness and exertional dyspnoea. The Submitted for publication 21 December 2013 ° Revised 18 June 2014 body temperature was 38.7 C. Auscultation revealed Accepted for publication 18 June 2014 vesicular breathing diminished bilaterally in the lower © 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 91–96 doi:10.1111/myc.12247 N. N. Klimko et al. parts of lungs. Respiration rate was 20–30 per minute. imipenem) were used. Fever above 38 °C persisted. On Blood pressure was 110/70 mm Hg, heart rate 99 per chest CT scan (October 6, 2010) were found local minute. On the left chest area, an unhealed postopera- infiltration in S2 of the right lung, focal lesion in S9 of tive wound was apparent. the left lung and right-sided pleural effusion. Patient’s medical history revealed that a tumour of On October 13, patient had developed intense pain the left breast was detected in June 2010. On August in the postoperative wound. The necrotic area of soft 10, 2010 Madden modified radical mastectomy of the tissue 2 cm in diameter was detected. Vancomycin left breast was performed. The examination revealed was added to the therapy. The next day the pain leucopoenia (2.2 9 109/l), thrombocytopenia (89 9 increased, the necrotic area enlarged to 10 cm in 109/l) and anaemia (Hb 97 g lÀ1). Body temperature diameter, body temperature went above 38 °C. The was above 38 °C during hospitalisation. material from postoperative wound area was obtained In the hospital, blood tests showed pancytopenia for mycological examinations. On microscopy non-sep- (RBC 2.6 9 1012/l, Hb 70 g lÀ1, WBC 2.5 9 109/l, tate non-pigmented hyphae were found. On October blasts 15%, promyelocytes 1%, neutrophils 6%, ba- 16, abundant growth of moulds was received. The cul- sophils 2%, lymphocytes 75%, monocytes 1%, PLT ture was identified as Lichtheimia corymbifera. Muco- 11 9 109/l). Immunophenotyping of the bone marrow rmycosis of skin and soft tissue of postoperative revealed the transformed cells with intermediate and wound was diagnosed. Therapy with amphotericin B high level of granularity with the total immunopheno- was started with a dose 1 mg kgÀ1 dÀ1 (7 days), than type CD45dim CD117+ CD33+ CD38+ MPO+. The 1.5 mg kgÀ1 dÀ1, and G-CSF (leykostim) 480 mcg dÀ1 absence of antigens CD34, HLA-DR, CD7 and high was used. Chest CT scan (October 18) showed infil- level of cells granularity was regarded. The diagnosis trate 1 9 1.4 9 2.1 cm in S2 of the right lung, fluid based on the survey was AML, condition after Madden in the pleural cavity, focal lesion 0.44 cm in S9 of the radical left-side mastectomy (August, 2010). left lung, non-homogenous infiltration 2.0 9 1.9 cm On September 30, 2010 cytostatic chemotherapy on the II-V intercostal level on the frontal and left-side ‘7 + 3’ (cytarabine + idarubicin) was started. During lateral surface (Fig. 1). the chemotherapy febrile neutropenia appeared and On October 21, surgical debridement was performed antibiotics (cefepime, ciprofloxacin, metronidazole, and of 25 9 15 cm necrotic skin and subcutaneous tissue (a) (c) (d) (b) Figure 1 (a) Necrosis of soft tissue in the postoperative wound (October 15, 2010); (b) CT scan of the chest – non-homoge- nous infiltration 2.0 9 1.9 cm on the II- (e) V intercostal level on the frontal and left side lateral surface; (c) direct microscopy non-septate non-pigmented hyphae (9400, material from post-operative wound area); (d) culture of Lichtheimia corymbifera (material from post-operative wound area); (e) histopathology of opera- tive material – wide non-septate, non-pig- mented hyphae. © 2014 Blackwell Verlag GmbH 92 Mycoses, 2014, 57, 91–96 Mucormycosis in haematological patients in Saint-Petersburg, Russia of the left breast area. During surgery all not-viable tissues of the pectoralis major muscle were removed. Thoracentesis and drainage of the left pleural cavity were performed. In histopathology of operative mate- rial wide non-septate, non-pigmented hyphae were found (Fig. 1). The culture was identified as Lichthei- mia corymbifera. On October 23, neutrophil count was restored (2.4 9 109/l). The total duration of severe neutropenia was more than 70 days. Despite the anti- fungal therapy the necrosis of soft tissue progressed (Fig. 2). Caspofungin 70 mg dÀ1, subsequently 50 mg dÀ1 was added to the therapy. On November 2, a second surgical debridement was performed of the soft tissues of the frontal chest wall Figure 3 Post-operative wound on November 6, 2010. and subperiostal resection of the IV, V ribs with the car- tilages in the area from the sternum to the anterior axil- lary line. Histopathology confirmed the presence of fungal structures in the cartilage. Combined antimycot- ic therapy was continued in the same mode with a posi- tive effect (Fig. 3). Repeated cultures from affected area were negative. During the same period clinical and labo- ratory remission AML was achieved. On chest CT scan signs of pulmonary fibrosis were found. Plastic surgery of the wound with a skin graft from the front surface of the left thigh was performed on December 1 (Fig. 4). On December 15, the combination antifungal ther- apy had been completed. Total duration of amphoteri- cin B and caspofungin treatment was 52 days. Further antimycotic therapy was continued with posa- conazole (800 mg dÀ1). Three courses of cytostatic chemotherapy for consolidation of AML remission Figure 4 Condition after skin graft plastic surgery on December were performed. Each course had been followed by a 22, 2010. period of severe neutropenia for 10–14 days. The patient continued to receive posaconazole, and total present, the patient is in good condition with complete duration of antimycotic therapy was 210 days. At remission of AML and mucormycosis. Material and methods The study was prospective, multicentre and observa- tional. Mucormycosis was diagnosed and antifungal treatment was evaluated according to the criteria of European Organization for Research and Treatment of Cancer (EORTC) and National Institute of Allergy and Infectious Diseases Mycoses Study Group (NIAID- MSG), USA.3,4 Species identification of mycormycetes was confirmed by sequencing of ITS/D1-D2 fragments of fungal ribosomal DNA.5 Results During the period 2004–2013, we observed 36 hae- Figure 2 Post-operative wound on October 29, 2010. matological patients aged 5–74 years (mean age © 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 91–96 93 N. N. Klimko et al. Table 1 Underlying diseases in hematological patient with muco- Table 3 Clinical forms of mucormycosis in hematological patient rmycosis (n = 36). with mucormycosis (n = 36). ICD-10 Nosology N % n % Acute myeloid leukemia 13 36 Pulmonary 23 64 Acute lymphoblastic leukemia 10 28 Rhinocerebral 8 22 Neuroblastoma 2 6 Gastrointestinal 6 16 Hodgkin lymphoma 2 6 Cutaneous 3 9 Non-Hodgkin lymphoma 1 3 Bone involvement 3 9 Aplastic anemia 1 3 ≥2 organs involvement 18 50 Fanconi’s anemia 1 3 Myelodysplastic syndrome 1 3 Myeloid sarcoma 1 3 Chronic lymphocytic leukemia 1 3 and median duration of corticosteroid use was Chronic myelogenous leukemia 1 3 48 days.
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