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 1
I. Metchnikov North-Western State Medical University, St. Petersburg, Russia, 2I. Pavlov Saint Petersburg State Medical University, St. Petersburg, Russia, Pediatric City Hospital No 1, St. Petersburg, Russia, 4City Hospital No 31, St. Petersburg, Russia and 5Leningrad Regional Clinical Hospital, St. Petersburg, Russia 3
Summary
We prospectively observed 36 haematological patients with mucormycosis from nine hospitals of St. Petersburg during 2004–2013. The most frequent underlying diseases were acute leukaemia (64%), and main risk factors were prolonged neutropenia (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 (echinocandins + 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 tissue, mucormycosis, pulmonary mucormycosis.
Introduction Mucormycosis (zygomycosis) is a severe opportunistic infection. At present, an increased frequency of mucormycosis is noted worldwide, particularly in patients with haematological malignancies. This is not only due to improvement of diagnostic methods for fungal infections, but rather because of more aggressive schemes of cytostatic therapy and more extensive use of haematopoietic stem cell transplantation.
Correspondence: Prof. N. Klimko, I. Metchnikov North-Western State Medical University, Department of Clinical Mycology, Allergology and Immunology str. Santiago-de-Cuba, 1/28; St.-Petersburg 194291, Russia. Tel.: +7812 3035146. Fax: +7812 5106277. E-mail: [email protected] Submitted for publication 21 December 2013 Revised 18 June 2014 Accepted for publication 18 June 2014
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 91–96
The range of underlying conditions in mucormycosis has changed. In the period 1980–1990, mucormycosis predominantly had developed in patients with decompensated diabetes mellitus. Over the last years, mucormycosis most frequently has been diagnosed in patients with haematological malignancies.1,2 We represent a clinical case of successful treatment of mucormycosis in a patient with acute myeloid leukaemia (AML), along with results of a prospective study of mucormycosis in haematological patients in St. Petersburg, Russia during the period (2004–2013).
Case report A 53-year-old woman was admitted to Leningrad Regional Clinical Hospital in September 2010. She was in severe condition, conscious but retarded. She had general weakness and exertional dyspnoea. The body temperature was 38.7 °C. Auscultation revealed vesicular breathing diminished bilaterally in the lower
doi:10.1111/myc.12247
N. N. Klimko et al.
parts of lungs. Respiration rate was 20–30 per minute. Blood pressure was 110/70 mm Hg, heart rate 99 per minute. On the left chest area, an unhealed postoperative wound was apparent. Patient’s medical history revealed that a tumour of the left breast was detected in June 2010. On August 10, 2010 Madden modified radical mastectomy of the left breast was performed. The examination revealed leucopoenia (2.2 9 109/l), thrombocytopenia (89 9 109/l) and anaemia (Hb 97 g l 1). Body temperature was above 38 °C during hospitalisation. In the hospital, blood tests showed pancytopenia (RBC 2.6 9 1012/l, Hb 70 g l 1, WBC 2.5 9 109/l, blasts 15%, promyelocytes 1%, neutrophils 6%, basophils 2%, lymphocytes 75%, monocytes 1%, PLT 11 9 109/l). Immunophenotyping of the bone marrow revealed the transformed cells with intermediate and high level of granularity with the total immunophenotype CD45dim CD117+ CD33+ CD38+ MPO+. The absence of antigens CD34, HLA-DR, CD7 and high level of cells granularity was regarded. The diagnosis based on the survey was AML, condition after Madden radical left-side mastectomy (August, 2010). On September 30, 2010 cytostatic chemotherapy ‘7 + 3’ (cytarabine + idarubicin) was started. During the chemotherapy febrile neutropenia appeared and antibiotics (cefepime, ciprofloxacin, metronidazole, and (a)
imipenem) were used. Fever above 38 °C persisted. On chest CT scan (October 6, 2010) were found local infiltration in S2 of the right lung, focal lesion in S9 of the left lung and right-sided pleural effusion. On October 13, patient had developed intense pain in the postoperative wound. The necrotic area of soft tissue 2 cm in diameter was detected. Vancomycin was added to the therapy. The next day the pain increased, the necrotic area enlarged to 10 cm in diameter, body temperature went above 38 °C. The material from postoperative wound area was obtained for mycological examinations. On microscopy non-septate non-pigmented hyphae were found. On October 16, abundant growth of moulds was received. The culture was identified as Lichtheimia corymbifera. Mucormycosis of skin and soft tissue of postoperative wound was diagnosed. Therapy with amphotericin B was started with a dose 1 mg kg 1 d 1 (7 days), than 1.5 mg kg 1 d 1, and G-CSF (leykostim) 480 mcg d 1 was used. Chest CT scan (October 18) showed infiltrate 1 9 1.4 9 2.1 cm in S2 of the right lung, fluid in the pleural cavity, focal lesion 0.44 cm in S9 of the left lung, non-homogenous infiltration 2.0 9 1.9 cm on the II-V intercostal level on the frontal and left-side lateral surface (Fig. 1). On October 21, surgical debridement was performed of 25 9 15 cm necrotic skin and subcutaneous tissue
(c)
(d)
(b) Figure 1 (a) Necrosis of soft tissue in the
(e)
92
postoperative wound (October 15, 2010); (b) CT scan of the chest – non-homogenous infiltration 2.0 9 1.9 cm on the IIV 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 operative material – wide non-septate, non-pigmented hyphae.
© 2014 Blackwell Verlag GmbH 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 material wide non-septate, non-pigmented hyphae were found (Fig. 1). The culture was identified as Lichtheimia 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 antifungal therapy the necrosis of soft tissue progressed (Fig. 2). Caspofungin 70 mg d 1, subsequently 50 mg d 1 was added to the therapy. On November 2, a second surgical debridement was performed of the soft tissues of the frontal chest wall and subperiostal resection of the IV, V ribs with the cartilages in the area from the sternum to the anterior axillary line. Histopathology confirmed the presence of fungal structures in the cartilage. Combined antimycotic therapy was continued in the same mode with a positive effect (Fig. 3). Repeated cultures from affected area were negative. During the same period clinical and laboratory 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 therapy had been completed. Total duration of amphotericin B and caspofungin treatment was 52 days. Further antimycotic therapy was continued with posaconazole (800 mg d 1). Three courses of cytostatic chemotherapy for consolidation of AML remission were performed. Each course had been followed by a period of severe neutropenia for 10–14 days. The patient continued to receive posaconazole, and total duration of antimycotic therapy was 210 days. At
Figure 3 Post-operative wound on November 6, 2010.
Figure 4 Condition after skin graft plastic surgery on December
22, 2010.
present, the patient is in good condition with complete remission of AML and mucormycosis.
Material and methods The study was prospective, multicentre and observational. 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 (NIAIDMSG), USA.3,4 Species identification of mycormycetes was confirmed by sequencing of ITS/D1-D2 fragments of fungal ribosomal DNA.5
Results Figure 2 Post-operative wound on October 29, 2010.
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 91–96
During the period 2004–2013, we observed 36 haematological patients aged 5–74 years (mean age
93
N. N. Klimko et al.
Table 1 Underlying diseases in hematological patient with mucormycosis (n = 36). ICD-10 Nosology
N
%
Acute myeloid leukemia Acute lymphoblastic leukemia Neuroblastoma Hodgkin lymphoma Non-Hodgkin lymphoma Aplastic anemia Fanconi’s anemia Myelodysplastic syndrome Myeloid sarcoma Chronic lymphocytic leukemia Chronic myelogenous leukemia Multiple myeloma
13 10 2 2 1 1 1 1 1 1 1 1
36 28 6 6 3 3 3 3 3 3 3 3
Table 2 Risk factors and background conditions in hematological patient with mucormycosis (n = 36).
Cytostatic chemotherapy Median number of courses of chemotherapy Severe neutropenia Median duration of neutropenia, days Lymphocytopenia Median duration of lymphocytopenia, days Corticosteroids Median duration of corticosteroid therapy, days Allogeneic HSCT
N
%
36 4 33 30 31 25 24 48 18
100 92 86 67 50
23 12 years) from nine hospitals of St. Petersburg. Among them 14 were children (38%, median age 11 3 years), and 22 adults (62%, median age 28 14 years): 18 males (53%), 16 females (47%). Almost all cases of mucormycosis developed after a long stay in the hospital (97%) with a median of 36 days. One case developed during outpatient followup after undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT). Most frequently mucormycosis developed in patients with acute myeloid and lymphoblastic leukaemia, AML and ALL (64%). Neuroblastoma, Hodgkin’s or non-Hodgkin’s lymphoma, aplastic anaemia, Fanconi’s anaemia, myelodysplastic syndrome, myeloid sarcoma and multiple myeloma were less frequent (Table 1). Mucormycosis mainly developed after four courses of cytostatic chemotherapy (Table 2). Prolonged severe neutropenia (
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 1
I. Metchnikov North-Western State Medical University, St. Petersburg, Russia, 2I. Pavlov Saint Petersburg State Medical University, St. Petersburg, Russia, Pediatric City Hospital No 1, St. Petersburg, Russia, 4City Hospital No 31, St. Petersburg, Russia and 5Leningrad Regional Clinical Hospital, St. Petersburg, Russia 3
Summary
We prospectively observed 36 haematological patients with mucormycosis from nine hospitals of St. Petersburg during 2004–2013. The most frequent underlying diseases were acute leukaemia (64%), and main risk factors were prolonged neutropenia (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 (echinocandins + 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 tissue, mucormycosis, pulmonary mucormycosis.
Introduction Mucormycosis (zygomycosis) is a severe opportunistic infection. At present, an increased frequency of mucormycosis is noted worldwide, particularly in patients with haematological malignancies. This is not only due to improvement of diagnostic methods for fungal infections, but rather because of more aggressive schemes of cytostatic therapy and more extensive use of haematopoietic stem cell transplantation.
Correspondence: Prof. N. Klimko, I. Metchnikov North-Western State Medical University, Department of Clinical Mycology, Allergology and Immunology str. Santiago-de-Cuba, 1/28; St.-Petersburg 194291, Russia. Tel.: +7812 3035146. Fax: +7812 5106277. E-mail: [email protected] Submitted for publication 21 December 2013 Revised 18 June 2014 Accepted for publication 18 June 2014
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 91–96
The range of underlying conditions in mucormycosis has changed. In the period 1980–1990, mucormycosis predominantly had developed in patients with decompensated diabetes mellitus. Over the last years, mucormycosis most frequently has been diagnosed in patients with haematological malignancies.1,2 We represent a clinical case of successful treatment of mucormycosis in a patient with acute myeloid leukaemia (AML), along with results of a prospective study of mucormycosis in haematological patients in St. Petersburg, Russia during the period (2004–2013).
Case report A 53-year-old woman was admitted to Leningrad Regional Clinical Hospital in September 2010. She was in severe condition, conscious but retarded. She had general weakness and exertional dyspnoea. The body temperature was 38.7 °C. Auscultation revealed vesicular breathing diminished bilaterally in the lower
doi:10.1111/myc.12247
N. N. Klimko et al.
parts of lungs. Respiration rate was 20–30 per minute. Blood pressure was 110/70 mm Hg, heart rate 99 per minute. On the left chest area, an unhealed postoperative wound was apparent. Patient’s medical history revealed that a tumour of the left breast was detected in June 2010. On August 10, 2010 Madden modified radical mastectomy of the left breast was performed. The examination revealed leucopoenia (2.2 9 109/l), thrombocytopenia (89 9 109/l) and anaemia (Hb 97 g l 1). Body temperature was above 38 °C during hospitalisation. In the hospital, blood tests showed pancytopenia (RBC 2.6 9 1012/l, Hb 70 g l 1, WBC 2.5 9 109/l, blasts 15%, promyelocytes 1%, neutrophils 6%, basophils 2%, lymphocytes 75%, monocytes 1%, PLT 11 9 109/l). Immunophenotyping of the bone marrow revealed the transformed cells with intermediate and high level of granularity with the total immunophenotype CD45dim CD117+ CD33+ CD38+ MPO+. The absence of antigens CD34, HLA-DR, CD7 and high level of cells granularity was regarded. The diagnosis based on the survey was AML, condition after Madden radical left-side mastectomy (August, 2010). On September 30, 2010 cytostatic chemotherapy ‘7 + 3’ (cytarabine + idarubicin) was started. During the chemotherapy febrile neutropenia appeared and antibiotics (cefepime, ciprofloxacin, metronidazole, and (a)
imipenem) were used. Fever above 38 °C persisted. On chest CT scan (October 6, 2010) were found local infiltration in S2 of the right lung, focal lesion in S9 of the left lung and right-sided pleural effusion. On October 13, patient had developed intense pain in the postoperative wound. The necrotic area of soft tissue 2 cm in diameter was detected. Vancomycin was added to the therapy. The next day the pain increased, the necrotic area enlarged to 10 cm in diameter, body temperature went above 38 °C. The material from postoperative wound area was obtained for mycological examinations. On microscopy non-septate non-pigmented hyphae were found. On October 16, abundant growth of moulds was received. The culture was identified as Lichtheimia corymbifera. Mucormycosis of skin and soft tissue of postoperative wound was diagnosed. Therapy with amphotericin B was started with a dose 1 mg kg 1 d 1 (7 days), than 1.5 mg kg 1 d 1, and G-CSF (leykostim) 480 mcg d 1 was used. Chest CT scan (October 18) showed infiltrate 1 9 1.4 9 2.1 cm in S2 of the right lung, fluid in the pleural cavity, focal lesion 0.44 cm in S9 of the left lung, non-homogenous infiltration 2.0 9 1.9 cm on the II-V intercostal level on the frontal and left-side lateral surface (Fig. 1). On October 21, surgical debridement was performed of 25 9 15 cm necrotic skin and subcutaneous tissue
(c)
(d)
(b) Figure 1 (a) Necrosis of soft tissue in the
(e)
92
postoperative wound (October 15, 2010); (b) CT scan of the chest – non-homogenous infiltration 2.0 9 1.9 cm on the IIV 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 operative material – wide non-septate, non-pigmented hyphae.
© 2014 Blackwell Verlag GmbH 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 material wide non-septate, non-pigmented hyphae were found (Fig. 1). The culture was identified as Lichtheimia 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 antifungal therapy the necrosis of soft tissue progressed (Fig. 2). Caspofungin 70 mg d 1, subsequently 50 mg d 1 was added to the therapy. On November 2, a second surgical debridement was performed of the soft tissues of the frontal chest wall and subperiostal resection of the IV, V ribs with the cartilages in the area from the sternum to the anterior axillary line. Histopathology confirmed the presence of fungal structures in the cartilage. Combined antimycotic therapy was continued in the same mode with a positive effect (Fig. 3). Repeated cultures from affected area were negative. During the same period clinical and laboratory 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 therapy had been completed. Total duration of amphotericin B and caspofungin treatment was 52 days. Further antimycotic therapy was continued with posaconazole (800 mg d 1). Three courses of cytostatic chemotherapy for consolidation of AML remission were performed. Each course had been followed by a period of severe neutropenia for 10–14 days. The patient continued to receive posaconazole, and total duration of antimycotic therapy was 210 days. At
Figure 3 Post-operative wound on November 6, 2010.
Figure 4 Condition after skin graft plastic surgery on December
22, 2010.
present, the patient is in good condition with complete remission of AML and mucormycosis.
Material and methods The study was prospective, multicentre and observational. 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 (NIAIDMSG), USA.3,4 Species identification of mycormycetes was confirmed by sequencing of ITS/D1-D2 fragments of fungal ribosomal DNA.5
Results Figure 2 Post-operative wound on October 29, 2010.
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 91–96
During the period 2004–2013, we observed 36 haematological patients aged 5–74 years (mean age
93
N. N. Klimko et al.
Table 1 Underlying diseases in hematological patient with mucormycosis (n = 36). ICD-10 Nosology
N
%
Acute myeloid leukemia Acute lymphoblastic leukemia Neuroblastoma Hodgkin lymphoma Non-Hodgkin lymphoma Aplastic anemia Fanconi’s anemia Myelodysplastic syndrome Myeloid sarcoma Chronic lymphocytic leukemia Chronic myelogenous leukemia Multiple myeloma
13 10 2 2 1 1 1 1 1 1 1 1
36 28 6 6 3 3 3 3 3 3 3 3
Table 2 Risk factors and background conditions in hematological patient with mucormycosis (n = 36).
Cytostatic chemotherapy Median number of courses of chemotherapy Severe neutropenia Median duration of neutropenia, days Lymphocytopenia Median duration of lymphocytopenia, days Corticosteroids Median duration of corticosteroid therapy, days Allogeneic HSCT
N
%
36 4 33 30 31 25 24 48 18
100 92 86 67 50
23 12 years) from nine hospitals of St. Petersburg. Among them 14 were children (38%, median age 11 3 years), and 22 adults (62%, median age 28 14 years): 18 males (53%), 16 females (47%). Almost all cases of mucormycosis developed after a long stay in the hospital (97%) with a median of 36 days. One case developed during outpatient followup after undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT). Most frequently mucormycosis developed in patients with acute myeloid and lymphoblastic leukaemia, AML and ALL (64%). Neuroblastoma, Hodgkin’s or non-Hodgkin’s lymphoma, aplastic anaemia, Fanconi’s anaemia, myelodysplastic syndrome, myeloid sarcoma and multiple myeloma were less frequent (Table 1). Mucormycosis mainly developed after four courses of cytostatic chemotherapy (Table 2). Prolonged severe neutropenia (
