mycoses
Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Original article
Epidemiology and outcomes of patients with invasive mould infections: a retrospective observational study from a single centre (2005–2009) Lena Klingspor,1 Baharak Saaedi,1 Per Ljungman2 and Attila Szakos3 1
Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden, 2Division of Haematology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden and 3Division of Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Summary
Invasive mould infection (IMI) is an important cause of morbidity and mortality in immunocompromised patients. However, Swedish epidemiology data are lacking. The aim of this study was to investigate the epidemiology and outcome of IMI. Cases of proven/probable IMI at Karolinska University Hospital, Stockholm, from 2005 to 2009, were included. A total of 100 patients with 104 episodes of IMI were enrolled. Identified isolates included 101 mould isolates. The majority of the isolates were Aspergillus spp. (74.3%), followed by Mucorales spp. (13.9%), Fusarium spp. (4.9%) and other mould spp. (6.9%). In 13% of the episodes, more than one mould caused the IMI. The lung was most often affected (88.5%). The most frequent underlying disease was haematological malignancies (70%). Following diagnosis, 83.7% initially received antifungal monotherapy, 9.6% received combination therapy and 6.7% no treatment. The overall 90-day and 1-year overall survival was 49% and 46% respectively. Survival at 90 days post diagnosis was 71.4% in the solid tumour cohort, 62.5% in patients with solid organ transplants, 43.5% in haematological malignancy (HMs) and 37% in those undergoing allogeneic haematopoietic stem cell transplantation (HSCT). Overall survival was poor in the studied cohort, but is variable among different host categories, with particular opportunities for improvement in patients with underlying HMs and allogeneic HSCT.
Key words: Invasive mould infection, epidemiology, outcome, aspergillosis, mucormycosis, fusariosis.
Introduction Invasive mould infections (IMIs) in immunocompromised patients are associated with high morbidity and mortality.1–4 The mortality rate from invasive aspergillosis (IA) is high, ranging from 50% to 100%, in Correspondence: L. Klingspor, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, F 72, Huddinge, SE-141 86 Stockholm, Sweden. Tel.: +46 8 58 58 78 39; +46 70 484 19 39. Fax: +46 8 58 58 11 25. E-mail: [email protected] Submitted for publication 9 April 2015 Revised 26 May 2015 Accepted for publication 26 May 2015
doi:10.1111/myc.12344
almost all groups of immune-compromised patients.1,3 Other moulds such as mucormycosis have emerged as the third most common cause of invasive fungal infection mycosis in order of importance after candidiasis and aspergillosis in patients with haematological and allogeneic haematopoietic stem cell transplantation (HSCT).2 Mucormycosis is also a threat in patients with diabetes mellitus (DM). For mucormycosis, the case fatality ranges from 35% among individuals with no underlying condition to 44% among patients with diabetes and 66% in patients with malignancies.2 Risk factors for developing IA and other moulds such as mucormycosis have been studied, but despite its incidence and severity there remains a lack of information on the contemporary epidemiology of these infections.
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 470–477
Epidemiology and outcome of mould infections
Epidemiological data concerning IMIs from Sweden are lacking. The aim of this retrospective study was to evaluate the epidemiology and spectrum of IMI, infection characteristics and outcomes of IMIs in patients with varied underlying conditions, such as haematological patients, allogeneic HSCT recipients, solid organ transplantation (SOT) recipients, patients with immune-deficiencies and critically ill patients in both adult and paediatric medical and surgical intensive care units at Karolinska University Hospital.
Patients and methods This study was approved by the Ethics Committee at Karolinska Institutet. This is a retrospective, registry study that collects microbiology, histopathology and clinical data and outcome in patients with proven and probable IMIs between 1 January 2005 and 31 December 2009, at Karolinska University Hospital, Stockholm, Sweden. The hospital is a regional centre for allogeneic HSCT, liver and kidney transplantation. Information collected included baseline demographical characteristics, underlying disease, type of transplant, time to diagnosis of IMI, infecting mould species, site of infection, antifungal therapies and outcome. Outcomes were recorded at 90 days and 1 year after IMI diagnosis, or until death or loss to follow-up. Microbiological data concerning direct microscopy, cultures, Aspergillus galactomannan antigen results and histological specimens were documented. Information was collected regarding the first systemic antifungal therapies administered following diagnosis, but not with specific doses and durations. Definitions
Invasive mould infections were diagnosed according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria.5 Patients were only included if they met the definition of proven or probable IA or IMI. Proven disease required mycological documentation from a normally sterile site, and probable disease required a host factor, clinical features and mycological evidence, which for IA could include a positive galactomannan assay.5 As no specific definitions or classic radiographic findings have been established in non-cancer patients (e.g. SOT), microbiological evidence of a mould
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 470–477
without an alternative aetiology was considered as probable IMI in the setting of dense consolidations and/or infiltrates on Chest CT.6,7 Aspergillus antigenaemia in patients with relevant clinical signs and symptoms was determined by using the serum galactomannan ELISA assay (Bio-Rad, Hercules, CA, USA), with IA defined according to the revised diagnostic criteria.5 Galactomannan cut-off was determined (optical density index of 0.5 for serum). Causative Aspergillus and other mould spp. were documented when available. The date of diagnosis was considered to be the date when the diagnosis of IMI was established by the clinical team at Karolinska University Hospital or, if undiagnosed, at autopsy. Primary antifungal therapy was defined as the first line antifungal treatment administered following diagnosis. Statistical analyses
Descriptive analysis was used for baseline characteristics and subgroup analysis. Descriptive survival analysis was performed based on the whole patient group and for subpopulations. The survival distribution function was estimated using the Kaplan–Meier method. Statistical analyses were performed using SAS version 9.2/Enterprise Guide 4.2 (SAS Institute Inc., Carey, NC, USA).
Results Baseline patient characteristics
Altogether, 100 patients with 104 episodes of IMI, diagnosed with proven or probable IMI, were included during a 60-month period from 1 January 2005, to 31 December 2009. The mean age was 49.7 years (range = 2 months–85 years), and the majority of the patients were males (60%). The most frequent underlying disease was haematological malignancy (HM; n = 70), with acute myelogenous leukaemia (AML) (n = 33), acute lymphatic leukaemia (ALL) (n = 10), non-Hodgkin’s lymphoma (n = 10) and chronic lymphocytic leukaemia (n = 7) being the most common HMs. Eight patients (8%) had undergone SOT and 27 had received an allogeneic HSCT from human leucocyte antigen-matched or unrelated donors. Of these 27 HSCT patients, 24 had underlying HMs and three patients had other underlying diseases, chronic granulomatous disease, kidney cancer and bile duct cancer (Table 1).
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Table 1 Patient baseline characteristics (n = 100). Patient characteristics Age, mean years (range) n (%) 18 and 65 Sex Male Underlying disease1 Haematological malignancy Solid organ transplant Allogeneic haematopoietic stem cell transplant Autologous haemapoietic stem cell transplant Solid tumour HIV/AIDS Inherited immunodeficiency disorder Other Type of haematological malignancy1 Acute myelogenous leukaemia Non-Hodgkin’s lymphoma Multiple myeloma Acute lymphocytic leukaemia Myelodysplastic syndrome Chronic lymphocytic leukaemia Other Type of haematopoietic stem cell transplant Allogeneic: HLA-matched related Allogeneic: HLA-matched unrelated Allogeneic: HLA mismatched Cord blood Allogeneic: data not available Autologous Type of solid organ transplantant1 Lung Kidney Liver Heart ECMO treatment1
Frequency of IMI No. of patients
11 66 24 60 70 8 32 1 10 1 3 8 33 10 2 10 4 7 4 12 10 2 2 1 1 1 2 3 2 42
HLA, human leucocyte antigen; ECMO, extra corporal membrane oxygenation; ALL, acute lymphocytic leukaemia. 1 Not mutually exclusive; patients could have >1 characteristics within a category. 2
Three children with ALL and mucormycoses and one adult with SLE and aspergillosis.
Of the 27 allogeneic HSCT patients, 20 developed an IMI within 1 year after transplantation. The median day post-HSCT was 158 days (mean = 138 days; range = 3–308 days). However, the median day postHSCT when IA was diagnosed was 205 days. Seven patients developed an IMI after more than 1 year. All these seven patients had a complicated medical history after transplantation such as chronic graft-versus-host disease, bacterial and viral infections, and relapse of the underlying diseases.
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In total, 354 allogeneic HSCT were performed during this 60-month period and 27 (7.6%) patients developed IMIs. In total, 275 liver transplants and 372 kidney transplants were performed and 3 (1.1%) and 2 (0.5%) patients developed IA within 1 year after transplantation respectively. The frequency could not be calculated for the other patient cohorts due to lack of information regarding the denominator. Invasive mould epidemiology
The 100 patients with IMI included 30 patients with proven and 70 patients (with 74 episodes) with probable IMI. In total, 75 patients had 79 episodes of IA. In addition, nine patients had mucormucosis (five proven and four probable), three fusariosis (two proven and one probable) and one each had (proven) Scedosporioum apiospermum, Acremonium and Alternaria infections respectively. Ten patients (seven proven and three probable) had mixed IMI, six with IA in combination with invasive mucormycoses, two with IA in combination with fusariosis, one with IA and S. apiospermum and Scyalidium dimediatum and one with IA and Fusarium solani, Saksenia vasiformis, S. apiospermum and S. dimediatum. For mould distribution, see Table 2. In the patients with HMs, IA was diagnosed in 39/50 (78%) episodes. In 8/50 (16%) episodes, a non-Aspergillus mould was diagnosed, and in 3/50 (6%) patients a mixed infection (Aspergillus and another mould) was recorded. In the allogeneic HSCT group (n = 27), IA was diagnosed in 81.5% of the patients. In four (18.5%) patients, a non-Aspergillus mould was isolated: one Lichteimia (Absidia) corymbifera, one Acremonium spp. infection, in two patients Aspergillus fumigatus was isolated together with Fusarium spp. and in one patient A. fumigatus was isolated with Rhizopus spp. The eight patients with SOT all had IA. Mould diagnostics
A total of 101 mould isolates from 81 patients were identified by culture (Table 3) with additional 17 patients with probable IA diagnosed by galactomannan assays and two patients with IMI diagnosed with mucormycosis by direct microscopy. Furthermore, histopathology of biopsies from 28 patients and cytology in one patient showed mould hyphae.
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 470–477
Epidemiology and outcome of mould infections
Table 2 Mould spp. and positive Aspergillus antigen tests distribution by patient (n = 100; 104 episodes). Patient category Haematological malignancy AML + ALL Other Allogeneic HSCT Solid organ transplant Solid tumour HIV/AIDS Inherited immuno-deficiency Other Total Age group (years) 65
A. fum
10 7 16 7 4 1 2 2
4 39 5
A. spp.
5 4 41 21 1 0 11 0
0 12 5
Asp ag
Mucor sp.
Fusarium
Mixed spp.
Other
Total episodes
8 5 2 0 0 0 2 0
4 0 1 0 1 0 0 3
2 1 0 0 0 0 0 0
3 0 4 0 1 0 0 2
1 0 1 0 0 0 0 1
33 17 27 8 7 1 4 8 104 (100 patients)
2 6 9
4 2 3
0 2 1
1 2 0
0 2 1
11 65 24
Asp ag, Aspergillus antigen; ALL, acute lymphocytic leukaemia; AML, acute myelogenous leukaemia; and HSCT, haematopoietic stem cell transplant. 1 Three patients had two Aspergillus species isolated (A. fumigatus and A. flavus, A. fumigatus and A. niger, and A. fumigatus and A. nidulans respectively).
Table 3 From in total 100 patients (with 104 episodes of IMI) 101 mould spp. were isolated in 81 patients and 19 unspecified patients (includes 17 patients with probable IA diagnosed by galactomannan assays and two patients with IMI diagnosed with mucormycosis by microscopy).
Species A. fumigatus A. flavus A. niger A. glaucus A. nidulans Aspergillus species Mucor racemosus Lichthemia (Absidia) corymbifera Rhizopus oryzae Rhizopus microspores Saksenia vasiformis Rhizomucor miehei Rhizomucor pusillus Rhizopus species Mucor species Fusarium species Scedosporion apiospermum Scytalidium dimediatum Alternaria sp. Acremonium Unspecified2 Total
Number of isolates1
% of identified isolates
56 9 3 1 1 5 1 3
55.5 8.9 3.0 0.9 0.9 4.5 0.9 3.0
2 2 1 1 1 2 1 5 3 2 1 1 19 120
2.0 2.0 0.9 0.9 0.9 2.0 0.9 4.9 3.0 2.0 0.9 0.9
IMI, invasive mould infection; IA, invasive aspergillosis. 1
Patients could have more than one species.
2
Includes 17 patients with probable IA diagnosed by galactomannan assays and two mucormycosis diagnosed by microscopy.
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 470–477
Cultures
Of the 101 mould isolates identified, the majority were Aspergillus spp. (74.3%). The majority of the Aspergillus isolates were A. fumigatus (55.5%) followed by A. flavus (8.9%). In three patients with probable IA, two Aspergillus species were isolated. Mucorales spp. comprised 13.9% of the isolates followed by Fusarium spp. (4.9%) and other mould spp. (6.9%) (Table 3). Clinical presentation and outcome within 90 days after diagnosis of IMI
Aspergillus In the 75 patients with 79 episodes of IA, the lung was the most frequent site of infection, with 70 episodes (88.6%) in 67 patients having IA lung infection only. Five patients had evidence of infection in more than one anatomic site, but all five of those also included infection of the lungs. Exclusive infection to a single site other than the lungs included the tracheobronchial tree (n = 1), sinuses (n = 1), pleura (n = 1) and eye (n=). Of the 75 patients, 36 (48%) died within 90 days from diagnosis. Mucormycosis Nine patients were diagnosed with mucormycosis: four with abdominal infection (the underlying diseases were AML, ALL, solid tumour and DM type 1 plus
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abdominal surgery respectively), two with pulmonary infection, two with disseminated infection (including pulmonary) and one with mastoiditis. Six of the nine patients with mucormycoses died within 90 days (66.7%). Fusariosis Three patients had invasive fusariosis: one pulmonary, one infection in the spleen and one disseminated fusariosis (with positive blood culture). All patients with fusariosis died within 90 days. Multiple mould infection
Thirteen patients had more than one mould species causing proven IMI in seven patients and probable in six patients. Three patients had two Aspergillus species isolated (A. fumigatus and A. flavus, A. fumigatus and A. niger and A. fumigatus and A. nidulans respectively), and 10 patients had mixed infections: IA and fusariosis (n = 2), IA and mucormycosis (n = 6) and two patients had IA in combination with several other moulds (Table 2). Mixed infections Disseminated: Two patients after allogeneic HSCT had proven IA and fusariosis and one AML patient had IA and mucormycoses. Pulmonary: One AML patient had pulmonary aspergillosis and pleural mucormycosis. Two patients had pulmonary aspergillosis and mucormycosis: one after allogeneic HSCT and one cancer patient in extra corporal membrane oxygenation (ECMO) treatment respectively. Miscellaneous: One patient after allogeneic HSCT developed pulmonary IA and sinusitis with mucormycosis. One patient with AML had aspergillus and mucormycosis sinusitis.
Two patients had proven deep wound infections (tsunami catastrophe), one with A. flavus, F. solani, S. vasiformis, S. apiospermum and S. dimediatum infection and one with A. fumigatus, S. apiospermum and S. dimediatum infection. Both survived. Seven (87.5%) of the eight patients who were immunocompromised died within 90 days. Other mould infections One patient after allogeneic HSCT had probable Acremonium sinusitis and one patient with proven S. apiospermum osteomyelitis (after trauma) survived, whereas one patient with chronic lymphocytic leukaemia and proven joint infection with Alternaria sp. died. Antifungal therapy
A total of 93/100 patients with 104 episodes of IMI received antifungal treatment therapy in 97 of the episodes and 7 (7%) patients received no treatment (Table 4). Mortality
Survival within 90 days and 1 year after IMI diagnosis Overall 90-day post diagnosis Kaplain–Meier survival among the 99 patients (one patient was diagnosed at autopsy) with IMI was 49.5% (n = 49; Fig. 1). Survival in the patients with IA was 52%, and in the patients with other moulds, survival was 40%. In the four major subpopulations of patients, overall Kaplan–Meier survival at 90 days post diagnosis was greater in the solid tumour cohort (71.4%) compared with survival in patients with SOT (62.5%), HM (43.5%), or those undergoing allogeneic HSCT (37%). One-year survival in patients with IA was 48% and 40% in patients with other IMIs.
Table 4 Initial antifungal therapy.
Aspergillus spp. Mucor spp. Fusarium spp. Aspergillus + Fusarium spp. Aspergillus + Mucor spp. Aspergillus + multiple mould spp. Acremonium sp. Alternaria sp. Scedosporion apiospermum Total
amb
vz
pz
iz
12 5
44
2 1
2
2 2
caspo 8 1 1
vz + caspo
vz + amb
4 1
1 1
pz + amb
pz + caspo
2
Unknown
6 1
1 1
NT
1
1 1
1 1 22
1 47
4
2
10
5
4
1
1
7
1
Episodes 79 9 3 2 6 2 1 1 1 104
Amb, liposomal amphotericin B (ambisome); vz, voriconazole; pz, posaconazole; iz, itraconazole; caspo, caspofungin; NT, no treatment.
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Epidemiology and outcome of mould infections
Figure 1 Overall survival for 99 patients
with invasive mould infection.
Discussion This is the largest retrospective Swedish analysis of contemporary IMI reported to date. Invasive aspergillosis was the most common cause of infection followed by mucormycosis. Infections with more than one mould were found in as much as 13% of the patients, and most commonly IA together with mucormycosis. Male gender was most common as shown in other studies.1,4,7 As seen in other large studies,1,3,4 the most common underlying disease in patients with IA or other IMI was haematological malignancy (70%), particularly AML, non-Hodgkin’s lymphoma and ALL, and the lung was the most often affected organ (88.5%). The median day post-HSCT when IA was diagnosed was 205 days. This is in contrast to two other studies, where the median day post-SCT when IA was diagnosed was 97 days,8 similar to the median of 99 days found in the TRANSNET surveillance report of IA from 23 US transplant centres.9 Aspergillus was the only cause of mould infection in our eight patients who had received a SOT. In patients with HMs, IA alone was diagnosed in 39 episodes (78%) and in additional 6% of the episodes, Aspergillus together with another mould was isolated. Mucormycosis was diagnosed in our patients with HMs and after HSCT and was associated with high mortality. However, in 6% of the cases, co-infection with IA and mucormycosis was diagnosed. Co-infection with mucormycosis and aspergillosis is rare but has been reported in a few patients including AML.10 Extra corporal membrane oxygenation is a therapy which could be complicated with severe fungal nosocomial infections such as mucormycosis, but has so
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 470–477
far been described mainly in neonates.11,12 In this study, mucormycosis (two disseminated, one abdominal) was diagnosed in three children who all had ALL as the underlying disease and received ECMO therapy. All three died underscoring the severity of the disease. Gastrointestinal mucormycosis remains uncommon and have been reported mainly in premature neonates and malnourished children and patients with HMs, DM and corticosteroid use.2,13–15 The mortality rate is as high as 85%. Three of our four cases with gastrointestinal mucormycoses with ALL, AML, DM and abdominal surgery, and colon cancer, respectively, died. The infections can be transmitted by the inhalation of spores but also by direct inoculation on disrupted skin or mucosa.2 The latter was the case in the two patients with deep wound infections contracted in the tsunami catastrophe. Consistent with the observations of the literature concerning fusariosis, most patients in this survey had haematological malignancy or an HSCT as the underlying condition. Fusarium infection in such patients results in a poor prognosis, with death rates of up to 75%.4,16–19 In this study, the crude mortality was as high as 100%, including also the patients with mixed IA and fusariosis. The most common species identified in our survey was A. fumigatus (55.5%) followed by A. flavus (8.9%). If we look at our cases with IA only, A. fumigatus was isolated in 73.7% of the cases. This is in agreement with several other studies reporting a similar distribution.3,9,10,20 Most of the patients in this study were receiving appropriate therapy for IA that leaves six patients (6%) with no treatment at all. One case was diagnosed first at autopsy, and in three cases the diagnoses were
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made late, 1–2 days before death, and in one case the reason for not receiving treatment was not captured. Over half of the patients received monotherapy (86%), either with voriconazole or a liposomal amphotericin B (15.2%), followed by echinocandin (10.1%), itraconazole or posaconazole (2.5%). This is in agreement with both a French survey12 and a US study,3 in which 80% of patients received monotherapy, most commonly with voriconazole. However, in both these studies approximately 20% received combination antifungal therapy, most commonly with voriconazole and caspofungin. This is different compared with our study where only 6.3% received primary combination therapy, which is lower than reported in other studies.3 However, monotherapy is the recommended primary treatment for IA. Most patients were receiving liposomal amphotericin B treatment therapy for mucormycosis (Table 4). The overall 90-day survival in the 100 patients in our study of IMI was only 49.5% and the 1-year survival was 46.5%. In patients with IA only, 90-day survival was 52% compared to the PATH alliance registry study of IA where the 12-week overall survival was 64.4%. In our study, 1-year survival in IA was only 48%. In this study, 90-day survival rate ranged from 71.4% in solid tumour, 62.5% in SOT, 43.5% in HM to only 37% in allogeneic HSCT, leading to the worst survival of the major underlying conditions. Overall mortality after the diagnosis of IA and other mould infections has been historically high: one study reported that 78% of patients who developed IA after allogeneic HSCT died by 12 weeks or at the end of therapy.14 The TRANSNET study reported 12-week all-cause mortality rates of 57.5%, and a 1-year mortality of 74.6% among HSCT recipients with IA.15 This study has several limitations due to the lack of information on the total number of patients at risk (except for allogeneic HSCT (7.6%), liver (1.1%) and kidney (0.5%) transplant patients) in each category needed to calculate the incidence of infection within each patient subgroup. Our cases were diagnosed between 2005 and 2009. Galactomannan assay from broncho-alveolar lavage (BAL) was not performed at our hospital for diagnosis of IA during this period of time. However, additional IA and other mould strategies have developed since then – including BAL galactomannan, Aspergillus-PCR tests, sequencing and B-Dglucan test and the increased use of posaconazole and combination antifungal therapy. A recent study from
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Italy indicated that combination treatment were both well tolerated and seemed effective in haematological patients with invasive fungal diseases, but well-controlled studies are still required to determine the most efficacious antifungal combination therapies for specific fungal infections.21 In this analysis, A. fumigatus remains the most common causative species (54.2%) followed by other Aspergillus spp. (18.7%), although other mould species such as mucormycosis (14.4%), fusariosis (5.2%) and other moulds (7.2%) cause disease with variable rates in each host category. Outcomes as overall survival were poor, but are variable in different host categories, with particular opportunities for improvement in patients with underlying haematological malignancies and allogeneic HSCT. Posaconazole prophylaxis is nowadays given to our patients receiving allogeneic HSCT. This study provides significant information on IMI from our centre. The findings in our study emphasise the importance of establishing continual epidemiology surveillance programmes, both local and national, to follow the epidemiology of IMIs in different patient populations, and also to develop new sensitive and specific diagnostic tools for early diagnoses and better therapeutic interventions to improve the outcome of IMI. For the future we are planning to do an epidemiological follow-up study at Karolinska University Hospital from 2010 to 2014.
Acknowledgments We thank Yen Ngo (Stockholm, Sweden) for statistical analysis.
Conflicts of interest and source of funding Lena Klingspor has been a consultant to Astellas Pharma, Gilead Sciences, Merck & Co., and ScheringPlough. She has received research grants from Gilead and Schering-Plough/Merck & Co. Per Ljungman has research grants from Merck & Co., Pfizer AB and Gilead Sciences. The other authors have nothing to declare. This study was supported by an unrestricted grant from Merck, Sharp & Dohme, USA.
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Nichol PF, Corliss RF, Rajpal S, Helin M, Lund DP. Perforation of the appendix from intestinal mucormycosis in a neonate. J Pediatr Surg 2004; 39: 1133–5. Oh D, Notrica D. Primary cutaneous mucormycosis in infants and neonates: case report and review of the literature. J Pediatr Surg 2002; 37: 1607–11. Ashraf SI, Spellberg B, Walsh TJ, Kontoyiannis DP. Pathogenesis of mucormycosis. Clin Infect Dis 2012; 54(Suppl. 1): S16–22. Spellberg B, Edwards J Jr, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management. Clin Microbiol Rev 2005; 18: 5565–9. Skiada A, Pagano L, Groll A et al. Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007. Clin Microbiol Infect 2011; 17: 1859–67. Lortholary O, Obenga G, Biswas P et al. International retrospective analysis of 73 cases of invasive fusariosis treated with voriconazole. Antimicrob Agents Chemother 2010; 54: 4446–50. Campo M, Lewis RE, Kontoyiannis DP. Invasive fusariosis in patients with hematologic malignancies at a cancer center: 1998–2009. J Infect 2010; 60: 331–7. Nucci M, Anaissie E. Fusarium infections in immunocompromised patients. Clin Microbiol Rev 2007; 20: 695–704. Nucci M, Marr KA, Vehreschild MJGT et al. Improvement in the outcome of invasive fusariosis in the last decade. Clin Microbiol Infect 2014; 20: 580–5. Lortholary O, Gangneux JP, Sitbon K et al. Epidemiological trends in invasive aspergillosis in France: the SAIF network (2005–2007). Clin Microbiol Infect 2011; 17: 1882–9. Candoni A, Caira M, Cesaro S et al. Combination therapy: multicentre surveillance study on feasibility, safety and efficacy of antifungal combination therapy for proven or probable invasive fungal diseases in haematological patients: the SEIFEM real-life combo study. Mycoses 2014; 57: 342–50. doi:10.1111/myc.12161.
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Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Original article
Epidemiology and outcomes of patients with invasive mould infections: a retrospective observational study from a single centre (2005–2009) Lena Klingspor,1 Baharak Saaedi,1 Per Ljungman2 and Attila Szakos3 1
Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden, 2Division of Haematology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden and 3Division of Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Summary
Invasive mould infection (IMI) is an important cause of morbidity and mortality in immunocompromised patients. However, Swedish epidemiology data are lacking. The aim of this study was to investigate the epidemiology and outcome of IMI. Cases of proven/probable IMI at Karolinska University Hospital, Stockholm, from 2005 to 2009, were included. A total of 100 patients with 104 episodes of IMI were enrolled. Identified isolates included 101 mould isolates. The majority of the isolates were Aspergillus spp. (74.3%), followed by Mucorales spp. (13.9%), Fusarium spp. (4.9%) and other mould spp. (6.9%). In 13% of the episodes, more than one mould caused the IMI. The lung was most often affected (88.5%). The most frequent underlying disease was haematological malignancies (70%). Following diagnosis, 83.7% initially received antifungal monotherapy, 9.6% received combination therapy and 6.7% no treatment. The overall 90-day and 1-year overall survival was 49% and 46% respectively. Survival at 90 days post diagnosis was 71.4% in the solid tumour cohort, 62.5% in patients with solid organ transplants, 43.5% in haematological malignancy (HMs) and 37% in those undergoing allogeneic haematopoietic stem cell transplantation (HSCT). Overall survival was poor in the studied cohort, but is variable among different host categories, with particular opportunities for improvement in patients with underlying HMs and allogeneic HSCT.
Key words: Invasive mould infection, epidemiology, outcome, aspergillosis, mucormycosis, fusariosis.
Introduction Invasive mould infections (IMIs) in immunocompromised patients are associated with high morbidity and mortality.1–4 The mortality rate from invasive aspergillosis (IA) is high, ranging from 50% to 100%, in Correspondence: L. Klingspor, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, F 72, Huddinge, SE-141 86 Stockholm, Sweden. Tel.: +46 8 58 58 78 39; +46 70 484 19 39. Fax: +46 8 58 58 11 25. E-mail: [email protected] Submitted for publication 9 April 2015 Revised 26 May 2015 Accepted for publication 26 May 2015
doi:10.1111/myc.12344
almost all groups of immune-compromised patients.1,3 Other moulds such as mucormycosis have emerged as the third most common cause of invasive fungal infection mycosis in order of importance after candidiasis and aspergillosis in patients with haematological and allogeneic haematopoietic stem cell transplantation (HSCT).2 Mucormycosis is also a threat in patients with diabetes mellitus (DM). For mucormycosis, the case fatality ranges from 35% among individuals with no underlying condition to 44% among patients with diabetes and 66% in patients with malignancies.2 Risk factors for developing IA and other moulds such as mucormycosis have been studied, but despite its incidence and severity there remains a lack of information on the contemporary epidemiology of these infections.
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 470–477
Epidemiology and outcome of mould infections
Epidemiological data concerning IMIs from Sweden are lacking. The aim of this retrospective study was to evaluate the epidemiology and spectrum of IMI, infection characteristics and outcomes of IMIs in patients with varied underlying conditions, such as haematological patients, allogeneic HSCT recipients, solid organ transplantation (SOT) recipients, patients with immune-deficiencies and critically ill patients in both adult and paediatric medical and surgical intensive care units at Karolinska University Hospital.
Patients and methods This study was approved by the Ethics Committee at Karolinska Institutet. This is a retrospective, registry study that collects microbiology, histopathology and clinical data and outcome in patients with proven and probable IMIs between 1 January 2005 and 31 December 2009, at Karolinska University Hospital, Stockholm, Sweden. The hospital is a regional centre for allogeneic HSCT, liver and kidney transplantation. Information collected included baseline demographical characteristics, underlying disease, type of transplant, time to diagnosis of IMI, infecting mould species, site of infection, antifungal therapies and outcome. Outcomes were recorded at 90 days and 1 year after IMI diagnosis, or until death or loss to follow-up. Microbiological data concerning direct microscopy, cultures, Aspergillus galactomannan antigen results and histological specimens were documented. Information was collected regarding the first systemic antifungal therapies administered following diagnosis, but not with specific doses and durations. Definitions
Invasive mould infections were diagnosed according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria.5 Patients were only included if they met the definition of proven or probable IA or IMI. Proven disease required mycological documentation from a normally sterile site, and probable disease required a host factor, clinical features and mycological evidence, which for IA could include a positive galactomannan assay.5 As no specific definitions or classic radiographic findings have been established in non-cancer patients (e.g. SOT), microbiological evidence of a mould
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 470–477
without an alternative aetiology was considered as probable IMI in the setting of dense consolidations and/or infiltrates on Chest CT.6,7 Aspergillus antigenaemia in patients with relevant clinical signs and symptoms was determined by using the serum galactomannan ELISA assay (Bio-Rad, Hercules, CA, USA), with IA defined according to the revised diagnostic criteria.5 Galactomannan cut-off was determined (optical density index of 0.5 for serum). Causative Aspergillus and other mould spp. were documented when available. The date of diagnosis was considered to be the date when the diagnosis of IMI was established by the clinical team at Karolinska University Hospital or, if undiagnosed, at autopsy. Primary antifungal therapy was defined as the first line antifungal treatment administered following diagnosis. Statistical analyses
Descriptive analysis was used for baseline characteristics and subgroup analysis. Descriptive survival analysis was performed based on the whole patient group and for subpopulations. The survival distribution function was estimated using the Kaplan–Meier method. Statistical analyses were performed using SAS version 9.2/Enterprise Guide 4.2 (SAS Institute Inc., Carey, NC, USA).
Results Baseline patient characteristics
Altogether, 100 patients with 104 episodes of IMI, diagnosed with proven or probable IMI, were included during a 60-month period from 1 January 2005, to 31 December 2009. The mean age was 49.7 years (range = 2 months–85 years), and the majority of the patients were males (60%). The most frequent underlying disease was haematological malignancy (HM; n = 70), with acute myelogenous leukaemia (AML) (n = 33), acute lymphatic leukaemia (ALL) (n = 10), non-Hodgkin’s lymphoma (n = 10) and chronic lymphocytic leukaemia (n = 7) being the most common HMs. Eight patients (8%) had undergone SOT and 27 had received an allogeneic HSCT from human leucocyte antigen-matched or unrelated donors. Of these 27 HSCT patients, 24 had underlying HMs and three patients had other underlying diseases, chronic granulomatous disease, kidney cancer and bile duct cancer (Table 1).
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Table 1 Patient baseline characteristics (n = 100). Patient characteristics Age, mean years (range) n (%) 18 and 65 Sex Male Underlying disease1 Haematological malignancy Solid organ transplant Allogeneic haematopoietic stem cell transplant Autologous haemapoietic stem cell transplant Solid tumour HIV/AIDS Inherited immunodeficiency disorder Other Type of haematological malignancy1 Acute myelogenous leukaemia Non-Hodgkin’s lymphoma Multiple myeloma Acute lymphocytic leukaemia Myelodysplastic syndrome Chronic lymphocytic leukaemia Other Type of haematopoietic stem cell transplant Allogeneic: HLA-matched related Allogeneic: HLA-matched unrelated Allogeneic: HLA mismatched Cord blood Allogeneic: data not available Autologous Type of solid organ transplantant1 Lung Kidney Liver Heart ECMO treatment1
Frequency of IMI No. of patients
11 66 24 60 70 8 32 1 10 1 3 8 33 10 2 10 4 7 4 12 10 2 2 1 1 1 2 3 2 42
HLA, human leucocyte antigen; ECMO, extra corporal membrane oxygenation; ALL, acute lymphocytic leukaemia. 1 Not mutually exclusive; patients could have >1 characteristics within a category. 2
Three children with ALL and mucormycoses and one adult with SLE and aspergillosis.
Of the 27 allogeneic HSCT patients, 20 developed an IMI within 1 year after transplantation. The median day post-HSCT was 158 days (mean = 138 days; range = 3–308 days). However, the median day postHSCT when IA was diagnosed was 205 days. Seven patients developed an IMI after more than 1 year. All these seven patients had a complicated medical history after transplantation such as chronic graft-versus-host disease, bacterial and viral infections, and relapse of the underlying diseases.
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In total, 354 allogeneic HSCT were performed during this 60-month period and 27 (7.6%) patients developed IMIs. In total, 275 liver transplants and 372 kidney transplants were performed and 3 (1.1%) and 2 (0.5%) patients developed IA within 1 year after transplantation respectively. The frequency could not be calculated for the other patient cohorts due to lack of information regarding the denominator. Invasive mould epidemiology
The 100 patients with IMI included 30 patients with proven and 70 patients (with 74 episodes) with probable IMI. In total, 75 patients had 79 episodes of IA. In addition, nine patients had mucormucosis (five proven and four probable), three fusariosis (two proven and one probable) and one each had (proven) Scedosporioum apiospermum, Acremonium and Alternaria infections respectively. Ten patients (seven proven and three probable) had mixed IMI, six with IA in combination with invasive mucormycoses, two with IA in combination with fusariosis, one with IA and S. apiospermum and Scyalidium dimediatum and one with IA and Fusarium solani, Saksenia vasiformis, S. apiospermum and S. dimediatum. For mould distribution, see Table 2. In the patients with HMs, IA was diagnosed in 39/50 (78%) episodes. In 8/50 (16%) episodes, a non-Aspergillus mould was diagnosed, and in 3/50 (6%) patients a mixed infection (Aspergillus and another mould) was recorded. In the allogeneic HSCT group (n = 27), IA was diagnosed in 81.5% of the patients. In four (18.5%) patients, a non-Aspergillus mould was isolated: one Lichteimia (Absidia) corymbifera, one Acremonium spp. infection, in two patients Aspergillus fumigatus was isolated together with Fusarium spp. and in one patient A. fumigatus was isolated with Rhizopus spp. The eight patients with SOT all had IA. Mould diagnostics
A total of 101 mould isolates from 81 patients were identified by culture (Table 3) with additional 17 patients with probable IA diagnosed by galactomannan assays and two patients with IMI diagnosed with mucormycosis by direct microscopy. Furthermore, histopathology of biopsies from 28 patients and cytology in one patient showed mould hyphae.
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Table 2 Mould spp. and positive Aspergillus antigen tests distribution by patient (n = 100; 104 episodes). Patient category Haematological malignancy AML + ALL Other Allogeneic HSCT Solid organ transplant Solid tumour HIV/AIDS Inherited immuno-deficiency Other Total Age group (years) 65
A. fum
10 7 16 7 4 1 2 2
4 39 5
A. spp.
5 4 41 21 1 0 11 0
0 12 5
Asp ag
Mucor sp.
Fusarium
Mixed spp.
Other
Total episodes
8 5 2 0 0 0 2 0
4 0 1 0 1 0 0 3
2 1 0 0 0 0 0 0
3 0 4 0 1 0 0 2
1 0 1 0 0 0 0 1
33 17 27 8 7 1 4 8 104 (100 patients)
2 6 9
4 2 3
0 2 1
1 2 0
0 2 1
11 65 24
Asp ag, Aspergillus antigen; ALL, acute lymphocytic leukaemia; AML, acute myelogenous leukaemia; and HSCT, haematopoietic stem cell transplant. 1 Three patients had two Aspergillus species isolated (A. fumigatus and A. flavus, A. fumigatus and A. niger, and A. fumigatus and A. nidulans respectively).
Table 3 From in total 100 patients (with 104 episodes of IMI) 101 mould spp. were isolated in 81 patients and 19 unspecified patients (includes 17 patients with probable IA diagnosed by galactomannan assays and two patients with IMI diagnosed with mucormycosis by microscopy).
Species A. fumigatus A. flavus A. niger A. glaucus A. nidulans Aspergillus species Mucor racemosus Lichthemia (Absidia) corymbifera Rhizopus oryzae Rhizopus microspores Saksenia vasiformis Rhizomucor miehei Rhizomucor pusillus Rhizopus species Mucor species Fusarium species Scedosporion apiospermum Scytalidium dimediatum Alternaria sp. Acremonium Unspecified2 Total
Number of isolates1
% of identified isolates
56 9 3 1 1 5 1 3
55.5 8.9 3.0 0.9 0.9 4.5 0.9 3.0
2 2 1 1 1 2 1 5 3 2 1 1 19 120
2.0 2.0 0.9 0.9 0.9 2.0 0.9 4.9 3.0 2.0 0.9 0.9
IMI, invasive mould infection; IA, invasive aspergillosis. 1
Patients could have more than one species.
2
Includes 17 patients with probable IA diagnosed by galactomannan assays and two mucormycosis diagnosed by microscopy.
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Cultures
Of the 101 mould isolates identified, the majority were Aspergillus spp. (74.3%). The majority of the Aspergillus isolates were A. fumigatus (55.5%) followed by A. flavus (8.9%). In three patients with probable IA, two Aspergillus species were isolated. Mucorales spp. comprised 13.9% of the isolates followed by Fusarium spp. (4.9%) and other mould spp. (6.9%) (Table 3). Clinical presentation and outcome within 90 days after diagnosis of IMI
Aspergillus In the 75 patients with 79 episodes of IA, the lung was the most frequent site of infection, with 70 episodes (88.6%) in 67 patients having IA lung infection only. Five patients had evidence of infection in more than one anatomic site, but all five of those also included infection of the lungs. Exclusive infection to a single site other than the lungs included the tracheobronchial tree (n = 1), sinuses (n = 1), pleura (n = 1) and eye (n=). Of the 75 patients, 36 (48%) died within 90 days from diagnosis. Mucormycosis Nine patients were diagnosed with mucormycosis: four with abdominal infection (the underlying diseases were AML, ALL, solid tumour and DM type 1 plus
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abdominal surgery respectively), two with pulmonary infection, two with disseminated infection (including pulmonary) and one with mastoiditis. Six of the nine patients with mucormycoses died within 90 days (66.7%). Fusariosis Three patients had invasive fusariosis: one pulmonary, one infection in the spleen and one disseminated fusariosis (with positive blood culture). All patients with fusariosis died within 90 days. Multiple mould infection
Thirteen patients had more than one mould species causing proven IMI in seven patients and probable in six patients. Three patients had two Aspergillus species isolated (A. fumigatus and A. flavus, A. fumigatus and A. niger and A. fumigatus and A. nidulans respectively), and 10 patients had mixed infections: IA and fusariosis (n = 2), IA and mucormycosis (n = 6) and two patients had IA in combination with several other moulds (Table 2). Mixed infections Disseminated: Two patients after allogeneic HSCT had proven IA and fusariosis and one AML patient had IA and mucormycoses. Pulmonary: One AML patient had pulmonary aspergillosis and pleural mucormycosis. Two patients had pulmonary aspergillosis and mucormycosis: one after allogeneic HSCT and one cancer patient in extra corporal membrane oxygenation (ECMO) treatment respectively. Miscellaneous: One patient after allogeneic HSCT developed pulmonary IA and sinusitis with mucormycosis. One patient with AML had aspergillus and mucormycosis sinusitis.
Two patients had proven deep wound infections (tsunami catastrophe), one with A. flavus, F. solani, S. vasiformis, S. apiospermum and S. dimediatum infection and one with A. fumigatus, S. apiospermum and S. dimediatum infection. Both survived. Seven (87.5%) of the eight patients who were immunocompromised died within 90 days. Other mould infections One patient after allogeneic HSCT had probable Acremonium sinusitis and one patient with proven S. apiospermum osteomyelitis (after trauma) survived, whereas one patient with chronic lymphocytic leukaemia and proven joint infection with Alternaria sp. died. Antifungal therapy
A total of 93/100 patients with 104 episodes of IMI received antifungal treatment therapy in 97 of the episodes and 7 (7%) patients received no treatment (Table 4). Mortality
Survival within 90 days and 1 year after IMI diagnosis Overall 90-day post diagnosis Kaplain–Meier survival among the 99 patients (one patient was diagnosed at autopsy) with IMI was 49.5% (n = 49; Fig. 1). Survival in the patients with IA was 52%, and in the patients with other moulds, survival was 40%. In the four major subpopulations of patients, overall Kaplan–Meier survival at 90 days post diagnosis was greater in the solid tumour cohort (71.4%) compared with survival in patients with SOT (62.5%), HM (43.5%), or those undergoing allogeneic HSCT (37%). One-year survival in patients with IA was 48% and 40% in patients with other IMIs.
Table 4 Initial antifungal therapy.
Aspergillus spp. Mucor spp. Fusarium spp. Aspergillus + Fusarium spp. Aspergillus + Mucor spp. Aspergillus + multiple mould spp. Acremonium sp. Alternaria sp. Scedosporion apiospermum Total
amb
vz
pz
iz
12 5
44
2 1
2
2 2
caspo 8 1 1
vz + caspo
vz + amb
4 1
1 1
pz + amb
pz + caspo
2
Unknown
6 1
1 1
NT
1
1 1
1 1 22
1 47
4
2
10
5
4
1
1
7
1
Episodes 79 9 3 2 6 2 1 1 1 104
Amb, liposomal amphotericin B (ambisome); vz, voriconazole; pz, posaconazole; iz, itraconazole; caspo, caspofungin; NT, no treatment.
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Figure 1 Overall survival for 99 patients
with invasive mould infection.
Discussion This is the largest retrospective Swedish analysis of contemporary IMI reported to date. Invasive aspergillosis was the most common cause of infection followed by mucormycosis. Infections with more than one mould were found in as much as 13% of the patients, and most commonly IA together with mucormycosis. Male gender was most common as shown in other studies.1,4,7 As seen in other large studies,1,3,4 the most common underlying disease in patients with IA or other IMI was haematological malignancy (70%), particularly AML, non-Hodgkin’s lymphoma and ALL, and the lung was the most often affected organ (88.5%). The median day post-HSCT when IA was diagnosed was 205 days. This is in contrast to two other studies, where the median day post-SCT when IA was diagnosed was 97 days,8 similar to the median of 99 days found in the TRANSNET surveillance report of IA from 23 US transplant centres.9 Aspergillus was the only cause of mould infection in our eight patients who had received a SOT. In patients with HMs, IA alone was diagnosed in 39 episodes (78%) and in additional 6% of the episodes, Aspergillus together with another mould was isolated. Mucormycosis was diagnosed in our patients with HMs and after HSCT and was associated with high mortality. However, in 6% of the cases, co-infection with IA and mucormycosis was diagnosed. Co-infection with mucormycosis and aspergillosis is rare but has been reported in a few patients including AML.10 Extra corporal membrane oxygenation is a therapy which could be complicated with severe fungal nosocomial infections such as mucormycosis, but has so
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 470–477
far been described mainly in neonates.11,12 In this study, mucormycosis (two disseminated, one abdominal) was diagnosed in three children who all had ALL as the underlying disease and received ECMO therapy. All three died underscoring the severity of the disease. Gastrointestinal mucormycosis remains uncommon and have been reported mainly in premature neonates and malnourished children and patients with HMs, DM and corticosteroid use.2,13–15 The mortality rate is as high as 85%. Three of our four cases with gastrointestinal mucormycoses with ALL, AML, DM and abdominal surgery, and colon cancer, respectively, died. The infections can be transmitted by the inhalation of spores but also by direct inoculation on disrupted skin or mucosa.2 The latter was the case in the two patients with deep wound infections contracted in the tsunami catastrophe. Consistent with the observations of the literature concerning fusariosis, most patients in this survey had haematological malignancy or an HSCT as the underlying condition. Fusarium infection in such patients results in a poor prognosis, with death rates of up to 75%.4,16–19 In this study, the crude mortality was as high as 100%, including also the patients with mixed IA and fusariosis. The most common species identified in our survey was A. fumigatus (55.5%) followed by A. flavus (8.9%). If we look at our cases with IA only, A. fumigatus was isolated in 73.7% of the cases. This is in agreement with several other studies reporting a similar distribution.3,9,10,20 Most of the patients in this study were receiving appropriate therapy for IA that leaves six patients (6%) with no treatment at all. One case was diagnosed first at autopsy, and in three cases the diagnoses were
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made late, 1–2 days before death, and in one case the reason for not receiving treatment was not captured. Over half of the patients received monotherapy (86%), either with voriconazole or a liposomal amphotericin B (15.2%), followed by echinocandin (10.1%), itraconazole or posaconazole (2.5%). This is in agreement with both a French survey12 and a US study,3 in which 80% of patients received monotherapy, most commonly with voriconazole. However, in both these studies approximately 20% received combination antifungal therapy, most commonly with voriconazole and caspofungin. This is different compared with our study where only 6.3% received primary combination therapy, which is lower than reported in other studies.3 However, monotherapy is the recommended primary treatment for IA. Most patients were receiving liposomal amphotericin B treatment therapy for mucormycosis (Table 4). The overall 90-day survival in the 100 patients in our study of IMI was only 49.5% and the 1-year survival was 46.5%. In patients with IA only, 90-day survival was 52% compared to the PATH alliance registry study of IA where the 12-week overall survival was 64.4%. In our study, 1-year survival in IA was only 48%. In this study, 90-day survival rate ranged from 71.4% in solid tumour, 62.5% in SOT, 43.5% in HM to only 37% in allogeneic HSCT, leading to the worst survival of the major underlying conditions. Overall mortality after the diagnosis of IA and other mould infections has been historically high: one study reported that 78% of patients who developed IA after allogeneic HSCT died by 12 weeks or at the end of therapy.14 The TRANSNET study reported 12-week all-cause mortality rates of 57.5%, and a 1-year mortality of 74.6% among HSCT recipients with IA.15 This study has several limitations due to the lack of information on the total number of patients at risk (except for allogeneic HSCT (7.6%), liver (1.1%) and kidney (0.5%) transplant patients) in each category needed to calculate the incidence of infection within each patient subgroup. Our cases were diagnosed between 2005 and 2009. Galactomannan assay from broncho-alveolar lavage (BAL) was not performed at our hospital for diagnosis of IA during this period of time. However, additional IA and other mould strategies have developed since then – including BAL galactomannan, Aspergillus-PCR tests, sequencing and B-Dglucan test and the increased use of posaconazole and combination antifungal therapy. A recent study from
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Italy indicated that combination treatment were both well tolerated and seemed effective in haematological patients with invasive fungal diseases, but well-controlled studies are still required to determine the most efficacious antifungal combination therapies for specific fungal infections.21 In this analysis, A. fumigatus remains the most common causative species (54.2%) followed by other Aspergillus spp. (18.7%), although other mould species such as mucormycosis (14.4%), fusariosis (5.2%) and other moulds (7.2%) cause disease with variable rates in each host category. Outcomes as overall survival were poor, but are variable in different host categories, with particular opportunities for improvement in patients with underlying haematological malignancies and allogeneic HSCT. Posaconazole prophylaxis is nowadays given to our patients receiving allogeneic HSCT. This study provides significant information on IMI from our centre. The findings in our study emphasise the importance of establishing continual epidemiology surveillance programmes, both local and national, to follow the epidemiology of IMIs in different patient populations, and also to develop new sensitive and specific diagnostic tools for early diagnoses and better therapeutic interventions to improve the outcome of IMI. For the future we are planning to do an epidemiological follow-up study at Karolinska University Hospital from 2010 to 2014.
Acknowledgments We thank Yen Ngo (Stockholm, Sweden) for statistical analysis.
Conflicts of interest and source of funding Lena Klingspor has been a consultant to Astellas Pharma, Gilead Sciences, Merck & Co., and ScheringPlough. She has received research grants from Gilead and Schering-Plough/Merck & Co. Per Ljungman has research grants from Merck & Co., Pfizer AB and Gilead Sciences. The other authors have nothing to declare. This study was supported by an unrestricted grant from Merck, Sharp & Dohme, USA.
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