mycoses Prospective antifungal therapy (PATH) alliance â : focus on mucormycosis Summary Introduction

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1 mycoses Diagnosis,Therapy and Prophylaxis of Fungal Diseases Original article Prospective antifungal therapy (PATH) alliance â : focus on mucormycosis Dimitrios P. Kontoyiannis, 1 Nkechi Azie, 2 Billy Franks 2 and David L. Horn 3 1 Department of Infectious Diseases, University of Texas MD Anderson Cancer Center, Houston, TX, USA, 2 Astellas Scientific and Medical Affairs, Northbrook, IL, USA and 3 David Horn LLC, Doylestown, PA, USA Summary Mucormycosis is increasingly encountered in immunosuppressed patients, such as those with haematological malignancies or stem cell transplantation. We present a descriptive analysis of 121 cases of mucormycosis from the Prospective Antifungal Therapy Alliance â registry (July 2004 to December 2008). Patients with proven or probable mucormycosis were enrolled and followed prospectively for 12 weeks. The most common underlying disease and site of infection were haematologic malignancy (61.2%) and lungs (46.3%) respectively. Rhizopus (n = 63; 52.1%) was the most commonly isolated species, followed by Mucor (n = 28; 23.1%), other or unknown (n = 17; 14.0%), Rhizomucor (n = 9; 7.4%) and Lichtheimia (n = 4; 3.3%). The 12-week Kaplan Meier survival probability for all patients was 0.41; however, there was large variation in survival probabilities between species, with highest survival probability observed for Lichtheimia (0.5), followed by Rhizopus (0.47), Mucor (0.40), unknown Mucormycetes species (0.40), other Mucormycetes species (0.17) and Rhizomucor (0.15). Prior use of voriconazole decreased 12-week survival probability. Survival probability was higher in patients receiving amphotericin B by Day 3 (0.72) vs. those who started amphotericin B therapy after Day 3 (0.33). The low survival probability observed underscores the importance of further studies of mucormycosis. Optimal treatment selection and timing may improve prognosis. Key words: Epidemiology, mucormycosis, PATH alliance â, survival, treatment. Introduction To date, mucormycosis has been mainly a disease of patients with uncontrolled diabetes mellitus, iron overload and trauma. 1 However, in recent years it has been increasingly encountered in patients with chronic and severe immunosuppressive conditions, especially those with haematologic malignancy and/or stem cell Correspondence: D. P. Kontoyiannis, Department of Infectious Diseases, Infection Control and Employee Health, Unit 402, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel.: Fax: dkontoyi@mdanderson.org Submitted for publication 10 June 2013 Revised 2 September 2013 Accepted for publication 24 September 2013 transplantation. 2 Many of these cases have been attributed to prior use of antifungals that do not have activity against Mucorales, in particular voriconazole and the echinocandins. 3 Prospective surveillance networks can provide important information on uncommon infections such as mucormycosis; however, there is a paucity of such databases 2,4 as most studies are single institution retrospective analyses. 5 The prospective antifungal therapy (PATH) alliance â registry was created to undertake prospective surveillance of invasive fungal infections (IFIs) in patients hospitalised in tertiary care medical centres in North America. 6 Its aim was to collect detailed descriptions of the diagnosis, fungal species, underlying conditions, treatment regimens and outcomes of IFIs. In this analysis, we present results from the PATH Alliance â registry on the epidemiology, treatment and outcomes of patients with mucormycosis. doi: /myc.12149

2 Mucormycosis in PATH registry Patients and methods The PATH Alliance â registry collected data on patients with IFIs from 1 July 2004 to 31 December Patient enrolment and data collection were approved by the individual institutional review boards of the participating centres. Detailed description of data collection methodology has been published previously. 6 Patients those who met the criteria for proven or probable mucormycosis, as per the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group, 7 were enrolled in the registry and followed prospectively for 12 weeks, until they died or were lost to follow-up. The day a Mucormycetes infection was diagnosed microbiologically and/or histopathologically was termed as Day 1. Information was collected on patient baseline demographic characteristics, underlying disease and its status, use of corticosteroids and degree of neutropenia at baseline, surgical intervention antifungal therapies and survival rates. Information on the site of infection was collected via case report form as anatomic site(s) of infection. A separate field was used to capture site of diagnostic sample. The anatomic sites were collected as: blood, catheter site, central nervous system, gastrointestinal, genitourinary, heart, lung, sinus, skeleton, skin/soft tissue and other. Data collection was observational and did not involve clinical intervention. Due to the large heterogeneity of the mucormycosis population reported into the PATH Alliance registry, basic descriptive statistics have been provided and statistical inference has been avoided. Descriptive analyses were used for baseline characteristics and subgroup analyses. Descriptive survival analyses were performed based on the whole patient group and fungal species. The survival distribution was estimated using the Kaplan Meier method. Statistical analyses were performed using SAS version 9.2/Enterprise Guide 4.2 (SAS Institute, Carey, NC, USA). Results Baseline characteristics In total, 121 patients with proven or probable mucormycosis were identified within the PATH Alliance â database (Table 1). Of the 25 centres forming the PATH Alliance, 19 centres reported cases of mucormycosis (median 6, range 1 13, mean 6.4, standard deviation 3.82). Participating centres included specialty care providers, such as solid organ transplantation, stem cell transplantation, general oncology and those caring for adult and paediatric patients. 6 The distribution of cases broken down by region was South (n = 32), West (n = 29), Midwest (n = 37), Northeast (n = 20) and Canada (n = 3). 8 The mean age (standard deviation) was 49.1 (17.7) years; the majority of patients were male (n = 88; 72.7%) and white (n = 101; 83.5%). The most common risk factor for mucormycosis was haematological malignancy (n = 74; 61.2%), followed by diabetes mellitus (n = 28; 23.1%). Among patients with a haematological malignancy, 32 (43.2%) patients had received a haematopoietic stem cell transplant, 45 (60.8%) were neutropenic at baseline and 24 (32.4%) had diabetes mellitus. Almost half of the patients (n = 50; 41.3%) had a concomitant bacterial infection within 7 days prior to diagnosis. In addition, 50 (41.3%), 39 (32.2%), 36 (29.8%) and 30 (24.8%) patients had received treatment with voriconazole, lipid-based amphotericin B, fluconazole and echinocandins within 30 days prior to diagnosis of mucormycosis respectively. In particular, 40 (54.1%) patients with a haematological malignancy had received voriconazole in the 30 days prior to diagnosis of mucormycosis. Mucormycetes epidemiology and sites of infection Rhizopus (n = 63; 52.1%) was the most commonly isolated species, followed by Mucor (n = 28; 23.1%), Rhizomucor (n = 9; 7.4%) and Lichtheimia (n = 4; 3.3%) (Table 1). Seventeen patients (14.0%) had other or unknown species. Of the 17 cases of Other/Unknown, details were provided for six cases. There were four cases of Cunninghamella, and one case each of Cokeromyces and Syncephalastrum. Most patients with proven mucormycosis (n = 97; 80.2%) were diagnosed using histopathology or a combination of histopathology, culture and/or computed tomography scans (n = 72; 74.2%). Of the 121 patients with a reported episode of mucormycosis, 81 (66.9%) had a supporting histopathology, 106 (87.6%) had a supporting culture and no episodes had a supporting molecular diagnosis. Based on the anatomical site of sample, cultures were further defined as sterile (n = 2; 1.7%), likely sterile (n = 32; 26.4%), not likely sterile (n = 2; 1.7%) and not sterile (n = 70; 57.9%). Data are summarised according to most sterile culture reported. Although individual subgroups were small in size, underlying conditions were similar for different Mucorales (Table 1). The most common infection sites were the lungs (Table 2; n = 56; 46.3%), sinuses (n = 35; 241

3 D. P. Kontoyiannis et al. Table 1 Underlying conditions at baseline. Parameter All Rhizopus Mucor Rhizomucor Lichtheimia Other/unknown 1 N (%) n = 121 n = 63 (52.1) n = 28 (23.1) n = 9 (7.4) n = 4 (3.3) n = 17 (14.0) Haematological malignancy, n/n (%) 74/121 (61.2) 38/63 (60.3) 16/28 (57.1) 7/9 (77.8) 3/4 (75.0) 10/17 (58.8) Status: remission 17/74 (23.0) 8/38 (21.1) 3/16 (18.8) 1/7 (14.3) 2/3 (66.7) 3/10 (30.0) Status: non-remission 56/74 (75.7) 29/38 (76.3) 13/16 (81.3) 6/7 (85.7) 1/3 (33.3) 7/10 (70.0) Status: missing 1/74 (1.4) 1/38 (2.6) HSCT 32/74 (43.2) 17/38 (44.7) 5/16 (31.3) 2/7 (28.6) 2/3 (66.7) 6/10 (60.0) GVHD 10/74 (13.5) 6/38 (15.8) 1/7 (14.3) 1/3 (33.3) 2/10 (20.0) Diabetes mellitus, n/n (%) 24/74 (32.4) 16/38 (42.1) 4/16 (25.0) 1/7 (14.3) 1/3 (33.3) 2/10 (20.0) Corticosteroids, n/n (%) 54/74 (73.0) 30/38 (78.9) 11/16 (68.8) 7/7 (100) 1/3 (33.3) 5/10 (50.0) None 0/54 (0.0) Multiple 24/54 (44.4) 15/30 (50.0) 4/11 (36.4) 4/7 (57.1) 1/5 (20.0) Prednisone 11/54 (20.4) 7/30 (23.3) 2/11 (18.2) 1/7 (14.3) 1/5 (20.0) Methylprednisolone 8/54 (14.8) 4/30 (13.3) 3/11 (27.3) 1/5 (20.0) Dexamethasone 7/54 (13.0) 3/30 (10.0) 2/11 (18.2) 1/1 (100) 1/5 (20.0) Other 1/54 (1.9) 1/7 (14.3) Hydrocortisone 3/54 (5.6) 1/30 (3.3) 1/7 (14.3) 1/5 (20.0) Total corticosteroid dose, mean (SD), mg (1716) 1611 (1926) 1333 (1735) 761 (1000) 427 (NA) 1269 (1401) Neutropenia, n/n (%) 45/74 (60.8) 21/38 (55.3) 13/16 (81.3) 5/7 (71.4) 1/3 (33.3) 5/10 (50.0) Mean (SD) days, < (9.3) 9.8 (4.4) 20.2 (10.5) 17.6 (9.2) 9.0 (NA) 10.0 (12.3) Mean(SD) days, < (9.5) 12.5 (7.9) 21.0 (10.0) 18.6 (9.3) 18.0 (NA) 16.4 (11.4) Mean (SD) days, < (9.9) 12.4 (8.3) 20.3 (11.0) 19.0 (9.5) 26.0 (NA) 17.0 (10.5) Diabetes mellitus, n/n (%) 28/121 (23.1) 16/63 (25.4) 8/28 (28.6) 4/17 (23.5) Type I 5/28 (17.9) 3/16 (18.8) 1/8 (12.5) 1/4 (25.0) Type II 9/28 (32.1) 5/16 (31.3) 1/8 (12.5) 3/4 (75.0) Solid organ transplantation, n/n (%) 6/121 (5.0) 3/63 (4.8) 2/28 (7.1) 1/17 (5.9) Other, n/n (%) 3 13/121 (10.7) 6/63 (9.5) 2/28 (7.1) 2/9 (22.2) 1/4 (25.0) 2/17 (11.8) No. of main underlying conditions, n/n (%) 1 86/121 (71.1) 40/63 (63.5) 22/28 (78.6) 5/9 (55.6) 4/4 (100) 15/17 (88.2) =2 30/121 (24.8) 18/63 (28.6) 6/28 (21.4) 4/9 (44.4) 2/17 (11.8) Concomitant infection, n/n (%) Cytomegalovirus 7/121 (5.8) 2/63 (3.2) 1/28 (3.6) 2/9 (22.2) 2/17 (11.8) Bacterial infection 50/121 (41.3) 24/63 (38.1) 14/28 (50.0) 6/9 (66.7) 1/4 (25.0) 5/17 (29.4) Antifungals, 30 days prior, n/n (%) Echinocandins 30/121 (24.8) 16/63 (25.4) 6/28 (21.4) 3/9 (33.3) 5/17 (29.4) Amphotericin B deoxycholate 5/121 (4.1) 3/63 (4.8) 2/28 (7.1) Amphotericin B lipids 39/121 (32.2) 22/63 (34.9) 7/28 (25.0) 5/9 (55.6) 1/4 (25.0) 4/17 (23.5) Fluconazole 36/121 (29.8) 20/63 (31.7) 8/28 (28.6) 2/9 (22.2) 2/4 (50.0) 4/17 (23.5) 242

4 Mucormycosis in PATH registry Table 1 (Continued) Parameter All Rhizopus Mucor Rhizomucor Lichtheimia Other/unknown 1 Voriconazole 50/121 (41.3) 22/63 (34.9) 13/28 (46.4) 6/9 (66.7) 2/4 (50.0) 7/17 (41.2) Posaconazole 11/121 (9.1) 6/63 (9.5) 3/28 (10.7) 2/17 (11.8) Itraconazole 5/121 (4.1) 1/63 (1.6) 2/28 (7.1) 1/9 (11.1) 1/17 (5.9) GVHD, graft-vs-host disease; HSCT, haematopoietic stem cell transplant; IFI, invasive fungal infection; NA, not applicable; SD, standard deviation. 1 Other species include Cunninghamella, Syncephalastrum and Cokeromyces species. 2 Total prednisone equivalent dose of all corticosteroids administered in 30 days prior to diagnosis of IFI (n = 47). 3 Neonatal intensive care unit (n = 1), general medicine (n = 3), HIV (n = 1), HIV/surgery (non-transplant)/general medicine (n = 2), surgery (non-transplant; n=2), solid tumour/general medicine (n = 2) and surgery (non-transplant)/general medicine (2). 28.9%) and skin/soft tissue (n = 26; 21.5%). Of the 121 patients, 25 (20.7%) had evidence of disseminated infection as multiple anatomic sites were reported. Of the 72 cases of Rhizopus and Rhizomucor, four patients were reported to have sinus and central nervous system involvement suggesting a rhinocerebral infection. A higher percentage of patients with haematologic malignancy had lung involvement (51.4%) vs. those with diabetes mellitus (46.4%). Treatment and patient outcomes Ninety-one (75.2%) patients received therapy with antifungal agents (including those not recommended for mucormycosis treatment) on Day 3 postdiagnosis (Table 3). Of these, 55 (60.4%) received monotherapy and 36 (39.6%) received combination therapy. Thirty (24.8%) patients without a treatment record included 13 patients with missing data, three who had not received treatment before Day 3, and 14 who had received treatment before Day 3 but none on Day 3 itself. Most patients who received monotherapy were treated with lipid-based amphotericin B (n = 39), followed by posaconazole (n = 7). Combination therapy with amphotericin B plus posaconazole (n = 16) and amphotericin B plus echinocandins (n = 8) was most commonly prescribed; however, treatment scenarios were heterogeneous and did not permit assessment of a relationship between type, duration or sequence of therapy and outcome in the whole group or subgroups of individual Mucorales. Surgery was performed in 51 (42.1%) patients; surgical procedures included debridement (n = 30), resection/excision (n = 17), drainage (n = 2) and other (n = 2). Debridement was performed for infections in sinus (n = 18, 81.8%), skin or soft tissue (n = 5, 27.8%), skeleton (n = 1, 50.0%) and multiple sites (n = 11, 44%). The 12-week Kaplan Meier survival probability for all patients was 0.41; however, there was a large variation in survival probabilities among different Mucorales, with highest survival probability observed for Lichtheimia (0.5), followed by Rhizopus (0.47), Mucor (0.40), unknown Mucormycetes species (0.40), other Mucormycetes species (0.17) and Rhizomucor (0.15). Assessment of survival based on prior voriconazole exposure revealed a 12-week survival probability of 0.3 vs. 0.5 for patients not prescribed voriconazole before diagnosis of mucormycosis. Survival probability in patients treated with amphotericin B (n = 59) was For patients treated with amphotericin B by Day 243

5 D. P. Kontoyiannis et al. Table 2 Underlying conditions according to site of infection. Parameter Blood Lung Sinus Skin/soft tissue Other Skeleton Abdominal Orbital Multiple N (%) n = 1 (0.8) n = 46 (38.0) n = 22 (18.2) n = 18 (14.9) n = 1 (0.8) n = 2 (1.7) n = 5 (4.1) n = 1 (0.8) n = 25 (20.7) Haematological malignancy, 32/46 (69.6) 15/22 (68.2) 10/18 (55.6) 2/5 (40.0) 1/1 (100) 14/25 (56.0) n/n (%) Status: remission 9/32 (28.1) 3/15 (20.0) 2/10 (20.0) 3/14 (21.4) Status: non-remission 23/32 (71.9) 12/15 (80.0) 7/10 (70.0) 2/2 (100) 1/1 (100) 11/14 (78.6) Status: missing 1/10 (10.0) HSCT 14/32 (43.8) 6/15 (40.0) 5/10 (50.0) 1/2 (50.0) 1/1 (100) 5/14 (35.7) GVHD 4/32 (12.5) 2/15 (13.3) 3/10 (30.0) 1/14 (7.1) Diabetes mellitus, n/n (%) 8/32 (25.0) 6/15 (40.0) 3/10 (30.0) 1/2 (50.0) 1/1 (100) 5/14 (35.7) Corticosteroids, n/n (%) 22/32 (68.8) 13/15 (86.7) 7/10 (70.0) 1/2 (50.0) 1/1 (100) 10/14 (71.4) Multiple 10/22 (45.5) 4/13 (30.8) 4/7 (57.1) 1/1 (100) 1/1 (100) 4/10 (40.0) Prednisone 4/22 (18.2) 3/13 (23.1) 1/7 (14.3) 3/10 (30.0) Methylprednisolone 3/22 (13.6) 2/13 (15.4) 1/7 (14.3) 2/10 (20.0) Dexamethasone 1/22 (4.5) 4/13 (30.8) 1/7 (14.3) 1/10 (10.0) Other 1/22 (4.5) Hydrocortisone 3/22 (13.6) Total corticosteroid dose, 1065 (905) 1045 (1180) 3947 (3750) 655 (NA) 1253 (NA) 1248 (1317) mean (SD), mg 1 Neutropenia, n/n (%) 21/32 (65.6) 8/15 (53.3) 9/10 (90.0) 1/2 (50.0) 6/14 (42.9) Mean (SD) days, < (9.3) 25.6 (7.4) 11.5 (3.5) 6.0 (NA) 16.0 (9.7) Mean(SD) days, < (9.0) 21.1 (11.5) 18.7 (7.0) 7.0 (NA) 14.5 (11.0) Mean (SD) days, < (8.7) 19.1 (12.2) 17.2 (10.6) 7.0 (NA) 16.2 (11.2) Diabetes mellitus, n/n (%) 1 (100) 10/46 (21.7) 6/22 (27.3) 1/18 (5.6) 2/5 (40.0) 8/25 (32.0) Type I 1/10 (10.0) 3/6 (50.0) 1/8 (12.5) Type II 1 (100) 4/10 (40.0) 1/6 (16.7) 3/8 (37.5) Solid organ transplantation, n/n (%) 3/46 (6.5) 2/18 (11.1) 1/25 (4.0) Other, n/n (%) 1/46 (2.2) 1/22 (4.5) 5/18 (27.8) 1/1 (100) 2/2 (100) 1/5 (20.0) 2/25 (8.0) GVHD, graft-vs.-host disease; HSCT, haematopoietic stem cell transplant; IFI, invasive fungal infection; NA, not applicable; SD, standard deviation. 1 Total prednisone equivalent dose of all corticosteroids administered in 30 days prior to diagnosis of IFI (n = 47). 244

6 Mucormycosis in PATH registry Table 3 Antifungal treatment on Day 3 Parameter All Rhizopus Mucor Rhizomucor Lichtheimia Other/Unknown 1 N (%) n = 121 n = 63 (52.1) n = 28 (23.1) n = 9 (7.4) n = 4 (3.3) n = 17 (14.0) Monotherapy, n/n (%) Echinocandins 2/121 (1.7) 1/28 (3.6) 1/17 (5.9) Amphotericin B deoxycholate 5/121 (4.1) 3/63 (4.8) 2/28 (7.1) Amphotericin B lipids 39/121 (32.2) 27/63 (42.9) 6/28 (21.4) 1/9 (11.1) 1/4 (25.0) 4/17 (23.5) Fluconazole 2/121 (1.7) 1/28 (3.6) 1/17 (5.9) Posaconazole 7/121 (5.8) 2/63 (3.2) 4/28 (14.3) 1/17 (5.9) Combination therapy, n/n (%) Voriconazole + echinocandins 4/121 (3.3) 2/28 (7.1) 1/9 (11.1) 1/17 (5.9) Voriconazole + amphotericin B 1/121 (0.8) 1/63 (1.6) Amphotericin B + echinocandins 8/121 (6.6) 3/63 (4.8) 3/9 (33.3) 1/4 (25.0) 1/17 (5.9) Other setting 21/121 (17.4) 13/63 (20.6) 4/28 (14.3) 2/9 (22.2) 2/17 (11.8) Voriconazole + amphotericin 2/121 (1.7) 1/63 (1.6) 1/28 (3.6) B + echinocandins No treatment, n/n (%) 30/121 (24.8) 13/63 (20.6) 7/28 (25.0) 2/9 (22.2) 2/4 (50.0) 6/17 (35.3) 1 Other species include Cunninghamella, Syncephalastrum and Cokeromyces species. 3(n = 53), survival probability was 0.72, whereas for those treated after Day 3 (n = 6), survival dropped to Discussion In this analysis, we report results on epidemiology, treatment and outcomes from a 5-year prospective survey of 121 patients with mucormycosis. A large proportion of the patient population (61.2%) had a haematological malignancy, of which 43.2% were haematopoietic stem cell transplant recipients. The number of patients with these malignancies was greater than that observed by two recent analyses of patients with mucormycosis, which reported a prevalence of 44% and 50%. 9,10 Nonetheless, our result emphasises the importance of haematological malignancy as an underlying condition in mucormycosis. Other than haematological malignancy, risk factors for mucormycosis include poorly controlled diabetes with ketoacidosis, prolonged and severe neutropenia, graft-vs.-host disease, prolonged use of corticosteroids and iron overload. 11,12 Several of these risk factors, such as graft-vs.-host disease, use of corticosteroids and neutropenia, were observed in our patient population (Table 1); however, species-specific differences were not observed for these risk factors. Antifungal drugs, such as voriconazole, are commonly prescribed for prophylaxis in patients with haematologic malignancy. 3,4 Prior therapy with voriconazole, which lacks Mucormycetes-specific activity, has been linked to an increase in incidence of mucormycosis and a high mortality rate. 3 Fifty (41.3%) patients had received voriconazole within 30 days of diagnosis of fungal infection. In addition, 11 (9.1%) patients had received prophylaxis with posaconazole (Table 1). A recent study showed that prophylaxis with posaconazole can also lead to breakthrough mucormycosis 13 ; therefore, clinicians should not discount mucormycosis in patients receiving posaconazole prophylaxis. Recommended treatment for mucormycosis includes use of antifungal agents, surgical debridement and correction of the predisposing underlying condition. 1 Although there was variability in treatment practices, most patients (75.2%) in the current analysis received appropriate pharmacological therapy on Day 3 (Table 1) with lipid-based amphotericin B, which is recommended as first-line treatment. 14 Mortality rates for mucormycosis vary (20% 72%) depending on the underlying condition and the site of infection. 9,11,15 Survival probability for all patients in our analysis was 0.41, with rates as low as 0.15 for patients infected with Rhizomucor. Causes of high mortality with mucormycosis include active malignancy, neutropenia and a delay in treatment with recommended antifungals (e.g. amphotericin B). 5,16 Our analysis showed that the survival probability was higher in patients who initiated therapy with amphotericin B by Day 3 (0.72) vs. those who started therapy after Day 3 (0.33). These findings are consistent with those of Chamilos et al. [5], who found that a delay in initiation of therapy with amphotericin B for 6 days after the onset of symptoms can increase the mortality rate. Some limitations of this analysis should also be noted. It was not possible to calculate the incidence of mucormycosis because of a lack of information on 245

7 D. P. Kontoyiannis et al. total number of at-risk patients. Other limitations include heterogeneity in clinical practices across different medical centres, limited follow-up, inability to distinguish between sequential and concomitant therapy and a lack of data to assess relationship between treatment and impact of correction of underlying condition with response. Nonetheless, the underlying strength of our analysis lies in data obtained from 25 centres across North America from a large number of patients with a range of underlying conditions. In conclusion, no notable trends were observed for underlying risk groups, fungal species and mortality from the data collected by the PATH Alliance â registry over a 5-year period. However, it is apparent that the heterogeneity of scenarios surrounding mucormycosis poses a major challenge in devising validated algorithms for risk stratification and therapeutic strategies. In view of the poor 12-week survival rate, timely diagnosis appears to be critical for improving survival in patients with mucormycosis. Acknowledgments DPK acknowledges the Frances King Black Endowed Professorship for Cancer Research. The authors would like to acknowledge the contribution of all the PATH investigators who provided data for the PATH Alliance â registry. Editorial support, funded by Astellas, was provided by Radhika Bhatia, PhD, a medical writer at Envision Scientific Solutions. Statistical programming support was provided by Alan Fan from Astellas. Conflicts of interest This work was supported by Astellas. DPK has received research support from Pfizer, Astellas and Merck, and honoraria from Merck and Gilead. NA and BF are employees of Astellas. DH has received consultancy fees and honoraria from Astellas. References 1 Kontoyiannis DP, Lewis RE. Invasive zygomycosis: update on pathogenesis, clinical manifestations, and management. 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Diagnosis and treatment of mucormycosis in patients with haematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3). Haematologica 2013; 98: Hammond SP, Baden LR, Marty FM. Mortality in hematologic malignancy and hematopoietic stem cell transplant patients with mucormycosis, 2001 to Antimicrob Agents Chemother 2011; 55: Spellberg B, Kontoyiannis DP, Fredricks D et al. Risk factors for mortality in patients with mucormycosis. Med Mycol 2012; 50: