Advertisement

The epidemiology and clinical manifestations of mucormycosis: a systematic review and meta-analysis of case reports

  • W. Jeong
    Affiliations
    Centre for Medicine Use and Safety, Monash University, Melbourne, VIC, Australia
    Search for articles by this author
  • C. Keighley
    Affiliations
    Centre for Infectious Diseases and Microbiology Laboratory Services, ICPMR, New South Wales Health Pathology, Westmead Hospital, Sydney, NSW, Australia

    Marie Bashir Institute for Biosecurity and Emerging Infections, The University of Sydney, Sydney, NSW, Australia
    Search for articles by this author
  • R. Wolfe
    Affiliations
    Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia
    Search for articles by this author
  • W.L. Lee
    Affiliations
    Centre for Medicine Use and Safety, Monash University, Melbourne, VIC, Australia
    Search for articles by this author
  • M.A. Slavin
    Affiliations
    National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, VIC, Australia
    Search for articles by this author
  • D.C.M. Kong
    Affiliations
    Centre for Medicine Use and Safety, Monash University, Melbourne, VIC, Australia

    Pharmacy Department, Ballarat Health Services, Ballarat, VIC, Australia

    The National Centre for Antimicrobial Stewardship, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
    Search for articles by this author
  • S.C.-A. Chen
    Correspondence
    Corresponding author. S.C-A. Chen, Centre for Infectious Diseases and Microbiology Laboratory Services, 3rd level ICPMR Building, Westmead Hospital, Darcy Road, Westmead, NSW 2145, Australia.
    Affiliations
    Centre for Infectious Diseases and Microbiology Laboratory Services, ICPMR, New South Wales Health Pathology, Westmead Hospital, Sydney, NSW, Australia

    Marie Bashir Institute for Biosecurity and Emerging Infections, The University of Sydney, Sydney, NSW, Australia
    Search for articles by this author
Open ArchivePublished:July 20, 2018DOI:https://doi.org/10.1016/j.cmi.2018.07.011

      Abstract

      Background

      The epidemiology of mucormycosis in the era of modern diagnostics is relatively under-explored.

      Objectives

      To examine the contemporary epidemiology, clinical manifestations, diagnosis and causative pathogens of mucormycosis.

      Data sources

      Ovid MEDLINE and Ovid EMBASE from January 2000 to January 2017.

      Study eligibility criteria

      Published case reports/series of proven/probable mucormycosis.

      Participants

      Patients ≥18 years old.

      Methods

      Patient characteristics, disease manifestations and causative pathogens were summarized descriptively. Categorical variables were assessed by chi-square test or Fischer's exact test, and continuous variables by the Wilcoxon–Mann–Whitney or Kruskal–Wallis test. Risk factors for the different clinical manifestations of mucormycosis were identified using multivariate logistic regression.

      Results

      Initial database searches identified 3619 articles of which 600 (851 individual patient cases) were included in the final analysis. Diabetes mellitus was the commonest underlying condition (340/851, 40%) and was an independent risk for rhino-orbital-cerebral mucormycosis (odds ratio (OR) 2.49; 95% CI 1.77–3.54; p < 0.001). Underlying haematological malignancy was associated with disseminated infection (OR 3.86; 95% CI 1.78–8.37; p 0.001), whereas previous solid organ transplantation was associated with pulmonary (OR 3.19; 95% CI 1.50–6.82; p 0.003), gastrointestinal (OR 4.47; 95% CI 1.69–11.80; p 0.003), or disseminated (OR 4.20; 95% CI 1.68–10.46; p 0.002) mucormycosis. Eight genera (24 species) of Mucorales organisms were identified in 447/851 (53%) cases, of which Rhizopus spp. (213/447, 48%) was the most common. Compared with other genera, Rhizopus spp. was predominantly observed in patients with rhino-orbital-cerebral mucormycosis (75/213, 35% versus 34/234, 15%; p < 0.001). Death was reported in 389/851 (46%) patients. Mortality associated with Cunninghamella infections was significantly higher than those caused by other Mucorales (23/30, 71% versus 185/417, 44%; p < 0.001). However, Cunninghamella spp. were isolated primarily in patients with pulmonary (17/30, 57%) or disseminated disease (10/30, 33%).

      Conclusions

      Findings from the current review have helped ascertain the association between various manifestations of mucormycosis, their respective predisposing factors and causative organisms.

      Keywords

      Background

      The epidemiology of invasive fungal disease due to filamentous fungi in immunocompromised patients and other host groups is shifting with changing clinical practice [
      • Bitar D.
      • Lortholary O.
      • Le Strat Y.
      • Nicolau J.
      • Coignard B.
      • Tattevin P.
      • et al.
      Population-based analysis of invasive fungal infections, France, 2001–2010.
      ]. After Aspergillus, Mucorales fungi are the next commonest pathogens in patients with haematological malignancy, haematopoietic stem cell transplantation and solid organ transplantation [
      • Slavin M.
      • van Hal S.
      • Sorrell T.C.
      • Lee A.
      • Marriott D.J.
      • Daveson K.
      • et al.
      Invasive infections due to filamentous fungi other than Aspergillus: epidemiology and determinants of mortality.
      ,
      • Park B.J.
      • Pappas P.G.
      • Wannemuehler K.A.
      • Alexander B.D.
      • Anaissie E.J.
      • Andes D.R.
      • et al.
      Invasive non-Aspergillus mold infections in transplant recipients, United States, 2001–2006.
      ]. Additionally, Mucorales infections are increasingly recognized in individuals with diabetes mellitus [
      • Chakrabarti A.
      • Chatterjee S.S.
      • Das A.
      • Panda N.
      • Shivaprakash M.R.
      • Kaur A.
      • et al.
      Invasive zygomycosis in India: experience in a tertiary care hospital.
      ], after trauma or iatrogenic injury [
      • Lelievre L.
      • Garcia-Hermoso D.
      • Abdoul H.
      • Hivelin M.
      • Chouaki T.
      • Toubas D.
      • et al.
      Posttraumatic mucormycosis: a nationwide study in France and review of the literature.
      ,
      • Skiada A.
      • Rigopoulos D.
      • Larios G.
      • Petrikkos G.
      • Katsambas A.
      Global epidemiology of cutaneous zygomycosis.
      ] and have been associated with outbreaks following natural disasters [
      • Neblett Fanfair R.
      • Benedict K.
      • Bos J.
      • Bennett S.D.
      • Lo Y.C.
      • Adelbanjo T.
      • et al.
      Necrotizing cutaneous mucormycosis after a tornado in Joplin, Missouri, in 2011.
      ].
      A review of the epidemiology, diagnosis, treatment and outcomes of mucormycosis (then ‘zygomycosis’) by Roden et al. [
      • Roden M.M.
      • Zaoutis T.E.
      • Buchanan W.L.
      • Knudsen T.A.
      • Sakisova T.A.
      • Schaufele R.L.
      • et al.
      Epidemiology and outcome of zygomycosis: a review of 929 reported cases.
      ] has provided valuable insights into this important invasive fungal disease. However, this was conducted over 10 years ago and included infections caused by the Mucorales, as well as by the Entomophthorales. The latter are rare human pathogens and cause infections with different characteristics to those of mucormycosis [
      • Ribes J.A.
      • Vanover-Sams C.L.
      • Baker D.J.
      Zygomycetes in human disease.
      ]; hence, certain aspects of the review may not be applicable to mucormycosis. Indeed, the epidemiology of mucormycosis in the era of modern diagnostic tools warrants more study as these potentially lead to better delineation of infections caused by previously uncommon genera/species such as Apophysomyces [
      • Chakrabarti A.
      • Singh R.
      Mucormycosis in India: unique features.
      ] or Saksenaea complex [
      • Alvarez E.
      • Garcia-Hermoso D.
      • Sutton D.A.
      • Cano J.F.
      • Stchigel A.M.
      • Hoinard D.
      • et al.
      Molecular phylogeny and proposal of two new species of the emerging pathogenic fungus Saksenaea.
      ] and may identify new patient risk groups. Therefore, we performed a systematic review of cases of mucormycosis published between January 2000 and January 2017 to examine the contemporary epidemiology, clinical manifestations, diagnosis and causative pathogens of this invasive fungal disease.

      Methods

      This review was undertaken and reported in accordance with the preferred reporting items for systematic review and meta-analyses (PRISMA) guidelines [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ].

       Eligibility criteria

      Published case reports/series of proven/probable mucormycosis, as defined by the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria [
      • De Pauw B.
      • Walsh T.J.
      • Donnelly J.P.
      • Stevens D.A.
      • Edwards J.E.
      • Calandra T.
      • et al.
      Revised definitions of invasive fungal disease from 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 (EORTC/MSG) Consensus Group.
      ] in patients ≥ 18 years old were reviewed. For inclusion, the published cases must have had documentation of: (i) site(s) of infection, (ii) predisposing factors/underlying medical conditions [
      • Roden M.M.
      • Zaoutis T.E.
      • Buchanan W.L.
      • Knudsen T.A.
      • Sakisova T.A.
      • Schaufele R.L.
      • et al.
      Epidemiology and outcome of zygomycosis: a review of 929 reported cases.
      ,
      • Kennedy K.J.
      • Daveson K.
      • Slavin M.A.
      • Van Hal S.J.
      • Sorrell T.C.
      • Lee A.
      • et al.
      Mucormycosis in Australia: contemporary epidemiology and outcomes.
      ], (iii) method(s) of diagnosis, (iv) use of antifungal and/or other management strategies, and (v) patient outcomes. Conference abstracts, editorials, poorly described cases, review articles, or case series without primary data or where the analysis was pooled without description of individual patient data were excluded.

       Search strategies and information sources

      A systematic search using search strategies, comprising keywords and MeSH (see Supplementary material, Appendix S1), was carried out in Ovid MEDLINE and Ovid EMBASE. Searches were limited to studies involving humans published in English [
      • Morrison A.
      • Polisena J.
      • Husereau D.
      • Moulton K.
      • Clark M.
      • Flander M.
      • et al.
      The effect of English-language restriction on systematic review-based meta-analyses: a systematic review of empirical studies.
      ] from January 2000 to January 2017. The final search was performed in January 2017. Reference lists of relevant articles were also searched.

       Study selection

      Search strategies were implemented by WJ with initial results imported and merged into reference management software, Endnote® (version X7, Clarivate Analytics (formerly Thomson Reuters), Philadelphia, PA, USA). After removal of duplicates, the remaining titles and abstracts were assessed for inclusion. Full texts of relevant articles were retrieved and independently assessed by two groups of two authors (WJ & WL and SC & CK). Disagreements over study inclusion were resolved by consensus.

       Data collection process and data items

      Using standardized data extraction forms, data were extracted independently by the two author groups (as above) and compared. Discrepancies were discussed with MS and DK as adjudicators. Data extracted included country of origin of the published cases, year of publication, patient demographics, underlying conditions/co-morbidities, diagnosis (including method of diagnosis, time to diagnosis and causative pathogens), body sites of infections, and all-cause mortality during the course of mucormycosis. Clinical manifestations of mucormycosis (including rhino-orbital-cerebral, pulmonary, cutaneous, or disseminated) were classified according to the primary body sites affected and extent of infection at the time of diagnosis, using criteria adapted from previous definitions [
      • Roden M.M.
      • Zaoutis T.E.
      • Buchanan W.L.
      • Knudsen T.A.
      • Sakisova T.A.
      • Schaufele R.L.
      • et al.
      Epidemiology and outcome of zygomycosis: a review of 929 reported cases.
      ]. Histopathological and/or radiological features (by computed tomography scan or magnetic resonance imaging) suggestive of invasive fungal disease were used to assign site of involvement.

       Summary measures and statistical analysis

      Data analysis was conducted using Stata 14.0 software (Stata Corp, College Station, TX, USA). Patient characteristics, disease manifestations and causative pathogens were summarized descriptively. Categorical variables were assessed by chi-squared test or Fischer's exact test, and continuous variables by the Wilcoxon–Mann–Whitney or Kruskal–Wallis test. Risk factors for the different clinical manifestations of mucormycosis were identified using multivariate logistic regression. A p value ≤ 0.05 was statistically significant.

      Results

      The initial database search identified 3619 articles of which 600 (851 individual patient cases) were included in the final analysis (Fig. 1). The majority of the cases (290/851, 34%) were from Europe, followed by Asia (267/851, 31%) and North or South America (239/851, 28%). The remaining cases were from Africa (28/851, 3%), Australia and New Zealand (27/851, 3%). The list of articles included in this review is presented in the Supplementary material (Appendix S2).
      Fig. 1
      Fig. 1PRISMA diagram describing the cases selection process.

       Patient demographics, co-morbidities and predisposing factors

      Of 851 patients, the median (interquartile range) age was 51 (39–61) years and 531 (63%) were men. Diabetes mellitus was the most common underlying condition (340/851, 40%; 71 (20%) had documented ketoacidosis) followed by haematological malignancy (275/851, 32%; 116 (42%) had acute myeloid leukaemia) and solid organ transplantation (116/851, 14%; 67 (58%) had received a kidney transplant) (Table 1). Diabetes mellitus was more commonly reported in Asian or African countries than western countries (including Europe, North or South America, and Australia and New Zealand) (119/267, 46% versus 21/28, 75% versus 200/556, 36%; p < 0.001). Underlying chronic liver disease was uncommon (27/851, 3%). Fifty-one per cent (438/851) of cases involved individuals not receiving any form of immunosuppressive therapy, monoclonal antibodies and cancer chemotherapy.
      Table 1Underlying conditions and predisposing factors for 851 cases of mucormycosis
      Variablesn (%)
      Underlying conditions
       Diabetes mellitus340 (40%)
      Diabetic ketoacidosis
      Diabetic ketoacidosis status was unknown for 248 patients.
      71 (21%)
       Haematological malignancy275 (33%)
      Acute myeloid leukaemia116 (42%)
      Acute lymphoblastic leukaemia41 (15%)
      Lymphoma
      Lymphoma included three Hodgkin's lymphoma, 25 non-Hodgkin's lymphoma, eight unspecified lymphoma.
      36 (13%)
      Myelodysplastic syndrome26 (9%)
      Chronic myeloid leukaemia14 (5%)
      Chronic lymphocytic leukaemia6 (2%)
      Aplastic anaemia12 (5%)
      Multiple myeloma7 (3%)
      Other
      Others included three thrombopenic purpura, one myelofibrosis, two hairy cell leukaemia, eight unspecified leukaemia, one chronic granulomatous disease, one Wegener's granulomatosis and one eosinophilic granuloma.
      17 (6%)
       Solid organ transplantation116 (14%)
      Kidney67 (58%)
      Liver24 (20%)
      Heart10 (9%)
      Lung9 (8%)
      Other
      Others included two pancreas kidney, two heart and lungs, one heart and kidney, and one liver and kidney.
      6 (5%)
       Haematopoietic stem cell transplant90 (11%)
       Liver disease
      Included 15 Hepatitis B or C, seven alcoholic liver disease, two autoimmune hepatitis, one cryptogenic cirrhosis and two unspecified liver diseases.
      27 (3%)
       Other underlying conditions
      Included nine solid tumour, 16 human immunodeficiency virus positive, eight systemic lupus erythematosus, six inflammatory bowel disease and 12 rheumatoid diseases.
      51 (6%)
      No underlying conditions156 (18%)
      Predisposing factor
       Corticosteroid use273 (33%)
       Neutropenia169 (20%)
       Major trauma85 (10%)
      Motor vehicle accident28 (33%)
      Surgery26 (30%)
      Burn9 (11%)
      Natural disaster4 (5%)
      Other open wound trauma18 (21%)
      Minor trauma81 (10%)
      Injection sites34 (42%)
      Cuts/grazes11 (14%)
      Animal bites/scratches7 (9%)
      Dental10 (12%)
      Gardening7 (9%)
      Other minor injury12 (14%)
       Use of cancer chemotherapy149 (18%)
       Use of calcineurin inhibitors133 (16%)
       Use of biological therapy60 (7%)
       Use of renal replacement therapy27 (3%)
       Other predisposing factors
      Included six injectable drug use, five deferoxamine therapy, eight contaminated equipment.
      19 (2%)
       Prior antifungal prophylaxis92 (11%)
      Voriconazole48 (52%)
      Fluconazole23 (25%)
      Posaconazole oral suspension5 (5%)
      Others
      Included nine echinocandins and seven itraconazole.
      16 (17%)
      a Diabetic ketoacidosis status was unknown for 248 patients.
      b Lymphoma included three Hodgkin's lymphoma, 25 non-Hodgkin's lymphoma, eight unspecified lymphoma.
      c Others included three thrombopenic purpura, one myelofibrosis, two hairy cell leukaemia, eight unspecified leukaemia, one chronic granulomatous disease, one Wegener's granulomatosis and one eosinophilic granuloma.
      d Others included two pancreas kidney, two heart and lungs, one heart and kidney, and one liver and kidney.
      e Included 15 Hepatitis B or C, seven alcoholic liver disease, two autoimmune hepatitis, one cryptogenic cirrhosis and two unspecified liver diseases.
      f Included nine solid tumour, 16 human immunodeficiency virus positive, eight systemic lupus erythematosus, six inflammatory bowel disease and 12 rheumatoid diseases.
      g Included six injectable drug use, five deferoxamine therapy, eight contaminated equipment.
      h Included nine echinocandins and seven itraconazole.
      Of the predisposing factors (Table 1), corticosteroid use at time of presentation was the most common (273/851, 33%), followed by neutropenia (169/851, 20%) and major/minor trauma (166/851, 20%). The use of cancer chemotherapy or calcineurin inhibitors was documented in (149/851, 18%) or (133/851, 16%), respectively. Of the 85 major trauma-related infections, 28 (33%) were caused by motor vehicle accidents, while 26 (30%) were observed following major orthopaedic, gastrointestinal, gynaecological or cardiovascular procedures; only four cases (5%) were observed in tornado or tsunami survivors. Minor iatrogenic penetrating traumas, related to intravenous, intramuscular, insulin injections or catheter insertions were also commonly reported (34/81, 42%).
      Antifungal prophylaxis (Table 1) was administered in patients from Europe (39/92), North or South America (40/92), Asia (11/92), and Australia and New Zealand (2/92), although the duration of prophylaxis was not consistently reported. The use of voriconazole or posaconazole suspension prophylaxis was documented in 48/92 (52%) and 5/92 (5%) patients, respectively, primarily from the western countries; fluconazole was prescribed in 23 patients, of which 13 were from North or South America. The types of antifungal prophylaxis prescribed over time were not statistically different (p 0.237).

       Clinical manifestations

      Rhino-orbital-cerebral mucormycosis (ROCM) was the most commonly observed manifestation (288/851, 34%), followed by cutaneous (187/851, 22%) and pulmonary mucormycosis (172/851, 20%) (Table 2). Disseminated infection was reported for 111/851 patients (13%). However, the primary sites from which dissemination occurred were not clearly described. Of 72 cases of gastrointestinal mucormycosis, infection was mostly confined to the stomach, intestine and/or colon (53/72, 74%), with liver involvement in 16/72 patients (22%).
      Table 2Disease manifestations
      Generalized rhino-orbital-cerebral infections involved the paranasal sinuses, orbits and brain; deep extension pulmonary mucormycosis where infections involved the lungs, chest wall, heart, artery or aorta; deep extension cutaneous infections referred to skin infections with invasion to muscle, tendon, or bone; disseminated mucormycosis was defined as infection involving two or more non-contiguous sites or if Mucorales fungi were isolated from the blood; gastrointestinal mucormycosis included infections of the luminal gastrointestinal tracts and abdominal organs including the liver, spleen, pancreas and gallbladder.
      for 851 cases of mucormycosis
      Disease manifestationsNo of patients

      n (%)
      No of proven cases

      n (%)
      Overall mortality

      n (%)
      Rhino-orbito-cerebral mucormycosis288 (34%)254 (88%)120 (42%)
       Localized sinus158 (55%)136 (86%)53 (34%)
       Localized orbital6 (2%)6 (100%)2 (33%)
       Localized cerebral16 (6%)16 (100%)11 (69%)
       Sino-orbital82 (28%)75 (91%)35 (43%)
       Sino-cerebral20 (7%)16 (80%)15 (75%)
       Generalized rhino-orbital-cerebral6 (2%)5 (83%)4 (67%)
      Pulmonary mucormycosis172 (20%)132 (77%)87 (51%)
       Localized168 (98%)128 (76%)84 (50%)
       Deep extension4 (2%)4 (100%)3 (75%)
      Cutaneous mucormycosis187 (22%)172 (92%)58 (31%)
       Localized150 (80%)137 (91%)46 (31%)
       Deep extension37 (20%)35 (95%)12 (32%)
      Disseminated mucormycosis110 (13%)101 (92%)75 (68%)
      Gastrointestinal mucormycosis72 (8%)71 (99%)39 (54%)
      Others
      Others included twelve renal, three ear, three parotid gland, two heart, one lymph nodes and one uterus mucormycosis.
      22 (3%)20 (91%)10 (46%)
      a Generalized rhino-orbital-cerebral infections involved the paranasal sinuses, orbits and brain; deep extension pulmonary mucormycosis where infections involved the lungs, chest wall, heart, artery or aorta; deep extension cutaneous infections referred to skin infections with invasion to muscle, tendon, or bone; disseminated mucormycosis was defined as infection involving two or more non-contiguous sites or if Mucorales fungi were isolated from the blood; gastrointestinal mucormycosis included infections of the luminal gastrointestinal tracts and abdominal organs including the liver, spleen, pancreas and gallbladder.
      b Others included twelve renal, three ear, three parotid gland, two heart, one lymph nodes and one uterus mucormycosis.
      Associations between patient's underlying conditions/predisposing factors and mucormycosis manifestations are summarized in Table 3. ROCM was significantly more commonly observed in patients with diabetes mellitus than those without (173/340, 51% versus 115/511, 23%; p < 0.001). Conversely, cutaneous mucormycosis was more common among individuals with trauma (114/166, 69% versus 73/685, 11%; p < 0.001). Previous solid organ transplantation was associated with increased risk of pulmonary (odds ratio (OR) 3.19; 95% CI 1.50–6.82; p 0.003), gastrointestinal (OR 4.47; 95% CI 1.69–11.80; p 0.003) or disseminated infection (OR 4.20; 95% CI 1.68–10.46; p 0.002) compared with ROCM. Underlying haematological malignancy was associated with increased risk of dissemination (OR 3.86; 95% CI 1.78–8.37; p 0.001), whereas neutropenia was significant for pulmonary disease (OR 1.92; 95% CI 1.02–3.62; p 0.042). Corticosteroid use was not associated with any particular disease manifestation (Table 3).
      Table 3Multivariate logistic regression analysis of associations between various underlying conditions/predisposing factors and disease manifestations
      Underlying conditionsOdds ratio (95% CI); p
      Rhino-obital-cerebral mucormycosisPulmonary mucormycosis
      Compared with rhino-orbital-cerebral mucormycosis.
      Cutaneous mucormycosis
      Compared with rhino-orbital-cerebral mucormycosis.
      Disseminated mucormycosis
      Compared with rhino-orbital-cerebral mucormycosis.
      Gastrointestinal mucormycosis
      Compared with rhino-orbital-cerebral mucormycosis.
      Diabetic mellitus2.49 (1.77–3.54); <0.0010.85 (0.53–1.36); 04860.29 (0.17–0.48); <0.0010.39 (0.22–0.71); 0.0020.17 (0.09–0.34); <0.001
      Solid organ transplantation0.37 (0.20–0.69); 0.0023.19 (1.50–6.82); 0.0031.16 (0.48–2.78); 0.7374.20 (1.68–10.46); 0.0024.47 (1.69–11.80); 0.003
      Haematological malignancies0.76 (0.44–1.26); 0.2701.68 (0.86–3.29); 0.1300.84 (0.39–1.79); 0.6463.86 (1.78–8.37); 0.0010.77 (0.31–1.91); 0.569
      Haematopoietic stem cell transplantation0.73 (0.39–1.37); 0.3261.79 (0.86–3.72); 0.1200.48 (0.15–1.57); 0.2251.18 (0.54–2.59); 0.6811.33 (0.44–4.02); 0.608
      Corticosteroid use0.86 (0.57–1.29); 0.4721.19 (0.72–1.97); 0.5071.54 (0.85–2.80); 0.1551.37 (0.76–2.47); 0.2900.77 (0.36–1.64); 0.496
      Neutropenia0.70 (0.41–1.18); 0.1781.92 (1.02–3.62); 0.0420.75 (0.32–1.76); 0.5071.74 (0.88–3.41); 0.1101.28 (0.52–3.09); 0.594
      Major trauma0.12 (0.05–0.28); <0.0010.36 (0.04–3.04); 0.35125.64 (10.72–61.30); <0.0018.55 (2.84–25.73); <0.0012.74 (0.83–9.04); 0.098
      Minor trauma0.31 (0.17–0.57); <0.0010.26 (0.06–1.17); 0.08012.12 (6.25–23.51); <0.0011.79 (0.67–4.77); 0.2470.55 (0.12–2.52); 0.439
      Other underlying conditions were excluded from the model due to the small number of observations.
      a Compared with rhino-orbital-cerebral mucormycosis.

       Methods of diagnosis

      The majority of the cases reviewed (750/851, 88%) were classed as proven, and 101 (12%) as probable infections using the EORTC/MSG criteria [
      • De Pauw B.
      • Walsh T.J.
      • Donnelly J.P.
      • Stevens D.A.
      • Edwards J.E.
      • Calandra T.
      • et al.
      Revised definitions of invasive fungal disease from 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 (EORTC/MSG) Consensus Group.
      ]. Histopathological examination was employed in 710/851 cases (83%) of which 97% (688 cases) were reported to demonstrate broad, aseptate or sparsely septate, ribbon-like hyphae in the affected tissue. Culture was performed in 587/851 cases (69%) with a Mucorales grown in 463/587 (79%) instances. Hence, diagnosis was largely reliant on conventional phenotypic techniques. Specifically, 53% of cases (451/851) were diagnosed by combined histopathology and culture, while diagnosis by histopathology or culture alone was observed in 239/851 (28%) or 84/851 (10%), respectively. The median (interquartile range) time to diagnosis, available for 199 cases was 10 (5–17) days post-signs/symptoms presentation.
      The use of molecular techniques (105/851, 12%) was increasingly observed over the years: 10/105 cases (10%) between 2000 and 2005, 27/105 (26%) between 2006 and 2010, and 68/105 (64%) between 2011 and 2017 (p < 0.001). Their role, however, was limited to species identification of cultured isolates in 76/105 (72%) cases. Notably, in 27 cases (26%), these were directly performed on clinical samples (including tissues, blood and bronchial/pleural aspirates). However, in 3/27 instances, no Mucorales was detected despite histopathological and/or culture evidence of infection. DNA sequencing of the fungal internal transcribed spacer regions, was the most common approach (58/105; 55%), followed by sequencing of both the internal transcribed spacer and D1/D2 region of the 28S ribosomal DNA (rDNA) subunit (10/105, 10%). Other molecular targets included the 18S (n = 8) and 28S (n = 7) rDNA regions, while sequencing targets in the remaining 22 cases were not described. Neither the DNA extraction procedures nor format or conditions of various PCR assays used were consistently described.

       Causative pathogens

      A total of eight genera (24 species) of Mucorales organisms were identified in 447/851 (53%) cases, primarily by culture (Table 4). Rhizopus spp. (213/447, 48%) was the most common, followed by Mucor spp. (63/447, 14%). Among Rhizopus spp., Rhizopus arrhizus (formerly Rhizopus oryzae) was the most frequent (70/213, 33%). Most Mucor spp. were not identified to species level (47/63, 75%). Importantly, Mucorales were identified to the species level by molecular diagnostics in 13 cases reporting growth on culture, nine culture-negative cases, and in seven cases where culture was not performed. Additionally, molecular techniques contributed to the speciation of more unusual species, not identified by culture to species level including Apophysomyces trapeziformis, Apophysomyces variabilis, Thamnostylum lucknowense, Mucor velutinosus and Actinomucor elegans (Table 4).
      Table 4Genera and species of 447 causative Mucorales organisms and methods of diagnosis
      Organisms identifiedMethods of diagnosisTotal

      n (%)
      Overall mortality

      n (%)
      Culture

      (n)
      Molecular

      (n)
      Culture and molecular

      (n)
      Rhizopus213 (48%)101 (47%)
       Rhizopus arrhizus (formerly Rhizopus oryzae)5371070 (33%)
       Rhizopus microsporus209433 (15%)
       Rhizopus rhizopodiformis2002 (1%)
       Rhizopus homothallicus0022 (1%)
       Rhizopus azygosporus1001 (1%)
       Rhizopus stolonifer1001 (1%)
       Unspecified Rhizopus spp.10121104 (49%)
      Mucor63 (14%)26 (41%)
       Mucor irregularis1225 (8%)
       Mucor circinelloides2215 (8%)
       Mucor indicus1113 (5%)
       Mucor hiemalis1012 (3%)
       Mucor velutinosus0101 (2%)
       Unspecified Mucor spp.470047 (75%)
      Lichtheimia60 (13%)21 (35%)
       Lichtheimia corymbifera295741 (68%)
       Lichtheimia ramosa3407 (10%)
       Unspecified Lichtheimia spp.111012 (22%)
      Cunninghamella30 (7%)23 (77%)
       Cunninghamella bertholletiae193224 (80%)
       Unspecified Cunninghamella spp.6006 (20%)
      Apophysomyces34 (8%)15 (44%)
       Apophysomyces elegans220628 (83%)
       Apophysomyces trapeziformis01404 (12%)
       Apophysomyces variabilis0101 (3%)
       Unspecified Apophysomyces spp.0011 (3%)
      Rhizomucor28 (6%)11 (39%)
       Rhizomucor pusillus61411 (39%)
       Rhizomucor variabilis1203 (11%)
       Unspecified Rhizomucor spp.110314 (50%)
      Saksenaea complex12 (3%)6 (50%)
       Saksenaea vasiformis5139 (75%)
       Saksenaea erythrospora0123 (25%)
      Others7 (2%)5 (71%)
       Synchephalastrum racemosum2024 (57%)
       Thamnostylum lucknowense0101 (14%)
       Cokeromyces spp.1001 (14%)
       Actinomucor elegans0101 (14%)
      Compared with other genera, Rhizopus spp. were more often isolated in patients with ROCM (75/213, 35% versus 34/234, 15%; p < 0.001), whereas Cunninghamella spp. were more common in patients with pulmonary disease (17/30, 57% versus 82/417, 20%; p < 0.001) or disseminated disease (10/30, 33% versus 54/417, 13%; p 0.002). Apophysomyces spp. (22/34, 65%), Lichtheimia spp. (27/60, 45%) or Saksenaea complex (9/12, 75%) were more commonly isolated in patients with cutaneous mucormycosis (Fig. 2).
      Fig. 2
      Fig. 2Genera of causative Mucorales organism according to disease manifestations.
      Causative Mucorales appeared to vary by geographical region (Fig. 3). Apophysomyces infections were not observed in Europe or Africa, whereas those caused by Lichthemia were predominantly documented in Europe compared with other regions (40/173, 23% versus 20/275, 7%; p < 0.001). All three Saksenaea erythrospora isolates were reported in North or South America. Of the nine Saksenaea vasiformis isolates, four were from India and five were reported from Spain (n = 2), Australia (n = 2) and the USA (n = 1). As for the four Syncephalastrum racemosum cases, two were reported in Egypt, one in Australia and the other in the USA.
      Fig. 3
      Fig. 3Genera of causative Mucorales fungi according to geographical regions.

       Overall mortality

      Death was reported in 389/851 (46%) patients. Compared with that of other clinical manifestations, mortality (Table 2) was observed to be highest among patients with disseminated mucormycosis (68%) and lowest in those with cutaneous disease (31%). Notably, mortality associated with Cunninghamella infections was significantly higher than that caused by other Mucorales (23/30, 71% versus 185/417, 44%; p < 0.001; Table 4).

      Discussion

      We present here a large contemporary systematic review of published cases of mucormycosis, providing global insight into a diverse epidemiology, clinical manifestations and an increasing spectrum of causative pathogens of mucormycosis. The current review was undertaken and reported using the PRISMA guidelines, including only cases caused by the Mucorales. This review has provided an update on the epidemiology of mucormycosis in the era of modern fungal diagnostics.
      One major finding is that a significant proportion of the cases were observed in patients not receiving any type of immunosuppressive therapy. Although we did find an association between mucormycosis and underlying haematological malignancy and/or solid organ transplantation, this was more prevalent in developed western countries, potentially owing to the transplantation activity performed in these countries [
      • Kennedy K.J.
      • Daveson K.
      • Slavin M.A.
      • Van Hal S.J.
      • Sorrell T.C.
      • Lee A.
      • et al.
      Mucormycosis in Australia: contemporary epidemiology and outcomes.
      ,
      • Pagano L.
      • Offidani M.
      • Fianchi L.
      • Nosari A.
      • Candoni A.
      • Piccardi M.
      • et al.
      Mucormycosis in hematologic patients.
      ,
      • Skiada A.
      • Pagano L.
      • Groll A.
      • Zimmerli S.
      • Dupont B.
      • Lagrou K.
      • 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.
      ,
      • Lanternier F.
      • Dannaoui E.
      • Morizot G.
      • Elie C.
      • Garcia-Hermoso D.
      • Huerre M.
      • et al.
      A global analysis of mucormycosis in France: the RetroZygo study (2005–2007).
      ]. Diabetes mellitus, on the other hand, was the most commonly reported underlying condition in cases from Asian countries such as India [
      • Chakrabarti A.
      • Das A.
      • Mandal J.
      • Shivaprakash M.R.
      • George V.K.
      • Tarai B.
      • et al.
      The rising trend of invasive zygomycosis in patients with uncontrolled diabetes mellitus.
      ]. The impact of tighter blood glucose control on reducing the incidence of mucormycosis in these patients, however, has yet to be determined; we were unable to draw conclusions around this matter in our review.
      Consistent with previous findings [
      • Skiada A.
      • Rigopoulos D.
      • Larios G.
      • Petrikkos G.
      • Katsambas A.
      Global epidemiology of cutaneous zygomycosis.
      ,
      • Roden M.M.
      • Zaoutis T.E.
      • Buchanan W.L.
      • Knudsen T.A.
      • Sakisova T.A.
      • Schaufele R.L.
      • et al.
      Epidemiology and outcome of zygomycosis: a review of 929 reported cases.
      ], we also observed major/minor trauma to be a significant risk factor for cutaneous mucormycosis, potentially following direct inoculation of the fungal spores into the open wound. Notably, eight cases of cutaneous disease were attributed to the use of contaminated dressings, needles or intravenous access devices. Additionally, four cases of trauma-associated mucormycosis were documented in tornado/tsunami victims. Indeed, outbreaks of mucormycosis following contamination of medical supplies [
      • Rammaert B.
      • Lanternier F.
      • Zahar J.-R.
      • Dannaoui E.
      • Bougnoux M.E.
      • Lecuit M.
      • et al.
      Healthcare-associated mucormycosis.
      ,
      • Antoniadou A.
      Outbreaks of zygomycosis in hospitals.
      ] or natural disasters [
      • Neblett Fanfair R.
      • Benedict K.
      • Bos J.
      • Bennett S.D.
      • Lo Y.C.
      • Adelbanjo T.
      • et al.
      Necrotizing cutaneous mucormycosis after a tornado in Joplin, Missouri, in 2011.
      ] have been described. Although infrequent [
      • Antoniadou A.
      Outbreaks of zygomycosis in hospitals.
      ], mucormycosis outbreaks in health-care facilities are preventable and highlight the need for improving gaps in surveillance and diagnosis for these infections.
      Described as a risk factor for mucormycosis [
      • Roden M.M.
      • Zaoutis T.E.
      • Buchanan W.L.
      • Knudsen T.A.
      • Sakisova T.A.
      • Schaufele R.L.
      • et al.
      Epidemiology and outcome of zygomycosis: a review of 929 reported cases.
      ,
      • Skiada A.
      • Pagano L.
      • Groll A.
      • Zimmerli S.
      • Dupont B.
      • Lagrou K.
      • 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.
      ,
      • Lanternier F.
      • Dannaoui E.
      • Morizot G.
      • Elie C.
      • Garcia-Hermoso D.
      • Huerre M.
      • et al.
      A global analysis of mucormycosis in France: the RetroZygo study (2005–2007).
      ], corticosteroid use did not appear to be an independent risk factor for mucormycosis in the current study. Although it was observed in 33% of the cases, the dose and duration of the corticosteroid therapy were not consistently reported in the cases included. It is also important to note that this study was not designed to evaluate the independent risk factors for mucormycosis per se. Nevertheless, although a causal relationship between corticosteroid therapy and mucormycosis has yet to be established, increased risk for mucormycosis may arise from chronic corticosteroid use potentially mediated through macrophages/neutrophil dysfunction or hyperglycaemia [
      • Ribes J.A.
      • Vanover-Sams C.L.
      • Baker D.J.
      Zygomycetes in human disease.
      ,
      • Kontoyiannis D.P.
      • Lewis R.E.
      How I treat mucormycosis.
      ].
      Likewise, the impact of antifungal prophylaxis on the incidence of mucormycosis warrants further evaluation. Antifungal prophylaxis was primarily administered in patients from Europe (39/92) or North or South America (40/92), potentially owing to the transplantation performed in these countries. Widespread use of voriconazole prophylaxis has been linked with breakthrough mucormycosis [
      • Kontoyiannis D.P.
      • Lionakis M.S.
      • Lewis R.E.
      • Chamilos G.
      • Healy M.
      • Perego C.
      • et al.
      Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case–control observational study of 27 recent case.
      ,
      • Trifilio S.
      • Singhal S.
      • Williams S.
      • Frankfurt O.
      • Gordon L.
      • Evens A.
      • et al.
      Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole.
      ]. The reasons behind this observation, however, remain inconclusive, although it may partially be attributed to voriconazole's poor in vitro activity against the Mucorales. Importantly, the present review also identified five cases of Mucorales infections during posaconazole suspension prophylaxis supporting the findings of one study suggesting increasing incidence of breakthrough mucormycosis despite posaconazole prophylaxis [
      • Auberger J.
      • Lass-Flörl C.
      • Aigner M.
      • Clausen J.
      • Gastl G.
      • Nachbaur D.
      Invasive fungal breakthrough infections, fungal colonization and emergence of resistant strains in high-risk patients receiving antifungal prophylaxis with posaconazole: real-life data from a single-centre institutional retrospective observational study.
      ]. However, we are unable to determine if these observations were due to sub-therapeutic posaconazole through plasma concentrations given the absence of data. Moreover, the efficacy of posaconazole tablet in the prophylaxis of mucormycosis remains unclear. Of note, cases of breakthrough infection due to posaconazole-resistant Rhizopus spp. or Mucor spp. have been reported [
      • Lamoth F.
      • Chung S.J.
      • Damonti L.
      • Alexander B.D.
      Changing epidemiology of invasive mold infections in patients receiving azole prophylaxis.
      ]. Although the clinical breakpoints for Mucorales pathogens are yet to be defined, antifungal susceptibility testing is useful for epidemiological purposes and in providing a broad guide to therapy. Details of the antifungal susceptibility of the pathogens identified in the present review are discussed in ‘The contemporary management and clinical outcomes of mucormycosis: a systematic review’ (W. Jeong, C. Keighley, R. Wolfe, W. Lee, M. Slavin, S. Chen, and D. Kong, manuscript under review).
      Consistent with previous findings [
      • Roden M.M.
      • Zaoutis T.E.
      • Buchanan W.L.
      • Knudsen T.A.
      • Sakisova T.A.
      • Schaufele R.L.
      • et al.
      Epidemiology and outcome of zygomycosis: a review of 929 reported cases.
      ,
      • Skiada A.
      • Pagano L.
      • Groll A.
      • Zimmerli S.
      • Dupont B.
      • Lagrou K.
      • 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.
      ], the association between ROCM and diabetes mellitus was identified in the current study. Furthermore, neutropenia, a common co-morbidity among patients with underlying haematological malignancies and/or haematopoietic stem cell transplantation recipients was ascertained to be an independent risk factor for pulmonary mucormycosis. Additionally, our findings suggested that individuals undergoing solid organ transplantation were at increased risk of developing gastrointestinal mucormycosis. Although limited by the small number of observations, no difference in the pattern of infections among recipients of different organs was observed (p 0.120).
      The diagnostic utility of histopathological examination was clearly borne out by the findings of the present study where histopathology features contributed to the diagnosis in 97% of instances where the test was performed. However, one previous study reported only 79% of fungal organisms were correctly identified using histopathology [
      • Sangoi A.R.
      • Rogers W.M.
      • Longacre T.A.
      • Montoya J.G.
      • Baron E.J.
      • Banaei N.
      Challenges and pitfalls of morphologic identification of fungal infections in histologic and cytologic specimens: a ten-year retrospective review at a single institution.
      ]. Interpretation of septation or septal branching to distinguish between Mucorales hyphae and those of Aspergillus, for example, is often problematic especially when fungal hyphae are scant or distorted [
      • Sangoi A.R.
      • Rogers W.M.
      • Longacre T.A.
      • Montoya J.G.
      • Baron E.J.
      • Banaei N.
      Challenges and pitfalls of morphologic identification of fungal infections in histologic and cytologic specimens: a ten-year retrospective review at a single institution.
      ]. Nonetheless, the presence of broad, aseptate or pauci-septate hyphae with wide-angle branching in affected tissue with evidence of tissue invasion remains a criterion for classifying mucormycosis as a proven infection [
      • De Pauw B.
      • Walsh T.J.
      • Donnelly J.P.
      • Stevens D.A.
      • Edwards J.E.
      • Calandra T.
      • et al.
      Revised definitions of invasive fungal disease from 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 (EORTC/MSG) Consensus Group.
      ].
      Likewise, although Mucorales was grown on culture in about 79% of cases, morphological evaluation of cultured isolates was observed to aid genera/species identification of the Mucorales pathogens in only about 53% of cases. Identification to the genus or species level is important for epidemiological and/or outbreak investigation studies, informing management of mucormycosis [
      • Gomes M.Z.R.
      • Lewis R.E.
      • Kontoyiannis D.P.
      Mucormycosis caused by unusual mucormycetes, non-Rhizopus, -Mucor, and -Lichtheimia species.
      ], and antifungal susceptibility testing [
      • Espinel-Ingroff A.
      • Chakrabarti A.
      • Chowdhary A.
      • Cordoba S.
      • Dannaoui E.
      • Dufresne O.
      • et al.
      Multicenter evaluation of MIC distributions for epidemiologic cutoff value definition to detect amphotericin B, posaconazole, and itraconazole resistance among the most clinically relevant species of Mucorales.
      ,
      • Guinea J.
      • Escribano P.
      • Vena A.
      • Muñoz P.
      • Martinez-Jiménez M.D.C.
      • Padilla B.
      • et al.
      Increasing incidence of mucormycosis in a large Spanish hospital from 2007 to 2015: epidemiology and microbiological characterization of the isolates.
      ]. Importantly, although the proportion of causative pathogens identified by culture in the review by Roden et al. steadily rose from none in the 1940s to 71% in the 2000s [
      • Roden M.M.
      • Zaoutis T.E.
      • Buchanan W.L.
      • Knudsen T.A.
      • Sakisova T.A.
      • Schaufele R.L.
      • et al.
      Epidemiology and outcome of zygomycosis: a review of 929 reported cases.
      ], in the current review culture contributed to diagnosis only in about 79% of cases. This may suggest that improvement in culture techniques and/or clinical awareness since the early 2000s has been moderate at best. As such, modern molecular-based methods of species identification and diagnosis, including the direct detection of Mucorales from clinical specimens, are required [
      • Bernal-Martínez L.
      • Buitrago M.J.
      • Castelli M.V.
      • Rodriguez-Tudela J.L.
      • Cuenca-Estrella M.
      Development of a single tube multiplex real-time PCR to detect the most clinically relevant Mucormycetes species.
      ,
      • Alanio A.
      • Garcia-Hermoso D.
      • Mercier-Delarue S.
      • Lanternier F.
      • Gits-Muselli M.
      • Menotti J.
      • et al.
      Molecular identification of Mucorales in human tissues: contribution of PCR electrospray-ionization mass spectrometry.
      ,
      • Millon L.
      • Larosa F.
      • Lepiller Q.
      • Legrand F.
      • Rocchi S.
      • Daguindau E.
      • et al.
      Quantitative polymerase chain reaction detection of circulating DNA in serum for early diagnosis of mucormycosis in immunocompromised patients.
      ,
      • Millon L.
      • Herbrecht R.
      • Grenouillet F.
      • Morio F.
      • Alanio A.
      • Letscher-Bru V.
      • et al.
      Early diagnosis and monitoring of mucormycosis by detection of circulating DNA in serum: retrospective analysis of 44 cases collected through the French Surveillance Network of Invasive Fungal Infections (RESSIF).
      ].
      In the present review, it was observed that molecular techniques have assisted with species identification, including that of the less common Mucorales pathogens, which may otherwise have not been able to be identified (Table 4). Importantly, Mucorales DNA was detected in 89% of cases where molecular methods were performed on clinical specimens, positioning these techniques as tests that can be used preceding specimen receipt for histopathology and culture. However, the clinical utility of molecular methods is currently limited by lack of technique standardization and clinical validation [
      • Walsh T.J.
      • Gamaletsou M.N.
      • McGinnis M.R.
      • Hayden R.T.
      • Kontoyiannis D.P.
      Early clinical and laboratory diagnosis of invasive pulmonary, extrapulmonary, and disseminated mucormycosis (zygomycosis).
      ]. Large-scale clinical studies are needed to evaluate the role of molecular approaches as the primary diagnostic modality of mucormycosis [
      • Millon L.
      • Herbrecht R.
      • Grenouillet F.
      • Morio F.
      • Alanio A.
      • Letscher-Bru V.
      • et al.
      Early diagnosis and monitoring of mucormycosis by detection of circulating DNA in serum: retrospective analysis of 44 cases collected through the French Surveillance Network of Invasive Fungal Infections (RESSIF).
      ].
      Of note, the distribution of the Mucorales pathogens varied according to geographical regions, potentially reflective of the different natural habitats [
      • Ribes J.A.
      • Vanover-Sams C.L.
      • Baker D.J.
      Zygomycetes in human disease.
      ]. Consistent with findings in other studies [
      • Skiada A.
      • Pagano L.
      • Groll A.
      • Zimmerli S.
      • Dupont B.
      • Lagrou K.
      • 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.
      ,
      • Lanternier F.
      • Dannaoui E.
      • Morizot G.
      • Elie C.
      • Garcia-Hermoso D.
      • Huerre M.
      • et al.
      A global analysis of mucormycosis in France: the RetroZygo study (2005–2007).
      ,
      • Ambrosioni J.
      • Bouchuiguir-Wafa K.
      • Garbino J.
      Emerging invasive zygomycosis in a tertiary care center: epidemiology and associated risk factors.
      ,
      • Pagano L.
      • Valentini C.G.
      • Posteraro B.
      • Girmenia C.
      • Ossi C.
      • Pan A.
      • et al.
      Zygomycosis in Italy: a survey of FIMUA-ECMM (Federazione Italiana di Micopatologia Umana ed Animale and European Confederation of Medical Mycology).
      ], our review suggested that Lichtheimia was a common pathogen in Europe. Apophysomyces, on the other hand, was less commonly observed in Europe [
      • Skiada A.
      • Pagano L.
      • Groll A.
      • Zimmerli S.
      • Dupont B.
      • Lagrou K.
      • 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.
      ,
      • Lanternier F.
      • Dannaoui E.
      • Morizot G.
      • Elie C.
      • Garcia-Hermoso D.
      • Huerre M.
      • et al.
      A global analysis of mucormycosis in France: the RetroZygo study (2005–2007).
      ,
      • Ambrosioni J.
      • Bouchuiguir-Wafa K.
      • Garbino J.
      Emerging invasive zygomycosis in a tertiary care center: epidemiology and associated risk factors.
      ,
      • Pagano L.
      • Valentini C.G.
      • Posteraro B.
      • Girmenia C.
      • Ossi C.
      • Pan A.
      • et al.
      Zygomycosis in Italy: a survey of FIMUA-ECMM (Federazione Italiana di Micopatologia Umana ed Animale and European Confederation of Medical Mycology).
      ], and has mainly been reported in regions with tropical or warm climates [
      • Chakrabarti A.
      • Chatterjee S.S.
      • Das A.
      • Panda N.
      • Shivaprakash M.R.
      • Kaur A.
      • et al.
      Invasive zygomycosis in India: experience in a tertiary care hospital.
      ,
      • Chakrabarti A.
      • Singh R.
      Mucormycosis in India: unique features.
      ,
      • Kennedy K.J.
      • Daveson K.
      • Slavin M.A.
      • Van Hal S.J.
      • Sorrell T.C.
      • Lee A.
      • et al.
      Mucormycosis in Australia: contemporary epidemiology and outcomes.
      ,
      • Meis J.F.
      • Chakrabarti A.
      Changing epidemiology of an emerging infection: zygomycosis.
      ]. Knowledge of the global epidemiology may help to inform and guide clinical decision-making before identification of the causative pathogens. However, it is worth noting that the distribution of Mucorales reported herein may be biased given that identification of the fungal organisms to the genus level only occurred in 53% of the cases. Further surveillance is warranted.
      Notably, mucormycosis-associated overall mortality remained high (46%), comparable to previous reports [
      • Roden M.M.
      • Zaoutis T.E.
      • Buchanan W.L.
      • Knudsen T.A.
      • Sakisova T.A.
      • Schaufele R.L.
      • et al.
      Epidemiology and outcome of zygomycosis: a review of 929 reported cases.
      ,
      • Skiada A.
      • Pagano L.
      • Groll A.
      • Zimmerli S.
      • Dupont B.
      • Lagrou K.
      • 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.
      ]. Additionally, we observed higher mortality among patients with Cunninghamella infections. However, it is worth noting that this fungus was isolated predominantly in patients with pulmonary or disseminated disease, both of which were associated with >50% mortality. Furthermore, patients' underlying conditions and treatment strategies employed may potentially contribute to the observed outcome. Factors influencing mortality will be investigated in ‘The contemporary management and clinical outcomes of mucormycosis: a systematic review’ (W. Jeong, C. Keighley, R. Wolfe, W. Lee, M. Slavin, S. Chen, and D. Kong, manuscript under review).

       Strength and weakness

      The current review provides the most recent and largest overview of the clinical epidemiology, diagnosis, and causative pathogens of mucormycosis. Cases included in this review were identified from comprehensive search of databases using a systematic search strategy. However, despite having applied stringent inclusion criteria, we are unable to rule out the possibility of missing some important cases aggregated in larger series, given that some individual patient data were unavailable in these series. Publication bias is another limiting factor as case reports of rare or atypical observations are more likely to be published, so potentially excluding the more common findings [
      • Nissen T.
      • Wynn R.
      The clinical case report: a review of its merits and limitations.
      ].

       Practice and research implications

      Findings from the current review have helped ascertain the association between various manifestations of mucormycosis and their respective predisposing factors. The distribution of Mucorales organisms across various disease manifestations and/or geographical regions was noted. Histopathology and/or culture remain the most common means of diagnosis but the use of molecular approaches has good utility in providing species identity of the Mucorales, enabling identification of less common or novel pathogens. Future studies should focus on standardization and optimization of molecular techniques and evaluation of the merits of incorporating molecular techniques into routine diagnostic algorithms.

      Transparency declaration

      MAS and SCAC have received grants unrelated to the current work from Pfizer, Merck Sharp and Dohme (MSD) and Gilead Sciences. DCMK has sat on advisory boards for Pfizer and MSD, and received financial/travel support unrelated to the current work from Roche, Pfizer and MSD. All other authors have no conflicts of interest to declare.

      Acknowledgements

      Preliminary data from this work was presented as a poster presentation at the 27th European Congress of Clinical Microbiology and Infectious Diseases, Vienna, Austria (22–25 April 2017), abstract 2078.

      Funding

      This was an investigator-initiated study supported by internal funding.

      Appendix A. Supplementary data

      The following is the supplementary data related to this article:

      References

        • Bitar D.
        • Lortholary O.
        • Le Strat Y.
        • Nicolau J.
        • Coignard B.
        • Tattevin P.
        • et al.
        Population-based analysis of invasive fungal infections, France, 2001–2010.
        Emerg Infect Dis. 2014; 20: 1149-1155
        • Slavin M.
        • van Hal S.
        • Sorrell T.C.
        • Lee A.
        • Marriott D.J.
        • Daveson K.
        • et al.
        Invasive infections due to filamentous fungi other than Aspergillus: epidemiology and determinants of mortality.
        Clin Microbiol Infect. 2015; 21: 490.e1-10
        • Park B.J.
        • Pappas P.G.
        • Wannemuehler K.A.
        • Alexander B.D.
        • Anaissie E.J.
        • Andes D.R.
        • et al.
        Invasive non-Aspergillus mold infections in transplant recipients, United States, 2001–2006.
        Emerg Infect Dis. 2011; 17: 1855-1864
        • Chakrabarti A.
        • Chatterjee S.S.
        • Das A.
        • Panda N.
        • Shivaprakash M.R.
        • Kaur A.
        • et al.
        Invasive zygomycosis in India: experience in a tertiary care hospital.
        Postgrad Med J. 2009; 85: 573-581
        • Lelievre L.
        • Garcia-Hermoso D.
        • Abdoul H.
        • Hivelin M.
        • Chouaki T.
        • Toubas D.
        • et al.
        Posttraumatic mucormycosis: a nationwide study in France and review of the literature.
        Medicine (Balt). 2014; 93: 395-404
        • Skiada A.
        • Rigopoulos D.
        • Larios G.
        • Petrikkos G.
        • Katsambas A.
        Global epidemiology of cutaneous zygomycosis.
        Clin Dermatol. 2012; 30: 628-632
        • Neblett Fanfair R.
        • Benedict K.
        • Bos J.
        • Bennett S.D.
        • Lo Y.C.
        • Adelbanjo T.
        • et al.
        Necrotizing cutaneous mucormycosis after a tornado in Joplin, Missouri, in 2011.
        New Engl J Med. 2012; 367: 2214-2225
        • Roden M.M.
        • Zaoutis T.E.
        • Buchanan W.L.
        • Knudsen T.A.
        • Sakisova T.A.
        • Schaufele R.L.
        • et al.
        Epidemiology and outcome of zygomycosis: a review of 929 reported cases.
        Clin Infect Dis. 2005; 41: 634-653
        • Ribes J.A.
        • Vanover-Sams C.L.
        • Baker D.J.
        Zygomycetes in human disease.
        Clin Microbiol Rev. 2000; 13: 236-301
        • Chakrabarti A.
        • Singh R.
        Mucormycosis in India: unique features.
        Mycoses. 2014; 57: 85-90
        • Alvarez E.
        • Garcia-Hermoso D.
        • Sutton D.A.
        • Cano J.F.
        • Stchigel A.M.
        • Hoinard D.
        • et al.
        Molecular phylogeny and proposal of two new species of the emerging pathogenic fungus Saksenaea.
        J Clin Microbiol. 2010; 48: 4410-4416
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        BMJ (Clin Res Ed). 2009; 339: b2535
        • De Pauw B.
        • Walsh T.J.
        • Donnelly J.P.
        • Stevens D.A.
        • Edwards J.E.
        • Calandra T.
        • et al.
        Revised definitions of invasive fungal disease from 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 (EORTC/MSG) Consensus Group.
        Clin Infect Dis. 2008; 46: 1813-1821
        • Kennedy K.J.
        • Daveson K.
        • Slavin M.A.
        • Van Hal S.J.
        • Sorrell T.C.
        • Lee A.
        • et al.
        Mucormycosis in Australia: contemporary epidemiology and outcomes.
        Clin Microbiol Infect. 2016; 22: 775-781
        • Morrison A.
        • Polisena J.
        • Husereau D.
        • Moulton K.
        • Clark M.
        • Flander M.
        • et al.
        The effect of English-language restriction on systematic review-based meta-analyses: a systematic review of empirical studies.
        Int J Technol Assess Health Care. 2012; 28: 138-144
        • Pagano L.
        • Offidani M.
        • Fianchi L.
        • Nosari A.
        • Candoni A.
        • Piccardi M.
        • et al.
        Mucormycosis in hematologic patients.
        Haematologica. 2004; 89: 207-214
        • Skiada A.
        • Pagano L.
        • Groll A.
        • Zimmerli S.
        • Dupont B.
        • Lagrou K.
        • 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: 1859-1867
        • Lanternier F.
        • Dannaoui E.
        • Morizot G.
        • Elie C.
        • Garcia-Hermoso D.
        • Huerre M.
        • et al.
        A global analysis of mucormycosis in France: the RetroZygo study (2005–2007).
        Clin Infect Dis. 2012; 54: S35-S43
        • Chakrabarti A.
        • Das A.
        • Mandal J.
        • Shivaprakash M.R.
        • George V.K.
        • Tarai B.
        • et al.
        The rising trend of invasive zygomycosis in patients with uncontrolled diabetes mellitus.
        Med Mycol. 2006; 44: 335-342
        • Rammaert B.
        • Lanternier F.
        • Zahar J.-R.
        • Dannaoui E.
        • Bougnoux M.E.
        • Lecuit M.
        • et al.
        Healthcare-associated mucormycosis.
        Clin Infect Dis. 2012; 54: S44-S54
        • Antoniadou A.
        Outbreaks of zygomycosis in hospitals.
        Clin Microbiol Infect. 2009; 15: 55-59
        • Kontoyiannis D.P.
        • Lewis R.E.
        How I treat mucormycosis.
        Blood. 2011; 118: 1216-1224
        • Kontoyiannis D.P.
        • Lionakis M.S.
        • Lewis R.E.
        • Chamilos G.
        • Healy M.
        • Perego C.
        • et al.
        Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case–control observational study of 27 recent case.
        J Infect Dis. 2005; 191: 1350-1360
        • Trifilio S.
        • Singhal S.
        • Williams S.
        • Frankfurt O.
        • Gordon L.
        • Evens A.
        • et al.
        Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole.
        Bone Marrow Transplant. 2007; 40: 451-456
        • Auberger J.
        • Lass-Flörl C.
        • Aigner M.
        • Clausen J.
        • Gastl G.
        • Nachbaur D.
        Invasive fungal breakthrough infections, fungal colonization and emergence of resistant strains in high-risk patients receiving antifungal prophylaxis with posaconazole: real-life data from a single-centre institutional retrospective observational study.
        J Antimicrob Chemother. 2012; 67: 2268-2273
        • Lamoth F.
        • Chung S.J.
        • Damonti L.
        • Alexander B.D.
        Changing epidemiology of invasive mold infections in patients receiving azole prophylaxis.
        Clin Infect Dis. 2017; 64: 1619-1621
        • Sangoi A.R.
        • Rogers W.M.
        • Longacre T.A.
        • Montoya J.G.
        • Baron E.J.
        • Banaei N.
        Challenges and pitfalls of morphologic identification of fungal infections in histologic and cytologic specimens: a ten-year retrospective review at a single institution.
        Am J Clin Pathol. 2009; 131: 364-375
        • Gomes M.Z.R.
        • Lewis R.E.
        • Kontoyiannis D.P.
        Mucormycosis caused by unusual mucormycetes, non-Rhizopus, -Mucor, and -Lichtheimia species.
        Clin Microbiol Rev. 2011; 24: 411-445
        • Espinel-Ingroff A.
        • Chakrabarti A.
        • Chowdhary A.
        • Cordoba S.
        • Dannaoui E.
        • Dufresne O.
        • et al.
        Multicenter evaluation of MIC distributions for epidemiologic cutoff value definition to detect amphotericin B, posaconazole, and itraconazole resistance among the most clinically relevant species of Mucorales.
        Antimicrob Agents Chemother. 2015; 59: 1745-1750
        • Guinea J.
        • Escribano P.
        • Vena A.
        • Muñoz P.
        • Martinez-Jiménez M.D.C.
        • Padilla B.
        • et al.
        Increasing incidence of mucormycosis in a large Spanish hospital from 2007 to 2015: epidemiology and microbiological characterization of the isolates.
        PLoS ONE. 2017; 12e0179136
        • Bernal-Martínez L.
        • Buitrago M.J.
        • Castelli M.V.
        • Rodriguez-Tudela J.L.
        • Cuenca-Estrella M.
        Development of a single tube multiplex real-time PCR to detect the most clinically relevant Mucormycetes species.
        Clin Microbiol Infect. 2013; 19: E1-E7
        • Alanio A.
        • Garcia-Hermoso D.
        • Mercier-Delarue S.
        • Lanternier F.
        • Gits-Muselli M.
        • Menotti J.
        • et al.
        Molecular identification of Mucorales in human tissues: contribution of PCR electrospray-ionization mass spectrometry.
        Clin Microbiol Infect. 2015; 21: 594.e1-594.e5
        • Millon L.
        • Larosa F.
        • Lepiller Q.
        • Legrand F.
        • Rocchi S.
        • Daguindau E.
        • et al.
        Quantitative polymerase chain reaction detection of circulating DNA in serum for early diagnosis of mucormycosis in immunocompromised patients.
        Clin Infect Dis. 2013; 56: e95-e101
        • Millon L.
        • Herbrecht R.
        • Grenouillet F.
        • Morio F.
        • Alanio A.
        • Letscher-Bru V.
        • et al.
        Early diagnosis and monitoring of mucormycosis by detection of circulating DNA in serum: retrospective analysis of 44 cases collected through the French Surveillance Network of Invasive Fungal Infections (RESSIF).
        Clin Microbiol Infect. 2016; 22: 810.e1-810.e8
        • Walsh T.J.
        • Gamaletsou M.N.
        • McGinnis M.R.
        • Hayden R.T.
        • Kontoyiannis D.P.
        Early clinical and laboratory diagnosis of invasive pulmonary, extrapulmonary, and disseminated mucormycosis (zygomycosis).
        Clin Infect Dis. 2012; 54: S55-S60
        • Ambrosioni J.
        • Bouchuiguir-Wafa K.
        • Garbino J.
        Emerging invasive zygomycosis in a tertiary care center: epidemiology and associated risk factors.
        Int J Infect Dis. 2010; 14: e100-e103
        • Pagano L.
        • Valentini C.G.
        • Posteraro B.
        • Girmenia C.
        • Ossi C.
        • Pan A.
        • et al.
        Zygomycosis in Italy: a survey of FIMUA-ECMM (Federazione Italiana di Micopatologia Umana ed Animale and European Confederation of Medical Mycology).
        J Chemother. 2009; 21: 322-329
        • Meis J.F.
        • Chakrabarti A.
        Changing epidemiology of an emerging infection: zygomycosis.
        Clin Microbiol Infect. 2009; 15: 10-14
        • Nissen T.
        • Wynn R.
        The clinical case report: a review of its merits and limitations.
        BMC Res Notes. 2014; 7: 264