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During pulmonary mucormycosis, inhaled sporangiospores adhere to, germinate, and invade airway epithelial cells to establish infection. We provide evidence that HIF1α plays dual roles in airway epithelial cells during Mucorales infection. We observed an increase in HIF1α protein accumulation and increased expression of many known HIF1α-responsive genes during in vitro infection, indicating that HIF1α signaling is activated by Mucorales infection. Inhibition of HIF1α signaling led to a substantial decrease in the ability of R. delemar to invade cultured airway epithelial cells. Transcriptome analysis revealed that R. delemar infection induces the expression of many pro-inflammatory genes whose expression was significantly reduced by HIF1α inhibition. Importantly, pharmacological inhibition of HIF1α increased survival in a mouse model of pulmonary mucormycosis without reducing fungal burden. These results suggest that HIF1α plays two opposing roles during mucormycosis: one that facilitates the ability of Mucorales to invade the host cells and one that facilitates the ability of the host to mount an innate immune response., (© 2024. The Author(s).)

Background: Due to a delay in diagnosis by conventional techniques and high mortality, the development of a standardised and rapid non-culture-based technique is an unmet need in pulmonary, gastrointestinal, and disseminated forms of mucormycosis. Though limited studies have been conducted for molecular diagnosis, there are no established serologic tests for this highly fatal infection., Objective: To develop and evaluate an indirect in-house enzyme-linked immunosorbent assay (ELISA) utilising antigens of Rhizopus arrhizus for detecting anti-Rhizopus antibodies (IgG and IgM) in sera of patients with mucormycosis., Methods: We extracted both secretory and mycelial Rhizopus antigens using standardised protocols. Bradford assay was used for protein quantification. We then standardised an indirect ELISA using R. arrhizus mycelial and secretory antigens (10.0 μg/mL in bicarbonate buffer pH 9.2) for detecting anti-Rhizopus IgG and IgM antibodies in patient sera. We included patients with mucormycosis, other fungal infections, and healthy controls. Antibody index value (E-value) was calculated for each patient sample., Results: Asparagine broth culture filtrate utilising 85% ammonium sulphate salt fractionation and mycelial homogenate grown in yeast extract peptone dextrose (YPD) broth precipitated with trichloroacetic acid (TCA) yielded a large amount of good-quality protein for the assay. We included 55 patients with mucormycosis (rhino-orbito-cerebral mucormycosis [ROCM, n = 39], pulmonary [n = 15], gastrointestinal [n = 1]), 24 with other fungal infections (probable aspergillosis [n = 14], candidiasis [n = 10]), and healthy controls (n = 16). The sensitivity of the antibody test for diagnosing mucormycosis ranged from 83.6-92.7% for IgG and 72.7-87.3% for IgM, with a specificity of 91.7-92.5% for IgG and 80-82.5% for IgM. The sera from patients with other fungal infections and healthy individuals did not show significant cross-reactivity., Conclusion: The detection of anti-Rhizopus IgG antibody performed significantly better in comparison to IgM-based ELISA for diagnosing both ROCM (sensitivity of 84.6% vs. 69.2%) and pulmonary cases (86.6% vs. 80.0%). More extensive studies are required to confirm our findings., (© 2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

Mucormycosis, a group of opportunistic mycoses caused by Mucorales, present a significant threat to immunocompromised patients. In this report, we present the case of a 57-year-old male patient who underwent liver transplant for secondary biliary cirrhosis following inadvertent bile duct injury. Despite initial satisfactory postoperative evolution, the patient developed fever, and imaging revealed a suspicious lesion. Preliminary culture growth suggested a filamentous fungus, leading to initiation of liposomal amphotericin B. However, the lesion progressed, and a surgical debridement was necessary. During surgery, involvement of the liver dome and diaphragm was observed, and a nonanatomical hepatectomy was performed. Despite efforts, the patient's condition deteriorated, ultimately resulting in multiple organ failure and mortality. This case emphasizes the challenging nature of mucormycosis in livertransplant recipients.

Purpose: The aim was to evaluate patient profiles of rhino-orbital-cerebral mucormycosis (ROCM) cases with central retinal artery occlusion (CRAO) postcoronavirus disease 2019., Design: A nonrandomized retrospective case-control study., Methods: The ROCM cases presenting with CRAO were compared with a control ROCM group without CRAO at a tertiary care center. Demography, systemic status, clinical features, histopathology, imaging, and blood profile were assessed for any specific risk factors., Results: A total of 12 patients were seen in the CRAO group and 16 in the non-CRAO group. The male-to-female ratio was 3:1 with a mean age of 49.5 years. In the CRAO group, 75% had diabetes mellitus with mean hemoglobin A1c of 9.03%, and 66.7% had received steroid treatment. All cases were histopathologically confirmed positive for mucor. There was a significant difference in mean D-dimer and serum ferritin between the 2 groups, with higher level in the CRAO group. All patients with CRAO had light perception-negative vision, with total ophthalmoplegia and proptosis seen in 66.7% of cases. Four patients had orbital apex involvement, 5 had cavernous sinus involvement, and 8 had intracranial involvement in the CRAO group., Conclusions: Inflammatory markers D-dimer and serum ferritin were significantly associated with CRAO, suggestive of hyperinflammatory and hypercoagulable state. A high index of suspicion should be maintained in cases with elevated markers and prophylactic anticoagulants can be started to prevent CRAO in a subset of patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.)

The COVID-19 patients, both infected and recovered are rapidly contracting mucormycetes infections due to the 'Mucorales' order, under Zygomycetes class of fungi. The mucorales fungi commonly known to exist in our natural surroundings including soil, but the frequency of incidences was never rampant. This sudden spike in infections, is locally known as 'black fungus,' and is affecting various organs, including- eyes, sinuses, nose, brain, skin, intestine, lungs, etc. The severity of situation is ascertainable from the fact that, in certain cases surgical eye/jaws removal persists as the only viable option to avert mortality, as therapeutic interventions are limited. This epidemic situation intrigued experts to investigate the probable reason behind this unpredicted escalation in reported cases, including in recuperated COVID-19 patients, as person-to-person spread of infection is not common. The comparison of physiological parameters in healthy and COVID-19 afflicted patients highlights that the underlying conditions including diabetes mellitus, steroidal therapy, lymphopenia (decreased CD4+ and CD8+ lymphocytes), deregulated cytokine release storm, elevated free iron levels (hemosiderosis) in blood and insulin insensitivity are playing major roles in deteriorating conditions in rarely pathogenic fungal infections. This review is an attempt to explain the rationalities that makes people vulnerable to mucormycetes infection., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: It is an incontrovertible fact that the Rhino Orbital Cerebral Mucormycosis (ROCM) upsurge is being seen in the context of COVID-19 in India. Briefly presented is evidence that in patients with uncontrolled diabetes, a dysfunctional immune system due to SARS-COV-2 and injudicious use of corticosteroids may be largely responsible for this malady., Objective: To find the possible impact of COVID 19 infection and various co-morbidities on occurrence of ROCM and demonstrate the outcome based on medical and surgical interventions., Methodology: Prospective longitudinal study included patients diagnosed with acute invasive fungal rhinosinusitis after a recent COVID-19 infection. Diagnostic nasal endoscopy (DNE) was performed on each patient and swabs were taken and sent for fungal KOH staining and microscopy. Medical management included Injection Liposomal Amphotericin B, Posaconazole and Voriconazole. Surgical treatment was restricted to patients with RT PCR negative results for COVID-19. Endoscopic, open, and combined approaches were utilized to eradicate infection. Follow-up for survived patients was maintained regularly for the first postoperative month., Results: Out of total 131 patients, 111 patients had prior history of SARS COVID 19 infection, confirmed with a positive RT-PCR report and the rest 20 patients had no such history. Steroids were received as a part of treatment in 67 patients infected with COVID 19. Among 131 patients, 124 recovered, 1 worsened and 6 died. Out of 101 known diabetics, 98 recovered and 3 had fatal outcomes. 7 patients with previous history of COVID infection did not have any evidence of Diabetes mellitus, steroid intake or any other comorbidity., Conclusion: It can be concluded that ROCM upsurge seen in the context of COVID-19 in India was mainly seen in patients with uncontrolled diabetes, a dysfunctional immune system due to SARS-COV-2 infection and injudicious use of corticosteroids., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of interests We declare no competing interests.

Background: Mucormycosis (zygomycosis) is an invasive fungal infection that carries a high risk of morbidity and mortality. Uncontrolled diabetes mellitus and other immunocompromising conditions are risk factors for mucormycosis development. We here describe the differences in characteristics and outcomes of mucormycosis among solid organ transplant, hematological malignancy, and diabetes mellitus groups at our institution., Methods: We conducted a retrospective chart review over the period of 2009-2020, with identifying patients using the International Classification of Diseases, Ninth and Tenth Revisions. Clinical, laboratory, and outcome data were collected., Results: There were 28 patients identified: 7 solid organ transplant, 3 hematological malignancy, and 18 diabetes mellitus patients were included in the study. Three solid organ transplant patients experienced an episode of rejection, and another 3 had cytomegalovirus infection prior to presenting with mucormycosis. Four of seven solid organ transplant patients had a history of diabetes mellitus, but the median hemoglobin A1C was lower than in the diabetes mellitus group (6.3 vs 11.5; P = .006). The mortality rate difference between solid organ transplant and diabetes mellitus was not statistically significant: 2/7 (28.57%) vs 5/18 (27.78%); P = .66. Patients with bilateral disease (pulmonary or sinus) had significantly higher mortality (80% vs 13%, P = .008). There was no difference in mortality outcomes among the different types of antifungal therapies administered., Conclusion: A multispecialty approach is imperative in mucormycosis therapy. While the underlying risk factors were different, the outcomes were comparable for the solid organ transplant and diabetes mellitus groups. Future larger and longitudinal studies are recommended., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: In recent times, improved diagnostic techniques have revealed an alarming number of cases of mucormycosis in immunocompetent individuals. The Saksenaea species, is a rare cause of mucormycosis, and is often associated with skin and subcutaneous infection due to trauma in both immunocompromised and immunocompetent subjects. The purpose of this study was therefore, through a review of the literature, to investigate the problem of infections caused by Saksenaea Erythrospora, evaluating the clinical manifestations of the infection, the triggering factors, the therapies and patients' outcomes, implementing and updating what already reported in literature., Methods: A research of peer-reviewed literature in the electronic databases MEDLINE (PubMed) and Scopus was conducted in the period June 2020-January 2021 using the key word "Saksenaea erythrospora". Studies in Italian, English, French, Spanish focused on cases of Saksenaea erythrospora were included, without time restrictions. Studies that provided ambiguous or insufficient data were excluded., Results: Bibliographic research yielded 23 publications; 7 were included in the review. The studies were published between 2011 and 2015 and involved a total of 11 patients of average age 37.9 years (SD 17.23) hospitalized in several hospitals in: USA, India, Argentina, Colombia, Thailand. 6 patients were women, 5 men. All patients had an almost normal immune status. The causes of the infection were: injections, traumas, surgery. Two patients, despite surgical and medical therapy, died., Conclusions: Our review partially updated what already published, because only one new study was found. Serious necrotizing infections from Saksenaea erythrospora have been observed in recent years and a early identification and timely management are essential to reduce morbidity and mortality. A greater awareness and education about the risks deriving from carrying out surgical procedures abroad, especially in precarious hygiene situations, could be additional effective weapons to reduce the incidence of these infections., Competing Interests: Conflict of interest statement The authors declare no conflict of interest., (©2021 Pacini Editore SRL, Pisa, Italy.)

Alveolar macrophages (AM) are the first-line lung defense against Mucorales in pulmonary mucormycosis. Since corticosteroid use is a known risk factor for mucormycosis, the aim of this study was to describe the role of corticosteroids on AM capacities to control Lichtheimia corymbifera spore growth using a new ex vivo model. An in vivo mouse model was developed to determine the acetate cortisone dose able to trigger pulmonary invasive infection. Then, in the ex vivo model, male BALB/c mice were pretreated with the corticosteroid regimen triggering invasive infection, before AM collection through bronchoalveolar lavage. AMs from corticosteroid-treated mice and untreated control AMs were then exposed to L. corymbifera spores in vitro (ratio 1:5). AM control of fungal growth, adherence/phagocytosis, and oxidative burst were assessed using optical densities by spectrophotometer, flow cytometry, and 2', 7'-dichlorofluoresceine diacetate fluorescence, respectively. Cortisone acetate at 500 mg/kg, at D-3 and at D0, led to pulmonary invasive infection at D3. Co-incubated spores and AMs from corticosteroid-treated mice had significantly higher absorbance (fungal growth) than co-incubated spores and control AMs, at 24 h (P = .025), 36 h (P = .004), and 48 h (P = .001). Colocalization of spores with AMs from corticosteroid-treated mice was significantly lower than for control AMs (7.6 ± 1.9% vs 22.3 ± 5.8%; P = .003), reflecting spore adherence and phagocytosis inhibition. Finally, oxidative burst was significantly increased when control AMs were incubated with spores (P = 0.029), while corticosteroids hampered oxidative burst from treated AMs (P = 0.321). Corticosteroids enhanced fungal growth of L. corymbifera through AM phagocytosis inhibition and burst oxidative decrease in our ex vivo model., Lay Summary: The aim of this study was to describe the impact of corticosteroids on alveolar macrophage (AM) capacities to control Mucorales growth in a new murine ex vivo model. Corticosteroids enhanced fungal growth of L. corymbifera through AM phagocytosis inhibition and burst oxidative decrease., (© The Author(s) 2020. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Since the onset of COVID-19 pandemic, parallel opportunistic infections have also been emerging as another disease spectrum. Among all these opportunistic infection, mucormycosis has become a matter of concern with its rapid increase of cases with rapid spread as compared to pre-COVID-19 era. Cases have been reported in post-COVID-19-related immune suppression along with the presence of comorbidity which adds on the deadly outcome. There is no systematic review addressing the issue of COVID-19-associated mucormycosis. This is the first systematic review of published studies of mucormycosis associated with COVID-19. The aim was to analyze the real scenario of the disease statement including all the published studies from first November 2019 to 30th June to analyze the contemporary epidemiology, clinical manifestations, risk factor, prognosis, and treatment outcome of COVID-19 associated rhino-orbito-cerebral-mucormycosis. A comprehensive literature search was done in following databases, namely, PubMed, Google Scholar, Scopus, and EMBASE using keywords mucormycosis, rhino orbital cerebral mucormycosis, COVID-19, and SARS-CoV-2 (from November 01, 2019 to June 30, 2021). Our study shows that, while corticosteroids have proved to be lifesaving in severe to critical COVID-19 patients, its indiscriminate use has come with its price of rhino-orbito-cerebral mucormycosis epidemic, especially in India especially in patients with preexisting diabetes mellitus with higher mortality. Corticosteroid use should be monitored and all COVID-19 patients should be closely evaluated/monitored for sequelae of immunosuppression following treatment., Competing Interests: None

Mucormycosis is an invasive, life-threatening fungal infection that mainly affects immunocompromised hosts. We collected data of pediatric mucormycosis cases from all 7 Greek Hematology-Oncology Departments for the years 2008-2017. Six cases of invasive mucormycosis diagnosed during treatment for malignancies were included in the study. In 4 children (66%) mucormycosis occurred within the first 20 days after diagnosis of the underlying disease. Two cases were classified as proven mucormycosis and 4 as probable. The most frequently recorded species was Rhizopus arrhizus (2 patients), followed by Mucor spp (1), and Lichtheimia spp (1). All patients received liposomal amphotericin B. Combined antifungal treatment was used in 5 cases. Surgical excision was performed in 4 cases (66%). Two patients died at 6 and 12 months after the diagnosis, respectively, 1 (17%) because of mucormycosis. Our data suggest that mucormycosis may occur early after the initiation of intensive chemotherapy in children with malignancies., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Activation of mucosal-associated invariant T cells (MAIT cells) by certain bacteria, viruses, and yeast is well studied, but the activation potential of filamentous moulds from the order Mucorales is not known. Here, we show a rapid response of human MAIT cells against the Mucorales species Mucor circinelloides, Rhizopus arrhizus, and Rhizopus microsporus. This activation included upregulation of CD69 and degranulation marked by increased CD107a expression, while intracellular perforin and granzyme A expression were reduced. Furthermore, blocking of the antigen-presenting molecule major histocompatibility complex class I-related abrogated MAIT cell activation demonstrating a T cell receptor-dependent stimulation by Mucorales., (The Author(s) 2020. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Introduction: Rhinocerebral mucormycosis is a rare and severe form of opportunistic fungal infection that can develop rapidly and cause significant mortality, particularly among diabetic patients suffering from ketoacidosis. Diagnosing rhinocerebral mucormycosis during the early stages of infection is challenging., Case Presentation: We describe a case of rhinocerebral mucormycosis secondary to severe acute pancreatitis in a patient suffering from diabetic ketoacidosis. In this case, the condition was not diagnosed during the optimal treatment window. we therefore provide a thorough overview of related clinical findings and histopathological characteristics, and we discuss potential differential diagnoses., Conclusions: In summary, we described a case of rhinocerebral mucormycosis secondary to severe acute pancreatitis in a patient suffering from diabetic ketoacidosis, with the optimal treatment window for this condition having been missed. This report suggests that a definitive mucormycosis diagnosis can be made based upon tissue biopsy that reveals the presence of characteristic hyphae. Early diagnosis and treatment are essential in order to improve patient prognosis.

Mucor irregularis is a frequently found fungus in Asia, especially China, and it causes primary cutaneous mucormycosis with a high rate of disfigurement. Caspase recruitment domain-containing protein 9 (Card9) is an essential adaptor molecule downstream of C-type lectin receptors. It mediates the activation of nuclear factor kappa B (NF-κB), regulates T helper 1 (Th1) and Th17 differentiation, and plays an important role in fungal immune surveillance. CARD9 deficiency correlates with the increased susceptibility to many fungal infections, including cutaneous mucormycosis caused by M. irregularis However, the underlying immunological mechanisms were not elucidated. Our study established a murine model of subcutaneous M. irregularis infection, and we isolated immune cells, including bone marrow-derived macrophages, bone marrow-derived dendritic cells, naive T cells, and neutrophils, from wild-type (WT) and Card9 knockout ( Card9 -/- ) mice to examine the antifungal effect of Card9 on M. irregularis in vivo and in vitro Card9 -/- mice exhibited increased susceptibility to M. irregularis infection. Impaired local cytokine and chemokine production, NF-κB (p65) activation, and Th1/17 cell differentiation and partially impaired neutrophil-dependent antifungal immunity were observed in Card9 -/- mice. This work enriches our knowledge of the relationship between CARD9 deficiency and mucormycosis., (Copyright © 2021 American Society for Microbiology.)

Mucormycosis is an invasive mould that can cause aggressive infection, particularly in immunocompromised patients. Though oesophageal mucormycosis is relatively rare, it remains an elusive and devastating manifestation of this disease. The management is also challenging, due to surgical morbidity and contraindications such as thrombocytopenia in immunocompromised hosts. In this report, we present the case of a 60-year-old Lebanese man with newly diagnosed acute myeloid leukaemia who developed oesophageal mucormycosis after induction chemotherapy with idarubicin/cytarabine (7+3). The diagnosis was made when the patient developed febrile neutropenia and odynophagia. CT scan of the chest revealed a thickened oesophagus. Oesophagogastroduodenoscopy with biopsy, histopathology and PCR were performed, resulting in the diagnosis of Rhizopus microsporus The patient was successfully treated with liposomal amphotericin B and salvage posaconazole therapy without surgical intervention. We reviewed the clinical characteristics of the six published oesophageal mucormycosis reports from the literature., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Preseptal cellulitis and postseptal (orbital) cellulitis represent a spectrum of orbital infections which a primary care provider and ophthalmologist may see during practice. Most often these conditions occur through spread from the sinuses, though there are a variety of other inciting factors. These conditions can both present with erythema and edema, but a complete and thorough exam can help a practitioner differentiate the two. Patients should be treated with targeting the most common pathogens and followed very closely by their providers. This article will discuss the anatomy, pathogenesis, risk factors, diagnosis, management and prognosis of preseptal and orbital cellulitis., (Copyright © 2020. Published by Elsevier Inc.)

We describe an elderly diabetic patient presenting with sudden onset right-sided proptosis and vision loss secondary to rhino-orbital mucormycosis and central retinal vascular occlusion. He underwent orbital exenteration that was complicated by intraoperative cerebrospinal fluid (CSF) leak from lateral orbital wall. The leak was surgically repaired and the patient recovered well. We postulate the cause of the CSF leak to be twofold: necrotic periorbital tissue due to mucormycosis rendering the thin bones susceptible to damage and second, intraoperative manipulation and dissection at the orbital apex with monopolar cautery and instruments. We describe measures taken to successfully repair the CSF leak and the possible precautions that can be taken to avoid it., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To investigate MRI features in discriminating chronic invasive fungal rhinosinusitis (CIFRS) from sinonasal squamous cell carcinomas (SNSCC)., Methods: MRI findings of 33 patients with CIFRS and 47 patients with SNSCC were retrospectively reviewed and compared. Multivariate logistic regression analysis was performed to identify significant imaging features in distinguishing between CIFRS and SNSCC. The ROC curves and the AUC were used to evaluate diagnostic performance., Results: There were significant differences in cavernous sinus involvement (p < 0.001), sphenoid sinus involvement (p < 0.001), meningeal involvement (p = 0.024), T2 signal intensity (p = 0.006), and enhancement pattern (p < 0.001) between CIFRS and SNSCC. Multivariate logistic regression analysis identified cavernous sinus involvement (odds ratio [OR] = 0.06, 95% confidence interval [95% CI] = 0.02-0.20) and sphenoid sinus involvement (OR = 0.14, 95% CI = 0.05-0.45) as significant indicators for CIFRS and T2 isointensity to gray matter (OR = 4.44, 95% CI = 1.22-16.22) was a significant indicator for SNSCC. ROC curve analysis showed the AUC from a combination of three imaging features was 0.95 in differentiating CIFRS and SNSCC., Conclusions: MRI showed significant differences between CIFRS and SNSCC features. In immunocompromised patients, a sinonasal hypointense mass on T2WI with septal enhancement or loss of contrast enhancement, and involvement of cavernous sinus, sphenoid sinus, and meninges strongly suggest CIFRS., Key Points: • Chronic invasive fungal rhinosinusitis (CIFRS) is often difficult to distinguish from sinonasal squamous cell carcinomas (SNSCC) in clinical practice. • Cavernous sinus and sphenoid sinus involvement appear to be significant indicators for CIFRS. T2 isointensity to gray matter appears to be a significant indicator for SNSCC. • Loss of contrast enhancement and septal enhancement can be used to distinguish CIFRS from SNSCC with a high degree of specificity.

Pathogenic mucormycetes induce diseases with considerable morbidity and mortality in immunocompromised patients. Virulence data comparing different Mucorales species and various underlying risk factors are limited. We therefore compared the pathogenesis of inhalative infection by Rhizopus (R.) arrhizus and Lichtheimia (L.) corymbifera in murine models for predominant risk factors for onset of infection. Mice with diabetes or treated with cyclophosphamide or cortisone acetate were challenged via the intranasal route with an isolate of R. arrhizus or L. corymbifera, respectively. Clinical, immunological and inflammation parameters as well as efficacy of posaconazole prophylaxis were monitored over 14 days. Whereas immunocompetent mice showed no clinical symptoms after mucormycete infection, mice treated with either cyclophosphamide (CP) or cortisone acetate (CA) were highly susceptible. Animals infected with the isolate of R. arrhizus showed prolonged survival and lower mortality, compared to those exposed to the L. corymbifera isolate. This lower virulence of R. arrhizus was risk factor-dependent, since diabetic mice died only after infection with Rhizopus, whereas all Lichtheimia-infected diabetic animals survived. Under posaconazole prophylaxis, both mucormycetes were able to establish breakthrough infections in CA- and CP-treated mice, but the course of infection was significantly delayed. Detailed analysis revealed that susceptibility of CA- and CP-treated mice could not be mimicked by exclusive lack or downmodulation of neutrophils, platelets or complement, but can be supposed to be the consequence of a broad immunosuppressive effect induced by the drugs. Both Lichtheimia corymbifera and Rhizopus arrhizus induce invasive mycoses in immunocompromised hosts after inhalative infection. Key parameters such as virulence and immunopathogenesis vary strongly according to fungal species and underlying risk group. Selected neutropenia is no sufficient risk factor for onset of inhalative mucormycosis., Competing Interests: The authors have declared that no competing interests exist. As mentioned in the Funding Statement, the “INNPATH GmbH” is a diagnostic institute for clinical pathology and molecular pathology and is a 100% affiliate of the “Tirol Kliniken” (Tyrol Clinics). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Aim: To investigate the immune response of disseminated Ryzopus oryzae infection in immunocompetent mice. Methods: C57Bl/6, BALB/c and Swiss wild-type mice were intravenously infected with R. oryzae ; the parameters of infection and immune response were determined. Transcriptional signature of Th17 immune response and infection in Il17ra -/- mice were also evaluated. Results: All mouse strains showed an initial spread of R. oryzae in the target tissues; however, after 30 days, C57Bl/6 and BALB/c mice showed an effective fungal clearance associated with specific production of IL-17 and IL-2. We also observed that 60% of Il17ra -/- mice succumbed to infection within 16 days. Conclusion: This study has established an immunocompetent model for disseminated mucormycosis and highlighted the role of IL-17 signaling in immunity against R. oryzae .

Pulmonary mucormycosis (PM) is an uncommon fungal infection most often seen in immunocompromised patients. The fungus grows on decaying food, soil, and animal excrement. Patients usually become infected by inhalation of spores. The most common risk factors include diabetes mellitus, hematologic malignancy, and solid organ or stem cell transplant. PM can have a nonspecific appearance at imaging. For example, early imaging may show peribronchial ground-glass opacity. Later, the disease progresses to consolidation, nodules, or masses. Because patients are usually immunocompromised, the differential diagnosis often includes invasive pulmonary aspergillosis (IPA). Various radiologic findings suggestive of PM have been identified to help differentiate it from IPA. For example, the reverse halo sign is more closely associated with PM than with IPA. The reverse halo sign is an area of ground-glass opacity surrounded by a rim of consolidation. In addition, the presence of pleural effusions and more than 10 nodules is more suggestive of PM than it is of IPA. PM can progress rapidly in neutropenic patients. Identification of the hyphae in tissue by using endobronchial or percutaneous sampling can allow differentiation from IPA and help confirm the diagnosis of mucormycosis. Because of the high mortality rate associated with PM, early identification of the disease is critical for an improved likelihood of survival. A multimodality treatment approach with antifungal agents and surgical débridement has been shown to improve outcomes. The authors review the risk factors for PM, describe its imaging appearance and disease process, and describe the treatment of the disease. © RSNA, 2020.

Surgical-site mucormycosis infections in solid-organ transplant recipients are rare conditions, with only 15 previously reported cases. We describe a case of a 49-year-old man who received a liver transplant due to alcoholic cirrhosis. On postoperative day 14, necrosis was noticed at the surgical site. After mucormycosis was diagnosed, monotherapy with amphotericin was started along with surgical debridements. Due to continued clinical deterioration, triple antifungal therapy was started with amphotericin, micafungin and posaconazole. Treatment with a granulocyte-macrophage colony-stimulating factor was also started. Despite therapy, the patient expired on postoperative day 31. We review the risk factors for mucormycosis infection in solid-organ transplant recipients as well as evidence for current treatment options. We also review the 15 previously reported cases of surgical-site mucormycosis infections in solid-organ transplant recipients, including time to infection, infecting organisms, mortality and treatments., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

A 49-year-old man underwent ABO-incompatible kidney transplantation with a living donor. At day 33 post-transplantation, he presented with undiagnosed epilepsy with generalized tonic-clonic seizures. At day 44 post-transplantation, he developed left-sided pneumonia attributed to Aspergillus fumigatus and treatment with liposomal amphotericin B was initiated. At day 51 post-transplantation, necrotic skin lesions appeared. DNA sequencing in a fresh cutaneous biopsy finally identified Cunninghamella Spp., a member of the order Mucorales. Unfortunately, the necrotic lesions spread, and the patient died at day 60 post-transplantation. This case report highlights the infectious risk related to ABO-incompatible kidney transplantation and suggests a requirement for rapid identification of every skin lesion, even in the early phases of immunosuppression., (© 2019 Wiley Periodicals, Inc.)

Mucormycoses are life-threatening infections that affect patients suffering from immune deficiencies. We performed phagocytosis assays confronting various strains of Lichtheimia species with alveolar macrophages, which form the first line of defence of the innate immune system. To investigate 17 strains from four different continents in a comparative fashion, transmitted light and confocal fluorescence microscopy was applied in combination with automated image analysis. This interdisciplinary approach enabled the objective and quantitative processing of the big volume of image data. Applying machine-learning supported methods, a spontaneous clustering of the strains was revealed in the space of phagocytic measures. This clustering was not driven by measures of fungal morphology but rather by the geographical origin of the fungal strains. Our study illustrates the crucial contribution of machine-learning supported automated image analysis to the qualitative discovery and quantitative comparison of major factors affecting host-pathogen interactions. We found that the phagocytic vulnerability of Lichtheimia species depends on their geographical origin, where strains within each geographic region behaved similarly, but strongly differed amongst the regions. Based on this clustering, we were able to also classify clinical isolates with regard to their potential geographical origin., (© 2019 The Authors. Environmental Microbiology published by Society for Applied Microbiology and John Wiley & Sons Ltd.)

Card9 is a signalling adaptor protein in the downstream of many innate pattern recognition receptors (PRRs) and exerts a significant role in antifungal immunity. To date, Card9 deficiency has been reported to be related to increased susceptibility to many fungal infections. In this study, we established mucormycosis murine model of Rhizopus arrhizus (R. arrhizus) using wild-type (WT) mice and Card9 knockout (Card9 -/- ) mice to investigate the antifungal effect of Card9 against R. arrhizus infection. Card9 -/- mice were more susceptible to R. arrhizus infection than WT mice, which could be related to the impaired NF-κB pathway activation, local cytokine production and Th cell responses in Card9 -/- mice., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Mucormycosis is a severe infection in renal transplant recipients. Here, we report a case of maxillary sinus mucormycosis in a patient who presented with a facial pain complaint., Case: A 51-year-old female patient with renal transplantation due to autosomal dominant, polycystic kidney disease and diabetic nephropathy was admitted to our hospital with facial pain and minimal edema of the left half of her face on the 8th month of transplantation. On physical examination, there was only tenderness and slight edema on the left half of the face. On the paranasal computed tomography, extensive soft tissue densities involving septations, filling the left maxillary sinus, extending to the nasal cavity, and obliterating the left osteometeal unit were observed. Because facial pain was not relieved by antibiotics and several, potent analgesic drugs on the second day, mucormycosis infection with bone involvement was suspected. A left maxillary sinus excision was performed. Microscopic examination of the debridement specimen revealed necrotic bone interspersed with fungal hyphae, and culture isolated Rhizopus oryzae. Liposomal amphotericin B was started. The patient was on tacrolimus, prednisolone, and mycophenolate mofetil. Tacrolimus was switched to cyclosporine to regulate serum glucose levels. The left maxillary sinus was washed with liposomal amphoterin B daily and curetted with intervals. The patient started dialysis because of severe renal function loss. The patient was discharged on the 96th day of liposomal amphotericin B., Conclusion: It should be kept in mind that mucormycosis may be present in the sinuses even if there is no evidence for nasal, oral, and dental examination in renal transplant patients with facial pain., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Saksenaea vasiformis is an emerging human pathogen, belonging to the order Mucorales of the subphylum Mucormycotina, most often associated with rhino-cerebral, cutaneous and subcutaneous infections following trauma. A review of the published literature was attempted on the occasion of a cutaneous leg infection with favorable outcome in a young immunocompetent man after mild injury. The overall aim was the facilitation of the study and the integrated understanding of this kind of fungal infections., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Mucorales are fungal pathogens that cause mucormycosis, a lethal angioinvasive disease. Previously, we demonstrated that Rhizopus , the most common cause of mucormycosis, invades endothelial cells by binding of its CotH proteins to the host receptor GRP78. Loss of CotH3 renders the fungus noninvasive and attenuates Rhizopus virulence in mice. Here, we demonstrate that polyclonal antibodies raised against peptides of CotH3 protected diabetic ketoacidotic (DKA) and neutropenic mice from mucormycosis compared to mice treated with control preimmune serum. Passive immunization with anti-CotH3 antibodies enhanced neutrophil inlfux and triggered Fc receptor-mediated enhanced opsonophagocytosis killing of Rhizopus delemar . Monoclonal antibodies raised against the CotH3 peptide also protected immunosuppressed mice from mucormycosis caused by R. delemar and other Mucorales and acted synergistically with antifungal drugs in protecting DKA mice from R. delemar infection. These data identify anti-CotH3 antibodies as a promising adjunctive immunotherapeutic option against a deadly disease that often poses a therapeutic challenge.

Mucormycosis is a life-threatening fungal infection that occurs mainly in immunocompromised patients. Its occurrence isolated in the lung rare and carries a high mortality risk if untreated. We report the case of a 76-year old male immunocompetent patient, under treatment for pulmonary tuberculosis, admitted to the emergency department with hemoptysis. Bronchoscopy was performed and active bleeding from the middle lobe bronchus was found. Chest CT scan identified a solitary cavitary lesion in the middle lobe. The patient was proposed for urgent open middle lobectomy. Postoperative period was uneventful. Pulmonary mucormycosis was confirmed and adjuvant therapy with Amphotericin B was performed for 30 days. Despite its rarity, mucormycosis prevalence is expected to raise together with increasing number of immunocompromised patients. A high level of suspicion is recommended as early diagnosis can be determinant.

Pulmonary coinfection with Mucor and Aspergillus species has not been reported in organ transplant recipients. Here, we report a rare case of pulmonary coinfection with invasive fungal species in a renal transplant recipient with delayed graft function. The patient was first treated with a regime containing voriconazole, but the infection only worsened. Then, bronchoalveolar lavage fluid culture and internal transcribed spacer region sequencing were performed, and simultaneous pulmonary infection by Lichtheimia ramosa and Aspergillus fumigatus was clearly diagnosed. Susceptibility testing determined that the fungi were sensitive to amphotericin B and posaconazole. Therefore, a therapeutic regime containing posaconazole and amphotericin B liposome, which are less toxic to the kidney, was planned and resulted in resolution of the infectious symptoms. The present case demonstrates the importance of identifying fungal pathogens early and definitively, determining the effective anti-fungal medications, and administering the properly planned therapeutic regime in a timely manner to treat cases of coinfection in transplant recipients., (Copyright © 2018. Published by Elsevier Inc.)

Mucormycosis is an uncommonly encountered fungal infection in solid-organ transplantation, occurring most often gastrointestinally. The most common and fatal infectious disease is cytomegalovirus (CMV) pneumonia, which may result in acute respiratory distress syndrome (ARDS), with rapid onset. Early diagnosis, active treatment, and rational reduction of immunosuppressants are crucial for successful kidney transplantation. We performed successful treatment for both mucormycosis and CMV pneumonia and adjusted the tacrolimus dose accordingly. The case we describe was that of a 47-year-old woman with history of renal transplantation 1 month earlier. She presented with chest pain and gastrointestinal bleeding and was diagnosed with gastric mucormycosis and a secondary episode of hospital-acquired pneumonia. Preemptive therapy, which included liposomal amphotericin B and posaconazole, was adminstered when voriconazole proved to be unhelpful and before histologic reports of gastric mucormycosis. Moreover, CMV re-activation was confirmed by CMV antibody detection, and we administered gancyclovir and thymosin α1 but reduced the strength of the immunosuppressive drugs. Fourteen days after the aforementioned therapy, the patient began to recover and she was discharged on day 81 postoperatively. We conclude that preemptive treatment is critical for severe infection in renal transplant recipients, especially with the rarely seen gastric mucormycosis and with ARDS. In addition, immunoregulated agents, such as asthymosin α1, are also of great value in renal transplant recipients in the setting of opportunistic pathogen infections., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Tracheobronchial fungal infections (TBFI) cause life-threatening complications in immunocompromised hosts but are rarely reported. Misdiagnosis and delayed antifungal treatment are associated with the high mortality rate of patients with TBFI., Objectives: This study analyzed the bronchoscopic features of TBFI and their roles in the early diagnosis of TBFI., Methods: The demographic, clinical, radiologic, and bronchoscopic data of 53 patients diagnosed with TBFI in our department during a 15-year period were retrospectively analyzed., Results: Most of the TBFI patients were male, and mass was the most common radiologic abnormality. Obvious predilection in primary bronchus distributions was observed. 41.9% of the 43 Aspergillus tracheobronchitis (AT) patients, 70% of the 10 tracheobronchial mucormycosis (TM) patients, and 100% of the 3 endobronchial cryptococcosis patients had been misdiagnosed as having cancer on bronchoscopy because of the presence of tumor-like lesions. The most common features of AT were bronchial occlusion with a mass or mucosal necrosis, bronchial stenosis with mucosal hyperplasia, or uneven mucosa. The main descriptions of TM were bronchial stenosis or obstruction due to mucosal necrosis, uneven mucosa, or a mass. The endoscopic characteristics of endobronchial cryptococcosis included occlusion due to uneven mucosa or mass, or external compressive stricture., Conclusion: Immunocompromised patients and immunocompetent patients with underlying disease displaying tumor-like lesions on bronchoscopy should be differentially diagnosed with cancer. Bronchial biopsy is indispensable for the early diagnosis of TBFI., (© 2019 S. Karger AG, Basel.)

Invasive fungal infections in solid organ transplant recipients are associated with significant morbidity and mortality. Of these fungal infections, mucormycosis presents as an aggressive, frequently fatal angioinvasive infection. Immunocompromised hosts and diabetes are important risk factors. These infections are frequently difficult to diagnose. A high index of suspicion in the appropriate setting and early, aggressive treatment with the newer antifungal agents have altered the previously grave prognosis. We present the first reported case of cavitating pulmonary mucormycosis in a renal transplant recipient caused by an unusual species of Mucorales. The patient was treated with a combination of lobectomy and antifungal treatment comprising of amphotericin B and posaconazole. He remains free of disease recurrence on monotherapy with posaconazole., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Primary cutaneous mucormycosis is an opportunistic fungal infection caused by the order Mucorales, most frequently by the Rhizopus species. Both systemic factors, such as diabetes mellitus or malignancies and local factors disrupting the skin barrier are implicated in development of this entity. The initial manifestation is a red-to-black papule rapidly progressing to a necrotic and painful ulcer. Diagnosis is obtained by identification of fungal forms in a skin biopsy, typically showing branching and non-septate hyphae. The clinical course is highly variable and depends mostly on the fungal invasion of deep tissues. However, an early diagnosis is essential for implementation of prompt and optimal treatment, based upon antifungal therapy and aggressive surgical debridement.

Invasive aspergillosis and mucormycosis are life-threatening infections in solid organ and hematopoietic cell transplant recipients. Despite medical advancements in the care of these patients and the availability of new mold-active drugs, the outcomes remain suboptimal. Therefore, there has been increased interest in the use of combination antifungal therapy, in hopes that leveraging the possible in vitro synergy of these agents will improve the prognosis of invasive mold disease. However, there has been a large disconnect between the results of experimental and clinical investigations, as clinical studies have not unequivocally demonstrated the superiority of combination therapy over monotherapy. This is particularly true for mucormycosis, where the rarity of the condition has made it nearly impossible to prospectively study novel therapeutic strategies. We review the current standard of antifungal therapy and the preclinical and clinical data addressing the merit of combination therapy, and we provide guidance to optimize the management of these mycoses.

Pulmonary mucormycosis diagnosed immediately after hematopoietic stem cell transplantation frequently portends a poor prognosis. However, here we describe two cases in children that were treated successfully to highlight the efficacy of a multidisciplinary approach. Despite diagnosis in the immediate post-transplant period and requirement for ongoing immunosuppression to prevent or treat GVHD, both are long-term survivors due to early surgical debridement with transfusion support and prompt initiation of targeted antifungal therapy. In the absence of evidence-based treatment guidelines, survival of pulmonary mucormycosis is achievable even in high-risk patients with a multidisciplinary team to guide management., (© 2018 Wiley Periodicals, Inc.)

Background: Invasive mold infections (IMIs) are a leading cause of mortality among immunocompromised patients. Isavuconazole is a new drug that shows promise in the adult population for the treatment of IMIs. No data regarding the use of isavuconazole in pediatric patients have been published., Methods: Patients with a diagnosis of IMI from our pediatric hemato-oncology division, treated with isavuconazole between 2010 and 2016, were identified using the hospital's computerized database. Data including demographics, clinical course, and outcome were collected. Pharmacokinetic samples were obtained from two younger patients to guide dosing., Results: In total, three patients (4.5, 5, and 19 years of age) with invasive mucormycosis who were treated with isavuconazole were identified. All patients were treated with isavuconazole as a second line therapy and experienced improvement following the initiation of this treatment., Conclusions: Based on our limited clinical experience, isavuconazole may be a safe and effective treatment option for children and adolescents afflicted by IMI. Prospective clinical trials should be performed in order to evaluate the pharmakokinetics and safety of isavuconazole in the pediatric population., (© 2018 Wiley Periodicals, Inc.)

Introduction: Fungal infection burden related to Mucorales has been on the rise with significant associated morbidity and mortality. The major obstacle in the management has been lack of a non-invasive rapid and a reliable diagnostic test. Developing a culture-independent biomarker for the early diagnosis of mucormycosis is a major unmet need in modern mycology. Several approaches have been developed, such as immunohistochemistry (IHC) that can confirm the histopathologic diagnosis of the invasive mold infection, polymerase chain reaction (PCR) on formalin-fixed paraffin-embedded (FFPE) or fresh tissue, body fluids such as bronchoalveolar fluid (BAL), and detection directly from serum/blood. Serologic tests, matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS), metabolomics and metagenomic shotgun sequencing are other evolving technologies. Area covered: In this review paper, we report the current status of the molecular diagnostics in the diagnosis of mucormycosis: serologic tests, IHC, PCR, protein-based with MALDI-TOF, metabolomics and metagenomic sequencing. Expert commentary: This review will conclude with an expert commentary on the potential uses/challenges of the currently available tests and the future of molecular diagnostics for mucormycosis.