Lactoferrin, a potential iron-chelator as an adjunct treatment for mucormycosis - A comprehensive review.

Mucormycosis is a deadly infection which is caused by fungi of the order Mucorales including species belonging to the genus Rhizopus, Mucor, Mycocladus, Rhizomucor, Cunninghamella, and Apophysomyces. Despite antifungal therapy and surgical procedures, the mortality rate of this disease is about 90-100% which is exceptionally high. The hypersensitivity of patients with raised available serum iron indicates that the Mucorales are able to use host iron as a critical factor of virulence. This is because iron happens to be a crucial element playing its role in the growth of cells and development. In this review, we have described Lactoferrin (Lf) as a potential iron-chelator. Lf is a naturally occurring glycoprotein which is expressed in most of the biological fluids. Moreover, Lf possesses exclusive anti-inflammatory effects along with several anti-fungal effects that could prove to be helpful to the pathological physiology of inexorable mucormycosis cases. This literature summarises the biological insights into the Lf being considered as a potential fungistatic agent and an immune regulator. The review also proposes that unique potential of Lf as an iron-chelator can be exploited as the adjunct treatment for mucormycosis infection.

Mucormycosis.

Mucormycosis is a rare but aggressive fungal disease that mainly affects patients with poorly controlled diabetes mellitus and those who are severely immunocompromised, including patients with hematological malignancies and solid organ transplant recipients. Early recognition of infection is critical for treatment success, followed by prompt initiation of antifungal therapy with lipid formulation amphotericin B. Posaconazole and isavuconazole should be used for stepdown and salvage therapy. Surgical debridement is key for tissue diagnosis and treatment and should be pursued urgently whenever possible. In addition to surgery and antifungal therapy, reverting the underlying risk factor for infection is important for treatment response.

Mucoricin is a ricin-like toxin that is critical for the pathogenesis of mucormycosis.

Fungi of the order Mucorales cause mucormycosis, a lethal infection with an incompletely understood pathogenesis. We demonstrate that Mucorales fungi produce a toxin, which plays a central role in virulence. Polyclonal antibodies against this toxin inhibit its ability to damage human cells in vitro and prevent hypovolemic shock, organ necrosis and death in mice with mucormycosis. Inhibition of the toxin in Rhizopus delemar through RNA interference compromises the ability of the fungus to damage host cells and attenuates virulence in mice. This 17 kDa toxin has structural and functional features of the plant toxin ricin, including the ability to inhibit protein synthesis through its N-glycosylase activity, the existence of a motif that mediates vascular leak and a lectin sequence. Antibodies against the toxin inhibit R. delemar- or toxin-mediated vascular permeability in vitro and cross react with ricin. A monoclonal anti-ricin B chain antibody binds to the toxin and also inhibits its ability to cause vascular permeability. Therefore, we propose the name 'mucoricin' for this toxin. Not only is mucoricin important in the pathogenesis of mucormycosis but our data suggest that a ricin-like toxin is produced by organisms beyond the plant and bacterial kingdoms. Importantly, mucoricin should be a promising therapeutic target.

Mucormycosis at a tertiary-care center in Mexico. A 35-year retrospective study of 214 cases.

BACKGROUND: Mucormycosis is a rare, invasive disease associated with high mortality rates, produced by opportunistic pathogens related to the Mucorales order and characterised by a diverse range of clinical forms; acute rhino-orbital-cerebral and pulmonary symptoms are the most reported ones. OBJECTIVES: To report the experience of mucormycosis observed in a tertiary-care hospital in Mexico for 35 years. METHODS: This was a retrospective, descriptive and observational study on mucormycosis at a tertiary-care hospital in Mexico from January 1985 to December 2019. Demographic and clinical data and mycological and histopathological records were selected. RESULTS: Two hundred fourteen proven cases of mucormycosis for 35 years at a tertiary-care hospital in Mexico were included. Most of the cases were male patients with a median age of 45 years. The two most associated underlying diseases were diabetes mellitus (76.6%) and haematologic malignancy (15.4%). The three primary clinical forms were as follows: rhino-orbito-cerebral (75.9%), cutaneous (8.41%) and pulmonary (7.47%) mucormycosis. The most isolated agents were Rhizopus arrhizus (58.4%) and Lichtheimia corymbifera (12.3%). The overall therapeutic response was 58.5%, and the best response was observed with amphotericin B deoxycholate and surgical debridement. CONCLUSION: Mucormycosis is an emerging disease, and its incidence has increased at our hospital over the years. In this study, the rhino-cerebral clinical type was the most frequent in patients with uncontrolled diabetes; the main aetiological agent was R. arrhizus. Early diagnosis, control of the underlying disease and prompt management may increase the survival rate.

Breakthrough invasive fungal infections: Who is at risk?

The epidemiology of invasive fungal infections (IFIs) in immunocompromised individuals has changed over the last few decades, partially due to the increased use of antifungal agents to prevent IFIs. Although this strategy has resulted in an overall reduction in IFIs, a subset of patients develop breakthrough IFIs with substantial morbidity and mortality in this population. Here, we review the most significant risk factors for breakthrough IFIs in haematology patients, solid organ transplant recipients, and patients in the intensive care unit, focusing particularly on host factors, and highlight areas that require future investigation.

First Case of Rhinocerebral Mucormycosis Caused by Lichtheimia ornata, with a Review of Lichtheimia Infections.

BACKGROUND: Lichtheimia species are emerging opportunistic fungal pathogens in the Mucorales, causing serious skin and respiratory infections in immunocompromised patients. Established agents are Lichtheimia corymbifera and L. ramosa, while L. ornata is a novel agent. Available data on a species-specific analysis of Lichtheimia infections are limited. METHODS: The first case of a fatal rhino-orbital-cerebral infection in a hematopoietic stem cell transplantation recipient caused by L. ornata is reported; the agent was identified by sequencing the ITS ribosomal region. We reviewed the literature on mucormycosis due to Lichtheimia species between 2009 and 2018, with an analysis of risk factors and epidemiological and clinical data. RESULTS: In addition to our Lichtheimia ornata case, 44 cases of human Lichtheimia were analyzed. Lichtheimia predominated in Europe (68.2%), followed by Asia (16%), and Africa (9%). The most common underlying condition was hematological malignancy (36.3%), followed by trauma/major surgery (27.3%), while diabetes mellitus was rare (11.4%). Site of infection was mostly skin and soft tissues (45.5%) and lung (25%), while relatively few cases were disseminated (13.6%) or rhinocerebral (11.4%). Mortality (36.4%) was mainly due to disseminated and rhinocerebral infections. CONCLUSION: In contrast to Rhizopus, the most common agent of mucormycosis recorded in patients with diabetes mellitus, Lichtheimia infections were primarily associated with hematological malignancies and major skin barrier damage. Given the fact that classical rhinocerebral mucormycosis remains difficult to treat, independent of causative species, timely application of amphotericin B accessory to debridement may be required for patient survival.

Non-Aspergillus invasive mould infections in patients treated with ibrutinib.

BACKGROUND: Invasive mould infections (IMIs) are very rare in patients with lymphoid malignancies. However, IMIs, mostly due to Aspergillus species, have been increasingly reported in such patients receiving ibrutinib (IBR). There is paucity of information regarding non-Aspergillus invasive mould infections (NAIMIs) in this setting, OBJECTIVES: To review our recent experience and the published literature on the topic. PATIENTS/METHODS: We present a case of invasive sinusitis caused by Fusarium in a patient with refractory chronic lymphocytic leukaemia (CLL) who was treated with IBR and review the 12 published cases of NAIMIs during IBR. RESULTS: Nearly all cases of NAIMIs in the setting of IBR use were encountered in patients with CLL. Mixed fungal infections, brain involvement and late-onset infections were common. CONCLUSIONS: Although rare, NAIMIs should be considered in patients who receive IBR.

Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients.

Isavuconazole may be useful in treating and preventing fungal infections in solid-organ transplant (SOT) recipients due to its safety profile and activity against Aspergillus and some Mucorales Isavuconazole has favorable pharmacokinetics based on clinical trials in various patient populations, but data are limited in SOT recipients. We evaluated the steady-state pharmacokinetics of isavuconazole in 26 SOT recipients receiving the drug intravenously for prophylaxis. There was moderate interpatient variability in isavuconazole pharmacokinetic parameters (coefficients of variation of 51% for the area under the plasma concentration-versus-time curve [AUC] and 59% for the trough plasma concentration [Ctrough]). AUC and steady-state Ctrough were significantly lower in women, patients with a body mass index of ≥18.5 kg/m2, and those receiving hemodialysis. Trough plasma concentrations were highly correlated with AUCs (R2 = 0.94) and can serve as a suitable measure of isavuconazole exposure in patients. In conclusion, moderate interpatient variability in isavuconazole exposure, the identification of factors associated with lower exposure, the recognition that Ctrough is a surrogate marker for AUC, and the availability of a simple analytical method suggest that therapeutic drug monitoring (TDM) may be useful for guiding treatment in at least some SOT recipients. Future studies are needed to correlate isavuconazole exposure with patients' clinical outcomes and to determine the clinical role of TDM.

An Adult Zebrafish Model Reveals that Mucormycosis Induces Apoptosis of Infected Macrophages.

Mucormycosis is a life-threatening fungal infection caused by various ubiquitous filamentous fungi of the Mucorales order, although Rhizopus spp. and Mucor spp. are the most prevalent causal agents. The limited therapeutic options available together with a rapid progression of the infection and a difficult early diagnosis produce high mortality. Here, we developed an adult zebrafish model of Mucor circinelloides infection which allowed us to confirm the link between sporangiospore size and virulence. Transcriptomic studies revealed a local, strong inflammatory response of the host elicited after sporangiospore germination and mycelial tissue invasion, while avirulent and UV-killed sporangiospores failed to induce inflammation and were rapidly cleared. Of the 857 genes modulated by the infection, those encoding cytokines, complement factors, peptidoglycan recognition proteins, and iron acquisition are particularly interesting. Furthermore, neutrophils and macrophages were similarly recruited independently of sporangiospore virulence and viability, which results in a robust depletion of both cell types in the hematopoietic compartment. Strikingly, our model also reveals for the first time the ability of mucormycosis to induce the apoptosis of recruited macrophages but not neutrophils. The induction of macrophage apoptosis, therefore, might represent a key virulence mechanism of these fungal pathogens, providing novel targets for therapeutic intervention in this lethal infection.

Breaking the Mold: A Review of Mucormycosis and Current Pharmacological Treatment Options.

OBJECTIVE: To review the current literature for the pathogenesis of mucormycosis, discuss diagnostic strategies, and evaluate the efficacy of polyenes, triazoles, and echinocandins as pharmacological treatment options. DATA SOURCES: An electronic literature search was conducted in PubMed using the MESH terms Rhizopus, zygomycetes, zygomycosis, Mucorales and mucormycosis, with search terms amphotericin B, micafungin, anidulafungin, caspofungin, extended infusion amphotericin B, liposomal amphotericin B, combination therapy, triazole, posaconazole, isavuconazole, diagnosis, and clinical manifestations. STUDY SELECTION AND DATA EXTRACTION: Studies written in the English language from January 1960 to March 2016 were considered for this review article. All search results were reviewed, and the relevance of each article was determined by the authors independently. DATA SYNTHESIS: Mucormycosis is a rare invasive fungal infection with an exceedingly high mortality and few therapeutic options. It has a distinct predilection for invasion of endothelial cells in the vascular system, which is likely important in dissemination of disease from a primary focus of infection. Six distinct clinical syndromes can occur in susceptible hosts, including rhino-orbital-cerebral, pulmonary, gastrointestinal, cutaneous, widely disseminated, and miscellaneous infection. CONCLUSION: Diagnosis of mucormycosis is typically difficult to make based on imaging studies, sputum culture, bronchoalveolar lavage culture, or needle aspirate. Surgical debridement prior to dissemination of infection improves clinical outcomes. Surgery combined with early, high-dose systemic antifungal therapy yields greater than a 1.5-fold increase in survival rates. The Mucorales are inherently resistant to most widely used antifungal agents. Amphotericin B is appropriate for empirical therapy, whereas posaconazole and isavuconazole are best reserved for de-escalation, refractory cases, or patients intolerant to amphotericin B.

Impaired T cell responsiveness to interleukin-6 in hematological patients with invasive aspergillosis.

Invasive mold infections (IMI) are among the most devastating complications following chemotherapy and hematopoietic stem cell transplantation (HSCT), with high mortality rates. Yet, the molecular basis for human susceptibility to invasive aspergillosis (IA) and mucormycosis remain poorly understood. Herein, we aimed to characterize the immune profile of individuals with hematological malignancies (n = 18) who developed IMI during the course of chemotherapy or HSCT, and compared it to that of hematological patients who had no evidence of invasive fungal infection (n = 16). First, we measured the expression of the pattern recognition receptors pentraxin 3, dectin-1, and Toll-like receptors (TLR) 2 and 4 in peripheral blood of chemotherapy and HSCT recipients with IMI. Compared to hematological controls, individuals with IA and mucormycosis had defective expression of dectin-1; in addition, patients with mucormycosis had decreased TLR2 and increased TLR4 expression. Since fungal recognition via dectin-1 favors T helper 17 responses and the latter are highly dependent on activation of the signal transducer and activator of transcription (STAT) 3, we next used phospho-flow cytometry to measure the phosphorylation of the transcription factors STAT1 and STAT3 in response to interferon-gamma (IFN-γ) and interleukin (IL)-6, respectively. While IFN-γ/STAT1 signaling was similar between groups, naïve T cells from patients with IA, but not those with mucormycosis, exhibited reduced responsiveness to IL-6 as measured by STAT3 phosphorylation. Furthermore, IL-6 increased Aspergillus-induced IL-17 production in culture supernatants from healthy and hematological controls but not in patients with IA. Altogether, these observations suggest an important role for dectin-1 and the IL-6/STAT3 pathway in protective immunity against Aspergillus.

Human Fungal Pathogens of Mucorales and Entomophthorales.

In recent years, we have seen an increase in the number of immunocompromised cohorts as a result of infections and/or medical conditions, which has resulted in an increased incidence of fungal infections. Although rare, the incidence of infections caused by fungi belonging to basal fungal lineages is also continuously increasing. Basal fungal lineages diverged at an early point during the evolution of the fungal lineage, in which, in a simplified four-phylum fungal kingdom, Zygomycota and Chytridiomycota belong to the basal fungi, distinguishing them from Ascomycota and Basidiomycota. Currently there are no known human infections caused by fungi in Chytridiomycota; only Zygomycotan fungi are known to infect humans. Hence, infections caused by zygomycetes have been called zygomycosis, and the term "zygomycosis" is often used as a synonym for "mucormycosis." In the four-phylum fungal kingdom system, Zygomycota is classified mainly based on morphology, including the ability to form coenocytic (aseptated) hyphae and zygospores (sexual spores). In the Zygomycota, there are 10 known orders, two of which, the Mucorales and Entomophthorales, contain species that can infect humans, and the infection has historically been known as zygomycosis. However, recent multilocus sequence typing analyses (the fungal tree of life [AFTOL] project) revealed that the Zygomycota forms not a monophyletic clade but instead a polyphyletic clade, whereas Ascomycota and Basidiomycota are monophyletic. Thus, the term "zygomycosis" needed to be further specified, resulting in the terms "mucormycosis" and "entomophthoramycosis." This review covers these two different types of fungal infections.

Virulent strain of Lichtheimia corymbifera shows increased phagocytosis by macrophages as revealed by automated microscopy image analysis.

Lichtheimia corymbifera is a ubiquitous soilborne zygomycete fungus, which is an opportunistic human pathogen in immunocompromised patients. The fungus can cause life-threatening diseases by attacking the lung during early stages of invasion and by disseminating during later phases causing systemic infection. Since infections have drastically increased during the last decades, it is a major goal to investigate the mechanisms underlying pathogenicity of L. corymbifera. One of the first barriers, which the fungus needs to cope with in the lung tissue, is phagocytosis by alveolar macrophages. Here, we report on phagocytosis assays for murine alveolar macrophages co-incubated with resting, swollen and opsonised spores of a virulent and an attenuated L. corymbifera strain. A major finding of this study is the significantly increased phagocytosis ratio of the virulent strain if compared to the attenuated strain. We quantify the phagocytosis by performing automated analysis of fluorescence microscopy images and by computing ratios for (i) fungal phagocytosis, (ii) fungal adhesion to phagocytes and (iii) fungal aggregation and spore cluster distribution in space. Automation of the image analysis yields objective results that overcome the disadvantages of manual analyses being time consuming, error-prone and subjective. Therefore, it can be expected that automated image analysis of confrontation assays will play a crucial role in future investigations of host-pathogen interactions.

Pathogenesis and host defence against Mucorales: the role of cytokines and interaction with antifungal drugs.

Innate immune response, including macrophages, neutrophils and dendritic cells and their respective receptors, plays an important role in host defences against Mucorales with differential activity against specific fungal species, while adaptive immunity is not the first line of defence. A number of endogenous and exogenous factors, such as cytokines and growth factors as well as certain antifungal agents have been found that they influence innate immune response to these organisms. Used alone or especially in combination have been shown to exert antifungal effects against Mucorales species. These findings suggest novel ways of adjunctive therapy for patients with invasive mucormycosis.

El Subphylum Mucoromycotina: generalidades y aspectostaxonómicos recientes / Mucoromycotina Subphylum: overview and recent taxonomic aspects

El subphylum Mucoromycotina es un grupo de hongos ubicuos, saprobios, caracterizados por la presencia de hifas cenocíticas. También se caracterizan por presentar una fase sexual con la formación de una zigospora. Los mucormycetes son capaces de infectar plantas, animales y seres humanos. Recientemente, varios estudios han comunicado de la creciente incidencia de mucormicosis en pacientes inmunocomprometidos e inmunocompetentes. Dados los avances en biología molecular, la sistemática de este grupo de hongos ha experimentado varios cambios taxonómicos en los últimos años. Este artículo discutirá los principales cambios taxonómicos, en especial de los géneros y especies de interés clínico.

The subphylum Mucoromycotina is a group of fungi with several ubiquitous, and saprotrophic species which are characterized by the presence of coenocytic hyphae. Also have a sexual phase characterized by the formation of zygospores. The mucormycetes are able to infect plants, animals and humans. Recently, several studies have reported the increasing incidence of mucormycosis in both immunocompromised and immunocompetent patients. Given the advances in molecular biology, the systematic of this group of fungi has experimented several taxonomical changes. This paper will discuss the major taxonomic changes, particularly of those genera and species of clinical interest.

A non-fatal case of invasive zygomycete (Lichtheimia corymbifera) infection in an allogeneic haematopoietic cell transplant recipient.

Post-transplant infections in allogeneic haematopoietic cell transplant (allo-HCT) recipients often have severe consequences. This is especially the case when dealing with zygomycete infections where the result is often fatal. A major problem when dealing with zygomycete infections is the need for an accurate and fast diagnosis as the phylum is highly resistant towards the conventional antifungals. We herein describe a non-fatal case of Lichtheimia corymbifera infection in an allo-HCT recipient.

Epidemiology and clinical manifestations of mucormycosis.

Mucormycosis is an emerging angioinvasive infection caused by the ubiquitous filamentous fungi of the Mucorales order of the class of Zygomycetes. Mucormycosis has emerged as the third most common invasive mycosis in order of importance after candidiasis and aspergillosis in patients with hematological and allogeneic stem cell transplantation. Mucormycosis also remains a threat in patients with diabetes mellitus in the Western world. Furthermore, this disease is increasingly recognized in recently developed countries, such as India, mainly in patients with uncontrolled diabetes or trauma. Epidemiological data on this type of mycosis are scant. Therefore, our ability to determine the burden of disease is limited. Based on anatomic localization, mucormycosis can be classified as one of 6 forms: (1) rhinocerebral, (2) pulmonary, (3) cutaneous, (4) gastrointestinal, (5) disseminated, and (6) uncommon presentations. The underlying conditions can influence clinical presentation and outcome. This review describes the emerging epidemiology and the clinical manifestations of mucormycosis.

Into the winter whiteness.

A father recounts a transformative journey of love, loss, and learning as his son developed and eventually died of a fungal infection that occurred during a period of immunocompromise after a bone marrow transplantation to treat hypodiploid leukemia. He then thanks the many physicians, researchers, family members, and friends who came together to memorialize his son and create knowledge, hope, and wisdom, so that others will not have to suffer a similar journey.