Choanephora infundibulifera Rhinosinusitis in Man with Acute Lymphoblastic Leukemia, Tennessee, USA.

Choanephora infundibulifera is a member of the Mucorales order of fungi. The species is associated with plants as a saprophyte or parasite and may be responsible for spoilage or disease but is an uncommon cause of human infection. We describe C. infundibulifera rhinosinusitis in a young man with leukemia in Tennessee, USA.

Mucormycosis in Liver Allograft Following Transplant for Secondary Biliary Cirrhosis.

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.

Pulmonary mucormycosis diagnosed by ultrasound guided percutaneous biopsy: A case series.

Pulmonary mucormycosis is a rare but highly lethal fungal infection, usually affecting immunocompromised patients. Pulmonary mucormycosis was also a critical problem that complicated the later part of the clinical course of COVID-19 in India. Early diagnosis of the disease, combined with aggressive treatment, is crucial for patient survival. Fibreoptic bronchoscopy is a useful procedure for diagnosis of pulmonary mucormycosis, but image-guided percutaneous biopsy efficiently samples lesions abutting the chest wall. Biopsy is more yielding than cultures and imaging guided biopsy is required for lesions that cannot be microbiologically confirmed by fibreoptic bronchoscopy. We present a case series of four patients of pulmonary mucormycosis in whom ultrasound guided biopsy clinched the diagnosis. All the four patients were poor surgical candidates and underwent medical management with antifungal agents, and had successful clinical recovery and radiological resolution. Our case series illustrates the utility of ultrasound guided percutaneous biopsy as a diagnostic tool for sampling cavitatory disease due to pulmonary mucormycosis, when fibreoptic bronchoscopy failed to yield a diagnosis and the beneficial role antifungal agents as salvage therapy in poor surgical candidates.

Comprehensive Review on the Virulence Factors and Therapeutic Strategies with the Aid of Artificial Intelligence against Mucormycosis.

Mucormycosis, a rare but deadly fungal infection, was an epidemic during the COVID-19 pandemic. The rise in cases (COVID-19-associated mucormycosis, CAM) is attributed to excessive steroid and antibiotic use, poor hospital hygiene, and crowded settings. Major contributing factors include diabetes and weakened immune systems. The main manifesting forms of CAM─cutaneous, pulmonary, and the deadliest, rhinocerebral─and disseminated infections elevated mortality rates to 85%. Recent focus lies on small-molecule inhibitors due to their advantages over standard treatments like surgery and liposomal amphotericin B (which carry several long-term adverse effects), offering potential central nervous system penetration, diverse targets, and simpler dosing owing to their small size, rendering the ability to traverse the blood-brain barrier via passive diffusion facilitated by the phospholipid membrane. Adaptation and versatility in mucormycosis are facilitated by a multitude of virulence factors, enabling the pathogen to dynamically respond to various environmental stressors. A comprehensive understanding of these virulence mechanisms is imperative for devising effective therapeutic interventions against this highly opportunistic pathogen that thrives in immunocompromised individuals through its angio-invasive nature. Hence, this Review delineates the principal virulence factors of mucormycosis, the mechanisms it employs to persist in challenging host environments, and the current progress in developing small-molecule inhibitors against them.

Human Vγ9Vδ2 T cells exhibit antifungal activity against Aspergillus fumigatus and other filamentous fungi.

Invasive aspergillosis (IA) and mucormycosis are life-threatening diseases, especially among immunocompromised patients. Drug-resistant Aspergillus fumigatus strains have been isolated worldwide, which can pose a serious clinical problem. As IA mainly occurs in patients with compromised immune systems, the ideal therapeutic approach should aim to bolster the immune system. In this study, we focused on Vγ9Vδ2 T cells that exhibit immune effector functions and examined the possibility of harnessing this unconventional T cell subset as a novel therapeutic modality for IA. A potent antifungal effect was observed when A. fumigatus (Af293) hyphae were challenged by Vγ9Vδ2 T cells derived from peripheral blood. In addition, Vγ9Vδ2 T cells exhibited antifungal activity against hyphae of all Aspergillus spp., Cunninghamella bertholletiae, and Rhizopus microsporus but not against their conidia. Furthermore, Vγ9Vδ2 T cells also exhibited antifungal activity against azole-resistant A. fumigatus, indicating that Vγ9Vδ2 T cells could be used for treating drug-resistant A. fumigatus. The antifungal activity of Vγ9Vδ2 T cells depended on cell-to-cell contact with A. fumigatus hyphae, and degranulation characterized by CD107a mobilization seems essential for this activity against A. fumigatus. Vγ9Vδ2 T cells could be developed as a novel modality for treating IA or mucormycosis. IMPORTANCE: Invasive aspergillosis (IA) and mucormycosis are often resistant to treatment with conventional antifungal agents and have a high mortality rate. Additionally, effective antifungal treatment is hindered by drug toxicity, given that both fungal and human cells are eukaryotic, and antifungal agents are also likely to act on human cells, resulting in adverse effects. Therefore, the development of novel therapeutic agents specifically targeting fungi is challenging. This study demonstrated the antifungal activity of Vγ9Vδ2 T cells against various Aspergillus spp. and several Mucorales in vitro and discussed the mechanism underlying their antifungal activity. We indicate that adoptive immunotherapy using Vγ9Vδ2 T cells may offer a new therapeutic approach to IA.

Transcutaneous retrobulbar amphotericin B for rhino-orbital-cerebral mucormycosis: a multi-center retrospective comparative study.

PURPOSE: To assess whether transcutaneous retrobulbar amphotericin B injections (TRAMB) reduce exenteration rate without increasing mortality in rhino-orbital-cerebral mucormycosis (ROCM). METHODS: In this retrospective case-control study, 46 patients (51 eyes) with biopsy-proven ROCM were evaluated at 9 tertiary care institutions from 1998 to 2021. Patients were stratified by radiographic evidence of local orbital versus extensive involvement at presentation. Extensive involvement was defined by MRI or CT evidence of abnormal or loss of contrast enhancement of the orbital apex with or without cavernous sinus, bilateral orbital, or intracranial extension. Cases (+TRAMB) received TRAMB as adjunctive therapy while controls (-TRAMB) did not. Patient survival, globe survival, and vision/motility loss were compared between +TRAMB and -TRAMB groups. A generalized linear mixed effects model including demographic and clinical covariates was used to evaluate the impact of TRAMB on orbital exenteration and disease-specific mortality. RESULTS: Among eyes with local orbital involvement, exenteration was significantly lower in the +TRAMB group (1/8) versus -TRAMB (8/14) (p = 0.04). No significant difference in mortality was observed between the ±TRAMB groups. Among eyes with extensive involvement, there was no significant difference in exenteration or mortality rates between the ±TRAMB groups. Across all eyes, the number of TRAMB injections correlated with a statistically significant decreased rate of exenteration (p = 0.048); there was no correlation with mortality. CONCLUSIONS: Patients with ROCM with local orbital involvement treated with adjunctive TRAMB demonstrated a lower exenteration rate and no increased risk of mortality. For extensive involvement, adjunctive TRAMB does not improve or worsen these outcomes.

[Expert consensus on diagnosis and treatment of severe COVID-19 associated pulmonary aspergillosis and mucormycosis].

The incidence and mortality of COVID-19 associated pulmonary aspergillosis (CAPA) are high in critically ill patients. Although COVID-19 associated mucormycosis (CAPM) is relatively rare, its severity and often a delayed diagnosis or misdiagnosis lead to its high mortality. The diagnosis and treatment of CAPA and CAPM in critically ill patients are challenging. Early diagnosis and a standardized therapy are the two most important factors for a good outcome. Therefore, a working group of experts from Chinese Thoracic Society and Chinese Association of Chest Physicians Critical Care Group was organized to develop this consensus based on the current medical evidence and clinical practice, in order to improve the ability of clinical treatment for critically ill patients with CAPA and CAPM. The working group drafted a preliminary text based on the literature and clinical practice experience. Following two rounds of discussion, 16 final recommendations were made, with the recommendation strength divided into recommend, suggest and not recommend.-Utilization of chest images and bronchoscopy1. Chest CT, rather than chest X-ray, is recommended for possible CAPA or CAPM patients to provide diagnostic evidence and localization for bronchoscopy to obtain microbiological specimens. A diagnosis of CAPA could not be made on the basis of positive signs on chest CT alone. Chest contrast CT or pulmonary artery CT (CTPA) is recommended in patients with probable CAPM.2. In the case of possible CAPA or CAPM, it is recommended that bronchoscopy and BALF collection for microbiological examinations be pereformed as soon as possible.-The selection strategies of microbiological examinations3. Microscopic examination, culture, GM testing and PCR for aspergillus Spp. of BALF are recommended in patients with probable CAPA. Fungal staining and culture of BALF are suggested for possible CAPM. Selected appropriate specimens for molecular biological detection are suggested in critically ill patients and possible CAPM.-Diagnostic critieria4. The revised ECMM/ISHAM consensus statement is recommended as the diagnostic criteria for CAPA and the Delphi consensus statement is recommended as the diagnostic criteria for CAPM.-Appropriate time for antifungal therapy5. Prophylactic therapy of CAPA with amphotericin B or its liposomes is suggested for patients with severe COVID-19, especially those with risk factors for CAPA.6. It is recommended to start the empirical anti-Aspergillus therapy as soon as possible for possible CAPA, and obtain the microbiological evidence for aspergillosis at the same time.7. Prophylactic therapy for CAPM is not recommended for severe COVID-19 patients.8. Early initiation of empirical therapy for possible CAPM is recommended, and microbiological evidence should be obtained at the same time.-Clinical applications for antifungal agents9.Voriconazole or isavuconazole are recommended as initial treatment for CAPA. Amphotericin B liposomes are suggested as the initial treatment for CAPM. Isavuconazole or posaconazole may be an option in patients with renal insufficiency or amphotericin B liposome intolerance/unavailability.10. In CAPA patients with tracheobronchitis, antifungal drug inhalation is recommended in addition to systemic antifungal medication.11. Combination therapy is not recommended as initial therapy for CAPA, but may be used as a salvage therapy strategy. Triazole or amphotericin B in combination with caspofungin or micafungin is recommended; whereas amphotericin B in combination with triazole is not recommended. For CAPM patients with extensive lesions, rapid progression or poor general condition, a combination of amphotericin B liposome with isavuconazole or posaconazole is suggested.-Response assessment and treatment duration12. It is recommended that treatment response be assessed comprehensively according to the clinical symptoms/signs, imaging and microbiological examination of patients. CAPA can be evaluated in combination with the dynamic change in serum GM.13. The recommended treatment duration of CAPA is at least 6-12 weeks. A total course of at least 3-6 months is suggested for CAPM, and the sequential treatment should be considered according to the response to 4-6 weeks of intravenous therapy.-How to adjust the anti-inflammatory therapy14. In patients with severe COVID-19 combined with possible or probable filamentous fungal infection, it is suggested that of anti-inflammatory therapy be stopped or reduced appropriately, taking into account of the severity of the infection and inflammation of the disease course. The combination of baritinib and/or tozzizumab based on glucocorticoids is not suggested in these patients.-How to treat the underlying diseases15. In patients with diabetes, strict glycaemic control is suggested. In patients with long-term use of glucocorticoids and/or immunosuppressants, it is suggested to reduce the intensity of immunosuppression. Granulocyte colony-stimulating factor is suggested to use to improve the circulating granulocyte levels in patients with granulocyte deficiency due to various causes.-When an operation should be considered16. In patients with CAPA, surgery is not recommended unless large blood vessels, pericardium, or chest wall are involved, or the patient has recurrent or massive hemoptysis. For CAPM patients, early surgical removal of lesions after diagnosis is recommended. Surgery is a high-risk procedure in patients with severe COVID-19, and a multidisciplinary team discuss is suggested.

Gastric mucormycosis presenting as diffuse thickening of the gastric wall with enhancement.

We report the case of a 63-year-old woman who presented with abdominal distension and pain two months ago, which worsened after eating. An abdominal CT examination revealed uneven thickening of the gastric wall on the greater curvature side of the gastric body, with progressive obviously enhancement. She was then examined by an upper endoscopy, which showed mucosal swelling on the greater curvature side of the lower gastric body with exudation of necrotic materials. Biopsies of the lesion were taken and histological results revealed a large number of broad-based and non-septate hyphae, with positive expression of PAS (Periodic Acid-Schiff) and hexamine silver stains, The patient was treated with amphotericin B liposomal antifungal therapy and remained under surveillance for six months without evidence of disease progression by follow-up upper endoscopy.

[Local administration of amphotericin B by VAC instillation: Therapeutic aid in the treatment of mucormycosis]. / Application locale d'amphotéricine B par VAC instillation : aide thérapeutique dans le traitement de la mucormycose.

Mucormycosis is a rare and serious fungal infection, occurring mainly in immunocompromised, diabetic, polytrauma or burn patients. Current standard treatments include iterative carcinological surgical trimming, systemic treatment with liposomal amphotericin B and second-line Posaconazole or Isavuconazole. We report the case of a 37-year-old female patient with no previous medical history who developed a disseminated mucormycosis, with an estimated 25 % loss of skin substance and major decay of the chest wall. In addition to standard treatment, local instillations of amphotericin B using the VAC Veraflow® system were performed. We believe that local instillations of amphotericin B by VAC could improve the functional prognosis of patients with skin involvement.

Cutaneous Mucormycosis of the Eyelid Treated With Subcutaneous Liposomal Amphotericin B Injections.

Cutaneous mucormycosis is a rare, opportunistic fungal infection that typically affects immunocompromised hosts. Current treatment consists of systemic antifungal therapy, surgical debridement, and when applicable, restoration of immune function. Despite intervention, the morbidity and mortality of invasive fungal disease remains high. There are few reports of primary or secondary cutaneous mucormycosis involving the ocular adnexa. The authors describe the course of 2 children with cutaneous mucormycosis of the eyelid treated with subcutaneous liposomal amphotericin B (LAmB) injections (3.5 mg/ml) in an off-label application as an adjunct to debridement and systemic antifungal therapy. To the authors' knowledge, these are the first 2 cases of invasive fungal disease involving the eyelid treated with subcutaneous LAmB injections, and the first reported case of disseminated fungal infection with secondary cutaneous involvement of the eyelid.

Demonstration of the Rationale for Therapeutic Drug Monitoring of Isavuconazole: A Case Report with a Lung Transplant Recipient.

Mucormycosis is a rare invasive fungal disease diagnosed in immunocompromised patients, including those with diabetes or iron overload, and in patients treated for hematological malignancies or after transplantation. Isavuconazole is a triazole antifungal effective against Mucorales with good tolerability, but with potential for relatively high interindividual variability in pharmacokinetics. This report demonstrates the case of a lung transplant recipient treated with isavuconasole that exhibits a very long elimination half-life of 159 hours, and discusses the practical implications of this finding for dosage adjustment and need for therapeutic drug monitoring.

Practical issues related to non-Aspergillus invasive mold infections.

Infection by non-Aspergillus molds has been increasingly reported. The management of such infections is challenging both for diagnosis and treatment, including the need of well-trained mycologists to properly identify rare fungi, difficulties in distinguishing between contamination, colonization and infection, the lack of randomized studies comparing different drugs or regimens, poor activity of available antifungal agents, lack of correlation between in vitro antifungal susceptibility tests and clinical outcome, and poor prognosis. Mucormycosis and fusariosis are the most frequent non-Aspergillus mold infections. Mucormycosis occurs more frequently in four major groups of patients: solid organ transplant recipients, patients with hematologic malignancies receiving chemotherapy or hematopoietic cell transplantation, diabetic patients, and immunocompetent individuals who suffer various types of skin and soft tissue trauma. Invasive fusariosis occurs almost exclusively in patients with hematologic malignancies. In this review we discuss practical issues related to the management of these and other non-Aspergillus mold infections.

Mucormycosis in 2023: an update on pathogenesis and management.

Mucormycosis (MCR) is an emerging and frequently lethal fungal infection caused by the Mucorales family, with Rhizopus, Mucor, and Lichtheimia, accounting for > 90% of all cases. MCR is seen in patients with severe immunosuppression such as those with hematologic malignancy or transplantation, Diabetes Mellitus (DM) and diabetic ketoacidosis (DKA) and immunocompetent patients with severe wounds. The recent SARS COV2 epidemy in India has resulted in a tremendous increase in MCR cases, typically seen in the setting of uncontrolled DM and corticosteroid use. In addition to the diversity of affected hosts, MCR has pleiotropic clinical presentations, with rhino-orbital/rhino-cerebral, sino-pulmonary and necrotizing cutaneous forms being the predominant manifestations. Major insights in MCR pathogenesis have brought into focus the host receptors (GRP78) and signaling pathways (EGFR activation cascade) as well as the adhesins used by Mucorales for invasion. Furthermore, studies have expanded on the importance of iron availability and the complex regulation of iron homeostasis, as well as the pivotal role of mycotoxins as key factors for tissue invasion. The molecular toolbox to study Mucorales pathogenesis remains underdeveloped, but promise is brought by RNAi and CRISPR/Cas9 approaches. Important recent advancements have been made in early, culture-independent molecular diagnosis of MCR. However, development of new potent antifungals against Mucorales remains an unmet need. Therapy of MCR is multidisciplinary and requires a high index of suspicion for initiation of early Mucorales-active antifungals. Reversal of underlying immunosuppression, if feasible, rapid DKA correction and in selected patients, surgical debulking are crucial for improved outcomes.

Case Report and Literature Review of Prosthetic Cardiovascular Mucormycosis.

We report a rare case of aorto-bi-iliac prosthetic allograft mucormycosis in a 57-year-old immunocompetent patient in France. Outcome was favorable after surgery and dual antifungal therapy with liposomal amphotericin B and isavuconazole. In a literature review, we identified 12 other cases of prosthetic vascular or heart valve mucormycosis; mortality rate was 38%.

Virulence traits and novel drug delivery strategies for mucormycosis post-COVID-19: a comprehensive review.

The outbreak of a fatal black fungus infection after the resurgence of the cadaverous COVID-19 has exhorted scientists worldwide to develop a nutshell by repurposing or designing new formulations to address the crisis. Patients expressing COVID-19 are more susceptible to Mucormycosis (MCR) and thus fall easy prey to decease accounting for this global threat. Their mortality rates range around 32-70% depending on the organs affected and grow even higher despite the treatment. The many contemporary recommendations strongly advise using liposomal amphotericin B and surgery as first-line therapy whenever practicable. MCR is a dangerous infection that requires an antifungal drug administration on appropriate prescription, typically one of the following: Amphotericin B, Posaconazole, or Isavuconazole since the fungi that cause MCR are resistant to other medications like fluconazole, voriconazole, and echinocandins. Amphotericin B and Posaconazole are administered through veins (intravenously), and isavuconazole by mouth (orally). From last several years so many compounds are developed against invasive fungal disease but only few of them are able to induce effective treatment against the micorals. Adjuvant medicines, more particularly, are difficult to assess without prospective randomized controlled investigations, which are challenging to conduct given the lower incidence and higher mortality from Mucormycosis. The present analysis provides insight into pathogenesis, epidemiology, clinical manifestations, underlying fungal virulence, and growth mechanisms. In addition, current therapy for MCR in Post Covid-19 individuals includes conventional and novel nano-based advanced management systems for procuring against deadly fungal infection. The study urges involving nanomedicine to prevent fungal growth at the commencement of infection, delay the progression, and mitigate fatality risk.

Gastrointestinal mucormycosis following liver transplantation: lessons learnt.

Gastrointestinal mucormycosis (GIM) is an uncommonly encountered fungal infection following solid-organ transplantation. GIM is known to be associated with immunocompromised states, remains difficult to diagnose and often results in fatal outcomes. It is plausibly the delay in initiation of appropriate treatment strategies that leads to failure of response and patient demise. We report two cases of GIM following live donor liver transplantation, presenting with bleeding and perforation, respectively, highlighting the challenges in making a timely diagnosis of mucormycosis, particularly in immunocompromised patients.

Riesgo de mortalidad en infecciones invasivas por Mucor SPP. en niños con enfermedades hemato-oncológicas: revisión sistemática / Mortality risk of invasive Mucor spp. infections in children with cancer: A systematic review

Los estudios sobre la infección fúngica invasiva (IFI) por Mucor spp. en pacientes pediátricos con patología hematooncológica, son de baja solidez científica, lo que dificulta conocer en profundidad sus características y evolución. Con el objetivo de analizar la evolución fatal de esos pacientes, se llevó a cabo esta revisión sistemática (RS). Material y métodos: La búsqueda bibliográfica se realizó con fecha 23 de marzo de 2023, en las principales bases de datos (Medline (a través de Pubmed), Embase (a través de Embase-Elsevier), The Cochrane Library (a través de Wiley), Cinahl (a través de Ebsco HOST), SCI-EXPANDED, SciELO (a través de la WOS) y Scopus (a través de Scopus-Elsevier), libre (mediante el motor Google) y revisando las citas de los artículos incluidos. Resultados: Se rescataron 1393 artículos, de los cuales se descartaron 1386 por diversas razones. Mediante el análisis de los textos completos, finalmente se incluyeron 7 estudios. Todos los estudios eran series de casos (nivel 4). La mediana de la frecuencia de muerte observada fue de 36,6% (Q1 20% - Q347%). Conclusiones: Esta RS mostró en niños con patología hemato-oncológica, que la mortalidad por IFI por Mucor spp. alcanzó a casi un tercio de los pacientes (AU)

Studies on invasive fungal infection (IFI) by Mucor spp. in pediatric patients with cancer have a low level of evidence, which makes it difficult to elucidate its characteristics and progression. To analyze the fatal outcome of these patients, this systematic review (SR) was conducted. Material and methods: A literature search was carried out on March 23, 2023, in the following main databases (Medline (via Pubmed), Embase (via Embase-Elsevier), The Cochrane Library (via Wiley), Cinahl (via Ebsco HOST), SCI-EXPANDED, SciELO (via the WOS) and Scopus (via Scopus-Elsevier). Additionally, a complementary search was carried out using free search engines (such as Google) and by reviewing the references of the included articles. Results: A total of 1393 articles were retrieved, of which 1386 were excluded for various reasons. After a thorough analysis of the full-text articles, 7 studies were ultimately included in the review. All studies were case series (level 4). The median observed death rate was 36.6% (IQR, 20% - 47%). Conclusions: This SR showed that in children with hematological-oncological disease, mortality due to IFI by Mucor spp. affected almost one third of the patients (AU)

A Fatal Rhizopus Species Infection after Facial Injury in a Patient with Myelodysplastic Syndrome and Diabetes Mellitus.

A 73-year-old woman with myelodysplastic syndrome and diabetes mellitus, chronic renal failure and paroxysmal atrial fibrillation, received a diagnosis of facial cellulitis and was treated by antibiotics. However, her symptoms deteriorated. Facial magnetic resonance imaging (MRI) showed orbital cellulitis. She had weakness of visual acuity requiring changing the antibiotics. She also underwent steroid pulse treatment. Her symptoms temporarily improved, but she became comatose and died. Results of a molecular analysis of the residual cerebrospinal fluid indicated Rhizopus species infection. For immunocompromised hosts with refractory orbital cellulitis, mucormycosis should be considered as a differential diagnosis, and appropriate treatment should be promptly performed.