Baseline findings of a multicentric ambispective cohort study (2021-2022) among hospitalised mucormycosis patients in India.

In India, the incidence of mucormycosis reached high levels during 2021-2022, coinciding with the COVID-19 pandemic. In response to this, we established a multicentric ambispective cohort of patients hospitalised with mucormycosis across India. In this paper, we report their baseline profile, clinical characteristics and outcomes at discharge. Patients hospitalized for mucormycosis during March-July 2021 were included. Mucormycosis was diagnosed based on mycological confirmation on direct microscopy (KOH/Calcofluor white stain), culture, histopathology, or supportive evidence from endoscopy or imaging. After consent, trained data collectors used medical records and telephonic interviews to capture data in a pre-tested structured questionnaire. At baseline, we recruited 686 patients from 26 study hospitals, of whom 72.3% were males, 78% had a prior history of diabetes, 53.2% had a history of corticosteroid treatment, and 80% were associated with COVID-19. Pain, numbness or swelling of the face were the commonest symptoms (73.3%). Liposomal Amphotericin B was the commonest drug formulation used (67.1%), and endoscopic sinus surgery was the most common surgical procedure (73.6%). At discharge, the disease was stable in 43.3%, in regression for 29.9% but 9.6% died during hospitalization. Among survivors, commonly reported disabilities included facial disfigurement (18.4%) and difficulties in chewing/swallowing (17.8%). Though the risk of mortality was only 1 in 10, the disability due to the disease was very high. This cohort study could enhance our understanding of the disease's clinical progression and help frame standard treatment guidelines.

Metagenomic insights into fungal community composition of the nasopharyngeal region of COVID-19 associated mucormycosis patients from India.

Coronavirus disease 2019 (COVID-19) associated mucormycosis (CAM) was reported predominantly from India during the second wave of COVID-19  and has a high mortality rate. The present study aims to understand the fungal community composition of the nasopharyngeal region of CAM-infected individuals and compare it with severe COVID-19 patients and healthy controls. The fungal community composition was decoded by analyzing the sequence homology of the internal transcribed spacer-2-(ITS-2) region of metagenomic DNA extracted from the upper respiratory samples. The alpha-diversity indices were found to be significantly altered in CAM patients (p < 0.05). Interestingly, a higher abundance of Candida africana, Candida haemuloni, Starmerella floris, and Starmerella lactiscondensi was observed exclusively in CAM patients. The interindividual changes in mycobiome composition were well supported by beta-diversity analysis (p < 0.05). The current study provides insights into the dysbiosis of the nasal mycobiome during CAM infection. In conclusion, our study shows that severe COVID-19 and CAM are associated with alteration in mycobiome as compared to healthy controls. However, the sequential alteration in the fungal flora which ultimately leads to the development of CAM needs to be addressed by future studies.

Displacement of Zygomatic Implant in infratemporal region in a case of COVID-19 associated Mucormycosis.

Reconstruction of maxillary defects can be carried out by a variety of treatment modalities. The choice of modality depends on numerous factors including the size and extent of the defect, patient factors and existing comorbidities. One of the various options is reconstruction and rehabilitation using a fixed prosthesis supported over zygomatic implant. In maxillectomy cases, zygomatic implant can be used to improve the retention of the obturator prosthesis as loss of alveolar bone makes it impossible to use conventional endosseous implants. Even though the zygomatic implants are advocated to have high success rates, they are not complication free. We hereby present a rare complication associated with placement of zygomatic implant in an operated patient of COVID - 19 associated mucormycosis. This rare complication has never been reported before. The case report also highlights on the management of complication involving displacement of zygomatic implant in infratemporal region.

Effect of High Serum Ferritin on Extent of Involvement of COVID-19 Associated Mucormycosis.

Coronavirus disease 2019 attributed to severe acute respiratory syndrome has been implicated with life threatening opportunistic infections like mucormycosis. COVID-19 is a hyperferritinemic syndrome and emerging data project the role of iron in the susceptibility and pathogenesis of mucormycosis but whether high ferritin is an indicator of severity of mucormycosis is debated. The study aimed to determine the relationship between serum ferritin levels and the extent of involvement of COVID-19 associated mucormycosis. A hospital based observational study was conducted with a sample size of 70. All biopsy confirmed cases of COVID-19 associated mucormycosis were included. Retrospective data from hospital records prepared at the time of patient admission were retrieved. The imaging data was used to determine the extent of disease involvement and serum ferritin values were analysed. During the study period 40 patients had mild extent mucormycosis and 30 had severe extent. A statistically significant difference was seen in levels of serum ferritin between mild extent mucormycosis and severe extent involvement (p < 0.01). COVID-19 associated Mucormycosis patients tend to have higher serum ferritin values especially in severe extent disease and with active COVID-19 infection along with diabetes mellitus as a potent aggravating factor.

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.

[Mucormycosis in the time of COVID-19: risks and challenges]. / Die Mukormykose in Zeiten von COVID-19: Risiken und Herausforderungen.

The first patients positive for SARS-CoV-2 were registered in December 2019. In March 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a global pandemic, the beginning of a worldwide health crisis that revealed numerous medical challenges for healthcare systems and pandemic emergency strategies.Among these challenges, mucormycosis, a typically rare fungal infection, gained global attention. With an average global incidence of about 2 per 1 million people, mucormycosis is considered a very rare disease, an opportunistic infection mostly affecting the lungs or skin and soft tissues in immunocompromised patients. Poorly controlled diabetes mellitus is one of the leading risk factors for rhino-orbital mucormycosis. Countries with a high prevalence of diabetes and limited healthcare resources have higher mucormycosis rates, with India and Pakistan being among the nations with particularly high incidences.During the second wave of the COVID-19 pandemic in India, mucormycosis rates surged dramatically within a few weeks, with over 47,500 cases of COVID-19-associated mucormycosis (CAM) reported between May and August 2021. Mucormycosis is characterized by a high mortality rate of up to 90%, especially when the diagnosis is delayed, and treatment commences late. There were concerns about a potentially global threat.In this article, we explore the risk factors and mechanisms leading to this viral-fungal coinfection. We present global distribution patterns, clinical presentation, and challenges in the diagnosis and treatment of COVID-19-associated mucormycosis.

Oral mucormycosis associated with COVID-19 and diabetes mellitus: Case report and literature review / Mucormicosis oral asociada a COVID-19 y diabetes mellitus: descripción de un caso.

Mucormycosis is an invasive opportunistic fungal infection with high mortality, mainly detected in people with COVID-19, especially those with underlying diseases such as diabetes mellitus. Mucormycosis prevalence is 0.005 to 1.7 cases per million inhabitants, and it has been increasing in countries like India and Pakistan. This mycosis can affect different organs, and clinical manifestations reflect the transmission mechanism. Frequent forms are rhino-orbital-cerebral and pulmonary. This disease should be suspected in patients with necrotic injuries on mucous membranes or skin. We present a case of a patient with diabetes mellitus and diagnosed with oral mucormycosis associated with COVID-19.

La mucormicosis es una infección fúngica oportunista e invasiva, con una elevada tasa de mortalidad. Se ha detectado principalmente en pacientes con COVID-19, especialmente en personas con enfermedades concomitantes como la diabetes mellitus. La prevalencia de las mucormicosis es de 0,005 a 1,7 casos por millón de habitantes y ha ido en aumento en países como India y Pakistán; puede afectar diferentes órganos y su forma clínica refleja el mecanismo de transmisión. Entre las formas frecuentes están la rino-orbital-cerebral y la pulmonar, por ello, debe sospecharse mucormicosis en los pacientes con lesiones necróticas en mucosas o piel. Se presenta el caso de un paciente con antecedentes de diabetes mellitus que fue diagnosticado con mucormicosis oral asociada a la COVID-19.

Diagnosis of Mucormycosis Using Frozen Section, Histopathology, Culture, and Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) Techniques: A Comparative Study.

Mucormycosis usually occurs in immunocompromised patients or those with uncontrolled diabetes. Along the third wave of SARS-CoV-2, an associated angioinvasive opportunistic infection with Mucor, a life-threatening fungal infection, was rampant and emerging. With an increase in the usage of steroids in the COVID scenario, the rate of mucormycosis did take a rapid and alarming increase in King Edward Memorial Hospital, Pune, India. Any delay in the diagnosis and management of the disease was life-threatening. The most conventional methods to diagnose mucormycosis are microbiological culture and histopathology of the tissue. The microbiological culture method plays an important role in the diagnosis of mucormycosis. However, the technique is labour-intensive, taking seven to eight days. Histopathology leads to false-negative reports if the tissue is not biopsied from representative sites. On the other hand, molecular methods are rapid, reliable, and applicable to different body samples, such as tissue, paraffin-embedded tissue blocks, plasma, and urine. We aimed to use a reverse transcriptase polymerase chain reaction (RT-PCR) method to detect Mucor in plasma samples. Due to a lack of availability of fresh samples, nucleic acid was extracted from the tissue sections of 69 cases diagnosed as Mucor by histopathology. These samples were subjected to RT-PCR using the MucorGenius kit (Pathonostics, Maastricht, Netherlands). A total of 57 tissue samples were sent for culture, and 49% of our cases were positive by culture and equally by RT-PCR. There was 80% sensitivity and 76% specificity between culture and PCR techniques. However, the use of blood/plasma for RT-PCR for early diagnosis of mucormycosis will be the method of choice.

Covid-19-Associated Mucormycosis: Histopathology of the Deadly Fungal Infection.

Introduction Many patients suffered from rhino-orbital-cerebral mucormycosis during the coronavirus disease 2019 (COVID-19) pandemic in India. Diabetes is a known risk factor of COVID-19 infection and mucormycosis. Objective The present study was done to describe the clinical spectrum and histopathological findings of mucormycosis in COVID-19 patients and their outcomes. Methods A cross-sectional study was done over a period of two and half months. The biopsy samples or scrapings from sinonasal or periorbital tissue of 38 patients were analyzed. Hematoxylin & Eosin (H&E stain) slides were evaluated along with Grocott-Gomori methenamine-silver and Periodic acid-Schiff stains to highlight the fungal elements. Results The male to female ratio was 2.5:1, and the mean age of the subjects was 53 years old. A total of 68.4% ( n = 26/38) of the patients had diabetes as a comorbidity, 84.2% ( n = 32/38) had a history of steroid intake, and 55.3% ( n = 21/38) were given supplemental oxygen during their treatment. The common presentations were nasal blockage, discharge, eye pain, headache, and altered mentation. The sites of biopsy were: nasal cavity 76.3% ( n = 29/38), periorbital fat/orbit 21.1% ( n = 8/38), maxillary sinus 15.8% ( n = 6/38) and ethmoid sinus 13.2% ( n = 5/38). In 76.3% ( n = 29/38) cases, broad, irregular, nonseptate, and right-angle branching hyphae were seen on H&E-stained tissue sections. Conclusion COVID-19 led to various complications in individuals affected by it. Mucormycosis was one such lethal complication. An early diagnosis and prompt treatment is crucial to control the progression of the disease and improve outcomes.

Early Reconstruction with Locoregional-Free Flaps in Post-COVID-19 Rhino-orbital-cerebral Mucormycosis Craniofacial Deformities: A Single-Center Clinical Experience from India.

Aim of the Study Mucormycosis is a rare invasive and fatal fungal infection and its resurgence in coronavirus disease 2019 (COVID-19) patients has been a matter of grave concern. It is essentially a medical disease, but surgical debridement of necrotic tissues is of paramount importance leading to severe craniofacial deformities. In this case series, we present our experience with the feasibility of early reconstruction after surgical debridement. Case Series As a Dedicated COVID Center (DCH), the institute received the largest population of COVID-19 mucormycosis patients from the entire eastern region of the country between May 2021 and August 2021. More than 5,000 COVID-19 were admitted out of which 218 patients were diagnosed with mucormycosis. Nine patients, seven males and two females, with a mean age of 39 years with craniofacial mucormycosis underwent debridement and early reconstructions (2-4 weeks from first debridement and start of antifungal therapy) with free and pedicled flaps. All flaps survived and showed no evidence of recurrence. The average time of the early reconstruction after surgical debridement was 1.7 weeks once the course of systemic amphotericin B was received. Conclusion After aggressive surgical resection and a short course of antifungal therapy, early reconstruction can be done safely based on clinical criteria, as long as there is no evidence of hyphae invasion on wound edges in the intraoperative pathology examination.

Molecular mechanisms that govern infection and antifungal resistance in Mucorales.

SUMMARYThe World Health Organization has established a fungal priority pathogens list that includes species critical or highly important to human health. Among them is the order Mucorales, a fungal group comprising at least 39 species responsible for the life-threatening infection known as mucormycosis. Despite the continuous rise in cases and the poor prognosis due to innate resistance to most antifungal drugs used in the clinic, Mucorales has received limited attention, partly because of the difficulties in performing genetic manipulations. The COVID-19 pandemic has further escalated cases, with some patients experiencing the COVID-19-associated mucormycosis, highlighting the urgent need to increase knowledge about these fungi. This review addresses significant challenges in treating the disease, including delayed and poor diagnosis, the lack of accurate global incidence estimation, and the limited treatment options. Furthermore, it focuses on the most recent discoveries regarding the mechanisms and genes involved in the development of the disease, antifungal resistance, and the host defense response. Substantial advancements have been made in identifying key fungal genes responsible for invasion and tissue damage, host receptors exploited by the fungus to invade tissues, and mechanisms of antifungal resistance. This knowledge is expected to pave the way for the development of new antifungals to combat mucormycosis. In addition, we anticipate significant progress in characterizing Mucorales biology, particularly the mechanisms involved in pathogenesis and antifungal resistance, with the possibilities offered by CRISPR-Cas9 technology for genetic manipulation of the previously intractable Mucorales species.

Role of Imaging Spectrum Along With Other Diagnostic Modalities in Rhino-Orbital-Cerebral Mucormycosis (ROCM).

OBJECTIVES: Rhino-orbito-cerebral mucormycosis (ROCM), a rare angio-invasive fungal infection, had become a major outbreak during the second wave of the coronavirus disease (COVID-19) pandemic in India, with over 28,000 reported cases. The purpose of this study was to describe the imaging spectrum of ROCM, which may prove useful in prompt diagnosis, considering its grave prognosis in populations with a high load of immunosuppressed patients (e.g., COVID-19, HIV-AIDS, etc.). MATERIAL AND METHODS: Evaluation of the clinical data and imaging of patients with symptoms suspicious of mucormycosis of the craniofacial region was done. The diagnosis was made using computed tomography (CT) or magnetic resonance (MR) imaging, a biopsy, and culture. The data analysis was done using descriptive statistical methods. RESULTS: The sample group consisted of a total of 36 patients ranging from 33 years to 75 years of age, out of which 31 (86.11%) were male and five (13.8%) were female. A total of 30 (83.33%) patients had a positive correlation with COVID-19 infection, and 29 (80.55%) patients had a positive correlation with diabetes. The major presenting complaints were facial pain and swelling (20 patients; 55.55%). The intracranial spread was seen in 14 (38.88%) patients. Our study demonstrated a mortality rate of 38.88% (14 patients). CONCLUSION: ROCM, once considered to occur predominantly in diabetics, is increasingly being seen in other immunosuppressive patients, such as COVID-19. CT and MR imaging help provide an early diagnosis in conjunction with pathologic and microbiological correlations. Immediate correction of immunosuppression with the initiation of amphotericin B therapy combined with extensive and diligent surgical debridement of the diseased tissue is required.

Genome-based solutions for managing mucormycosis.

An uncommon opportunistic fungal infection known as mucormycosis is caused by a class of molds called mucoromycetes. Currently, antifungal therapy and surgical debridement are the primary treatment options for mucormycosis. Despite the importance of comprehensive knowledge on mucormycosis, there is a lack of well-annotated databases that provide all relevant information. In this study, we have gathered and organized all available information related to mucormycosis that include disease's genome, proteins, diagnostic methods. Furthermore, using the AlphaFold2.0 prediction tool, we have predicted the tertiary structures of potential drug targets. We have categorized the information into three major sections: "genomics/proteomics," "immunotherapy," and "drugs." The genomics/proteomics module contains information on different strains responsible for mucormycosis. The immunotherapy module includes putative sequence-based therapeutics predicted using established tools. Drugs module provides information on available drugs for treating the disease. Additionally, the drugs module also offers prerequisite information for designing computationally aided drugs, such as putative targets and predicted structures. In order to provide comprehensive information over internet, we developed a web-based platform MucormyDB (https://webs.iiitd.edu.in/raghava/mucormydb/).

Early trends of secondary acquired nasolacrimal duct obstruction in COVID-19 associated sino-orbital mucormycosis: SALDO update study (SUP) - Paper IV.

Purpose: To study the emerging trend of development of secondary acquired nasolacrimal duct obstruction (SALDO) in the cases treated for rhino-orbito-cerebral mucormycosis (ROCM). Observations: Prospective, interventional case series of five patients who developed SALDO post-surgical and medical management of ROCM. The mean age was 45.4 years (range: 40-62 years), all five being males. Right lacrimal drainage pathways was involved slightly more than the left (right:left = 3:2). Epiphora and discharge were the main presenting features. All five patients were treated with extensive debridement of the nose, sinuses, orbit and cerebral involvement as needed followed by medical management for ROCM. CT- Dacryocystography for all 5 patients showed obstruction at the lower end of the nasolacrimal duct. The patients underwent external dacryocystorhinostomy with mitomycin-C with or without intubation with good anatomical and functional outcomes at 6 months follow-up. Conclusions and importance: The present series highlights the possible etiology of development of SALDO in cases treated for ROCM, its management and discusses the role of Computed Tomography Dacryocystography (CT-DCG) in understanding the pathophysiology of the development of SALDO along with delineating the spatial relationship of the lacrimal drainage system with the surrounding structures.

An Unusual Presentation of Rhino-Orbital Mucormycosis with MDR-TB: an Unforeseen Challenge for Treatment Post COVID-19.

ROCM is an invasive fungal infection that has seen a substantial rise in the post covid-19 patients. Here we present an intriguing case of ROCM existing as a coinfection with MDR-TB. The purpose of this manuscript is to highlight the dilemma faced by the clinicians whether to take the risks associated with standard treatment protocols of mucormycosis contraindicated due to coexisting MDR-TB or to play safe and face the consequences of inadequate management.

Endoscopic Transnasal Navigation Guided Treatment of Clivus Abscess in Adult with Mucormycosis: A Rare Report.

Osteomyelitis and abscess of the clivus are rare conditions thought to arise from contiguous spread of infection from the paranasal sinuses. Clival osteomyelitis is a rare potentially life-threatening skull base infection which is generally challenging to diagnose and treat. It is typically seen in the pediatric population and is very rare in the adult population. The exact pathophysiology of osteomyelitis of the clivus is relatively uncertain. Here, we describe a case of a 32-year-old immunocompetent female with a primary complaint of headache, with no significant medical history of diabetes, hypertension or rhinosinusitis or SARS COV-2 for the past 18 months. This case report demonstrates an image-guided and endoscopic approach to surgical localization and treatment of abscesses in the clival area.

Hematological Indices in COVID-19 Patients with Rhinosinusitis Mucormycosis.

Introduction: Rhinosinusitis mucormycosis (RM) is an invasive opportunistic fungal infection, especially among COVID-19 patients. The current study aimed to assess the peripheral blood hematological disorders of COVID-19 patients-associated RM. Materials and Methods: During ten month, in two COVID-19 centers in Mashhad, Iran, from June 2021 to March 2022, eighty-three patients suspected of COVID-19 with rhinosinusitis or rhino-orbital mucormycosis participated in this study. The hematological indices of these patients were measured by independent sample T-test or Mann-Whitney test for quantitative data, and the qualitative variables were analyzed using Chi-square or Fisher's exact test in SPSS version 20 at a significance level of 0.05. Results: Of the COVID-19 patients, 40 (48.2%) were affected by RM, and leukocytosis due to neutrophilia was observed in 30% of them. Leukocyte counts were normal in 10 (25%) patients, but 1 (2.5%) and 3 (7.5%) had leukopenia and lymphopenia, respectively. Leukocytosis plus lymphopenia was observed in 7 (17.5%) patients. Also, the synchronicity of leukopenia and lymphopenia was seen in 5 (12.5%) patients. Leukopenia, lymphopenia, and neutropenia have occurred concurrently in 2 (5%) patients. The complete blood count (CBC) showed that RBCs, hemoglobin (Hb), hematocrit (HCT), MCH, MCHC, platelet (PLT), and lymphocytes decreased while neutrophils increased. Conclusion: Among the hematological parameters, leukocytosis due to neutrophilia and reduction in Hb, HCT, and PLT are more dominant factors in COVID-19 patients-associated RM.

Pulmonary Mucormycosis: Beyond Classic COVID-19-Associated Fungal Infections.

Coronavirus disease 2019 (COVID-19) is often linked to a broad range of opportunistic bacterial and fungal infections. The second wave of the COVID-19 pandemic has witnessed an unprecedented surge in mucormycosis cases, predominantly in India, while the disease remained relatively rare in Europe. The authors describe the case of a 62-year-old female patient admitted to the hospital for consolidation therapy with chemotherapy as a part of the treatment protocol for acute myeloid leukemia. During hospitalization, she was diagnosed with nosocomial COVID-19, which later progressed to respiratory deterioration. COVID-19 with bacterial superinfection was presumed, leading to the initiation of empirical antibiotic therapy. A bronchoscopy was performed several days later due to a lack of improvement, revealing an infection by the Rhizopus microsporus complex. Despite antifungal treatment, the patient experienced an unfavorable clinical course and ultimately died. Given the high index of suspicion required to diagnose pulmonary mucormycosis, which can lead to delays in appropriate treatment and increase the burden of disease, the authors are aiming to enhance its awareness.