Figure - available from: Current Fungal Infection Reports
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Photomicrographs showing a thrombotic occlusion with narrowed lumen due to invasion by fungal hyphae; b acute vasculitis and fungal hyphae within media and intima; c & d perineural and intraneural invasion by fungus in the adjacent soft tissue; e involvement of the optic nerve by the fungal hyphae; f optic nerve with neutrophilic infiltrate; g micro-abscess in the optic nerve (H&E × 100)
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Purpose of Review
There is global increase in the incidence of mucormycosis. However, a sudden increase in the COVID-associated mucormycosis (CAM) was noted, particularly in India, during the second wave of the COVID-19 pandemic. The interplay of factors involved in the pathogenesis is complex. In this review, the influence of pre-existing disease,...
Citations
... The fungus invades the body by breaching the physical barriers of the skin or respiratory system and encounters the components of the innate immune system, including macrophages, neutrophils, and dendritic cells. If the innate immune system fails to eliminate the fungal spores, the fungus is able to germinate and proliferate (Radotra & Challa, 2022). ...
The global concern surrounding emerging and re-emerging infectious diseases has reached paramount levels. These diseases encompass novel infections that have recently manifested within a population, or those that have existed but are now experiencing a rapid surge in both occurrence and geographical spread. Within the context of the Philippines, a developing country, the battle against infectious diseases is uniquely challenging. The intricacies of these challenges are deeply interwoven with factors such as poverty, densely packed living conditions, and limited accessibility to healthcare services. This intricate web of circumstances cultivates an environment that substantially amplifies the susceptibility to transmission and proliferation of infectious diseases, particularly within urban settings. Consequently, there emerges an urgent need for all-encompassing and sustainable strategies capable of effectively managing and alleviating the impact of infectious diseases, and thus safeguarding the health and overall well-being of the Filipino populace. This chapter delves into the latest insights regarding emerging and re-emerging infectious diseases in the Philippines. It encompasses a spectrum of conditions including influenza, dengue, Zika, HPV, HIV, TB, meningococcemia, leptospirosis, aspergillosis, candidiasis, mucormycosis, cryptococcosis, soil-transmitted helminthiasis, and schistosomiasis. The aim of this chapter is to provide a comprehensive overview of the present state of these disease,while highlighting the trends in ongoing research endeavors and the collective pursuit of effective control and mitigation strategies.
... All Mucorales fungi were detected, including the most common causes of mucoromycosis worldwide, namely Lichtheimia spp., Mucor circinelloides, Rhizopus arrhizus, and Rhizopus microsporus var. rhizopodiformis (Roden et al., 2005;Gomes et al., 2011;Skiada et al., 2011;Laternier et al., 2012;Zaki et al., 2014;Prakash and Chakrabarti, 2019;Skiada et al., 2020;Radotra and Challa, 2022;Özbek et al., 2023;Pham et al., 2023;Yang et al., 2023), and also rarer, emerging, or more regionally-prevalent causes of the disease (Gomes et al., 2011;Skiada et al., 2020) including Actinomucor (Tully et al., 2009), Apophysomyces (Chander et al., 2015), Cunninghamella (Mita et al., 2022), other Mucor spp. (Deja et al., 2006;Álvarez et al., 2011;Lu et al., 2013;Chander et al., 2018), Rhizomucor (Chander et al., 2018;Schober et al., 2021), other Rhizopus spp. ...
Mucoromycosis is a highly aggressive angio-invasive disease of humans caused by fungi in the zygomycete order, Mucorales. While Rhizopus arrhizus is the principal agent of mucoromycosis, other Mucorales fungi including Apophysomyces, Cunninghamella, Lichtheimia, Mucor, Rhizomucor and Syncephalastrum are able to cause life-threatening rhino-orbital-cerebral, pulmonary, gastro-intestinal and necrotising cutaneous infections in humans. Diagnosis of the disease currently relies on non-specific CT, lengthy and insensitive culture from invasive biopsy, and time-consuming histopathology of tissue samples. At present, there are no rapid antigen tests that detect Mucorales-specific biomarkers of infection, and which allow point-of-care diagnosis of mucoromycosis. Here, we report the development of an IgG2b monoclonal antibody (mAb), TG11, which binds to extracellular polysaccharide (EPS) antigens of between 20 kDa and 250 kDa secreted during hyphal growth of Mucorales fungi. The mAb is Mucorales-specific and does not cross-react with other yeasts and molds of clinical importance including Aspergillus, Candida, Cryptococcus, Fusarium, Lomentospora and Scedosporium species. Using the mAb, we have developed a Competitive lateral-flow device that allows rapid (30 min) detection of the EPS biomarker in human serum and bronchoalveolar lavage (BAL), with a limit of detection (LOD) in human serum of ~100 ng/mL serum (~224.7 pmol/L serum). The LFD therefore provides a potential novel opportunity for detection of mucoromycosis caused by different Mucorales species.
... 1 Mucormycosis was earlier considered a rare life threatening invasive fungal infection. 2 However, there is a rise in COVID19 associated Mucormycosis (CAM) due to immune dysregulation, comorbidities like diabetes, transplants and cancers. 3 In COVID19 cases there is damage in airway epithelium. ...
... Other causes of hyperglycaemia could be corticosteroids and cytokine storm. 11,12 COVID 19 can worsen acidosis due to direct renal tropism, renal infection and diabetic ketoacidosis, thrombosis and ischemia etc. 2 There is also an increase in free iron due to cytokine storm, glycosylation of ferritin and transferrin induced by hyperglycaemia. Increased reactive oxygen species are attributable to increase ferritin and hepcidin. ...
A wide range of fungal and bacterial infections are associated with Corona virus disease (COVID19). There was a surge of mucormycosis during COVID19 pandemic in 2021. This study elaborates the histopathological findings observed in fungal infections of head and neck in COVID 19 patients.
A retrospective observational study of histopathological findings of invasive fungal infection in COVID 19 case was conducted in our laboratory. All the tissue samples diagnosed as post COVID fungal infections during January 2021 to June 2021 were analyzed. Representative sections were taken and slides were stained with Hematoxylin & Eosin, Periodic Acidic Schiff (PAS) and Gomori Methenamine silver (GMS) stains. Histopathological features were studied.
There were total 32 cases which had invasive fungal infections associated with COVID 19. The most affected age group was 31 to 50 years of age (50%), with male preponderance (87.5%). Diabetes was present in 62.5% cases, and steroid use during the treatment was present in 31.3% of the cases. The most common site was maxillary sinus (53.1%) followed by nasal cavity (34.4%). Isolated infection by mucor was seen in 68.8% cases, there were cases of secondary bacterial infection and candida with aspergillus infection. Angioinvasion was present in 56.3% cases and bone destruction in 15.6% cases.
COVID 19 infection results in immune dysregulation and background of diabetes and over use of steroids increases risk of mucormycosis. An early histopathological diagnosis provides early diagnosis.
... 8 Radotra and Challa in their review quoted that hyperglycemia, acidosis, availability of free iron, lowered host defenses, and fungal virulence were the factors that promoted the growth of Mucorales. 11 The COVID-19 treatment modality might have resulted in dysregulation of the glycemic control and predisposition to secondary fungal infections, especially in the setting of comorbid factors like DM. Amalanathan et al reported a case of Mucormycosis that presented as orbital cellulitis in a patient of COVID-19 pneumonia with steroid dependence and uncontrolled DM. 7 Singh et al studied fungal infections among COVID-19 patients over a 1-month period and observed 10 cases of mixed fungal disease. DM as a comorbid factor was evident in all their patients and all were treated with steroids as per protocol. ...
... The culture correlation (though less sensitive, but diagnostic) was confirmatory for the diagnosis of invasive fungal disease. 11 The tissue diagnosis of fungal disease was even more challenging, particularly in conventional H&E stains. In suspected cases, additional histochemical stains like GMS or PAS need to be applied for better visualization of fungi admixed with a gamut of tissue reaction patterns and can augment and aid pathologist for its early diagnosis. ...
Coronavirus disease 2019 (COVID-19) is a recent global pandemic that is caused by the novel severe acute respiratory syndrome coronavirus 2. The patients of COVID-19 are susceptible to a diverse range of secondary infections, fungal being the most common. The increased risk is proposed to be due to the generous use of steroids for the treatment of COVID-19 infection and the presence of comorbidities, such as diabetes mellitus, hypertension, preexisting lung diseases, and/or old age. Invasive mixed fungal disease is potentially life-threatening to the patients of COVID-19. In the present series of seven cases, the authors intend to discuss the clinicopathological profile and gamut of histopathological findings in invasive mixed fungal infection comprising of Mucor and Aspergillus in treated patients of COVID-19. Six patients had a clinical diagnosis of sinonasal–orbital invasive fungal disease, while there was a case of lung infection. The acquaintance and knowledge about histomorphology of invasive fungi and the multidisciplinary diagnostic approach not only will aid in early and accurate diagnosis but can guide the clinician for necessary surgical intervention and initiation of appropriate antifungal medications in patients of COVID-19.
... The pathophysiology is thought to involve the interplay of hyperglycaemia, diabetic ketoacidosis, immunosuppression, free iron availability, immune dysregulation, and pulmonary damage from COVID-19 predisposing to tissue invasion [83]. The detailed pathogenesis of CAM is beyond the scope of this review, but the reader is referred to several comprehensive reviews on this topic [84][85][86]. ...
Mucormycosis is an uncommon, yet deadly invasive fungal infection caused by the Mucorales moulds. These pathogens are a WHO-assigned high-priority pathogen group, as mucormycosis incidence is increasing, and there is unacceptably high mortality with current antifungal therapies. Current diagnostic methods have inadequate sensitivity and specificity and may have issues with accessibility or turnaround time. Patients with diabetes mellitus and immune compromise are predisposed to infection with these environmental fungi, but COVID-19 has established itself as a new risk factor. Mucorales also cause healthcare-associated outbreaks, and clusters associated with natural disasters have also been identified. Robust epidemiological surveillance into burden of disease, at-risk populations, and emerging pathogens is required. Emerging serological and molecular techniques may offer a faster route to diagnosis, while newly developed antifungal agents show promise in preliminary studies. Equitable access to these emerging diagnostic techniques and antifungal therapies will be key in identifying and treating mucormycosis, as delayed initiation of therapy is associated with higher mortality.
... It is an angioinvasive disease caused by fungi belonging to the order mucorales of class zygomycetes [2]. The most common mode of infection is through inhalation of sporangiospores and could also occur through direct inoculation from disrupted skin or mucosal surfaces [3]. The fungus is highly vasotropic in nature causing tissue infarctions and becomes rapidly disseminated specially in immuno-compromised patients (diabetics, glucocorticoid therapy, patients with malignancy receiving chemotherapy, allogenic stem cell transplant recipients) [4]. ...
Background:
Mucormycosis necessitates rapid diagnosis and treatment. Microscopy and culture have been considered the gold standard for diagnosis but both take time of 3 - 5 days. KOH mount is another method for fungal identification that takes 1 - 2 h, but it has its own limitations. This study evaluated crush smear as a means of rapid cytological diagnosis.
Methods:
Biopsy tissue (pre-treatment) from clinically suspicious mucormycosis patients (n = 52) was received in normal saline and crush/imprint smears were prepared; the remaining tissue was processed as routine biopsy specimen. After the rapid initial cytological identification, the patients were managed according to the standard clinical protocol. Random post-therapeutic biopsy samples of some of these patients (n = 19) were also obtained and again evaluated cytologically.
Results:
Crush smears showed sensitivity/specificity of 77.7%/75.0% with histopathology and 72.2%/62.5% with culture, respectively, while KOH mount had values of 71.4%/70.5% with histopathology and 79.3%/69.5% with culture, respectively. Degenerative fungal morphological characteristics and cellular inflammatory infiltrate (predominantly neutrophilic) in the vicinity of fungal hyphae were compared in pre- and post-treatment groups, and we found a statistically significant difference (P < 0.05) between them.
Conclusion:
Our preliminary results suggest that crush smear cytology is a simple, rapid, cost-effective and easily available method for diagnosing mucormycosis. Moreover, crush smears also demonstrated morphological alteration in hyphal structure and accompanying immune cell infiltration which may provide valuable insights into mechanism of therapy/host immune response against fungal pathogen.
Mucormycosis is the third most frequent invasive mycosis, following candidiasis and aspergillosis. It is frequently neglected due to its rare occurrence; but recently attend the status of notifiable disease due to its higher incidence in both developed and developing nations. India has received global notice since its estimated instances were greater than the global estimated figures. Mucormycosis has several clinical manifestations, including rhino-orbital-cerebral (ROCM), pulmonary, gastrointestinal, cutaneous, renal, and diffuse Mucormycosis. ROCM is the most frequent clinical manifestation in India, although pulmonary mucormycosis is prevalent worldwide. This review also discusses host defenses, pre disposing risk factors and fungal virulence factors that impair host's ability to prevent fungus invasion and disease establishment. The diagnosis of the disease depends on clinical interventions, histological or microbiological procedures along with molecular methods to obtain timely results. But there are still unmet challenges for rapid diagnosis of the disease. Treatment of the disease is achieved by multimodal approaches such as reversal of underlying predisposing factors, rapid administration of antifungals in optimal doses and surgical procedures to remove infected tissues. Liposomal Amphotericin B, Posaconazole and Isavuconazoles are preferred as the first line of treatment procedures. clinical trials. Different studies have improved the existing drug and under clinical trials while several studies predicted the new potential targets as CotH and Ftr1 as shown in infection and in vitro models. Therefore, current scenario demands a multidisciplinary approach is needed to investigate the prevalence, pathogenesis which is highly important for the advancement of rapid diagnosis and effective treatment.
This study aimed to investigate the risk factors associated with intracranial involvement in COVID-19-associated mucormycosis (CAM) and to develop a nomogram model for predicting the risk of intracranial involvement, with a specific focus on perineural spread. An ambispective analysis was conducted on 275 CAM patients who received comprehensive treatment. Univariable and multivariable logistic regression analyses were performed to identify independent risk factors, and a nomogram was created based on the results of the multivariable analysis. The performance of the nomogram was evaluated using a receiver operating characteristic (ROC) curve, and the discriminatory capacity was assessed using the area under the curve (AUC). The model's calibration was assessed through a calibration curve and the Hosmer Lemeshow test. In the results, the multivariable logistic regression analysis revealed that age (OR: 1.23, 95% CI 1.06–3.79), HbA1c (OR: 7.168, 95% CI 1.724–25.788), perineural spread (OR: 6.3, 95% CI 1.281–19.874), and the disease stage were independent risk factors for intracranial involvement in CAM. The developed nomogram demonstrated good discriminative capacity with an AUC of 0.821 (95% CI 0.713–0.909) as indicated by the ROC curve. The calibration curve showed that the nomogram was well-calibrated, and the Hosmer Lemeshow test yielded a p value of 0.992, indicating a good fit for the model.
On concluding, this study found that CAM particularly exhibits perineural spread, which is a predictive factor for intracranial involvement. A nomogram model incorporating age, HbA1c, disease stage, and perineural spread was successfully developed for predicting intracranial involvement in CAM patients in both in-patient and out-patient settings.
Introduction
Mucormycosis is an invasive fungal infection caused by Mucorales that has been increasingly recognized over the years, particularly during the COVID-19 pandemic. Nevertheless, in Peru, there has been limited research on this disease. This study seeks to provide insights into the demographics, clinical presentations, treatment, and outcomes of patients with mucormycosis, before and during the COVID-19 pandemic.
Materials and methods
We conducted a retrospective case series by reviewing the medical records of Peruvian patients hospitalized at a referral medical center between 2017 and 2021. The selection criteria included patients aged 18 years or older with clinical features of rhino-orbito-cerebral mucormycosis supported by radiological imaging. We extracted data related to risk factors for mucormycosis infection, clinical presentation, management, and hospitalization. Data analysis was performed using Stata software (StataCorp LLC, College Station, Texas, USA) to compare patient groups before and during the COVID-19 pandemic.
Results
Nineteen cases met our selection criteria: 11 men and eight women with an average age of 57.6 ± 10.6 years. All 19 patients had type 2 diabetes mellitus as comorbidity, with 13 cases exhibiting uncontrolled diabetes. Six patients presented before the COVID-19 pandemic, while 13 during its course. Within the group of patients diagnosed during the pandemic, nine were diagnosed with SARS-CoV-2 infection. Regarding the site of mucormycosis infection, the paranasal sinuses were predominantly involved. Survival analysis indicated that patients who developed mucormycosis during the COVID-19 pandemic, those with uncontrolled diabetes, or those who did not undergo surgery had lower probabilities of survival.
Conclusion
Mucormycosis is a rare infection associated with high mortality and morbidity with increased frequency during the COVID-19 pandemic. Early diagnosis, timely administration of antifungal treatment, surgery, and effective management of comorbidities can have life-saving implications. Unfortunately, despite the availability of various diagnostic tests and less toxic antifungal options such as liposomal amphotericin-B, such resources are not accessible in Peru's national hospitals.
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.
