COVID-19 associated rhino-orbital-cerebral mucormycosis: An observational study from Eastern India, with special emphasis on neurological spectrum.

AIMS: 1: Describe the epidemiology and determine risk factors for COVID-19 associated mucormycosis. 2: Elaborate the clinical spectrum of Rhino-Orbital-Cerebral Mucormycosis (ROCM), pattern of neuroaxis involvement and it's radiological correlates. METHODS: Observational study. Consecutive, confirmed cases of mucormycosis (N = 55) were included. A case of mucormycosis was defined as one who had clinical and radiological features consistent with mucormycosis along with demonstration of the fungus in tissue via KOH mount/culture/histopathological examination (HPE). Data pertaining to epidemiology, risk factors, clinico-radiological features were analysed using percentage of total cases. RESULTS: Middle aged, diabetic males with recent COVID-19 infection were most affected. New onset upper jaw toothache was a striking observation in several cases. Among neurological manifestations headache, proptosis, vision loss, extraocular movement restriction; cavernous sinus, meningeal and parenchymal involvement were common. Stroke in ROCM followed a definitive pattern with watershed infarction. CONCLUSIONS: New onset upper jaw toothache and loosening of teeth should prompt an immediate search for mucormycosis in backdrop of diabetic patients with recent COVID-19 disease, aiding earlier diagnosis and treatment initiation. Neuroaxis involvement was characterized by a multitude of features pertaining to involvement of optic nerve, extraocular muscles, meninges, brain parenchyma and internal carotid artery.

CT and MRI Findings of Invasive Mucormycosis in the Setting of COVID-19: Experience From a Single Center in India.

An increasing incidence of rhinoorbitocerebral mucormycosis (ROCM) among patients with COVID-19 has recently been reported in India. We report the imaging findings for 25 patients with COVID-19 and invasive ROCM at a single hospital in India. Findings included sinus wall erosions (n = 20), air within bony sinus structures (n = 11), and focal mucosal nonenhancement (n = 8). Orbital, vascular, and intracranial complications were also observed. Radiologists should recognize the increasing incidence of ROCM among patients with COVID-19 to facilitate early diagnosis.

Cryptococcosis caused by cryptococcus gattii: 2 case reports and literature review.

Cryptococcosis caused by Cryptococcus gattii, is a life threatening fungal infection with recently increasing prevalence. C. gattii is a species complex comprising multiple independent species. However, many biological characteristics and clinical features of cryptococcosis due to C. gattii are relatively less well defined. In this paper, we identify two cases of C. gattii infection, and laboratory findings of genotype VGI and VGII in two groups of apparently immunocompetent Chinese individuals respectively. Upon detailed review of all 35 cases of C. gattii infections, it was observed that C. gattii can cause debilitating illness in both immunocompetent and immunocompromised individuals. Cryptococcosis due to C. gattii is a serious systemic fungal infection, with pulmonary central nervous system tropism. Epidemiologically, C. gattii infection is not only restricted in tropical and subtropical regions, but also in other geographical settings.

Infectious Myelitis.

Myelitis refers to inflammation of the spinal cord which can result in a spectrum of neurologic impairment. Infectious pathogens are an important etiologic category, and can result in myelitis through direct pathogenic effect or through immune-mediated parainfection; this review focuses on the former category. The spectrum of clinical manifestations is summarized and a diagnostic workup provided to aid clinicians in developing an approach to patients presenting with symptoms suggestive of infectious myelitis. This is followed by an overview of the important viral, bacterial, parasitic, and fungal causes of infectious myelitis. The typical presentations, diagnostic modalities, and treatment approaches are outlined for key pathogens culprit in infectious myelitis to allow clinicians to promptly recognize and diagnose specific infectious etiologies of myelitis.

Update on fungal infections of the central nervous system: emerging pathogens and emerging diagnostics.

PURPOSE OF REVIEW: Fungal infections of the central nervous system (CNS) are relatively uncommon but associated with significant morbidity and mortality. We reviewed recent literature highlighting new approaches to management of these complex patients. RECENT FINDINGS: Fungal infections are increasingly recognized as important causes of CNS disease in both immunocompromised and immunocompetent hosts. Globally, cryptococcal meningitis remains a leading cause of death in HIV-infected persons in resource-limited settings. Emerging fungal pathogens with increased virulence and resistance to numerous classes of antifungal agents have been identified and represent a management challenge. Newer diagnostic techniques focused on antigen detection or molecular amplification of fungal pathogens offer promise in the expediated diagnosis and treatment of CNS fungal infections. SUMMARY: Meningitis and brain abscess because of invasive fungal pathogens are frequently fatal infections. Newer laboratory tests allowing antigen detection or molecular amplification from cerebrospinal fluid are more sensitive than culture and allow earlier initiation of effective therapy.

Fungal infections of the central nervous system and paranasal sinuses in onco-haematologic patients. Epidemiological study reporting the diagnostic-therapeutic approach and outcome in 89 cases.

Invasive fungal infections (IFI) of the Central Nervous System (IFI-CNS) and Paranasal Sinuses (IFI-PS) are rare, life-threatening infections in haematologic patients, and their management remains a challenge despite the availability of new diagnostic techniques and novel antifungal agents. In addition, analyses of large cohorts of patients focusing on these rare IFI are still lacking. Between January 2010 and December 2016, 89 consecutive cases of Proven (53) or Probable (36) IFI-CNS (71/89) and IFI-PS (18/89) were collected in 34 haematological centres. The median age was 40 years (range 5-79); acute leukaemia was the most common underlying disease (69%) and 29% of cases received a previous allogeneic stem cell transplant. Aspergillus spp. were the most common pathogens (69%), followed by mucormycetes (22%), Cryptococcus spp. (4%) and Fusarium spp. (2%). The lung was the primary focus of fungal infection (48% of cases). The nervous system biopsy was performed in 10% of IFI-CNS, and a sinus biopsy was performed in 56% of IFI-PS (P = 0.03). The Galactomannan test on cerebrospinal fluid has been performed in 42% of IFI-CNS (30/71), and it was positive in 67%. Eighty-four pts received a first-line antifungal therapy with Amphotericine B in 58% of cases, Voriconazole in 31% and both in 11%. Moreover, 58% of patients received 2 or more lines of therapy and 38% were treated with a combination of 2 or more antifungal drugs. The median duration of antifungal therapy was 60 days (range 5-835). A surgical intervention was performed in 26% of cases but only 10% of IFI-CNS underwent neurosurgical intervention. The overall response rate to antifungal therapy (complete or partial response) was 57%, and 1-year overall survival was 32% without significant differences between IFI-CNS and IFI-PS. The overall mortality was 69% but the IFI attributable mortality was 33%. Mortality of IFI-CNS/PS remains high but, compared to previous historical data, it seems to be reduced probably due to the availability of newer antifungal drugs. The results arising from this large contemporary cohort of cases may allow a more effective diagnostic and therapeutic management of these very rare IFI complications in haematologic patients.

Visceral Mycoses in Autopsied Cases in Japan from 1989 to 2013.

BACKGROUND AND METHODS: Our group has continuously studied the epidemiology of visceral mycoses (VM) among autopsy cases in Japan from 1989 to 2013. RESULTS: First, from a total of 11,149 autopsied cases, 571 (5.1%) cases of VM were observed in 2013. It was significantly higher than those of 2005 (p < 0.05) and earlier. Notably, incidence of cases with mucormycetes (Muc) in 2013 was higher than that of 1997 and earlier (p < 0.001), especially in leukemia cases. Muc cases also showed higher rate of "severe infection" compared with other cases (p < .0001). Emerging diseases were also observed. Severe fever with thrombocytopenia syndrome cases showed high incidence of VM as a complication. In addition, we observed cases with the rare mycoses caused by Phialopohra verrucosa and Rhodotorula spp. in our analysis. Moreover, the predominant fungal agent of central nervous system infections changed from Cryptococcus spp. to Aspergillus spp. in 2013. This may be considered a breakthrough infection. CONCLUSION: The prevalence of VM in 2013 became higher than those of 2005 (p < 0.05) and earlier, with a notable increase of incidence in cases with Muc. The occurrence of breakthrough VM and emerging mycoses deserve attention.

Cryptococcal infection in lung transplant recipients: A 5-year retrospective review at an Australian transplant center.

Cryptococcosis is a common invasive fungal infection (IFI) in solid organ transplant (SOT) recipients. Little is known about cryptococcosis in lung transplant (LTx) recipients despite having one of the highest risks of infection. The aim of this study was to describe demographic and clinical features of cryptococcal infection in LTx recipients. We performed a retrospective, observational study of cryptococcal infection in LTx recipients at The Alfred Hospital in Melbourne, Australia, from 2012 to 2017. A total of 11 cases were identified. Seven patients (64%) were male and the median age was 54.7 years (range 34-69 years). Diagnosis occurred at a median of 233 days (range 1-3650 days) post-transplant. Nine patients (82%) had isolated pulmonary infection of whom 7 (78%) were asymptomatic. All were treated with oral antifungal therapy and 1 required surgical resection of infected lung. Two patients (18%) had disseminated infection; 1 with pulmonary and central nervous system (CNS) infection and 1 with isolated CNS infection. Both patients presented with headache and brain imaging demonstrated cerebral edema, myelinosis, and leptomeningeal enhancement. One of these patients died. This study highlights the fact that cryptococcal infection should remain a consideration in asymptomatic LTx recipients, especially in the presence of non-specific nodules on chest imaging, and that the presence of headache in these patients requires urgent investigation for CNS infection.

Neuroinfections caused by fungi.

BACKGROUND: Fungal infections of the central nervous system (FIs-CNS) have become significantly more common over the past 2 decades. Invasion of the CNS largely depends on the immune status of the host and the virulence of the fungal strain. Infections with fungi cause a significant morbidity in immunocompromised hosts, and the involvement of the CNS may lead to fatal consequences. METHODS: One hundred and thirty-five articles on fungal neuroinfection in PubMed, Google Scholar, and Cochrane databases were selected for review using the following search words: "fungi and CNS mycoses", CNS fungal infections", "fungal brain infections", " fungal cerebritis", fungal meningitis", "diagnostics of fungal infections", and "treatment of CNS fungal infections". All were published in English with the majority in the period 2000-2018. This review focuses on the current knowledge of the epidemiology, clinical presentations, diagnosis, and treatment of selected FIs-CNS. RESULTS: The FIs-CNS can have various clinical presentations, mainly meningitis, encephalitis, hydrocephalus, cerebral abscesses, and stroke syndromes. The etiologic factors of neuroinfections are yeasts (Cryptococcus neoformans, Candida spp., Trichosporon spp.), moniliaceous moulds (Aspergillus spp., Fusarium spp.), Mucoromycetes (Mucor spp., Rhizopus spp.), dimorphic fungi (Blastomyces dermatitidis, Coccidioides spp., Histoplasma capsulatum), and dematiaceous fungi (Cladophialophora bantiana, Exophiala dermatitidis). Their common route of transmission is inhalation or inoculation from trauma or surgery, with subsequent hematogenous or contiguous spread. As the manifestations of FIs-CNS are often non-specific, their diagnosis is very difficult. A fast identification of the etiological factor of neuroinfection and the application of appropriate therapy are crucial in preventing an often fatal outcome. The choice of effective drug depends on its extent of CNS penetration and spectrum of activity. Pharmaceutical formulations of amphotericin B (AmB) (among others, deoxycholate-AmBd and liposomal L-AmB) have relatively limited distribution in the cerebrospinal fluid (CSF); however, their detectable therapeutic concentrations in the CNS makes them recommended drugs for the treatment of cryptococcal meningoencephalitis (AmBd with flucytosine) and CNS candidiasis (L-AmB) and mucormycosis (L-AmB). Voriconazole, a moderately lipophilic molecule with good CNS penetration, is recommended in the first-line therapy of CNS aspergillosis. Other triazoles, such as posaconazole and itraconazole, with negligible concentrations in the CSF are not considered effective drugs for therapy of CNS fungal neuroinfections. In contrast, clinical data have shown that a novel triazole, isavuconazole, achieved considerable efficacy for the treatment of some fungal neuroinfections. Echinocandins with relatively low or undetectable concentrations in the CSF do not play meaningful role in the treatment of FIs-CNS. CONCLUSION: Although the number of fungal species causing CNS mycosis is increasing, only some possess well-defined treatment standards (e.g., cryptococcal meningitis and CNS aspergillosis). The early diagnosis of fungal infection, accompanied by identification of the etiological factor, is needed to allow the selection of effective therapy in patients with FIs-CNS and limit their high mortality.

Geographical evaluation of Neuroparacoccidioidomycosis and Paracoccidioidomycosis in Southern Brazil.

Paracoccidioidomycosis (PCM) is the most prevalent systemic mycosis among immunocompetent patients in Latin America. This study aimed to describe the expansion over time and the geographical distribution of confirmed Neuroparacoccidioidomycosis (NPCM) and PCM cases, and relate it to environmental characteristics such as climate, soil types and coffee crops. This was a retrospective study of autopsy and biopsy reports between 1951 and 2014 from the Medical Pathology Section of the Hospital de Clinicas, Universidade Federal do Paraná (UFPR), Curitiba, Southern Brazil. PCM was predominant in male agricultural workers. PCM cases predominated in areas with subtropical climate with hot summers in North West Parana state. NPCM cases were distributed statewide more frequent in rural than metropolitan area. There was no association with climate, soil type, or coffee crop culture. Most of the PCM cases were in the metropolitan area of the capital, chiefly due to migration fluxes. Even though the history is predominantly agricultural, PCM cases were distributed mainly in the metropolitan area of the state capital, there was no association with climate and soil. NPCM cases were numerically more frequent in rural than metropolitan area.

Autopsy and biopsy study of paracoccidioidomycosis and neuroparacoccidioidomycosis with and without HIV co-infection.

Paracoccidioidomycosis (PCM) is a systemic mycosis prevalent among immunocompetent patients in Latin America. This study aimed to describe the frequency, demographics and clinical characteristics of central nervous system PCM (NPCM) and PCM in an endemic region, and the impact of human immunosuppression virus (HIV) co-infection. This was a retrospective study of autopsy and biopsy reports from the Medical Pathology Section of the Hospital de Clinicas, UFPR, Curitiba, Southern Brazil, between 1951 and 2014. PCM was present in 0.1% of 378,323 cases examined, with 5.7% being NPCM. Infection was prevalent in working-age men, agricultural workers and rural residents. Numbers of HIV autopsy cases increased over time, while those of PCM cases decreased. Prevalence of co-infection of HIV/PCM and HIV/NPCM was 1.6%, and 0.4%, respectively. Adrenals were affected more frequently in the NPCM group compared with the PCM group. Mortality was higher on NPCM group. The clinical course of PCM in HIV patients resembles an acute/sub-acute infection. Association of NPCM and HIV is rare, while diagnosis of NPCM is difficult, it should be considered a differential diagnosis in HIV patients who live in, or have visited, endemic areas and present with neurological symptoms.

Invasive mold infections of the central nervous system in patients with hematologic cancer or stem cell transplantation (2000-2016): Uncommon, with improved survival but still deadly often.

BACKGROUND: Historically considered to have very poor outcome, there is paucity of recent data regarding invasive mold infections (IMIs) of the central nervous system (CNS) in patients with hematologic cancer (HC) or stem cell transplantation (SCT). METHODS: We reviewed the records of HC patients and/or SCT recipients who were diagnosed with CNS IMIs (EORTC/MSG criteria) at MD Anderson Cancer Center (1/1/2000-6/31/2016). Risk factors for survival at day (d) 42 post diagnosis were assessed. RESULTS: We identified 40 such patients (16 with proven infection). The incidence density was 3.8 cases/100000 patient days and mortality remained stable throughout the study period. Most patients had active HC and neutropenia at diagnosis (95% and 53% respectively). Of the 25 patients with a microbiological diagnosis, Aspergillus spp and Mucorales accounted for 85% of cases. CNS IMIs were deemed to be secondary to hematogenous spread in 31 (77%), mostly (90%) fungal pneumonia. CNS lesions typically presented as solitary ring-enhancing abscesses in MRI (26; 65%). Most patients (34; 85%) received lipid AMB and were treated with combination therapy (33; 83%); Mortality 42d was 48%. In univariate analysis, lack of surgical drainage (p = 0.01), absence of giant cells (p = 0.01) and granulomas (p = 0.03) were associated with increased 42d mortality. In multivariate analysis, co-infection was associated with increased (p = 0.005), while steroid tapering was associated with decreased mortality (p = 0.01). CONCLUSIONS: Although less lethal, improved outcome in these uncommon infections was related only to immune response in histopathology, steroid tapering and possibly surgical drainage. In a contemporary 16-year cohort of 40 patients with hematologic cancer and mold infections of Central Nervous System, 42-day mortality was 48%. Improved survival was related to immune response in histopathology, absence of co-infections, corticosteroid tapering and possibly surgical drainage.

Fungal Infections of the Central Nervous System in Children.

Although uncommon in children, fungal infections of the central nervous system can be devastating and difficult to treat. A better understanding of basic mycologic, immunologic, and pharmacologic processes has led to important advances in the diagnosis and management of these diseases, but their mortality rates remain unacceptably high. In this focused review, we examine the epidemiology and clinical features of the most common fungal pathogens of the central nervous system in children and explore recent advances in diagnosis and antifungal therapy.

Clinical characteristics and prognosis of pediatric cryptococcosis in Beijing Children's Hospital, 2002-2014.

Cryptococcosis is a rare pediatric disease. The aim of the study is to describe clinical characteristics and prognosis of pediatric cryptococcosis from 2002 to 2014 in Beijing Children's Hospital. A total of 53 cases of cryptococcosis were identified, 69.8% of which were males. The mean age was 7 years. Forty-one (77.4%) patients had no underlying conditions. Fever, headache, and vomiting were the most common symptoms. The most common sites were the central nervous system (CNS), followed by the lungs. Most patients received a combination of amphotericin B and fluconazole with or without flucytosine as their initial regimen. Twenty-seven patients received a follow-up and six patients (22.2%) had died. The factors associated with neurological complications or death were headache (P = 0.008), seizures (P = 0.006), visual impairment (P = 0.011), neck stiffness (P = 0.008), low erythrocyte sedimentation rate (ESR) (P = 0.024), and a cerebral spinal fluid (CSF) cryptococcal antigen titer ≥ 1:1024 (P = 0.038). CONCLUSIONS: The majority of cryptococcosis cases in China occurred in children without underlying conditions, causing multiple organ damage. The CNS was the most common site. Patients who had headaches, seizures, or high CSF antigen titers experienced neurological complications or died. What is known: • Cryptococcosis is a rare cause of infection in children. What is new: • This review gives a brief overview over pediatric cryptococcosis in China.

Central nervous system infection due to Cryptococcus gattii sensu lato in India: Analysis of clinical features, molecular profile and antifungal susceptibility.

Cryptococcus gattii species complex has evolved as a pathogen in the last two decades causing infection among both immunocompetent and immunocompromised hosts. We aimed to analyse the clinical features of CNS infection caused by C. gattii sensu lato, molecular and antifungal susceptibility profile of this pathogen. Cases diagnosed to have CNS cryptococcosis were included in the study. Cryptococcus recovered from patient's specimen was identified by standard protocol. Species confirmation, mating type and molecular type determination were performed by PCR based methods. Antifungal susceptibility was tested in VITEK2C to amphotericin B, 5-flucytosine, fluconazole and voriconazole. Among 199 cases, 20 (10%) were due to C. gattii, comprising of 75% cryptococcal meningitis and 25% cryptococcoma cases. Young adult males were commonly affected. Headache and vomiting were prominent symptoms and 50% were immunocompromised. Among the isolates, 75%, 20% and 5% were C. tetragattii, C. gattii sensu stricto and C. bacillisporus respectively and all had mating type α. Four (20%) isolates of C. tetragattii and the only isolate of C. bacillisporus were resistant to fluconazole. The most common species isolated from south India is C. tetragattii. The study contributes to the epidemiology of C. gattii and reiterates the need for genotyping and antifungal susceptibility testing.

An updated comprehensive systematic review of Cladophialophora bantiana and analysis of epidemiology, clinical characteristics, and outcome of cerebral cases.

Cladophialophora bantiana is a phaeoid fungus that only rarely has been isolated from sources other than the human brain. It has a particular tropism for the central nervous system (CNS). We have integrated and updated large-scale data related to several aspects of C. Bantiana and reviewed all the available reports on its cerebral infections, focusing on their geographical distribution, infection routes, immune status of infected individuals, type and location of infections, clinical manifestations and treatment and outcome, briefly looking over the spectrum of other disease entities associated with C. bantiana, that is, extra-cerebral and animal infections and on the environmental sources of this fungus. Among the agents of phaeohyphomycosis, a term used to describe an infection caused by a dark pigmented fungus, C. bantiana has some significant specific features. A total of 120 case reports were identified with a significantly higher percentage of healthy subjects than immune-debilitated patients (58.3% vs. 41.7%). Infections due to C. bantiana occur worldwide. The main clinical manifestations are brain abscess (97.5%), coinfection of brain tissue and meninges (14.2%) and meningitis alone (2.5%). Among immunocompetent patients, cerebral infection occurred in the absence of pulmonary lesions. The mortality rate is 65.0% regardless of the patient's immune status. The therapeutic options used include surgery or antifungals alone, and the combination of both, in most cases the fatal outcome being rapid after admission. Since the fungus is a true pathogen, laboratory workers should be made aware that BioSafety Level-3 precautions might be necessary.

Cryptococcosis in non-HIV/non-transplant patients: A Brazilian case series.

Cryptococcosis is a classical systemic opportunistic mycosis, primarily occurring among patients with significant immunologic impairment. However, this disease could also affect patients without any recognized immunologic defects, that is, phenotypically normal patients. The medical records of 29 non-HIV/nontransplant patients with cryptococcal disease during the period 2007-2014 were retrospectively reviewed. The most common site of infection was the central nervous system (n = 25, 86.2%), followed by the pulmonary system (n = 11, 37.9%) and blood (n = 2, 6.8%). Thoracic- and brain-computed tomography demonstrated abnormalities of 81.2% (n = 13) and 62.5% (n = 15), respectively. In sum, 22% (n = 6) of the patients experienced a significant underlying condition. More than one therapeutic regimen was used in 77.8% (n = 21) of the patients. The isolates were identified as being Cryptococcus neoformans species complex (n = 4, 36.4%) and Cryptococcus gattii species complex (n = 7, 63.6%). The overall mortality was 20.7% (n = 6). Herein, we presented the first case series of cryptococcosis in this specific population in São Paulo City, Brazil. The incidence of cryptococcosis in our hospital has not increased in recent years, and 77.8% (n = 21) of cases had no obvious predisposing factor. However, this disease remains associated with high mortality.

Fungal Infections of the Central Nervous System.

PURPOSE OF REVIEW: This article summarizes current knowledge on the epidemiology, clinical presentations, diagnosis, and management of selected fungal infections of the central nervous system (CNS). Key syndromes, differential diagnoses, and therapeutic interventions according to host immune status and exposure are reviewed. RECENT FINDINGS: Advancements in imaging of the brain and spinal cord, and molecular DNA and antigen-based laboratory diagnostics afford improved sensitivity for CNS mycoses. Newer therapeutic strategies may improve outcomes if provided early and host immunosuppression is abrogated. Adjunctive corticosteroid use for disabling neuroinflammation and cerebral edema in the setting of microbiological control may be considered. In addition, nonspecific presentations and absence of fevers in patients without human immunodeficiency virus suggest that screening for Cryptococcus meningitis be performed in all patients with subcortical dementias using a simple CSF or serum antigen test. SUMMARY: CNS fungal infections comprise a wide spectrum of clinical syndromes, including abscesses, meningitis/meningoencephalitis, focal masses, stroke/vasculitides, immune reconstitution inflammatory syndrome (IRIS), and spinal pathologies such as arachnoiditis. The main etiologies include Aspergillus, Cryptococcus, Candida, Mucorales, dematiaceous molds, and dimorphic endemic fungi, with the route of acquisition being respiratory or traumatic inoculation with subsequent spread hematogenously or contiguously. Proper management focuses on early effective antifungal therapy and surgery for large or compressive mass lesions. While adjunctive recombinant cytokine or growth factor use has been supported in certain hosts with refractory infections, IRIS-like reactions may occur, suggesting alternative approaches such as high-dose pulse corticosteroids followed by taper.