Rhino-orbital-cerebral-mucormycosis in COVID-19: A systematic review.

Since the onset of COVID-19 pandemic, parallel opportunistic infections have also been emerging as another disease spectrum. Among all these opportunistic infection, mucormycosis has become a matter of concern with its rapid increase of cases with rapid spread as compared to pre-COVID-19 era. Cases have been reported in post-COVID-19-related immune suppression along with the presence of comorbidity which adds on the deadly outcome. There is no systematic review addressing the issue of COVID-19-associated mucormycosis. This is the first systematic review of published studies of mucormycosis associated with COVID-19. The aim was to analyze the real scenario of the disease statement including all the published studies from first November 2019 to 30th June to analyze the contemporary epidemiology, clinical manifestations, risk factor, prognosis, and treatment outcome of COVID-19 associated rhino-orbito-cerebral-mucormycosis. A comprehensive literature search was done in following databases, namely, PubMed, Google Scholar, Scopus, and EMBASE using keywords mucormycosis, rhino orbital cerebral mucormycosis, COVID-19, and SARS-CoV-2 (from November 01, 2019 to June 30, 2021). Our study shows that, while corticosteroids have proved to be lifesaving in severe to critical COVID-19 patients, its indiscriminate use has come with its price of rhino-orbito-cerebral mucormycosis epidemic, especially in India especially in patients with preexisting diabetes mellitus with higher mortality. Corticosteroid use should be monitored and all COVID-19 patients should be closely evaluated/monitored for sequelae of immunosuppression following treatment.

Estimated deaths and illnesses averted during fungal meningitis outbreak associated with contaminated steroid injections, United States, 2012-2013.

During 2012-2013, the US Centers for Disease Control and Prevention and partners responded to a multistate outbreak of fungal infections linked to methylprednisolone acetate (MPA) injections produced by a compounding pharmacy. We evaluated the effects of public health actions on the scope of this outbreak. A comparison of 60-day case-fatality rates and clinical characteristics of patients given a diagnosis on or before October 4, the date the outbreak was widely publicized, with those of patients given a diagnosis after October 4 showed that an estimated 3,150 MPA injections, 153 cases of meningitis or stroke, and 124 deaths were averted. Compared with diagnosis after October 4, diagnosis on or before October 4 was significantly associated with a higher 60-day case-fatality rate (28% vs. 5%; p<0.0001). Aggressive public health action resulted in a substantially reduced estimated number of persons affected by this outbreak and improved survival of affected patients.

Lack of IL-6 increases blood-brain barrier permeability in fungal meningitis.

The pathogenesis of increased blood-brain barrier permeability during Cryptococcus meningitis is still largely unknown. Interleukin (IL-6) is a multifunctional cytokine, and numerous studies have shown that IL-6 influences the integrity of the blood-brain barrier. In this study we investigated the role of IL-6 in Cryptococcus meningitis. First, wild-type or IL-6(-/-) mice were injected with Cryptococcus neoformans (C. neoformans) and the survival time in both groups was recorded. Second, the number of fungi was measured in the brains of IL-6(-/-) wild-type mice. Finally, the blood-brain barrier permeability index was detected in infected IL-6(-/-) mice treated with recombinant human IL-6. The blood-brain barrier permeability index was measured in infected wild-type mice treated with anti-IL-6 antibodies as well. The survival of IL-6(-/-) mice injected with C. neoformans was significantly lower than that of identically challenged wild-type mice. The infected IL-6(-/-) mice had significantly larger brain fungal burdens than wild-type mice. Furthermore, increased blood-brain barrier index was found in infected IL-6(-/-) mice when compared with that in infected control mice. Similar results were obtained when mice challenged with C. neoformans were treated systemically with neutralizing anti-IL-6 antibodies, resulting in an elevation of vascular permeability. Our data revealed that IL-6 reduced the blood-brain barrier permeability during Cryptococcus meningitis, and it might provide an explanation for the significantly lower survival of infected IL-6(-/-) mice.

Invasive infections due to filamentous fungi other than Aspergillus: epidemiology and determinants of mortality.

The epidemiology of invasive fungal disease (IFD) due to filamentous fungi other than Aspergillus may be changing. We analysed clinical, microbiological and outcome data in Australian patients to determine the predisposing factors and identify determinants of mortality. Proven and probable non-Aspergillus mould infections (defined according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria) from 2004 to 2012 were evaluated in a multicentre study. Variables associated with infection and mortality were determined. Of 162 episodes of non-Aspergillus IFD, 145 (89.5%) were proven infections and 17 (10.5%) were probable infections. The pathogens included 29 fungal species/species complexes; mucormycetes (45.7%) and Scedosporium species (33.3%) were most common. The commonest comorbidities were haematological malignancies (HMs) (46.3%) diabetes mellitus (23.5%), and chronic pulmonary disease (16%); antecedent trauma was present in 21% of cases. Twenty-five (15.4%) patients had no immunocompromised status or comorbidity, and were more likely to have acquired infection following major trauma (p <0.01); 61 (37.7%) of cases affected patients without HMs or transplantation. Antifungal therapy was administered to 93.2% of patients (median 68 days, interquartile range 19-275), and adjunctive surgery was performed in 58.6%. The all-cause 90-day mortality was 44.4%; HMs and intensive-care admission were the strongest predictors of death (both p <0.001). Survival varied by fungal group, with the risk of death being significantly lower in patients with dematiaceous mould infections than in patients with other non-Aspergillus mould infections. Non-Aspergillus IFD affected diverse patient groups, including non-immunocompromised hosts and those outside traditional risk groups; therefore, definitions of IFD in these patients are required. Given the high mortality, increased recognition of infections and accurate identification of the causative agent are required.

Clinical findings for fungal infections caused by methylprednisolone injections.

BACKGROUND: Since September 18, 2012, public health officials have been investigating a large outbreak of fungal meningitis and other infections in patients who received epidural, paraspinal, or joint injections with contaminated lots of methylprednisolone acetate. Little is known about infections caused by Exserohilum rostratum, the predominant outbreak-associated pathogen. We describe the early clinical course of outbreak-associated infections. METHODS: We reviewed medical records for outbreak cases reported to the Centers for Disease Control and Prevention before November 19, 2012, from the six states with the most reported cases (Florida, Indiana, Michigan, New Jersey, Tennessee, and Virginia). Polymerase-chain-reaction assays and immunohistochemical testing were performed on clinical isolates and tissue specimens for pathogen identification. RESULTS: Of 328 patients without peripheral-joint infection who were included in this investigation, 265 (81%) had central nervous system (CNS) infection and 63 (19%) had non-CNS infections only. Laboratory evidence of E. rostratum was found in 96 of 268 patients (36%) for whom samples were available. Among patients with CNS infections, strokes were associated with an increased severity of abnormalities in cerebrospinal fluid (P<0.001). Non-CNS infections were more frequent later in the course of the outbreak (median interval from last injection to diagnosis, 39 days for epidural abscess and 21 days for stroke; P<0.001), and such infections developed in patients with and in those without meningitis. CONCLUSIONS: The initial clinical findings from this outbreak suggest that fungal infections caused by epidural and paraspinal injection of a contaminated glucocorticoid product can result in a broad spectrum of clinical disease, reflecting possible variations in the pathogenic mechanism and in host and exposure risk factors. (Funded by the Centers for Disease Control and Prevention.).

Candida infection of the central nervous system following neurosurgery: a 12-year review.

BACKGROUND: Candida infection of the central nervous system (CNS) following neurosurgery is relatively unusual but is associated with significant morbidity and mortality. We present our experience with this infection in adults and discuss clinical characteristics, treatment options, and outcome. METHODS: All episodes of Candida isolated from the central nervous system were identified by searching our laboratory database. Review of the cases was performed by means of a retrospective chart review. RESULTS: Eleven episodes of Candida CSF infection following neurosurgery were identified over a 12-year period. Candida albicans was the predominant species isolated (n = 8, 73%). All infections were associated with foreign intracranial material, nine with external ventricular drains (82%), one with a ventriculoperitoneal shunt, one with a lumbar drain, and one with Gliadel wafers (1,3-bis [2-chloroethyl]-1-nitrosurea). Fluconazole or liposomal amphotericin B were the most common anti-fungal agents used. The mortality rate identified in our series was 27%. CONCLUSIONS: Candida infection following neurosurgery remains a relatively rare occurrence but one that causes significant mortality. These are complex infections, the management of which benefits from a close liaison between the clinical microbiologist and neurosurgeon. Prompt initiation of antifungal agents and removal of infected devices offers the best hope of a cure.

Repeat lumbar punctures in infants with meningitis in the neonatal intensive care unit.

OBJECTIVE: The purpose of this study is to examine the results of repeat lumbar puncture in infants with initial positive cerebrospinal fluid (CSF) cultures in order to determine the clinical characteristics and outcomes of infants with repeat positive cultures. STUDY DESIGN: Cohort study of infants with an initial positive CSF culture undergoing repeat lumbar puncture between 1997 and 2004 at 150 neonatal intensive care units managed by the Pediatrix Medical group. We compared the clinical outcomes of infants with repeat positive cultures and infants with repeat negative cultures. RESULT: We identified 118 infants with repeat CSF cultures. Of these, 26 infants had repeat positive cultures. A higher proportion with repeat positive cultures died compared with those with repeat negative cultures, 6/23 (26%) vs. 6/81 (7%), respectively (P=0.02). CONCLUSION: Among infants with a positive CSF culture, a repeat positive CSF culture is common. The presence of a second positive culture is associated with increased mortality.

Comparative efficacies of lipid-complexed amphotericin B and liposomal amphotericin B against coccidioidal meningitis in rabbits.

In separate previous studies, we have shown that lipid-complexed amphotericin B (Abelcet [ABLC]) and liposomal amphotericin B (AmBisome [AmBi]) are efficacious against coccidioidal meningitis in rabbits. Here, we compared ABLC and AmBi directly in a coccidioidal meningitis model. Male New Zealand White rabbits were infected with 5 x 10(4) Coccidioides posadasii arthroconidia by direct cisternal puncture. Therapy with intravenous ABLC or AmBi at 7.5 or 15 mg/kg of body weight or sterile 5% dextrose water (D5W) began 5 days later. Clinical assessments were done daily; cerebrospinal fluid and blood samples were obtained on day 15 and upon euthanasia. Survivors to day 25 were euthanatized, the numbers of CFU in their tissues were determined, and histology analyses of the brains and spinal cords were done. Controls showed progressive disease, whereas animals treated with either dose of either drug showed few clinical signs of infection. All ABLC- or AmBi-treated rabbits survived, whereas eight of nine D5W-treated rabbits were euthanatized before day 25 (P < 0.0001). Numbers of CFU in the brains and spinal cords of ABLC- or AmBi-treated animals were 100- to 10,000-fold lower than those in the corresponding tissues of D5W-treated animals (P < 0.0006 to 0.0001). However, only two or fewer given a regimen of ABLC or AmBi were cured of infection in both tissues. Fewer ABLC-treated rabbits (four of eight treated with 7.5 mg/kg and five of eight treated with 15 mg/kg) than controls (nine of nine) had meningitis at any level of severity (P, 0.015 or 0.043 for animals treated with ABLC at 7.5 or 15 mg/kg, respectively). Although groups of rabbits treated with AmBi regimens did not have significantly fewer animals with meningitis than the control group (P > 0.05), ABLC and AmBi were not significantly different. In this model, intravenous ABLC and AmBi were similarly highly effective, with few clinical signs of infection, 100% survival, and significantly reduced fungal burdens among treated animals. There appeared to be little benefit in using the 15-mg/kg dosage of either formulation. There was no significant advantage of one drug over the other for this indication. Further studies are required to determine the lowest effective doses of these formulations.

Fungal neuroinfections: rare disease but unacceptably high mortality.

Within last 25 years we have observed 20 cases of fungal meningitis and/or cerebral abscesses. Commonest etiologic agens was Candida spp. (C. albicans 9 of 20). Molds were responsible for 4 cases of brain abscess. Mortality was 50% what seems to be very high. Extremely high mortality is caused by delayed onset of therapy, severe underlying disease and multiresistant fungal organisms such as Mucorales, Fusarium solani and Aureobasidium.

Neuroimaging as a guide to predict outcomes for patients with coccidioidal meningitis.

Sixty-two patients with coccidioidal meningitis underwent neuroimaging. Magnetic resonance imaging detected neuroimaging abnormalities in 76% of patients, and computed tomography scanning detected neuroimaging abnormalities in 41.6%. The most common abnormal neuroimaging findings were hydrocephalus (51.6%), basilar meningitis (46.8%), and cerebral infarction (38.7%). Significantly elevated mortality rates were associated with hydrocephalus and hydrocephalus coexisting with infarction. Basilar meningitis did not influence outcome. Patients without neuroimaging abnormalities had a mortality rate of 7.7%.

Craniocerebral aspergillosis of sinonasal origin in immunocompetent patients: clinical spectrum and outcome in 25 cases.

OBJECTIVE: Craniocerebral aspergillosis of sinonasal origin has been reported mainly in immunocompromised patients with high mortality, and it has been described very infrequently in immunocompetent hosts. This retrospective study focuses on clinical outcome in relation to anatomic locations of invasive aspergillosis of sinonasal origin in immunocompetent patients with emphasis on our preliminary experience with use of preoperative orally administered itraconazole. METHODS: Medical records of patients treated in two tertiary care hospitals from 1991 to 2003 were reviewed retrospectively. All patients had radiological evidence of disease in the paranasal sinuses with or without intracranial extension. The study cohort was divided into three types on the basis of area of involvement revealed by computed tomographic or magnetic resonance imaging scans of brain. All patients underwent surgical intervention and treatment with antifungal therapy. Preoperative orally administered itraconazole therapy was used in four patients on the basis of neuroradiological features. Clinical outcome was assessed with the Glasgow Outcome Scale, and univariate analysis of prognostic factors was performed with 95% confidence interval (P = 0.05). RESULTS: Mean patient age was 36.5 years (range, 14-74 yr) with a male preponderance (male-to-female ratio, 23:2). Nasal stuffiness (n = 13), headaches (n = 10), proptosis (n = 9), and nasal discharges (n = 7) were major presenting clinical features. Radiological data were obtained by computed tomographic (n = 25) and magnetic resonance imaging (n = 20) scans of the brain, and diagnoses were established by histopathological analysis (n = 20) or/and fungal cultures (n = 15). Preoperative orally administered itraconazole was given in four patients with intracerebral aspergillosis. Overall mortality was 28% and was highest in patients with Type 1 aspergillosis (66.7%). Type 3 aspergillosis and use of preoperative itraconazole remained statistically significant prognostic factors. CONCLUSION: Craniocerebral aspergillosis in immunocompetent hosts has three patterns of presentation that seem to correlate with clinical outcomes. Intracerebral aspergillosis (Type 1) is associated with the worst clinical outcome. Patients with orbital and cranial base aspergillosis (Type 3) had good recovery. Intracranial extradural aspergillosis (Type 2) remained intermediate on the Glasgow Outcome Scale. Preoperative orally administered itraconazole therapy may improve clinical outcome in patients with intracerebral aspergillosis. Prospective clinical studies are required to make firm clinical therapeutic recommendations.

Rhino-orbital and rhino-orbito-cerebral mucormycosis.

BACKGROUND: Rhino-orbito-cerebral mucormycosis (ROCM) is a devastating infection of immunocompromised hosts. We present our experience with 19 ROCM cases and attempt to define preferred diagnostic and treatment protocols. METHODS: All had tissue biopsies obtained studied by direct smear, histologic studies, and cultures. Imaging was obtained in 14 cases. RESULTS: Sixteen patients presented between August and November. Six had mixed fungal infections. Seven patients had end-stage underlying disease or infection and did not undergo surgery and 4 had an indolent form of disease. Patients were treated by surgery and by amphotericin B. The overall survival was 47%. CONCLUSIONS: ROCM may have seasonal incidence peaking in the fall and early winter. The therapeutic approach should be unchanged in cases of mixed fungal infections. Amphotericin B with aggressive debridement remains the mainstay of treatment. Early recognition and treatment are essential. A presentation and survival-dependent classification of ROCM are offered.

Candidal meningitis in children with cancer.

Candidal meningitis is a rare disease that is seen most frequently in neonates, neurosurgical patients, and the immunocompromised host. We describe a series of 12 children with cancer (all of whom had leukemia) who had candidal meningitis develop. Univariate analysis revealed that duration of fever, antibiotic therapy, and profound neutropenia and use of total parenteral nutrition were significantly associated (P<.05) with candidal meningitis in children with cancer, compared with matched control subjects. Only duration of profound neutropenia (P=.08) and use of total parenteral nutrition (P=.06) approached significance in the multivariate analysis. One species of Candida, Candida tropicalis, was responsible for 11 of the 12 cases, indicating increased pathogenicity of this organism in CNS disease. The cases were invariably fatal, supporting aggressive treatment of candidal meningitis in immunocompromised patients and further study of the prevention, diagnosis, and management of C. tropicalis meningitis.

The central nervous system and infection by Candida species.

In this paper we have reviewed the main clinico-pathologic disease groups of neurocandidiasis: the microabscesses, the macroabscesses, and the meningitis. Special attention has been paid to the predisposing conditions for the appearance of neurocandidiasis, the neuroimaging techniques, and the study of the cerebrospinal fluid, needed for diagnosis. We have also discussed the differential diagnosis with other illnesses. Treatment should be given with amphotericin-B and 5-fluorocytosine. The use of other antifungal drugs for neurocandidiasis is also discussed.

Meningitis in pediatric cancer patients: a review of forty cases from a single institution.

BACKGROUND: Although the clinical features of bacterial meningitis in adult cancer patients and in healthy children have been described, no previous large series has described the clinical features of meningitis in pediatric cancer patients. We performed a retrospective review of bacterial or fungal meningitis in pediatric cancer patients to determine its clinical presentation, microbiology and outcome. METHOD: We reviewed the medical records of all patients younger than 18 years old with a diagnoses of any malignancy and bacterial or fungal meningitis at Children's Hospital and Regional Medical Center in Seattle, WA, from January, 1981, to June, 1998. RESULTS: During the study period there were 40 cases of bacterial or fungal meningitis in 36 pediatric cancer patients. Most patients (65%) had recent neurosurgery, a central nervous system device or cerebrospinal fluid leak. Neutropenia was present in 30% of patients. Fever and altered mental status were the most consistent signs at presentation. In addition at least one additional symptom or sign of meningitis (headache, neck pain or rigidity, seizures or photophobia) was present in 77% of cases. Staphylococcus aureus and Streptococcus pneumoniae were the most common microbiologic isolates. The five patients with fatal outcome were neutropenic. Neutropenia and seizures within 2 days of presentation were associated with long neurologic sequelae. CONCLUSIONS: Meningitis in pediatric cancer patients was associated with significant morbidity and mortality. Pediatric cancer patients with meningitis had clinical features and microbiology distinctly different from those of adult cancer patients and normal children with meningitis.

Clinical significance of Candida species isolated from cerebrospinal fluid following neurosurgery.

Twenty-one patients for whom adequate clinical data were available were identified in a retrospective review of cases of Candida species isolated from cerebrospinal fluid (CSF) following neurosurgery; 86% had indwelling cerebrospinal devices (shunts). Candida species were isolated from multiple CSF samples from 10 patients; CSF samples from seven of 10 were initially drawn through indwelling devices and those from nine of 10 were obtained by subsequent lumbar punctures. All of these patients were treated with antifungals, although therapy was delayed in 50% of cases until the second positive culture was reported. In 11 cases, Candida was the only isolate recovered from CSF samples drawn through indwelling devices; cultures of subsequent CSF samples obtained by lumbar puncture were negative in 10 of 11 cases. Only two patients for whom a single culture was positive for Candida species were treated with antifungals (both of whom were symptomatic), and none of the untreated patients died of infection. The clinical significance of a single positive CSF sample drawn through an indwelling device is difficult to assess, and a definitive diagnosis may require repeated cultures of CSF samples obtained by lumbar puncture.

Comparative study of mortality and morbidity in premature infants (birth weight, < 1,250 g) with candidemia or candidal meningitis.

Little information is available on long-term neurodevelopment of premature neonates with invasive candidal infections. We retrospectively studied the outcomes for 25 premature neonates (birth weight, < 1,250 g) with candidemia or candidal meningitis (cases) and compared them with 25 neonates matched for birth weight (+/- 100 g) and gestational age (+/- 1 week) (controls). Durations of antibiotic therapy, artificial ventilation, invasive catheterizations, and hyperalimentation were longer for cases than for controls. Cases had a higher final grade of intraventricular hemorrhage than did controls (median: 3.0 vs. 2.5, respectively; P < .05). Forty-four percent (11 of 25) of cases and 16% (4 of 25) of controls died (P > .05), and 29% (4 of 14) of surviving cases and 14% (3 of 21) of controls were disabled (P > .05). More cases had combined mortality and neurodevelopmental disabilities than did controls (60% vs. 28%, respectively; P < .05). Use of invasive therapies should be minimized for premature neonates at risk for invasive candidal infection that is associated with adverse outcomes.

Pathology of post meningitic hydrocephalus.

Meningitis of bacterial (including tubercular) or non bacterial origin is a common and lethal infection of central nervous system in children. Although, with the use of modern medical facilities including antibiotics, the mortality rates of meningitis have decreased, yet the number of patients surviving with complications such as hydrocephalus have greatly increased. In this article the etiopathogenesis of post meningitis hydrocephalus has been reviewed. Effective use of appropriate antibiotics and shunt procedures have improved the outcome of post meningitic hydrocephalus of bacterial origin but the same is not true with that of fungal origin, which still carries high mortality and morbidity.

Meningitis caused by Candida species: an emerging problem in neurosurgical patients.

Three cases of candida meningitis were encountered in a 3-year period in our hospital; all occurred in neurosurgical patients. We describe these three cases and review the 15 cases of neurosurgery-related candida meningitis previously reported in the English-language literature. Data regarding these 18 patients formed the basis for our review. Most patients with candida meningitis had recently received antibacterial agents, and it is notable that 50% of patients suffered from antecedent bacterial meningitis. The CSF analysis revealed neutrophilic pleocytosis that was indistinguishable from that of bacterial meningitis. The overall mortality was 11%. Administration of amphotericin B combined with flucytosine appeared to be the best therapeutic approach for candida meningitis.