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.

Candida meningitis in an immunocompetent patient detected through (1→3)-beta-d-glucan.

A 44-year-old female presented with a 3-month history of headache, dizziness, nausea, and vomiting. Her past medical history was significant for long-standing intravenous drug abuse. Shortly after admission, the patient became hypertensive and febrile, with fever as high as 38.8°C. The lumbar puncture profile supported an infectious process; however multiple cultures of blood and cerebrospinal fluid (CSF) did not initially show growth of organisms. Finally after 9 days of incubation, a CSF culture showed evidence of a few colonies of Candida albicans. To confirm the diagnosis, preserved CSF from that sample was tested for (1→3)-ß-d-glucan, showing levels >500pg/ml. This report illustrates a rare complication of intravenous drug use in an immunocompetent patient and demonstrates the utility of (1→3)-ß-d-glucan testing in possible Candida meningitis.

Chronic Candida albicans Meningitis in a 4-Year-Old Girl with a Homozygous Mutation in the CARD9 Gene (Q295X).

A 4-year-old Turkish girl of consanguineous parents was hospitalized for the evaluation of headaches and recurrent febrile episodes of unknown origin. Her medical history was unremarkable except for a few episodes of uncomplicated oral thrush. Meningitis was diagnosed, and Candida albicans was the only pathogen identified by polymerase chain reaction and culture. Despite systemic antifungal multidrug therapy, a prolonged course of 16 months of therapy was necessary to clear C. albicans from the cerebrospinal fluid. Molecular genetic analysis revealed a homozygous caspase recruitment domain 9 (CARD9) mutation (Q295X), which was reported to predispose to chronic mucocutaneous candidiasis. Immunologic workup excluded predisposing B-cell and T-cell defects. In addition, T cells producing interleukin-17 were repeatedly measured within the normal range. Analyses of neutrophils demonstrated normal nicotinamide adenine dinucleotide phosphate oxidase activity in response to various stimuli including Staphylococcus aureus and C. albicans. Additional neutrophilic functional testing, however, showed a decreased cytotoxicity to nonopsonized C. albicans, indicating an impaired killing mechanism against Candida spp. independent from the production of reactive oxygen species by the nicotinamide adenine dinucleotide phosphate oxidase system. Because this defect was only demonstrated in the absence of opsonins, it might especially predispose to chronic C. albicans infections in the central nervous system where opsonin concentrations are usually low. We, therefore, suggest that due to an additional neutrophil dependent defect CARD9 deficiency predisposes not only to chronic mucocutaneous candidiasis, but also to invasive chronic Candida infections, especially of the central nervous system.

A case of hypertrophic cranial pachymeningitis associated with invasive Aspergillus mastoiditis.

We report a rare case of hypertrophic cranial pachymeningitis (HCP) associated with invasive Aspergillus mastoiditis. A 63-year-old man with diabetes mellitus underwent mastoidectomy because of chronic discharge from his left ear. The mastoidectomy was unsuccessful in resolving purulent otorrhea; moreover, 7 months later, the patient developed left abducens nerve palsy. Magnetic resonance imaging revealed HCP at the left middle cranial fossa. Although the pathogen could not be identified, an Aspergillus infection was considered based on elevated serum ß-d-glucan and a positive Aspergillus antigen test result. Voriconazole treatment resolved diplopia and left otorrhea and dramatically improved HCP.

Mannose-binding lectin serum levels are low in persons with clinically active coccidioidomycosis.

BACKGROUND: Mannose-binding lectin (MBL) is a circulating collectin that is part of the innate immune response. We explored the serum levels of MBL in persons with different forms of coccidioidomycosis. METHODS: Serum MBL was measured by ELISA from samples obtained from healthy donors with immunity to Coccidioides, and those with various forms of active coccidioidomycosis. Blood cell specimens from a subgroup of subjects with active coccidioidomycosis were examined for single nucleotide polymorphisms of the MBL gene and promoter regions. RESULTS: The control group comprised 29 healthy immune subjects. Patient groups with active coccidioidomycosis consisted of 20 patients with symptomatic primary pulmonary coccidioidomycosis, 26 with non-meningeal disseminated coccidioidomycosis, and nine with coccidioidal meningitis. The group with active coccidioidomycosis was significantly older and more likely to be male than the control group (for both, P < 0.001). The mean +/- SEM level of serum MBL in the healthy controls was 169.4 +/- 28.6 ng/ml, significantly higher than the 79.2 +/- 10.9 ng/ml for all active groups (P < 0.001). Moreover, the active coccidioidomycosis group was significantly more likely to have serum MBL level

Rhinocerebral mucormycosis in an adolescent with type 1 diabetes mellitus: case report.

Rhinocerebral mucormycosis is a severe opportunistic infection affecting immunocompromised patients. A 14-year-old boy with rhino-orbito-cerebral mucormycosis and type 1 diabetes is described. He responded well to amphotericin B lipid complex followed by itraconazole.

Multiple Aspergillus brain abscesses in immuno-competent patient with severe cranio-facial trauma.

Aspergillosis of the central nervous system (CNS) is a rare, but well described disease in immuno-competent patients. We present a 65-year-old patient who developed neuro-aspergillosis 10 months after severe cranio-facial trauma (Le Fort III). He was treated successfully with surgery including stereotactic drainage and, with Amphotericin B, Liposomal Amphotericin B, and Itraconazol.

Candida meningitis in a suspected immunosuppressive patient--a case report.

Meningitis due to fungal agents represents an AIDS-defining event and occurs typically with very low CD4+ lymphocyte count. Candida meningitis is still a rare clinical condition, although it is becoming frequently reported in the background of immune suppressive states such as: drug addicts, cancer patients, organ transplant recipients and HIV/AIDS patients. In this report we highlight a case of candida meningitis, in a 25- year old female patient. She presented with vulva swelling, vaginal discharge and fever, with rapid progression to tonic-clonic convulsions and loss of consciousness. She fully recovered after treatment with fluconazole.

Investigation of the basis of virulence in serotype A strains of Cryptococcus neoformans from apparently immunocompetent individuals.

Cryptococcus neoformans serotype A strains commonly infect immunocompromised patients to cause fungal meningitis. To understand the basis of serotype A cryptococcal infections in apparently immunocompetent patients, we tested two hypotheses: the strains were naturally occurring hypervirulent pkr1 (PKA regulatory subunit) mutants, or the strains were hybrids with C. neoformans var. gattii strains that normally infect immunocompetent individuals. Analysis of clinical isolates obtained from apparently immunocompetent individuals from three continents revealed that none were pkr1 mutants, but several exhibited phenotypes consistent with perturbations in cAMP signaling. Additionally, none of the strains were unusual hybrids with gattii strains. Except for one strain that was an AD hybrid, all others were serotype A (var. grubii) isolates. Taken together, our findings indicate that the ability of these clinical isolates to infect apparently normal individuals may be attributable to mutations other than pkr1 and/or underlying immune system impairment in patients.

Fatal biphasic brainstem and spinal leptomeningitis with Cryptococcus neoformans in a non-immunocompromised child.

Cryptococcal meningitis is one of the most common life-threatening, invasive fungal infections of the central nervous system in patients with defective T-lymphocyte function. It is, however, unusual in children. We report on a non-immunocompromised 10-y-old boy without evidence of immunological abnormality who developed headache, vomiting, disturbances of consciousness and areflexia. Magnetic resonance imaging of the brain and the spinal cord revealed enlargement of the ventricles and high signal lesions in the leptomeninges at the level of the cerebral peduncles and the cervical and thoracic cord. Cerebrospinal fluid analysis was positive for Cryptococcus neoformans. He was treated with amphotericin B and was symptom-free within 1 wk. Despite an extended course of therapy his symptoms suddenly relapsed and he succumbed to the medical complications of cardiac and respiratory failure. Central nervous system appearances at postmortem were those of cryptococcal leptomeningitis.

A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. National Institute of Allergy and Infectious Diseases Mycoses Study Group.

This study was designed to compare the effectiveness of fluconazole vs. itraconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. HIV-infected patients who had been successfully treated (achieved negative culture of CSF) for a first episode of cryptococcal meningitis were randomized to receive fluconazole or itraconazole, both at 200 mg/d, for 12 months. The study was stopped prematurely on the recommendation of an independent Data Safety and Monitoring Board. At the time, 13 (23%) of 57 itraconazole recipients had experienced culture-positive relapse, compared with 2 relapses (4%) noted among 51 fluconazole recipients (P = .006). The factor best associated with relapse was the patient having not received flucytosine during the initial 2 weeks of primary treatment for cryptococcal disease (relative risk = 5.88; 95% confidence interval, 1.27-27.14; P = .04). Fluconazole remains the treatment of choice for maintenance therapy for AIDS-associated cryptococcal disease. Flucytosine may contribute to the prevention of relapse if used during the first 2 weeks of primary therapy.

HIV combination therapy: partial immune restitution unmasking latent cryptococcal infection.

OBJECTIVE: To describe two cases of cryptococcal meningitis and one re-exacerbation of Cryptococcus-associated meningitis occurring in temporal association with commencement of highly active antiretroviral therapy (HAART) in patients with advanced HIV infection (CD4 cells < 50 x 10(6)/l), which suggests that partial immune restitution can facilitate development of clinically apparent meningitis in response to Cryptococcus or its antigen. DESIGN: All HIV-infected patients with culture-proven cryptococcal meningitis diagnosed at a tertiary referral centre specialist infectious diseases unit from 1 January 1996 to 31 December 1996 were reviewed to examine the clinical and immunological parameters prior to and after commencing antiretroviral therapy. RESULTS: Three patients were diagnosed with clinically apparent meningitis within 7-39 days of changing or altering antiretroviral combination therapy consisting of zidovudine or stavudine, in combination with lamivudine and saquinavir. All patients had CD4 cell counts below 50 x 10(6)/l at initiation of therapy. Following institution of HAART, evidence of immune restitution was suggested by the following: (i) significant increases (3.7-14-fold) in numbers of CD4 cells (all three patients), (ii) significantly reduced (> 2-4 log10 reduction) HIV viral loads (two out of three patients), and (iii) prominent inflammatory changes in cerebrospinal fluid (white blood cells > 10 x 10(6)/l) at diagnosis (two out of three patients). CONCLUSIONS: Our report suggests that in patients with advanced HIV infection, partial immune restitution induced by HAART can precipitate onset of clinically apparent meningitis in those patients with latent cryptococcal central nervous system infection or with residual cryptococcal antigen present in the cerebrospinal fluid.

High human immunodeficiency virus type 1 RNA load in the cerebrospinal fluid from patients with lymphocytic meningitis.

Thirty-seven matched cerebrospinal fluid (CSF) and plasma samples from 34 human immunodeficiency virus type 1 (HIV-1)-infected patients with suspected meningitis were analyzed for levels of HIV-1 RNA and markers of inflammation. Patients with tuberculous (n = 9) or cryptococcal (n = 6) meningitis had the highest CSF virus loads, which in many cases exceeded the levels in plasma, compared with patients with meningococcal meningitis (n = 3), aseptic meningitis (n = 8), tuberculoma (n = 2), or AIDS dementia complex (n = 4) or with normal lumbar punctures (n = 3). CSF virus load correlated significantly with the number of infiltrating lymphocytes (r = .60, P < .001) but not with plasma virus load, the levels of beta2-microglobulin in the CSF, or the integrity of the blood-brain barrier. These data suggest significant intrathecal HIV-1 replication in patients with lymphocytic meningeal infections such as tuberculous and cryptococcal meningitis.

Interleukin-8 in cerebrospinal fluid from patients with meningitis of different etiologies: its possible role as neutrophil chemotactic factor.

Interleukin (IL)-8 concentrations were analyzed in 70 cerebrospinal fluid (CSF) samples from patients with meningitis of different etiologies and in 34 normal CSF samples. Patient groups included those with pyogenic meningitis, viral meningitis, self-resolving aseptic meningitis without a specific diagnosis, and meningitis of other etiologies and normal CSF from patients with and without neurologic disease. All samples from patients with pyogenic meningitis (18) but only 3 from patients with meningitis of other etiologies and with CSF polymorphonuclear leukocyte (PMNL) counts > or = 80% had IL-8 levels > or = 2.5 ng/mL. IL-8 was above the normal level (< or = 0.5 ng/mL) in samples from 5 of 13 viral and 8 of 23 self-resolving aseptic meningitis patients and in 7 of 13 samples from patients with meningitis caused by other microorganisms. There was a significant relationship between IL-8 levels and CSF PMNL counts in patients with nonpyogenic meningitis. The data suggest a possible role of IL-8 as PMNL chemotactic factor in different infections of the subarachnoid space, not only in pyogenic meningitis.

Coccidioidal antigen reactive CD4+ T-lymphocytes in the cerebrospinal fluid in coccidioides immitis meningitis.

CSF lymphocytes from patients with Coccidioides immitis meningitis exhibited a significant antigen-specific response to in vitro stimulation with C. immitis antigens. In some patients, lesser responses to control antigens (Candida and PPD) were also detected. Antigen-specific responses by CSF lymphocytes were seen early in the course of this disease as well as several years after patients had entered remission. When compared to CSF cells, the response of autologous peripheral blood mononuclear cells was similar but of a much smaller magnitude and at times undetectable. Fluorescence activated cell sorting revealed an increased percentage of CD3+ (T-cells), CD4+ (helper/inducer) and CD3+/HLA-DR+ (activated T-cell) cells in the CSF of C. immitis meningitis patients compared to their blood. Most of the antigen-specific proliferative response resided in the CD4+ lymphocyte subset. CSF T-cell proliferation assays may have a role in the diagnosis of C. immitis meningitis.

Glioblastoma, transforming growth factor-beta, and Candida meningitis: a potential link.

The development of Candida meningitis in a patient following partial resection of a glioblastoma raised suspicion that transforming growth factor (TGF-beta), an immunosuppressive cytokine known to be produced by this tumor, would be elevated in his cerebrospinal fluid (CSF). By using a highly specific bioassay, the concentration of TGF-beta was found to be 609 pg/mL, which was 10-fold greater than the mean CSF TGF-beta value in control subjects with no neurologic disease. Increased CSF TGF-beta levels were also detected in patients with other central nervous system (CNS) diseases: malignancies and AIDS dementia complex. These findings suggest that TGF-beta may play an immunopathogenetic role in the CNS.