Journal of Fungi

Research

Jump to: Review

8 pages, 244 KiB

Open AccessCommunication

Antifungal Drugs: Special Problems Treating Central Nervous System Infections

by Elizabeth Dodds Ashley

J. Fungi 2019, 5(4), 97; https://doi.org/10.3390/jof5040097 - 11 Oct 2019

Cited by 20 | Viewed by 4730

Abstract

Treating fungal infections in the central nervous system (CNS) remains a challenge despite the availability of new antifungal agents. Therapy is limited by poor understanding of the kinetic properties of antifungal drugs in the CNS compounded by lack of data for many agents. [...] Read more.

Treating fungal infections in the central nervous system (CNS) remains a challenge despite the availability of new antifungal agents. Therapy is limited by poor understanding of the kinetic properties of antifungal drugs in the CNS compounded by lack of data for many agents. In some cases, clinical response rates do not correspond to data on drug concentrations in the cerebral spinal fluid and/or brain parenchyma. In order to better characterize the use of antifungal agents in treating CNS infections, a review of the essential principles of neuroPK are reviewed. Specific data regarding antifungal drug concentrations in the cerebral spinal fluid and brain tissue are described from human data where available. Alternative dosing regimens and the role of antifungal drug concentration monitoring in treating fungal infections in the CNS are also discussed. Having a better understanding of these key concepts will help guide clinicians in determining the best treatment courses for patients with these devastating infections. Full article

(This article belongs to the Special Issue Fungal Infections of the Central Nervous System)

15 pages, 2057 KiB

Open AccessArticle

HIV-Associated Cryptococcal Immune Reconstitution Inflammatory Syndrome Is Associated with Aberrant T Cell Function and Increased Cytokine Responses

by David B. Meya, Samuel Okurut, Godfrey Zziwa, Stephen Cose, David R. Boulware and Edward N. Janoff

J. Fungi 2019, 5(2), 42; https://doi.org/10.3390/jof5020042 - 23 May 2019

Cited by 11 | Viewed by 4038

Abstract

Cryptococcal meningitis remains a significant opportunistic infection among HIV-infected patients, contributing 15–20% of HIV-related mortality. A complication of initiating antiretroviral therapy (ART) following opportunistic infection is immune reconstitution inflammatory syndrome (IRIS). IRIS afflicts 10–30% of HIV-infected patients with cryptococcal meningitis (CM), but its [...] Read more.

Cryptococcal meningitis remains a significant opportunistic infection among HIV-infected patients, contributing 15–20% of HIV-related mortality. A complication of initiating antiretroviral therapy (ART) following opportunistic infection is immune reconstitution inflammatory syndrome (IRIS). IRIS afflicts 10–30% of HIV-infected patients with cryptococcal meningitis (CM), but its immunopathogenesis is poorly understood. We compared circulating T cell memory subsets and cytokine responses among 17 HIV-infected Ugandans with CM: 11 with and 6 without CM-IRIS. At meningitis diagnosis, stimulation with cryptococcal capsule component, glucuronoxylomannan (GXM) elicited consistently lower frequencies of CD4⁺ and CD8⁺ T cell memory subsets expressing intracellular cytokines (IL-2, IFN-γ, and IL-17) among subjects who subsequently developed CM-IRIS. After ART initiation, T cells evolved to show a decreased CD8⁺ central memory phenotype. At the onset of CM-IRIS, stimulation more frequently generated polyfunctional IL-2⁺/IL-17⁺ CD4⁺ T cells in patients with CM-IRIS. Moreover, CD8⁺ central and effector memory T cells from CM-IRIS subjects also demonstrated more robust IL-2 responses to antigenic stimulation vs. controls. Thus, ART during CM elicits distinct differences in T cell cytokine production in response to cryptococcal antigens both prior to and during the development of IRIS, suggesting an immunologic foundation for the development of this morbid complication of CM infection. Full article

(This article belongs to the Special Issue Fungal Infections of the Central Nervous System)

► Show Figures

Figure 1

Review

Jump to: Research

8 pages, 470 KiB

Open AccessReview

Central Nervous System Infections Due to Aspergillus and Other Hyaline Molds

by Marisa H. Miceli

J. Fungi 2019, 5(3), 79; https://doi.org/10.3390/jof5030079 - 30 Aug 2019

Cited by 25 | Viewed by 4785

Abstract

Central nervous system infections due to Aspergillus spp and other hyaline molds such as Fusarium and Scedosporium spp are rare but fatal conditions. Invasion of the central nervous system (CNS) tends to occur as a result of hematogenous dissemination among immunocompromised patients, and [...] Read more.

Central nervous system infections due to Aspergillus spp and other hyaline molds such as Fusarium and Scedosporium spp are rare but fatal conditions. Invasion of the central nervous system (CNS) tends to occur as a result of hematogenous dissemination among immunocompromised patients, and by local extension or direct inoculation secondary to trauma in immunocompetent hosts. Efforts should be directed to confirm the diagnosis by image-guided stereotactic brain biopsy when feasible. Non-culture methods could be useful to support the diagnosis, but they have not been validated to be performed in cerebral spinal fluid. Treatment of these infections is challenging given the variable susceptibility profile of these pathogens and the penetration of antifungal agents into the brain. Full article

(This article belongs to the Special Issue Fungal Infections of the Central Nervous System)

► Show Figures

Figure 1

23 pages, 312 KiB

Open AccessReview

Central Nervous System Cryptococcal Infections in Non-HIV Infected Patients

by Justin Beardsley, Tania C. Sorrell and Sharon C.-A. Chen

J. Fungi 2019, 5(3), 71; https://doi.org/10.3390/jof5030071 - 02 Aug 2019

Cited by 65 | Viewed by 8313

Abstract

Central nervous system (CNS) cryptococcosis in non-HIV infected patients affects solid organ transplant (SOT) recipients, patients with malignancy, rheumatic disorders, other immunosuppressive conditions and immunocompetent hosts. More recently described risks include the use of newer biologicals and recreational intravenous drug use. Disease is [...] Read more.

Central nervous system (CNS) cryptococcosis in non-HIV infected patients affects solid organ transplant (SOT) recipients, patients with malignancy, rheumatic disorders, other immunosuppressive conditions and immunocompetent hosts. More recently described risks include the use of newer biologicals and recreational intravenous drug use. Disease is caused by Cryptococcus neoformans and Cryptococcus gattii species complex; C. gattii is endemic in several geographic regions and has caused outbreaks in North America. Major virulence determinants are the polysaccharide capsule, melanin and several ‘invasins’. Cryptococcal plb1, laccase and urease are essential for dissemination from lung to CNS and crossing the blood–brain barrier. Meningo-encephalitis is common but intracerebral infection or hydrocephalus also occur, and are relatively frequent in C. gattii infection. Complications include neurologic deficits, raised intracranial pressure (ICP) and disseminated disease. Diagnosis relies on culture, phenotypic identification methods, and cryptococcal antigen detection. Molecular methods can assist. Preferred induction antifungal therapy is a lipid amphotericin B formulation (amphotericin B deoxycholate may be used in non-transplant patients) plus 5-flucytosine for 2–6 weeks depending on host type followed by consolidation/maintenance therapy with fluconazole for 12 months or longer. Control of raised ICP is essential. Clinicians should be vigilant for immune reconstitution inflammatory syndrome. Full article

(This article belongs to the Special Issue Fungal Infections of the Central Nervous System)

10 pages, 385 KiB

Open AccessReview

Central Nervous System Infection with Histoplasma capsulatum

by James Riddell IV and L. Joseph Wheat

J. Fungi 2019, 5(3), 70; https://doi.org/10.3390/jof5030070 - 24 Jul 2019

Cited by 18 | Viewed by 7305

Abstract

Histoplasmosis is an endemic fungal infection that may affect both immune compromised and non-immune compromised individuals. It is now recognized that the geographic range of this organism is larger than previously understood, placing more people at risk. Infection with Histoplasma capsulatum may occur [...] Read more.

Histoplasmosis is an endemic fungal infection that may affect both immune compromised and non-immune compromised individuals. It is now recognized that the geographic range of this organism is larger than previously understood, placing more people at risk. Infection with Histoplasma capsulatum may occur after inhalation of conidia that are aerosolized from the filamentous form of the organism in the environment. Clinical syndromes typically associated with histoplasmosis include acute or chronic pneumonia, chronic cavitary pulmonary infection, or mediastinal fibrosis or lymphadenitis. Disseminated infection can also occur, in which multiple organ systems are affected. In up to 10% of cases, infection of the central nervous system (CNS) with histoplasmosis may occur with or without disseminated infection. In this review, we discuss challenges related to the diagnosis of CNS histoplasmosis and appropriate treatment strategies that can lead to successful outcomes. Full article

(This article belongs to the Special Issue Fungal Infections of the Central Nervous System)

► Show Figures

Figure 1

17 pages, 2673 KiB

Open AccessReview

Diagnosis and Management of Central Nervous System Cryptococcal Infections in HIV-Infected Adults

by Caleb Skipper, Mahsa Abassi and David R Boulware

J. Fungi 2019, 5(3), 65; https://doi.org/10.3390/jof5030065 - 19 Jul 2019

Cited by 22 | Viewed by 6029

Abstract

Cryptococcal meningitis persists as a significant source of morbidity and mortality in persons with HIV/AIDS, particularly in sub-Saharan Africa. Despite increasing access to antiretrovirals, persons presenting with advanced HIV disease remains common, and Cryptococcus remains the most frequent etiology of adult meningitis. We [...] Read more.

Cryptococcal meningitis persists as a significant source of morbidity and mortality in persons with HIV/AIDS, particularly in sub-Saharan Africa. Despite increasing access to antiretrovirals, persons presenting with advanced HIV disease remains common, and Cryptococcus remains the most frequent etiology of adult meningitis. We performed a literature review and herein present the most up-to-date information on the diagnosis and management of cryptococcosis. Recent advances have dramatically improved the accessibility of timely and affordable diagnostics. The optimal initial antifungal management has been newly updated after the completion of a landmark clinical trial. Beyond antifungals, the control of intracranial pressure and mitigation of toxicities remain hallmarks of effective treatment. Cryptococcal meningitis continues to present challenging complications and continued research is needed. Full article

(This article belongs to the Special Issue Fungal Infections of the Central Nervous System)

► Show Figures

Figure 1

15 pages, 252 KiB

Open AccessReview

Central Nervous System Infection with Other Endemic Mycoses: Rare Manifestation of Blastomycosis, Paracoccidioidomycosis, Talaromycosis, and Sporotrichosis

by Carol A. Kauffman

J. Fungi 2019, 5(3), 64; https://doi.org/10.3390/jof5030064 - 18 Jul 2019

Cited by 22 | Viewed by 4603

Abstract

The central nervous system (CNS) is not a major organ involved with infections caused by the endemic mycoses, with the possible exception of meningitis caused by Coccidioides species. When CNS infection does occur, the manifestations vary among the different endemic mycoses; mass-like lesions [...] Read more.

The central nervous system (CNS) is not a major organ involved with infections caused by the endemic mycoses, with the possible exception of meningitis caused by Coccidioides species. When CNS infection does occur, the manifestations vary among the different endemic mycoses; mass-like lesions or diffuse meningeal involvement can occur, and isolated chronic meningitis, as well as widely disseminated acute infection that includes the CNS, are described. This review includes CNS infection caused by Blastomyces dermatitidis, Paracoccidioides brasiliensis, Talaromyces marneffei, and the Sporothrix species complex. The latter is not geographically restricted, in contrast to the classic endemic mycoses, but it is similar in that it is a dimorphic fungus. CNS infection with B. dermatitidis can present as isolated chronic meningitis or a space-occupying lesion usually in immunocompetent hosts, or as one manifestation of widespread disseminated infection in patients who are immunosuppressed. P. brasiliensis more frequently causes mass-like intracerebral lesions than meningitis, and most often CNS disease is part of disseminated infection found primarily in older patients with the chronic form of paracoccidioidomycosis. T. marneffei is the least likely of the endemic mycoses to cause CNS infection. Almost all reported cases have been in patients with advanced HIV infection and almost all have had widespread disseminated infection. Sporotrichosis is known to cause isolated chronic meningitis, primarily in immunocompetent individuals who do not have Sporothrix involvement of other organs. In contrast, CNS infection in patients with advanced HIV infection occurs as part of widespread disseminated infection. Full article

(This article belongs to the Special Issue Fungal Infections of the Central Nervous System)

11 pages, 238 KiB

Open AccessReview

CNS Infections Caused by Brown-Black Fungi

by Jon Velasco and Sanjay Revankar

J. Fungi 2019, 5(3), 60; https://doi.org/10.3390/jof5030060 - 10 Jul 2019

Cited by 27 | Viewed by 3952

Abstract

Central nervous system (CNS) infections caused by brown-black or dematiaceous fungi are distinctly rare and represent a small proportion of infections termed phaeohyphomycoses. However, these are becoming more commonly reported. Though many fungi have been implicated in disease, most cases are caused by [...] Read more.

Central nervous system (CNS) infections caused by brown-black or dematiaceous fungi are distinctly rare and represent a small proportion of infections termed phaeohyphomycoses. However, these are becoming more commonly reported. Though many fungi have been implicated in disease, most cases are caused by only a few species, Cladophialophora bantiana being the most common. Most of the fungi described are molds, and often cause infection in immunocompetent individuals, in contrast to infection with other more common molds such as Aspergillus, which is usually seen in highly immunocompromised patients. Diagnosis is challenging, as there are no specific tests for this group of fungi. In addition, these infections are often refractory to standard drug therapies, requiring an aggressive combined surgical and medical approach to improve outcomes, yet mortality remains high. There are no standardized treatments due to a lack of randomized clinical trials, though guidelines have been published based on available data and expert opinion. Full article

(This article belongs to the Special Issue Fungal Infections of the Central Nervous System)

20 pages, 545 KiB

Open AccessReview

Mucormycosis of the Central Nervous System

by Amanda Chikley, Ronen Ben-Ami and Dimitrios P Kontoyiannis

J. Fungi 2019, 5(3), 59; https://doi.org/10.3390/jof5030059 - 08 Jul 2019

Cited by 64 | Viewed by 5790

Abstract

Mucormycosis involves the central nervous system by direct extension from infected paranasal sinuses or hematogenous dissemination from the lungs. Incidence rates of this rare disease seem to be rising, with a shift from the rhino-orbital-cerebral syndrome typical of patients with diabetes mellitus and [...] Read more.

Mucormycosis involves the central nervous system by direct extension from infected paranasal sinuses or hematogenous dissemination from the lungs. Incidence rates of this rare disease seem to be rising, with a shift from the rhino-orbital-cerebral syndrome typical of patients with diabetes mellitus and ketoacidosis, to disseminated disease in patients with hematological malignancies. We present our current understanding of the pathobiology, clinical features, and diagnostic and treatment strategies of cerebral mucormycosis. Despite advances in imaging and the availability of novel drugs, cerebral mucormycosis continues to be associated with high rates of death and disability. Emerging molecular diagnostics, advances in experimental systems and the establishment of large patient registries are key components of ongoing efforts to provide a timely diagnosis and effective treatment to patients with cerebral mucormycosis. Full article

(This article belongs to the Special Issue Fungal Infections of the Central Nervous System)

► Show Figures

Figure 1

12 pages, 235 KiB

Open AccessReview

Central Nervous System Infections Due to Coccidioidomycosis

by Niki R. Jackson, Janis E. Blair and Neil M. Ampel

J. Fungi 2019, 5(3), 54; https://doi.org/10.3390/jof5030054 - 28 Jun 2019

Cited by 24 | Viewed by 4550

Abstract

Coccidioidomycosis is a common infection in the western and southwestern United States as well as parts of Mexico and Central and South America and is due to the soil-dwelling fungi Coccidioides. Central nervous system (CNS) infection is an uncommon manifestation that is [...] Read more.

Coccidioidomycosis is a common infection in the western and southwestern United States as well as parts of Mexico and Central and South America and is due to the soil-dwelling fungi Coccidioides. Central nervous system (CNS) infection is an uncommon manifestation that is nearly always fatal if untreated. The presentation is subtle, commonly with headache and decreased mentation. The diagnosis should be considered in patients with these symptoms in association with a positive serum coccidioidal antibody test. The diagnosis can only be established by analysis of cerebrospinal fluid (CSF), which typically demonstrates a lymphocytic pleocytosis, hypoglycorrhachia, elevated protein, and positive CSF coccidioidal antibody. Cultures are infrequently positive but a proprietary coccidioidal antigen test has reasonable sensitivity. Current therapy usually begins with fluconazole at 800 mg daily but other triazole antifungals also have efficacy and are often used if fluconazole fails. Triazole therapy should be lifelong. Intrathecal amphotericin B, the original treatment, is now reserved for those in whom triazoles have failed. There are several distinct complications of CNS coccidioidal infection, the most common of which is hydrocephalus. This is nearly always communicating and requires mechanical shunting in addition to antifungal therapy. Other complications include cerebral vasculitis, brain abscess, and arachnoiditis. Management of these is difficult and not well established. Full article

(This article belongs to the Special Issue Fungal Infections of the Central Nervous System)

Journal Menu

Journal Browser

Fungal Infections of the Central Nervous System

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (10 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI