Invasive fungal infections pose an important threat to public health and are an under-recognized component of antimicrobial resistance, an emerging crisis worldwide. Across a period of profound ...global environmental change and expanding at-risk populations, human-infecting pathogenic fungi are evolving resistance to all licensed systemic antifungal drugs. In this Review, we highlight the main mechanisms of antifungal resistance and explore the similarities and differences between bacterial and fungal resistance to antimicrobial control. We discuss the research and innovation topics that are needed for risk reduction strategies aimed at minimizing the emergence of resistance in pathogenic fungi. These topics include links between the environment and One Health, surveillance, diagnostics, routes of transmission, novel therapeutics and methods to mitigate hotspots for fungal adaptation. We emphasize the global efforts required to steward our existing antifungal armamentarium, and to direct the research and development of future therapies and interventions.
HIV-associated cryptococcal meningitis is by far the most common cause of adult meningitis in many areas of the world that have high HIV seroprevalence. In most areas in Sub-Saharan Africa, the ...incidence of cryptococcal meningitis is not decreasing despite availability of antiretroviral therapy, because of issues of adherence and retention in HIV care. In addition, cryptococcal meningitis in HIV-seronegative individuals is a substantial problem: the risk of cryptococcal infection is increased in transplant recipients and other individuals with defects in cell-mediated immunity, and cryptococcosis is also reported in the apparently immunocompetent. Despite therapy, mortality rates in these groups are high. Over the past 5 years, advances have been made in rapid point-of-care diagnosis and early detection of cryptococcal antigen in the blood. These advances have enabled development of screening and pre-emptive treatment strategies aimed at preventing the development of clinical infection in patients with late-stage HIV infection. Progress in optimizing antifungal combinations has been aided by evaluation of the clearance rate of infection by using serial quantitative cultures of cerebrospinal fluid (CSF). Measurement and management of raised CSF pressure, a common complication, is a vital component of care. In addition, we now better understand protective immune responses in HIV-associated cases, immunogenetic predisposition to infection, and the role of immune-mediated pathology in patients with non-HIV associated infection and in the context of HIV-associated immune reconstitution reactions.
Fungal infections in HIV/AIDS Limper, Andrew H; Adenis, Antoine; Le, Thuy ...
The Lancet infectious diseases,
11/2017, Letnik:
17, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Fungi are major contributors to the opportunistic infections that affect patients with HIV/AIDS. Systemic infections are mainly with Pneumocystis jirovecii (pneumocystosis), Cryptococcus neoformans ...(cryptococcosis), Histoplasma capsulatum (histoplasmosis), and Talaromyces (Penicillium) marneffei (talaromycosis). The incidence of systemic fungal infections has decreased in people with HIV in high-income countries because of the widespread availability of antiretroviral drugs and early testing for HIV. However, in many areas with high HIV prevalence, patients present to care with advanced HIV infection and with a low CD4 cell count or re-present with persistent low CD4 cell counts because of poor adherence, resistance to antiretroviral drugs, or both. Affordable, rapid point-of-care diagnostic tests (as have been developed for cryptococcosis) are urgently needed for pneumocystosis, talaromycosis, and histoplasmosis. Additionally, antifungal drugs, including amphotericin B, liposomal amphotericin B, and flucytosine, need to be much more widely available. Such measures, together with continued international efforts in education and training in the management of fungal disease, have the potential to improve patient outcomes substantially.
Fungal cells change shape in response to environmental stimuli, and these morphogenic transitions drive pathogenesis and niche adaptation. For example, dimorphic fungi switch between yeast and hyphae ...in response to changing temperature. The basidiomycete Cryptococcus neoformans undergoes an unusual morphogenetic transition in the host lung from haploid yeast to large, highly polyploid cells termed Titan cells. Titan cells influence fungal interaction with host cells, including through increased drug resistance, altered cell size, and altered Pathogen Associated Molecular Pattern exposure. Despite the important role these cells play in pathogenesis, understanding the environmental stimuli that drive the morphological transition, and the molecular mechanisms underlying their unique biology, has been hampered by the lack of a reproducible in vitro induction system. Here we demonstrate reproducible in vitro Titan cell induction in response to environmental stimuli consistent with the host lung. In vitro Titan cells exhibit all the properties of in vivo generated Titan cells, the current gold standard, including altered capsule, cell wall, size, high mother cell ploidy, and aneuploid progeny. We identify the bacterial peptidoglycan subunit Muramyl Dipeptide as a serum compound associated with shift in cell size and ploidy, and demonstrate the capacity of bronchial lavage fluid and bacterial co-culture to induce Titanisation. Additionally, we demonstrate the capacity of our assay to identify established (cAMP/PKA) and previously undescribed (USV101) regulators of Titanisation in vitro. Finally, we investigate the Titanisation capacity of clinical isolates and their impact on disease outcome. Together, these findings provide new insight into the environmental stimuli and molecular mechanisms underlying the yeast-to-Titan transition and establish an essential in vitro model for the future characterization of this important morphotype.
Prior to the SARS-CoV-2 pandemic, antibiotic resistance was listed as the major global health care priority. Some analyses, including the O'Neill report, have predicted that deaths due to ...drug-resistant bacterial infections may eclipse the total number of cancer deaths by 2050. Although fungal infections remain in the shadow of public awareness, total attributable annual deaths are similar to, or exceeds, global mortalities due to malaria, tuberculosis or HIV. The impact of fungal infections has been exacerbated by the steady rise of antifungal drug resistant strains and species which reflects the widespread use of antifungals for prophylaxis and therapy, and in the case of azole resistance in Aspergillus, has been linked to the widespread agricultural use of antifungals. This review, based on a workshop hosted by the Medical Research Council and the University of Exeter, illuminates the problem of antifungal resistance and suggests how this growing threat might be mitigated.
We study the sudden optical and ultraviolet (UV) brightening of 1ES 1927+654, which until now was known as a narrow-line active galactic nucleus (AGN). 1ES 1927+654 was part of the small and peculiar ...class of "true Type-2" AGNs that lack broad emission lines and line-of-sight obscuration. Our high-cadence spectroscopic monitoring captures the appearance of a blue, featureless continuum, followed several weeks later by the appearance of broad Balmer emission lines. This timescale is generally consistent with the expected light travel time between the central engine and the broadline emission region in (persistent) broadline AGN. Hubble Space Telescope spectroscopy reveals no evidence for broad UV emission lines (e.g., C iv λ1549, C iii λ1909, Mg ii λ2798), probably owing to dust in the broadline emission region. To the best of our knowledge, this is the first case where the lag between the change in continuum and in broadline emission of a "changing look" AGN has been temporally resolved. The nature and timescales of the photometric and spectral evolution disfavor both a change in line-of-sight obscuration and a change of the overall rate of gas inflow as driving the drastic spectral transformations seen in this AGN. Although the peak luminosity and timescales are consistent with those of tidal disruption events seen in inactive galaxies, the spectral properties are not. The X-ray emission displays a markedly different behavior, with frequent flares on timescales of hours to days, and will be presented in a companion publication.
Understanding the host immune response during cryptococcal meningitis (CM) is of critical importance for the development of immunomodulatory therapies. We profiled the cerebrospinal fluid (CSF) ...immune-response in ninety patients with HIV-associated CM, and examined associations between immune phenotype and clinical outcome. CSF cytokine, chemokine, and macrophage activation marker concentrations were assayed at disease presentation, and associations between these parameters and microbiological and clinical outcomes were examined using principal component analysis (PCA). PCA demonstrated a co-correlated CSF cytokine and chemokine response consisting primarily of Th1, Th2, and Th17-type cytokines. The presence of this CSF cytokine response was associated with evidence of increased macrophage activation, more rapid clearance of Cryptococci from CSF, and survival at 2 weeks. The key components of this protective immune-response were interleukin (IL)-6 and interferon-γ, IL-4, IL-10 and IL-17 levels also made a modest positive contribution to the PC1 score. A second component of co-correlated chemokines was identified by PCA, consisting primarily of monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α). High CSF chemokine concentrations were associated with low peripheral CD4 cell counts and CSF lymphocyte counts and were predictive of immune reconstitution inflammatory syndrome (IRIS). In conclusion CSF cytokine and chemokine profiles predict risk of early mortality and IRIS in HIV-associated CM. We speculate that the presence of even minimal Cryptococcus-specific Th1-type CD4+ T-cell responses lead to increased recruitment of circulating lymphocytes and monocytes into the central nervous system (CNS), more effective activation of CNS macrophages and microglial cells, and faster organism clearance; while high CNS chemokine levels may predispose to over recruitment or inappropriate recruitment of immune cells to the CNS and IRIS following peripheral immune reconstitution with ART. These results provide a rational basis for future studies of immune modulation in CM, and demonstrate the potential of baseline immune profiling to identify CM patients most at risk of mortality and subsequent IRIS.
Measures of working memory capacity (WMC), such as complex span tasks (e.g., operation span), have become some of the most frequently used tasks in cognitive psychology. However, due to the length of ...time it takes to complete these tasks many researchers trying to draw conclusions about WMC forgo properly administering multiple tasks. But can the complex span tasks be shortened to take less administration time? We address this question by splitting the tasks into three blocks of trials, and analyzing each block’s contribution to measuring WMC and predicting fluid intelligence (Gf). We found that all three blocks of trials contributed similarly to the tasks’ ability to measure WMC and Gf, and the tasks can therefore be substantially shortened without changing what they measure. In addition, we found that cutting the number of trials by 67 % in a battery of these tasks still accounted for 90 % of the variance in their measurement of Gf. We discuss our findings in light of administering the complex span tasks in a method that can maximize their accuracy in measuring WMC, while minimizing the time taken to administer.
Summary Background Mortality in people in Africa with HIV infection starting antiretroviral therapy (ART) is high, particularly in those with advanced disease. We assessed the effect of a short ...period of community support to supplement clinic-based services combined with serum cryptococcal antigen screening. Methods We did an open-label, randomised controlled trial in six urban clinics in Dar es Salaam, Tanzania, and Lusaka, Zambia. From February, 2012, we enrolled eligible individuals with HIV infection (age ≥18 years, CD4 count of <200 cells per μL, ART naive) and randomly assigned them to either the standard clinic-based care supplemented with community support or standard clinic-based care alone, stratified by country and clinic, in permuted block sizes of ten. Clinic plus community support consisted of screening for serum cryptococcal antigen combined with antifungal therapy for patients testing antigen positive, weekly home visits for the first 4 weeks on ART by lay workers to provide support, and in Tanzania alone, re-screening for tuberculosis at 6–8 weeks after ART initiation. The primary endpoint was all-cause mortality at 12 months, analysed by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISCRTN 20410413. Findings Between Feb 9, 2012, and Sept 30, 2013, 1001 patients were randomly assigned to clinic plus community support and 998 to standard care. 89 (9%) of 1001 participants in the clinic plus community support group did not receive their assigned intervention, and 11 (1%) of 998 participants in the standard care group received a home visit or a cryptococcal antigen screen rather than only standard care. At 12 months, 25 (2%) of 1001 participants in the clinic plus community support group and 24 (2%) of 998 participants in the standard care group had been lost to follow-up, and were censored at their last visit for the primary analysis. At 12 months, 134 (13%) of 1001 participants in the clinic plus community support group had died compared with 180 (18%) of 998 in the standard care group. Mortality was 28% (95% CI 10–43) lower in the clinic plus community support group than in standard care group (p=0·004). Interpretation Screening and pre-emptive treatment for cryptococcal infection combined with a short initial period of adherence support after initiation of ART could substantially reduce mortality in HIV programmes in Africa. Funding European and Developing Countries Clinical Trials Partnership.
Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of ...America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)–infected individuals, (2) organ transplant recipients, and (3) non–HIV-infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary cryptococcosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole; (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS; and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients.
PDF
