We evaluated the expression of biomarkers of innate and adaptive immune response in correlation with underlying conditions in 144 patients with chronic pulmonary aspergillosis (CPA). Patients with ...complete medical and radiological records, white cell counts, and a complete panel of CD3, CD4, CD8, CD19, and CD56 lymphocyte subsets were included. Eighty-four (58%) patients had lymphopenia. Six (4%) patients had lymphopenia in all five CD variables. There were 62 (43%) patients with low CD56 and 62 (43%) patients with low CD19. Ten (7%) patients had isolated CD19 lymphopenia, 18 (13%) had isolated CD56 lymphopenia, and 15 (10%) had combined CD19 and CD56 lymphopenia only. Forty-eight (33%) patients had low CD3 and 46 (32%) had low CD8 counts. Twenty-five (17%) patients had low CD4, 15 (10%) of whom had absolute CD4 counts <200/μL. Multivariable logistic regression showed associations between: low CD19 and pulmonary sarcoidosis (Odds Ratio (OR), 5.53; 95% Confidence Interval (CI), 1.43-21.33;
= 0.013), and emphysema (OR, 4.58; 95% CI; 1.36-15.38;
= 0.014), low CD56 and no bronchiectasis (OR, 0.27; 95% CI, 0.10-0.77;
= 0.014), low CD3 and both multicavitary CPA disease (OR, 2.95; 95% CI, 1.30-6.72;
= 0.010) and pulmonary sarcoidosis (OR, 4.94; 95% CI, 1.39-17.57;
= 0.014). Several subtle immune defects are found in CPA.
The human respiratory tract is exposed daily to airborne fungi, fungal enzymes, and secondary metabolites. The endemic fungi Histoplasma capsulatum, Coccidioides spp, Blastomyces dermatitidis, and ...Paracoccidioides brasiliensis, and occasionally Aspergillus fumigatus, are primary pulmonary pathogens of otherwise healthy people. Such infections resolve in most people, and only a few infections lead to disease. However, many fungi are directly allergenic by colonising the respiratory tract or indirectly through contact with cell wall constituents and proteases, causing or exacerbating allergic disease. Increasing evidence implicates high indoor fungal exposures as a precipitant of asthma in children and in worsening asthma symptoms. Lung or airways infection by endemic fungi or aspergillus can be diagnosed with respiratory sample culture or serum IgG testing. Sputum, induced sputum, or bronchial specimens are all suitable specimens for detecting fungi; microscopy, fungal culture, galactomannan antigen, and aspergillus PCR are useful tests. Antifungal treatment is indicated in almost all patients with chronic cavitary pulmonary infections, chronic invasive and granulomatous rhinosinusitis, and aspergillus bronchitis. Most patients with fungal asthma benefit from antifungal therapy. Adverse reactions to oral azoles, drug interactions, and azole resistance in Aspergillus spp limit therapy. Environmental exposures, genetic factors, and structural pulmonary risk factors probably underlie disease but are poorly understood.
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Cryptococcal meningitis is the most common cause of meningitis in adults living with HIV in sub-Saharan Africa. The estimates of national, regional, and global burden of cryptococcal meningitis are ...essential to guide prevention strategies and determine needs for diagnostic tests and treatments. We present a 2020 estimate of the global burden of HIV-associated cryptococcal infection (antigenaemia), cryptococcal meningitis, and cryptococcal-associated deaths.
We defined advanced HIV disease as adults with a CD4 count of less than 200 cells/μL, as this group is at highest risk for cryptococcosis. We used UNAIDS estimates (2019–20) and population-based HIV impact assessment surveys (2016–18) to estimate the number of adults with CD4 counts of less than 200 cells/μL at risk for cryptococcosis, by country and region. Secondly, we summarised cryptococcal antigenaemia prevalence in those with a CD4 count of less than 200 cells/μL by reviewing published literature. Thereafter, we calculated the number of cryptococcal antigen (CrAg)-positive people in each country and region by multiplying the number with advanced HIV disease at risk for cryptococcal infection by the cryptococcal antigenaemia prevalence of the respective country or region. We estimated progression from cryptococcal antigenaemia to meningitis or death based on estimates from the published literature.
We estimated that there were 4·3 million (IQR 3·0–4·8) adults with HIV and CD4 counts of less than 200 cells/μL globally in 2020. We calculated a mean global cryptococcal antigenaemia prevalence of 4·4% (95% CI 1·6–7·4) among HIV-positive people with CD4 counts of less than 200 cells/μL, corresponding to 179 000 cases (IQR 133 000–219 000) of cryptococcal antigenaemia globally in 2020. Annually, we estimated that there are 152 000 cases (111 000–185 000) of cryptococcal meningitis, resulting in 112 000 cryptococcal-related deaths (79 000–134 000). Globally, cryptococcal disease accounts for 19% (13–24) of AIDS-related mortality.
Despite a reduction in the estimated absolute global burden of HIV-associated cryptococcal meningitis compared with 2014, likely to be due to antiretroviral therapy expansion, cryptococcal disease still accounts for 19% of AIDS-related deaths, similar to 2014 estimates. To end cryptococcal meningitis deaths by 2030, cryptococcal diagnostics, meningitis treatments, and implementation of preventive screening are urgently needed.
None.
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The fungal kingdom includes at least 6 million eukaryotic species and is remarkable with respect to its profound impact on global health, biodiversity, ecology, agriculture, manufacturing, and ...biomedical research. Approximately 625 fungal species have been reported to infect vertebrates, 200 of which can be human associated, either as commensals and members of our microbiome or as pathogens that cause infectious diseases. These organisms pose a growing threat to human health with the global increase in the incidence of invasive fungal infections, prevalence of fungal allergy, and the evolution of fungal pathogens resistant to some or all current classes of antifungals. More broadly, there has been an unprecedented and worldwide emergence of fungal pathogens affecting animal and plant biodiversity. Approximately 8,000 species of fungi and Oomycetes are associated with plant disease. Indeed, across agriculture, such fungal diseases of plants include new devastating epidemics of trees and jeopardize food security worldwide by causing epidemics in staple and commodity crops that feed billions. Further, ingestion of mycotoxins contributes to ill health and causes cancer. Coordinated international research efforts, enhanced technology translation, and greater policy outreach by scientists are needed to more fully understand the biology and drivers that underlie the emergence of fungal diseases and to mitigate against their impacts. Here, we focus on poignant examples of emerging fungal threats in each of three areas: human health, wildlife biodiversity, and food security.
It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or ...special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
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This article provides a perspective on the current status of drug therapy for invasive fungal diseases, together with priorities for the future development of novel compounds. Key opportunities for ...new drugs include production of orally bioavailable agents for the treatment of invasive aspergillosis, invasive candidiasis, cryptococcal meningitis and mucosal and urinary Candida infections. Orally bioavailable agents for the treatment of chronic pulmonary and allergic aspergillosis are also required, as well as new potent drugs against a range of medically important moulds. Antifungal resistance is a problem in certain contexts, but is generally less of a problem than bacterial infections. Earlier and more complete mycological diagnosis and improvements in underlying risk estimation will improve outcomes. The limitations of the current antifungal agents and opportunities for new developments are discussed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background. Invasive aspergillosis (IA) is an important cause of morbidity and mortality among immunocompromised patients. Echinocandins are novel antifungal molecules with in vitro and in vivo ...activity against Aspergillus species. Methods. We investigated the efficacy and safety of caspofungin in the treatment of IA. Ninety patients with IA who were refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B, or triazoles were enrolled to receive caspofungin. Results. Efficacy was assessed for 83 patients who had infection consistent with definitions of IA and who received ⩾1 dose of study drug. Common underlying conditions included hematologic malignancy (48% of patients), allogeneic blood and marrow transplantation (25% of patients), and solid-organ transplantation (11% of patients). Seventy-one patients (86%) were refractory to and 12 patients (14%) were intolerant of previous therapy. A favorable response to caspofungin therapy was observed in 37 (45%) of 83 patients, including 32 (50%) of 64 with pulmonary aspergillosis and 3 (23%) of 13 with disseminated aspergillosis. Two patients discontinued caspofungin therapy because of drug-related adverse events. Drug-related nephrotoxicity and hepatotoxicity occurred infrequently. Conclusion. Caspofungin demonstrated usefulness in the salvage treatment of IA.
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Abstract
Aspergillus colonization of the lower respiratory airways is common in normal people, and of little clinical significance. However, in some patients, colonization is associated with severe ...disease including poorly controlled asthma, allergic bronchopulmonary aspergillosis (ABPA) with sputum plugs, worse lung function in chronic obstructive pulmonary aspergillosis (COPD), invasive aspergillosis, and active infection in patients with chronic pulmonary aspergillosis (CPA). Therefore, understanding the pathophysiological mechanisms of fungal colonization in disease is essential to develop strategies to avert or minimise disease. Aspergillus cell components promoting fungal adherence to the host surface, extracellular matrix, or basal lamina are indispensable for pathogen persistence. However, our understanding of individual differences in clearance of A. fumigatus from the lung in susceptible patients is close to zero.
The global incidence and diagnosis of fungal keratitis Brown, Lottie; Leck, Astrid K; Gichangi, Michael ...
Lancet. Infectious diseases/The Lancet. Infectious diseases,
March 2021, 2021-03-00, 20210301, Volume:
21, Issue:
3
Journal Article
Peer reviewed
Open access
Fungal keratitis is a severe corneal infection that often results in blindness and eye loss. The disease is most prevalent in tropical and subtropical climates, and infected individuals are ...frequently young agricultural workers of low socioeconomic status. Early diagnosis and treatment can preserve vision. Here, we discuss the fungal keratitis diagnostic literature and estimate the global burden through a complete systematic literature review from January, 1946 to July, 2019. An adapted GRADE score was used to evaluate incidence papers—116 studies provided the incidence of fungal keratitis as a proportion of microbial keratitis and 18 provided the incidence in a defined population. We calculated a minimum annual incidence estimate of 1 051 787 cases (736 251–1 367 323), with the highest rates in Asia and Africa. If all culture-negative cases are assumed to be fungal, the annual incidence would be 1 480 916 cases (1 036 641–1 925 191). In three case series, 8–11% of patients had to have the eye removed, which represents an annual loss of 84 143–115 697 eyes. As fungal keratitis probably affects over a million people annually, an inexpensive, simple diagnostic method and affordable treatment are needed in every country.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Echinocandin antifungal drugs Denning, David W
The Lancet (British edition),
10/2003, Volume:
362, Issue:
9390
Journal Article
Peer reviewed
The echinocandins are large lipopeptide molecules that are inhibitors of β-(1,3)-glucan synthesis, an action that damages fungal cell walls. In vitro and in vivo, the echinocandins are rapidly ...fungicidal against most Candida spp and fungistatic against Aspergillus spp. They are not active at clinically relevant concentrations against Zygomycetes, Cryptococcus neoformans, or Fusarium spp. No drug target is present in mammalian cells. The first of the class to be licensed was caspofungin, for refractory invasive aspergillosis (about 40% response rate) and the second was micafungin. Adverse events are generally mild, including (for caspofungin) local phlebitis, fever, abnormal liver function tests, and mild haemolysis. Poor absorption after oral administration limits use to the intravenous route. Dosing is once daily and drug interactions are few. The echinocandins are widely distributed in the body, and are metabolised by the liver. Results of studies of caspofungin in candidaemia and invasive candidiasis suggest equivalent efficacy to amphotericin B, with substantially fewer toxic effects. Absence of antagonism in combination with other antifungal drugs suggests that combination antifungal therapy could become a general feature of the echinocandins, particularly for invasive aspergillosis.
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DOBA, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SIK, UILJ, UKNU, UL, UM, UPCLJ, UPUK, VSZLJ
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