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1.
JAMA ; 322(17): 1673-1681, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31688884

RESUMO

Importance: Children, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds. Objective: To compare the efficacy of caspofungin vs fluconazole prophylaxis against proven or probable invasive fungal disease and invasive aspergillosis during neutropenia following acute myeloid leukemia chemotherapy. Design, Setting, and Participants: This multicenter, randomized, open-label, clinical trial enrolled patients aged 3 months to 30 years with newly diagnosed de novo, relapsed, or secondary acute myeloid leukemia being treated at 115 US and Canadian institutions (April 2011-November 2016; last follow-up June 30, 2018). Interventions: Participants were randomly assigned during the first chemotherapy cycle to prophylaxis with caspofungin (n = 257) or fluconazole (n = 260). Prophylaxis was administered during the neutropenic period following each chemotherapy cycle. Main Outcomes and Measures: The primary outcome was proven or probable invasive fungal disease as adjudicated by blinded central review. Secondary outcomes were invasive aspergillosis, empirical antifungal therapy, and overall survival. Results: The second interim efficacy analysis and an unplanned futility analysis based on 394 patients appeared to have suggested futility, so the study was closed to accrual. Among the 517 participants who were randomized (median age, 9 years [range, 0-26 years]; 44% female), 508 (98%) completed the trial. The 23 proven or probable invasive fungal disease events (6 caspofungin vs 17 fluconazole) included 14 molds, 7 yeasts, and 2 fungi not further categorized. The 5-month cumulative incidence of proven or probable invasive fungal disease was 3.1% (95% CI, 1.3%-7.0%) in the caspofungin group vs 7.2% (95% CI, 4.4%-11.8%) in the fluconazole group (overall P = .03 by log-rank test) and for cumulative incidence of proven or probable invasive aspergillosis was 0.5% (95% CI, 0.1%-3.5%) with caspofungin vs 3.1% (95% CI, 1.4%-6.9%) with fluconazole (overall P = .046 by log-rank test). No statistically significant differences in empirical antifungal therapy (71.9% caspofungin vs 69.5% fluconazole, overall P = .78 by log-rank test) or 2-year overall survival (68.8% caspofungin vs 70.8% fluconazole, overall P = .66 by log-rank test) were observed. The most common toxicities were hypokalemia (22 caspofungin vs 13 fluconazole), respiratory failure (6 caspofungin vs 9 fluconazole), and elevated alanine transaminase (4 caspofungin vs 8 fluconazole). Conclusions and Relevance: Among children, adolescents, and young adults with acute myeloid leukemia, prophylaxis with caspofungin compared with fluconazole resulted in significantly lower incidence of invasive fungal disease. The findings suggest that caspofungin may be considered for prophylaxis against invasive fungal disease, although study interpretation is limited by early termination due to an unplanned interim analysis that appeared to have suggested futility. Trial Registration: ClinicalTrials.gov Identifier: NCT01307579.


Assuntos
Antifúngicos/uso terapêutico , Caspofungina/uso terapêutico , Fluconazol/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Micoses/prevenção & controle , Adolescente , Adulto , Antifúngicos/efeitos adversos , Aspergilose/epidemiologia , Aspergilose/prevenção & controle , Caspofungina/efeitos adversos , Criança , Pré-Escolar , Término Precoce de Ensaios Clínicos , Feminino , Fluconazol/efeitos adversos , Humanos , Lactente , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/complicações , Masculino , Neutropenia/complicações , Adulto Jovem
2.
Beijing Da Xue Xue Bao Yi Xue Ban ; 51(5): 977-980, 2019 Oct 18.
Artigo em Chinês | MEDLINE | ID: mdl-31624410

RESUMO

Among the various drug induced dermatological entities toxic epidermalnecrolysis (TEN) and Stevens-Johnson syndrome (SJS) occupy a primary place in terms of mortality. Toxic epidermal necrolysis also known as Lyell's syndrome was first described by Lyell in 1956. Drugs are by far the most common cause of toxic epidermal necrolysis, in which large sheets of skin are lost from the body surface making redundant the barrier function of the skin, with its resultant complications. Drug-induced toxic epidermal necrolysis are severe adverse cutaneous drug reactions to various precipitating agents that predominantly involve the skin and mucous membranes. Toxic epidermal necrolysis is rare but considered medical emergencies as they are potentially fatal. Drugs are the most common cause accounting for about 65%-80% of the cases. The most common offending agents are sulfonamides, NSAIDs, butazones and hydrantoins. An immune mechanism is implicated in the pathogenesis, but its nature is still unclear. There is a prodormal phase in which there is burning sensation all over the skin and conjunctivae, along with skin tenderness, fever, malaise and arthralgias. Early sites of cutaneous involvement are the presternal region of the trunk and the face, but also the palms and soles, rapidly spread to their maximum extent, the oral mucosa and conjunctiva being affected. Initial lesions are macular, followed by desquamateion, or may be from atypical targets with purpuriccenters that coalesce, from bullae, then slough. The earlier a causative agent is withdrawn the better is the prognosis. Several treatment modalities given in addition to supportive care are reported in the literature, such as systemicsteroids, high-dose intravenous immunoglobulins, ciclosporin, TNF antagonists. Recovery is slow over a period of 14-28 days and relapses are frequent. Mortality is 25%-50% and half the deaths occur due to secondary infection. Here we report a 50-year-old female of drug-induced toxic epidermal necrolysis. She was admitted to the dermatology ward with extensive peeling of skin over the trunk and limbs. She had taken alamotrigine for epilepsy. A week after taking the tablets, the patient developed a severe burning sensation all over the body and followed by a polymorphic erythematous dermatitis and widespread peeling of skin. We treated this patient with high dose corticosteroids, high-dose intravenous immunoglobulins and etanercept, but eventually she died of secondary aspergillus fumigatus infection.


Assuntos
Aspergilose/diagnóstico , Síndrome de Stevens-Johnson/microbiologia , Corticosteroides , Aspergillus fumigatus , Ciclosporina , Feminino , Humanos , Pessoa de Meia-Idade , Pele
3.
Nat Commun ; 10(1): 4275, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537789

RESUMO

Calcineurin is important for fungal virulence and a potential antifungal target, but compounds targeting calcineurin, such as FK506, are immunosuppressive. Here we report the crystal structures of calcineurin catalytic (CnA) and regulatory (CnB) subunits complexed with FK506 and the FK506-binding protein (FKBP12) from human fungal pathogens (Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans and Coccidioides immitis). Fungal calcineurin complexes are similar to the mammalian complex, but comparison of fungal and human FKBP12 (hFKBP12) reveals conformational differences in the 40s and 80s loops. NMR analysis, molecular dynamic simulations, and mutations of the A. fumigatus CnA/CnB-FK506-FKBP12-complex identify a Phe88 residue, not conserved in hFKBP12, as critical for binding and inhibition of fungal calcineurin. These differences enable us to develop a less immunosuppressive FK506 analog, APX879, with an acetohydrazine substitution of the C22-carbonyl of FK506. APX879 exhibits reduced immunosuppressive activity and retains broad-spectrum antifungal activity and efficacy in a murine model of invasive fungal infection.


Assuntos
Antifúngicos/farmacologia , Aspergillus fumigatus/metabolismo , Inibidores de Calcineurina/farmacologia , Calcineurina/metabolismo , Cryptococcus neoformans/metabolismo , Proteína 1A de Ligação a Tacrolimo/metabolismo , Tacrolimo/farmacologia , Animais , Aspergilose/tratamento farmacológico , Aspergilose/microbiologia , Aspergillus fumigatus/efeitos dos fármacos , Sítios de Ligação , Candida albicans/efeitos dos fármacos , Candida albicans/metabolismo , Células Cultivadas , Coccidioides/efeitos dos fármacos , Coccidioides/metabolismo , Criptococose/tratamento farmacológico , Criptococose/microbiologia , Cryptococcus neoformans/efeitos dos fármacos , Cristalografia por Raios X , Descoberta de Drogas/métodos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Tacrolimo/metabolismo
4.
Public Health ; 175: 145-147, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31494335

RESUMO

OBJECTIVES: Aspergillus spp could be responsible of nosocomial aspergillosis in immunocompromised patients. In 2018, it was decided to demolish a building of Careggi Hospital (Florence, Italy), the Chief Medical Officer ordered a 9-months-long air and surface microbiological sampling and extraordinary preventive measures. STUDY DESIGN: A 9-months-long prospective study. METHODS: After mapping the at-risk areas, air and surface samples were collected in different locations: in corridors, in rooms (high efficiency particulate air filter (HEPA) filtered or not), and outdoors. The samples were collected during the critical phases of the demolition. Air temperature and weather conditions were determined and recorded at the beginning of each sampling. RESULTS: Seventy-eight air samples and 72 surface samples were collected. The results showed highest contamination at time zero (before extraordinary preventive measures) and in the wards without HEPA filtered air. No specific prophylaxis strategy was implemented at our hospital for immunocompromised patients, and no cases of aspergillosis were recorded. CONCLUSIONS: Our results showed that extraordinary protective measures, the use of air treatment systems, and a continuous monitoring could be associated with decreased Aspergillus air contamination during construction, renovation, or demolition works.


Assuntos
Microbiologia do Ar , Aspergilose/prevenção & controle , Aspergillus/isolamento & purificação , Infecção Hospitalar/prevenção & controle , Arquitetura Hospitalar , Aspergilose/epidemiologia , Infecção Hospitalar/epidemiologia , Humanos , Itália/epidemiologia , Estudos Prospectivos
5.
Chemotherapy ; 64(2): 57-61, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31484176

RESUMO

Invasive fungal infections are one of the main infectious complications in allogeneic stem cell transplantation (SCT). Triazoles (voriconazole, posaconazole) are the main prophylactic and therapeutic options for the treatment of invasive aspergillosis. However, pharmacological interactions and hepatotoxicity limit its use. Isavuconazole (ISV) is a recently approved azole with a promising interaction and safety profile. We present a case with invasive aspergillosis in the post-allogeneic SCT setting in a critically ill patient with severe multiorgan failure due to veno-occlusive disease. The patient was treated with ISV and B amphotericin during severe kidney and liver failure and multiple immunosuppressants, without significant drug-related toxicity and with favorable outcome. The interaction and safety profile of ISV is discussed along the reported experience. ISV can be an effective salvage therapy even in complex clinical situations with multiple potential interactions.


Assuntos
Antifúngicos/uso terapêutico , Aspergilose/terapia , Transplante de Células-Tronco Hematopoéticas , Nitrilos/uso terapêutico , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Adulto , Aspergilose/tratamento farmacológico , Aspergillus fumigatus/genética , Aspergillus fumigatus/isolamento & purificação , DNA Fúngico/metabolismo , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Tórax/diagnóstico por imagem , Transplante Homólogo/efeitos adversos
6.
Cochrane Database Syst Rev ; 9: CD009551, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31478559

RESUMO

BACKGROUND: This is an update of the original review published in the Cochrane Database of Systematic Reviews Issue 10, 2015.Invasive aspergillosis (IA) is the most common life-threatening opportunistic invasive mould infection in immunocompromised people. Early diagnosis of IA and prompt administration of appropriate antifungal treatment are critical to the survival of people with IA. Antifungal drugs can be given as prophylaxis or empirical therapy, instigated on the basis of a diagnostic strategy (the pre-emptive approach) or for treating established disease. Consequently, there is an urgent need for research into both new diagnostic tools and drug treatment strategies. Increasingly, newer methods such as polymerase chain reaction (PCR) to detect fungal nucleic acids are being investigated. OBJECTIVES: To provide an overall summary of the diagnostic accuracy of PCR-based tests on blood specimens for the diagnosis of IA in immunocompromised people. SEARCH METHODS: We searched MEDLINE (1946 to June 2015) and Embase (1980 to June 2015). We also searched LILACS, DARE, Health Technology Assessment, Web of Science and Scopus to June 2015. We checked the reference lists of all the studies identified by the above methods and contacted relevant authors and researchers in the field. For this review update we updated electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 3) in the Cochrane Library; MEDLINE via Ovid (June 2015 to March week 2 2018); and Embase via Ovid (June 2015 to 2018 week 12). SELECTION CRITERIA: We included studies that: i) compared the results of blood PCR tests with the reference standard published by the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG); ii) reported data on false-positive, true-positive, false-negative and true-negative results of the diagnostic tests under investigation separately; and iii) evaluated the test(s) prospectively in cohorts of people from a relevant clinical population, defined as a group of individuals at high risk for invasive aspergillosis. Case-control and retrospective studies were excluded from the analysis. DATA COLLECTION AND ANALYSIS: Authors independently assessed quality and extracted data. For PCR assays, we evaluated the requirement for either one or two consecutive samples to be positive for diagnostic accuracy. We investigated heterogeneity by subgroup analyses. We plotted estimates of sensitivity and specificity from each study in receiver operating characteristics (ROC) space and constructed forest plots for visual examination of variation in test accuracy. We performed meta-analyses using the bivariate model to produce summary estimates of sensitivity and specificity. MAIN RESULTS: We included 29 primary studies (18 from the original review and 11 from this update), corresponding to 34 data sets, published between 2000 and 2018 in the meta-analyses, with a mean prevalence of proven or probable IA of 16.3 (median prevalence 11.1% , range 2.5% to 57.1%). Most patients had received chemotherapy for haematological malignancy or had undergone hematopoietic stem cell transplantation. Several PCR techniques were used among the included studies. The sensitivity and specificity of PCR for the diagnosis of IA varied according to the interpretative criteria used to define a test as positive. The summary estimates of sensitivity and specificity were 79.2% (95% confidence interval (CI) 71.0 to 85.5) and 79.6% (95% CI 69.9 to 86.6) for a single positive test result, and 59.6% (95% CI 40.7 to 76.0) and 95.1% (95% CI 87.0 to 98.2) for two consecutive positive test results. AUTHORS' CONCLUSIONS: PCR shows moderate diagnostic accuracy when used as screening tests for IA in high-risk patient groups. Importantly the sensitivity of the test confers a high negative predictive value (NPV) such that a negative test allows the diagnosis to be excluded. Consecutive positives show good specificity in diagnosis of IA and could be used to trigger radiological and other investigations or for pre-emptive therapy in the absence of specific radiological signs when the clinical suspicion of infection is high. When a single PCR positive test is used as the diagnostic criterion for IA in a population of 100 people with a disease prevalence of 16.3% (overall mean prevalence), three people with IA would be missed (sensitivity 79.2%, 20.8% false negatives), and 17 people would be unnecessarily treated or referred for further tests (specificity of 79.6%, 21.4% false positives). If we use the two positive test requirement in a population with the same disease prevalence, it would mean that nine IA people would be missed (sensitivity 59.6%, 40.4% false negatives) and four people would be unnecessarily treated or referred for further tests (specificity of 95.1%, 4.9% false positives). Like galactomannan, PCR has good NPV for excluding disease, but the low prevalence of disease limits the ability to rule in a diagnosis. As these biomarkers detect different markers of disease, combining them is likely to prove more useful.


Assuntos
Aspergilose/sangue , Aspergilose/diagnóstico , Hospedeiro Imunocomprometido , Infecções Oportunistas , Reação em Cadeia da Polimerase/métodos , Estudos de Casos e Controles , Humanos , Infecções Oportunistas/sangue , Infecções Oportunistas/diagnóstico , Valor Preditivo dos Testes , Sensibilidade e Especificidade
7.
J Med Life ; 12(2): 128-132, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31406513

RESUMO

Aspergillus species (sp.) that causes opportunistic infections have been increasingly found in human mainly immunosuppressive patients around the world every year. The main objective was to use a rapid and cheap molecular method for monitoring Aspergillus infections and epidemiological approaches. In order to identity Aspergilli species (spp.), a number of molecular methods including restriction fragment length polymorphism (RFLP) have been employed in accordance with ribosomal RNA amplification. The focus of this study - a group of hospitalized patients with clinical and subclinical signs of infection. All of the collected clinical specimens were transported to the medical mycology lab and examined for Aspergillus identification. The environmental specimens were collected from air and surfaces inspected for the Aspergillus within the hospital sources. At first, growth characteristics and microscopic features on mycological media for the identification of Aspergillus sp. were performed. For the confirmation of Aspergillus isolates which similarly found in clinical and environmental sources, molecular method polymerase chain reaction/restriction fragment length polymorphism was carried out. From the mentioned specimens, 102 fungal isolates included Candida spp., Aspergillus spp. and other fungi. Aspergillus flavus (47%), Aspergillus fumigatus (29.4%) and Aspergillus niger (23.5%) all were found as the most common clinical isolates. In addition, Aspergillus isolates from environmental were Aspergillus niger (43.7%), Aspergillus flavus (41.7%), Aspergillus fumigatus (14.6%). Therefore, polymerase chain reaction-restriction fragment length polymorphism with a single restriction enzyme can be very useful in the identification of Aspergillus spp., because of its facility in use, speed, robust, and high sensitivity of diagnosis.


Assuntos
Aspergilose/microbiologia , Aspergillus/fisiologia , Infecção Hospitalar/microbiologia , Meio Ambiente , Hospitais Universitários , Aspergillus/isolamento & purificação , Humanos , Polimorfismo de Fragmento de Restrição
9.
BMJ Case Rep ; 12(8)2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31420430

RESUMO

A male patient in his mid-60s presented with a severe pneumonia following return to the UK after travel to Crete. He was diagnosed with Legionnaire's disease (caused by an uncommon serogroup of Legionella pneumophila). He was pancytopenic on admission, and during a long stay on critical care he was diagnosed with a disseminated Aspergillus infection. Bone marrow aspiration revealed an underlying hairy cell leukaemia that undoubtedly contributed to his acute presentation and subsequent invasive fungal infection.


Assuntos
Aspergillus , Legionella pneumophila , Doença dos Legionários/microbiologia , Pneumonia/microbiologia , Doença Relacionada a Viagens , Aspergilose/microbiologia , Grécia , Humanos , Leucemia de Células Pilosas/microbiologia , Masculino , Pessoa de Meia-Idade , Reino Unido
12.
ACS Chem Biol ; 14(7): 1643-1651, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31265232

RESUMO

Fungal secondary metabolites (SMs) include medically valuable compounds as well as compounds that are toxic, carcinogenic, and/or contributors to fungal pathogenesis. It is consequently important to understand the regulation of fungal secondary metabolism. McrA is a recently discovered transcription factor that negatively regulates fungal secondary metabolism. Deletion of mcrA (mcrAΔ), the gene encoding McrA, results in upregulation of many SMs and alters the expression of more than 1000 genes. One gene strongly upregulated by the deletion of mcrA is llmG, a putative methyl transferase related to LaeA, a major regulator of secondary metabolism. We artificially upregulated llmG by replacing its promoter with strong constitutive promoters in strains carrying either wild-type mcrA or mcrAΔ. Upregulation of llmG on various media resulted in increased production of the important toxin sterigmatocystin and compounds from at least six major SM pathways. llmG is, thus, a master SM regulator. mcrAΔ generally resulted in greater upregulation of SMs than upregulation of llmG, indicating that the full effects of mcrA on secondary metabolism involve genes in addition to llmG. However, the combination of mcrAΔ and upregulation of llmG generally resulted in greater compound production than mcrAΔ alone (in one case more than 460 times greater than the control). This result indicates that deletion of mcrA and/or upregulation of llmG can likely be combined with other strategies for eliciting SM production to greater levels than can be obtained with any single strategy.


Assuntos
Aspergillus nidulans/genética , Proteínas Fúngicas/genética , Regulação Fúngica da Expressão Gênica , Metiltransferases/genética , Aspergilose/microbiologia , Aspergillus nidulans/metabolismo , Proteínas Fúngicas/metabolismo , Humanos , Metiltransferases/metabolismo , Metabolismo Secundário , Esterigmatocistina/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação para Cima
13.
J Microbiol Immunol Infect ; 52(5): 728-735, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302087

RESUMO

BACKGOUND: Conventional diagnosis of invasive fungal disease from blood cultures is often notoriously delayed and inadequately sensitive. We aimed to develop a universal primers-based polymerase chain reaction (PCR) assay and restriction fragment length polymorphisms (RFLP) for rapid identification of invasive fungal disease (IFD). METHODS: We evaluated 16 clinical fungal species using a combination of PCR assays with 3 different restriction endonucleases targeting various internal transcribed spacer (ITS) regions and high resolution melting analysis (HRMA). Serial samples from 75 patients suspected to have IFD were analyzed for clinical verification. RESULTS: We have designed a universal PCR capable of amplifying a portion of the 18S rRNA gene of 16 clinically important fungal species. The restriction patterns of most PCR products generated by EcoRI or double digested by ClaI and AvaI were different, except Aspergillus niger and Aspergillus flavus had a similar pattern, and Aspergillus fumigatus and Aspergillus terreus had a similar pattern. All these species had a unique melting curve shape using the HRMA. Both HRMA and universal PCR had adequate sensitivity, and all sixteen reference fungal species can be clearly distinguished by the universal PCR-RFLP-HRMA assay. With a reference library of 176 clinically relevant fungal strains, and 75 clinical samples from patients with suspicious IFD were tested, our assay identified 100% and 61.1% of isolates from the reference library and clinical samples, respectively. CONCLUSIONS: Universal PCR and RFLP coupled with HRMA could be a highly discriminative and useful molecular diagnostic that could enhance the current diagnostic, treatment, and surveillance methods of invasive fungal disease.


Assuntos
Primers do DNA , Enzimas de Restrição do DNA , Fungos/isolamento & purificação , Espécies Introduzidas , Técnicas de Tipagem Micológica/métodos , Micoses/microbiologia , Reação em Cadeia da Polimerase/métodos , Aspergilose/diagnóstico , Aspergilose/microbiologia , Aspergillus/classificação , Aspergillus/genética , Aspergillus/isolamento & purificação , Candida/classificação , Candida/genética , Candida/isolamento & purificação , DNA Fúngico/genética , Fungos/classificação , Fungos/genética , Humanos , Micoses/diagnóstico , Polimorfismo de Fragmento de Restrição , RNA Ribossômico 18S/genética , Sensibilidade e Especificidade
14.
J Med Microbiol ; 68(9): 1341-1352, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31355743

RESUMO

Introduction. Timely detection of invasive aspergillosis (IA) caused by fungal pathogens, i.e. Aspergillus fumigatus and Aspergillus flavus, in immunocompromised patients is crucial in preventing high mortality.Aim. To develop a simple immunoassay for the detection of galactomannan (GM), an IA biomarker.Methodology. GM from A. fumigatus and A. flavus clinical strains was purified and characterized by X-ray diffraction, IR spectroscopy and 13C/1H nuclear magnetic resonance (NMR) for polyclonal antibody (pAb) production in rabbits. An enzyme-linked immunosorbent assay (ELISA) was standardized using concanavalin A to capture Aspergillus GM and pAbs to detect it. Gold nanoparticles (AuNPs) were synthesized and conjugated to pAbs for the development of a dot-blot immunoassay. The developed dot-blot was evaluated with 109 clinical serum and bronchoalveolar lavage samples.Results. Spectroscopy studies characterized the d-galactofuranosyl groups of GM responsible for the immune response and generation of pAbs. The ELISA employing pAbs showed a sensitivity of 1 ng ml-1 for Aspergillus GM. Furthermore, a sensitive, visual, rapid dot-blot assay developed by the conjugation of pAbs to AuNPs (~24±5 nm size, -36±2 mV zeta potential) had a detection limit of 1 pg ml-1 in serum. The pAbs interacted with Aspergillus spp. but did not cross-react with other fungal pathogen genera such as Penicillium and Candida. Evaluation of the dot-blot with 109 clinical samples showed high sensitivity (80 %) and specificity (93.2 %), with an overall assay accuracy of 89%.Conclusion. The developed nano-gold immunodiagnostic assay has immense potential for practical use in rapid, specific and sensitive on-site diagnosis of IA, even under resource-limited settings.


Assuntos
Aspergilose/diagnóstico , Ouro/química , Testes Imunológicos/métodos , Nanopartículas Metálicas/química , Animais , Anticorpos Antibacterianos/química , Anticorpos Antibacterianos/imunologia , Antígenos de Fungos/sangue , Antígenos de Fungos/imunologia , Aspergillus/imunologia , Aspergillus/isolamento & purificação , Aspergillus flavus/imunologia , Aspergillus flavus/isolamento & purificação , Aspergillus fumigatus/imunologia , Aspergillus fumigatus/isolamento & purificação , Humanos , Immunoblotting , Mananas/análise , Mananas/imunologia , Testes Imediatos , Coelhos , Sensibilidade e Especificidade
15.
Mycoses ; 62(9): 765-772, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31162731

RESUMO

The aim of this study was to describe the characteristics of patients with chronic pulmonary aspergillosis (CPA) in a tertiary care centre in Spain. Retrospective cohort study of all patients diagnosed with CPA between January 2010 and December 2015. The patients were identified through the Microbiology Registry. Demographic, clinical, laboratory, radiological, microbiological and clinical data were recorded. Patients were followed up for 12 months. Fifty-three patients were included; median age was 61.5 years. Forty-seven had a lung condition, 25 suffered from COPD, 19 an active malignancy, 10 had previous pulmonary tuberculosis and 9 lung interstitial disease. Twenty-eight patients presented with chronic cavitary pulmonary form (CCPA) and 20 with subacute invasive aspergillosis (SAIA). Species identified were A fumigatus (34), A niger (5), A terreus (4) and A flavus (3). All-cause 1-year mortality was 56%. Predictors of mortality were cancer history (OR, 9.5; 95% CI, 2.54-35.51; P < 0.01) and SAIA (OR, 5.49; 95% CI, 1.49-19.82; P < 0.01). Previous pulmonary tuberculosis, surgery for the treatment of CPA and CCPA were found to be associated with lower mortality (OR, 0.05; 95% CI, <0.01-0.47; P < 0.01; OR, 0.16; 95% CI, 0.03-0.88; P = 0.035 and OR 0.2, 95% CI, 0.01-0.67; P = 0.01, respectively). This is the first study providing an overview of the features of CPA in patients from Spain. CCPA was the most frequent form of CPA and A fumigatus the most frequently isolated species. Patients with cancer history and SAIA had a worse prognosis.


Assuntos
Pulmão/microbiologia , Aspergilose Pulmonar/microbiologia , Idoso , Aspergilose/complicações , Aspergillus , Doença Crônica , Feminino , Humanos , Pulmão/patologia , Pneumopatias/complicações , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/microbiologia , Prognóstico , Aspergilose Pulmonar/diagnóstico , Aspergilose Pulmonar/mortalidade , Sistema de Registros , Estudos Retrospectivos , Espanha , Centros de Atenção Terciária
16.
World Neurosurg ; 129: 292-294, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31203084

RESUMO

BACKGROUND: Invasive sinonasal aspergillosis is rarely seen in immunocompetent individuals. It may involve adjacent intracranial and intraorbital structures causing high morbidity and mortality. CASE DESCRIPTION: We report a rare case of invasive Aspergillus sinusitis in a young, immunocompetent woman causing headache and vision loss. Endoscopic débridement under general anesthesia was complicated by rupture of a mycotic cavernous carotid artery aneurysm. This was managed by packing with muscle and fascia followed by endovascular coiling. Subsequently, the aneurysm extended intradurally and caused fatal subarachnoid hemorrhage. CONCLUSIONS: This case emphasizes the need for early diagnosis of invasive fungal sinusitis to prevent intracranial complications and fatal outcome. When the diagnosis is made, aggressive treatment with surgical débridement and adjuvant antifungal therapy is required. Internal carotid artery involvement is a rare but life-threatening complication of invasive fungal sinusitis.


Assuntos
Aneurisma Infectado/etiologia , Aspergilose/complicações , Doenças das Artérias Carótidas/etiologia , Sinusite/complicações , Aneurisma Roto/etiologia , Artéria Carótida Interna/patologia , Endoscopia/efeitos adversos , Evolução Fatal , Feminino , Humanos , Hemorragia Subaracnóidea/etiologia , Adulto Jovem
17.
Clin Microbiol Infect ; 25(9): 1096-1113, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31158517

RESUMO

SCOPE: Presenting symptoms, distributions and patterns of diseases and vulnerability to invasive aspergillosis (IA) are similar between children and adults. However, differences exist in the epidemiology and underlying conditions, the usefulness of newer diagnostic tools, the pharmacology of antifungal agents and in the evidence from interventional phase 3 clinical trials. Therefore, the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and the European Confederation of Medical Mycology (ECMM) have developed a paediatric-specific guideline for the diagnosis and management of IA in neonates and children. METHODS: Review and discussion of the scientific literature and grading of the available quality of evidence was performed by the paediatric subgroup of the ESCMID-ECMM-European Respiratory Society (ERS) Aspergillus disease guideline working group, which was assigned the mandate for the development of neonatal- and paediatric-specific recommendations. QUESTIONS: Questions addressed by the guideline included the epidemiology of IA in neonates and children; which paediatric patients may benefit from antifungal prophylaxis; how to diagnose IA in neonates and children; which antifungal agents are available for use in neonates and children; which antifungal agents are suitable for prophylaxis and treatment of IA in neonates and children; what is the role of therapeutic drug monitoring of azole antifungals; and which management strategies are suitable to be used in paediatric patients. This guideline provides recommendations for the diagnosis, prevention and treatment of IA in the paediatric population, including neonates. The aim of this guideline is to facilitate optimal management of neonates and children at risk for or diagnosed with IA.


Assuntos
Antifúngicos/uso terapêutico , Aspergilose/diagnóstico , Aspergilose/tratamento farmacológico , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/tratamento farmacológico , Antibioticoprofilaxia/métodos , Antibioticoprofilaxia/normas , Aspergillus/efeitos dos fármacos , Criança , Gerenciamento Clínico , Monitoramento de Medicamentos , Humanos , Recém-Nascido
18.
J Med Case Rep ; 13(1): 172, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31164170

RESUMO

BACKGROUND: Aspergillus terreus, a saprophytic fungus, is recognized as an emerging pathogen in various infections in humans. However, bone and joint involvement is uncommon. To the best of our knowledge, only seven cases of spondylodiscitis caused by Aspergillus terreus have been reported previously in humans. We report a case of a patient with Aspergillus terreus spondylodiscitis following an abdominal stab wound. CASE PRESENTATION: A 74-year-old Japanese man with no particular medical history fell from a ladder and sustained a left abdominal stab wound from an L-shaped metal peg. Computed tomography showed the trace of the L-shaped metal peg from the left abdomen to the left rib and left kidney. The scan also showed an anterolateral bone avulsion of the left side of the T12 vertebral body, as well as fractures of the L1 left transverse process and the left 10th-12th ribs. He was hospitalized and treated with conservative therapy for 6 weeks. He was readmitted to the hospital with complaints of sudden back pain, numbness of both legs, and inability to walk 13 weeks after the fall. Magnetic resonance imaging findings were typical of spondylodiscitis. Gadolinium-enhanced T1-weighted magnetic resonance imaging indicated increased signal intensity at T11-T12 vertebral bodies and severe cord compression and epidural abscess at T11-T12 associated with infiltration of soft paravertebral tissues. On the seventh day after admission, he underwent partial laminectomy at T11 and posterior fusion at T9 to L2. The result of his blood culture was negative, but Aspergillus terreus was isolated from the material of T11-T12 intervertebral disc and vertebral bodies. His Aspergillus antigen was positive in a blood examination. Histological examination showed chronic suppurative osteomyelitis. On the 35th day after admission, he underwent anterior fusion at T11 and T12 with a rib bone graft. For 5 months, voriconazole was administered, and he wore a rigid corset. Posterior partial laminectomy at T11 and anterior fusion at T11 and T12 resulted in a good clinical course. The patient's neurological dysfunction was completely recovered, and his back pain disappeared. Two years after the operation, computed tomography was performed and showed bone fusion at T11 and T12. Magnetic resonance imaging revealed no evidence of increased signal intensity at T11-T12 vertebral bodies and severe cord compression and epidural abscess at T11-T12. CONCLUSIONS: To our knowledge, this is the first report of spondylodiscitis caused by Aspergillus terreus after an abdominal penetrating injury. The histological finding of chronic suppurative osteomyelitis and the radiological findings strongly suggested direct inoculation of Aspergillus terreus.


Assuntos
Traumatismos Abdominais/diagnóstico por imagem , Aspergilose/diagnóstico por imagem , Discite/diagnóstico por imagem , Abscesso Epidural/diagnóstico por imagem , Osteomielite/diagnóstico por imagem , Ferimentos Perfurantes/diagnóstico por imagem , Traumatismos Abdominais/complicações , Acidentes por Quedas , Idoso , Antifúngicos/uso terapêutico , Aspergilose/etiologia , Aspergilose/terapia , Discite/etiologia , Discite/terapia , Abscesso Epidural/etiologia , Abscesso Epidural/terapia , Fratura Avulsão/complicações , Fratura Avulsão/diagnóstico por imagem , Humanos , Laminectomia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/lesões , Imagem por Ressonância Magnética , Masculino , Osteomielite/etiologia , Osteomielite/terapia , Fraturas das Costelas/complicações , Fraturas das Costelas/diagnóstico por imagem , Compressão da Medula Espinal/diagnóstico por imagem , Compressão da Medula Espinal/etiologia , Compressão da Medula Espinal/terapia , Fraturas da Coluna Vertebral/complicações , Fraturas da Coluna Vertebral/diagnóstico por imagem , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/lesões , Voriconazol/uso terapêutico , Ferimentos Perfurantes/complicações
19.
mBio ; 10(3)2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164462

RESUMO

Aspergillus fumigatus is a leading cause of invasive fungal infections. Resistance to first-line triazole antifungals has led to therapy with echinocandin drugs. Recently, we identified several high-minimum-effective-concentration (MEC) A. fumigatus clinical isolates from patients failing echinocandin therapy. Echinocandin resistance is known to arise from amino acid substitutions in ß-(1,3)-d-glucan synthase encoded by the fks1 gene. Yet these clinical isolates did not contain mutations in fks1, indicating an undefined resistance mechanism. To explore this new mechanism, we used a laboratory-derived strain, RG101, with a nearly identical caspofungin (CAS) susceptibility phenotype that also does not contain fks1 mutations. Glucan synthase isolated from RG101 was fully sensitive to echinocandins. Yet exposure of RG101 to CAS during growth yielded a modified enzyme that was drug insensitive (4 log orders) in kinetic inhibition assays, and this insensitivity was also observed for enzymes isolated from clinical isolates. To understand this alteration, we analyzed whole-enzyme posttranslational modifications (PTMs) but found none linked to resistance. However, analysis of the lipid microenvironment of the enzyme with resistance induced by CAS revealed a prominent increase in the abundances of dihydrosphingosine (DhSph) and phytosphingosine (PhSph). Exogenous addition of DhSph and PhSph to the sensitive enzyme recapitulated the drug insensitivity of the CAS-derived enzyme. Further analysis demonstrated that CAS induces mitochondrion-derived reactive oxygen species (ROS) and that dampening ROS formation by antimycin A or thiourea eliminated drug-induced resistance. We conclude that CAS induces cellular stress, promoting formation of ROS and triggering an alteration in the composition of plasma membrane lipids surrounding glucan synthase, rendering it insensitive to echinocandins.IMPORTANCE Resistance to first-line triazole antifungal agents among Aspergillus species has prompted the use of second-line therapy with echinocandins. As the number of Aspergillus-infected patients treated with echinocandins is rising, clinical observations of drug resistance are also increasing, indicating an emerging global health threat. Our knowledge regarding the development of clinical echinocandin resistance is largely derived from Candida spp., while little is known about resistance in Aspergillus. Therefore, it is important to understand the specific cellular responses raised by A. fumigatus against echinocandins. We discovered a new mechanism of resistance in A. fumigatus that is independent of the well-characterized FKS mutation mechanism observed in Candida This study identified an off-target effect of CAS, i.e., ROS production, and integrated oxidative stress and sphingolipid alterations into a novel mechanism of resistance. This stress-induced response has implications for drug resistance and/or tolerance mechanisms in other fungal pathogens.


Assuntos
Antifúngicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Farmacorresistência Fúngica/genética , Equinocandinas/farmacologia , Glucosiltransferases/genética , Estresse Fisiológico , Aspergilose/microbiologia , Aspergillus fumigatus/enzimologia , Proteínas Fúngicas/genética , Humanos , Testes de Sensibilidade Microbiana , Estresse Oxidativo , Processamento de Proteína Pós-Traducional , Espécies Reativas de Oxigênio/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo
20.
Mycoses ; 62(9): 773-779, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31165504

RESUMO

BACKGROUND: The incidence of false-positive serum galactomannan (GM) enzyme-linked immunosorbent assay test results has been scarcely examined among older subjects. Additionally, previous studies have highlighted the influence of serum immunoglobulin G (IgG) levels on GM test results. We hypothesised that age-related IgG level elevation might also be associated with false-positive GM test results in older subjects. OBJECTIVES: This study aimed to examine the association between false-positive GM test results and age or serum IgG levels. PATIENTS/METHODS: We investigated the association between false-positive serum GM test results and age in 1071 healthy adult subjects. Then, we validated this association and further explored the correlation with serum IgG levels by retrospectively identifying 700 patients with newly diagnosed haematologic disorders without probable or proven invasive aspergillosis. RESULTS: Healthy subjects with false-positive GM test results were significantly older than those without false-positive results (P < 0.001). Among patients with haematologic disorders, IgG myeloma patients showed significantly higher false-positive rates (57/125 [45.6%]) than patients with other haematologic disorders (non-Hodgkin lymphoma: 48/315 [15.2%], myelodysplastic syndrome/aplastic anaemia: 19/141 [13.5%]; both P < 0.001) or other types of myeloma (IgA myeloma: 13/60 [21.7%], light chain myeloma: 9/52 [17.3%]; both P < 0.01). Furthermore, among non-multiple myeloma patients, advanced age and higher IgG level were also significantly associated with the high frequency of false-positive GM test results. CONCLUSIONS: False-positive serum GM test results were frequent among older subjects and patients with elevated serum IgG levels. These results suggested that age- and/or disease-related IgG level elevation could induce this phenomenon.


Assuntos
Antígenos de Fungos/imunologia , Aspergilose/diagnóstico , Aspergilose/imunologia , Imunoglobulina G/sangue , Mananas/sangue , Adulto , Fatores Etários , Idoso , Ensaio de Imunoadsorção Enzimática , Reações Falso-Positivas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
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