RESUMO
BACKGROUND: The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics. METHODS: An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%, respectively. RESULTS: We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500â IU·mL-1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response. CONCLUSION: We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research.
Assuntos
Aspergilose Broncopulmonar Alérgica , Aspergilose Pulmonar Invasiva , Adulto , Criança , Humanos , Aspergilose Broncopulmonar Alérgica/diagnóstico , Aspergilose Broncopulmonar Alérgica/tratamento farmacológico , Imunoglobulina E , Aspergilose Pulmonar Invasiva/diagnóstico , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Itraconazol/uso terapêutico , Micologia , PrednisolonaRESUMO
In this study, we explored the sphingolipid (SL) landscape in Candida auris, which plays pivotal roles in fungal biology and drug susceptibility. The composition of SLs exhibited substantial variations at both the SL class and molecular species levels among clade isolates. Utilizing principal component analysis, we successfully differentiated the five clades based on their SL class composition. While phytoceramide (PCer) was uniformly the most abundant SL class in all the isolates, other classes showed significant variations. These variations were not limited to SL class level only as the proportion of different molecular species containing variable number of carbons in fatty acid chains also differed between the isolates. Also a comparative analysis revealed abundance of ceramides and glucosylceramides in fluconazole susceptible isolates. Furthermore, by comparing drug-resistant and susceptible isolates within clade IV, we uncovered significant intraclade differences in key SL classes such as high PCer and low long chain base (LCB) content in resistant strains, underscoring the impact of SL heterogeneity on drug resistance development in C. auris. These findings shed light on the multifaceted interplay between genomic diversity, SLs, and drug resistance in this emerging fungal pathogen.
Assuntos
Antifúngicos , Candida , Antifúngicos/farmacologia , Candida auris , Esfingolipídeos , Farmacorresistência Fúngica , Testes de Sensibilidade MicrobianaRESUMO
Acrophialophora is implicated in superficial and invasive infections, especially in immunosuppressed individuals. The present study was undertaken to provide clinical, microbiological, phylogenetic, and antifungal susceptibility testing (AFST) profile of Acrophialophora isolated from India. All the isolates identified as Acrophialophora species at the National Culture Collection for Pathogenic Fungi, Chandigarh, India were revived. Phenotypic and molecular characterization was performed, followed by temperature studies, scanning electron microscopy (SEM), and AFST. We also performed systematic review of all the cases of Acrophialophora species reported till date. A total of nine isolates identified as Acrophialophora species were identified by molecular method as A. fusispora (n = 8) and A. levis (n = 1), from brain abscess (n = 4), respiratory tract (n = 3), and corneal scraping (n = 2). All patients but two had predisposing factors/co-morbidities. Acrophialophora was identified as mere colonizer in one. Temperature studies and SEM divulged variation between both species. Sequencing of the internal transcribed spacer ribosomal DNA and beta-tubulin loci could distinguish species, while the LSU ribosomal DNA locus could not. AFST showed the lowest minimum inhibitory concentrations (MICs) for triazoles and the highest for echinocandins. Systematic literature review revealed 16 cases (11 studies), with ocular infections, pulmonary and central nervous system infections, and A. fusispora was common species. All the patients except three responded well. High MICs were noted for fluconazole, micafungin, and caspofungin. This is the first study delineating clinical, phenotypic, and genotypic characteristics of Acrophialophora species from India. The study highlights microscopic differences between both species and emphasizes the role of molecular methods in precise identification. Triazoles appear to be the most effective antifungals for managing patients.
We describe clinical, phenotypic, and genotypic characteristics of Acrophialophora species. This species causes mild infection to fatal infection in immunosuppressed individuals. Triazoles are effective in treating such infections.
Assuntos
Antifúngicos , Testes de Sensibilidade Microbiana , Micoses , Filogenia , Índia , Humanos , Antifúngicos/farmacologia , Adulto , Masculino , Micoses/microbiologia , Feminino , Pessoa de Meia-Idade , Ascomicetos/efeitos dos fármacos , Ascomicetos/genética , Ascomicetos/isolamento & purificação , Ascomicetos/classificação , DNA Fúngico/genética , Análise de Sequência de DNA , DNA Espaçador Ribossômico/genética , Microscopia Eletrônica de Varredura , Fenótipo , Tubulina (Proteína)/genética , Idoso , Adulto Jovem , CriançaRESUMO
The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal priority pathogens list (FPPL). This systematic review aimed to evaluate the epidemiology and impact of invasive fungal disease due to Mucorales. PubMed and Web of Science were searched to identify studies published between January 1, 2011 and February 23, 2021. Studies reporting on mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence during the study time frames were selected. Overall, 24 studies were included. Mortality rates of up to 80% were reported. Antifungal susceptibility varied across agents and species, with the minimum inhibitory concentrations lowest for amphotericin B and posaconazole. Diabetes mellitus was a common risk factor, detected in 65%-85% of patients with mucormycosis, particularly in those with rhino-orbital disease (86.9%). Break-through infection was detected in 13.6%-100% on azole or echinocandin antifungal prophylaxis. The reported prevalence rates were variable, with some studies reporting stable rates in the USA of 0.094-0.117/10 000 discharges between 2011 and 2014, whereas others reported an increase in Iran from 16.8% to 24% between 2011 and 2015. Carefully designed global surveillance studies, linking laboratory and clinical data, are required to develop clinical breakpoints to guide antifungal therapy and determine accurate estimates of complications and sequelae, annual incidence, trends, and global distribution. These data will provide robust estimates of disease burden to refine interventions and better inform future FPPL.
Assuntos
Antifúngicos , Mucorales , Mucormicose , Organização Mundial da Saúde , Humanos , Mucorales/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Mucormicose/epidemiologia , Mucormicose/microbiologia , Mucormicose/tratamento farmacológico , Mucormicose/mortalidade , Fatores de Risco , Infecções Fúngicas Invasivas/epidemiologia , Infecções Fúngicas Invasivas/microbiologia , Infecções Fúngicas Invasivas/prevenção & controle , Infecções Fúngicas Invasivas/tratamento farmacológico , Testes de Sensibilidade Microbiana , Prevalência , Farmacorresistência Fúngica , Incidência , Saúde Global/estatística & dados numéricosRESUMO
The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal priority pathogens list. This systematic review aimed to evaluate the epidemiology and impact of eumycetoma. PubMed and Web of Science were searched to identify studies published between 1 January 2011 and 19 February 2021. Studies reporting on mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence during the study time frames were selected. Overall, 14 studies were eligible for inclusion. Morbidity was frequent with moderate to severe impairment of quality of life in 60.3%, amputation in up to 38.5%, and recurrent or long-term disease in 31.8%-73.5% of patients. Potential risk factors included male gender (56.6%-79.6%), younger age (11-30 years; 64%), and farming occupation (62.1%-69.7%). Mycetoma was predominantly reported in Sudan, particularly in central Sudan (37%-76.6% of cases). An annual incidence of 0.1/100 000 persons and 0.32/100 000 persons/decade was reported in the Philippines and Uganda, respectively. In Uganda, a decline in incidence from 3.37 to 0.32/100 000 persons between two consecutive 10-year periods (2000-2009 and 2010-2019) was detected. A community-based, multi-pronged prevention programme was associated with a reduction in amputation rates from 62.8% to 11.9%. With the pre-specified criteria, no studies of antifungal drug susceptibility, mortality, and hospital lengths of stay were identified. Future research should include larger cohort studies, greater drug susceptibility testing, and global surveillance to develop evidence-based treatment guidelines and to determine more accurately the incidence and trends over time.
Assuntos
Antifúngicos , Micetoma , Organização Mundial da Saúde , Humanos , Micetoma/epidemiologia , Micetoma/microbiologia , Incidência , Antifúngicos/uso terapêutico , Fatores de Risco , Masculino , Feminino , Qualidade de VidaRESUMO
Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of invasive infections caused by Aspergillus fumigatus to inform the first FPPL. The pre-specified criteria of mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence were used to search for relevant articles between 1 January 2016 and 10 June 2021. Overall, 49 studies were eligible for inclusion. Azole antifungal susceptibility varied according to geographical regions. Voriconazole susceptibility rates of 22.2% were reported from the Netherlands, whereas in Brazil, Korea, India, China, and the UK, voriconazole susceptibility rates were 76%, 94.7%, 96.9%, 98.6%, and 99.7%, respectively. Cross-resistance was common with 85%, 92.8%, and 100% of voriconazole-resistant A. fumigatus isolates also resistant to itraconazole, posaconazole, and isavuconazole, respectively. The incidence of invasive aspergillosis (IA) in patients with acute leukemia was estimated at 5.84/100 patients. Six-week mortality rates in IA cases ranged from 31% to 36%. Azole resistance and hematological malignancy were poor prognostic factors. Twelve-week mortality rates were significantly higher in voriconazole-resistant than in voriconazole-susceptible IA cases (12/22 [54.5%] vs. 27/88 [30.7%]; P = .035), and hematology patients with IA had significantly higher mortality rates compared with solid-malignancy cases who had IA (65/217 [30%] vs. 14/78 [18%]; P = .04). Carefully designed surveillance studies linking laboratory and clinical data are required to better inform future FPPL.
Assuntos
Antifúngicos , Aspergilose , Aspergillus fumigatus , Farmacorresistência Fúngica , Organização Mundial da Saúde , Humanos , Aspergillus fumigatus/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Aspergilose/epidemiologia , Aspergilose/microbiologia , Aspergilose/mortalidade , Voriconazol/farmacologia , Voriconazol/uso terapêutico , Incidência , Testes de Sensibilidade Microbiana , Infecções Fúngicas Invasivas/epidemiologia , Infecções Fúngicas Invasivas/microbiologia , Infecções Fúngicas Invasivas/mortalidade , Infecções Fúngicas Invasivas/tratamento farmacológico , Fatores de RiscoRESUMO
Recognising the growing global burden of fungal infections, the World Health Organization (WHO) established an advisory group consisting of experts in fungal diseases to develop a Fungal Priority Pathogen List. Pathogens were ranked based on their research and development needs and perceived public health importance using a series of global surveys and pathogen characteristics derived from systematic reviews. This systematic review evaluates the features and global impact of invasive disease caused by Candida glabrata (Nakaseomyces glabrata). PubMed and Web of Science were searched for studies reporting on mortality, morbidity (hospitalization and disability), drug resistance (including isolates from sterile and non-sterile sites, since these reflect the same organisms causing invasive infections), preventability, yearly incidence, diagnostics, treatability, and distribution/emergence in the last 10 years. Candida glabrata (N. glabrata) causes difficult-to-treat invasive infections, particularly in patients with underlying conditions such as immunodeficiency, diabetes, or those who have received broad-spectrum antibiotics or chemotherapy. Beyond standard infection prevention and control measures, no specific preventative measures have been described. We found that infection is associated with high mortality rates and that there is a lack of data on complications and sequelae. Resistance to azoles is common and well described in echinocandins-in both cases, the resistance rates are increasing. Candida glabrata remains mostly susceptible to amphotericin and flucytosine. However, the incidence of the disease is increasing, both at the population level and as a proportion of all invasive yeast infections, and the increases appear related to the use of antifungal agents.
Assuntos
Antifúngicos , Candida glabrata , Farmacorresistência Fúngica , Organização Mundial da Saúde , Candida glabrata/efeitos dos fármacos , Candida glabrata/isolamento & purificação , Humanos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candidíase/epidemiologia , Candidíase/microbiologia , Candidíase/tratamento farmacológico , Saúde Global , IncidênciaRESUMO
The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal pathogen priority list. This systematic review aimed to evaluate the epidemiology and impact of infections caused by Talaromyces marneffei, Coccidioides species, and Paracoccidioides species. PubMed and Web of Sciences databases were searched to identify studies published between 1 January 2011 and 23 February 2021 reporting on mortality, complications and sequelae, antifungal susceptibility, preventability, annual incidence, and trends. Overall, 25, 17, and 6 articles were included for T. marneffei, Coccidioides spp. and Paracoccidioides spp., respectively. Mortality rates were high in those with invasive talaromycosis and paracoccidioidomycosis (up to 21% and 22.7%, respectively). Hospitalization was frequent in those with coccidioidomycosis (up to 84%), and while the duration was short (mean/median 3-7 days), readmission was common (38%). Reduced susceptibility to fluconazole and echinocandins was observed for T. marneffei and Coccidioides spp., whereas >88% of T. marneffei isolates had minimum inhibitory concentration values ≤0.015 µg/ml for itraconazole, posaconazole, and voriconazole. Risk factors for mortality in those with talaromycosis included low CD4 counts (odds ratio 2.90 when CD4 count <200 cells/µl compared with 24.26 when CD4 count <50 cells/µl). Outbreaks of coccidioidomycosis and paracoccidioidomycosis were associated with construction work (relative risk 4.4-210.6 and 5.7-times increase, respectively). In the United States of America, cases of coccidioidomycosis increased between 2014 and 2017 (from 8232 to 14 364/year). National and global surveillance as well as more detailed studies to better define sequelae, risk factors, outcomes, global distribution, and trends are required.
Assuntos
Antifúngicos , Coccidioides , Paracoccidioides , Talaromyces , Organização Mundial da Saúde , Talaromyces/isolamento & purificação , Talaromyces/classificação , Talaromyces/efeitos dos fármacos , Humanos , Paracoccidioides/isolamento & purificação , Paracoccidioides/efeitos dos fármacos , Paracoccidioides/classificação , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Coccidioides/isolamento & purificação , Coccidioides/classificação , Coccidioides/efeitos dos fármacos , Micoses/epidemiologia , Micoses/microbiologia , Micoses/mortalidade , Paracoccidioidomicose/epidemiologia , Paracoccidioidomicose/microbiologia , Paracoccidioidomicose/tratamento farmacológico , Coccidioidomicose/epidemiologia , Coccidioidomicose/microbiologia , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND: Over the past decades, the increasing incidence of recurrent dermatophytosis associated with terbinafine-resistant Trichophyton has posed a serious challenge in management of dermatophytosis. Independent reports of failure of treatment and high minimum inhibitory concentrations (MIC) of antifungals are available, but data correlating MIC and clinical outcomes is still sparse. Therefore, the present study was conducted to evaluate the outcomes of systemic treatment of dermatophytosis and its correlation with MIC of the etiological agents isolated from such patients. METHODS: Retrospective analysis of 587 consecutive patients with dermatophytosis was done from March 2017 to March 2019. Demographic and clinical details of the patients were noted, along with the results of direct microscopy and fungal culture. The isolates were identified by sequencing the internal transcribed spacer region of rDNA. Antifungal susceptibility testing was performed following the CLSI M38 protocol. Mutation in the squalene epoxidase (SE) gene was detected by DNA sequencing and ARMS-PCR. Based on the culture-positivity and prescribed systemic antifungal, patients were categorised into Group I culture-positive cases treated with systemic terbinafine and Group II culture-positive cases treated with systemic itraconazole, each for a total period of 12 weeks. RESULTS: In the present study, 477 (81.39%) were culture-positive; however, 12 weeks follow-up was available for 294 patients (Group I-157 and Group II-137) who were included for statistical analysis. In both groups [Group I-37/63 (51.4%) and Group II-14/54 (58.3%)], a better cure rate was observed if the initiation of therapy was performed within <6 months of illness. Treatment outcome revealed that if therapy was extended for 8-12 weeks, the odds of cure rate are significantly better (p < .001) with either itraconazole (Odd Ratio-15.5) or terbinafine (Odd Ratio-4.34). Higher MICs for terbinafine were noted in 41 cases (cured-18 and uncured-23) in Group I and 39 cases (cured-16 and uncured-23) in Group II. From cured (Group I-17/18; 94.4% and Group II-14/16; 87.5%) and uncured (Group I-20/23; 86.9% and Group II-21/23; 91.3%) cases had F397L mutation in the SE gene. No significant difference in cure rate was observed in patients with Trichophyton spp. having terbinafine MIC ≥ 1or <1 µg/mL (Group I-p = .712 and Group II-p = .69). CONCLUSION: This study revealed that prolonging terbinafine or itraconazole therapy for beyond 8 weeks rather than the standard 4 weeks significantly increases the cure rate. Moreover, no correlation has been observed between antifungal susceptibility and clinical outcomes. The MIC remains the primary parameter for defining antifungal activity and predicting the potency of antifungal agents against specific fungi. However, predicting therapeutic success based solely on the MIC of a fungal strain is not always reliable, as studies have shown a poor correlation between in vitro data and in vivo outcomes. To address this issue, further correlation of antifungal susceptibility testing (AFST) data with clinical outcomes and therapeutic drug monitoring is needed. It also highlights that initiation of the treatment within <6 months of illness increases cure rates and reduces recurrence. Extensive research is warranted to establish a better treatment regime for dermatophytosis.
Assuntos
Antifúngicos , Itraconazol , Mutação , Esqualeno Mono-Oxigenase , Terbinafina , Tinha , Trichophyton , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Antifúngicos/uso terapêutico , Antifúngicos/farmacologia , Farmacorresistência Fúngica/genética , Itraconazol/farmacologia , Itraconazol/uso terapêutico , Testes de Sensibilidade Microbiana , Estudos Retrospectivos , Esqualeno Mono-Oxigenase/genética , Terbinafina/uso terapêutico , Terbinafina/farmacologia , Tinha/tratamento farmacológico , Tinha/microbiologia , Resultado do Tratamento , Trichophyton/efeitos dos fármacos , Trichophyton/genéticaRESUMO
BACKGROUND: Sensitization to Aspergillus fumigatus (AS) has been recently described in chronic obstructive pulmonary disease (COPD) patients. However, there is no data on the community prevalence of AS in COPD. OBJECTIVES: To assess the prevalence of AS among COPD subjects. The secondary objectives were to (1) assess the prevalence of allergic bronchopulmonary aspergillosis (ABPA) in COPD and (2) compare the lung function in COPD subjects with and without AS. METHODS: We conducted a cross-sectional study in rural (29 villages) and urban (20 wards) communities in North India. We identified individuals with respiratory symptoms (IRS) through a house-to-house survey using a modified IUATLD questionnaire. We then diagnosed COPD through specialist assessment and spirometry using the GOLD criteria. We assayed A.fumigatus-specific IgE in COPD subjects. In those with A. fumigatus-specific IgE ≥0.35 kUA/L (AS), ABPA was diagnosed with raised serum total IgE and raised A.fumigatus-specific IgG or blood eosinophil count. RESULTS: We found 1315 (8.2%) IRS among 16,071 participants >40 years and diagnosed COPD in 355 (2.2%) subjects. 291 (82.0%) were men and 259 (73.0%) resided in rural areas. The prevalence of AS and ABPA was 17.7% (95% CI, 13.9-21.8) and 6.6% (95% CI, 4.4-8.8). We found a lower percentage predicted FEV1 in COPD subjects with AS than those without (p =.042). CONCLUSIONS: We found an 18% community prevalence of AS in COPD subjects in a specific area in North India. Studies from different geographical areas are required to confirm our findings. The impact of AS and ABPA on COPD requires further research.
Assuntos
Aspergilose Broncopulmonar Alérgica , Aspergillus fumigatus , Imunoglobulina E , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Índia/epidemiologia , Masculino , Estudos Transversais , Feminino , Aspergilose Broncopulmonar Alérgica/epidemiologia , Pessoa de Meia-Idade , Prevalência , Aspergillus fumigatus/imunologia , Idoso , Adulto , Imunoglobulina E/sangue , Anticorpos Antifúngicos/sangue , População Rural/estatística & dados numéricos , População Urbana/estatística & dados numéricosRESUMO
BACKGROUND: Aspergillus fumigatus-specific IgG estimation is crucial for diagnosing allergic bronchopulmonary aspergillosis (ABPA). A point-of-care LDBio immunochromatographic lateral flow assay (LFA) had 0%-90% sensitivity to detect IgG/IgM antibodies against A. fumigatus. OBJECTIVE: To assess the accuracy of LDBio-LFA in diagnosing ABPA, using the modified ISHAM-ABPA working group criteria as the reference standard. The secondary objective was to compare the diagnostic performance between LDBio-LFA and A. fumigatus-specific IgG (cut-offs, 27 and 40 mgA/L), using a multidisciplinary team (blinded to A. fumigatus-IgG and LDBio-LFA results) diagnosis of ABPA as the reference standard. METHODS: We prospectively enrolled adult subjects with asthma and ABPA. We performed the LDBio-LFA per the manufacturer's recommendations. We used the commercially available automated fluorescent enzyme immunoassay for measuring serum A. fumigatus-specific IgG. We used the same serum sample to perform both index tests. The tests were performed by technicians blinded to the results of other tests and clinical diagnoses. RESULTS: We included 123 asthmatic and 166 ABPA subjects, with a mean ± SD age of 37.4 ± 14.4 years. Bronchiectasis and high-attenuation mucus were seen in 93.6% (146/156) and 24.3% (38/156) of the ABPA subjects. The sensitivity and specificity of LDBio-LFA in diagnosing ABPA were 84.9% and 82.9%, respectively. The sensitivity of serum A. fumigatus-specific IgG ≥27 mgA/L was 13% better than LDBio-LFA, with no difference in specificity. There was no significant difference in sensitivity and specificity between LDBio-LFA and serum A. fumigatus-IgG ≥40 mgA/L. CONCLUSION: LDBio-LFA is a valuable test for diagnosing ABPA. However, a negative test should be confirmed using an enzyme immunoassay.
Assuntos
Aspergilose Broncopulmonar Alérgica , Asma , Adulto , Humanos , Adulto Jovem , Pessoa de Meia-Idade , Aspergillus fumigatus , Imunoglobulina E , Anticorpos Antifúngicos , Aspergillus , Asma/complicações , Asma/diagnóstico , Imunoglobulina GRESUMO
BACKGROUND AND OBJECTIVES: The mechanisms underlying COVID-19-associated pulmonary mucormycosis (CAPM) remain unclear. We use a transcriptomic analysis of the innate immune cells to investigate the host immune and metabolic response pathways in patients with CAPM. PATIENTS AND METHODS: We enrolled subjects with CAPM (n = 5), pulmonary mucormycosis (PM) without COVID-19 (n = 5), COVID-19 (without mucormycosis, n = 5), healthy controls (n = 5) without comorbid illness and negative for SARS-CoV-2. Peripheral blood samples from cases were collected before initiating antifungal therapy, and neutrophils and monocytes were isolated. RNA sequencing was performed using Illumina HiSeqX from monocytes and neutrophils. Raw reads were aligned with HISAT-2 pipeline and DESeq2 was used for differential gene expression. Gene ontology (GO) and metabolic pathway analysis were performed using Shiny GO application and R packages (ggplot2, Pathview). RESULTS: The derangement of core immune and metabolic responses in CAPM patients was noted. Pattern recognition receptors, dectin-2, MCL, FcRγ receptors and CLEC-2, were upregulated, but signalling pathways such as JAK-STAT, IL-17 and CARD-9 were downregulated; mTOR and MAP-kinase signalling were elevated in monocytes from CAPM patients. The complement receptors, NETosis, and pro-inflammatory responses, such as S100A8/A9, lipocalin and MMP9, were elevated. The major metabolic pathways of glucose metabolism-glycolysis/gluconeogenesis, pentose phosphate pathway, HIF signalling and iron metabolism-ferroptosis were also upregulated in CAPM. CONCLUSIONS: We identified significant alterations in the metabolic pathways possibly leading to cellular iron overload and a hyperglycaemic state. Immune responses revealed altered recognition, signalling, effector functions and a pro-inflammatory state in monocytes and neutrophils from CAPM patients.
Assuntos
COVID-19 , Mucormicose , Humanos , Mucormicose/microbiologia , SARS-CoV-2 , Perfilação da Expressão Gênica , Imunidade InataRESUMO
BACKGROUND: Post-tuberculosis lung abnormality (PTLA) is the most common risk factor for chronic pulmonary aspergillosis (CPA), and 14%-25% of the subjects with PTLA develop CPA. The pathogenesis and the host immune response in subjects with PTLA who develop CPA need to be better understood. METHODS: We prospectively compared the innate and adaptive immune responses mounted by patients of PTLA with or without CPA (controls). We studied the neutrophil oxidative burst (by dihydrorhodamine 123 test), classic (serum C3 and C4 levels) and alternative (mannose-binding lectin [MBL] protein levels) complement pathway, serum immunoglobulins (IgG, IgM and IgA), B and T lymphocytes and their subsets in subjects with PTLA with or without CPA. RESULTS: We included 111 subjects (58 CPA and 53 controls) in the current study. The mean ± SD age of the study population was 42.6 ± 15.7 years. The cases and controls were matched for age, gender distribution and body weight. Subjects with CPA had impaired neutrophil oxidative burst, lower memory T lymphocytes and impaired Th-1 immune response (lower Th-1 lymphocytes) than controls. We found no significant difference between the two groups in the serum complement levels, MBL levels, B-cell subsets and other T lymphocyte subsets. CONCLUSION: Subjects with CPA secondary to PTLA have impaired neutrophil oxidative burst and a lower Th-1 response than controls.
Assuntos
Imunidade Adaptativa , Imunidade Inata , Aspergilose Pulmonar , Tuberculose Pulmonar , Humanos , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/complicações , Estudos Prospectivos , Aspergilose Pulmonar/imunologia , Aspergilose Pulmonar/complicações , Neutrófilos/imunologia , Pulmão/imunologia , Explosão Respiratória , Adulto JovemRESUMO
BACKGROUND: Post-tuberculosis lung abnormality (PTLA) is the most common risk factor for developing chronic pulmonary aspergillosis (CPA). However, the prevalence and incidence of CPA in PTLA patients in India remain unknown. OBJECTIVES: We aimed to ascertain the incidence and prevalence of CPA in subjects with PTLA. METHODS: We identified a cohort of pulmonary tuberculosis who completed anti-tuberculosis therapy (ATT) before November 2019 from the records of the 12 tuberculosis treatment centers attached to the national program. We recorded the clinical and demographic details. We performed computed tomography (CT) of the chest and estimated serum A. fumigatus-specific IgG. We categorised subjects as PTLA with or without CPA using a composite of clinical, radiological, and microbiological features. We resurveyed the subjects at 6 months (or earlier) for the presence of new symptoms. We calculated the prevalence and the incidence rate (per 100-person years) of CPA. RESULTS: We included 117 subjects with PTLA, with a median of 3 years after ATT completion. Eleven subjects had CPA in the initial survey, and one additional case developed CPA during the second survey. The prevalence of CPA in PTLA subjects was 10.3% (12/117). The total observation period was 286.7 person-years. The median (interquartile range) time to develop CPA after ATT completion was 12.5 (5-36.7) months. We found the CPA incidence rate (95% confidence interval) of 4.2 (1.8-6.5) per 100-person years. CONCLUSION: Chronic pulmonary aspergillosis complicates 10% of PTLA subjects after successful outcomes with ATT. Four new CPA cases may develop per 100-persons years of observation after ATT completion. We suggest screening patients with PTLA who develop new symptoms for CPA.
Assuntos
Pneumopatias , Aspergilose Pulmonar , Tuberculose Pulmonar , Humanos , Incidência , Prevalência , Aspergilose Pulmonar/complicações , Aspergilose Pulmonar/epidemiologia , Aspergilose Pulmonar/diagnóstico , Pneumopatias/complicações , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/epidemiologia , Pulmão/diagnóstico por imagem , Pulmão/microbiologia , Inquéritos e Questionários , Doença CrônicaRESUMO
BACKGROUND: Due to a delay in diagnosis by conventional techniques and high mortality, the development of a standardised and rapid non-culture-based technique is an unmet need in pulmonary, gastrointestinal, and disseminated forms of mucormycosis. Though limited studies have been conducted for molecular diagnosis, there are no established serologic tests for this highly fatal infection. OBJECTIVE: To develop and evaluate an indirect in-house enzyme-linked immunosorbent assay (ELISA) utilising antigens of Rhizopus arrhizus for detecting anti-Rhizopus antibodies (IgG and IgM) in sera of patients with mucormycosis. METHODS: We extracted both secretory and mycelial Rhizopus antigens using standardised protocols. Bradford assay was used for protein quantification. We then standardised an indirect ELISA using R. arrhizus mycelial and secretory antigens (10.0 µg/mL in bicarbonate buffer pH 9.2) for detecting anti-Rhizopus IgG and IgM antibodies in patient sera. We included patients with mucormycosis, other fungal infections, and healthy controls. Antibody index value (E-value) was calculated for each patient sample. RESULTS: Asparagine broth culture filtrate utilising 85% ammonium sulphate salt fractionation and mycelial homogenate grown in yeast extract peptone dextrose (YPD) broth precipitated with trichloroacetic acid (TCA) yielded a large amount of good-quality protein for the assay. We included 55 patients with mucormycosis (rhino-orbito-cerebral mucormycosis [ROCM, n = 39], pulmonary [n = 15], gastrointestinal [n = 1]), 24 with other fungal infections (probable aspergillosis [n = 14], candidiasis [n = 10]), and healthy controls (n = 16). The sensitivity of the antibody test for diagnosing mucormycosis ranged from 83.6-92.7% for IgG and 72.7-87.3% for IgM, with a specificity of 91.7-92.5% for IgG and 80-82.5% for IgM. The sera from patients with other fungal infections and healthy individuals did not show significant cross-reactivity. CONCLUSION: The detection of anti-Rhizopus IgG antibody performed significantly better in comparison to IgM-based ELISA for diagnosing both ROCM (sensitivity of 84.6% vs. 69.2%) and pulmonary cases (86.6% vs. 80.0%). More extensive studies are required to confirm our findings.
Assuntos
Anticorpos Antifúngicos , Antígenos de Fungos , Ensaio de Imunoadsorção Enzimática , Imunoglobulina G , Imunoglobulina M , Mucormicose , Rhizopus , Sensibilidade e Especificidade , Testes Sorológicos , Mucormicose/diagnóstico , Mucormicose/microbiologia , Mucormicose/imunologia , Humanos , Rhizopus/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Antígenos de Fungos/imunologia , Antígenos de Fungos/análise , Testes Sorológicos/métodos , Anticorpos Antifúngicos/sangue , Imunoglobulina M/sangue , Imunoglobulina G/sangue , Feminino , Masculino , Pessoa de Meia-IdadeRESUMO
Innate and adaptive immunity play a crucial role in allergic bronchopulmonary aspergillosis (ABPA) pathogenesis. We performed next-generation sequencing using the Illumina TruSight One panel (4,811 human disease-associated genes, at least 20 × coverage) and selected 22 known immune genes (toll-like receptors (TLRs), C-type lectin, interleukin-4 receptor, and others). We included ABPA (n = 18), asthma without ABPA (n = 12), and healthy controls (n = 8). We analyzed 3011 SNPs from 22 genes and identified 145 SNPs (13 genes) that were present only in the disease groups and absent in controls. The SNP frequency overall was significantly higher in ABPA than in asthmatics (89/145 [61.4%] vs. 56/145 [38.6%], p = 0.0001). The SNP frequency in the TLR10 gene was also significantly higher in ABPA than in asthma (p = 0.017). Association analysis further revealed three genes having significant associations. Of these, NOS3 and HLA-DQB1 are associated with antimicrobial activity and adaptive immunity. More extensive studies are required to confirm our findings.
Assuntos
Aspergilose Broncopulmonar Alérgica , Asma , Humanos , Aspergilose Broncopulmonar Alérgica/complicações , Aspergilose Broncopulmonar Alérgica/genética , Polimorfismo de Nucleotídeo Único , Asma/complicações , Asma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Lectinas Tipo CRESUMO
We retrospectively reviewed consecutive cases of mucormycosis reported from a tertiary-care center in India to determine the clinical and mycologic characteristics of emerging Rhizopus homothallicus fungus. The objectives were ascertaining the proportion of R. homothallicus infection and the 30-day mortality rate in rhino-orbital mucormycosis attributable to R. homothallicus compared with R. arrhizus. R. homothallicus accounted for 43 (6.8%) of the 631 cases of mucormycosis. R. homothallicus infection was independently associated with better survival (odds ratio [OR] 0.08 [95% CI 0.02-0.36]; p = 0.001) than for R. arrhizus infection (4/41 [9.8%] vs. 104/266 [39.1%]) after adjusting for age, intracranial involvement, and surgery. We also performed antifungal-susceptibility testing, which indicated a low range of MICs for R. homothallicus against the commonly used antifungals (amphotericin B [0.03-16], itraconazole [0.03-16], posaconazole [0.03-8], and isavuconazole [0.03-16]). 18S gene sequencing and amplified length polymorphism analysis revealed distinct clustering of R. homothallicus.
Assuntos
Mucorales , Mucormicose , Humanos , Mucormicose/diagnóstico , Mucormicose/tratamento farmacológico , Mucormicose/microbiologia , Mucorales/genética , Estudos Retrospectivos , Rhizopus/genética , Antifúngicos/farmacologia , Antifúngicos/uso terapêuticoRESUMO
BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is complicated by exacerbations in more than one-third of the subjects. Whether nebulized amphotericin B (NAB) therapy prevents ABPA exacerbations remains unclear. OBJECTIVES: The primary objective of this systematic review and meta-analysis was to determine the frequency of subjects remaining exacerbation-free, one year after initiating NAB. The key secondary objectives were the time to first exacerbation and the safety of NAB therapy. METHODS: We searched the PubMed and Embase databases for studies evaluating ≥5 subjects of ABPA managed with NAB. We report the pooled proportion of ABPA subjects remaining exacerbation free after one year. For the randomized controlled trials (RCTs), we estimate the pooled risk difference (RD) of exacerbation-free status at one year with NAB versus the control arm. RESULTS: We included five studies for our analysis; three were observational (n = 28) and two RCTs (n = 160). The pooled proportion (95% confidence interval [CI]) of subjects remaining exacerbation free with NAB at one year was 76% (62-88). The pooled RD (95% CI) of an exacerbation-free status at one year was 0.33 (-0.12 to 0.78) and was not significantly different between the NAB and control arms. The time to first exacerbation was longer with NAB than with the standard therapy. No serious adverse events were reported with NAB. CONCLUSION: NAB does not improve exacerbation-free status at one year; however, weak evidence suggests it delays ABPA exacerbations. More research using different dosing regimens is required.
Assuntos
Anfotericina B , Aspergilose Broncopulmonar Alérgica , Humanos , Anfotericina B/efeitos adversos , Antifúngicos/efeitos adversos , Aspergilose Broncopulmonar Alérgica/tratamento farmacológico , Aspergilose Broncopulmonar Alérgica/induzido quimicamente , Bases de Dados Factuais , Estudos Observacionais como AssuntoRESUMO
The estimates of the minimal important difference (MID) for the Saint George's respiratory questionnaire (SGRQ) score in CPA remain unknown. We performed a retrospective analysis on treatment-naïve CPA subjects (n = 148) treated with six-month oral itraconazole therapy and completed SGRQ at baseline and six months. The study's objective was to estimate the MID for SGRQ. We used an anchor-based method to determine the MID and found the MID for SGRQ of 7.3.
The estimates of the minimal important difference (MID) for the Saint George's respiratory questionnaire (SGRQ) score in CPA remain unknown. Using an anchor-based method, we found theMID for SGRQ of 7 in CPA.
RESUMO
BACKGROUND: Whether chronic pulmonary aspergillosis (CPA) has different immunophenotypes remains unknown. OBJECTIVE: To identify different CPA immunophenotypes using cluster analysis. METHODS: We used a subject-centred multivariate clustering approach without prior assumptions to identify CPA phenotypes. We retrospectively included the data of treatment-naïve subjects with CPA and excluded subjects with asthma and allergic bronchopulmonary aspergillosis (ABPA). We performed a scalable two-step cluster analysis using the log-likelihood distance measures to identify CPA phenotypes based on the blood immunological profile (total IgE, eosinophil count and Aspergillus-specific IgE and IgG). RESULTS: We included 351 CPA subjects and found two clusters. Cluster 2 (n = 118) had significantly higher serum total IgE, peripheral blood eosinophil count, and serum A. fumigatus-specific IgE and IgG than cluster 1 (n = 233). Cluster 2 subjects had a lower FEV1:FVC ratio on spirometry and were more likely to have a fungal ball (88 [74.6%] vs. 145 (62.2%), p = .023) on the CT thorax than cluster 1. After treatment discontinuation, cluster 2 had a longer median (interquartile range) time to relapse than cluster 1 (11.5 [7.3-27.4] vs. 4 [1.1-8.9] months, p = .005). CONCLUSION: We identified two distinct CPA phenotypes, type-2 dominant and non-type-2, with different clinical and radiological findings and treatment outcomes. Future studies should confirm our findings and investigate different treatment strategies based on CPA phenotypes.