Aspergillus and cystic fibrosis

Felton, Imogen; Simmonds, Nicholas J.

doi:10.1097/mcp.0000000000000106

Cited by 19 publications

(16 citation statements)

References 62 publications

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“…CF is the most common autosomal recessive disease in Caucasians (Felton and Simmonds, 2014). Mutations in the CFTR (cystic fibrosis transmembrane regulator gene) affects the chloride transportation causing dysregulated fluid transport in the epithelial cells of multiple organs (Felton and Simmonds, 2014). Clinically, CF disease is dominated by infectious pulmonary complications (Felton and Simmonds, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in the CFTR (cystic fibrosis transmembrane regulator gene) affects the chloride transportation causing dysregulated fluid transport in the epithelial cells of multiple organs (Felton and Simmonds, 2014). Clinically, CF disease is dominated by infectious pulmonary complications (Felton and Simmonds, 2014). The respiratory tract is often colonized with molds especially A. fumigatus, which is found in 16 to 56.7% of airway samples (Pihet et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…The respiratory tract is often colonized with molds especially A. fumigatus, which is found in 16 to 56.7% of airway samples (Pihet et al, 2009). Aspergillus may cause a diversity of manifestations ranging from asymptomatic colonization to serological sensitization, allergic bronchopulmonary aspergillosis (ABPA), Aspergillus bronchitis, and aspergilloma in CF patients (Felton and Simmonds, 2014). The most common is ABPA (Pihet et al, 2009), which occurs in approximately 10% of CF patients (Burgel et al, 2016;Carsin et al, 2017) and is the cause of hypersensitivity response to Aspergillus antigens (Williams et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Azole-Resistant Aspergillus fumigatus Among Danish Cystic Fibrosis Patients: Increasing Prevalence and Dominance of TR34/L98H

et al. 2020

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Azole-resistant (azole-R) Aspergillus is an increasing challenge worldwide. Patients with cystic fibrosis (CF) are at risk of Aspergillus colonization and disease due to a favorable lung environment for microorganisms. We performed a nationwide study in 2018 of azole-non-susceptible Aspergillus in CF patients and compared with data from two prior studies. All airway samples with mold isolates from patients monitored at the two CF centers in Denmark (RH, Jan-Sept and AUH, Jan-Jun) were included. Classical species identification (morphology and thermo-tolerance) was performed and MALDI-TOF/β-tubulin sequencing was performed if needed. Susceptibility was determined using EUCAST E.Def 10.1, and E.Def 9.3.2. cyp51A sequencing and STRAf genotyping were performed for azole-non-susceptible isolates and relevant sequential isolates. In total, 340 mold isolates from 159 CF patients were obtained. The most frequent species were Aspergillus fumigatus (266/340, 78.2%) and Aspergillus terreus (26/340, 7.6%). Azole-R A. fumigatus was cultured from 7.3% (10/137) of patients, including 9.5% (9/95) of patients at RH and 2.4% at AUH (1/42), respectively. In a 10-year perspective, azole-non-susceptibility increased numerically among patients at RH (10.5% in 2018 vs 4.5% in 2007-2009). Cyp51A resistance mechanisms were found in nine azole-R A. fumigatus from eight CF patients. Five were of environmental origin (TR 34 /L98H), three were human medicine-driven (two M220K and one M220R), and one was novel (TR 34 3 /L98H) and found in a patient who also harbored a TR 34 /L98H isolate. STRAf genotyping identified 27 unique genotypes among 45 isolates and ≥2 genotypes in 8 of 12 patients. This included one patient carrying two unique TR 34 /L98H isolates, a rare phenomenon. Genotyping of sequential TR 34 3 /L98H and TR 34 /L98H isolates from the same patient showed only minor differences in 1/9 markers. Finally, azole-R A. terreus

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Azole-Resistant Aspergillus fumigatus Among Danish Cystic Fibrosis Patients: Increasing Prevalence and Dominance of TR34/L98H

et al. 2020

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“…CF patients typically develop an extreme form of asthma, named allergic bronchopulmonary aspergillosis (ABPA), characterized by an exaggerated hypersensitivity reaction and associated with progressive lung function decline. More severe manifestations of Aspergillus -related diseases, such as IA, are rare in CF patients (3). In contrast, severe IA occur in severely immunocompromised patients such as those diagnosed with acute leukemia and chronic lymphoproliferative disorders, or recipients of allogeneic hematopoietic stem cell and solid-organ transplants (4).…”

Section: Introductionmentioning

confidence: 99%

Genetic Polymorphisms Affecting IDO1 or IDO2 Activity Differently Associate With Aspergillosis in Humans

et al. 2019

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Aspergillus is the causative agent of human diseases ranging from asthma to invasive infection. Genetic and environmental factors are crucial in regulating the interaction between the host and Aspergillus . The role played by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the first and rate-limiting step of tryptophan catabolism along the kynurenine pathway, is increasingly being recognized, but whether and how genetic variation of IDO1 influences the risk of aspergillosis in susceptible patients is incompletely understood. In addition, whether the closely related protein IDO2 plays a similar role remains unexplored. In the present study, we performed genetic association studies in two different cohorts of susceptible patients [cystic fibrosis (CF) patients and recipients of hematopoietic stem cell transplantation (HSCT)], and identified IDO1 polymorphisms that associate with the risk of infection in both cohorts. By using human bronchial epithelial cells and PBMC from CF and HSCT patients, respectively, we could show that the IDO1 polymorphisms appeared to down-modulate IDO1 expression and function in response to IFNγ or Aspergillus conidia, and to associate with an increased inflammatory response. In contrast, IDO2 polymorphisms, including variants known to profoundly affect protein expression and function, were differently associated with the risk of aspergillosis in the two cohorts of patients as no association was found in CF patients as opposed to recipients of HSCT. By resorting to a murine model of bone marrow transplantation, we could show that the absence of IDO2 more severely affected fungal burden and lung pathology upon infection with Aspergillus as compared to IDO1, and this effect appeared to be linked to a deficit in the antifungal effector phagocytic activity. Thus, our study confirms and extends the role of IDO1 in the response to Aspergillus , and shed light on the possible involvement of IDO2 in specific clinical settings.

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“…6 7 In CF, Aspergillus prevalence has increased recently, particularly involving Aspergillus fumigatus in the adolescent and adult age groups. [8][9][10] Allergic bronchopulmonary aspergillosis 11 and Aspergillus sensitisation 12 are the most common clinical disorders associated with finding Aspergillus in CF patients and can be accompanied by deteriorating lung function. Aspergillus in children is also linked with an increased risk of pulmonary exacerbations requiring hospitalisation.…”

Section: Introductionmentioning

confidence: 99%

Pseudomonas aeruginosaeradication therapy and risk of acquiringAspergillusin young children with cystic fibrosis

Harun

Holford

Grimwood

et al. 2019

Thorax

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BackgroundWhile Aspergillus detection rates in adults, adolescents and older children with cystic fibrosis (CF) have increased, the risk of acquiring this fungal pathogen in young children is unknown.AimTo determine the risk and explanatory factors of acquiring Aspergillus in children with CF by age 5 years.MethodsCross-sectional analysis of clinical, bronchoalveolar lavage and treatment data from the Australasian Cystic Fibrosis Bronchoalveolar Lavage study was used to identify predictive factors for detecting Aspergillus at age 5 years. A parametric repeated time-to-event model quantitatively described the risk and factors associated with acquiring Aspergillus and Pseudomonas aeruginosa from birth until age 5 years.ResultsCross-sectional analysis found that the number of P. aeruginosa eradication courses increased the odds of detecting Aspergillus at age 5 years (OR 1.61, 95% CI 1.23 to 2.12). The median (IQR) age for the first P. aeruginosa positive culture was 2.38 (1.32–3.79) years and 3.69 (1.68–4.74) years for the first Aspergillus positive culture. The risk of P. aeruginosa and Aspergillus events changes with time after the first year of study entry. It also decreases for P. aeruginosa after completing P. aeruginosa eradication (HR 0.15, 95% CI 0.00 to 0.79), but increases for Aspergillus events (HR 2.75, 95% CI 1.45 to 5.41). The risk of acquiring both types of events increases after having had a previous event.ConclusionIn young children with CF, completing P. aeruginosa eradication therapy and previous Aspergillus events are associated with increased risk of acquiring Aspergillus.

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Aspergillus and cystic fibrosis

Cited by 19 publications

References 62 publications

Azole-Resistant Aspergillus fumigatus Among Danish Cystic Fibrosis Patients: Increasing Prevalence and Dominance of TR34/L98H

Azole-Resistant Aspergillus fumigatus Among Danish Cystic Fibrosis Patients: Increasing Prevalence and Dominance of TR34/L98H

Genetic Polymorphisms Affecting IDO1 or IDO2 Activity Differently Associate With Aspergillosis in Humans

Pseudomonas aeruginosaeradication therapy and risk of acquiringAspergillusin young children with cystic fibrosis

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