Optimization of antimicrobials in the treatment of cystic fibrosis pulmonary exacerbations:  II. Therapies for allergic bronchopulmonary aspergillosis

Epps, Quovadis J; Epps, Kevin; Zobell, Jeffery T.; Young, David C.

doi:10.1002/ppul.25080

Cited by 8 publications

(15 citation statements)

References 59 publications

(82 reference statements)

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“…CF, cystic fibrosis. fungus A. fumigatus destroys lung function if left untreated (8,24). In some patients the Spl-directed IgE response was very strong, and we propose that this could be an unrecognized cause of allergic lung exacerbation in CF patients harboring S. aureus in their airways.…”

Section: Discussionmentioning

confidence: 84%

“…Prevention and therapy of chronic bacterial and fungal inflammation are therefore key in the treatment regimen of CF (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, recurrent pulmonary exacerbations gradually worsen the lung function and clinical condition of CF patients ( 6 ). Prevention and therapy of chronic bacterial and fungal inflammation are therefore key in the treatment regimen of CF ( 6 – 8 ).…”

Section: Introductionmentioning

confidence: 99%

“…Besides infections, allergic immune responses play a crucial role in disease progression of CF. These are frequently associated with sensitization to A. fumigatus with 1-15% of patients suffering from allergic bronchopulmonary aspergillosis (ABPA), accelerating the decline of respiratory function ( 8 , 9 ).…”

Section: Introductionmentioning

confidence: 99%

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Allergic Reactions to Serine Protease-Like Proteins of Staphylococcus aureus

et al. 2021

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In cystic fibrosis (CF) infectious and allergic airway inflammation cause pulmonary exacerbations that destroy the lungs. Staphylococcus aureus is a common long-term colonizer and cause of recurrent airway infections in CF. The pathogen is also associated with respiratory allergy; especially the staphylococcal serine protease-like proteins (Spls) can induce type 2 immune responses in humans and mice. We measured the serum IgE levels specific to 7 proteases of S. aureus by ELISA, targeting 5 Spls (76 CF patients and 46 controls) and the staphopains A and B (16 CF patients and 46 controls). Then we compared cytokine release and phenotype of T cells that had been stimulated with Spls between 5 CF patients and 5 controls. CF patients had strongly increased serum IgE binding to all Spls but not to the staphopains. Compared to healthy controls, their Spl-stimulated T cells released more type 2 cytokines (IL-4, IL-5, IL-13) and more IL-6 with no difference in the secretion of type 1- or type 3 cytokines (IFNγ, IL-17A, IL-17F). IL-10 production was low in CF T cells. The phenotype of the Spl-exposed T cells shifted towards a Th2 or Th17 profile in CF but to a Th1 profile in controls. Sensitization to S. aureus Spls is common in CF. This discovery could explain episodes of allergic inflammation of hitherto unknown causation in CF and extend the diagnostic and therapeutic portfolio.

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Section: Discussionmentioning

confidence: 84%

“…Prevention and therapy of chronic bacterial and fungal inflammation are therefore key in the treatment regimen of CF (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Allergic Reactions to Serine Protease-Like Proteins of Staphylococcus aureus

et al. 2021

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“…Although recent studies have observed positive effects with voriconazole therapy in ABPA patients, in CF patients antifungal treatment varies widely across patients and centers (94). Drug interactions often preclude prolonged use of both azoles and CF medications, and the indeterminate clinical importance of treatment of A. fumigatus in CF further complicates treatment decisions (95).…”

Section: Discussionmentioning

confidence: 99%

Aspergillus fumigatusIn-Host HOG pathway mutation for Cystic Fibrosis Lung Microenvironment Persistence

Ross

Lofgren

Ashare

et al. 2021

Preprint

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The prevalence of Aspergillus fumigatus colonization in individuals with Cystic Fibrosis (CF) and subsequent fungal persistence in the lung is increasingly recognized. However, there is no consensus for clinical management of A. fumigatus in CF individuals, due largely to uncertainty surrounding A. fumigatus CF pathogenesis and virulence mechanisms. To address this gap in knowledge, a longitudinal series of A. fumigatus isolates from an individual with CF were collected over 4.5 years. Isolate genotypes were defined with whole genome sequencing that revealed both transitory and persistent A. fumigatus in the lung. Persistent lineage isolates grew most readily in a low oxygen culture environment and conidia were more sensitive to oxidative stress inducing conditions compared to non-persistent isolates. Closely related persistent isolates harbor a unique allele of the high osmolarity glycerol (HOG) pathway mitogen activated protein kinase kinase, Pbs2 (pbs2C2). Data suggest this novel pbs2C2allele arose in vivo and is necessary for the fungal response to osmotic stress in a low oxygen environment through hyperactivation of the HOG (SakA) signaling pathway. Hyperactivation of the HOG pathway through pbs2C2 comes at the cost of decreased conidia stress resistance in the presence of atmospheric oxygen levels. These novel findings shed light on pathoadaptive mechanisms of A. fumigatus in CF, lay the foundation for identifying persistent A. fumigatus isolates that may require antifungal therapy, and highlight considerations for successful culture of persistent fungal CF isolates.

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State of the art in cystic fibrosis pharmacology optimization of antimicrobials in the treatment of cystic fibrosis pulmonary exacerbations: III. Executive summary

Epps

Young

et al. 2021

Pediatric Pulmonology

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Acute pulmonary exacerbations are complications of cystic fibrosis (CF) and are associated with increased morbidity and mortality. Methicillin‐resistant Staphylococcus aureus (MRSA) and Aspergillus fumigatus are organisms that have been detected in the lungs of CF patients. The focus of this review is to provide an overview of the classes of antimicrobials used for MRSA and allergic bronchopulmonary aspergillosis (ABPA), a hypersensitivity reaction caused by A. fumigatus. The current anti‐MRSA antibiotics and medications for ABPA dosing recommendations are discussed. This article also reviews the findings from the MRSA utilization surveys and the pharmacokinetic and pharmacodynamic differences between CF and non‐CF patients. Antimethicillin S. aureus antibiotics include ceftaroline, clindamycin, fluoroquinolone derivatives (ciprofloxacin, levofloxacin), glycopeptide derivatives (telavancin, vancomycin), linezolid, rifampin, sulfamethoxazole/trimethoprim, and tetracycline derivatives (doxycycline, minocycline, tigecycline). Medications used for ABPA include corticosteroids, amphotericin B, azole antifungals (isavuconazole, itraconazole, posaconazole, voriconazole), and a monoclonal antibody, omalizumab.

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Optimization of antimicrobials in the treatment of cystic fibrosis pulmonary exacerbations:  II. Therapies for allergic bronchopulmonary aspergillosis

Cited by 8 publications

References 59 publications

Allergic Reactions to Serine Protease-Like Proteins of Staphylococcus aureus

Allergic Reactions to Serine Protease-Like Proteins of Staphylococcus aureus

Aspergillus fumigatusIn-Host HOG pathway mutation for Cystic Fibrosis Lung Microenvironment Persistence

State of the art in cystic fibrosis pharmacology optimization of antimicrobials in the treatment of cystic fibrosis pulmonary exacerbations: III. Executive summary

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Optimization of antimicrobials in the treatment of cystic fibrosis pulmonary exacerbations: II. Therapies for allergic bronchopulmonary aspergillosis

Cited by 8 publications

References 59 publications

Allergic Reactions to Serine Protease-Like Proteins of Staphylococcus aureus

Allergic Reactions to Serine Protease-Like Proteins of Staphylococcus aureus

Aspergillus fumigatusIn-Host HOG pathway mutation for Cystic Fibrosis Lung Microenvironment Persistence

State of the art in cystic fibrosis pharmacology optimization of antimicrobials in the treatment of cystic fibrosis pulmonary exacerbations: III. Executive summary

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Optimization of antimicrobials in the treatment of cystic fibrosis pulmonary exacerbations:  II. Therapies for allergic bronchopulmonary aspergillosis