Allergic Bronchopulmonary Aspergillosis in Children with Cystic Fibrosis: An Update on the Newest Diagnostic Tools and Therapeutic Approaches

Cystic fibrosis (CF), the most common autosomal-recessive genetic disease in the Caucasian population, is characterized by frequent respiratory infections and progressive lung disease. Fungal species are commonly found in patients with CF, and among them, Aspergillus fumigatus is the most frequently isolated. While bacteria, particularly Pseudomonas aeruginosa, have a well-established negative effect on CF lung disease, the impact of fungal infections remains unclear. In patients with CF, inhalation of Aspergillus conidia can cause allergic bronchopulmonary aspergillosis (ABPA), a Th2-mediated lung disease that can contribute to disease progression. Clinical features, diagnostic criteria and treatment of ABPA are still a matter of debate. Given the consequences of a late ABPA diagnosis or the risk of ABPA overdiagnosis, it is imperative that the diagnostic criteria guidelines are reviewed and standardized. Along with traditional criteria, radiological features are emerging as tools for further classification as well as novel immunological tests. Corticosteroids, itraconazole and voriconazole continue to be the bedrock of ABPA therapy, but other molecules, such as posaconazole, vitamin D, recombinant INF-γ and Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators, have been showing positive results. However, few studies have been conducted recruiting CF patients, and more research is needed to improve the prevention and the classification of clinical manifestations as well as to personalize treatment. Early recognition and early treatment of fungal infections may be fundamental to prevent progression of CF disease. The aim of this narrative review is to give an update on ABPA in children with CF.

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A Prospective Real-World Study of the Impact of an Antifungal Stewardship Program in a Tertiary Respiratory-Medicine Setting

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00402-18 ◽

2018 ◽

Vol 62 (10) ◽

Cited By ~ 4

Author(s):

Lisa Nwankwo ◽

Jimstan Periselneris ◽

Jamie Cheong ◽

Keith Thompson ◽

Peter Darby ◽

...

Keyword(s):

Lung Disease ◽

Fungal Infections ◽

Health Care Systems ◽

Allergic Bronchopulmonary Aspergillosis ◽

Defined Daily Dose ◽

Antifungal Stewardship ◽

Team Meetings ◽

Stewardship Program ◽

Care Systems ◽

The Impact

ABSTRACT There has been an increase in fungal infections in patients with chronic lung disease over the past decades, which is associated with rapidly increasing costs to health care systems. An antifungal stewardship team was introduced to a tertiary cardiopulmonary hospital, consisting of a medical mycologist and pharmacy support providing weekly stewardship ward rounds, twice-monthly multidisciplinary team meetings, and a dedicated weekly outpatient clinic. A database was set up to record the activity of the stewardship team. During the first 18 months of implementation, the antifungal stewardship team had reviewed 178 patients, with 285 recommendations made to inpatients, and 287 outpatient visits. The commonest diagnoses treated were allergic bronchopulmonary aspergillosis and chronic pulmonary aspergillosis. Cystic fibrosis was the largest patient group treated, followed by asthma and interstitial lung disease. There was a significant sustained reduction in monthly antifungal expenditure (P = 0.005) by £130,000 per month. There was also a significant reduction in antifungal use, measured as the defined daily dose/100 bed days (P = 0.017). There were no significant changes in expenditure on diagnostic tests. There has been a trend toward more patients having therapeutic levels of voriconazole (P = 0.086) and a significant increase in therapeutic levels of posaconazole (P < 0.0001). This study shows that an effective antifungal stewardship program can significantly reduce expenditure in a specialist respiratory service.

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Fungal Infection and Inflammation in Cystic Fibrosis

Pathogens ◽

10.3390/pathogens10050618 ◽

2021 ◽

Vol 10 (5) ◽

pp. 618

Author(s):

T. Spencer Poore ◽

Gina Hong ◽

Edith T. Zemanick

Keyword(s):

Cystic Fibrosis ◽

Lung Disease ◽

Clinical Outcomes ◽

Fungal Infections ◽

Allergic Bronchopulmonary Aspergillosis ◽

Lower Airway ◽

Future Research ◽

Isolation And Identification ◽

Helper Cell Type

Fungi are frequently recovered from lower airway samples from people with cystic fibrosis (CF), yet the role of fungi in the progression of lung disease is debated. Recent studies suggest worsening clinical outcomes associated with airway fungal detection, although most studies to date are retrospective or observational. The presence of fungi can elicit a T helper cell type 2 (Th-2) mediated inflammatory reaction known as allergic bronchopulmonary aspergillosis (ABPA), particularly in those with a genetic atopic predisposition. In this review, we discuss the epidemiology of fungal infections in people with CF, risk factors associated with development of fungal infections, and microbiologic approaches for isolation and identification of fungi. We review the spectrum of fungal disease presentations, clinical outcomes after isolation of fungi from airway samples, and the importance of considering airway co-infections. Finally, we discuss the association between fungi and airway inflammation highlighting gaps in knowledge and future research questions that may further elucidate the role of fungus in lung disease progression.

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Update on Respiratory Fungal Infections in Cystic Fibrosis Lung Disease and after Lung Transplantation

Journal of Fungi ◽

10.3390/jof6040381 ◽

2020 ◽

Vol 6 (4) ◽

pp. 381

Author(s):

Sabine Renner ◽

Edith Nachbaur ◽

Peter Jaksch ◽

Eleonora Dehlink

Keyword(s):

Cystic Fibrosis ◽

Lung Disease ◽

Bacterial Infections ◽

Fungal Infections ◽

Chloride Transport ◽

Lung Damage ◽

Western World ◽

Detection Rates ◽

Airway Infections ◽

The Impact

Cystic fibrosis is the most common autosomal-recessive metabolic disease in the Western world. Impaired trans-membrane chloride transport via the cystic fibrosis transmembrane conductance regulator (CFTR) protein causes thickened body fluids. In the respiratory system, this leads to chronic suppurative cough and recurrent pulmonary infective exacerbations, resulting in progressive lung damage and respiratory failure. Whilst the impact of bacterial infections on CF lung disease has long been recognized, our understanding of pulmonary mycosis is less clear. The range and detection rates of fungal taxa isolated from CF airway samples are expanding, however, in the absence of consensus criteria and univocal treatment protocols for most respiratory fungal conditions, interpretation of laboratory reports and the decision to treat remain challenging. In this review, we give an overview on fungal airway infections in CF and CF-lung transplant recipients and focus on the most common fungal taxa detected in CF, Aspergillus fumigatus, Candida spp., Scedosporium apiospermum complex, Lomentospora species, and Exophiala dermatitidis, their clinical presentations, common treatments and prophylactic strategies, and clinical challenges from a physician’s point of view.

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Allergic Diseases Caused by Aspergillus Species in Patients with Cystic Fibrosis

Antibiotics ◽

10.3390/antibiotics10040357 ◽

2021 ◽

Vol 10 (4) ◽

pp. 357

Author(s):

Aidan K. Curran ◽

David L. Hava

Keyword(s):

Cystic Fibrosis ◽

Fungal Infections ◽

Allergic Bronchopulmonary Aspergillosis ◽

Hyphal Growth ◽

Allergic Diseases ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Th2 Immune Response ◽

Difficulty Breathing ◽

Oral Corticosteroids

Aspergillus spp. are spore forming molds; a subset of which are clinically relevant to humans and can cause significant morbidity and mortality. A. fumigatus causes chronic infection in patients with chronic lung disease such as asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). In patients with CF, A. fumigatus infection can lead to allergic disease, such as allergic bronchopulmonary aspergillosis (ABPA) which is associated with high rates of hospitalizations for acute exacerbations and lower lung function. ABPA results from TH2 immune response to Aspergillus antigens produced during hyphal growth, marked by high levels of IgE and eosinophil activation. Clinically, patients with ABPA experience difficulty breathing; exacerbations of disease and are at high risk for bronchiectasis and lung fibrosis. Oral corticosteroids are used to manage aspects of the inflammatory response and antifungal agents are used to reduce fungal burden and lower the exposure to fungal antigens. As the appreciation for the severity of fungal infections has grown, new therapies have emerged that aim to improve treatment and outcomes for patients with CF.

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The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

Diagnostics ◽

10.3390/diagnostics10121102 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1102

Author(s):

Fatima Domenica Elisa De Palma ◽

Valeria Raia ◽

Guido Kroemer ◽

Maria Chiara Maiuri

Keyword(s):

Cystic Fibrosis ◽

Respiratory Infections ◽

Current Knowledge ◽

Pancreatic Insufficiency ◽

Clinical Manifestations ◽

Predictive Biomarkers ◽

Loss Of Function ◽

Gene Encoding ◽

Multisystemic Disease

Cystic fibrosis (CF) is a lifelong disorder affecting 1 in 3500 live births worldwide. It is a monogenetic autosomal recessive disease caused by loss-of-function mutations in the gene encoding the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR), the impairment of which leads to ionic disequilibria in exocrine organs. This translates into a chronic multisystemic disease characterized by airway obstruction, respiratory infections, and pancreatic insufficiency as well as hepatobiliary and gastrointestinal dysfunction. Molecular characterization of the mutational heterogeneity of CFTR (affected by more than 2000 variants) improved the understanding and management of CF. However, these CFTR variants are linked to different clinical manifestations and phenotypes, and they affect response to treatments. Expanding evidence suggests that multisystemic disease affects CF pathology via impairing either CFTR or proteins regulated by CFTR. Thus, altering the expression of miRNAs in vivo could constitute an appealing strategy for developing new CF therapies. In this review, we will first describe the pathophysiology and clinical management of CF. Then, we will summarize the current knowledge on altered miRNAs in CF patients, with a focus on the miRNAs involved in the deregulation of CFTR and in the modulation of inflammation. We will highlight recent findings on the potential utility of measuring circulating miRNAs in CF as diagnostic, prognostic, and predictive biomarkers. Finally, we will provide an overview on potential miRNA-based therapeutic approaches.

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Fungal Infection in Cystic Fibrosis

Current Respiratory Medicine Reviews ◽

10.2174/1573398x17666210520175847 ◽

2021 ◽

Vol 17 (2) ◽

pp. 118-124

Author(s):

Amirmehdi Sarvestani ◽

Mohammad Almasian ◽

Amirhossein Nafari

Keyword(s):

Cystic Fibrosis ◽

Fungal Infection ◽

Fungal Pathogens ◽

Respiratory Infections ◽

Fungal Infections ◽

Genetic Disorder ◽

Medical Science ◽

Resistant Species ◽

Online Databases ◽

New Treatments

Background: The prevalence of fungal infections has been increasing in recent years. Cystic fibrosis (CF) is a genetic disorder that affects organs such as the intestines, liver, pancreas, and especially the lungs. Introduction: Fungal pathogens are becoming a challenge in CF. Advanced medical science is associated with longer life expectancy in some patient groups. Method: A review was conducted on studies found on online databases, including Google Scholar, PubMed, and Scopus. Internet-based searches were performed on these databases for cystic fibrosis, respiratory infections, and fungal infection profiling to identify all relevant studies published between 2010 and 2020. Result: Fungal pathogens most frequently isolated from the respiratory tract include the Aspergillus genus, the Candida genus, Scedosporium apiospermum, and the Rasamsonia genus. In cystic fibrosis, these organisms usually colonize the respiratory and intestinal tracts and cause hypersensitivity responses and invasive diseases. Conclusion: Fungus-patient interactions are complicated and depend on various factors. Moreover, the emergence of drug-resistant species is a serious health issue, and the development of new treatments is crucial.

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The Role of Gene Editing in Neurodegenerative Diseases

Cell Transplantation ◽

10.1177/0963689717753378 ◽

2018 ◽

Vol 27 (3) ◽

pp. 364-378 ◽

Cited By ~ 5

Author(s):

Hueng-Chuen Fan ◽

Ching-Shiang Chi ◽

Yih-Jing Lee ◽

Jeng-Dau Tsai ◽

Shinn-Zong Lin ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Gene Editing ◽

Clinical Manifestations ◽

Zinc Finger Nucleases ◽

Diagnostic Tools ◽

Pathological Feature ◽

Transcription Activator ◽

Substantial Impact ◽

Parkinson’S Diseases ◽

The Impact

Neurodegenerative diseases (NDs), at least including Alzheimer’s, Huntington’s, and Parkinson’s diseases, have become the most dreaded maladies because there are no precise diagnostic tools or definite treatments for these debilitating diseases. The increased prevalence and a substantial impact on the social–economic and medical care of NDs propel governments to develop policies to counteract the impact. Although the etiologies of NDs are still unknown, growing evidence suggests that genetic, cellular, and circuit alternations may cause the generation of abnormal misfolded proteins, which uncontrolledly accumulate to damage and eventually overwhelm the protein-disposal mechanisms of these neurons, leading to a common pathological feature of NDs. If the functions and the connectivity can be restored, alterations and accumulated damages may improve. The gene-editing tools including zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats–associated nucleases (CRISPR/CAS) have emerged as a novel tool not only for generating specific ND animal models for interrogating the mechanisms and screening potential drugs against NDs but also for the editing sequence-specific genes to help patients with NDs to regain function and connectivity. This review introduces the clinical manifestations of three distinct NDs and the applications of the gene-editing technology on these debilitating diseases.

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Posaconazole therapy in children with cystic fibrosis and Aspergillus-related lung disease

Medical Mycology ◽

10.1093/mmy/myz015 ◽

2019 ◽

Vol 58 (1) ◽

pp. 11-21 ◽

Cited By ~ 4

Author(s):

Deepa Patel ◽

Sarah Popple ◽

Alison Claydon ◽

Deborah E Modha ◽

Erol A Gaillard

Keyword(s):

Cystic Fibrosis ◽

Lung Disease ◽

Plasma Levels ◽

Allergic Bronchopulmonary Aspergillosis ◽

Tablet Formulation ◽

Full Blood Count ◽

Systemic Corticosteroids ◽

Liquid Preparation ◽

A Prospective Study

Abstract There is emerging evidence for the role of posaconazole in the management of Aspergillus-related cystic fibrosis (CF) lung disease. The tolerability and efficacy of posaconazole in paediatric CF is not well established. We report a prospective study over a fifty-three month period evaluating the safety, tolerability, and efficacy of posaconazole in pediatric CF. Fourteen children (seven males, median age 13 years, range 3–17 years) received a total of twenty-three courses of posaconazole (13 oral suspension and 10 tablet formulation). Of these patient episodes, nine received posaconazole for emerging or active allergic bronchopulmonary aspergillosis (ABPA) and two required a combination of posaconazole and systemic corticosteroids for difficult-to-treat ABPA. A subgroup of patients (n = 12) with persistent isolates of Aspergillus fumigatus, in the absence of serological markers of ABPA, received posaconazole monotherapy for pulmonary exacerbations not responding to conventional broad-spectrum antibiotic treatment. Posaconazole levels, full blood count, electrolytes, and liver function were monitored on day 7 of treatment and then monthly. Posaconazole was well tolerated in all but three patients. Therapeutic plasma levels >1 mg/l were achieved in all receiving the tablet formulation in comparison to 60% on the liquid preparation. There was a modest but significant improvement in FEV1 (% predicted) demonstrated for the cohort as a whole (p = 0.015) following posaconazole therapy. Posaconazole is well tolerated in children as young as six years old, improvements in lung function are observed, and therapeutic plasma levels are readily achieved in patients taking the tablet formulation and in adherent patients taking the liquid formulation.

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Genomic Diversity and Antimicrobial Resistance of Haemophilus Colonizing the Airways of Young Children with Cystic Fibrosis

mSystems ◽

10.1128/msystems.00178-21 ◽

2021 ◽

Vol 6 (4) ◽

Author(s):

Stephen C. Watts ◽

Louise M. Judd ◽

Rosemary Carzino ◽

Sarath Ranganathan ◽

Kathryn E. Holt

Keyword(s):

Cystic Fibrosis ◽

Antimicrobial Resistance ◽

Young Children ◽

Lung Disease ◽

Respiratory Infections ◽

Genomic Diversity ◽

Disease Development ◽

Acute Respiratory Infections ◽

Early Disease ◽

Advanced Stages

Cystic fibrosis (CF) lung disease begins during infancy, and acute respiratory infections increase the risk of early disease development and progression. Microbes involved in advanced stages of CF are well characterized, but less is known about early respiratory colonizers.

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Defective Ion Channel in Cystic Fibrosis: Current Development in Treatment of Cystic Fibrosis

Asian Journal of Biochemistry, Genetics and Molecular Biology ◽

10.9734/ajbgmb/2020/v4i130099 ◽

2020 ◽

pp. 28-34

Author(s):

Ngoga Godfrey ◽

M. M. Ganyam ◽

G.O. Ibiang ◽

C. A. Difa ◽

Nelson Christian

Keyword(s):

Cystic Fibrosis ◽

Ion Transport ◽

Ion Channel ◽

Lung Disease ◽

Defense Mechanisms ◽

Respiratory Infections ◽

The Body ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Airway Defense

Cystic fibrosis is an inherited disorder that causes severe damage to the lungs, digestive system and other organs in the body. Cystic fibrosis transmembrane conductance regulator (CFTR) is involved in the production of mucus, sweat and digestive juices. These secreted fluids are normally thin and slippery. But in people with cystic fibrosis, a defective gene in CFTR causes the secretions to become sticky and thick. Instead of acting as a lubricant, the secretions plug up tubes, ducts and passage ways, especially in the lungs and pancreas. This mucus leads to the formation of bacterial microenvironments known as biofilms (a niche that harbors bacteria; Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa ) that are difficult for immune cells and antibiotics to penetrate. Viscous secretions and persistent respiratory infections repeatedly damage the lung by gradually remodeling the airways, which makes infection even more difficult to eradicate. CFTR, a Cl– selective ion channel, is a prototypic member of the ATP-binding cassette transporter super family that is expressed in several organs. Understanding how these complexes regulate the intracellular trafficking and activity of CFTR provides a unique insight into the aetiology of cystic fibrosis and other diseases associated to it. Cystic fibrosis patients exhibit lung disease consistent with a failure of innate airway defense mechanisms. The link between abnormal ion transport, disease initiation and progression is not fully understood, but airway mucus dehydration seems paramount in the initiation of CF lung disease. New therapies are currently in development that target the ion transport defects in CF with the intention of rehydrating airway surfaces.

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