Ann Am Thorac Soc. 2024 Aug 22. doi: 10.1513/AnnalsATS.202402-201OC. Online ahead of print.

ABSTRACT

RATIONALE: Clinical trials show that lumacaftor/ivacaftor (LUM/IVA) treatment has the potential to modify early cystic fibrosis (CF) disease progression in children as young as 2 years of age.

OBJECTIVE: To assess the long-term impact of LUM/IVA treatment on CF disease progression in children aged 2 through 5 years.

METHODS: This phase 2 trial had two parts: Part 1, a 48-week, randomized, double-blind, placebo-controlled study of LUM/IVA in children aged 2 through 5 years (previously reported) was followed by a 48-week open-label treatment period where all children received LUM/IVA (Part 2; reported here). Endpoints assessed in Part 2 included absolute changes from baseline in chest magnetic resonance imaging (MRI) global score at week 96; weight-for-age, stature-for-age, and body mass index (BMI)-for-age z-scores at week 96; lung clearance index (LCI2.5) through week 96; chest MRI morphological score, chest MRI perfusion score, weight, stature, BMI, and microbiology cultures (oropharyngeal swabs) at week 96; sweat chloride, serum levels of immunoreactive trypsinogen, fecal elastase-1 levels, and fecal calprotectin through week 96; and number of pulmonary exacerbations (PEx), time-to-first PEx, and number of CF-related hospitalizations.

RESULTS: Forty-nine children received ≥1 dose of LUM/IVA in the open-label period (33 in the LUM/IVA to LUM/IVA group and 16 in the placebo to LUM/IVA group); mean exposure 47.1 (SD, 5.2) weeks. The mean absolute change in MRI global score (negative value = improvement) from baseline at Week 96 was -2.7 (SD 7.0; 95% CI, -5.2 to -0.1) in the LUM/IVA to LUM/IVA group and -5.6 (SD 6.9; 95% CI, -9.2 to -1.9) in the placebo to LUM/IVA group. Improvements in LCI2.5, sweat chloride concentration, and markers of pancreatic function and intestinal inflammation were also observed in both groups. Growth parameters remained stable in both groups. The majority of children had adverse events (AEs) considered mild (38.8%) or moderate (40.8%). Two (4.1%) children discontinued LUM/IVA treatment due to AEs (distal intestinal obstruction syndrome [n=1] and alanine aminotransferase increase [n=1]).

CONCLUSION: These findings confirm the potential for early LUM/IVA treatment to alter the trajectory of CF disease progression, including CF lung disease, in children as young as 2 years of age. Clinical trial registration available at www.

CLINICALTRIALS: gov, ID: NCT03625466.

PMID:39173175 | DOI:10.1513/AnnalsATS.202402-201OC

J Clin Psychopharmacol. 2024 Aug 22. doi: 10.1097/JCP.0000000000001906. Online ahead of print.

NO ABSTRACT

PMID:39173037 | DOI:10.1097/JCP.0000000000001906

Radiographics. 2024 Sep;44(9):e240008. doi: 10.1148/rg.240008.

ABSTRACT

Cystic fibrosis is a genetic disease with multisystem involvement and associated morbidity and mortality that are most directly related to progressive lung disease. The hallmark findings of cystic fibrosis in the lungs are chronic inflammation and infection, leading to progressive loss of pulmonary function and often requiring lung transplant. Predominant lung findings include mucous plugging, bronchiectasis, and air trapping, often with associated atelectasis, consolidation, and emphysema; these findings form the basis of several clinical scoring systems that are used for imaging assessment. Recently, there have been major breakthroughs in the pharmacologic management of cystic fibrosis, including highly effective modulator therapies that directly target the underlying cystic fibrosis transmembrane conductance regulator molecular defect, often leading to remarkable improvements in lung function and quality of life with corresponding significant improvements in imaging markers. The authors review current guidelines regarding cystic fibrosis with respect to disease monitoring, identifying complications, and managing advanced lung disease. In addition, they discuss the evolving role of imaging, including current trends, emerging technologies, and proposed updates to imaging guidelines endorsed by international expert committees on cystic fibrosis, which favor increased use of cross-sectional imaging to enable earlier detection of structural changes in early disease and more sensitive detection of acute changes in advanced disease. It is important for radiologists to be familiar with these trends and updates so that they can most effectively assist clinicians in guiding the management of patients with cystic fibrosis in all stages of disease. ©RSNA, 2024.

PMID:39172707 | DOI:10.1148/rg.240008

J Aerosol Med Pulm Drug Deliv. 2024 Aug;37(4):202-218. doi: 10.1089/jamp.2024.29117.mk.

ABSTRACT

An increasing growth in nanotechnology is evident from the growing number of products approved in the past decade. Nanotechnology can be used in the effective treatment of several pulmonary diseases by developing therapies that are delivered in a targeted manner to select lung regions based on the disease state. Acute or chronic pulmonary disorders can benefit from this type of therapy, including respiratory distress syndrome (RDS), chronic obstructive pulmonary disease (COPD), asthma, pulmonary infections (e.g. tuberculosis, Yersinia pestis infection, fungal infections, bacterial infections, and viral infections), lung cancer, cystic fibrosis (CF), pulmonary fibrosis, and pulmonary arterial hypertension. Modification of size and surface property renders nanoparticles to be targeted to specific sites, which can serve a vital role in innovative pulmonary drug delivery. The nanocarrier type chosen depends on the intended purpose of the formulation and intended physiological target. Liquid nanocarriers and solid-state nanocarriers can carry hydrophilic and hydrophobic drugs (e.g. small molecular weight drug molecules, large molecular weight drugs, peptide drugs, and macromolecular biological drugs), while surface modification with polymer can provide cellular targeting, controlled drug release, and/or evasion of phagocytosis by immune cells, depending on the polymer type. Polymeric nanocarriers have versatile architectures, such as linear, branched, and dendritic forms. In addition to the colloidal dispersion liquid state, the various types of nanoparticles can be formulated into the solid state, offering important unique advantages in formulation versatility and enhanced stability of the final product. This chapter describes the different types of nanocarriers, types of inhalation aerosol device platforms, liquid aerosols, respirable powders, and particle engineering design technologies for inhalation aerosols.

PMID:39172256 | DOI:10.1089/jamp.2024.29117.mk

J Leukoc Biol. 2024 Aug 22:qiae185. doi: 10.1093/jleuko/qiae185. Online ahead of print.

NO ABSTRACT

PMID:39171927 | DOI:10.1093/jleuko/qiae185

Curr Opin Pulm Med. 2024 Aug 23. doi: 10.1097/MCP.0000000000001115. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Advanced cystic fibrosis lung disease remains the main cause of death in people with cystic fibrosis (pwCF). Cystic fibrosis transmembrane regulator (CFTR) modulators have changed the disease burden for eligible pwCF with access to this therapy.

RECENT FINDINGS: Real-world data show that there are no safety concerns for patients with advanced cystic fibrosis lung disease treated with highly effective triple CFTR modulator therapy. The improvements are comparable to those in other people with cystic fibrosis and in part even better. Mortality and rates of lung transplantation have decreased since the approval of CFTR modulator therapy and, especially, highly effective triple CFTR modulator therapy. Nevertheless, at least 10% of people with cystic fibrosis are not eligible for highly effective CFTR modulator therapy, and the development of alternative treatments remains important.

SUMMARY: The approval of highly effective CFTR modulator therapies has been a breakthrough in treatment for most people with cystic fibrosis, especially those with advanced lung disease, improving survival and reducing the burden of the disease.

PMID:39171565 | DOI:10.1097/MCP.0000000000001115

J Allergy Clin Immunol Glob. 2024 Jul 3;3(4):100298. doi: 10.1016/j.jacig.2024.100298. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a rare airway disorder primarily affecting patients with asthma and cystic fibrosis. Persistent airway inflammation brought on by Aspergillus fumigatus exacerbates the underlying condition and can cause significant respiratory damage. Treatments center on reducing inflammation with the use of corticosteroids and antifungals. PANoptosis is a new concept in the field of cell death and inflammation that posits the existence of cross talk and a master control system for the 3 programmed cell death (PCD) pathways, namely, apoptosis, pyroptosis, and necroptosis. This concept has revolutionized the understanding of PCD and opened new avenues for its exploration. Studies show that Aspergillus is one of the pathogens that is capable of activating PANoptosis via the Z-DNA binding protein 1 (ZBP1) pathway and plays an active role in the inflammation caused by this organism.

OBJECTIVE: This article explores the nature of inflammation in ABPA and ways in which PCD could lead to novel treatment options.

METHOD: PubMed was used to review the literature surrounding Aspergillus infection-related inflammation and PANoptosis.

RESULTS: There is evidence that apoptosis and pyroptosis protect against Aspergillus-induced inflammation, whereas necroptosis promotes inflammation.

CONCLUSION: Experimental medications, in particular, necroptosis inhibitors such as necrosulfonamide and necrostatin-1, should be studied for use in the treatment of ABPA.

PMID:39170913 | PMC:PMC11338086 | DOI:10.1016/j.jacig.2024.100298

Transpl Int. 2024 Aug 7;37:12973. doi: 10.3389/ti.2024.12973. eCollection 2024.

ABSTRACT

Humoral immunity is a major waypoint towards chronic allograft dysfunction in lung transplantation (LT) recipients. Though allo-immunization and antibody-mediated rejection (AMR) are well-known entities, some diagnostic gaps need to be addressed. Morphological analysis could be enhanced by digital pathology and artificial intelligence-based companion tools. Graft transcriptomics can help to identify graft failure phenotypes or endotypes. Donor-derived cell free DNA is being evaluated for graft-loss risk stratification and tailored surveillance. Preventative therapies should be tailored according to risk. The donor pool can be enlarged for candidates with HLA sensitization, with strategies combining plasma exchange, intravenous immunoglobulin and immune cell depletion, or with emerging or innovative therapies such as imlifidase or immunoadsorption. In cases of insufficient pre-transplant desensitization, the effects of antibodies on the allograft can be prevented by targeting the complement cascade, although evidence for this strategy in LT is limited. In LT recipients with a humoral response, strategies are combined, including depletion of immune cells (plasmapheresis or immunoadsorption), inhibition of immune pathways, or modulation of the inflammatory cascade, which can be achieved with photopheresis. Altogether, these innovative techniques offer promising perspectives for LT recipients and shape the 21st century's armamentarium against AMR.

PMID:39170865 | PMC:PMC11336419 | DOI:10.3389/ti.2024.12973

Front Endocrinol (Lausanne). 2024 Aug 7;15:1411317. doi: 10.3389/fendo.2024.1411317. eCollection 2024.

ABSTRACT

Cystic fibrosis (CF) is the most common life-threatening genetic disease in the United States and among people of European descent. Despite the widespread distribution of the cystic fibrosis transmembrane conductance regulator (CFTR) along kidney tubules, specific renal phenotypes attributable to CF have not been well documented. Recent studies have demonstrated the downregulation of the apical Cl-/HCO3 - exchanger pendrin (Slc26a4) in kidney B-intercalated cells of CF mouse models. These studies have shown that kidneys of both mice and humans with CF have an impaired ability to excrete excess HCO3 -, thus developing metabolic alkalosis when subjected to excess HCO3 - intake. The purpose of this minireview is to discuss the latest advances on the role of pendrin as a molecule with dual critical roles in acid base regulation and systemic vascular volume homeostasis, specifically in CF. Given the immense prevalence of vascular volume depletion, which is primarily precipitated via enhanced chloride loss through perspiration, we suggest that the dominant presentation of metabolic alkalosis in CF is due to the impaired function of pendrin, which plays a critical role in systemic vascular volume and acid base homeostasis.

PMID:39170739 | PMC:PMC11335532 | DOI:10.3389/fendo.2024.1411317

Clin Chem Lab Med. 2024 Aug 19. doi: 10.1515/cclm-2024-0909. Online ahead of print.

NO ABSTRACT

PMID:39166745 | DOI:10.1515/cclm-2024-0909

Pediatr Pulmonol. 2024 Aug 21. doi: 10.1002/ppul.27184. Online ahead of print.

ABSTRACT

Newborn screening for cystic fibrosis (CF) occasionally results in an inconclusive diagnosis of this disease, and these individuals are designated as CFTR-related metabolic syndrome (CRMS) in the United States, and CF Screen Positive Inconclusive Diagnosis (CFSPID) in other countries. Some of these asymptomatic individuals will progress to symptomatic disease, but risk factors associated with disease progression are not well understood. This scoping review was conducted to comprehensively map nonbiological risk factors in the CRMS/CFSPID literature and to identify understudied topics. Six electronic databases were systematically searched, resulting in 2951 studies. Forty nine eligible works were identified as including information on nonbiological risk factors related to CRMS/CFPSID. Eligible studies were published from 2002 to 2024, most prevalently in the United States (36.7%), and as quantitative data (81.6%). Of the 49 eligible works, 23 articles contributed only intellectual conjecture, while 26 articles contained original data, which underwent full-text qualitative content analysis. Key themes identified in descending order of content coverage included Psychological Impact, Management Care, Newborn Screening and Diagnostics, Communicating Diagnosis, and Lifestyle and External Exposures. This scoping review identified that while nonbiological risk factors are being studied in the CRMS/CFSPID literature, there was nearly equal distribution of works gathering original data to those citing previously published information. These findings indicate a critical need for original data collection on these risk factors, particularly on understudied topics identified herein.

PMID:39166713 | DOI:10.1002/ppul.27184

J Bras Pneumol. 2024 Aug 19;50(3):e20240218. doi: 10.36416/1806-3756/e20240218.

NO ABSTRACT

PMID:39166596 | DOI:10.36416/1806-3756/e20240218

Eur J Hum Genet. 2024 Aug 20. doi: 10.1038/s41431-024-01683-y. Online ahead of print.

ABSTRACT

The main limitation to long-term lung transplant (LT) survival is chronic lung allograft dysfunction (CLAD), which leads to irreversible lung damage and significant mortality. Individual factors can impact CLAD, but no large genetic investigation has been conducted to date. We established the multicentric Genetic COhort in Lung Transplantation (GenCOLT) biobank from a rich and homogeneous sub-part of COLT cohort. GenCOLT collected DNA, high-quality GWAS (genome-wide association study) genotyping and robust HLA data for donors and recipients to supplement COLT clinical data. GenCOLT closely mirrors the global COLT cohort without significant variations in variables like demographics, initial disease and survival rates (P > 0.05). The GenCOLT donors were 45 years-old on average, 44% women, and primarily died of stroke (54%). The recipients were 48 years-old at transplantation on average, 45% women, and the main underlying disease was chronic obstructive pulmonary disease (45%). The mean follow-up time was 67 months and survival at 5 years was 57.3% for the CLAD subgroup and 97.4% for the non-CLAD subgroup. After stringent quality controls, GenCOLT gathered more than 7.3 million SNP and HLA genotypes for 387 LT pairs, including 91% pairs composed of donor and recipient of European ancestry. Overall, GenCOLT is an accurate snapshot of LT clinical practice in France and Belgium between 2009 and 2018. It currently represents one of the largest genetic biobanks dedicated to LT with data available simultaneously for donors and recipients. This unique cohort will empower to run comprehensive GWAS investigations of CLAD and other LT outcomes.

PMID:39164465 | DOI:10.1038/s41431-024-01683-y

Nat Microbiol. 2024 Aug 20. doi: 10.1038/s41564-024-01778-8. Online ahead of print.

ABSTRACT

Salmonella translocate to the gut epithelium via microfold cells lining the follicle-associated epithelium (FAE). How Salmonella localize to the FAE is not well characterized. Here we use live imaging and competitive assays between wild-type and chemotaxis-deficient mutants to show that Salmonella enterica serotype Typhimurium (S. Typhimurium) localize to the FAE independently of chemotaxis in an ex vivo mouse caecum infection model. Electrical recordings revealed polarized FAE with sustained outward current and small transepithelial potential, while the surrounding villus is depolarized with inward current and large transepithelial potential. The distinct electrical potentials attracted S. Typhimurium to the FAE while Escherichia coli (E. coli) localized to the villi, through a process called galvanotaxis. Chloride flux involving the cystic fibrosis transmembrane conductance regulator (CFTR) generated the ionic currents around the FAE. Pharmacological inhibition of CFTR decreased S. Typhimurium FAE localization but increased E. coli recruitment. Altogether, our findings demonstrate that bioelectric cues contribute to S. Typhimurium targeting of specific gut epithelial locations, with potential implications for other enteric bacterial infections.

PMID:39164392 | DOI:10.1038/s41564-024-01778-8

mBio. 2024 Aug 20:e0085224. doi: 10.1128/mbio.00852-24. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen that thrives in environments associated with human activity, including soil and water altered by agriculture or pollution. Because L-lactate is a significant product of plant and animal metabolism, it can serve as a carbon source for P. aeruginosa in the diverse settings that it inhabits. In this study, we evaluate the production and use of two redundant P. aeruginosa L-lactate dehydrogenases, termed LldD and LldA. We confirm that the protein LldR represses lldD and identify a new transcription factor, called LldS, that activates lldA; these distinct regulators and the genomic contexts of lldD and lldA contribute to their differential expression. We demonstrate that the lldD and lldA genes are conditionally controlled in response to lactate isomers as well as to glycolate and ɑ-hydroxybutyrate, which, like lactate, are ɑ-hydroxycarboxylates. We also show that lldA is induced when iron availability is low. Our examination of lldD and lldA expression across depth in biofilms indicates a complex pattern that is consistent with the effects of glycolate production, iron availability, and cross-regulation on enzyme preference. Finally, macrophage infection assays reveal that both lldD and lldA contribute to persistence within host cells, underscoring the potential role of L-lactate as a carbon source during P. aeruginosa-eukaryote interactions. Together, these findings help us understand the metabolism of a key resource that may promote P. aeruginosa's success as a resident of contaminated environments and animal hosts.IMPORTANCEPseudomonas aeruginosa is a major cause of lung infections in people with cystic fibrosis, of hospital-acquired infections, and of wound infections. It consumes L-lactate, which is found at substantial levels in human blood and tissues. In this study, we investigated the spatial regulation of two redundant enzymes, called LldD and LldA, which enable L-lactate metabolism in P. aeruginosa biofilms. We uncovered mechanisms and identified compounds that control the preference of P. aeruginosa for LldD versus LldA. We also showed that both enzymes contribute to its ability to survive within macrophages, a behavior that is thought to augment the chronicity and recalcitrance of infections. Our findings shed light on a key metabolic strategy used by P. aeruginosa and have the potential to inform the development of therapies targeting bacterial metabolism during infection.

PMID:39162563 | DOI:10.1128/mbio.00852-24

mSphere. 2024 Aug 20:e0043424. doi: 10.1128/msphere.00434-24. Online ahead of print.

ABSTRACT

Chelsey VanDrisse works in the field of microbial physiology, studying how acylation of small molecules and proteins affects the development of Pseudomonas biofilms. In this mSphere of Influence article, she reflects on the paper "Community composition shapes microbial-specific phenotypes in a cystic fibrosis polymicrobial model system" by Jean-Pierre et al. This paper prompted her to reassess her approach to studying antibiotic tolerance and her design of experiments that search for disease-relevant mutants and phenotypes in the laboratory.

PMID:39162472 | DOI:10.1128/msphere.00434-24

Eur Clin Respir J. 2024 Aug 16;11(1):2381307. doi: 10.1080/20018525.2024.2381307. eCollection 2024.

ABSTRACT

OBJECTIVE: Initiated by the Severe Asthma Network Italy (SANI), this study aims to explore asthma patients' perceptions of disease severity, differentiating between mild and severe asthma. The objective is to identify factors influencing tailored treatment strategies for varying disease severities and to provide insights into asthma care in Italy.

METHODS: Conducted between November 2020 and January 2021, a survey using Computer-Assisted Personal Interviewing (CAPI) collected data from 308 Italian adults, representing the population. A 25 item multiple choice questionnaire covered asthma diagnosis, symptoms, treatment approaches, associated conditions, and quality of life.

RESULTS: Among participants, 83.8% reported having mild asthma, while 16.2% had severe asthma. Severe asthma patients had longer disease durations, more severe symptoms, frequent exacerbations, and higher hospital/ER visits. Although treatment adherence and symptom profiles generally aligned with international guidelines for self reported severe asthma, 22% of self identified mild asthmatics experienced severe respiratory symptoms. Oral corticosteroid (OCS) use was observed in 50% of severe cases and 22% of mild cases. Adherence was higher in severe asthma patients (76%) versus mild asthma patients (28%). Both groups experienced comorbidities, with 96% of severe asthmatics and 72% of mild asthmatics reporting impaired quality of life.

CONCLUSION: This study highlights the disparity between clinical categorization and patient perceptions of asthma severity. The prevalence of self reported severe asthma exceeds literature data. The burden of mild asthma remains significant, with treatment approaches not fully aligned, particularly regarding disproportionate OCS use. Addressing this gap requires enhancing patient education, improving diagnostic practices, and promoting adherence.

PMID:39161972 | PMC:PMC11332286 | DOI:10.1080/20018525.2024.2381307

J Med Microbiol. 2024 Aug;73(8). doi: 10.1099/jmm.0.001869.

ABSTRACT

Introduction. Mycobacterium abscessus (MABS) is a pathogenic bacterium that can cause severe lung infections, particularly in individuals with cystic fibrosis. MABS colonies can exhibit either a smooth (S) or rough (R) morphotype, influenced by the presence or absence of glycopeptidolipids (GPLs) on their surface, respectively. Despite the clinical significance of these morphotypes, the relationship between GPL levels, morphotype and the pathogenesis of MABS infections remains poorly understood.Gap statement. The mechanisms and implications of GPL production and morphotypes in clinical MABS infections are unclear. There is a gap in understanding their correlation with infectivity and pathogenicity, particularly in patients with underlying lung disease.Aim. This study aimed to investigate the correlation between MABS morphology, GPL and infectivity by analysing strains from cystic fibrosis patients' sputum samples.Methodology. MABS was isolated from patient sputum samples and categorized by morphotype, GPL profile and replication rate in macrophages. A high-content ex vivo infection model using THP-1 cells assessed the infectivity of both clinical and laboratory strains.Results. Our findings revealed that around 50 % of isolates displayed mixed morphologies. GPL analysis confirmed a consistent relationship between GPL content and morphotype that was only found in smooth isolates. Across morphotype groups, no differences were observed in vitro, yet clinical R strains were observed to replicate at higher levels in the THP-1 infection model. Moreover, the proportion of infected macrophages was notably higher among clinical R strains compared to their S counterparts at 72 h post-infection. Clinical variants also infected THP-1 cells at significantly higher rates compared to laboratory strains, highlighting the limited translatability of lab strain infection data to clinical contexts.Conclusion. Our study confirmed the general correlation between morphotype and GPL levels in smooth strains yet unveiled more variability within morphotype groups than previously recognized, particularly during intracellular infection. As the R morphotype is the highest clinical concern, these findings contribute to the expanding knowledge base surrounding MABS infections, offering insights that can steer diagnostic methodologies and treatment approaches.

PMID:39158416 | DOI:10.1099/jmm.0.001869

Clin Microbiol Rev. 2024 Aug 19:e0021521. doi: 10.1128/cmr.00215-21. Online ahead of print.

ABSTRACT

SUMMARYThis guidance presents recommendations for clinical microbiology laboratories for processing respiratory samples from people with cystic fibrosis (pwCF). Appropriate processing of respiratory samples is crucial to detect bacterial and fungal pathogens, guide treatment, monitor the epidemiology of cystic fibrosis (CF) pathogens, and assess therapeutic interventions. Thanks to CF transmembrane conductance regulator modulator therapy, the health of pwCF has improved, but as a result, fewer pwCF spontaneously expectorate sputum. Thus, the collection of sputum samples has decreased, while the collection of other types of respiratory samples such as oropharyngeal and bronchoalveolar lavage samples has increased. To optimize the detection of microorganisms, including Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, and Burkholderia cepacia complex; other less common non-lactose fermenting Gram-negative bacilli, e.g., Stenotrophomonas maltopholia, Inquilinus, Achromobacter, Ralstonia, and Pandoraea species; and yeasts and filamentous fungi, non-selective and selective culture media are recommended for all types of respiratory samples, including samples obtained from pwCF after lung transplantation. There are no consensus recommendations for laboratory practices to detect, characterize, and report small colony variants (SCVs) of S. aureus, although studies are ongoing to address the potential clinical impact of SCVs. Accurate identification of less common Gram-negative bacilli, e.g., S. maltopholia, Inquilinus, Achromobacter, Ralstonia, and Pandoraea species, as well as yeasts and filamentous fungi, is recommended to understand their epidemiology and clinical import.

PMID:39158301 | DOI:10.1128/cmr.00215-21

World Allergy Organ J. 2024 Jul 24;17(8):100933. doi: 10.1016/j.waojou.2024.100933. eCollection 2024 Aug.

ABSTRACT

BACKGROUND: Type 2 inflammation is the principal determinant of asthma in children, and it leads to the downstream activation of eosinophils (EOS), the production of immunoglobulin-E (IgE), and increased levels of fraction of exhaled nitric oxide (FeNO). Dupilumab received the approval for the treatment of uncontrolled severe Type 2 asthma in children.

OBJECTIVE: The aim of this analysis was to calculate the Type 2 severe asthma paediatric population who would be eligible for treatment with dupilumab in Italy and characterize them by expected biomarker status.

METHODS: The calculation of the dupilumab-eligible population employed a two-phase approach: 1) estimating the total number of children aged 6-11 years with uncontrolled severe asthma; and 2) stratifying the severe uncontrolled asthma population, based on appropriate biomarker levels, thus identifying patients eligible for treatment with dupilumab. The VOYAGE study provided the data for this analysis.

RESULTS: The two-phase approach utilizing VOYAGE data revealed that the average number of paediatric patients with uncontrolled severe asthma was N = 1007. Stratification of these patients, as per VOYAGE data, indicated that the majority (N = 740; 73.5%) would have ≥2 elevated biomarkers, and over one-third patients (N = 434, 43.1%) would exhibit simultaneously elevated levels of EOS, FeNO and IgE. Of the paediatric patients, N = 864 were identified as eligible to dupilumab treatment, constituting 85.8% of the target population. Notably, nearly half eligible patients (N = 454) displayed elevated levels of both EOS and FeNO biomarkers, while the substantial majority (81.1%) exhibited at least an increase of EOS levels (N = 817). Patients with increased FeNO levels without a concurrent increase in EOS were less frequent (N = 47; 5.4% of the eligible population).

CONCLUSION: The simultaneous testing of multiple biomarkers during baseline patient assessment and disease follow-up is highly recommended. Utilizing cost-effective tests, physicians can estimate the prevalence of severe Type 2 asthma, categorize patients into distinct phenotypes (eosinophilic, allergic, or mixed), and consequently identify and prescribe the most suitable therapeutic interventions. This approach also facilitates the ongoing evaluation and adjustment of the treatment strategies based on individual patient responses.

PMID:39156597 | PMC:PMC11327463 | DOI:10.1016/j.waojou.2024.100933