Ann Clin Microbiol Antimicrob. 2024 Jun 17;23(1):54. doi: 10.1186/s12941-024-00709-z.

ABSTRACT

BACKGROUND: Achromobacter spp. are opportunistic pathogens, mostly infecting immunocompromised patients and patients with cystic fibrosis (CF) and considered as difficult-to-treat pathogens due to both intrinsic resistance and the possibility of acquired antimicrobial resistance. Species identification remains challenging leading to imprecise descriptions of resistance in each taxon. Cefiderocol is a broad-spectrum siderophore cephalosporin increasingly used in the management of Achromobacter infections for which susceptibility data remain scarce. We aimed to describe the susceptibility to cefiderocol of a collection of Achromobacter strains encompassing different species and isolation sources from CF or non-CF (NCF) patients.

METHODS: We studied 230 Achromobacter strains (67 from CF, 163 from NCF patients) identified by nrdA gene-based analysis, with available susceptibility data for piperacillin-tazobactam, meropenem and trimethoprim-sulfamethoxazole. Minimal inhibitory concentrations (MICs) of cefiderocol were determined using the broth microdilution reference method according to EUCAST guidelines.

RESULTS: Strains belonged to 15 species. A. xylosoxidans represented the main species (71.3%). MICs ranged from ≤ 0.015 to 16 mg/L with MIC50/90 of ≤ 0.015/0.5 mg/L overall and 0.125/2 mg/L against 27 (11.7%) meropenem-non-susceptible strains. Cefiderocol MICs were not related to CF/NCF origin or species although A. xylosoxidans MICs were statistically lower than those of other species considered as a whole. Considering the EUCAST non-species related breakpoint (2 mg/L), 228 strains (99.1%) were susceptible to cefiderocol. The two cefiderocol-resistant strains (A. xylosoxidans from CF patients) represented 3.7% of meropenem-non-susceptible strains and 12.5% of MDR strains.

CONCLUSIONS: Cefiderocol exhibited excellent in vitro activity against a large collection of accurately identified Achromobacter strains, irrespective of species and origin.

PMID:38886694 | DOI:10.1186/s12941-024-00709-z

IEEE J Biomed Health Inform. 2024 Jun 17;PP. doi: 10.1109/JBHI.2024.3415479. Online ahead of print.

ABSTRACT

Cough is an important symptom in children with acute and chronic respiratory disease. Daily cough is common in Cystic Fibrosis (CF) and increased cough is a symptom of pulmonary exacerbation. To date, cough assessment is primarily subjective in clinical practice and research. Attempts to develop objective, automatic cough counting tools have faced reliability issues in noisy environments and practical barriers limiting long-term use. This single-center pilot study evaluated usability, acceptability and performance of a mechanoacoustic sensor (MAS), previously used for cough classification in adults, in 36 children with CF over brief and multi-day periods in four cohorts. Children whose health was at baseline and who had symptoms of pulmonary exacerbation were included. We trained, validated, and deployed custom deep learning algorithms for accurate cough detection and classification from other vocalization or artifacts with an overall area under the receiver-operator characteristic curve (AUROC) of 0.96 and average precision (AP) of 0.93. Child and parent feedback led to a redesign of the MAS towards a smaller, more discreet device acceptable for daily use in children. Additional improvements optimized power efficiency and data management. The MAS's ability to objectively measure cough and other physiologic signals across clinic, hospital, and home settings is demonstrated, particularly aided by an AUROC of 0.97 and AP of 0.96 for motion artifact rejection. Examples of cough frequency and physiologic parameter correlations with participant-reported outcomes and clinical measurements for individual patients are presented. The MAS is a promising tool in objective longitudinal evaluation of cough in children with CF.

PMID:38885105 | DOI:10.1109/JBHI.2024.3415479

J Thorac Dis. 2024 May 31;16(5):2767-2775. doi: 10.21037/jtd-23-1392. Epub 2024 May 8.

ABSTRACT

BACKGROUND: Bronchiectasis is a common respiratory disease with neutrophilic inflammation being the predominant pathophysiology. Systemic immune-inflammation index (SII) is a simple and readily available biomarker being studied in various conditions including asthma, chronic obstructive pulmonary disease, and interstitial lung disease, but not in bronchiectasis. We aim to investigate the prognostic role of SII in bronchiectasis with this study.

METHODS: A retrospective cohort study in Chinese patients with non-cystic fibrosis (CF) bronchiectasis was conducted in Hong Kong, to investigate the association between baseline SII and of hospitalized bronchiectasis exacerbation risk over 4.5 years of follow-up, as well as correlating with disease severity in bronchiectasis. The baseline SII in 2018 was calculated based on stable-state complete blood count.

RESULTS: Among 473 Chinese patients with non-CF bronchiectasis were recruited, 94 of the patients had hospitalized bronchiectasis exacerbation during the follow-up period. Higher SII was associated with increased hospitalized bronchiectasis exacerbation risks with adjusted odds ratio (aOR) of 1.001 [95% confidence interval (CI): 1.000-1.001, P=0.003] for 1 unit (cells/µL) increase in SII count and aOR of 1.403 (95% CI: 1.126-1.748, P=0.003) for 1 standard deviation (SD) increase in SII. SII was found to have significant negative association with baseline forced expiratory volume in the first second (FEV1) (in litre and percentage predicted), forced vital capacity (FVC) in percentage; and significant positive correlation with the extent of bronchiectasis and baseline neutrophil to lymphocyte ratio (NLR).

CONCLUSIONS: SII could serve as biomarker to predict the risks of hospitalized exacerbation in bronchiectasis patients, as well as correlating with the disease severity.

PMID:38883640 | PMC:PMC11170410 | DOI:10.21037/jtd-23-1392

J Thorac Dis. 2024 May 31;16(5):3366-3370. doi: 10.21037/jtd-23-1648. Epub 2024 May 16.

ABSTRACT

Mycobacterium gordonae (M. gordonae) is a species of nontuberculous mycobacteria (NTM) that rarely causes infection. It has previously been labeled the most common NTM contaminant. Bronchiectasis is a disease characterized by abnormal airway dilation leading to chronic cough, sputum production and pulmonary infections. Patients with bronchiectasis are at higher risk of NTM-lung disease with more pathogenic NTM species including Mycobacterium avium complex (MAC) and Mycobacterium abscessus (M. abscessus). The relationship between bronchiectasis and less-pathogenic NTM species such as M. gordonae is less well understood. We performed a retrospective study on patients who had M. gordonae isolated from respiratory specimens at UConn Health between May 2nd, 2010 and October 18th, 2022. M. gordonae was isolated 74 times from 56 patients. It was isolated 35 (47.3%) times from 31 patients with bronchiectasis and 39 (52.7%) times from 26 patients without bronchiectasis. Data was available on all mycobacterial cultures sent from May 2nd 2018 to October 18th 2022. Mycobacterial cultures sent from patients with bronchiectasis were significantly more likely to grow M. gordonae than patients without bronchiectasis (4.3% vs. 1.6%, P=0.007). Furthermore, when considered at the patient level, there remained a significant increased rate of M. gordonae isolation among patients with bronchiectasis (7.1% vs. 2.2%, P<0.001). We then looked at past and future isolation of more pathogenic NTM species and found a non-statistically increased rate of isolation of more pathogenic NTM species including MAC and M. abscessus in patients with bronchiectasis (45.2% vs. 29%, P=0.09). Based on our results, isolation of M. gordonae should raise suspicion of chronic airway disease and defects in host immune response, such as those seen in bronchiectasis. Furthermore, isolation of M. gordonae may suggest increased risk of infection with more pathogenic NTM species such as MAC and M. abscessus.

PMID:38883635 | PMC:PMC11170426 | DOI:10.21037/jtd-23-1648

Allergy. 2024 Jun 16. doi: 10.1111/all.16198. Online ahead of print.

NO ABSTRACT

PMID:38881035 | DOI:10.1111/all.16198

Lancet. 2024 Jun 15;403(10444):2591-2592. doi: 10.1016/S0140-6736(24)00247-2.

NO ABSTRACT

PMID:38879249 | DOI:10.1016/S0140-6736(24)00247-2

Diagn Microbiol Infect Dis. 2024 May 5;110(1):116327. doi: 10.1016/j.diagmicrobio.2024.116327. Online ahead of print.

ABSTRACT

Whether cross-infection of respiratory pathogens between patients with non-cystic fibrosis bronchiectasis occurs is debated. Investigation with traditional microbiological culture risks simplifying the lung microbiome. We demonstrate the use of culture-independent Multilocus sequence typing to screen for Haemophilus influenzae strain types in a cohort of twenty-eight patients with non-cystic fibrosis bronchiectasis.

PMID:38878342 | DOI:10.1016/j.diagmicrobio.2024.116327

J Allergy Clin Immunol. 2024 Jun 12:S0091-6749(24)00420-2. doi: 10.1016/j.jaci.2024.03.029. Online ahead of print.

ABSTRACT

BACKGROUND: Biologic therapies inhibiting the IL-4 or IL-5 pathways are very effective in the treatment of asthma and other related conditions. However, the cytokines IL-4 and IL-5 also play a role in the generation of adaptive immune responses. Although these biologics do not cause overt immunosuppression, their effect in primary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization has not been studied completely.

OBJECTIVE: Our aim was to evaluate the antibody and cellular immunity after SARS-CoV-2 mRNA vaccination in patients on biologics (PoBs).

METHODS: Patients with severe asthma or atopic dermatitis who were taking benralizumab, dupilumab, or mepolizumab and had received the initial dose of the 2-dose adult SARS-CoV-2 mRNA vaccine were enrolled in a prospective, observational study. As our control group, we used a cohort of immunologically healthy subjects (with no significant immunosuppression) who were not taking biologics (NBs). We used a multiplexed immunoassay to measure antibody levels, neutralization assays to assess antibody function, and flow cytometry to quantitate Spike-specific lymphocytes.

RESULTS: We analyzed blood from 57 patients in the PoB group and 46 control subjects from the NB group. The patients in the PoB group had lower levels of SARS-CoV-2 antibodies, pseudovirus neutralization, live virus neutralization, and frequencies of Spike-specific B and CD8 T cells at 6 months after vaccination. In subgroup analyses, patients with asthma who were taking biologics had significantly lower pseudovirus neutralization than did subjects with asthma who were not taking biologics.

CONCLUSION: The patients in the PoB group had reduced SARS-CoV-2-specific antibody titers, neutralizing activity, and virus-specific B- and CD8 T-cell counts. These results have implications when considering development of a more individualized immunization strategy in patients who receive biologic medications blocking IL-4 or IL-5 pathways.

PMID:38878020 | DOI:10.1016/j.jaci.2024.03.029

Clin Transl Med. 2024 Jun;14(6):e1733. doi: 10.1002/ctm2.1733.

ABSTRACT

BACKGROUND AND AIMS: Smoking is recognised as an independent risk factor in the development of chronic pancreatitis (CP). Cystic fibrosis transmembrane conductance regulator (CFTR) function and ductal fluid and bicarbonate secretion are also known to be impaired in CP, so it is crucial to understand the relationships between smoking, pancreatic ductal function and the development of CP.

METHODS: We measured sweat chloride (Cl-) concentrations in patients with and without CP, both smokers and non-smokers, to assess CFTR activity. Serum heavy metal levels and tissue cadmium concentrations were determined by mass spectrometry in smoking and non-smoking patients. Guinea pigs were exposed to cigarette smoke, and cigarette smoke extract (CSE) was prepared to characterise its effects on pancreatic HCO3 - and fluid secretion and CFTR function. We administered cerulein to both the smoking and non-smoking groups of mice to induce pancreatitis.

RESULTS: Sweat samples from smokers, both with and without CP, exhibited elevated Cl- concentrations compared to those from non-smokers, indicating a decrease in CFTR activity due to smoking. Pancreatic tissues from smokers, regardless of CP status, displayed lower CFTR expression than those from non-smokers. Serum levels of cadmium and mercury, as well as pancreatic tissue cadmium, were increased in smokers. Smoking, CSE, cadmium, mercury and nicotine all hindered fluid and HCO3 - secretion and CFTR activity in pancreatic ductal cells. These effects were mediated by sustained increases in intracellular calcium ([Ca2+]i), depletion of intracellular ATP (ATPi) and mitochondrial membrane depolarisation.

CONCLUSION: Smoking impairs pancreatic ductal function and contributes to the development of CP. Heavy metals, notably cadmium, play a significant role in the harmful effects of smoking.

KEY POINTS: Smoking and cigarette smoke extract diminish pancreatic ductal fluid and HCO3 - secretion as well as the expression and function of CFTR Cd and Hg concentrations are significantly higher in the serum samples of smokers Cd accumulates in the pancreatic tissue of smokers.

PMID:38877637 | DOI:10.1002/ctm2.1733

J Cyst Fibros. 2024 Jun 13:S1569-1993(24)00080-8. doi: 10.1016/j.jcf.2024.06.003. Online ahead of print.

NO ABSTRACT

PMID:38876833 | DOI:10.1016/j.jcf.2024.06.003

J Bodyw Mov Ther. 2024 Jul;39:323-329. doi: 10.1016/j.jbmt.2024.02.036. Epub 2024 Mar 12.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a severe genetic condition that affects multiple organ systems and imposes a substantial treatment burden. Regarding the lungs and airways, the progressive pathophysiological changes place a significant strain on the musculoskeletal components of the respiratory system for people with CF. This pilot study investigated the effectiveness of manual therapy interventions (MTIs) on thoracic mobility, respiratory muscle strength, lung function, and musculoskeletal pain.

METHOD: A study with a pretest-posttest design was conducted with 15 eligible people with CF at the Sahlgrenska University Hospital CF Centre. After an initial set of diagnostic tests at baseline, the participants underwent eight weekly 30-min MTIs. The MTIs included passive joint mobilisation and soft tissue manipulation of primary and secondary anatomical areas of the musculoskeletal respiratory system. On the day of the final intervention, the baseline measurements were repeated.

RESULTS: Trends of increased thoracic mobility were observed following the intervention, with a statistically significant increase in respiratory muscle strength. No change in lung function was observed. Musculoskeletal pain before and after the intervention showed a significant decrease in tender points, and all participants reported positive experiences with MTIs.

CONCLUSION: MTIs may improve thoracic mobility, alleviate pain, and enhance respiratory muscle strength in people with CF. Further research is needed to confirm their potential role as a CF physiotherapy supplement.

CLINICAL TRIAL ID: NCT04696198.

PMID:38876647 | DOI:10.1016/j.jbmt.2024.02.036

Arch Dis Child. 2024 Jun 14:archdischild-2024-327056. doi: 10.1136/archdischild-2024-327056. Online ahead of print.

ABSTRACT

BACKGROUND: Neutrophils are key contributors to chronic airway inflammation in cystic fibrosis (CF) lung disease, although airway and blood-based neutrophil markers are seldom used. The neutrophil-to-lymphocyte ratio (NLR) is an accessible biomarker, the clinical utility of which has not been adequately studied.

OBJECTIVE: This study aimed to investigate the characteristics of the NLR in children with CF and its correlations with acute pulmonary exacerbations and spirometry.

DESIGN: A previous study had collected clinical data from children with CF for a 3-year period between 2016 and 2021. Retrospectively, NLR values were categorised according to patients' clinical status during blood sample collection as 'stable', 'acute pulmonary exacerbation' or 'elective admission for chronic clinical concern'.

MAIN OUTCOME MEASURES: Demographic characteristics associated with the NLR; changes in NLR values in relation to clinical status; relationship between NLR and lung function.

RESULTS: 141 children with CF were included. NLR values during clinical stability were higher in females and increased with age. For children admitted for intravenous antibiotics, NLR values significantly increased from clinical stability (median (IQR)=1.13 (0.75-1.51)) to acute pulmonary exacerbations (median (IQR)=1.50 (0.96-2.65), p=0.001), but similar changes were not observed in elective admissions. The NLR was not associated with lung function.

CONCLUSIONS: The NLR demonstrated associations with clinical status in children with CF with significant elevations during acute pulmonary exacerbations. While its utility as a single-marker measure is limited, monitoring the NLR over time may help identify periods of increased inflammation.

PMID:38876505 | DOI:10.1136/archdischild-2024-327056

Arch Biochem Biophys. 2024 Jun 12:110050. doi: 10.1016/j.abb.2024.110050. Online ahead of print.

ABSTRACT

Mutation of phenylalanine at position 508 in the cystic fibrosis transmembrane conductance regulator (F508del CFTR) yields a protein unstable at physiological temperatures that is rapidly degraded in the cell. This mutation is present in about 90% of cystic fibrosis patients, hence there is great interest in compounds reversing its instability. We have previously reported the expression of the mutated protein at low temperature and its purification in detergent. Here we describe the use of the protein to screen compounds present in a library of Federal Drug Administration (FDA) - approved drugs and also in a small natural product library. The kinetics of unfolding of F508del CFTR at 37°C were probed by the increase in solvent-exposed cysteine residues accessible to a fluorescent reporter molecule. This occurred in a bi-exponential manner with a major (≈60%) component of half-life around 5 minutes and a minor component of around 60 minutes. The faster kinetics match those observed for loss of channel activity of F508del CFTR in cells at 37°C. Most compounds tested had no effect on the fluorescence increase, but some were identified that significantly slowed the kinetics. The general properties of these compounds, and any likely mechanisms for inducing stability in purified CFTR are discussed. These experimental data may be useful for artificial intelligence - aided design of CFTR-specific drugs and in the identification of stabilizing additives for membrane proteins (in general).

PMID:38876247 | DOI:10.1016/j.abb.2024.110050

Physiotherapy. 2024 Jan 5;124:101-105. doi: 10.1016/j.physio.2023.12.006. Online ahead of print.

ABSTRACT

OBJECTIVES: To estimate the carriage of Neisseira meningitidis (meningococci) in expectorated sputum from people with cystic fibrosis (CF) and to evaluate potential ramifications of such carriage for the health and (NM) wellbeing of physiotherapists performing airway clearance techniques.

DESIGN: Descriptive observational study.

MAIN OUTCOME MEASURES: Meningococcal carriage rate, CFTR mutation type and time to first meningococcal culture were determined.

RESULTS: Microbiological data was examined from 100 patients from birth to present (31/12/2021), equating to 2455 patient years. NM was isolated from 6/100 (6%) adult CF patients who had F508del/F508del (homozygous), F508del/other (heterozygous) and other mutations. The median and mean time to first isolation of NM was 213 months and 230 months (standard deviation = 27.6 months), respectively, shortest time was 209 months, longest time 278 months.

CONCLUSIONS: Physiotherapists should be aware of the risks to themselves of acquiring Neisseria meningtidis from CF patients' respiratory aerosols, whilst performing airway clearance techniques. Physiotherapists with underlying medical conditions or with specific concerns about meningococcal disease should discuss their circumstances with their occupational health team, to ensure optimal protection.

PMID:38875837 | DOI:10.1016/j.physio.2023.12.006

Proc Natl Acad Sci U S A. 2024 Jun 18;121(25):e2320782121. doi: 10.1073/pnas.2320782121. Epub 2024 Jun 14.

ABSTRACT

Human bocavirus 1 (HBoV1) is a human parvovirus that causes lower respiratory tract infections in young children. It contains a single-stranded (ss) DNA genome of ~5.5 kb that encodes a small noncoding RNA of 140 nucleotides known as bocavirus-encoded small RNA (BocaSR), in addition to viral proteins. Here, we determined the secondary structure of BocaSR in vivo by using DMS-MaPseq. Our findings reveal that BocaSR undergoes N6-methyladenosine (m6A) modification at multiple sites, which is critical for viral DNA replication in both dividing HEK293 cells and nondividing cells of the human airway epithelium. Mechanistically, we found that m6A-modified BocaSR serves as a mediator for recruiting Y-family DNA repair DNA polymerase (Pol) η and Pol κ likely through a direct interaction between BocaSR and the viral DNA replication origin at the right terminus of the viral genome. Thus, this report represents direct involvement of a viral small noncoding RNA in viral DNA replication through m6A modification.

PMID:38875150 | DOI:10.1073/pnas.2320782121

Clin Nutr ESPEN. 2024 Jun 4;62:285-295. doi: 10.1016/j.clnesp.2024.05.009. Online ahead of print.

ABSTRACT

Micronutrients (MN), i.e. trace elements and vitamins, are essential organic molecules, which are required in the diet in relatively small amounts in any form of nutrition (oral, enteral, parenteral). The probability of MN depletion or deficiencies should be considered in all chronic illnesses, especially in those that can interfere with intake, digestion, or intestinal absorption. Low socio-economic status and food deprivation are recognized as the most prevalent reasons for MN deficiencies world-wide. Elderly multimorbid patients with multimodal therapy, as well as patients with long-lasting menu restrictions, are at high risk for both disease related malnutrition as well as multiple MN deficiencies, needing careful specific follow-up. The importance of monitoring MN blood levels along with CRP is essential for optimal care. Drug interactions are also highlighted. In patients with chronic conditions depending on medical nutrition therapy, the provision of adequate dietary reference intakes (DRI) of MN doses and monitoring of their adequacy belongs to standard of care.

PMID:38875118 | DOI:10.1016/j.clnesp.2024.05.009

Pediatr Allergy Immunol. 2024 Jun;35(6):e14173. doi: 10.1111/pai.14173.

ABSTRACT

BACKGROUND: Little is known about the immune responses during acute asthma exacerbation. In this study, we examined immune responses in children following an acute asthma exacerbation.

METHODS: We evaluated pro-inflammatory cytokine levels and gene expression profiles in blood samples from pediatric patients admitted for acute asthma exacerbation. Viral PCR was performed to differentiate between viral or non-viral-associated exacerbations.

RESULTS: Following informed consent, clinical data were obtained from 20 children with asthma (median [interquartile range, IQR]: age 11.5 [8.0, 14.2]) years and 14 healthy age-matched controls (10.5 [7.0, 13.0]). Twelve had positive nasopharyngeal Polymerase chain reaction (PCR) for viral infection (11 rhinoviruses and 1 respiratory syncytial virus (RSV)). Nine were in the pediatric intensive care unit (PICU) and among them five required continuous positive airway pressure (CPAP). Mean (±SD) days on systemic steroids before drawing blood sample were 2.5 ± 1.6. Twelve had history of environmental allergies with 917 (274, 1396) IU/mL total IgE (median (IQR)). Compared with controls, IL-1RA and IL-10 levels were significantly increased and TNF-α significantly decreased in asthma subjects (p < .05 for all). RNA-seq analysis revealed 852 differentially expressed genes in subjects with asthma. Pathway analysis found upregulated genes and pathways involved in innate immune responses in subjects with asthma. Significantly reduced genes included pathways associated with T helper cell differentiation and activation.

CONCLUSIONS: In acute asthma exacerbation, innate immune pathways remained increased while adaptive immune responses related to T helper cells are blunted and are independent of trigger or asthma severity. Our novel findings highlight the need to identify new therapies to target persistent innate immune responses to improve outcomes in acute asthma.

PMID:38873916 | DOI:10.1111/pai.14173

Front Pediatr. 2024 May 30;12:1345265. doi: 10.3389/fped.2024.1345265. eCollection 2024.

ABSTRACT

BACKGROUND: Primary ciliary dyskinesia (PCD) is considered a rare cause of chronic rhinosinusitis with nasal polyposis (CRSwNP), which is reported in 6% of children with PCD. The forms of PCD associated with the variants of the GAS8 gene identified so far seem to be linked to recurrent respiratory infections (sinusitis, otitis, and bronchiectasis) without situs inversus.

CASE PRESENTATION: We report a case of an 11-year-old girl with recurrent otitis media, productive cough, and chronic rhinosinusitis with nasal polyposis with homozygosity for a novel nonsense mutation in the GAS8.

CONCLUSION: Children with CRSwNP should be treated in a multidisciplinary manner (ENT, pulmonologist, allergist, pathologist, pediatrician, and geneticist) because nasal polyposis often hides etiologies that must be recognized.

PMID:38873586 | PMC:PMC11169881 | DOI:10.3389/fped.2024.1345265

Eur Respir J. 2024 Jun 13:2301769. doi: 10.1183/13993003.01769-2023. Online ahead of print.

ABSTRACT

BACKGROUND: Primary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterized by deficient ciliary airway clearance that can be associated with laterality defects. We aimed to describe the underlying gene defects, geographical differences in genotypes and their relationship to diagnostic findings and clinical phenotypes.

METHODS: Genetic variants and clinical findings (age, sex, body mass index, laterality defects, FEV1) were collected from 19 countries using the ERN LUNG International PCD Registry. Genetic data were evaluated according to ACMG guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV1.

RESULTS: 1236 individuals carried 908 distinct pathogenic DNA variants in 46 PCD genes. We found considerable variation in the distribution of PCD genotypes across countries due to the presence of distinct founder variants. The prevalence of PCD genotypes associated with pathognomonic ultrastructural defects (mean 72%; 47-100%) and laterality defects (mean 42%; 28-69%) varied widely among the countries. The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). The PCD cohort had a reduced median FEV1 z-score (-1.66). In the group of individuals with CCNO (-3.26), CCDC39 (-2.49), and CCDC40 (-2.96) variants, FEV1 z-scores were significantly lower, while the group of DNAH11 (-0.83) and ODAD1 (-0.85) variant individuals had significantly milder FEV1 z-score reductions compared to the whole PCD cohort.

CONCLUSION: This unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of genetic epidemiology of PCD and provides prediction of diagnostic and phenotypic features such as the course of lung function.

PMID:38871375 | DOI:10.1183/13993003.01769-2023

Chest. 2024 Jun 11:S0012-3692(24)00698-6. doi: 10.1016/j.chest.2024.05.019. Online ahead of print.

ABSTRACT

BACKGROUND: Historically, studies show that females with cystic fibrosis (CF) have worse pulmonary outcomes than males, including decreased life expectancy. It is unknown whether this disparity persists in the new era of highly effective modulator therapies (HEMTs). Ivacaftor has been available in the United States for over ten years, allowing for the opportunity to understand the impact this therapy may have on sex disparities in CF. We hypothesize that females will continue to have worse outcomes as we suspect the disparity is not solely driven by ion channel dysfunction.

RESEARCH QUESTION: Does a male female difference in outcomes persist after the initiation of ivacaftor in people with CF?

STUDY DESIGN AND METHODS: We conducted a retrospective cohort study using the CF Foundation Patient Registry (CFFPR) comparing changes in pulmonary exacerbation rate, lung function (ppFEV1), and presence of Pseudomonas aeruginosa among males versus females pre- and post- initiation of treatment with the highly effective modulator, ivacaftor.

RESULTS: Our cohort consisted of 1900 people with CF who were treated with ivacaftor between 2010-2017; 928 (48.84%) were male and 972 (51.16%) were female with a mean age of 33.09 years. Males had a significant decrease in pulmonary exacerbations post-ivacaftor (0.38 to 0.34, adjusted rate ratio of 0.89, p = 0.028) while females did not (0.48 to 0.45, adjusted rate ratio 0.95, p = 0.174). ppFEV1 similarly decreased in both males and females pre- vs post-ivacaftor. P. aeruginosa prevalence decreased to a similar extent in both males and females post-ivacaftor.

INTERPRETATION: Our findings demonstrate that sex disparities in CF persist in those treated with ivacaftor due to differences in pulmonary exacerbations. More research is needed to determine the specific pathophysiologic drivers of this disparity.

PMID:38871282 | DOI:10.1016/j.chest.2024.05.019