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Reducing treatment burden is a priority for people with cystic fibrosis, whose health has benefited from using new modulators that substantially increase CFTR protein function. The SIMPLIFY study aimed to assess the effects of discontinuing nebulised hypertonic saline or dornase alfa in individuals using the CFTR modulator elexacaftor plus tezacaftor plus ivacaftor (ETI).The SIMPLIFY study included two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials at 80 participating clinics across the USA in the Cystic Fibrosis Therapeutics Development Network. We included individuals with cystic fibrosis aged 12-17 years with percent predicted FEVFrom Aug 25, 2020, to May 25, 2022, a total of 672 unique participants were screened for eligibility for one or both trials, resulting in 847 total random assignments across both trials with 594 unique participants. 370 participants were randomly assigned in the hypertonic saline trial and 477 in the dornase alfa trial. Participants across both trials had an average ppFEVIn individuals with cystic fibrosis on ETI with relatively well preserved pulmonary function, discontinuing daily hypertonic saline or dornase alfa for 6 weeks did not result in clinically meaningful differences in pulmonary function when compared with continuing treatment.

RATIONALE: People with cystic fibrosis (CF) experience acute worsening of respiratory symptoms and lung function known as pulmonary exacerbations. Treatment with intravenous antimicrobials is common; however, there is scant evidence to support a standard treatment duration. OBJECTIVES: To test differing durations of intravenous antimicrobials for CF exacerbations. METHODS: STOP2 (Standardized Treatment of Pulmonary Exacerbations 2) was a multicenter, randomized, controlled clinical trial in exacerbations among adults with CF. After 7–10 days of treatment, participants exhibiting predefined lung function and symptom improvements were randomized to 10 or 14 days’ total antimicrobial duration; all others were randomized to 14 or 21 days’ duration. MEASUREMENTS AND MAIN RESULTS: The primary outcome was percent predicted FEV(1) (ppFEV(1)) change from treatment initiation to 2 weeks after cessation. Among early responders, noninferiority of 10 days to 14 days was tested; superiority of 21 days compared with 14 days was compared for the others. Symptoms, weight, and adverse events were secondary. Among 982 randomized people, 277 met improvement criteria and were randomized to 10 or 14 days of treatment; the remaining 705 received 21 or 14 days of treatment. Mean ppFEV(1) change was 12.8 and 13.4 for 10 and 14 days, respectively, a ‒0.65 difference (95% CI [‒3.3 to 2.0]), excluding the predefined noninferiority margin. The 21- and 14-day arms experienced 3.3 and 3.4 mean ppFEV(1) changes, a difference of ‒0.10 (‒1.3 to 1.1). Secondary endpoints and sensitivity analyses were supportive. CONCLUSIONS: Among adults with CF with early treatment improvement during exacerbation, ppFEV(1) after 10 days of intravenous antimicrobials is not inferior to 14 days. For those with less improvement after one week, 21 days is not superior to 14 days. Clinical trial registered with www.clinicaltrials.gov (NCT02781610).

Achromobacter xylosoxidans is increasingly recognized as a colonizer of cystic fibrosis (CF) patients, but the role that A. xylosoxidans plays in pathology remains unknown. This knowledge gap is largely due to the lack of model systems available to study the toxic potential of this bacterium. Recently, a phospholipase A(2) (PLA(2)) encoded by a majority of A. xylosoxidans genomes, termed AxoU, was identified. Here, we show that AxoU is a type III secretion system (T3SS) substrate that induces cytotoxicity to mammalian cells. A tissue culture model was developed showing that a subset of A. xylosoxidans isolates from CF patients induce cytotoxicity in macrophages, suggestive of a pathogenic or inflammatory role in the CF lung. In a toxic strain, cytotoxicity is correlated with transcriptional activation of axoU and T3SS genes, demonstrating that this model can be used as a tool to identify and track expression of virulence determinants produced by this poorly understood bacterium.

A 27-year-old lady with a history of neurofibromatosis-1 and cognitive impairment, presented with several days of progressive dyspnea. She had recently delivered a healthy baby and for some time her dyspnea had been attributed to her pregnancy. On exam, she hadinnumerable neurofibromas on face, back, trunk and extremities. Breath sounds were absent in the left hemithorax, along with dullness to percussion. Chest X ray showed complete opacification of the left hemithorax (Figure 1). CT chest showed large partially necrotic left perihilar mass with extension into thebronchial tree, left lung collapse and left pleural effusion (Figure 2). PET scan showed the lung mass to be PET avid (Figure 3). Bronchoscopy revealed the tumor to be completely obstructing left mainstem bronchus, biopsies were obtained. Histopathology showed a hypercellular spindle cell neoplasm with immunohistochemistry confirmingmalignant peripheral nerve sheath tumor (MPNST). Patient was treated with radiation to the left hemithorax. After 5 fractions of radiation therapy, significant decrease was noted in the tumor size (Figure 4). MPNSTs are a rare type of soft tissue sarcomas with incidence of 0.001% in the general population; however incidence substantially increases with neurofibromatosis-1 [1] Most of the cases originate in the extremities and abdomen, with lungs being an extremely unusual site for a primary MPNST. Even though MPNSTs are relatively more common with neurofibromatosis-1, almost all cases of primary lung MPNSTs have been described in patients without neurofibromatosis [2,3]. We believe our case to be one of the first reports of primary pulmonary MPNST in a patient with neurofibromatosis-1.

Cystic fibrosis (CF) patients suffer from chronic lung inflammation. This inflammation may activate platelets. There are limited data on the role of platelet-secreted cytokines in CF. Platelet cytokines with inflammatory effects include vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1). As levels of these cytokines are tenfold greater in serum than plasma due to platelet release, serum levels may be one index of platelet content, but a more specific index is release during the aggregation of isolated platelets. We postulated that altered release of these platelet cytokines occurs in CF. We obtained sera and plasma from CF outpatients (n = 21) and from healthy controls (n = 20), measured VEGF and TGF-β1, assessed for correlations with platelet number, analyzed cytokine release during platelet aggregation to collagen, and analyzed differences in maximal platelet aggregation. Platelet number and maximal aggregation levels were higher in CF. Plasma and serum levels of TGF-β1 and VEGF were higher in CF, but these levels were similar after adjusting for platelet number (serum cytokines correlated with platelet count). The release of VEGF and TGF-β1 during aggregation was decreased in CF platelets (by 52 and 29 %, respectively). Platelet release is not a source of the elevated blood proinflammatory cytokines TGF-β1 and VEGF in CF, as platelets from CF patients actually release less of these cytokines. These data provide further evidence for platelet defects in CF.

Background/Objectives Following repair of congenital heart disease (CHD), adult patients are at risk for reduced exercise capacity. Restrictive lung disease (RLD) may contribute to reduced exercise capacity in this population. The aim of this study was to determine the prevalence of RLD and its impact on exercise tolerance in the adult with CHD. Methods One hundred consecutive adult patients with CHD, who underwent routine cardiopulmonary exercise testing with spirometry, were evaluated. Clinical data were obtained by retrospective chart review. Results Patients from 10 major diagnostic groups were identified. The median age for the cohort was 31 years (range 18–63) and included 43 males and 57 females. Most patients, 79%, had at least one previous surgical procedure. Based on spirometry and flow/volume loops, 50 patients were classified as normal pulmonary function, 44 patients had patterns suggestive of RLD, 4 suggestive of mixed (obstructive and restrictive), and 2 indeterminate. Risk factors associated with RLD include history of multiple thoracotomies (odds ratio = 9.01, P =.05) and history of atrial arrhythmias (odd ratio = 4.25, P =.05). Overall, 56% of the patients had abnormal exercise capacity. Spirometry suggestive of RLD was a significant risk factor for decreased exercise capacity (odds ratio = 3.65, P =.03). Patients with spirometry suggesting RLD also had lower exercise duration (P =.004) and a higher New York Heart Association Functional Class (P =.02). History of previous surgery and decreased heart rate reserve were also significant risk factors for decreased exercise capacity. Conclusion Abnormal spirometry suggestive of RLD is common in the adult with CHD and is a significant risk factor for decreased exercise tolerance in this population. Further studies are needed to evaluate the relationship between RLD and exercise intolerance and its relationship to mortality in the adult with CHD.

Anemia is associated with increased morbidity and mortality in many chronic diseases. Little is known about anemia in cystic fibrosis (CF). Because the majority of patients with CF die of lung disease, the objective of this study was to identify the frequency, severity, and mechanisms of anemia in CF and to determine if there was an association between anemia and poor lung function in these patients. Vitamin deficiency was used to assess the association of malabsorption and anemia.Charts of 218 CF patients (ages1 month to 61 years) were reviewed. Information extracted included medical history, complete blood counts, iron studies, pulmonary function tests, vitamin levels, serum creatinine levels, and medications.As patients aged, anemia increased from 12% in those16 to 58.3%or = age 40. Anemic patients had poorer lung function than nonanemic patients. Mean forced expiratory volume (FEV(1)) and forced vital capacity (FVC) were 51.6% (SEM +/- 10.3) and 69.7% (SEM +/- 9.3) in anemic and 82.5% (SEM +/- 9.2) and 95% (SEM +/- 8.3) in nonanemic patients, respectively (P.001). Of vitamin-deficient patients, 90% were anemic whereas only 59.5% of nonvitamin-deficient patients were anemic (P = .02). Complete iron studies were only available in 17 of 48 anemic patients and 11 were diagnosed with iron deficiency.Anemia in CF is associated with poor lung function and vitamin deficiency. Although anemia was often incompletely evaluated, iron deficiency was common. Recognition and complete evaluation of anemia might be important for continued improvement of care in CF.

Purpose of review Treatment options for individuals with cystic fibrosis (CF) have improved survival significantly over the past two decades. One important treatment modality is inhaled antibiotics to treat chronic infection of the airways. This review includes those antibiotics that are currently in use, those that are in clinical trials. It also includes review of nonantibiotic antimicrobials, a growing area of investigation in CF. Recent findings There are currently three inhaled antibiotics that are approved for use in patients with cystic fibrosis: tobramycin, aztreonam, and colistimethate. Tobramycin and colistimethate now are available as solution and new dry powder formulations, which are helping the treatment burden which has increased in CF. New antibiotics are in trial, although recently two did not meet primary outcomes in large clinical trials. Of particular interest is the development of nonantibiotic antimicrobials, which may allow treatment of intrinsically antibiotic resistant organisms. Summary Inhaled antibiotics remain an important treatment option in cystic fibrosis due to chronic airway infection as a hallmark of the disease. Although there are now multiple options for treatment, improvements in this treatment class are needed to treat intrinsically resistant organisms. New formulation of antibiotics and nonantibiotic antimicrobials are being evaluated to add to our armamentarium.

Recent studies have reported acidification of exhaled breath condensate (EBC) in inflammatory lung diseases. This phenomenon, designated "acidopnea," has been attributed to airway inflammation.To determine whether salivary acids and bases can influence EBC pH in chronic obstructive pulmonary disease (COPD).Measurements were made of pH, electrolytes, and volatile bases and acids in saliva and EBC equilibrated with air in 10 healthy subjects and 10 patients.The average EBC pH in COPD was reduced (normal, 7.24 +/- 0.24 SEM; range, 6.11-8.34; COPD, 6.67 +/- 0.18; range, 5.74-7.64; p = 0.079). EBCs were well buffered by NH(4)(+)/NH(3) and CO(2)/HCO(3)(-) in all but four patients, who had NH(4)(+) concentrations under 60 micromol/L, and acetate concentrations that approached or exceeded those of NH(4)(+). Saliva contained high concentrations of acetate (approximately 6,000 micromol/L) and NH(4)(+) (approximately 12,000 micromol/L). EBC acetate increased and EBC NH(4)(+) decreased when salivary pH was low, consistent with a salivary source for these volatile constituents. Nonvolatile acids did not play a significant role in determining pH of condensates because of extreme dilution of respiratory droplets by water vapor (approximately 1:12,000). Transfer of both acetic acid and NH(3) from the saliva to the EBC was in the gas phase rather than droplets.EBC acidification in COPD can be affected by the balance of volatile salivary acids and bases, suggesting that EBC pH may not be a reliable marker of airway acidification. Salivary acidification may play an important role in acidopnea.

Objective To evaluate several alternative measures of forced expiratory volume in 1 second percent predicted (FEV 1 %pred) variability as potential predictors of future FEV 1 %pred decline in patients with cystic fibrosis. Study design We included 13 827 patients age ≥6 years from the Epidemiologic Study of Cystic Fibrosis 1994-2002 with ≥4 FEV 1 %pred measurements spanning ≥366 days in both a 2-year baseline period and a 2-year follow-up period. We predicted change from best baseline FEV 1 %pred to best follow-up FEV 1 %pred and change from baseline to best in the second follow-up year by using multivariable regression stratified by 4 lung-disease stages. We assessed 5 measures of variability (some as deviations from the best and some as deviations from the trend line) both alone and after controlling for demographic and clinical factors and for the slope and level of FEV 1 %pred. Results All 5 measures of FEV 1 %pred variability were predictive, but the strongest predictor was median deviation from the best FEV 1 %pred in the baseline period. The contribution to explanatory power (R 2 ) was substantial and exceeded the total contribution of all other factors excluding the FEV 1 %pred rate of decline. Adding the other variability measures provided minimal additional value. Conclusions Median deviation from the best FEV 1 %pred is a simple metric that markedly improves prediction of FEV 1 %pred decline even after the inclusion of demographic and clinical characteristics and the FEV 1 %pred rate of decline. The routine calculation of this variability measure could allow clinicians to better identify patients at risk and therefore in need of increased intervention.

Evaluation of the utility of exhaled breath condensates in chronic obstructive pulmonary disease.Exhaled breath condensates have recently been introduced as a simple, noninvasive method of sampling respiratory fluid in inflammatory lung disorders, including chronic obstructive pulmonary disease. Increases in condensate concentrations of at least 12 markers of inflammation have been reported in these disorders. Furthermore, condensate pH appears to be decreased in both chronic obstructive lung disease and bronchial asthma. This has been referred to as acidopnea and could reflect airway acidification by inflammatory cells. Although safer and more convenient than bronchoalveolar lavage, interpretation of condensate data is complicated by uncertainty regarding the source of condensate solutes and by variable dilution of respiratory droplets from condensed water vapor, which represents more than 99.9% of condensate volumes. This dilution can be estimated from the dilution of plasma constituents such as urea or electrolytes. Because the principal buffer in condensate is NH4, much of which is derived from bacterial degradation of urea in the mouth, condensate pH measurements may not provide accurate estimates of airway pH. Nevertheless, acidification of condensate may be indicative of gastroesophageal reflux, which frequently occurs in obstructive lung diseases and may contribute to cough and bronchospasm.It is too early to tell how useful condensate studies will be to pulmonary investigators and clinicians. Realization of the enormous potential of this approach will require a thorough understanding of the manner in which these solutions are generated and how they should be analyzed.

There is an urgent need for diagnostic procedures that can detect aspiration of oral and gastrointestinal (GI) secretions into the respiratory tract. Current approaches are limited by poor sensitivity and specificity. These techniques include (1) adding indicators to feedings; (2) recovery of lipid-filled macrophages in respiratory secretions; (3) measurement of changes in the pH of the upper GI and respiratory tracts; (4) endoscopic visualization of reflux events; and (5) measurement of increased glucose concentrations in respiratory secretions. Ideally, specific markers from various sites in the oral and GI tracts might be discovered in respiratory secretions, but conventional bronchoalveolar lavage for sampling respiratory secretions is not practical and involves some risk. Noninvasive measurements of indicators in the exhaled breath condensates could be used to detect aspiration, but a number of theoretical and practical aspects of such studies must be considered before this approach can be applied to the problem of aspiration.

This study examined the effectiveness of a cognitive behavioral intervention for young adults with cystic fibrosis (CF). Four young adults were referred for the therapy by medical staff because of perceived problems with anxiety, anger, or coping. Treatment impact was assessed on measures of anxiety, anger, perceptions of functional disability, and coping. A multiple baseline design across subjects was used. Overall, the impact of the cognitive behavioral intervention for young adults with CF was mixed. If participants had elevated baseline scores on anxiety, anger, or perceived functional disability, then some improvement was shown. However, only one participant had elevated baseline anxiety and anger scores, while two had higher functional disability scores. For coping, only one participant clearly displayed a greater use of approach relative to avoidance coping by the end of treatment. Results are discussed in terms of treatment implications, assessment, and coping issues.

Aspiration of acid from the stomach and water from the mouth can cause significant lung injury. Animal experiments suggest that acid entering the lungs is normally neutralized by bicarbonate derived from the plasma. It is hypothesized that this process may be impaired in patients with cystic fibrosis and that some of the airway injury that they experience may be related to this defect. This disease is characterized by abnormalities in the cystic fibrosis transmembrane conductance regulator, which normally conducts bicarbonate and chloride exchange. Evidence is discussed regarding the role of water channels (aquaporins) in transporting water from the airspaces into the vasculature.

Examined the effectiveness of a cognitive behavioral intervention to help adolescents with cystic fibrosis (CF) cope with daily stressors. Five youths were referred for the therapy by medical staff because of perceived problems with anxiety or coping. Treatment impact was assessed on measures of coping, anxiety, perceptions of functional disability, and parental reports of behavior. A multiple baseline design across subjects was used. Reductions in anxiety, a decrease in maladaptive coping efforts with CF-related problems, and an increase in positive coping with CF-related problems were obtained. Youths also reported a decrease in functional disability due to CF after the initiation of the intervention. Follow-up assessment indicated that most youths maintained gains in anxiety and perceived functional disability, but not coping efforts. Results suggest that cognitive behavioral treatment is a viable intervention for anxious youths with CF.

The exhaled breath condensate (EBC) approach provides a convenient and noninvasive approach for sampling the pulmonary epithelial lining fluid (ELF). Increased EBC concentrations of more than a dozen inflammatory markers and hydrogen ions have been reported in lung diseases associated with inflammation. However, the usefulness of EBC is compromised by uncertainties concerning the sources of the EBC droplets and by the extreme and variable dilution of ELF droplets with condensed water vapor (∼20,000-fold). Reported increases in EBC concentrations may reflect proportionate increases in the total volume rather than the concentration of ELF droplets in the collected samples. Conclusions regarding ELF concentrations can only be made if this dilution is estimated with a dilutional indicator (e.g., conductivity of lyophilized EBC). In normal EBC samples, pH is effectively set by oral contamination with NH3, and EBC pH cannot provide reliable information regarding ELF pH in normal subjects. Acidification of EBC observed in asthma and other conditions may reflect acidification of ELF, decreases in NH3 added to the EBC, and/or the presence of gastric droplets in the EBC.

Exhaled breath condensates have been widely used to detect inflammatory mediators in the fluid that covers airway surfaces of patients with inflammatory lung disorders. This approach is much less invasive than bronchoalveolar lavage, but respiratory droplets are markedly diluted by large and variable amounts of water vapor. We estimated the dilution of respiratory droplets by comparing concentrations of nonvolatile, reference indicators (total nonvolatile cations, urea or conductivity) in 18 normal subjects with normal plasma concentrations by assuming similar concentrations in the respiratory fluid and plasma. The volatile cation, NH4+ (most of which is delivered as NH3 gas from the mouth), represented 93 +/- 3% (SEM) of the condensate cations. More than 99% of the NH4+ was removed by lyophilization, making it possible to use conductivity to estimate total nonvolatile ionic concentrations and facilitating analysis of urea. Conductivity was significantly correlated with electrolyte and urea concentrations. Estimates of dilution based on total cations, conductivity, and urea were not significantly different (cations: 20,472 +/- 2,516; conductivity: 21,019 +/- 2,427; and urea: 18,818 +/- 2,402). These observations suggest that the conductivity of lyophilized samples can be used as an inexpensive, simple, and reliable method for estimating dilution of nonvolatile, hydrophilic mediators in condensates.

Studies of transport across the membranes that separate the pulmonary vasculature from the alveoli have been associated with theoretical and practical problems which have challenged the ingenuity of investigators for decades. It is difficult to distinguish between alveolar and airway transport in the intact lung, or to define the relative roles of different cells that line the alveoli. Monolayers of type II pneumocytes have been used to characterize solute transport in the distal lungs, but uncertainties persist regarding the identity and properties of these cells (Mason et al., 1982; Crandall et al., 1982). The morphology of isolated alveolar cells changes in culture from that of type II pneumocytes to flatter cells, which appear to be similar to type I pneumocytes. Since the former cover less than 5% of the surface of the lungs, they may not be representative of the normal barrier that separates the gaseous phase from the blood flowing through the lungs. Whether the cells that have been in culture for longer intervals have transport properties similar to those of the type I pneumocytes will remain uncertain unless the function of these cells can be compared with that of cells in the intact lung.

CF is a chronic disease associated with inflammation and an unknown prevalence of anemia. In other settings anemia is associated with increased morbidity and mortality, and recognition and correction of anemia in CF patients might lead to better outcomes. We hypothesized that chronic inflammation (ACI), iron deficiency (IDA) and malabsorption may be important mechanisms contributing to the anemia in CF patients. METHODS: Clinical charts and portCF.org visit logs of 218 patients of all ages (1 m to 61 yrs) with CF were reviewed for as many years as charts permitted (range 1–7 yrs). The following data were extracted: CBC, iron studies, pulmonary function tests (PFTs), vitamins A, D, and E levels, creatinine, pertinent medical history, and current medications. Anemia was defined by age- and gender-specific WHO criteria. Patients were considered anemic if low Hb was present on two separate occasions at least two months apart, or average annual Hb met WHO criteria. PFTs in 176 patients (all >6 yrs) included forced expiratory volume (FEV1) and forced vital capacity (FVC) as percent predicted of normal and were considered a reflection of patient performance. The most representative annual PFT from at least 4 annual tests was chosen for analysis since acute infection adversely influences daily performance. Semiannual vitamin levels of 47 adults were correlated with corresponding Hb values. RESULTS: 61 of 218 patients, ages 1 m to 61 yrs, were anemic (prevalence 28%). The percent of anemia in different age groups varied. Children 18 yrs, 48 were anemic (43%) with a progressive age-related increase in the prevalence of anemia reaching 58% in patients >40 yrs. Complete iron studies were available in 16/48 patients. 7 were identified as IDA, 4 as ACI, and 3 as combined; 2 others had renal failure. In 32 patients, iron studies were incomplete, but renal failure, hemoptysis, hematochezia and solid organ transplants were contributing factors in half. PFTs obtained in 176 patients >7 yrs were compared in anemic and non-anemic patients. Mean FEV1 and FVC at all ages were statistically significantly poorer in the anemic patients (p CONCLUSIONS: The prevalence of anemia in CF patients is high and increases with age. In patients for whom iron studies were available, IDA was the prominent underlying mechanism, followed by ACI or a combination of both. There was no correlation between fat soluble vitamin levels and Hb, indicating malabsorption is not a major contributor to the anemia. There was a strikingly significant association between anemia and poor pulmonary function in all age groups. In addition, a group of non-anemic patients with poor lung function had relative iron deficiency. Our results indicate that iron deficiency in anemic CF patients, as well as relative iron deficiency in non-anemic CF patients might be underrecognized and undertreated. Since anemia is associated with poor pulmonary function, correction of anemia should be attempted. Identification of relative iron-deficient states in non- or borderline anemic CF patients with poor lung function could be important since iron supplementation might allow Hb levels to increase as an appropriate response to hypoxia.

As extra-cranial metastasis of glioblastoma multiforme (GBM) is rare, it may create a diagnostic dilemma especially during interpretation of fine needle aspiration biopsy (FNAB) cytology.