What the nose knows of cystic fibrosis microbes and hypertonic saline.

We are very uncertain if regular use of nebulised hypertonic saline by adults and children over the age of 12 years with CF results in an improvement in lung function after four weeks (three trials; very low-certainty evidence); there was no difference seen at 48 weeks (one trial; low-certainty evidence). Hypertonic saline improved LCI modestly in children under the age of six years. Evidence from one small cross-over trial in children indicates that rhDNase may lead to better lung function than hypertonic saline at three months; qualifying this, we highlight that while the study did demonstrate that the improvement in FEV₁ was greater with daily rhDNase, there were no differences seen in any of the secondary outcomes. Hypertonic saline does appear to be an effective adjunct to physiotherapy during acute exacerbations of lung disease in adults. However, for the outcomes assessed, the certainty of the evidence ranged from very low to low at best, according to the GRADE criteria. The role of hypertonic saline in conjunction with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy now needs to be considered, and future research needs to focus on this aspect.

Background: Inhalation of hypertonic saline (HS) is standard of care in patients with cystic fibrosis (CF). However, it is unclear if adding salbutamol has-besides bronchodilation-further benefits, for example, on the mucociliary clearance. We assessed this in vitro by measuring the ciliary beating frequency (CBF) and the mucociliary transport rate (MCT) in nasal epithelial cells (NECs) of healthy volunteers and patients with CF. Aims: To investigate the effect of HS, salbutamol, and its combination on (muco)ciliary activity of NECs in vitro, and to assess potential differences between healthy controls and patients with CF. Methods: NECs obtained from 10 healthy volunteers and 5 patients with CF were differentiated at the air-liquid interface and aerosolized with 0.9% isotonic saline ([IS] control), 6% HS, 0.06% salbutamol, or combined HS and salbutamol. CBF and MCT were monitored over 48-72 hours. Results: In NECs of healthy controls, the absolute CBF increase was comparable for all substances, but CBF dynamics were different: HS increased CBF slowly and its effect lasted for an extended period, salbutamol and IS increased CBF rapidly and the effect subsided similarly fast, and HS and salbutamol resulted in a rapid and long-lasting CBF increase. Results for CF cells were comparable, but less pronounced. Similar to CBF, MCT increased after the application of all the tested substances. Conclusion: CBF and MCT of NECs of healthy participants and CBF of patients with CF increased upon treatment with aerosolized IS, HS, salbutamol, or HS and salbutamol, showing a relevant effect for all tested substances. The difference in the CBF dynamics can be explained by the fact that the properties of the mucus are changed differently by different saline concentrations.

Background Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline (HS) enhances mucociliary clearance in vitro and may lessen the destructive inflammatory process in the airways. Objectives To investigate the effects of nebulised HS in CF compared to placebo or other treatments for mucociliary clearance. Search methods We searched the Cochrane CF and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 31 July 2008. Selection criteria Controlled trials assessing HS compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity). Data collection and analysis Two authors independently reviewed all identified trials and data; and assessed trial quality. Main results Twelve trials (442 participants, aged 6 to 46 years) were included; five excluded and two await classification. In two placebo-controlled trials, HS (3% to 7%, 10 ml twice-a-day) significantly increased forced expiratory volume at one second (FEV1) at four weeks, mean difference (MD) 4.15 (95% CI 1.14 to 7.16); but not significantly after 48 weeks, MD 2.31 (95% CI -2.72 to 7.34). Two trials compared a similar dose of HS to recombinant deoxyribonuclease (RhDNAse). One three-week trial showed a non-significant difference, MD 1.60 (95% CI -7.96 to 11.16). However, in the second trial, after 12 weeks, RhDNAse led to a greater increase in FEV1 than HS (5 ml twice-daily), in participants with moderate to severe lung disease, MD 8.00 (95% CI 2.00 to 14.00). One 48-week placebo-controlled trial showed significant improvements in frequency of antibiotic use and quality of life; also that HS did not increase the concentration of Pseudomonas aeruginosa or Staphylococcus aureus. Authors' conclusions Treatment with 7% HS for 48 weeks showed a small improvement in FEV1 at four weeks; however, this was not sustained at 48 weeks (primary outcome measure of the only long-term trial). Unlike RhDNAse, HS can't, in the long term, be said to improve lung function. However, it did improve quality of life and reduce pulmonary exacerbations. Delivered following a bronchodilator, HS appears inexpensive and safe with no increased infection risk. We believe there is sufficient evidence to recommend using HS in CF; qualifying this we highlight that the only long-term trial failed to demonstrate a significant difference in its primary outcome (lung function) with improvements only in secondary outcomes.

<b>Obective:</b> Hypertonic saline(HS) and recombinant human deoxyribonuclease(rhDNase) are used to force airway clearance in cystic fibrosis(CF) patients. We aimed to evaluate the efficacy of ihaled HS therapy in CFpatients receiving daily rhDNase. <b>Method:</b> A retrospective case-control study was conducted by using the data of our national CF registry. The efficacy of HS was analyzed among patients who used only HS(n:35) and who didnot receive any hydrator therapy(n:227)(control group) between 2017-2019. The efficacy of HS was mainly evaluated by comparing pulmonary functions and body mass index(BMI). <b>Result:</b> Patients(n:271) who had annual records between 2017-2019 and used neither inhaled HS nor inhaled mannitol in2017 were included in the study. The ppFEV1,FEV1z-scores of the group in whom HS treatment was initiated were significantly lower than the control group(p:0.002,p:0.037);presence of chronic bacterial colonization(p:0.010),inhaled antibiotic usage(p&lt;0.001),O2 and NIMV requirements(p:0.030,p&lt;0.001) were significantly hihgher also. At the end of the study in the records of2019, absolute changes in FEV1,FEV1/FVCz-scores and BMIz-score did not differ significantly between groups. Absolute changes in FVCwere better in the control group(p:0.006). The paired analyses showed no significant improvement in spirometry indices of the HS treament group. There was a significant improvement in pulmonary functions and BMI in the control group at the end of the study. <b>Conclusions:</b> HS was started mostly in patients who had severe clinical status;but unfortunately HS didnot significantly improve the FEV1,FVC,FEV1/FVC and BMI of CF,whose respiratory functions are unaffected or mildly affected.

The effect of inhaled hypertonic saline on lung structure in children aged 3–6 years with cystic fibrosis (SHIP-CT): a multicentre, randomised, double-blind, controlled trial

Chinese experts consensus statement: diagnosis and treatment of cystic fibrosis (2023)

To review the literature concerning the use of hypertonic saline (HS) in patients with cystic fibrosis and explain the rationale for its use. A MEDLINE search was conducted through February 2007. Search terms included hypertonic saline, mucociliary clearance, cystic fibrosis, and human DNASE 1 protein. Additional data were identified through subsequent bibliographic reviews. All articles in English identified from the data sources were evaluated. Pertinent studies using HS in patients with cystic fibrosis were included in the analysis. Cystic fibrosis is caused by a deficiency in the cystic fibrosis transmembrane regulator gene, resulting in reduced chloride secretion and excessive sodium absorption. The most significant changes are seen in the airway lumen of the lungs. HS has been shown to improve mucociliary clearance versus placebo. A short-term efficacy trial showed a modest and variable increase in forced expiratory volume in 1 second (FEV(1)) over a 2 week period (15.0 +/- 16.0% from baseline vs 2.8 +/- 13.1% with HS 6% and NaCl 0.9%, respectively; p = 0.004). A long-term efficacy trial of either HS 7% or NaCl 0.9% twice daily for 48 weeks has shown a modest sustained improvement in FEV(1) and a significantly increased exacerbation-free survival rate (76% vs 62% for HS 7% and NaCl 0.9%, respectively; p = 0.03). HS preceded by a bronchodilator is an inexpensive, safe, effective additional therapy in cystic fibrosis patients with stable lung function. Its use has been associated with a modest improvement in lung function and reduced frequency of pulmonary exacerbations.

Lung disease in cystic fibrosis is characterised by impaired mucociliary clearance. Hypertonic saline has been shown to enhance mucociliary clearance in vitro and this may act to lessen the destructive inflammatory process in the airways. To investigate the effects of treatment with nebulised hypertonic saline on people with cystic fibrosis compared to placebo and or other treatments that enhance mucociliary clearance. 'We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Most recent search of the Trials Register: September 2004. All controlled trials assessing the effect of hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with cystic fibrosis of any age or severity. Two authors independently reviewed all identified trials and all data collected. Trial quality was assessed along with allocation concealment. Fourteen controlled trials were identified. Nine trials met the inclusion criteria involving 235 participants with an age range of 6 years to 46 years. Two short-term trials of immediate effect on mucociliary clearance demonstrated that hypertonic saline increased isotope clearance compared to control. Lung function, measured by improvement in forced expiratory volume at one second (FEV1 litre per minute), was observed in four trials. When 3% to 7% saline was used in a volume of 10 ml twice-a-day, in comparison to placebo, hypertonic saline led to a significant increase in FEV1, weighted mean difference 12.20 (95%CI 4.28 to 20.10). Two further trials compared a similar concentration and volume of hypertonic saline to recombinant deoxyribonuclease. Over a three-week period one trial showed a non-significant difference, mean difference 1.60 (95% CI -7.96 to 11.16). However, in a further trial, after 12 weeks treatment in participants with moderate to severe lung disease, recombinant deoxyribonuclease led to a greater increase in FEV1 than hypertonic saline (5 ml twice-daily), mean difference 8.00 (95%CI 2.00 to 14.00). No serious adverse events were noted. Nebulised hypertonic saline improves mucociliary clearance in short-term clinical trials and appears to increase lung function compared to control. In comparison to recombinant deoxyribonuclease it may be less effective at improving lung function after three months. Currently there is insufficient evidence to support the use of hypertonic saline as routine treatment for people with cystic fibrosis.

Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline (HS) enhances mucociliary clearance in vitro and may lessen the destructive inflammatory process in the airways. To investigate the effects of nebulised HS in CF compared to placebo or other treatments for mucociliary clearance. We searched the Cochrane CF and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 31 July 2008. Controlled trials assessing HS compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity). Two authors independently reviewed all identified trials and data; and assessed trial quality. Twelve trials (442 participants, aged 6 to 46 years) were included; five excluded and two await classification.In two placebo-controlled trials, HS (3% to 7%, 10 ml twice-a-day) significantly increased forced expiratory volume at one second (FEV1) at four weeks, mean difference (MD) 4.15 (95% CI 1.14 to 7.16); but not significantly after 48 weeks, MD 2.31 (95% CI -2.72 to 7.34). Two trials compared a similar dose of HS to recombinant deoxyribonuclease (RhDNAse). One three-week trial showed a non-significant difference, MD 1.60 (95% CI -7.96 to 11.16). However, in the second trial, after 12 weeks, RhDNAse led to a greater increase in FEV1 than HS (5 ml twice-daily), in participants with moderate to severe lung disease, MD 8.00 (95% CI 2.00 to 14.00).One 48-week placebo-controlled trial showed significant improvements in frequency of antibiotic use and quality of life; also that HS did not increase the concentration of Pseudomonas aeruginosa or Staphylococcus aureus. Treatment with 7% HS for 48 weeks showed a small improvement in FEV1 at four weeks; however, this was not sustained at 48 weeks (primary outcome measure of the only long-term trial). Unlike RhDNAse, HS can't, in the long term, be said to improve lung function. However, it did improve quality of life and reduce pulmonary exacerbations. Delivered following a bronchodilator, HS appears inexpensive and safe with no increased infection risk.We believe there is sufficient evidence to recommend using HS in CF; qualifying this we highlight that the only long-term trial failed to demonstrate a significant difference in its primary outcome (lung function) with improvements only in secondary outcomes.

Background:The clinical effectiveness of hypertonic saline (HS) in individuals with cystic fibrosis (CF) can be compromised by adverse effects. The objective of this study was to examine the efficacy of hyaluronic acid (HA) in mitigating these negative occurrences.Methods:A comprehensive review of the literature was carried out using three electronic databases: Medline, Cochrane Central, and Embase. This systematic review and meta-analysis investigate the efficacy of hypertonic saline (HS) with and without hyaluronic acid (HA) in treating cystic fibrosis. Primary outcomes include the incidence of cough, throat irritation, unpleasant taste, and changes in FEV1. Our findings suggest that adding HA to HS significantly reduces adverse effects and enhances patient tolerability, marking a potential improvement in cystic fibrosis therapy. Risk ratios (RRs) and mean differences (MDs) with 95% CI were used to present evaluations. The quality of RCTs was evaluated using the Cochrane Risk of Bias Tool (CRBT). The quality of the observational study was evaluated using the Newcastle–Ottawa Scale.Results:From the 1960 articles retrieved from the initial search, five relevant studies (n=236 patients) were included in the final analysis. Compared with patients only on HS, patients with HS and HA were significantly less likely to experience cough (RR: 0.45; 95% CI, 0.28–0.72, P=0.001), throat irritation (RR: 0.43; 95% CI, 0.22–0.81, P=0.009), and unpleasant smell (RR: 0.43; 95% CI, 0.23–0.80, P=0.09). In addition, patients with HS with HA had significantly less forced expiratory volume (FEV1) (MD: −2.97; 95% CI, −3.79–−2.15, P=0.52), compared to patients only on HS. Patients on HA + HS had significantly lower rates of cough (RR: 0.45; 95% CI, 0.28–0.72, P=0.001), throat irritation (RR: 0.43; 95% CI, 0.22–0.81, P=0.009), and bad smell (RR: 0.43; 95% CI, 0.23–0.80, P=0.09) when compared to patients on HS alone. Furthermore, compared to patients solely on HS, patients with HS plus HA exhibited a substantially lower forced expiratory volume (FEV1) (MD: −2.97; 95% CI, −3.79 to −2.15, P=0.52) as well.Conclusion:For CF patients who need ongoing HS therapy and have a history of poor therapy tolerance, adding HA is beneficial.

Discontinuation versus continuation of hypertonic saline or dornase alfa in modulator treated people with cystic fibrosis (SIMPLIFY): results from two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials.

BackgroundThis crossover, randomized, double-blind study (conducted over a 32-week period) was performed to determine, in clinically stable Cystic fibrosis (CF) preschool children: the effects of 7% inhaled hypertonic saline on spirometry and interrupter resistance technique (Rint), and the possible side effects.MethodsTwelve CF children (6M, mean age ± SD: 5.7 ± 0.8 yrs) were enrolled and randomly assigned to receive hypertonic saline (HS-4 ml 7% sodium chloride), or normal saline (NS-0.9% sodium chloride) twice a day. After a 16 weeks period, therapy was exchanged to allow all the patients enrolled in the study to carry out both treatments. Monitoring visits, spirometry (COSMED Quark PFT4 ergo) and Rint were scheduled at 0,4,16,20,32 weeks. At T0, spirometric measurements and Rint were performed immediately before and 30 min after the inhalation therapy. Salbutamol (400 mcg) was administered before the drug at each visit.ResultsAfter a 16-weeks treatment with HS an improvement of FVC (p = 0.02) and a favorable trend of FEV1 were registered. A worsening of FEV1 (p < 0.0001) and of FEF25-75 (p = 0.019) were found in NS group. No differences were found in expiratory and inspiratory Rint in both groups. No serious adverse events occurred.ConclusionsSeven percent hypertonic saline therapy proved to be a useful and safe treatment in young CF children with clinically stable conditions.Trial registrationISRCTN12345678.

Rationale: Cystic fibrosis (CF) lung disease starts in early infancy, suggesting that preventive treatment may be most beneficial. Lung clearance index (LCI) and chest magnetic resonance imaging (MRI) have emerged as promising endpoints of early CF lung disease; however, randomized controlled trials testing the safety and efficacy of preventive therapies in infants with CF are lacking. Objectives: To determine the feasibility, safety, and efficacy of preventive inhalation with hypertonic saline (HS) compared with isotonic saline (IS) in infants with CF, including LCI and MRI as outcome measures. Methods: In this randomized, double-blind, controlled trial, 42 infants with CF less than 4 months of age were randomized across five sites to twice-daily inhalation of 6% HS (n = 21) or 0.9% IS (n = 21) for 52 weeks. Measurements and Main Results: Inhalation of HS and IS was generally well tolerated by infants with CF, and the number of adverse events did not differ between groups (P = 0.49). The change in LCI from baseline to Week 52 was larger in infants with CF treated with HS (-0.6) than in those treated with IS (-0.1; P < 0.05). In addition, weight gain was improved in infants with CF treated with HS (P < 0.05), whereas pulmonary exacerbations and chest MRI scores did not differ in the HS group versus the IS group. Conclusions: Preventive inhalation with HS initiated in the first months of life was safe and well tolerated and resulted in improvements in LCI and weight gain in infants with CF. Our results support the feasibility of LCI as an endpoint in randomized controlled trials in infants with CF. Clinical trial registered with www.clinicaltrials.gov (NCT01619657).

Dornase alfa and hypertonic saline are mucoactive therapies that can improve respiratory symptoms in people with cystic fibrosis (CF). A recent randomized control trial showed that participants with well-preserved pulmonary function taking elexacaftor + tezacaftor + ivacaftor (ETI) who discontinued dornase alfa or hypertonic saline for 6 weeks had no clinically meaningful decline in lung function. This may prompt discussions with care providers regarding ongoing use of these medications. To compare the costs of outpatient medications between people taking ETI who continued or discontinued (1) dornase alfa or (2) hypertonic saline from 2 clinical trials and project cost differences in the US CF population if these 2 medications were used only intermittently for symptom relief instead of chronically. The SIMPLIFY study was 2 parallel multicenter trials that randomized participants 1:1 to either continue or discontinue therapy. To estimate costs, we used data from the Merative MarketScan Databases to identify people with CF from 2020 to 2021. Our primary outcomes were differences in costs of outpatient prescription drugs among those who continued vs discontinued dornase alfa and, separately, hypertonic saline. We obtained adjusted differences in median costs. To estimate the annual cost savings if the population of people with CF taking ETI used these medications only intermittently, we multiplied the proportion of people in MarketScan with CF diagnoses who were taking each of these medications by the median cost savings per year and subtracted the cost of "rescue" use. A total of 392 participants from the dornase alfa trial and 273 from the hypertonic saline trial were included in analyses. The adjusted difference in median medication costs was not significant for the hypertonic saline trial, but we observed a significantly decreased 6-week cost of medications in the dornase alfa trial (adjusted median difference in costs between discontinue and continue of $5,860 (95% CI = $4,870-$6,850); P < 0.0001). We estimated that two-thirds of people with CF use ETI and dornase alfa in the United States; if they discontinued dornase alfa except for intermittent use, the resulting annual savings would be $1.21 billion. Although the costs of dornase alfa and hypertonic saline are smaller compared with ETI, reduction in use would lead to substantial prescription drug cost savings and reduce the treatment burden. However, individual benefits of these therapies should be considered, and decisions regarding changes in therapy remain an important discussion between people with CF and their providers. Study registration number: NCT04378153.

Physical exercise with increased ventilation leads to a considerable rise in water loss from the airways. The mechanisms underlying the regulation of transepithelial fluid transport necessary to compensate for these losses are unknown but may include changes in luminal ion channel conductance. The present study was designed to examine the effects of an increase in luminal chloride and sodium concentrations which may locally occur during hyperventilation on luminal ion conductance in the respiratory epithelium of healthy controls and patients diagnosed with cystic fibrosis (CF). Changes in luminal chloride and sodium conductance were inferred by recording nasal potential difference in eight healthy subjects and 10 patients with CF, using superfusing solutions based on isotonic saline (150 mM) on one occasion and solutions based on hypertonic saline (300 mM) on the other. Switching from isotonic to hypertonic saline superfusion decreased potential difference in controls and CF patients significantly. Amiloride induced a decrease of potential difference which was larger with isotonic than with hypertonic saline (controls 9.5 +/- 6.1 vs. 3.7 +/- 4.6 mV; CF 17.2 +/- 7.2 vs. 9.8 +/- 7.6 mV). Chloride conductance stimulated with solutions low in chloride and containing isoproterenol was not significantly changed by hypertonic saline solutions compared with isotonic solutions in both groups. The findings indicate a significant inhibition of luminal sodium conductance by high luminal sodium concentrations. This mechanism may be involved in the regulation of fluid transport across the respiratory epithelium during exercise and in the improvement of mucociliary clearance and lung functions with inhalation of hypertonic saline in CF.