This is to our knowledge the first clinical trial assessing a chronic non-antimicrobial pulmonary therapy in children with CF < 6 years of age. Hypertonic saline did not reduce the rate of pulmonary exacerbations in these young children. In addition, hypertonic saline did not demonstrate any significant effects on secondary endpoints including weight, height, respiratory rate, oxygen saturation, antibiotic use, or parent report of respiratory signs and symptoms.
Previous studies in older children and adults with CF have documented benefits of inhaled hypertonic saline 7–9, 21, 22
. In the multi-center Australian study in patients >6 years of age, treatment with hypertonic saline did not demonstrate a significant effect on the primary outcome measure, the rate of change of lung function, but was associated with a significant reduction in the rate of pulmonary exacerbations9
. Pulmonary exacerbation rate was chosen as the primary outcome in the current trial because of the important effect observed in the Australian hypertonic saline trial9
and because pulmonary exacerbations are a clinical endpoint (affecting how a person feels, functions or survives)23
that have been associated with survival in CF24, 25
. The pulmonary exacerbation definition in the current study differed from that in the Australian study, in which pulmonary exacerbations were defined as treatment with intravenous antibiotics for pre-defined signs and symptoms, or the occurrence of those signs and symptoms independent of treatment. Our definition, similar to that used in 2 prior studies in young CF patients26, 27
, was designed to capture all events in which several days of new respiratory signs or symptoms triggered treatment with oral, inhaled or intravenous antibiotics, the standard clinical practice for CF patients in this age range. In the current study, while the vast majority of pulmonary exacerbations were treated with oral antibiotics, there was no difference between the 2 groups in the rate of exacerbations even if limited to those treated with intravenous antibiotics, nor in respiratory symptoms. Thus, it is unlikely that the difference in our results is due to a different pulmonary exacerbation definition.
As opposed to older patients, pulmonary exacerbations in infants and young children are frequently triggered by viral infections. It is thus possible that hypertonic saline has less ability to prevent exacerbations in children <6 years of age than in older CF patients. Previous studies have demonstrated that viral infections occur at similar rates in CF and non CF infants, but that the severity and duration of symptoms is increased in CF patients28
. Thus hypertonic saline, even if not affecting the rate of pulmonary exacerbations in young children with CF, might reduce the severity and duration of symptoms, similar to its observed effect in non-CF infants with bronchiolitis29
. However, the current study provides no evidence that the severity or duration of pulmonary exacerbations was influenced by hypertonic saline, as parent-reported respiratory signs and symptoms and days of antibiotic therapy did not differ between groups.
We estimated the expected pulmonary exacerbation rate based on data from an ongoing U.S. observational study of early CF lung disease, the EPIC Observational Study30
. The rate of pulmonary exacerbations in the current study (mean 2.3 events per person-year) was very similar to that observed in the EPIC Observational Study (2.22 per person-year), indicating that the trial was adequately designed to observe the predefined treatment effect. In addition, the participants in the current study had baseline characteristics () similar to the overall patient population in the U.S. CF National Patient Registry in this age range, suggesting that our findings are generalizable to the overall CF population <6 years of age.
This study was designed to primarily demonstrate an effect on clinically meaningful events rather than on prevention of lung disease progression. Our choice of endpoints was limited by the fact that validated outcome measures commonly used in older patients are lacking for very young children with CF. It could be argued that an intervention targeting mucociliary clearance in a population with limited clinical lung disease is unlikely to improve any short-term clinical outcome measure and that a more realistic goal would be to slow progression of structural airway damage or improve lung function. We conducted a substudy of infant pulmonary function tests as an exploratory endpoint at selected sites in order to gain information to adequately power future studies using this endpoint. Interestingly, the mean change in FEV0.5 over the treatment period was significantly greater in the hypertonic saline group compared to the isotonic saline group. While these findings may be due to chance, they also may reflect improvement in airflow limitation in the hypertonic saline group that was not detectable with our primary or secondary outcome measures. Due to the relatively silent nature of early CF lung disease, sensitive endpoints are critical.
When the current study was being planned, protocols for chest CT and multiple breath washout for multiple age ranges were not adequately developed and multi-center experience in infants and young children with these techniques was limited. The availability of appropriate multi-center protocols and networks as well as increased expertise in these techniques suggests that adequately powered trials using physiologic measures as outcomes may be conducted. Future studies of hypertonic saline in young children utilizing these or other endpoints will allow evaluation of the effects of this treatment on early structural airway damage and lung function, including ventilation inhomogeneity.
In both the current study and the Australian hypertonic saline trial, isotonic saline served as the control agent. It is possible that isotonic saline has a more pronounced effect on mucus hydration in the very young than in older patients. In addition, participants in both arms received albuterol prior to each dose of study drug. Both of these factors might have limited our ability to detect a difference in outcomes between the 2 groups. The fact that the exacerbation rate in the control group was very similar to that in an untreated historical cohort would suggest that there was not an important effect of isotonic saline on the primary endpoint. Unfortunately, it is not feasible to perform a true placebo controlled study of hypertonic saline as no inhaled agent is completely inert.
Treatment with hypertonic saline was well tolerated and adherence to therapy was overall high. Chronic inhaled therapy could pose a risk of new acquisition of bacterial pathogens if nebulizers are not properly cleaned and disinfected31
. As this study did not include an untreated control group, this potential side effect of inhalation therapy cannot be excluded. However, the rate of new acquisition of organisms did not differ significantly from that reported in the CF Registry or in the EPIC Observational Study32
. Therefore, while not showing a decrease in pulmonary exacerbation rate, this study supports previous smaller series demonstrating that inhalation of hypertonic saline is safe in infants and young children.
In conclusion, among infants and children with CF less than 6 years old, the use of inhaled hypertonic saline compared with isotonic saline did not reduce the rate of pulmonary exacerbations over 48 weeks of treatment. Further study with physiologic endpoints is warranted to better understand how this drug may slow progression of structural airway damage or improve lung function in the youngest population.