Introduction
Cystic Fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene encoding the CFTR protein. This protein is an ion channel that carries chloride ions and water across cell membranes. It is also involved in regulating the functioning of other important channels in mucociliary clearance and innate defense mechanisms [
1]. To date, therapeutic advances have resulted in a notable increase in life expectancy [
2]. Recommended beneficial treatments include pancreatic enzymes, airway clearance, mucolytics, inhaled antibiotics, anti-inflammatory agents and CFTR modulators [
3,
4]. CF-causing mutations are classified into 6 categories, according to their impact on the production, trafficking, functioning or stability of the CFTR channel [
5‐
8]. Mutations belonging to classes I, II and III usually result in little to no CFTR activity, leading to severe clinical outcomes, whilst mutations from classes IV, V and VI allow significant residual CFTR function leading to milder phenotypes [
5‐
8]. These alterations affect the glands that produce mucus, sweat, saliva, tears, and digestive enzymes. In normal conditions, mucus acts as a barrier to protect the airways by trapping inhaled particles and pathogens, thereby preventing infections. Mucus is a complex and viscous secretion containing proteins, lipids, ions and water. In patients with CF, the defect of the CFTR protein causes a reduced secretion of chloride and a marked absorption of sodium, and therefore of water, through the epithelium, resulting in the formation of thickened secretions in organs such as the pancreas or lung. These viscous secretions lead to airway obstruction, chronic infection and inflammation resulting in progressive lung damage, bronchiectasis and eventual respiratory failure [
9,
10]. In healthy subjects, the main component of mucus is a glycoprotein called mucin, but the secretions of people with CF contain very little mucin. In fact, pus, polymerized DNA and filamentous actin (F-actin) proteins derived from dead inflammatory cells and epithelial cells trapped in mucus prevail [
11]. This has important therapeutic implications, as substances that act against mucin components are ineffective.
Nowadays lung disease remains the most common cause of death in people with CF. [
1,
2] For this reason, acting against the accumulation of secretions and the evolution of lung damage is one of the best therapeutic strategies. Mucolytic agents are drugs that reduce mucus viscosity by degrading mucin polymers, DNA or F-actin in the airways secretions. This allows for better elimination of sputum with coughing [
12].
Symptomatic mucolytic therapy today is mainly based on inhalation of DNase, hypertonic saline or mannitol in combination with physiotherapy.
Mucolytic agents break down the gelatinous structure of mucus and therefore decrease its elasticity and viscosity, reducing the pulmonary exacerbation frequency and to improve and stabilize lung function. However, high quality studies comparing these mucolytic drugs are still lacking, and the individual experiences of patients and caregivers explain the high variability of their use globally.
This review summarizes the current knowledge on hypertonic saline in the treatment of CF lung disease. Furthermore, we report the real-world prescription of inhaled mucolytic agents in CF. A systematic review of peer-reviewed literature was conducted using Medline/PubMed, Cochrane and Google Scholar.
Discussion
The systematic reviews conclude that there is no superiority of hypertonic saline than other mucolytic agents [
13,
32,
33]. Guidelines generally do not provide recommendations on which to start first. Since these agents have different mechanisms of action, it is possible benefit from the use of more than one at the same time [
34]. We think that the choice of the inhalation mucolytic therefore requires careful clinical evaluation and sharing with patients and their families, having considered all available options. Hypertonic saline solution can be useful in paediatric age to promote the expectoration or, in most cases, especially with the progression of the disease, combined with other mucolytic agents, such as dornase alfa or inhalation preparations such as antibiotics, bronchodilators and corticosteroids. Specific mucolytic agents for CF patients and related devices represent a limited number. The main used in CF are reported in Table
1.
Table 1
Main mucolytic agents used in Cystic Fibrosis, with indication of the methods of preparation and storage, devices recommended and indications for use
Hypertonic saline solution 7% of NaCl + hyaluronic acid | > 6 | Ready-made 5 ml vial 2vv/die | Room temperature | - Jet nebulizer - Mesh nebulizer |
Hypertonic saline solution 7% of NaCl + sodium bicarbonate | > 6 | Ready-made 5 ml vial 2vv/die | Temperature 5 °C - 25 °C | - Jet nebulizer - Mesh nebulizer |
Hypertonic saline solution 7% of NaCl | > 6 | Ready-made 4 ml vial 2vv/die | Temperature 4 °C–25 °C. | - Jet nebulizer - Mesh nebulizer |
Hypertonic saline solution 6% of NaCl | > 6 | Ready-made 4 ml vial 2vv/die | Room temperature | - Jet nebulizer - Mesh nebulizer - Ultrasonic nebulizers |
Hypertonic saline solution 3% of NaCl | Every age | Ready-made 3–5 ml vial | Room temperature | - Jet nebulizer - Mesh nebulizer - Ultrasonic nebulizers |
Mannitol 40 mg | > 18 | 10 capsules to be inhaled with specific device 400 mg × 2 times/die | Temperature < 30 °C In absence of humid environment | Specific inhaler |
Dornase alfa | > 5 | Ready-made 2.5 ml vial 1 time/die > 21 years 2 times/die (for severe patients) | Temperature: 2 °C - 8 °C max 30 °C for 24 h | - Jet nebulizer - Mesh nebulizer - Adaptive aerosol delivery system. No ultrasonic nebulizers |
Few studies compared the effectiveness of the hypertonic solution to dornase alfa; Suri et al. carried out a cross-over trial on 48 children, comparing the effect on FEV
1 of DNAse and hypertonic saline at 7% (5 ml twice a day), used for 12 weeks. DNAse determined a much greater increase in FEV
1 (16% vs 3%) albeit at higher economic costs. There was no significant difference between the two groups about the number of respiratory exacerbations [
35]. A subsequent study by Ballmann et al. was conducted on 14 children with mild or moderate lung disease who took DNAse or hypertonic saline for 3 weeks with a subsequent 3-week washout period. Both drugs determined an increase of the FEV
1: 9.3% in the DNAse group vs 7.7 in the 7% hypertonic solution group. Patients treated with DNAse more likely showed a clinically relevant increase in FEV
1 (> 10%) but without statistically significant differences compared to the group treated with hypertonic solution (OR 1.00) [
36]. Similarly, Adde et al. showed no changes in FEV
1, bacterial colonization and symptoms in two groups of children (# 18) treated for 2 weeks with DNAse and 6% hypertonic saline. Both drugs were well tolerated [
37]. The combined analysis shows no differences between treatments after 3 weeks of therapy (very low level of evidence), but a greater effect of DNAse after 3 months of therapy [
13,
32]. Saline hypertonic is certainly a cheaper drug but requires longer administration time than DNAse and this can affect the compliance of treatment [
35,
36] There are no differences in the rate of adverse events, although acute bronchospasm remains a possible finding after administration of hypertonic saline.
In children under 5 years of age, dornase alfa and the solution hypertonic saline should be considered based on the assessment individual clinic [
38].
The UK guidelines (NICE, 2018) recommend the dornase alfa as the first choice in routine treatment. If the clinical response is inadequate, hypertonic saline is also proposed alone or in combination with dornase alfa.
The guidelines published by the CF Foundation recommend long-term use term of dornase alfa to preserve lung function and reduce exacerbations in patients with lung disease of moderate to severe degree. Dornase alfa is also recommended for patients with mild or asymptomatic lung disease or in children under the age of 5 years, based on individual assessment [
39,
40]. Use chronic hypertonic saline is recommended from 6 years of age [
39].
On the other hand, only one trial has been published comparing the effect of 6% hypertonic solution and mannitol in 12 CF patients. The main outcome evaluated was the ability to improve mucus clearance, which was found to be insufficient for both drugs. A fall in FEV
1 was reported for both, mostly after the use of mannitol but without statistically significant differences (7.3% ± 2.5% vs 5.8% ± 1.2%) [
41].
Guidelines of European CF Society, consider dornase alfa as the mucolytic agent to be used in long-term maintenance therapy, indicate the potential use of hypertonic saline in patients with moderate to severe pulmonary impairment and the use of mannitol to improve lung function and to reduce the treatment times [
38]. Inhalation of mannitol is also recommended in adults with rapidly declining lung function or in case of lack response to other medications [
41].
To date there is not a clear indication in asymptomatic CF patients or with mild disease [
26]. In these cases, it is important to involve the patient and her family in common decision-making process and identify the best device, in order to integrate it in the real program. This choice depends on the age of the patient, the severity of the lung disease, the amount and quality of inhaled drugs in the treatment plan.
The role of the care team is to select together with the patient the best drug for the clinical characteristics of the patient, and the devices with which to administer it. Since saline hypertonicity and mannitol can produce bronchospasm during or after inhalation, a premedication with bronchodilator drugs and the execution of the tolerance test are recommended [
39]. About the chronology with which to inhale the mucolytic agents compared to performing respiratory physiotherapeutic release there is not yet sufficient scientific evidence.
A recent review on hypertonic saline solution suggests that the timing of the inhalation does little or no difference in lung function [
42]. However, inhalation before or during airway removal techniques can maximize effectiveness and perceived satisfaction by the patient. The long-term effectiveness of the saline solution hypertonic was established with bi-daily administrations; however, if only one dose per day is tolerated, that is the time in which to perform the inhalation is indicated on the tolerance and the patient preference [
42].
To date, the best timing for inhalation of dornase alfa is still debated. It seems that the drug requires at least 30 min of time inside the lung to show changes in sputum viscosity. It follows therefore that better results would be expected if at least thirty minutes were expected before performing the drainage session secretions. It has been demonstrated on a sample of young subjects that there was no difference when dornase alfa was inhaled shortly before night rest or later in the day, earlier of the execution of respiratory physiotherapy [
43].
It can be suggested not to inhale immediately before unblocking respiratory physiotherapy, also leaving to the patient the choice of a time that best suits the life style and subjective efficacy in relation to the drug [
44].
We propose a chronological order of execution of the various therapies in Table
2. Nevertheless, the listed therapies are variously associated in clinical practice and there is no agreement on the correct sequence. For example, inhalation antibiotic therapy can also be performed at the end of the physiotherapy cycle [
39]. Finally, we recommend an annual verification of the prescription, in order to optimize the therapy, increase compliance and solve any problems in progress (Table
3).
Table 2
Practical example of the temporal sequence for the execution of daily inhalation therapy
1. Bronchodilator; |
2. Wait 5–15 min; |
3. Mucolytic such as saline hypertonic or mannitol; |
4. Airway clearance techniques; |
5. Inhaled antibiotics; |
6. Long-acting bronchodilators / inhaled steroids; |
7. Dornase alfa. |
Table 3
Annual check list
Have the objectives of aerosol therapy been clarified? | | | | | | |
Has the action of the individual drugs been explained? | | | | | | |
Does the person agree on the prescribed therapy? | | | | | | |
Have the drugs in the prescription been checked? | | | | | | |
Have the type of dilutions been checked? | | | | | | |
Has the patient’s nebulizer equipment been checked? | | | | | | |
It has been asked if they are used? | | | | | | |
Have they been checked by the physiotherapist? | | | | | | |
Were verbal instructions given? | | | | | | |
Has the patient been given the opportunity to directly show how to manage and use the devices? | | | | | | |
Written instructions: have they been delivered? | | | | | | |
Written instructions: have they been understood? | | | | | | |
Has the patient been given time and means to reformulate the educational and technical aspects, express doubts, ask for clarification? | | | | | | |
Was the opinion on the feeling of effectiveness of the drug asked? | | | | | | |
Has the duration of aerosol therapy with individual drugs been asked? | | | | | | |
Is the aerosol completely taken? | | | | | | |
Has the logic of the drug intake sequence in relation to physiotherapy been clarified? | | | | | | |
Has the last replacement of the hose, filters, head, nebulizer, engineering review, etc. been checked? | | | | | | |
Is the difference between cleaning and disinfection clear? | | | | | | |
Has it been investigated how cleaning and disinfection are done? | | | | | | |
And the frequency of cleaning and disinfection? | | | | | | |
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