Statement 1: Treatment with mucoactive agents should be
proposed at the first evidence of pulmonary involvement in order to
prevent or slow the decline in lung function through indirect control of
inflammation, with reduction of mucus accumulation and, consequently, of
the infectious process.
The expert panel reached consensus on starting the use of mucoactive
agents in CF patients at the first evidence of pulmonary involvement(Figure 1A ). In final consensus meeting, there was no unanimous
response to this statement.
The pathophysiology of CF is characterized by a continuous cycle of
obstruction, infection, and neutrophil-dominated
inflammation14. In addition, necrosis of neutrophils
leads to the accumulation of extracellular DNA and actin, increasing the
viscosity of mucous and producing further obstruction. Reduction of high
molecular weight DNA into smaller fragments by using dornase alfa has
been proposed as a treatment to reduce the mucus viscosity and improve
mucus clearance from obstructed airways in CF
patients15.
Given the role of the inflammatory process as a driver of irreversible
lung destruction, there is an increasing interest in therapies with
anti-inflammatory effects to slow disease progression when used early in
the course of disease16. Dornase alfa has
well-documented beneficial clinical effects on the obstruction and
infection components of the disease process and has also shown positive
effects on markers of inflammation16.
Dornase alfa was shown to exhert a beneficial effect on metalloproteases
in BAL fluid of patients with CF, supporting the positive impact of this
mucoactive agent on airway inflammation in CF17. In
particular, a randomized trial including 105 CF patients with mild lung
disease (FEV1 >80% predicted) demonstrated
this potential anti-inflammatory effect. Based on an initial
bronchoalveolar lavage, patients were divided into two groups, those
with airway inflammation and those without. CF patients with
inflammation were then randomized to treatment with dornase alfa or not.
In patients treated with dornase alfa, there was no change in
inflammatory responses as measured by elastase and IL-8 levels and
neutrophils number.
CF patients not treated with dornase alfa and patients who did not have
inflammation at baseline all had worsening neutrophilic inflammation on
follow-up. In addition, in treated patients FEV1 dropped
by 1.99% predicted per year, as compared to a 3.26% predicted drop per
year in patients not treated with dornase alfa17.
Statement 2: Treatment with mucoactive agents
should be proposed in patients with CF with frequent pulmonary
exacerbations of lung disease.The complete agreement of the expert panel on this statement is relevant
as it shows that the frequency of exacerbations is considered a marker
for the use of mucoactive therapy (Figure 1B ).
In final consensus meeting, there was no unanimous response for this
statement.
A recent Cochrane review of randomized and quasi-randomized controlled
trials comparing dornase alfa to placebo,
standard therapy or other medications that have a positive impact
on airway clearance, showed that compared with placebo, therapy with
dornase alfa improved lung function in people with CF in trials lasting
from one month to two years and led to a decrease in pulmonary
exacerbations in trials of six months or longer18.