Discussion
Cystic fibrosis landscape is expected to change significantly over the next years. The place in CF therapy of each CFTRm by indication is still to be fully understood, especially with regards to expected long term effects and potential benefits of early intervention, in particular in very young patients. Physicians opinion will predictably evolve as more real world data are being collected and with increasing experience. We undertook this survey to see how clinical use of CFTRm changed over time with their increasing availability in Italy. Ivacaftor and lumacaftor/ivacaftor were the only CFTRm available at the time of our study, the latter available for F508del homozygous patients above 12 years of age at the time of the first survey conducted in 2015, its indication extended to younger ages at the time of the 2018 survey. No drug was available for patients with residual function mutations until 2018, however tezacaftor/ivacaftor phase III data on both patients homozygous for F508del mutation and those carrying a residual function mutation had already been published in the scientific literature. Considering that these new indications or extensions introduced the use of CFTRm in new patient groups, we designed the questionnaire to explore physicians attitude in F508delhomozygous patients aged 12 years and above as an historical group compared to younger F508del homozygous patients and those with residual function mutations. Reaching out to all CF physicians was facilitated by the centralization of care in CF centers evenly distributed on the national territory. Response rate of 76% was satisfactory and similar to that of previous survey14, showing the willingness of Italian health care professionals to share their experience and allowing to consider the outcome as representative of the general opinion in Italy. Of note, most respondents had significant experience in the field of CF, with at least 5 years of work in a CF center. A general overview of responses to the different questions shows that traditional parameters such as lung function and nutrition status remain key evaluation criteria in relation to initiation and monitoring of CFTRm in all groups and physicians expect to observe improvement, consistently with clinical trial results. Nutritional status is considered a fundamental parameter in relation to initiation of CFTRm across all the different patient groups and growth percentiles is considered a useful parameter to monitor in pediatric patients. This is in line with literature data showing that improvement of nutritional status is directly linked with increased survival in CF patients. With regard to pulmonary outcomes, it should be underlined that more than FEV1, the number of exacerbations is considered particularly relevant in all groups for both initiation and monitoring of therapy. This is consistent with the expected deleterious effect of increasing number of exacerbations on FEV1 decline and survival. We also observed interest in measuring exercise tolerance and patient related outcomes such as ability to conduct daily activities as well as in tools that can help detect early manifestations of disease such as LCI and imaging. LCI was deemed particularly relevant in the younger age group, with 36% of physicians who judged this test very useful inF508del homozygous patients under 12 years of age. Imaging can also be useful in all patient groups to identify early lung damage and as such, was viewed as useful by clinicians for initiation and monitoring of CFTRm therapy. For follow up in particular, imaging can provide objective signs of the effects of CFTRm on lung parenchyma. A few studies report CT scan parameters combined through a scoring system as exploratory endpoints. In particular, reduction of mucus plugging, bronchiectasis15,16 and airway wall thickness17 were observed after one year of treatment with ivacaftor, while improvement of bronchiectasis and air trapping were seen after 6 months of lumacaftor/ivacaftor treatment18. Limitations related to cumulative exposure to ionizing radiation might be overcome by tools such as Magnetic Resonance Imaging that look promising for closer monitoring of the effect of CFTRm19. Relatively little emphasis was given to pancreatic function, but this is consistent with the start of CFTRm (at the time of conduct of the survey) at an age deemed too old to expect great impact. Encouraging data on modification of biological markers with younger age of CFTRm start raises some hopes on possibility of changing pancreas exocrine function status with very early intervention with this class of drugs20. Sweat chloride measurement was also mentioned as useful monitoring tool and it is likely used by physicians to estimate adherence. When asked about treatment initiation according to clinical presentation and disease stage, health care professionals provided similar responses in homozygous F508del patients under or over 12 years of age and residual function patients as well, showing that severity/instability of disease prevails on this decision and is not influenced by mutation type or age range. A relatively small proportion of physicians would treat systematically asymptomatic patients with less than 20% for youngerF508del homozygous patients or those with residual function mutations and somewhat more (27%) for F508del homozygous over 12 years of age. Intention to initiate treatment increases considerably (over 50% in all groups) when patients show light manifestations of disease. Further explorations of what is meant by light manifestations would be interesting to understand biomarkers of interest to detect initial organ damage before symptoms occur. Willingness to initiate CFTRm treatment reaches 69-78% in case of fully expressed disease and exceeds 90% in patients with worsening disease. Interestingly, compared to survey conducted in 201513, intention to initiate CFTRm treatment in F508del homozygous over 12 years of age increased by 8-11% in all severity categories and even doubled for patients in terminal stage, showing increasing confidence of physicians with increasing experience of CFTRm. Nevertheless, some concern on initiating CFTRm in asymptomatic pediatric patients actually exists and this might be related to lack of long term experience of CFTRm in pediatric CF patients. This is in contrast with general belief in early intervention which is at the basis of CF care with all efforts made to intervene as soon as possible once diagnosis of disease is made, in order to warrant optimal long term outcomes. Continued observation will help us understand the magnitude of long term impact of early use of CFTRm. For now, simulation models can be used to predict long term effects, showing increased survival up to 23.4 years in pediatric CF patients treated early with lumacaftor/ivacaftor21. Registry data will allow documentation of effect of CFTRm on hard outcomes such as mortality and transplant, already shown for ivacaftor22. Limitations of this study are inherent to surveys based on voluntary participation, however high response rate allows to consider the sample as representative of the opinion in the Italian CF community. Survey can be conducted quickly and can inform how health care professional opinion is formed as new tools are made available and this could be of particular value in a rare disease field. We are not aware of any other published survey similar to ours.
In conclusion, the introduction of CFTRm in the therapeutic armamentarium is progressively changing treatment protocols in CF. Early intervention with drugs that act on the causal mechanism of disease have the potential to change the progression of disease, stimulating some physicians to start treatment regardless of symptoms. Our survey shows that CF HCPs have high expectations on CFTRm effectiveness. Pulmonary exacerbations represent the most important outcome to consider in CF patient both for start a CFTRm and as a monitoring parameter. This is consistent with the attitude of physicians to consider CFTRm treatment according to disease stage, considering more severe disease or non stable disease as priorities. On the other hand, there is increasing interest in parameters such as imaging and above all LCI as useful tools in order to predict disease progression in asymptomatic and/or pediatric patients. It is arguable that with increased experience with CFTRm and with new insight into the understanding of disease progression the attitude towards early intervention could become more prominent. Treatment scenario is rapidly changing and will call for revision of current guidelines.