Comment

Cystic fibrosis lung disease and bronchiectasis

In a Lancet Respiratory Medicine Commission report, Emerging threats—including multidrug resistance, Lancet Respir Med 2019

experts in cystic fibrosis from 18 countries present their increased fungal infections (particularly with Published Online
September 27, 2019
view of the future of cystic fibrosis care.1 The Commission Aspergillus species), and increased non-tuberculous [Link]
is a landmark at a point in time when the demography mycobacteria infections—are growing in importance, S2213-2600(19)30335-2
See Online/The Lancet
and management of cystic fibrosis are changing rapidly. and the potential for patient-to-patient transmission Respiratory Medicine
The Commission comprehensively addresses future or a pandemic spread of Mycobacterium abscessus is a Commission
[Link]
uncertainties and challenges for the field, including those particular cause for concern.6 Therefore, new therapies S2213-2600(19)30337-6
associated with the management of lung disease.1 for cystic fibrosis beyond CFTR modulation need to be
Improvements in the survival of patients with cystic developed, including new inhaled antibiotics to treat
fibrosis over the past 60 years have been remarkable.2 both gram-negative infections such as P aeruginosa and
As highlighted in the Commission, one uncertainty increasingly prevalent challenges such as meticillin-
is whether, or at what stage, survival improvements resistant Staphylococcus aureus and non-tuberculous
in cystic fibrosis will plateau, or whether patients will mycobacteria infections. Anti-inflammatory therapies
ultimately achieve a life expectancy equivalent to that including those that target neutrophils have been
of the general population. The European Cystic Fibrosis largely unsuccessful to date but remain an area of
Society Patient Registry has forecast that the adult intense study.
population will increase by 75% between 2010 and A key challenge is how the pipeline of new
2025. This forecast is likely to underestimate population therapeutics to treat bronchiectasis in cystic fibrosis
growth, as it did not account for new advances in can be maintained against a moving target of changing
corrector and potentiator therapies.2 Much of the background therapies, CFTR modulation, and evolving
Commission therefore rightly focuses on the need to demography. Endpoints related to FEV1, which were
develop structures of care that can cope with a growing used for regulatory approvals of drugs such as inhaled
and ageing adult population.1 tobramycin in the past, cease to have relevance in
Nevertheless, respiratory disease and bronchiectasis populations that have largely preserved lung function,
remain the leading causes of morbidity and mortality and evidence suggests that such endpoints are less
in patients with cystic fibrosis and can be expected responsive in the adult cystic fibrosis population than
to remain so for the foreseeable future. To date, little the paediatric population.7 Pulmonary exacerbations
evidence exists that cystic fibrosis transmembrane
conductance regulator (CFTR) modulator therapy will
have a major effect in regressing bronchiectasis or
correcting chronic infection with organisms such as
Pseudomonas aeruginosa. CFTR modulator therapies
were initially expected to produce substantial reductions
in airway bacterial burden and inflammation through
improved mucociliary clearance;3–5 however, some
studies have found no immediate influence of ivacaftor
treatment on bacterial pathogens or inflammation.3,4
Conversely, Hisert and colleagues found rapid reductions
in airway P aeruginosa burden within 48 hours of starting
PhotoStock-Israel/Science Photo Library

treatment with ivacaftor, with continued declines in

the first year of treatment. In the second year, however,
P aeruginosa burden increased.5 The mechanism for this
effect is not known; nevertheless, the message is clear
that highly effective CFTR modulator therapy will not
resolve all aspects of an established vicious cycle.

[Link]/respiratory Published online September 27, 2019 [Link] 1

 Comment

remain a key driver of morbidity and mortality in cystic regarded as having non-cystic fibrosis bronchiectasis. The
fibrosis, but widespread recognition of this has led to group of patients with clinical features of cystic fibrosis,
advances in care to prevent exacerbations, which mean such as diffuse bronchiectasis, but with CFTR variants
that the average exacerbation frequency in cystic fibrosis that do not meet the current criteria for cystic fibrosis
populations is historically low and projected to fall and with intermediate sweat chloride measurements (ie,
further as CFTR modulators also reduce exacerbations.8 those with CFTR-related disorder) is increasingly being
Improved physiological measures, such as lung clearance recognised. The percentage of the so-called non-cystic
index, and imaging modalities (ie, CT and MRI), allow fibrosis bronchiectasis population that is ultimately
bronchiectasis to be characterised as never before, but found to have some degree of CFTR dysfunction and
these are surrogates that do not answer the crucial undiagnosed CFTR-related disorder remains to be seen,10
regulatory question of whether medication changes how but the lines between these conditions are becoming
a patient feels, functions, or survives. increasingly blurred.
How to develop feasible trials that can be adequately The future of cystic fibrosis care promises longer,
powered during an era of profound change requires healthier lives thanks to decades of exemplary clinical and
careful consideration. Trial programmes are planned translational research that many other fields would like
years in advance and uncertainty about future patient to emulate. The Lancet Respiratory Medicine Commission
populations and endpoints can act as a disincentive to provides an opportunity to reflect on past successes
drug developers to invest in cystic fibrosis therapies. while preparing for the many future challenges.
This issue was the topic of a US Food and Drug
Administration workshop in 2018.7 James D Chalmers
Large parts of the world will remain unable to access Scottish Centre for Respiratory Research, University of Dundee,
Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
CFTR modulator therapies because of cost and other
jchalmers@[Link]
considerations, such as access to and availability of
I report grants and personal fees from GlaxoSmithKline, AstraZeneca,
care, but randomised trials are increasingly looking to Boehringer-Ingelheim, Bayer HealthCare Pharmaceuticals, Grifols, and Insmed,
such low-income and middle-income countries (LMICs) and personal fees from Napp Pharmaceuticals, Aradigm, and Zambon, outside
of the submitted work.
to enrol patients for clinical trials. Recruitment of trial
1 Bell SC, Mall MA, Gutierrez H, et al. The future of cystic fibrosis care: a global
participants in countries that cannot offer equivalent perspective. Lancet Respir Med 2019; published online Sept 27. [Link]
org/10.1016/S2213-2600(19)30337-6.
care or access to drugs presents notable ethical concerns, 2 Burgel PR, Bellis G, Olesen H, et al. Future trends in cystic fibrosis
not least because participants might not, ultimately, demography in 34 European countries. Eur Respir J 2015; 46: 133–41.
3 Rowe SM, Heltshe SL, Gonska T, et al. Clinical mechanism of the cystic
have access to tested medications. The selection of trial fibrosis transmembrane conductance regulator potentiator ivacaftor in
sites in LMICs also raises the question of how such data G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 2014;
190: 175–84.
can be extrapolated to the new reality in countries such 4 Bernarde C, Keravec M, Mounier J, et al. Impact of the CFTR-potentiator
as the UK and the USA. Inequality in disease outcomes ivacaftor on airway microbiota in cystic fibrosis patients carrying a G551D
mutation. PLoS One 2015; 10: e0124124.
globally is already a reality but has the potential to 5 Hisert KB, Heltshe SL, Pope C, et al. Restoring cystic fibrosis transmembrane
conductance regulator function reduces airway bacteria and inflammation
increase dramatically in the coming years.9 in people with cystic fibrosis and chronic lung infections.
The focus of cystic fibrosis care is shifting from the Am J Respir Crit Care Med 2017; 195: 1617–28.
6 Bryant JM, Grogono DM, Rodriguez-Rincon D, et al. Emergence and spread
treatment of established bronchiectasis in young people of a human-transmissible multidrug-resistant nontuberculous
and adults to the prevention of bronchiectasis and mycobacterium. Science 2016; 354: 751–57.
7 Nichols DP, Durmowicz AG, Field A, Flume PA, VanDevanter DR,
delaying of the onset of lung disease. The introduction of Mayer-Hamblett N. Developing inhaled antibiotics in cystic fibrosis: current
challenges and opportunities. Ann Am Thorac Soc 2019; 16: 534–39.
CFTR-directed therapies has the potential to prevent or at
8 Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in
least markedly delay the development of bronchiectasis patients with cystic fibrosis homozogous for Phe508del. N Engl J Med 2017;
377: 2013–23.
such that in the future, patients might be developing 9 McCormick J, Mehta G, Olesen HV, Viviani L, Macek M Jr, Mehta A.
disease in their third, fourth, or fifth decade of life, or Comparative demographics of the European cystic fibrosis population:
a cross-sectional database analysis. Lancet 2010; 375: 1007–13.
later, at ages more associated with the onset of non- 10 Bienvenu T, Sermet-Gaudelus I, Burgel PR, et al. Cystic fibrosis
cystic fibrosis bronchiectasis. Advances in CFTR genetics transmembrane conductance regulator channel dysfunction in non-cystic
fibrosis bronchiectasis. Am J Respir Crit Care Med 2010; 181: 1078–84.
and in CFTR functional assessment are expanding the
spectrum of cystic fibrosis to include patients previously

2 [Link]/respiratory Published online September 27, 2019 [Link]