1 2 Key Points: The respiratory system delivers oxygen to the - - PDF document

1

2

Key Points:

• The respiratory system delivers oxygen to the bloodstream and removes carbon

dioxide, a metabolic waste product. It consists of the lungs, the airways, and the diaphragm and other muscles used for breathing1

• The lungs are surrounded by a pleural membrane that facilitates lung expansion and

contraction during respiration. The left lung consists of 2 lobes and is smaller than the right to allow room for the heart. The right lung has 3 lobes1,2

• The airways begin at the nose and extend through mouth and throat to the trachea,

which splits into the left and right primary bronchi. The bronchi enter the lungs and further divide into secondary bronchi, which form channels into the 3 lobes of the right lung and the 2 lobes of the left. Within the lobes, the bronchi continue dividing into tertiary bronchi and then bronchioles, which spread throughout the lungs in smaller and smaller branches until they form terminal bronchioles. These feed air into the alveoli, the capillary-wrapped air sacks where gas exchange takes place1 References

• 1. Tu J, et al. IN: Computational fluid and particle dynamics in the human respiratory
• system. 2013: XVIII, pp. 1-374. www.springer.com
• 2. Taylor T. Inner body: respiratory system. Available at:

https://www.innerbody.com/anatomy/respiratory. Accessed February 12, 2016.

3

4

5 Key Points:

• Shown here is the pathophysiologic cascade of CF lung disease,

demonstrating the progression from:

• CFTR gene mutations; to
• Reduced total CFTR channel activity, which is the result of the

quantity and/or degree of function of CFTR channels; to

• Abnormal chloride transport on the apical epithelial cell membrane
• Depletion of the airway surface liquid and, since this liquid is

essential to support ciliary stability and functioning, ciliary collapse and defective mucociliary clearance

• These pathophysiologic changes result in mucus obstruction, chronic lung

infections and inflammation

• This destructive cycle leads to scarring and progressive lung disease,

ultimately culminating in end-stage lung disease Reference Ratjen FA. Respir Care 2009;54:595–605

Key Points:

• Ion transport through CFTR channels regulates fluid and electrolyte balance in many
• rgan systems, including the lung, pancreas, gastrointestinal tract, sinuses, liver,

reproductive tract, and sweat glands. In the normal airway, as exemplified in this animation, the ability to regulate airway surface liquid (ASL) volume depends on coordination of sodium (Na+) absorption and Cl- secretion via CFTR

• Under normal circumstances, the outward flow of negatively charged Cl- ions is
• pposed by Na+ reabsorption – Na+ absorption activity is down-regulated by CFTR

function

• In an epithelium that lacks functional CFTR, failure of Cl- secretion and unregulated

Na+ absorption results in dehydration of the ASL Supporting Information

• The CFTR protein is responsible for directing the activity of other ion channels in the

cells (such as those responsible for Na+ absorption from the luminal membrane surface) and cells with defective CFTR exhibit excessive Na+ absorption

• Airway dehydration results in mucus adhesion – promoting bacterial infection and

inflammation References

• MacDonald KD, et al. Paediatr Drugs 2007;9:1–10
• Goralsk JL, et al. Curr Opin Pharmacol 2010;10:294–9
• Rowe SM, et al. N Engl J Med 2005;352:1992–2001

6

Key Point:

• CFTR mutations can be grouped based on the type of molecular defect in the CFTR protein. There are 6 mutation

classes, which generally speaking, can be grouped into 2 main categories:

• Mutations that reduce the function of CFTR protein
• Mutations that reduce the quantity of CFTR protein

Additional Information

• Different CFTR mutations cause disruptions at various stages of CFTR protein synthesis or in several aspects of
• function. Mutations have been grouped in 6 classes based on the molecular consequences
• The nonsense or frameshift mutations comprising Class I produce a premature stop (or termination) codon. This

results in either truncated non-functional CFTR or the prevention of full translation of mRNA so that no CFTR protein is expressed

• Class II CFTR mutations affect post-translational folding and transport of the CFTR protein to the cell surface.

These misfolded proteins are recognised as misfolded and targeted for degradation, and so fail to reach the Golgi

• apparatus. As a result, no CFTR protein or only a very small quantity of dysfunctional CFTR protein reaches the cell

surface

• Other mutations result in CFTR protein that does reach the apical membrane (Classes III–IV). With some mutations,

the CFTR protein channel does not open properly, which is known as a gating defect (Class III), or it has impaired chloride movement, or a conductance defect (Class IV). Both of these defects result in diminished chloride transport across the cell membrane

• Class V mutations result in a gene-splicing defect in CFTR mRNA that is not properly processed. Although some

functional protein is produced, the amount of CFTR at the cell surface is decreased in comparison with normal levels

• Finally, with Class VI mutations, functional protein is produced but is very unstable at the cell surface and

undergoes accelerated turnover

• As we have described, these CF-associated mutations in the CFTR gene can result in little or no CFTR protein

reaching the cell surface or CFTR protein at the cell surface that is dysfunctional References

• Wilschanski M & Durie PR. Gut 2007;56:1153–63
• Rowe SM et al. N Engl J Med 2005;352:1992–2001
• MacDonald KD et al. Paediatr Drugs 2007;9:1–10

7

Key Points:

• Lung health depends on the concerted action of the lung clearance

mechanisms shown here.

• First, the airway surface liquid (ASL), which is maintained through ionic

secretion of chloride (Cl-) and bicarbonate (HCO3-) through cystic fibrosis transmembrane conductance regulator (CFTR) channels, contains endogenous antimicrobial agents that kill bacteria.

• CFTR channels also control mucus secretion from submucosal glands and

goblet cells and help maintain appropriate mucous viscosity. Bacteria and

• ther contaminants are trapped in mucus and swept out of airways by the

action of motile cilia.1 Reference Stoltz DA, Meyerholz DK, Welsh MJ. Origins of cystic fibrosis lung disease. N Engl J Med. 2015;372(4):351-362. 8

9

Key Points:

• Under normal circumstances in the airway, the balance of fluid and electrolytes is necessary to

maintain the airway surface liquid (ASL), a layer of fluid that allows the cilia to efficiently beat and clear mucus, particles and pathogens to maintain airway health

• In CF disease, dysfunction of CFTR channels can disrupt Cl– transport balance
• Lack of ENaC regulation results in Na+ hyper-absorption – note a significant increase in

Na+ absorption in the lower panel, this is due an reduced amount (quantity) and/or activity (function) of CFTR in the apical membrane

• The change in the concentration gradient of Cl– is thought to affect fluid balance,

contributing to the dehydration of the ASL. As a result, mucus builds up on the cilia, and pathogens and particles become trapped Additional Information

• In the epithelial cells, Na+ absorption is mediated by the ENaC channels and the Na+/K+-ATPase

pump, while the Cl- transport is mediated via the CFTR and Ca2+-activated Cl- channels

• In the airways, excess liquid removal from airway surfaces is mediated by transepithelial Na+

transport; ENaC channels are highly active when ASL volume is large and inhibited when normal. When ENaC channels are inhibited, Cl- secretion is initiated and this transport is mediated by CFTR

• In the absence of CFTR, Na+ absorption is thus upregulated and Cl- secretion is not initiated

References

• Rowe SM et al. N Engl J Med 2005;352:1992–2001
• Proesmans M et al. Eur J Pediatr 2008;167:839–49
• Boucher RC. Eur Respir J 2004;23:146–58

Key Points:

• Lung clearance, or the expulsion of inhaled particles and infectious agents from the

respiratory system, depends on the secretion and transport of mucus out of the airways.1,2

• In the lungs, the airway surface liquid (ASL) coats the airway epithelium, which comprises

columnar epithelial cells and mucin-secreting goblet cells. The ASL consists a mucus layer that sits atop the periciliary liquid (PCL), in which the cilia on the apical surfaces of epithelial cells are bathed in fluid that supports ciliary beating and also lubricates the cell surface.1,2

• Goblet cells interspersed throughout the epithelium secrete mucins, which are proteins that

form a viscous mucus that traps inhaled particles. The cilia sweep the mucus out of the lungs into the trachea and the pharynx, where it can be swallowed and digested in the gastrointestinal tract.2,3 References 1. Button B, Cai LH, Ehre C, et al. A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science. 2012;337(6097):937-941. 2. Stoltz DA, Meyerholz DK, Welsh MJ. Origins of cystic fibrosis lung disease. N Engl J Med. 2015;372(4):351-362. 3. Taylor T. Inner body: respiratory system. Available at: https://www.innerbody.com/anatomy/respiratory. Accessed February 12, 2016.

Disclaimer Acknowledgement: The material within in this slide show that was originally published in the European Respiratory Journal has not been reviewed prior to release by the European Respiratory Society (ERS); therefore the ERS may not be responsible for any errors, omissions or inaccuracies, or for any consequences arising there from, in the content. Products mentioned should not be construed as an endorsement of the product or the manufacturer’s

• claims. Viewers are encouraged to contact the manufacturer with any questions about the features or limitations of the

products mentioned. The viewer is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other health care professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. An effort has been made to check generic and trade names, and to verify drug doses. The ultimate responsibility, however, lies with the prescribing physician.

10

Key Points:

• Impaired chloride transport through CFTR channels dramatically alters

mucociliary clearance and ultimately lung health, as shown in this flow chart.

• Decreased chloride secretion, due to mutations that cause a shortage of

CFTR channels or CFTR channel malfunction, leads to reduced ASL volume and mucus concentration. Osmotic pressure draws water out of the PCL, causing it to collapse and and the cilia to fold over. The cilia can no longer beat in a coordinated fashion to sweep the mucus away. The thickened, immobilized mucus begins to adhere to the epithelium and further resists clearance by coughing as well as ciliary action.

• Mucus plugging eventually results, along with chronic bacterial infection,

inflammation, and bronchiectasis. Reference

• 1. Button BM, Button B. Structure and function of the mucus clearance system
• f the lung. Cold Spring Harb Perspect Med. 2013;3(8). pii: a009720. doi:

10.1101/cshperspect.a009720. 11

Key Points:

• Impaired chloride transport through CFTR channels dramatically alters

mucociliary clearance and ultimately lung health, as shown in this flow chart.

• Decreased chloride secretion, due to mutations that cause a shortage of

CFTR channels or CFTR channel malfunction, leads to reduced ASL volume and mucus concentration. Osmotic pressure draws water out of the PCL, causing it to collapse and and the cilia to fold over. The cilia can no longer beat in a coordinated fashion to sweep the mucus away. The thickened, immobilized mucus begins to adhere to the epithelium and further resists clearance by coughing as well as ciliary action.

• Mucus plugging eventually results, along with chronic bacterial infection,

inflammation, and bronchiectasis. Reference

• 1. Button BM, Button B. Structure and function of the mucus clearance system
• f the lung. Cold Spring Harb Perspect Med. 2013;3(8). pii: a009720. doi:

10.1101/cshperspect.a009720. 12

Key Points:

• In a series of experiments, that used newborn piglets with modified CFTR genes to determine whether

mucus viscosity is altered at birth, the authors found that:1

• ASL viscosity is increased in CF from birth, demonstrating it is a primary defect
• ASL viscosity is increased by
• Lower pH
• Increased calcium concentration
• Viscosity is not affected by bicarbonate (HCO3-) secretion; instead, bicarbonate secretion

through CFTR channels decreases pH, which in turn increases viscosity

• CFTR channel mutations also appear to cause mucus tethering, another factor in defective mucociliary

transport.2,3

• Abnormally acidic ASL in CF lungs contributes not only to mucus adhesion but also impairs antibacterial
• action. Meanwhile, thickened mucus favors survival of nonmotile bacteria, which tend to aggregate in

response to neutrophil elastase. These bacterial aggregates resist killing by both host defenses and antibiotics, and develop into chronic infections with resultant inflammation and remodeling.2,4

• CFTR channel mutations also appear to cause mucus tethering, another factor in defective mucociliary

transport.2, Reference 1. Tang XX, Ostedgaard LS, Hoegger MJ, et al. Acidic pH increases airway surface liquid viscosity in cystic fibrosis. J Clin Invest. 2016 Jan 25. pii: 83922. doi: 10.1172/JCI83922. 2. Stoltz DA, Meyerholz DK, Welsh MJ. Origins of cystic fibrosis lung disease. N Engl J Med. 2015;372(4):351-362. 3. Hoegger MJ, Fischer AJ, McMenimen JD, et al. Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis. Science. 2014;345(6198):818-822. 4. Staudinger BJ, Muller JF, Halldórsson S, et al. Conditions associated with the cystic fibrosis defect promote chronic Pseudomonas aeruginosa infection. Am J Respir Crit Care Med. 2014;189(7):812- 824.

13

14

Key Points:

• Although lung disease does take time to develop, symptoms nevertheless

begin very early in life, as shown here. The Epidemiologic Study of Cystic Fibrosis was a prospective, multicenter, encounter-based, longitudinal

• bservational study that ran from 1994 to 2005 and was designed to

characterize the natural history of CF in a large population of patients in the US and Canada.

• The analysis shown here includes 6784 patients who were ≤4 years old at

enrollment and had at least 2 years of follow-up data. The mean age of enrollment was 1.4 years, and the mean duration of follow-up was 7 years.

• Cough was the most common persistent symptom, occurring in 82% of
• patients. The median age of cough onset was 2.3 years.

Reference

• 1. McColley SA, Ren CL, Schechter MS, et al. Risk factors for onset of

persistent respiratory symptoms in children with cystic fibrosis. Pediatr

• Pulmonol. 2012;47(10):966-972.

15

Key Points:

• Infants with CF may already show evidence of bronchiectasis on CT scans, and the

percentage increases through the early years of life

• The extent of bronchiectasis also increased with age (P = .001)
• The extent of bronchiectasis was associated with indicators of neutrophilic

inflammation, with relationships seen between bronchiectasis and total cell count (r = 0.21, P = .04); absolute number of neutrophils (r = 0.25, P = .03), and neutrophil elastase activity (r = 0.43, P = .001)

• Air trapping and bronchial wall thickening were very common in CF patients from the

first year of life

• Data are from the Australian Respiratory Early Surveillance Team for Cystic Fibrosis

(AREST CF) in patients who were diagnosed following newborn screening

• Data were collected as part of a unique early surveillance program (ESP) of

newborns diagnosed with CF after NBS in Perth and Melbourne, Australia.

• The ESP includes annual bronchoalveolar lavage (BAL) and chest CT scans

Reference

Stick SM, et al. Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after newborn screening. J Pediatr. 2009;155:623-628

16

Key Points:

• Infants with CF may already have lung damage, as revealed by a prospective

study of all infants with CF through newborn screening in Western Australia and Victoria.1

• The CT scans on the left show differences between CF lungs compared with

healthy lungs in infants with a mean age of 28 days. The CT scans reveal bronchial dilatation and wall thickening as well as gas trapping.1

• Another study of 71 infants (mean age 39 weeks) with positive CF screening

demonstrated that LCI was significantly higher than that of healthy infants (mean age 40 weeks), while forced expiratory volume (FEV), forced vital capacity (FVC), forced expiratory flow (FEF), and functional residual capacity (FRC)—all of which were tested using the raised volume technique during quiet sleep—were significantly lower. In addition, the CF infants exhibited hyperinflation and gas trapping.2 References

• 1. Sly PD, Brennan S, Gangell C, et al. Lung disease at diagnosis in infants with cystic

fibrosis detected by newborn screening. Am J Respir Crit Care Med. 2009;180(2):146-152.

• 2. Hoo AF, Thia LP, Nguyen TT, et al. Lung function is abnormal in 3-month-old infants

with cystic fibrosis diagnosed by newborn screening. Thorax. 2012;67(10):874-881.

17

Key Points:

• Bronchiectasis is an irreversible lung abnormality that marks the presence of permanent lung
• damage. It is also the first irreversible change seen in children with CF. Among 127

participants in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) program, 29.3% had evidence of bronchiectasis at 3 months, which increased to 83.7% at 3 years.1

• The computed tomography images are from 3 different patients with varying degrees of

bronchiectasis (aged 13.5 to 15.5 years). Greater severity of bronchiectasis was associated with the presence of Pseudomonas aeruginosa, and mucoid P. aeruginosa was associated with the most severe bronchiectasis and overall lung disease.2

• In this study, total lung disease scores were based on the extent and severity of

bronchiectasis, mucous plugging, peribronchial thickening, parenchymal opacity, ground- glass opacity, cysts or bullae, and air trapping. The maximum score for each lobe was 12. Bronchiectasis was defined as airway lumen diameter greater than the diameter of the accompanying artery or an artery equidistant from the hilum, nontapering bronchi, or a bronchus extending to the pleural surface2

• Another study involving 81 children with CF aged 6.6 to 17 years confirmed the association of

mucoid but not nonmucoid P. aeruginosa with bronchiectasis, and also revealed that damage is more severe in upper lung quadrants, particularly on the right side. The author speculated that P. aeruginosa might be more likely to aggregate in these areas due to a combination of aspiration, gastroesophageal reflux, and reduced bicarbonate secretion through CFTR channels.3 References 1. Sly PD, Gangell CL, Chen L, et al. Risk factors for bronchiectasis in children with cystic

• fibrosis. N Engl J Med. 2013;368(21):1963-1970.

2. Farrell PM, Collins J, Broderick LS, et al. Association between mucoid Pseudomonas infection and bronchiectasis in children with cystic fibrosis. Radiology. 2009;252(2):534-543. 3. Li Z, Sanders DB, Rock MJ, Kosorok MR, Collins J, Green CG, Brody AS, Farrell PM. Regional differences in the evolution of lung disease in children with cystic fibrosis. Pediatr

• Pulmonol. 2012;47(7):635-640.

18

Key Points:

• Percent predicted FEV1 shows the greatest rate of decline through

adolescence, and continues to decline through age 29 according to the data in the US CFFPR.1

• The general pattern shows that the ppFEV1 slowly decreases until the age of

30-34, and then levels out. The patients in the oldest age groups are patients that survived, and may therefore represent the patients with less disease severity.2 Additional Information

• These graphs shows the median ppFEV1 (the value that separates the

highest and lowest half of the patients) by age group in the US CFFPR and the ECFSPR.2 References

• 1. Cystic Fibrosis Foundation. Patient Registry 2014 Annual Data Report to the

Center Directors. Bethesda, MD. 2015.

• 2. Zolin A, et al. ECFSPR Annual Report 2013, 2.2016.

19

Key Points

• Lower FEV1 values are strongly associated with increased rates of death

(FEV1 less than 30% predicted correlates with a mortality rate of 50% at 2 years)1

• The leading cause of death in patients with CF is respiratory disease

according to the CFF Patient Registry (2014 data) and the ECSF Patient Registry (2013 data).2,3 Additional Information

• The ppFEV1 analysis cohort consisted of 673 patients with CF who were

followed at the Hospital for Sick Children, Toronto, between 1977 and 19891

• The cause-of-death analyses are based on 461 reported deaths in 2014 in the

US CFFPR2 and 347 reported deaths in 2013 in the ECFSPR.3 References

• 1. Kerem E et al. N Engl J Med. 1992;324(18):1187-1191.
• 2. Cystic Fibrosis Foundation. Patient Registry 2014 Annual Data Report to the

Center Directors. Bethesda, MD. 2015.

• 3. Zolin A, et al. ECFSPR Annual Report 2013, 2.2016.

20

Key Points

• LCI detects early airway disease in children before noticeable FEV1 decline
• Healthy controls and patients with CF had their lung function tested by both

FEV1 and LCI

• 11 of 22 children with CF had a FEV1 within the normal range, with some of

these children having a FEV1 z-score greater than 0 – Only 1 of 22 patients with CF had a normal LCI Additional Information

• In healthy children there was no relationship between LCI and FEV1, but in

children with CF, LCI and FEV1 were negatively correlated (r2=0.63, P<0.0005)

• Subjects with CF: n=22, aged 6.4 to 16.5 years
• Heathy controls: n=33, aged 5.9 to 16.8 years
• MBW testing was done SF6 and monitored with mass spectrometry
• FEV1 results were converted into standard deviation scores (z-scores) using

published reference data, with a z-score of less than -1.96 being categorized as abnormal Reference Aurora P, Gustafsson P, Bush A, et al. Multiple breath inert gas washout as a measure of ventilation distribution in children with cystic fibrosis. Thorax. 2004;59(12):1068-1073. 21

Key Points:

• Nutrition and lung function are intertwined. Poor nutritional status and poor

somatic growth secondary to pancreatic insufficiency likely affects lung growth as well as the ability to repair lung disease.

• Pulmonary disease affects linear growth through appetite suppression and

increased energy expenditures. Reference Amin R, Ratjen F. Cystic fibrosis: a review of pulmonary and nutritional

• therapies. Ann Pediatr. 2008;55:99-121.

22

Key Points

• In cystic fibrosis, nutritional deficiency is common due to pancreatic insufficiency and

malabsorption.1 Evidence shows that growth and nutritional status is strongly associated with pulmonary function in children with cystic fibrosis2,3

• Patient Registry data show a strong association between a higher BMI percentile and better lung

function in children with CF2 – The graph above on the left shows the association between higher BMI percentile and better lung function in children ages 6 through 19 years. The bar in the middle is the BMI 50th percentile goal for children with CF2

• Shown in the figure on the right, relative weight gain from age 3 to 6 was associated with improved

pulmonary function at age 6 (when FEV1 becomes a reliable measure)3

• Data suggest that early nutritional intervention may improve pulmonary health2,3

Additional Information

• A large cohort of patients were prospectively followed and evaluated for growth indexes and

pulmonary health measures between age 3 and 62

• Data revealed that patients with lower growth indexes at age 3 had lower pulmonary function at age
• 6. This was strongest for measures of weight for age2
• As shown in the figure, relative weight gain from age 3 to 6 was also associated with better

pulmonary function at age 62 – Children whose weight for age was greater than the 10th percentile at age 3 and remained greater than the 10th percentile at age 6 had the highest FEV1 scores – Conversely, patients whose weight for age was less than the 10th percentile at age 3 and remained less than the 10th percentile at age 6 had the lowest FEV1 scores

References 1. O’Sullivan BP, Freedman SD. Lancet. 2009;373:1891-1904. 2. Konstan et al. J Pediatr. 2003;142:624-630. 3. Cystic Fibrosis Foundation. Patient Registry 2013 Annual Data Report to the Center Directors. Bethesda, MD. 2014.

24

Key Points:

• The Fuchs criteria to define pulmonary exacerbation consist of IV antibiotic

treatment for any 4 of a list of 12 clinical signs and symptoms as shown on the slide1

• In a study involving 11,630 patients from the Cystic Fibrosis Foundation

patient Registry (CFFPR), the number of acute exacerbations ranked as the third highest risk factor for death after Burkholderia cepacia infection and diabetes mellitus2

• Each acute pulmonary exacerbation within the year had an unexpectedly

large, negative impact on 5-year survival equal to subtracting 12% from the measured % predicted FEV1 value2 References

• 1. Fuchs HJ, et al. N Engl J Med. 1994;331:637-642.
• 2. Liou TG, Adler FR, Fitzsimmons SC, et al. Predictive 5-year survivorship

model of cystic fibrosis. Am J Epidemiol. 2001;153(4):345-352. 25

Key Points:

• Lower percent predicted FEV1 is associated with a higher risk of pulmonary

exacerbation Additional Information

• This study shows data on the annual rate of pulmonary exacerbation per

decile of mean ppFEV1 for 2004 in the US CF Registry in each decile of the population (each decile represents 10% of the total population).

• The charts show the relation in patients with CF who were <18 years of age

and patients ≥18 years of age; in each case, lower FEV1 is associated with higher risk of pulmonary exacerbation. Reference Goss CH, Burns JL. Exacerbations in cystic fibrosis. 1: Epidemiology and

• pathogenesis. Thorax. 2007;62(4):360-367.

26

Key Points:

• Of the 8,479 evaluable subjects with pulmonary exacerbations, a total of

2,159 (25%) failed to recover to baseline ppFEV1 within the 3 months after treatment. Additional Information

• Data from the Cystic Fibrosis Foundation Patient Registry (2003-2006) were

analyzed to evaluate the recovery of lung function following IV antibiotic treatment for pulmonary exacerbation.

• Patients were at least 6 years old, were treated with IV antibiotics for at least

1 pulmonary exacerbation, and had at least 12 months of data in the CFFPR prior to any pulmonary exacerbation during the study.

• Baseline FEV1 was defined as the best FEV1 in the 6 months before the

pulmonary exacerbation. Recovery to baseline was defined as any FEV1 in the 3 months after treatment that was greater than or equal to 90% of the baseline FEV1. Reference Sanders DB, et al. Am J Resp Crit Care Med. 2010;182:627–632. 27

Key Points:

• The data shown on this slide are from the US CFF Registry and show data by

center using box and whisker plots. Each plot shows the median (yellow line), the variability across CF centers (width of blue box), and the minimum and maximum values (ends of black lines through middle of each box). The median is the value for which half of the responses fall above and half fall below, so the boxes show the 2 center quartiles, and the black lines show lower and upper quartiles. Median, minimum, and maximum values are also shown in columns on the right.

• The median length of treatment for both children and adults with CF was >1 to

2 weeks. Center-level data show marked variation in the treatment of exacerbations, highlighting opportunities for further research and quality improvement

• This table reports the median length of hospitalization per exacerbation; the

mean number of days of hospitalization for pulmonary exacerbation per year is 20.0. Reference CFF Patient Registry. 2014 Annual Data Report to the Center Directors. 2015. 28

Key Points

• The effect of prior-year PEx on hazard rates was an order of magnitude

greater than that of any of the remaining covariates, with 3 or more PEx in the prior year associated with a 25-fold higher hazard rate compared with none in the prior year Additional Information

• This analysis employs data from patients of record at the Cleveland CF

Center obtained from the Cystic Fibrosis Foundation Patient Registry

• To be included, patients had to have had a confirmed diagnosis of CF, have

been treated with IV antibiotics for pulmonary exacerbation (a pulmonary exacerbation care episode) on or after January 1, 2010, and have had at least 1 subsequent clinic visit (encounter) after the end of IV treatment by September 2014

• Median time to next pulmonary exacerbation for the entire population and

among categorical subgroups was determined by Kaplan-Meier survival analyses

• Six covariates (prior-year PEx, IV treatment duration, percentage of treatment

in hospital, chronic treatment with inhaled aminoglycosides, chronic treatment with leukotriene modifiers, and chronic treatment with high-dose ibuprofen) were retained in the final multivariate Cox regression model Reference VanDevanter DR et al. J Cyst Fibros. 2015;14(6):763-769. 29

Key Points

• Patients who experience pulmonary exacerbations on a frequent basis are at

greater risk for death or lung transplant

• This study shows that patients who experience more than 2 exacerbations

per year are at a significantly greater risk (4-fold increase) for death or lung transplantation

• An important goal of CF treatment is to reduce the frequency and the

severity of pulmonary exacerbations Additional Information

• Kaplan-Meier plot comparing time to death or lung transplant over 3 years per

exacerbation group. Analyses were adjusted for age, sex, body mass index (BMI), infection with Burkholderia cepacia, transmissible Pseudomonas aeruginosa, baseline FEV1, CF comorbidities, and maintenance therapies. The population included 446 adults with CF

• Studies have shown that each acute pulmonary exacerbation in a year has

the equivalent effect on the risk of death as subtracting 12 percentage points from the measured percent predicted FEV1 (ppFEV1) value Reference de Boer K et al. Thorax. 2011;66(8):680-685 30

31

Key Points:

• The graph is from the CFF Patient Registry, and shows pathogen prevalence by age.1
• Pseudomonas aeruginosa infection is present in over 50% of CF patients, and the mucoid,

nonmotile, aggregating form of this pathogen is associated with more severe lung damage in

• CF. Mucoid P. aeruginosa are associated with a stronger biofilm, are more difficult to treat

with antibiotics, and can survive and reproduce more readily than nonmucoid P. aeruginosa.2,3 In addition, most P. aeruginosa strains are multidrug resistant (MRD-PA), and antibiotic selection pressure can promote development of the mucoid form.2 The good news is, the prevalence of this species is decreasing.1

• Staphylococcus aureus, is on the rise and currently infects 70% of CF patients.1 Moreover,

methicillin-resistant S. aureus (MRSA) in CF has increased in parallel with MRSA in the general population.1,2

• Only 3% to 4% of patients have infections with Burkholderia cepacia and related species,2 but

some studies have found greater morbidity and mortality associated with Burkholderia than with P. aeruginosa.4 References

1. Cystic Fibrosis Foundation Patient Registry. 2014 Annual Data Report. Bethesda, Maryland: Cystic Fibrosis Foundation; 2015. 2. LiPuma JJ. Clin Microbiol Rev. 2010;23(2):299-323. 3. Staudinger BJ, et al. Am J Resp Crit Care Med. 2014;189:812-824. 4. Folescu TW, et al. BMC Pulm Med. 2015;15:158. doi: 10.1186/s12890-015-0148-2.

32

Key Points

• The term ‘microbiome’ describes the complex microbial ecosystems that exist within the human body
• In CF, a reduction in bacterial diversity is associated with disease progression and pathogen

colonisation (e.g. Staphylococcus aureus, Burkholderia cepacia and Pseudomonas aeruginosa)

• The low bacterial diversity observed in CF has been associated with increased inflammation, a more

advanced disease stage, and a worse prognosis

• Furthermore, low microbiota diversity also precedes the development of an exacerbation
• Further studies are required to allow a better understanding of how changes in microbial composition

and microbiota structure determine CF disease progression and exacerbations Additional Information

• Techniques such as microbial epigenetics are helping to define the role the microbiome plays in health,

as well as disease, states

• While there is evidence indicating that microbiota (bacteria, viruses and fungi) exert an important

physiological function in shaping the immune response of the airway mucosa, there is also increasing recognition of the presence of cross-talk between the gut and lung mucosa

• Ultimately, the gut and lung mucosa may function as a single aero-digestive system, and both share the

physiological function of pathogen surveillance and shaping the immune response

• It is likely that dynamic changes of airway microbiota occur over time, such that the switch from a

‘healthy’ well-balanced polymicrobial microbiome to an ‘unhealthy’ restricted airway microbiota renders the airway more susceptible to a dominant pathogen and consequent lung injury

• Improved understanding of the non-bacterial composition of the microbiome will also be necessary in
• rder to elucidate the interactions of the microbial community in its entirety within the settings of both

health and disease Reference Segal LN et al. Ann Am Thorac Soc 2014;11:108–16

33

34

35

36

37

38

39

40

41

• In the mucociliary clearance (MCC) test, the patient inhales radiolabeled,

nonabsorbable marker such as nebulized technetium sulfur colloid (Tc-SC) aerosols, which contain submicronic particles 0.3 µm in size. Very little Tc-SC penetrates into bloodstream; the majority of it remains suspended in mucus layer.1

• After inhaling the marker, the study subject sits or lies recumbent in front of g-

radiation camera. Thin plates known as collimators are used to filter out scatter and ensure a focused image. The inhaled Tc-SC dose, camera resolution, and thickness of collimator together determine the sensitivity and spatial resolution of the test.1

• Studies have shown that the rates of MCC varies by lung region. Particles

move slower in the small airways (~1 mm/min) and faster in larger airways (up to 2 cm/min).1 Reference

• 1. Donaldson SH, Corcoran TE, Laube BL, Bennett WD. Mucociliary clearance

as an outcome measure for cystic fibrosis clinical research. Proc Am Thorac

• Soc. 2007;4(4):399-405.

42

Key Points1

• LCI is a numerical value derived from multiple breath washout (MBW) test data
• LCI is the number of breaths it takes to reduce the tracer gas to 1/40th the starting concentration
• The reason for using 1/40th is historical, as this represented the limits of the operating range (2% to

80%) of early nitrogen analyzers. However, it remains a workable compromise between ending a washout too soon and having an excessively long procedure

• More technically, LCI is the cumulative expired volume (CEV) divided by the functional residual capacity

(FRC)

• CEV is the volume of air required to wash out the tracer. In other words, this is the amount of air

breathed by the subject to wash out the tracer (to 1/40th the starting concentration). FRC is the volume

• f air in the lungs at the start of the test. This value increases with a subject’s size (height) and acts as a

factor that normalizes LCI across populations

• Diseased lungs will require more breaths, and therefore a higher CEV, to wash out the tracer.

Therefore, the higher the LCI, the more severe the lung disease Additional Information2

• Details on line graph

– Mean expired nitrogen concentration curve for a 19-year-old male patient with CF (ppFEV1 = 53%) and for the matched control subject (ppFEV1 = 83%) – Solid red line is the point at which the tracer gas reached 1/40th the starting concentration – Dotted lines indicate the LCIs for the healthy control and the patient with CF (6.1 and 10.2, respectively) References 1. Horsley A. Lung clearance index in the assessment of airways disease. Respir Med. 2009;103(6):793- 799. 2. Verbank S, Paiva M, Paeps E, et al. Lung clearance index in adult cystic fibrosis patients: the role of convection-dependent lung units. Eur Resp J. 2013;42(2):380-388.

Disclaimer Acknowledgement: The material within in this slide show that was originally published in the European Respiratory Journal has not been reviewed prior to release by the European Respiratory Society (ERS); therefore the ERS may not be responsible for any errors, omissions or inaccuracies, or for any consequences arising there from, in the content. Products mentioned should not be construed as an endorsement of the product or the manufacturer’s

• claims. Viewers are encouraged to contact the manufacturer with any questions about the features or limitations of the

products mentioned. The viewer is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other health care professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. An effort has been made to check generic and trade names, and to verify drug doses. The ultimate responsibility, however, lies with the prescribing physician.

43

• In hyperpolarized gas magnetic resonance imaging (HP-MRI), the patient

inhales a hyperpolarized form of helium or xenon (3He or 129Xe), which serve as a contrast medium. Both helium and xenon are inert and nontoxic. Helium has stronger magnetic resonance signal than xenon, which provides for superior resolution and a lower signal-to-noise ratio.1,2

• On MRI images, the hyperpolarized gas causes ventilated regions of the lung

to appear bright while poorly ventilated regions appear dark.1

• This technique permits high temporal and spatial resolution that may reflect

important functional changes in CF, including mucus plugging and airway

• bstruction.1

Reference

• 1. Mentore K, Froh DK, de Lange EE, Brookeman JR, Paget-Brown AO, Altes
• TA. Hyperpolarized HHe 3 MRI of the lung in cystic fibrosis: assessment at

baseline and after bronchodilator and airway clearance treatment. Acad

• Radiol. 2005;12(11):1423-1429.
• 2. Fain SB, Korosec FR, Holmes JH, O'Halloran R, Sorkness RL, Grist TM.

Functional lung imaging using hyperpolarized gas MRI. J Magn Reson

• Imaging. 2007;25(5):910-923.

44

• Chronic rhinosinusitis is increasingly recognized as an important feature of
• CF. Nearly all CF patients have this condition, and 86% have nasal polyps.

This is no surprise, since the same mucus transport mechanisms and inflammatory and infectious process that affect lung airways affect nasal

• passages. Moreover, CF-associated inflammation and remodeling promote

nasal polyp formation. In addition, the sinuses serve as a bacterial reservoir that transmits disease to lower airways.1

• Chronic rhinosinusitis may be diagnosed according to the criteria shown at

left. Reference

• 1. Illing EA, Woodworth BA. Management of the upper airway in cystic fibrosis.

Curr Opin Pulm Med. 2014;20(6):623-631. 45