Saturday, October 26, 2013

Up for Debate

Every year at the NACFC, one symposium session is dedicated to debating hot topics in CF clinical care. This year's symposium addressed three important issues, where specialists have significant differences in opinion.  One expert presents the PRO argument, another presents the CON argument, and then the audience "votes" for the winner by applause.

This year, 3 important issues were debated--
1) Can Exercise Substitute for Airway Clearance?

2) Which should be the first drug introduced to manage CF--Hypertonic Saline or Dornase Alfa (Pulmozyme)?

3) Should glucose intolerance be treated aggressively in CF, or not?

I love these debate sessions each year because they expose the wide range of opinions that exist among CF professionals regarding the "right" way to treat patients.  Some people never question their Doc, because it is assumed that they always know best...  These sessions help illustrate why CF care can vary so much from center to center!  Feel free to put in your two cents on any of these topics in a comment!

Can Exercise Substitute for Airway Clearance?
Pro argument given by Dr.Cecilia Rodriguez Hortal.

For the purposes of this argument, Dr. Hortal suggests that vigorous exercise, with built in breaks for patients to "huff cough" and expectorate mucus, could be used as an alternative to regular airway clearance techniques, particularly in pediatric populations with milder lung disease.  She discusses the success of the "Swedish model"--which utilizes exercise and specialized breathing techniques as a form of airway clearance.  She also presents a few scientific studies showing the benefits of physical exercise on CF lung disease.  Exercise has been proven to reduce the viscosity of mucus, improve airway hydration, increase cilia beat frequency in the airways, and reduce markers of inflammation.

Dr. Hortal goes on to explain that physical exercise (both aerobic and anaerobic) offers health benefits far beyond airway clearance, and can be a fun, non-stressful way for patients to perform their airway clearance.  In her opinion, exercise is a more kid-friendly technique that could encourage patients to develop healthy habits for life.  She goes on to discuss one scientific study which showed exercise to be as effective as regular airway clearance techniques for children with CF. 

Can Exercise Substitute for Airway Clearance?  
Con argument presented by Dr. Shruti Paranjape

First, Dr. Paranjape presented the current guidelines for Airway Clearance Therapy:

He went on to explain that there are many methods currently available for effective airway clearance, and that the selection of technique should be tailored to meet the individual patient's needs.  

Even though Dr. Paranjape was presenting the CON argument in this debate, he spent a lot of time discussing the irrefutable benefits of exercise in the CF population.  Dr. Paranjape believes that exercise should absolutely be promoted to improve the health of CF patients--but should be an adjunctive therapy rather than a replacement for airway clearance.   

In the end, both presenters agreed that exercise is an extremely beneficial part of the CF care regimen, but Dr. Paranjape believes exercise should be thought of as an additional "prescription," rather than a replacement for other airway clearance therapies.  There was some discussion about the technique required to move mucus from the peripheral lung (small airways) to the central lung, where it could be coughed out.  Apparently, this peripheral lung clearance happens best during periods of long expiration (long breaths out).  There was concern that if a patient was exercising at an aerobic level, respiration rate would be too rapid for peripheral lung clearance to effectively occur.  It seemed that Dr. Paranjape won the audience vote by applause.  

Which drug should be the first used to treat CF?
Hypertonic Saline argument given by Dr. Margaret Rosenfeld.

Dr. Rosenfeld began her argument by showing some data from the ARESTCF study conducted in Australia.  This revealing study showed that structural lung damage and decreased lung function occur very early in children with CF--even in the absence of symptoms.  Furthermore, this lung damage was found to be progressive.  The ARESTCF study scared me big time when I first saw the data presented at the 2011 NACFC and I wrote a whole blog entry about it:  The ARESTCF study utilized CT scan to detect structural lung damage like bronchiectasis in infants with CF.  They also utilized the BronchoAlveolar Lavage (BAL) technique to determine the microbiome in the CF infant lung.  BAL is much more sensitive and accurate at detecting infection than the more commonly used oropharyngeal "throat swab." BAL found that infants with CF begin colonizing harmful bacteria long before symptoms appeared, and prior to testing positive for infection on a throat culture.  

The idea is that earlier intervention may be able to PREVENT bronchiectasis (irreversible widening of the airways).  Dr. Rosenfeld believes that Hypertonic Saline is an attractive candidate for first use because it has been shown to hydrate mucus--improving mucociliary clearance. 

She shows that Hypertonic Saline acts fairly early in the cascade of dysfunction that leads to disease in the lungs, by improving water absorption.  

She also shows evidence that Hypertonic Saline has a positive impact on reducing exacerbations in patients over the age of 6...

...But Dr. Rosenfeld has one big strike against her in this argument, and she acknowledges the results of the ISIS study--which failed to show any benefits of Hypertonic Saline use in infants.  

Dr. Rosenfeld believes that the endpoints of the ISIS study may not be the most appropriate to show true benefit in this age group, and suggests that further studies, using alternate endpoints like LCI (Lung Clearance Index, which has been shown to be a much better prediction of lung function in infants than FEV or exacerbation status) or CT scan, may support use of this cheap, readily available drug in the infant population.  After her call for further studies, Dr. Rosenfeld sort of concedes her position before the other presenter even takes the mic!

Which drug should be the first used to treat CF?
Dornase alfa argument presented by Dr. Ran Anbar

Dr. Anbar opens with a little refresher course on what Pulmozyme is designed to accomplish in the lungs.  Neutrophils are white blood cells, which attack foreign organisms in the human body.  Neutrophils are an essential part of fighting infection, but these cells also secrete harmful substances that can cause lung damage (neutrophil elastase).  Neutrophil levels can be elevated in CF lungs, and when these cells die, they leave behind long strands of DNA that act to bind together thick sticky mucus (think about adding a bunch of cooked spaghetti to your jello mold--it is going to strengthen that otherwise flimsy structure.  All those internal connections encourage formation of the mucus "biofilm.").  Pulmozyme is designed to cut up the long strands of extracellular DNA left behind by neutrophils, allowing for better mobilization of mucus.  Dr. Anbar then goes on to present the evidence of Pulmozyme's benefits in patients.  For example, studies show that Pulmozyme slows the rate of lung function decline in CF, and also reduces the burden of infection.

Dr. Anbar says that Pulmozyme interrupts the vicious cycle of infection, inflammation, and obstruction in two crucial ways.

In conclusion, Dr. Anbar felt that the evidence for Dornase alfa to be the first drug used to treat CF was on his side, and the audience agreed.  I am, however, still curious to see what benefits might be seen using Hypertonic Saline in infants if different study endpoints were selected.  For now, Pulmozyme got the win from this crowd.  

    The last question debated dealt with the topic of treating glucose intolerance in CF patients.
Non-fasting Hyperglycemia Should be Treated Aggressively.
Pro argument given by Dr. Deepa Kirk.

Dr. Kirk, an adult endocrinologist, explained that there are guidelines to treat full blown Cystic Fibrosis Related Diabetes (CFRD)--but there is a grey area when it comes to treating early signs of glucose intolerance in CF.  She explains that CFRD develops differently than Type II diabetes.  Rather than a linear progression to disease, glucose tolerance in CF patients sort of toggles back and forth between normal range and CFRD range.  

She explains that glucose intolerance is also known as "pre-diabetes," and in other patient groups (pregnant women, steroid treated patients, the elderly) there is evidence that early treatment can have a positive effect on patient health.  Dr. Kirk goes on to explain how untreated hyperglycemia (high blood sugar), can lead to impaired lung function and further impairment of insulin regulation.  

Dr. Kirk described some small studies on CF patients that showed patients with impaired glucose tolerance gained weight and improved pulmonary function after initiation of insulin therapy.  Since BMI and pulmonary function often begin to decline YEARS before a diagnosis of CFRD, Dr. Kirk feels that early interventions to improve sugar control could lead to an overall improvement in health outcomes for patients.  She notes that untreated hyperglycemia can cause unpleasant quality of life issues for patients that should also be considered (headaches and fatigue).  She maintains that early interventions would not necessarily have to be as burdensome as managing constant insulin injections--in fact, the first therapies for impaired glucose tolerance may likely be dietary modifications, oral meds, or low dose insulin.  

Non-fasting Hyperglycemia Should be Treated Aggressively
Con argument given by Dr. Irl Hirsch

Dr. Hirsch defends the current line of thinking in the CF world right now, which is that non-fasting hyperglycemia does NOT warrant aggressive treatment.  First, he describes the criteria used to officially diagnose diabetes--hyperglycemia resulting in vascular damage known as retinopathy.  He argues that CF patients with non-fasting hyperglycemia do not present with retinopathy.  He goes on to explain the huge range of glucose levels considered normal or "average."  He claims that it is completely unclear how much of the "complications pie" in CF comes from impaired glucose tolerance, and that there is no data to support insulin therapy in this group.  Dr. Hirsch claims that the link between impaired glucose intolerance and lung function represents a "chicken or egg" argument.  Will interventions to improve sugar control improve lung function?  Or do unstable sugars simply go along with worsening CF lung disease and steroid use?  Dr. Hirsch feels that the treatment burden associated with an insulin intervention is too high for the modest benefits that might be seen by patients.    The crowd vote was pretty evenly split between the two presenters.  Regardless of the outcome of this debate, I think CFRD and glucose intolerance are going to be topics that we will hear more and more about in the coming years as scientists unravel the mechanism behind CFRD.  

No wonder it is so difficult to determine the "correct" way to treat CF...even the experts disagree!  I hope this entry inspires some further debate on these topics--ideally with your own clinical team! What additional perspectives could patients add to these pro/con arguments?  


  1. Thank you so much for sharing this information with us! My son is actually taking part in the ARESTCF study and it seems as though they have some good results from it so far. He has an annual bronchoscopy, BAL and CT scan, and it's meant that we have been able to treat problems before they start causing damage or even symptoms. There's so much happening in CF research these days. It's very exciting!