CF lung disease: Does symptomless = safe?

Everything is going along great.  Brady seems to be breathing well, sleeping well, and has lots of energy.  At his last CF Clinic appointment, his nurse performed a “throat culture” to check for infections growing in his lungs.  We got the call that his culture came back with “normal flora.”  Good news, but what does this information actually mean?  We also discussed that Brady will undergo a chest CT scan in a few weeks to better assess his lung health and determine whether it will be safe to pull him off of some of his breathing treatments now that he has begun Kalydeco. With this in mind, I can’t stop thinking about this talk I attended at the NACFC entitled: Early CF Lung Disease—No Time to Waste.  I consider it the most shocking information I learned about CF at the Conference and be warned that it might rattle you too.  I wrote about it briefly at the Conference, but have been avoiding summarizing it in detail because it is kind of scary and I try to keep my blog both optimistic and informative.  The last thing I want to do is scare people with this entry…but there is no doubt that this is important information and let’s be honest—MANY things you learn about CF are less than pleasant, so here goes. 

Early CF Lung Disease—No Time to Waste, Stephen Stick, Perth, University of Western Australia presented the data from his project AREST CF, which commenced in 2005.

AREST CF: Australian Respiratory Early Surveillance Team for Cystic Fibrosis.  “Arest CF seeks to improve the detection, prevention, and treatment of early respiratory disease in young children with cystic fibrosis in order to improve clinical outcomes and quality of life for patients and their families.”  This study was funded in large part by the U.S. Cystic Fibrosis Foundation.    

Dr. Stick then went on to use several different types of data to illustrate the importance of the period of time between birth and 6 years of age for cystic fibrosis patients.  He compared FEV1 data collected from the U.S. national Registry in 1990 to data from 2008 to show that “while FEV1 has increased in general over time, after about 12 years of age, the lines become parallel.  Furthermore, although there has been an improvement in the adult FEV1, most of the improvement is already evident by 6 years of age.”  This data prompted them to start looking more closely at what was happening to the CF lung in the early years of life, to examine whether the current protocol of detection and treatment is the best path.  Basically, they wanted to use the most sophisticated techniques available today to look as closely as possible at a group of children over the course of 6 years in Australia to see what is structurally going on inside the CF lung beginning at birth.

First, Dr. Stick describes the methods they used in their study and why these methods were chosen over commonly used throat culture and FEV1 measurements. 

--Based on data from an earlier study, Dr. Stick’s group determined that a technique called “Bronchoalveolar lavage” is a more sensitive method of detecting lung infections than the commonly used oropharyngeal swab (throat culture).  Bronchoalveolar lavage or BAL is a medical procedure where a bronchoscope is inserted into the lung via the nose or mouth and a liquid is squirted into a portion of the lung and then recollected for examination.  The term lavage means “to wash.”  By rinsing the lining of the lung and culturing that liquid, imagine how much more information could be found about active lung infections than by swabbing the back of the throat.  It makes sense that this technique would be more sensitive; the downside is that it is not nearly as simple to perform on patients.

--Dr. Stick also cites several studies about why they chose to employ CT scans rather than FEV1 as a means of tracking lung health in these young children (Fred Long, Journal of Pediatrics. 2004, Pim de Jong Thorax 2006).  These and more emerging studies show the ability of CT scan to detect dilatation of the airways, mucus plugging, gas trapping, and bronchiectasis in young children, even in the presence of normal FEV1 scores.  In Dr. Stick’s words, “FEV1 actually was a poor surrogate for what was happening in the lungs in terms of structural lung disease.” 

The AREST CF study commenced in 2005 was designed to examine the following criteria on children at age 3 mo., 1 yr., and then annually to 6 years.

·         Clinical Progress

·         Infant Lung Function

·         Chest CT Scan

·         Bronchoalveolar Lavage

·         Epithelial Samples

Dr. Stick briefly goes into how they performed/measured each of these outcomes, but puts the focus of the remainder of the talk mainly on the CT scan data in relation to development of structural lung disease.  These scans were performed under general anesthesia, and were “volume controlled” to give data on both inspiration and expiration. 

Detectable Structural Lung Disease

The major surprise on CT scans in young children with CF was the prevalence of bronchiectasis.  Bronchiectasis is defined as irreversible localized dilation/destruction of the airways and is “clearly visible as widening of the airway” in CT scans.  The data showed an increasing prevalence of bronchiectasis in the children studied—with over 80% exhibiting bronchiectasis visible in CT scan by age 6.  Once bronchiectasis was detected via CT, the majority of cases persisted or worsened by the time of the next CT—showing that this is a progression of disease, rather than just a transient phenomenon.

Summary of findings:

Prevalence of bronchiectasis in children, detected via volumetric CT scan

Age 1: 20% of children scanned exhibited bronchiectasis

Age 2: approximately 40%

Age 3: just over 50%

Age 4: 60%

Age 5: 70%

Age 6: over 80%

Air trapping and mucus plugging are also visible on CT in increasing prevalence as children approach age 6. 

Bronchoalveolar Lavage Data

Inflammation

Researchers can obtain information about the inflammatory response in the lungs by measuring the “neutrophil elastase” in the BAL fluid.  An elevated level of neutrophil elastase in the BAL fluid indicates greater inflammation in the lungs.  This inflammation marker was increased in children showing bronchial dilatation on their CT scan.  Children whose lungs harbored infection by one or multiple organisms also had higher neutrophil elastase levels.   

 Infection

Dr. Stick doesn’t believe the “throat culture” method is an effective way to detect lung infections.  Their BAL results showed much greater rates of infection than were revealed through throat swab.  According to their data, and in Dr. Stick’s words, “All of the organisms that we associate with CF have been found in the first BAL at 3 months, from pseudomonas right through to more unusual ones like Stenotrophomonas.”  This means that even if when patients receive “normal flora” results from a throat culture, there still may be many organisms growing within the CF lung detectable only through more sensitive techniques like BAL.  This doesn’t mean that every child with CF has ALL these organisms actively growing in their lungs.   It simply means that in their cohort of sampled children, ALL of the bad bugs associated with CF had been found in some children by 3 months of age.  In other words, very young children are susceptible to CF infections from birth.  This is seen as evidence that the disease progression begins very early in life, and often in the absence of symptoms.   

“The Salutory Lesson”

On the slide entitled “The Salutory Lesson,” Dr. Stick presents CT data from a completely asymptomatic 3 month old that has a “normal” throat culture.  Using prevalent methods of clinical analysis (throat culture and FEV1), this child would not raise any red flags in terms of progression of lung disease...BUT

The CT scan for this asymptomatic child revealed bronchiectasis and the bronchoalveolar lavage revealed infection with pseudomonas. 

Important Messages

Dr. Stick reiterates the most important findings from the AREST CF study:

-“Bronchiectasis is present in 20% of infants by age 1.  It persists in 100% of infants and progresses (worsens) in over 90% of infants.”

-“There is a window of approximately 6 mo. after birth where lung function is maintained” relatively well.

-“Must intervene at diagnosis to prevent lung disease and maintain normal lung function”

Dr. Stick concludes his discussion by showing the small amount of CF research spending that occurs for children under 6.  He believes that the FDA approved endpoints for clinical studies in CF (spirometry, quality of life, and pulmonary exacerbation) are neither feasible, nor appropriate for children under 6.   

“Essentially, infants are being excluded from trials of these potentially disease modifying drugs that may well be coming to market in the next 5-10 years.  I think it is time we actually got our heads out of the sand, in particular the FDA, and realize that if disease modifying therapies are available…then it may be fiscally irresponsible, morally unacceptable, and medically inappropriate to have infants on lifelong therapy with drugs that have only been demonstrated to show small changes in FEV1 in adults or older children.” 

Hopefully this sheds some light on why I walked out of this talk at the Conference feeling pretty freaked out, why I wanted Brady on Kalydeco a.s.a.p., and why I am anxious about Brady’s upcoming CT scan.    Brady is “symptomless” and has normal throat culture result, but does that mean anything??  We shall soon see.  There is no denying that this is extremely relevant information to parents of young kids with CF.  The reason I felt the need to share this summary is that, even though it was difficult for me to hear, I’m glad I know…and I think others should know.  This is the most detailed information ever collected on the early progression of CF in actual human lungs and Dr. Stick is promoting CT scan as the new “gold standard” of lung disease detection in CF!      

It is important to remember that there are plenty of adult role models in the CF community who have proven that you can have a positive impact on lung health at ANY POINT during life with choices like: adherence to treatments, regular exercise, and good nutrition.  This entry is not meant to be about doom and gloom.  My aim is simply to share information.  I have heard some criticism within the CF community about putting children under 6 on Kalydeco “off-label,” as we have done with Brady.  This research made a big impression on me at the NACFC and has certainly factored into our benefit vs. risk analysis of beginning Kalydeco right now as opposed to waiting.  There are going to be more and more studies featuring CT scan data as a way to measure CF lung disease and I think that this new information is going to change the protocol of treatment for the CF infant/child, even “symptomless” ones, to include more early preventative treatments.  This is just my opinion.  While Dr. Stick did not give the breathing treatment schedule of the monitored children in the study, he did remark that the use of Pulmozyme is currently regulated by the Australian government and is limited to children ages 5+.  Brady’s first CT scan is coming up in about 2 weeks.  Look for a detailed report!  I'm feeling optimistic, but also anxious.  According to Dr. Stick, most of the data we have collected about Brady's lung health really doesn't mean much...so you never know what we are going to find on the CT!