mi 2.2.1 cystic fibrosis case study

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Chapter 19:  Case Study: Cystic Fibrosis

Julie M. Skrzat; Carole A. Tucker

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Introduction.

• Examination: Age 2 Months
• Evaluation, Diagnosis, and Prognosis
• Intervention
• Conclusion of Care
• Examination: Age 8 Years
• Examination: Age 16 Years
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C ystic fibrosis (CF) is an autosomal recessive condition affecting approximately 30,000 Americans and 70,000 people worldwide. According to the Cystic Fibrosis Foundation ( Cystic Fibrosis Foundation, 2019a ), approximately 1,000 new cases are diagnosed yearly in the United States, with a known incidence of 1 per 3,900 live births. The disease prevalence varies greatly by ethnicity, with the highest prevalence occurring in Western European descendants and within the Ashkenazi Jewish population.

The CF gene, located on chromosome 7, was first identified in 1989. The disease process is caused by a mutation to the gene that encodes for the CF transmembrane conductance regulator (CFTR) protein. This mutation alters the production, structure, and function of cyclic adenosine monophosphate (cAMP), a dependent transmembrane chloride channel carrier protein found in the exocrine mucus glands throughout the body. The mutated carrier protein is unable to transport chloride across the cell membrane, resulting in an electrolyte and charge imbalance. Diffusion of water across the cell membrane is thus impaired, resulting in the development of a viscous layer of mucus. The thick mucus obstructs the cell membranes, traps nearby bacteria, and incites a local inflammatory response. Subsequent bacterial colonization occurs at an early age and ultimately this repetitive infectious process leads to progressive inflammatory damage to the organs involved in individuals with CF.

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Maggie’s Illness

Protein Structure and Function in Cystic Fibrosis

By Michaela Gazdik Stofer

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This directed case study examines the molecular basis of cystic fibrosis to emphasize the relationship between the genetic code stored in a DNA sequence and the encoded protein’s structure and function. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein that functions to help maintain salt and water balance along the surface of the lung and gastrointestinal tract. This case introduces students to “Maggie,” who has just been diagnosed with cystic fibrosis. The students must identify the mutation causing Maggie’s disease by transcribing and translating a portion of the wildtype and mutated CFTR gene. Students then compare the three-dimensional structures of the resulting proteins to better understand the effect a single amino acid mutation can have on the overall shape of a protein. Students also review the concepts of tonicity and osmosis to examine how the defective CFTR protein leads to an increase in the viscosity of mucus in cystic fibrosis patients. This case was developed for use in an introductory college-level biology course but could also be adapted for use in an upper-level cell or molecular biology course.

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• Generate a protein sequence through transcription and translation of a given DNA gene sequence.
• Explain the chemistry of amino acid side chains and their importance in protein folding.
• Describe how a mutation in a protein sequence leads to changes in the overall tertiary structure of the protein.
• Examine various levels of protein structure using Cn3D to view three-dimensional protein structures from NCBI’s Entrez Structure database.
• Relate the loss of function of the CFTR protein to the physiological causes of cystic fibrosis.

Protein structure; transcription; translation; DNA mutation; cystic fibrosis; genetic disease; protein function; protein folding; protein; CFTR; Cn3D

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EDUCATIONAL LEVEL

Undergraduate lower division, Undergraduate upper division

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Materials & Media

Supplemental materials.

The following two files should be viewed with the Cn3D software to view a single domain of the CFTR and ∆F508 CFTR proteins.

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• Gene Therapy

Gene Therapy Case Study: Cystic Fibrosis

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Cystic Fibrosis Patents: A Case Study of Successful Licensing

Mollie a. minear.

* Center for Public Genomics, Duke Institute for Genome Sciences & Policy (IGSP)

Cristina Kapustij

# Congressional Fellow with the American Society for Human Genetics and National Human Genome Research Institute, formerly with the Center for Public Genomics

Kaeleen Boden

^ Case Western Reserve University, and IGSP summer student fellow, 2009

Subhashini Chandrasekharan

Robert cook-deegan.

From 2006–2010, Duke University’s Center for Public Genomics prepared eight case studies examining the effects of gene patent licensing practices on clinical access to genetic testing for ten clinical conditions. One of these case studies focused on the successful licensing practices employed by the University of Michigan and the Hospital for Sick Children in Toronto for patents covering the CFTR gene and its ΔF508 mutation that causes a majority of cystic fibrosis cases. Since the licensing of these patents has not impeded clinical access to genetic testing, we sought to understand how this successful licensing model was developed and whether it might be applicable to other gene patents. We interviewed four key players who either were involved in the initial discussions regarding the structure of licensing or who have recently managed the licenses and collected related documents.

Important features of the licensing planning process included thoughtful consideration of potential uses of the patent; anticipation of future scientific discoveries and technological advances; engagement of relevant stakeholders, including the Cystic Fibrosis Foundation; and using separate licenses for in-house diagnostics versus kit manufacture. These features led to the development of a licensing model that has not only allowed the patent holders to avoid the controversy that has plagued other gene patents, but has also allowed research, development of new therapeutics, and wide-spread dissemination of genetic testing for cystic fibrosis. Although this licensing model may not be applicable to all gene patents, it serves as a model in which gene patent licensing can successfully enable innovation, investment in therapeutics research, and protect intellectual property while respecting the needs of patients, scientists, and public health.

Introduction

From 2006–2010, Duke University’s Center for Public Genomics * prepared case studies on whether and how gene patenting and licensing practices affected clinical access to genetic testing, at the request of the Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS). Eight case studies covering ten clinical conditions were published in the April 2010 Supplement to Genetics in Medicine 1 – 8 . One case study focused on genetic testing for cystic fibrosis (CF) 2 . In the process of preparing this case study, we found no evidence that the licensing practices employed by the patent holders were impeding access to genetic testing. In order to learn more about how this successful licensing model came about, we expanded the previous case study by interviewing key players in the process:

• Francis Collins, M.D., Ph.D.: co-discoverer of the CFTR gene and its important ΔF508 mutation that causes cystic fibrosis;
• David Ritchie, Ph.D.: Senior Technology Licensing Specialist at the University of Michigan Office of Technology Transfer (now retired) who managed the licensing agreements for the CFTR patents from 1998 to 2011;
• Anne C. DiSante, MBA, CLP: former Senior Technology Licensing Specialist at the University of Michigan’s Technology Management Office (now the Office of Technology Transfer) who was present during the CFTR patent application filing and licensing discussions; and
• Diana Wetmore, Ph.D.: who was the Vice President of Development and Alliance Management for the Cystic Fibrosis Therapeutics Foundation at the time of the interview.

This paper summarizes what we learned from these interviews and offers suggestions for implementation of a similar licensing model for other gene patents. It begins with a brief overview of CF and the science exploring the genetic basis of a devastating disease.

Identifying the genetic basis of cystic fibrosis

Cystic fibrosis (CF) is a genetic disorder long known to be inherited as an autosomal recessive character, and to be highly variable in its severity, duration, and spectrum of symptoms. It can be devastating, but treatment has improved dramatically in the past several decades. An early diagnosis is the first step in effectively managing the disease, and genetic testing has been used in carrier screening, prenatal genetic testing, and diagnosis.

CF affects an estimated 70,000 people worldwide 9 , over 30,000 of whom are in the United States 10 which makes this one of the most common genetic disorders in the United States. CF is most common among those of European descent, with an estimated 1/25 non-Hispanic Caucasians carrying a CF risk allele 11 . CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene on chromosome 7, which encodes a chloride ion channel. That is, mutations affect a large protein pore responsible for conducting negatively charged chloride atoms through the cell membrane. Mutated CFTR protein results in a buildup of thick, viscous mucus in the lungs, digestive tract, and reproductive system. This mucus makes it difficult for patients to clear lung infections, which are the leading cause of death in CF. Indeed, improved management of pulmonary infections is one of the main reasons that mortality and morbidity of CF have dramatically fallen. Other symptoms include malnutrition caused by an inability to adequately absorb nutrients because pancreatic enzymes cannot reach the intestines, salty-tasting skin, wheezing and/or persistent cough, abnormal bowel movements, and infertility (especially in males) 12 .

The most frequent mutation in CF is known as ΔF508, which is a deletion of three nucleotides that removes a single amino acid, phenylalanine, from the CFTR protein. This single mutation is present on 67% of chromosomes of Caucasian patients with CF worldwide 13 and patients with two copies of this mutation (about half of all patients) have a severe form of CF 14 . Part of the variability in CF is due to a large number of genetic mutations that have variable effects on CFTR protein function. In July 2012, the Human Gene Mutation Database listed 1538 mutations in the CFTR gene 15 . Some variants do not cause CF symptoms; others are quite severe. Interaction with other genes and medical management of symptoms, like taking measures to prevent infections, add to mutational variability to make the clinical course of CF unpredictable.

The search for the genetic underpinning of CF began in the 1950s with unsuccessful attempts to identify linkage with known blood groups 16 , 17 . As genetic mapping technologies improved, especially in the 1980s with the discovery and implementation of restriction fragment length polymorphisms, the pace of discovery rapidly increased. In 1987, Dr. Francis Collins, then at the University of Michigan (U of M), and Dr. Lap-Chee Tsui and Dr. John Riordan, both then at the Hospital for Sick Children (HSC) in Toronto, formed a “very intense” collaboration to speed up the pace of discovery by pooling their complementary approaches and skills 18 . Two years later, in 1989, the collaboration paid off: discovery of the ΔF508 mutation and CFTR gene was announced in three sequential papers in Science by Lap-Chee Tsui 19 , John Riordan 20 , and Francis Collins 21 .

Initial discussions on CFTR patenting and licensing schemes

When the CFTR gene was discovered, Francis Collins called Anne DiSante at the University of Michigan (U of M) Technology Management Office (now the Office of Technology Transfer) to tell her the news; even 20+ years later, she still gets chills thinking about that phone call. 22 While the initial plan was to file a patent application prior to the publication of the findings, there was a news leak that the CF gene had been found so the technology licensing offices had to rush to file the application. DiSante recalls that they only had 2–3 days to complete the patent application so that it could be filed before they could publicly confirm that the gene had been identified. (In the United States, an inventor can publicize the discovery or invention before filing a patent application, but many other jurisdictions do not have such a grace period and any public announcement vitiates the subsequent ability to get worldwide patent protection.)

All of the interested stakeholders, including the U of M, the Toronto HSC, the Cystic Fibrosis Foundation (CFF) as represented through Robert Beall, and the Howard Hughes Medical Institute (which funded Dr. Collins as an HHMI Investigator), supported filing for a patent to protect this discovery. It was obvious that diagnostic and therapeutic applications might develop from understanding the molecular details of the gene mutated in CF. The development of therapeutics, in particular, would require substantial investments over long periods, and might benefit from patent incentives. Therefore, patenting made sense to the scientists, their nonprofit institutions, and disease advocacy groups.

In spite of the rush to file the patent application, considerable thought and attention were devoted to constructing an appropriate licensing strategy to allow use of the CFTR gene sequence in various applications, including carrier screening, diagnostics, therapeutics, and research. The primary issue considered during these deliberations was anticipating who the potential licensees might be as well as how they might use the technology. One group of potential licensees was clearly interested: clinics and hospital laboratories that wanted licenses to perform CF testing. The U of M and the HSC wanted to make a distinction between the companies and hospitals that would do in-house testing (so-called “homebrew diagnostics” or laboratory-developed tests) and companies that would manufacture and sell diagnostic kits. Broad access to diagnostics was important to the U of M, the HSC, and the CFF, and Anne DiSante recalls that they wanted to make sure that everyone who wanted to do “homebrew diagnostics” had the right to do so. This meant that the license had to be affordable to small nonprofit operations. 22 Moreover, it was clear that although the ΔF508 mutation was present in 70% of CF cases, there were an unknown number of additional mutations that would be discovered in the future that would also need to be screened for diagnostic and carrier screening purposes. The optimal test approach might depend in part on mutational complexity that was not known when the patent application was filed. Francis Collins recounts that “it was not clear over the long term what the actual diagnostic platform would be that would be most appropriate for getting the highest sensitivity for detecting CF carriers.” 18 If the ΔF508 mutation was exclusively licensed to a single entity, the platform for detecting CF mutations might not evolve as rapidly as technological changes would, thereby potentially “squash[ing] the field in the long run by tying yourself to one company that might not have the best technology…[to] reduc[e] cost and improv[e] accuracy” 18 .

Licensing the CFTR patents was also a tool for managing the quality of genetic testing on at least one occasion 2 . In that instance, the U of M was informed that a laboratory was advertising CF testing, while not adhering to quality control standards or the professional medical guidelines for testing and counseling. David Richie from the U of M called the laboratory, letting them know about the U of M’s patent rights and suggesting they get a nonexclusive license, but also noting that such licensing came with commitments to abide by professional standards 23 . No notification letter was sent, and apparently the laboratory quietly withdrew from the market, or at least stopped advertising its CF testing service so publicly. Discussions with several other non-licensed companies are currently ongoing, suggesting that enforcement issues are always present with any patented technology.

Considerations for therapeutics were entirely different. Companies wanting to develop CF therapeutics would face a long slog. Not much was known about whether a potential protein-based therapeutic could be developed, since the function of the CFTR gene was not yet known, other than hints it was an ion channel for chloride. However, gene transfer was a very hot technology in the late 1980s and hopes were high that gene transfer could become gene therapy, a “cure” for CF, by replacing the defective CFTR gene in mucus-secreting cells of the lung epithelium and other tissues. Because the development of any therapeutic would require significant investment from a biotechnology or pharmaceutical company to bring a product through proof of clinical mechanism, clinical testing, and U.S. Food and Drug Administration (FDA) approval, companies researching therapeutic options would want some form of exclusivity to protect those long-term, large investments. Indeed, DiSante recalls receiving many phone calls from biotechnology companies interested in taking out exclusive licenses for gene therapy research. However, the main challenge posed by conferring exclusivity to a gene therapy company was that there were several potential venues through which exclusivity could be granted: (1) the CFTR gene sequence itself that would be inserted into a CF patient, (2) the vector or other delivery vehicle that would deliver and insert the new gene into cells, or (3) the CFTR protein. There were many different biotech companies at the time, exploring different delivery vehicles and with different technical approaches, and some U of M/Toronto patents were potentially relevant to these approaches. The U of M and the HSC had no way of knowing which of these approaches had the best chance of treatment success—Anne DiSante recalls that she asked Francis Collins which of the companies had the “right vector” and he didn’t know, so she thought “…well if Francis can’t figure it out then how the heck am I going to figure it out?” 22 Since different companies were pursuing their own delivery vehicles and vector control mechanisms, the expertise each company had with their vehicle gave them a “de facto exclusivity” 22 that didn’t seem to warrant an exclusive licensing agreement on the gene sequence. As DiSante recalled, “We felt the exclusivity [with respect to gene therapy] would come [with] the delivery vehicle.” 22 There was one exception, a patent that was exclusively licensed. It was a U of M patent (US patent, 5,240,846) stemming from the original August 22, 1989 patent, but as granted it only included James Wilson and Francis Collins as inventors, both from the U of M. It was exclusively licensed to Wilson’s startup firm when he moved to the University of Pennsylvania. Exclusive licensing is quite common as an incentive to startups, and in this case a particular vector system was covered. But the U of M did not want to exclusively license the gene itself, because that would block development of alternative delivery and insertion systems for gene transfer, as well as using the CFTR gene or CFTR protein as therapeutic targets.

The inclusion and active participation of the CFF patient advocacy organization was another important factor in the initial patenting and licensing discussions. It distinguished the CF licensing process from patenting and licensing of Canavan Disease 4 and BRCA 5 patents for genetic testing, where patent-related controversy dogged the history of genetic diagnostics. CFF’s Diana Wetmore said that the foundation felt very strongly about non-exclusive licensing for the CFTR gene patents, a message relayed back to the U of M through Francis Collins, who advocated on behalf of the CFF. 24 DiSante recalls that even though the final decision was not up to Collins, “his thoughts, his feelings, his concerns were very important to us, so we listened to those.” 22 , 25 † Wetmore notes that the CFF was at the table during all of the important discussions about how to license the patent, and U of M “listen[ed] to us when we said that we felt strongly that [the license] needed to be non-exclusive.” 24 Anne DiSante of the U of M also recalls that the CFF was “very active in the licensing process.” 22 When asked whether she thought the licensing scheme would have ultimately had a non-exclusive component had the CFF not expressed its position, Wetmore responded “I don’t think that’s a given.” 24

One further, somewhat surprising, feature of the CF licensing scheme was the humanitarian licensing of some of the same patents for developing ways to prevent or manage diarrheal diseases. Diarrheal disease is a major cause of mortality in resource-poor regions, killing an estimated 1.5 million children each year 26 . It turns out that chloride channel biology may be relevant to some common diarrheal diseases, and inhibiting the CFTR ion channel’s action might help manage symptoms, even when caused by infectious agents. The U of M licensed some CFTR patents to OneWorld Health, a nongovernment organization focused on fostering products and services for developing countries 2 . The U of M gets a small payment if OneWorld Health sub-licenses to a developer, but gets no running royalties on products or services. One result of this was a three-year development agreement that Novartis and OneWorld Health signed in 2009 to develop anti-diarrheal therapies 27 . From the perspective of the U of M’s technology licensing office, this left management of CFTR licensing to a trusted nonprofit entity with much greater expertise in global health, while promoting the U of M’s goal of ensuring worldwide use of the technology. This comported with Point 9 of the “Nine Points to Consider” document 28 , and in the spirit of global health technology licensing for humanitarian purposes proposed in many guidance documents by the University of California, Berkeley; University of British Columbia; Technology Managers for Global Health; Universities Allied for Essential Medicines (UAEM) 29 ; the Association of University Technology Managers (AUTM) 30 , 31 ; the “ipHandbook of Best Practices” 32 assembled by the Centre for Management of Intellectual Property (MIHR) and Public Intellectual Property Resource for Agriculture (PIPRA) and other groups wanting to promote global health through sophisticated use of intellectual property.

A final important factor that played into the licensing discussions was the mission of the U of M Technology Management Office. DiSante recalls that their office’s primary mission was not to maximize revenues for the U of M, but rather to benefit the public. Since the U of M is a public university, the main goal was to get the gene sequence and associated technology out so that it could reduce the health toll of CF for the public’s benefit. If the technologies were successful, then the university would benefit in other areas, through advancing and enhancing its reputation and providing a royalty stream to support education and research. DiSante recalls that there wasn’t a particular individual or institution that they were trying to target with their licensing strategy; the main thing was to help the public and CF patients. 22

Licensing strategy developed for the CFTR gene patent

The licensing strategy developed by the U of M and the HSC had a three-pronged approach intended to satisfy the needs of key stakeholders. A single exclusive license would be issued for the vector and for therapeutics developed from it to James Wilson’s startup firm, non-exclusive licensing would be done for gene therapy (for many delivery systems and vectors and for the gene sequence itself) and other therapeutics development, and non-exclusive licensing would be used for diagnostic purposes with different fees applying to in-house use and kit manufacture. In addition, a “most favored nation” clause was added to the non-exclusive licensing terms, so that licensees would be assured they would get the same deal as others if licensing terms changed. The U of M holds all licenses within the U.S. and the HSC holds the licenses for the rest of the world. However, because the ΔF508 licenses are executed by both institutions, both institutions share their royalty streams from these particular license agreements with one another. The patent landscape is complex and includes many other patents jointly held by the HSC and the U of M, a few patents only assigned to the HSC or the U of M, and patents awarded to Third Wave Technologies, Johns Hopkins, and others (see Appendix 1 of Chandrasekharan, et al ., 2010 2 ). While the U of M administers all U.S. ΔF508 licenses, the U of M granted the CFF a license allowing the CFF to sub-license limited fields of the technology to interested parties.

DiSante was flooded with phone calls from companies interested in securing an exclusive license from the U of M. There was pressure to select one of these companies for an exclusive agreement, in part because it would have been more lucrative initially. Yet in spite of this pressure, only one exclusive license was ever issued, to James Wilson’s startup firm for use of a particular adenovirus vector that carried the CFTR gene, for a particular approach to gene therapy. This was largely because the vector’s inventor moved from Michigan to Pennsylvania and wanted to start a biotech firm. 23 If successful, this would have been a very expensive product to develop and test for safety and effectiveness, and so exclusive licensing made sense, while it did not block others from developing alternative vector systems or doing research on CFTR as a therapeutic target. Beyond this single exclusive license, DiSante does not recall “ever exploring the terms and conditions of an exclusive arrangement.” 22 All other license agreements for gene therapy research, three in total, were non-exclusive for the use of DNA to be incorporated into a vector. 23

Diagnostics

The U of M developed two license agreements for diagnostic purposes, one for hospitals, clinics, and diagnostic companies for in-house genetic testing, and the other for companies to manufacture and sell diagnostic kits. The terms for these two agreements were different: the overall price of an in-house testing license was less than a kit license, and this made entry into CF diagnostics less expensive 23 thereby making CF genetic testing more readily accessible to patients. The up-front payment for kits was $25,000, and for laboratory-developed tests was $15,000 (and could be negotiated); the standard royalty for laboratory developed tests was 6% but depending on volume and other factors, the actual royalty rate was often in the range of 3.6% 2 . Ritchie and Wetmore both believe that making this distinction between laboratory-developed tests and commercial test kits was a crucial decision; Wetmore “suspect[ed] that the CFF would have tried to advocate for more reasonable pricing” 24 if the in-house diagnostic license fees were prohibitive; however, the price appeared to be reasonable since several companies took out diagnostic license agreements with the U of M 2 . Several firms also developed different multi-allele or full gene sequence-based tests or test kits that became available commercially. The patents did not therefore produce a single-source testing service, the business model adopted by Athena Diagnostics, Myriad Genetics, and others that has been accompanied by intense controversy (see case studies on genetic testing for long-QT and other cardiac channelopathies 1 , breast and ovarian vs. colorectal cancer 5 , and Canavan vs. Tay-Sachs disease 4 ).

The licensing practices used for CFTR patents followed the “Best Practices” suggested by NIH’s Office of Technology Licensing. The U of M licensing officials were familiar with discussions at NIH. Many of the licenses predated the 2003–2004 development of “Best Practices Guidelines” that were eventually published in the Federal Register. The CFTR licensing scheme is an illustration that some of the ideas later promulgated by NIH’s Office of Technology Transfer were already in the air. The nonexclusive licensing for CFTR genetic testing comported well with recommendations of the Nuffield Council on Ethics in its 2002 report on “The ethics of patenting DNA,” 33 as well as the 2006 “Guidelines for the Licensing of Genetic Inventions” 34 developed by the Organization for Economic Cooperation and Development in Paris, and with Point 2 of the “Nine Points.”

“Most favored nation” clause

A “most favored nation” clause states that the licensor (here, the U of M/HSC) agrees to give a licensee (here, a biotech company or other institution) the best terms it makes available to other licensees. Although such a clause was not initially written into the non-exclusive license, the first licensee insisted that such a clause be added to the terms of the license agreement. The clause was incorporated into every license the U of M has issued since. Ritchie argues that this clause helped maintain the long-term viability of the CFTR licensing structure by serving as a valuable tool during negotiations with companies. Although a company may try to argue for better licensing terms by using arguments like “the technology is over 15 years old and therefore is not worth much,” or “the ΔF508 mutation is just one of thousands of mutations that can cause CF and therefore should be worth a smaller percentage of the overall royalty stream,” Ritchie counters with the fact that the “most favored nation” clause has been a part of all of their licensing agreements and that the U of M is not willing to change that because it would require a cascade of changes for all licensees. 23 However, this clause is only present in the diagnostic kit manufacturing license agreement; it is absent from the in-house diagnostics license, which means that the upfront license fee and royalty rates can be more easily adjusted for in-house diagnostic purposes to make it easier for hospitals and companies to offer CF genetic testing services. 23

Sub-licensing through the CFF

According to Wetmore, the CFF holds a license from the U of M and HSC that gives CFF the right to sub-license to entities that wish to create reagents using the CFTR gene and for the application of a cell line that contains the CFTR ΔF508 mutation to identify modulators of CFTR activity. This license is for research purposes only; the CFF license is not for diagnostic purposes. Wetmore says that there was “no need” for the CFF to hold a diagnostic license 24 since the non-exclusive diagnostic license agreements developed by the U of M enabled companies to compete in the diagnostic market, thus preventing a monopoly that might have driven up the price of diagnostic testing. This lower diagnostic testing price has had the additional benefit of enabling many states to implement CF screening into newborn screening programs.

Part of the CFF’s goal of developing better treatments and cures for CF patients is to fund basic research. The cell line that carries the ΔF508 CFTR mutation can be used as a tool to help screen small molecules so that those with the ability to correct the CF ion transport defect can be identified and pushed into further clinical testing. This cell line is covered by a U of M patent, so if the CFF funded this type of research without sub-licensing rights, the funded company would have to apply for a license with the U of M to do their research. Instead, because the U of M gave the CFF the right to sub-license, companies only need to deal with the CFF, thereby reducing the amount of time they have to deal with obtaining a license from the U of M and expediting their research by a few months. Furthermore, as a part of their agreement with the U of M, the CFF pays an up-front fee for each sub-license it grants; this earns a small royalty stream for U of M but does not limit CFF’s freedom to operate, and its licensing costs are small and predictable. Thus, CFF research funding can be directly used for research purposes without concern for downstream licensing risks. The CFF, in turn, gives the U of M an annual report detailing its active licensees. Other CFTR licenses from the U of M, beyond the CFF and OneWorld Health examples cited in this report, do not have sub-licensing rights; additionally, the license agreement between the U of M and the CFF is not exclusive, meaning the U of M can issue additional non-exclusive licenses to other entities. 23 , 24

One of the benefits of this arrangement for the U of M is that the CFF handles all the administrative aspects of non-exclusive licenses for CFF research collaborations. Although a few companies have gone directly to the U of M for a non-exclusive research license, the university prefers that companies work through the CFF. 24 Because the university wants to benefit the public by helping the CFF achieve their mission of helping CF patients, they have a lower licensing fee for the CFF license than they otherwise might have obtained because keeping costs low helps the CFF fund research projects to which they then offer sub-licenses. The sub-license fees are paid by the CFF on an annual basis, which gives them an opportunity to make sure that sub-licensees are actively working on the research project; if work ceases then the CFF stops paying the sub-license fee for that company. In addition, when working with a company the CFF is able to offer an enticing deal—a license that will be needed for research on CFTR that will be “free” to the company since the CFF will pay for it, the CFF will handle the administrative burden of obtaining that license, and the CFF will fund the research project. 24

The diagnostic-therapeutic nexus

The recent development of the drug ivacaftor (Kalydeco®, Vertex Pharmaceuticals) is worth noting, because it illustrates the tight linkage that is emerging between some genetic subtypes and treatment. It is also a major success in the two-decade quest for better CF therapeutics building on the CFTR gene discovery. In January 2012, the Food and Drug Administration approved ivacaftor to treat the roughly four percent of CF patients with the p.G551D mutation in the CFTR gene 35 . This is one of several mutations clustered in exon 11 of CFTR that was covered by a patent (US 5,407,796) held by Johns Hopkins University (JHU) on mutations discovered several years after the more common ΔF508 mutation. The Hopkins patent expired in April 2012. The drug has only been approved for those with a p.G551D mutation who are over 6 years old, although it is now being tested for other uses and in children as young as 2.

The drug developed from a long collaboration between CFF and Vertex, including funding from both institutions. Use of the drug is tied directly to subtyping through genetic testing. This story has a successful ending, but it also shows how the complex patent landscape could have thwarted its development, because the final treatment necessarily involves several patented technologies. The original CFTR patents held by the HSC and the U of M, the exon 11 CFTR patents from JHU, and the patent on the inhibitory drug itself (US patent 7,495,103, expiring May 20, 2027) are all embodied in the clinical decision pathway. The final therapeutic patent is exclusively controlled by Vertex (with a royalty agreement to CFF), but if the CFTR DNA sequence, method, and mutation patents had been exclusively licensed, developing and using ivacaftor would have been contingent on clearing diagnostic rights, making the situation more complex. Such multi-lateral licensing schemes are possible, indeed they are becoming more common, but they also require negotiation, additional cost, and a risk of failure.

It is also worth noting that the drug resulted from a partnership between a disease advocacy organization and a for-profit firm, and the three-month priority approval process at FDA was expedited by trials that involved 213 patients, ages 6 to 11. Only 1200 total US patients are estimated to have the requisite mutations. The two clinical trials thus required access to patients and their families, a drug-development team, and rigorous clinical efficacy and safety trials that drew heavily on the resources and organization of the collaborating partners, as well as illustrating the new model of therapeutics developed for genomic subtypes. The story of ivacaftor development has been detailed by Feldman & Graddy Reed, in a paper presented at the “Making Quantum Leaps in University Technology Transfer” Workshop held at Johns Hopkins University, Baltimore, MD on April 19, 2012.

Long-term success of the CFTR licensing strategy

As of 2009, the U of M was issuing about 1–2 license agreements each year, a rate that has stayed constant since 1998 when David Ritchie joined the U of M’s Office of Technology Transfer. There were 18–20 active licenses at the time of our 2009 interview. Three or four licenses had lapsed because research on gene therapy failed to progress to market. 23 The CFF had six active sub-licenses in 2009, five of which were for therapeutic research and the sixth for generating a cell line. 24 The nonexclusive terms of the license also avoid the potential problem of patents on individual genes hindering whole-genome or all-exome analysis, a topic of current concern for genes that have been exclusively licensed.

After ten years of working with the CFTR licensing strategy, Ritchie thinks that there is very little, if anything, that he would change about it, and that this strategy would be suitable for other universities and institutions to use:

“…the fact is that this was a well-designed license agreement. It’s held up well over these years through maybe 20 different negotiations with different companies, and companies end up doing the license agreement with it. A lot of times they’ll want to come back and will want to change multiple aspects of it, but in the end after sometimes six months of negotiations we end up with kind of the same language. … [I]t’s done its job well.” 23

Although this particular licensing strategy is currently only used by the U of M with respect to the CFTR patent, Ritchie does draw from it to help draft other licensing agreements with other entities:

“There are often times situations that arise during negotiations that I may have with another company where…my mind will immediately revert to certain terms in the CF license. And I can use that license as kind of a separate template to carry on further discussions in terms of offering the company here’s an alternative to the licensing design for the agreement we’ve been talking about, ‘Let’s try this other thing, okay?’ One example is that sometimes companies will want to do both in-house testing as well as make products and so I’ll immediately suggest that we do two separate licenses for that, when they initially want to come in and do one license. We don’t use CF as a template for all other agreements, but we take bits and pieces out of it here and there to fit into our standard agreement if, in fact, a situation warrants.” 23

Applicability of the CFTR licensing strategy to other gene patents

Although the licensing strategy developed by the U of M, the HSC, and the CFF has worked well for CF and the CFTR gene patent, this strategy would not necessarily be successful when applied to other diseases or other gene patents. A major factor in the strategy’s success is the involvement of the CFF, a patient advocacy organization that took on some of the administrative aspects of licensing to make this process more streamlined for companies engaging in therapeutics research. The CFF was founded in 1955 and has grown to become a savvy non-profit organization with the staff and resources required to take on the administrative burden of sub-licensing; not all diseases have such sophisticated patient advocacy organizations with the resources to take on this burden. Additionally, the CFF was able to attract more interest in therapeutics research by performing a market analysis to predict how much a pharmaceutical company might expect to make if it were to develop a successful CF treatment. 24 Another factor is the prevalence of CF. It is common enough to attract attention, and indeed the success of ivacaftor shows there was sufficient commercial interest to develop a therapeutic for a genetic subtype of low prevalence (earning Orphan Drug designation). Prior to this analysis, there was an assumption that with CF being a rare, orphan disease that any CF treatment would not generate much revenue. However, by showing that there were enough patients, that CF would require a chronic therapy (as opposed to a one-time therapy or one used just when symptoms are exacerbated), and that a therapy would add to CF patients’ life expectancy, an estimated $200–800 million per year could be generated by a CF treatment. 24 Not all of these factors will hold true for rarer diseases or for diseases that would not require a chronic therapy. And indeed the ivacaftor model will be held up as a success only if it generates sufficient revenue to warrant future similar investments, and if its high cost does not hinder utilization. Furthermore, if a patient advocacy organization lacks the monetary resources required to fully fund the initial stages of therapeutic research and to cover the cost of sub-licensing, then this licensing strategy might not be as successful as it has been for the CFTR patents.

Conclusions

Discovery of the CFTR gene and its CF-causing ΔF508 mutation in 1989 culminated an intense years-long “race” to find the gene mutated in those with cystic fibrosis. Despite the rush to publicize an important discovery and a news leak that forced quick action to preserve world-wide patent rights, careful deliberation and engagement of key stakeholders enabled the U of M and the HSC to develop a licensing strategy that held up well over time. It enabled continuing research, wide-spread CF diagnostic testing and newborn and carrier screening, and facilitated development of CF therapeutics. One vital aspect of this licensing strategy was the engagement of the CFF, a patient advocacy organization that reached a licensing agreement with the U of M that enabled it to offer sub-licenses to companies that wish to pursue CF therapeutic research, with the caveat that the CFF fully fund the initial stages of such research. This agreement benefits the U of M since the CFF takes over the administrative burden of handling non-exclusive licenses, and it benefits the CFF by having a low sub-licensing fee agreement with the U of M. Different license agreements between in-house diagnostic testing and kit manufacture and sale make it possible for many hospitals and clinics to offer in-house CF genetic testing by removing the large financial barrier imposed by a high licensing fee. The patent royalties received by one patent inventor, Francis Collins, are donated to the CFF and have provided the CFF with a revenue stream that helps funds therapeutic development, as highlighted by the recent success of the drug Kalydeco®. Although this model may not be successful when applied to patents that cover genetic mutations that influence rare diseases or diseases without a stable and savvy patient advocacy organization, it has held up well over the past two decades through negotiations with a variety of companies.

Perhaps the most impressive detail to emerge from this case study is the change in CF patients’ life expectancy. When the CFF was founded in 1955, a child born with CF was not expected to survive until elementary school; in contrast, the life expectancy today is over 37 years, and is increasing at the rate of about one year per year. 24 Obviously, many factors contribute to this progress, but one important factor has been earlier diagnosis that enables early aggressive management of CF symptoms and lung infections. The successful nonexclusive licensing structure developed for the CFTR gene has made CF genetic testing widespread, thus enabling newborn screening to help diagnose CF early in life. Additionally, development of novel therapeutics like Kalydeco® has helped to increase the lifespan of CF patients with the p.G551D mutation.

The precise molecular definition of CF led to genetic subtyping; to earlier and much more precise diagnosis, and thus improved medical management; and to the first genotype-specific treatment. Wide access to genetic testing and screening made it easier for states and hospitals to implement newborn screening programs; earlier detection of CF meant that patients could be started on nutritional supplementation sooner; and medical care providers could more aggressively intervene to prevent lung infections, a leading cause of death among CF patients. Had CF diagnostic testing not become as accessible as it was, these life expectancy improvements may have been less impressive or happened later. Patenting and licensing are only a small part of the story. They are perhaps most important for how they managed to keep out of the way—how the licensing strategy retained freedom to do research and creative use of the patent incentive to promote promising therapeutics while also permitting many approaches to screening and diagnosis by many providers and generating modest revenue for further research and education.

Acknowledgments

This research is funded by the National Human Genome Research Institute (P50 HG 003391), and the Ewing Marion Kauffman Foundation. The contents of this publication are solely the responsibility of the Center for Public Genomics (Duke University) and not necessarily the views of NIH, NHGRI, or the Kauffman Foundation.

* The Center for Public Genomics is a national Center of Excellence for Ethical, Legal and Social Implications Research, funded by the National Human Genome Research Institute under grant P50 HG 003391. From 2004–2009 it was also co-funded by the US Department of Energy. The Center for Public Genomics is administered by Duke’s Institute for Genome Sciences & Policy, and also includes the DNA Patent Database, a core facility at Georgetown University.

† Dr. Collins also donated all of his patent royalties to the CFF, rather than accepting them as personal income. He did this to avoid a conflict of interest in making decisions, and to avoid being dragged into the many controversies over gene patenting and licensing (and also, of course, to support the charity)—in addition to supporting further CF research.

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New drugs, new challenges in cystic fibrosis care

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Cystic fibrosis (CF) is a genetic disease caused by variants in the gene encoding for the CF transmembrane conductance regulator (CFTR) protein, a chloride and bicarbonate channel. CFTR dysfunction results in a multiorgan disease with the main clinical features being exocrine pancreatic insufficiency and diffuse bronchiectasis with chronic airway infection leading to respiratory failure and premature death. Over the past decades, major progress has been made by implementing multidisciplinary care, including nutritional support, airway clearance techniques and antibiotics in specialised CF centres. The past decade has further seen the progressive development of oral medications, called CFTR modulators, for which around 80% of people with CF are genetically eligible in Europe. CFTR modulators partially restore ion transport and lead to a rapid and major improvement in clinical manifestations and lung function, presumably resulting in longer survival. CFTR modulators have been game-changing in the care of people with CF. However, many questions remain unanswered, such as the long-term effects of CFTR modulators, especially when treatment is started very early in life, or the new CF-related disease emerging due to CFTR modulators. Moreover, severe complications of CF, such as diabetes or cirrhosis, are not reversed on CFTR modulators and around 20% of people with CF bear CFTR variants leading to a CFTR protein that is unresponsive to CFTR modulators. Challenges also arise in adapting CF care to a changing disease. In this review article, we highlight the new questions and challenges emerging from this revolution in CF care.

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Cystic fibrosis, a very severe genetic disease, has changed dramatically with CFTR modulator therapies. Long-term effects and adaptation of models of care are some of the new questions and challenges arising from this revolution in cystic fibrosis care. https://bit.ly/3V0zxFo

• Introduction

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator ( CFTR ) gene [ 1 ]. It is the most common life-shortening genetic disease in the Caucasian population, affecting at least 100 000 individuals worldwide [ 2 ]. The CFTR gene encodes the CFTR protein, which is a chloride and bicarbonate channel expressed at the cell membrane of many epithelial cells and other cell types, including inflammatory cells [ 3 , 4 ]. CF is a multisystem disease affecting organs and tissues where CFTR is expressed. The main clinical features are exocrine pancreatic insufficiency and diffuse bronchiectasis with chronic airway infection leading to respiratory failure and premature death [ 5 ]. The principles of CF care were established as early as the 1960s and have steadily evolved with a better understanding of the disease and the availability of new drugs. They are based on a holistic approach to care and intensive symptomatic treatment. Specialised CF centres formed by multidisciplinary teams experienced in CF are the established model of care for people with CF (pwCF) [ 6 ]. The principles of symptomatic treatment are maintenance of good nutrition, compensation of pancreatic insufficiency with pancreatic enzymes, enhancement of mucociliary clearance with physiotherapy and mucolytic agents, prevention and aggressive treatment of pulmonary infection, and early identification and treatment of complications [ 6 , 7 ]. As a result of this structured care in dedicated centres, the life expectancy for pwCF has increased from a matter of a few years to around 50 years [ 8 ]. Similarly, in several countries, the number of adults with CF is currently larger than the number of children with CF [ 9 ].

The CFTR gene was cloned in 1989, around 2100 variants were identified and the various resulting CFTR protein abnormalities were studied. This led to very active research on new treatments termed CFTR modulators, which aim to correct the defective CFTR protein [ 10 ]. The first CFTR modulator was approved in 2012 and there are, to date, four approved CFTR modulators with more than 80% of pwCF in Europe genetically eligible for at least one of them. CFTR modulators treat the root cause of the disease and they have been game-changing in the care of pwCF. The goals of this review article are to provide an overview of the new questions and challenges emerging from this revolution in CF care.

• Search strategy

We searched PubMed for research related to CF and CFTR modulators to identify relevant articles. We mainly selected recent publications (from the past 5 years) describing randomised-controlled trials or large real-world studies. We also included highly regarded older publications and review articles to provide readers with more details. The reference lists of included studies and relevant reviews were screened for relevant papers and these were added for assessment at the full-text stage.

• New drugs for CF

CFTR modulators are small oral drugs that bind to the CFTR protein and improve its function. There are two classes of CFTR modulators, namely potentiators that increase the open probability of the CFTR protein expressed at the cell membrane and correctors that improve the intracellular processing of the CFTR protein. Since 2012, four CFTR modulators have been marketed, ivacaftor, which is a potentiator marketed for specific CFTR variants carried by around 3% of pwCF, and a combination of correctors and ivacaftor: lumacaftor and ivacaftor, tezacaftor and ivacaftor, and elexacaftor, tezacaftor and ivacaftor (ETI). Lumacaftor/ivacaftor and tezacaftor/ivacaftor are mainly marketed for pwCF homozygous for F508del , the most frequent CFTR variant. They are now supplanted by the more effective triple combination, ETI, which is marketed in Europe for pwCF bearing at least one F508del variant. Around 80% of pwCF in Europe bear at least one F508del variant, although there are large disparities between countries due to genetic heterogeneity ( figure 1 ) [ 11 ].

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Geographical distribution of the F508del variant in countries participating in the European Registry which gathers data for more than 54 000 people with cystic fibrosis. Reproduced from [ 11 ], with permission. Names of countries are abbreviated according to the International Organization for Standardization.

Ivacaftor and ETI were shown to be well tolerated and to have similar responses in pivotal phase 3 placebo-controlled trials in eligible children (≥6 years old) and adults with a sustained and robust improvement in respiratory function (mean increase of 10% or more in predicted forced expiratory volume in 1 s (FEV 1 )), a gain in weight and a decrease in the rate of pulmonary exacerbations [ 12 – 15 ]. Ivacaftor and ETI are sometimes called “highly effective modulator therapy” to differentiate them from lumacaftor/ivacaftor and tezacaftor/ivacaftor, which are much less effective [ 16 ]. In Europe, ivacaftor is currently approved for pwCF aged 4 months and above bearing at least one variant, called a gating variant, and ETI is approved for pwCF aged 2 years and above bearing at least one F508del variant. Most European countries have access to ETI through licensing and reimbursement or through varied special access programmes ( figure 2 ).

Access to elexacaftor/tezacaftor/ivacaftor (ETI) in Europe through licensing and reimbursement or through special access programmes. Names of countries are abbreviated according to the International Organization for Standardization.

Results from real-world studies have confirmed data from clinical trials and showed that even in adults with severe lung disease who were not included in clinical trials, restoring CFTR function with ivacaftor or ETI significantly improved lung function and slowed disease progression [ 17 , 18 ]. Registry studies of large patient cohorts over a follow-up of 5 years showed sustained favourable effects of ivacaftor therapy on disease progression with better preserved lung function, improved nutritional status and decreased risk of pulmonary exacerbations than in an untreated comparator population [ 19 ]. Similarly, analysis of data from clinical trials and registries showed that the clinical benefits of ETI were durable and on average there was no loss of pulmonary function over a 3-year period [ 20 , 21 ]. Moreover, a major decrease in lung transplantation for end-stage pwCF has been observed after ETI availability [ 22 , 23 ]. It will take years before the gain in survival of pwCF under long-term treatment with CFTR modulators can be truly observed. Estimates have been generated using different models. An analysis using a person-level microsimulation model predicted that treating pwCF homozygous for the F508del variant with ETI would result in a substantial increase in survival to around 70 years [ 24 ]. Conclusions of this model need to be verified by future data. Nevertheless, this impressive increased survival under ETI did not reach the life expectancy of the general reference population, which was more than 80 years.

PwCF on ivacaftor or ETI have seen their daily life and future perspectives transformed. They often no longer cough and/or expectorate, feel physically stronger, and have fewer and less severe exacerbations. These improvements lead to an improved quality of life and new life goals [ 25 ]. However, many questions on the long-term use of CFTR modulators remain, especially when treatment is started very early in life and before the occurrence of irreversible lung structural disease. Studies are ongoing in an attempt to answer them. A new CF disease has emerged when on CFTR modulators and CF care has already evolved to monitor, treat and adapt to a large diversity of CF disease severity and to an ageing population. Thus, groundbreaking CFTR modulator therapy has transformed CF disease and CF care, leading to new questions and challenges that we highlight in this review.

• How to improve the prescription of CFTR modulators?

Acquire knowledge on long-term safety

CFTR modulators are not a curative treatment. To be effective, they need to be taken daily and their effects disappear rapidly when the treatment is interrupted. Therefore, CFTR modulators are a lifelong treatment and knowledge about their long-term safety is critical. Clinical trials and real-world studies show that they are usually well tolerated. In phase 3 studies on ETI, adverse events were usually mild or moderate, leading to only 1% of drug discontinuations [ 14 , 26 ]. They mainly consisted of rash, headache, abdominal pain, abnormal liver function tests and elevated creatine kinase level. This good safety profile was confirmed in real-world studies on pwCF treated with ETI. However, the association between ETI and drug-induced liver injury was confirmed in an analysis using the Food and Drug Administration adverse event reporting system [ 27 ], confirming the need to periodic liver monitoring as recommended. Possible mitigation strategies, such as dose reduction, need to be studied further. Moreover, neuropsychiatric adverse events such as anxiety, low mood, insomnia or “brain fog” were reported in a minority of pwCF on ETI. Depression, including suicidal ideation and suicide attempts, was also reported, usually occurring within 3 months of treatment initiation and in patients with a history of psychiatric disorders. In some cases, symptoms improved after dose reduction or treatment discontinuation. Although rates of depression-related adverse events on ETI could be consistent with background epidemiology of depression in the CF population, monitoring of depressed mood, suicidal thoughts or changes in behaviour is recommended in pwCF on ETI [ 28 , 29 ].

The timing of CFTR modulator initiation in pwCF with minimal or no detectable lung disease is still an open question, although the possibility of preserving lung function, or even pancreatic function in infants, with the early use of CFTR modulators is very attractive [ 30 , 31 ]. Observational studies in the paediatric population are underway, such as the BEGIN study ( NCT04509050 ) in infants and young children and the PROMISE paediatric study ( NCT04613128 ). They are critical to acquire knowledge on biological and clinical effects, including effects on growth and development, of CFTR modulators in the paediatric population. Long-term safety data on the use of CFTR modulators in infants and children will enable risk–benefit analyses to inform decisions on initiating therapy in this population with limited disease.

Assess restoration of CFTR function

Measurement of sweat chloride concentrations is a well-known, easy and standardised method to assess CFTR function in vivo . Data from clinical trials on the different CFTR modulators are in favour of a relationship between the degree of CFTR function improvement, as shown by sweat chloride concentrations, and important clinical outcomes such as gain in respiratory function [ 32 ]. This might not be as straightforward in individuals, but many CF centres use sweat chloride concentrations as a tool to monitor the degree of CFTR restoration. However, the degree of sweat chloride improvement to expect varies with the genotype and the CFTR modulator studied, and this needs to be further characterised. Moreover, we do not yet know if the magnitude of improvement in sweat chloride concentrations to normal values (<30 mmol·L −1 ) or intermediate values (between 30 and 59 mmol·L −1 ) on CFTR modulators can be predictive of the long time course of CF disease. Similarly, how to interpret and deal with a poor correlation between sweat chloride improvement and clinical disease needs to be further investigated.

Develop tools for therapeutic drug monitoring

After dosing of an oral drug, plasma concentrations are influenced by many factors, such as individual clinical characteristics like malabsorption, renal or liver disease, obesity, gender, or pregnancy, as well as diet, pharmacogenetic variants or concurrent medication use. Altered absorption, specific metabolism, distribution and clearance of drugs are well recognised in pwCF and known to have pronounced impact on drug efficacy. Moreover, diet and concurrent medication are known to influence absorption and metabolism of CFTR modulators. Clinical response depends in part on plasma concentration, which is one variable that can be followed through therapeutic drug monitoring, allowing personalised dose adjustment until optimised outcomes are reached. Although titration of CFTR modulators would be a useful tool to optimise drug response, it is not currently used due to a lack of detailed pharmacokinetic data, assays for monitoring and data on associations between blood concentrations and clinical response and adverse events [ 33 ]. Improved access to serum drug-level monitoring of CFTR modulators and their metabolites may help determine whether differences in drug metabolism can account for the occurrence of adverse reactions or low responsiveness to modulator therapy and facilitate dose adjustment in patients with adverse reactions or a poor response [ 34 ].

• What is the new CF disease on CFTR modulators?

The phenotypic features of CF disease on CFTR modulators and knowledge gaps are summarised in table 1 .

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Phenotypic features of cystic fibrosis (CF) disease on cystic fibrosis transmembrane conductance regulator (CFTR) modulators and knowledge gaps

Respiratory disease

When ivacaftor or ETI are started in pwCF with existing respiratory disease, a rapid and marked reduction in cough and expectoration usually occurs, together with an improvement in their respiratory function shown by an increase in FEV 1 and a decreased number of exacerbations. Monitoring of this less severe respiratory disease is still possible with the usual outcome measures, such as spirometry and lung imaging [ 35 ]. The effects of CFTR modulators on lung function are ascribed to their effects on mucociliary clearance [ 36 ]. CFTR modulators are usually thought not to be able to reverse structural lesions such as bronchiectasis [ 37 ], although limited reversal has been described in specific cases [ 38 ].

When CFTR modulators are started in pwCF with minimal or no respiratory disease, monitoring clinical progression over time can be difficult as more sensitive measures than FEV 1 are needed. At present, lung clearance index (LCI), chest computed tomography (CT) and chest magnetic resonance imaging (MRI) are the main methods for detecting and monitoring early lung disease in CF. The pros and cons of these biomarkers for reliably detecting early lung damage have been discussed elsewhere [ 39 – 41 ]. To summarise, LCI is sensitive to early disease and is feasible in the very young. However, it is not an easy technique and requires specialised equipment and trained personnel. CT is the gold standard for imaging pulmonary structures and it is sensitive to early disease and disease progression. However, it is qualitative and scoring is not easy and not yet automatic. Moreover, radiation exposure remains an important consideration, especially in children. MRI, possibly with the addition of inhaled gases, is emerging as an attractive alternative to CT imaging as it is radiation-free. However, standardisation across centres is difficult and it needs further investigation before it can be implemented in routine use [ 35 ]. Over the last few years, CF-related patient-reported outcomes captured by many questionnaires and tools were developed. They focus primarily on symptoms rather than objective data. They might enhance our ability to monitor lung disease, but their use in clinical practice is not yet clear.

Microbiology and pulmonary exacerbations

Clinical trials and real-world studies all showed lower frequencies of pulmonary exacerbations on CFTR modulators. A large analysis of US and UK patient registries showed that this drop in pulmonary exacerbation frequency was sustained over 5 years in ivacaftor-treated patients [ 19 ]. This lower frequency of pulmonary exacerbations is not clearly linked with clearance of airway pathogens. PwCF with intermittent Pseudomonas aeruginosa -positive sputum cultures tend to stop testing positive for the infection when on ivacaftor. However, for pwCF and chronic P. aeruginosa infection, studies in ivacaftor- or ETI-treated patients showed that after a first drop in sputum bacterial burden, P. aeruginosa abundance tended to return to baseline levels after a few years despite improved FEV 1 levels and reduced pulmonary symptoms [ 42 , 43 ]. In pwCF without airway colonisation with CF-traditional pathogens when starting CFTR modulators, it is not known whether CFTR modulators may delay or prevent airway colonisation and longitudinal studies will answer this question. Neutrophilic inflammation is a key driver of structural lung damage progression in CF. After 1 year on ETI, a reduction in airway inflammation was reported, but residual protease burden was still observed [ 44 ]. Long-term data are required to determine the evolution of this residual inflammation and its role on progression of structural lung damage. Monitoring of airway infection is made more complex by the absence of spontaneous sputum in many patients on ETI. Other sampling methods are available and well known to paediatricians who have dealt with nonexpectorating children for many years. Induced sputum, throat swabs and upper airway samples are less invasive than bronchoscopy, but have lower sensitivity to detect pulmonary microbes, with induced sputum having the best concordance with bronchoscopy [ 45 – 47 ]. The use of exhaled breath analyses or serology to identify pathogens of interest are promising methods that require further study [ 48 ]. As a new respiratory disease emerges on CFTR modulators with fewer symptoms, little or no spontaneous sputum and fewer exacerbations with possibly different airway pathogens, a whole area of research is opening up to establish the relevance of previous definitions and guidelines for pulmonary exacerbations, bacterial monitoring and treatment of exacerbations.

Exocrine pancreatic insufficiency

Some clinical trials or small paediatric case series suggested that ivacaftor could preserve or improve exocrine pancreatic function in infants and young children [ 30 , 49 , 50 ]. This was not observed in older children and adults. In a large observational US study in pwCF aged 12 years and above, there was no change in pancreatic insufficiency 6 months after ETI treatment [ 51 ]. In analyses of the US and UK registries, there was a decline in the use of pancreatic enzyme replacement therapy after ivacaftor licensing in the US CF population, but these results were not replicated in the UK CF population [ 52 ]. Longitudinal and large studies in pwCF on ETI are needed to evaluate the possible effects of CFTR modulators on exocrine pancreatic function and requirements of pancreatic enzyme replacement therapy.

Gastrointestinal disease and nutrition

Gastrointestinal symptoms are a regular complaint of pwCF and they impact their quality of life. CFTR modulators have been reported to reduce intestinal inflammation, change proximal intestinal pH and positively impact the gastrointestinal microbiome, thus contributing to improved nutrient absorption and improved intestinal transit [ 53 , 54 ]. Despite these effects, changes in gastrointestinal symptoms were not clinically meaningful in pwCF after 6 months on ETI [ 51 ]. CFTR modulators may contribute to the increased number of pwCF who are overweight or obese. Increase in body mass index was a regular feature in clinical trials on CFTR modulators [ 12 – 15 ] and in real-world studies [ 55 , 56 ]. To prevent obesity-associated comorbidities, changes in the CF diet and lifestyle are recommended [ 57 ]. New studies are needed to define optimal nutrition for pwCF on CFTR modulators. At present, no effect of CFTR modulators was reported on established biliary complications such as cholelithiasis, hepatic steatosis and end-stage liver disease (cirrhosis and portal hypertension). Future studies will tell if CFTR modulators can prevent these complications.

CF-related diabetes (CFRD)

Analyses of the US and the UK CF registries showed a lower prevalence of CFRD in pwCF on ivacaftor versus comparators [ 19 ]. Several small observational studies suggest that CFTR modulators reduce insulin requirements and improve diabetes control, possibly through improvement in insulin sensitivity [ 58 , 59 ]. However, more robust data are needed. Moreover, longitudinal data will determine if CFTR modulators can prevent or reverse CFRD.

There has been no report of men on CFTR modulators recovering fertility. Obstruction in the genital tract happens during fetal development and reversal of bilateral absence of vas deferens is unlikely to happen, even if CFTR modulators are prescribed very early in life. However, this needs to be investigated.

In women, there has been a notable rise in the number of pregnancies since the introduction of CFTR modulators [ 60 , 61 ]. This is thought to be related to improved viscoelastic properties of cervical secretions, favourable uterine pH and a change in nutritional status. CFTR modulators cross the placenta, but to date there has been no evidence that CFTR modulators may cause abnormalities in fetal development. In contrast, some women who stopped CFTR modulators during pregnancy have experienced a decline in lung function. These data come from small observational series or case reports and there is a need for a better overview of the outcomes in mothers and infants when mothers use CFTR modulators during pregnancy and lactation. The prospective MAYFLOWERS ( NCT04828382 ) study will provide some important data on this topic [ 62 ].

Chronic rhinosinusitis

Improvement of chronic rhinosinusitis symptoms and/or CT scan findings with ivacaftor and ETI has been reported [ 63 – 65 ]. However, symptom scores remain high in many patients [ 64 ]. It is not known if early treatment may prevent nasal polyposis development.

Bone disease

An improvement of bone mineral density upon ivacaftor or ETI were reported in very small case series [ 66 , 67 ]. CFTR modulators may improve CF bone disease either by a direct effect on CFTR expressed in osteoblasts and osteoclasts, or by improving clinical factors affecting bone health, such as nutritional status and physical activity levels [ 68 ]. Larger and longer studies will elucidate the effects of CFTR modulators on bone in pwCF and on their mechanisms of action.

• How do we address the burden of treatment in patients receiving CFTR modulators?

CFTR modulators are usually prescribed on top of all other medications and patients with CF have a high burden of treatment with a median of seven medications per day [ 69 ]. As CF disease is less severe on CFTR modulators, it is tempting to withdraw some of the symptomatic medications and some withdrawal studies have begun. In adolescents and adults with CF on ETI with well-preserved lung function (mean baseline FEV 1 of 97%), discontinuing mucociliary agents such as hypertonic saline or dornase alfa for 6 weeks did not result in a meaningful difference in lung function when compared with continuing treatment [ 70 ]. However, this was a short study in patients with minimal disease. Another ongoing study is investigating the withdrawal of mucoactive drugs. It is a 52-week study in adolescents and adults and enrols patients with an FEV 1 as low as 40%. These studies are very important but difficult to run. Data from the European Registry already suggest that the prescription of several symptomatic treatments in children and adults decreases while CFTR modulators prescription increases ( figure 3 ) [ 11 ]. However, it is still very important to establish whether therapies designed for CF airway disease before the use of modulators are optimal, effective or necessary in the era of modulator therapy.

Use of therapies among children and adults from 2011 to 2021. Reproduced from [ 11 ], with permission. CFTR: cystic fibrosis transmembrane conductance regulator; rhDNase: recombinant human deoxyribonuclease.

• What are the effects of CFTR modulators in an ageing population?

With structured care in dedicated centres and more effective symptomatic therapies, the life expectancy of pwCF has increased over recent last decades and adults have outnumbered children in the European Registry since 2019 ( figure 4 ) [ 11 ]. A further increase in survival is expected with the broad use of CFTR modulators [ 24 ]. This means that comorbidities usually linked with ageing, such as cardiovascular disease or cancer, may be seen more frequently and the possible effects of CFTR modulators on these comorbidities are still unclear.

Number of people with cystic fibrosis (pwCF) and percentage of adults and children from 2008 to 2021. Reproduced from [ 11 ], with permission.

Traditional cardiac risk factors, such as high body mass index, smoking, lipid metabolism, hypertension and ageing, were not usually a concern in CF. However, with increased longevity, CFRD, traditional high-salt high-fat high-carbohydrate diets, relative inactivity, as well as chronic inflammation, pwCF are now recognised as having an increased risk of cardiac disease [ 71 ]. This was recently shown in a multinational retrospective cohort study [ 72 ]. It is still impossible to predict how CFTR modulators may affect cardiovascular disease. They may increase cardiovascular risk by their contribution in increasing longevity, body mass index, body fat content, cholesterol levels and blood pressure. However, they may also have protective effects though decreases in oxidative stress and systemic inflammation, as well as better glucose control [ 73 ].

Several cohort or registry studies have shown an increased risk of cancer, mainly bowel cancer, in nontransplanted pwCF as compared with the general population, and this increases with age [ 74 – 76 ]. The pathogenesis of digestive cancer in CF remains unclear, but inflammation and the role of CFTR have been discussed. With pwCF living longer, this risk of digestive cancer or other cancers may increase further. The relationship between long-term CFTR modulator treatment and cancer risk will be important to evaluate.

• How to adapt models of care for a heterogeneous CF population?

There has always been a large diversity in CF disease severity, depending mainly on genetics and the extent of CFTR dysfunction caused by CFTR variants. However, home environment, socioeconomic status, access to healthcare and medication, as well as adherence to treatment are all known to play a role in CF disease severity [ 77 ]. When the only therapeutic option was symptomatic therapies and the only course for the disease was aggravation, the goal for the mutidisciplinary team was to slow disease progression. With the advent of CFTR modulators, a larger diversity in CF disease is expected, depending not only on eligibility for these new treatments, but also on starting age and on the severity of the disease at starting age. Moreover, the goal is not only to slow disease progression, but also to possibly prevent the disease from occurring, even though the new CF disease on CFTR modulators is not yet well known. PwCF on CFTR modulators have a less severe disease and feel better, leading to new horizons opening up regarding education, work, family and long-term plans. Models of care need to adapt to satisfy the growing needs of pwCF while also being careful to capture and address events known to trigger disease progression. Some key principles for the care of pwCF are still valid: centre-based care with a multidisciplinary team with expertise for all stages of CF, a close integration of associated specialties and regular visits and assessments based on international and national guidelines. However, new avenues need to be considered and have already been put in place in many centres, including virtual consultations, care closer to home with fewer hospital visits, stronger links with specialties such as obstetrics and with primary care, home monitoring with use of connected devices, and screening for new comorbidities such as cancers and cardiovascular disease [ 6 ]. As the field moves on, CF teams face challenges such as the need to maintain severe CF disease expertise, even though severe disease is becoming rarer. It is also critical to continue working closely with patients to identify changing clinical patterns and more subtle presentations, and to stress how adherence to CFTR modulators is paramount.

• How to increase eligibility and access to CFTR modulators?

The European Medicines Agency (EMA) has approved ETI for pwCF bearing at least one F508del variant based on pivotal phase 3 studies [ 14 , 15 ]. However, more pwCF could benefit from the treatment as additional CFTR variants lead to a CFTR protein responsive to ETI. This was shown in in vitro data generated in nonhuman cell lines and led the Food and Drug Administration (FDA) in the US to also approve ETI for pwCF bearing at least one among 177 rare variants. A clinical trial in pwCF bearing some rare non- F508del variants recently showed a statistically significant improvement in respiratory function on ETI compared to placebo [ 78 ]. These data have been used to support an application to extend the approval of ETI currently being examined by the EMA. Several real-world reports of a few patients or of small cohorts also supported a clinical benefit of ETI in pwCF bearing some non- F508del variants [ 79 – 81 ]. The French health authorities adopted a more extensive and pragmatic approach with a compassionate programme that was first aimed at pwCF bearing no F508del variant and with severe disease [ 82 ]. It was then extended to all pwCF bearing no F508del variant regardless of the severity of their disease. With this programme, pwCF are granted 4–6 weeks of ETI and effectiveness is evaluated by a centralised adjudication committee in terms of clinical manifestations, sweat chloride concentration and respiratory function. Among the first 84 pwCF included in the programme, 45 pwCF (54%) were responders and continued ETI. Of interest, 22 pwCF (49%) bore a rare CFTR variant that was not included on the FDA list of 177 rare variants [ 82 ]. Due the scarcity of pwCF bearing rare CFTR variants, it is impossible to conduct clinical trials fulfilling all the requirements of clinical research for each rare variant. The pragmatic and rational French approach is possible because there are strong clinical biomarkers of ETI effectiveness and there are minimal safety concerns associated with ETI. This approach should be advocated as it grants a fair opportunity for all patients to test a truly transformative therapy, addresses an unmet medical need and promotes equity of care.

• Need to continue research into curative and symptomatic therapies

Around 10% of CFTR variants result in the absence of CFTR protein and CFTR modulators cannot be effective as they have no target to act upon. For pwCF bearing these variants, other strategies are initiated, such as read-through agents for nonsense variants or nucleic acid-based therapies that benefit all patients. For nucleic acid-based therapies, several approaches have been developed based on DNA or RNA transfer with viral or nonviral vectors. Some of these approaches are currently undergoing early clinical trials [ 83 ]. Even with CFTR modulators, CF is not cured and there is still a need to continue developing better symptomatic treatments to improve mucociliary clearance with inhibitors of the epithelial sodium channel, agonists of alternative chloride channels or mucoytics; to decrease airway inflammation with neutrophil elastase inhibitors or other new anti-inflammatories; and to improve anti-infective agents with new antibiotics or novel anti-infective approaches [ 83 ].

CFTR modulators that treat the root cause of the disease are now available for more than 80% of pwCF and they represent a paradigm shift for pwCF, who see a rapid and dramatic improvement in their respiratory disease and the alleviation of some extrapulmonary symptoms. The long-term effects of CFTR modulators on both the respiratory system and other affected organs need to be thoroughly evaluated, as well as the possible prevention of the disease with early prescription. Tools should be developed for therapeutic drug monitoring and new methods should be assessed to monitor the new CF disease emerging on CFTR modulators. Models of care need to be rethought in order to maintain the expertise gained in all stages of CF built over decades and to adapt to the new needs of pwCF. All pwCF who could benefit from these revolutionary drugs should have access to them and research should continue so that all pwCF have access to a curative treatment.

Points for clinical practice

CFTR modulators partially restore ion transport and lead to a rapid and major improvement in respiratory symptoms and lung function.

CFTR modulators may also improve pancreatic insufficiency in young children.

CFTR modulators may improve diabetes control.

CFTR modulators improve fertility in females.

CFTR modulators improve chronic rhinosinusitis.

Questions for future research

What will be the extent of improved survival on CFTR modulators?

What will be the long-term progression of lung function on CFTR modulators?

What will be the long-term effect of CFTR modulators on airway pathogens and inflammation?

What will be the CF disease of pwCF when CFTR modulators are started in infancy or early childhood?

How will the usual complications of CF evolve on CFTR modulators?

Provenance: Commissioned article, peer reviewed.

Conflict of interest: I. Fajac reports grants from AbbVie, Bayer, Boehringer Ingelheim, Insmed, GSK, Vertex Pharmaceuticals and Zambon; consulting fees from AbbVie, Boehringer Ingelheim, Genvade, Kither Biotech and Vertex Pharmaceuticals; lecture honoraria from Vertex Pharmaceuticals; and a leadership role as President of the European Cystic Fibrosis Society, outside the submitted work. P-R. Burgel reports grants from Vertex Pharmaceuticals and GSK; consulting fees from AstraZeneca, Chiesi, GSK, Insmed, Vertex, Viatris and Zambon; and travel support from AstraZeneca and Chiesi, outside the submitted work. C. Martin reports lecture honoraria from AstraZeneca, Chiesi and Zambon; travel support from Chiesi, Sanofi and Zambon; and advisory board participation with Vertex, Zambon and GSK, outside the submitted work.

• Received March 5, 2024.
• Accepted May 9, 2024.
• Copyright ©The authors 2024

This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions{at}ersnet.org

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Cystic fibrosis and survival to 40 years: a case–control study

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The clinical course of patients with cystic fibrosis (CF) is variable and probably determined by many interacting factors. We aimed to examine the influence of early social and clinical factors on long-term survival.

A case–control study of adult CF patients was used to compare long-term survivors (aged ≥40 yrs) with patients who died before reaching 30 yrs of age. Each case (n = 78) was matched by birth date with at least one control (n = 152), after exclusion of “late diagnosis” patients. Probability-weighted logistic regression models were used to identify influences on survival.

Factors resulting in increased probabilities of survival included high body mass index (OR 1.76, 95% CI 1.40–2.22), forced expiratory volume in 1 s (OR per 5% increase 1.54, 95% CI 1.32–1.80), and forced vital capacity (OR per 5% increase 1.54, 95% CI 1.33–1.78) at transfer to the adult clinic and the exclusive use of oral antibiotics (OR 8.31, 95% CI 3.02–22.88). Factors resulting in decreased probabilities of survival were Pseudomonas aeruginosa acquisition (OR 0.18, 95% 0.05–0.65) or pneumothorax before transfer to the adult clinic (OR 0.02, 95% CI 0.004–0.08) and referral from a paediatric clinic in a deprived area (OR 0.13, 95% CI 0.04–0.38).

Long-term survival is associated with the clinical features present by the time of referral to an adult clinic. Even “early-diagnosis” disease appears to have different phenotypes, possibly independent of CF gene function, that have different survival patterns.

• cystic fibrosis

The life expectancy of patients with cystic fibrosis (CF) has been steadily increasing despite the lack of a cure for the underlying cellular defect. Patients born today are expected to have a median survival into their 6th decade 1 . The improvement has been explained in several ways including through the introduction of pancreatic enzymes, better nutrition, specialist-centre care, improved physiotherapy and more intensive antimicrobial treatment 2 – 4 .

CF covers a wide spectrum of disease, from milder phenotypes with “non-classic” disease (with pancreatic sufficiency, milder lung disease and a later diagnosis), to more severe cases with a “classic” phenotype 5 . However, even within different groups there is variation in the rate of disease progression; some patients with features of classic disease run a mild course and indeed an important proportion of patients with the common “severe” δF508 mutation survive beyond 40 yrs of age with relatively well-maintained lung function and weight 6 , 7 .

Thus, it has been hypothesised that other factors influence survival in CF. These include variations in the function of the responsible gene, the cystic fibrosis transmembrane conductance regulator ( CFTR ), and other independent genetic factors (“modifier” genes). None, however, has yet been shown directly to influence survival 8 . Other potential, nongenetic determinants of survival are so-called environmental influences; these cover a diverse range of factors, broadly divided into biological effectors ( e.g. microorganisms, nutrition, sex and pollutants), social and cultural influences ( e.g. socioeconomic status and adherence to treatment) and healthcare-related factors, such as access to care and interclinic treatment variations 9 . Evidence for or against these factors is variable and when they are most influential, or when an individual is most vulnerable to them, is not well understood. In view of this, we conducted a case–control study of long-term survival among patients registered with a specialist adult CF clinic with the aim of identifying early potential influences of long-term survival in patients diagnosed with CF in childhood.

Since 1965, details of all patients referred to the adult unit at Royal Brompton Hospital (RBH; London, UK) and confirmed to have CF have been entered onto a database. The diagnosis is based on clinical features and a positive sweat sodium (>70 mmol·L −1 ) or chloride (>60 mmol·L −1 ) test or, in cases with a borderline or negative sweat test result, the presence of a known disease-causing mutation on each CFTR gene, or of an abnormal nasal potential difference measurement. Patients were referred as adults from an adult physician or by their general practitioner, or directly through transition from paediatric clinics (at ∼15 yrs of age). Clinical and demographic details are collected at the first consultation and are subsequently updated at annual review.

We studied only patients with a diagnosis of CF before the age of 17 yrs. These were identified from the database and classified as cases or controls as follows. Cases (long-term survivors) were all patients with complete records who had reached 40 yrs of age without transplantation by December 31, 2004. Controls were selected from all patients with complete records who had died before 30 yrs of age or required transplantation at <30 yrs of age by December 31, 2004. We excluded controls (n = 27) who had died from a non-CF related cause ( e.g. road traffic accident).

80 cases and 400 controls were identified from the original population. To ensure that cases and controls were similar in terms of era of birth, as it is likely that this would have influenced the nature of care received, cases were matched by date of birth (±365 days) to all eligible controls. Of the 80 cases identified, 78 were matched to at least one control. Each control was matched with as many cases as eligible and controls could be matched to more than one case. Of the 400 controls identified, 152 were matched to at least one case.

Information on source of referral, guardian's occupation, genotype and clinical state (weight, height, lung function, sputum microbiology, diabetic status, use of pancreatic enzymes, previous pneumothoraces, episodes of major haemoptysis and number of previous hospital admissions or antibiotic courses) prior to and at referral was collected from the initial assessment at the adult clinic; the remaining data were collected from annual reviews (school disruption, number of Advanced (“A”)-level school examinations and number of siblings). Antibiotic treatments before first attendance at the adult clinic were categorised as oral, aerosolised or i.v.

Statistical analysis

Differences between cases and controls were described by frequencies and proportions for categorical variables, and medians and interquartile ranges for continuous variables. Development of CF-related diabetes (CFRD) and the acquisition of Staphylococcus aureus , Pseudomonas aeruginosa and Haemophilus influenzae were assessed in terms of whether the patient developed these conditions before the age of 16 yrs. As such, analyses of these variables were limited to those who arrived at RBH by 16 yrs of age (69 cases and 109 controls). Physical measurements at initial assessment, history of antibiotic use and number of hospital admissions prior to initial assessment were limited to those arriving at RBH by the age of 15 yrs (73 cases and 131 controls).

We used probability-weighted logistic regression models to assess the association between possible predictors and survival to 40 yrs of age (case status). Using this method, controls were weighted according to the cases to which they were matched; thus, making the distribution of the matching variable (date of birth) similar in both groups. Each control was weighted by the sum, across its matched case, of 1/(number of controls to which the case is matched). Cases were allocated a weight of 1. Model results are presented as OR and 95% CI. Since patients were transferred to the adult clinic at varying ages, ORs for physical measures and medical history prior to initial assessment (use of antibiotics, prior hospital admissions, history of pneumothorax and major haemoptysis prior to initial assessment) were adjusted for age at assessment. ORs for physical measures were also adjusted for sex. Analyses were conducted in SAS v9.1 (SAS Institute, Cary, NC, USA) or STATA (StataCorp LP, College Station, TX, USA).

All patients consented for their anonymised data to be included in the database for research purposes. The study was approved by the RBH Research Ethics Committee.

Clinical characteristics

Half of the participants were born between 1960 and 1965 and most (80.4%) were diagnosed with CF before the age of 5 yrs ( table 1 ). 70% were first seen in the adult clinic before 21 yrs of age. 97% had pancreatic insufficiency and there were similar proportions of males in cases (long-term survivors) and controls. Genotyping was only possible for patients surviving beyond 1989 ( i.e. the year CFTR was discovered); therefore, genetic data were available for 74 patients (67 cases). Of the long-term survivors genotyped (86%), 32 (48%) were homozygous for δF508, 13 (19%) were compound heterozygous for δF508 and 19 (28%) were heterozygous for δF508 (with an unidentifiable second CF mutation). The remaining three cases were 621+1G→T, R553X (both with unidentifiable second genes) and R347P/3659delC. The seven controls genotyped were homozygous δF508.

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Features significantly associated with case status ( i.e. long-term survivors) included diagnosis after 5 yrs of age. Patients whose initial presentation had been with respiratory disease were significantly less likely to be cases. Patients who had suffered a pneumothorax prior to referral to the adult clinic were significantly less likely to be cases after adjusting for age at first attendance. There was little heterogeneity in the distributions of pancreatic insufficiency, haemoptysis and CFRD prior to referral; none was associated with case status. After adjusting for age at initial assessment and sex, the probability of survival to 40 yrs increased with increasing height, weight, body mass index (BMI), forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity as recorded at the initial assessment in the adult clinic.

Sociodemographic factors and patients’ educational background

Associations between long-term survival and measures of socio-economic status and educational attainment are shown in table 2 . Patients referred from paediatric clinic B (paediatric clinic in a low social economic status area) were less likely to be cases. Those whose guardians were in managerial or manual (skilled or unskilled) occupations were more likely to be cases than those in professional occupations, but the difference was not statistically significant. Patients classified as having “mildly” or “grossly” disrupted schooling were statistically more likely to be controls, but there was no association between case status and the number of A-levels achieved. We found no association between sibling number (with or without CF) and case status.

Sputum microbiology, antibiotic courses and hospital admissions

Table 3 displays the association between long-term survival and sputum microbiology, antibiotic courses and hospital admissions prior to referral to the adult clinic. Acquiring P. aeruginosa, but not H. influenza e or S. aureus, in the sputum prior to 16 yrs of age, was associated with a reduced probability of being a case.

Patients who had received oral antibiotics (as intermittent courses and/or long-term/prophylaxis), and had not received aerosolised or i.v. antibiotics, were significantly more likely to be cases than those who had not taken oral antibiotics. Conversely, the prior use of aerosolised or i.v. antibiotics was inversely associated with case status. Patients requiring annual or more frequent hospital admissions were significantly less likely to be cases.

This carefully matched case–control study is the first to report on the potential early influences of long-term survival in patients diagnosed with CF in childhood. Patients with a later diagnosis ( i.e. at 5–16 yrs of age), those whose CF did not present with respiratory disease and those with higher weight, height, BMI and lung function (% predicted) at the time of their first assessment at the adult clinic were statistically more likely to reach 40 yrs of age. Acquiring P. aeruginosa , but not H. influenza e or S. aureus , in the sputum prior to 16 yrs of age, was associated with a reduced probability of long-term survival. Factors that did not influence long-term survival included sex, parental occupation and major haemoptysis or the development of diabetes before 16 yrs of age. These findings suggest that the long-term survival of adults diagnosed with CF in childhood is determined predominantly by an intrinsically severe phenotype in early life, with little evidence of major modification by socioeconomic influences, and that maintaining good health in childhood is an important determinant of long-term survival.

We elected to study only patients whose disease had been diagnosed during childhood, and thus remove the bias associated with the good prognosis of disease when diagnosed in adulthood 10 , 11 . Moreover, by studying long-term survivors under the care of a single institution and by matching them with “controls” born within a year of their birth date, we reduced the effects of different adult treatment strategies between centres and changing strategies over time, each of which may have independent effects on survival 9 . We may, in this way, have “over-matched” patients, leaving insufficient heterogeneity of exposure to examine some important determinants of survival. For example, it is widely accepted that socioeconomic factors have a strong influence on prognosis 9 , 12 , 13 but our findings demonstrated only limited evidence of this. In contrast to a previous UK study in 1989, we found no correlation of parental occupation (an index of family socioeconomic status) with long-term survival 14 . The association of poor survival with referral from paediatric clinic B (situated in an area of relatively low socioeconomic status) may reflect differences in resources and provision of care, as well as patients’ sociodemographics.

However, the present study provides an important extra dimension to published studies on predictors of mortality. The earliest, observational, studies recognised the association of poor nutritional status and low FEV 1 with a worse outcome 15 – 17 . Since then, more robust epidemiological studies have confirmed this correlation, including a large population study of the Canadian Patient Data Registry 3 . More recently, an Irish study investigated factors relating to mortality in their adult patients, concluding that lower FEV 1 and BMI, and higher infection rates of P. aeruginosa and Burkholderia cepacia were associated with patients who had died 18 . They assessed differences in predetermined clinical parameters between patients who died during a 10-yr period and those who remained alive, therefore making it difficult to draw conclusions about the timing of the events ( i.e. when they were most influential). Our study adds to this by clearly showing the importance of these factors at an early stage.

The present study demonstrated a worse outcome in patients diagnosed with CF early (before 5 yrs of age) and also in those with an initial disease presentation of respiratory symptoms. This supports the findings of a US registry-based study, demonstrating variable survival among patients with inherently different degrees of baseline risk, reflected by their age at diagnosis and their degree of disease severity at presentation 19 . They also showed that meconium ileus was associated with reduced survival, which provides an explanation for the lack of correlation found in our study, as only a few patients presenting with meconium ileus survived to adulthood. Contrary to their findings, we found that sex did not predict survival, which, in part, might be explained by the historical higher mortality among CF females, particularly around puberty, taking its toll, thus leaving those who have a predetermined survival advantage to progress through to the adult clinic 20 . However, others have argued that the so-called “gender gap” does not exist, highlighting the complex interaction of this much-debated relationship 21 . Patients with an increased baseline risk are predisposed to developing worse lung disease and an accelerated decline in their general health. Consequently, they develop more complications and ultimately require more hospital admissions and i.v. antibiotic courses, as demonstrated by the strong correlation of these factors with control status in our study.

The negative impact on survival of P. aeruginosa infection is consistent with previous studies and, although there is still some controversy regarding causality and ascertainment bias, it should be regarded as a poor prognostic factor 22 , 23 . The insignificant impact of H. influenzae and S. aureus is consistent with other studies. A European cross-sectional study demonstrated that S. aureus was not associated with worse pulmonary status and others have shown a deleterious effect on symptoms only, including the risk of massive haemoptysis 24 – 26 . The finding of a survival benefit for patients receiving oral antibiotics (without aerosolised or i.v. antibiotics) is interesting, as oral flucloxicillin is usually given as long-term prophylactic anti-staphylococcal treatment, suggesting indirectly that S. aureus may be relevant to survival, although this association may also be an indicator of milder disease 27 .

We were unable to explore the impact on survival of specific CFTR mutations, as the majority of controls died before the discovery of the CF gene in 1989, making regression analysis impossible 28 . However, as 48% of the long-term survivors were homozygous for δF508 (compared with 50% in the total UK adult CF population 29 ), their survival advantage cannot be attributed to “milder” genotypes with less severe disease expression. We chose to use 17 yrs of age as our age criterion, as it has been demonstrated previously that this differentiates two distinct phenotypes of long-term survivors 11 . We acknowledge that we cannot be certain that all non-classic phenotypes have been excluded but combined with the genotype data and the fact that 97% of the total study population had pancreatic insufficiency, bias from genuine non-classic disease would have been minimal. Additionally, the use of a younger age of diagnosis would have further selected out “mild” cases; but with the recognition of significant disease heterogeneity even for homozygous δF508, reducing the age would have excluded patients with “classic” disease genotypes that follow a milder disease course ( e.g. due to gene modifiers), i.e. the group of patients of particular interest to this study.

There are several limitations to our findings. The incidence of complications such as CFRD and major haemoptysis increase with age 24 , thus numbers were small in both groups at the time of assessment in the adult clinic, limiting the likelihood of finding an effect on survival. We were unable to assess the impact of B. cepacia complex infection as the importance of this pathogen in CF became apparent only in the mid-1980s 30 . Asymptomatic patients, diagnosed at birth through neonatal screening, are also not included in this study, as such programmes have only recently been introduced. The study was further limited by the data available to us and, therefore, in some instances, proxy markers ( e.g. parental occupation) had to be used and patient numbers were small, making interpretation difficult. The information on socioeconomic status was therefore limited, as the broad category of “parental occupation” and the recognised limitations of “source of referral” do not allow for definitive conclusions to be made.

In summary, this study demonstrates the importance for long-term survival of achieving optimal growth and lung health by the time a patient attends an adult clinic. Effective clinical care is needed to facilitate this but, from our findings, we conclude that longevity is determined early, possibly by factors independent of CFTR function ( e.g. gene modifiers) that determine early phenotype, disease severity and, ultimately, the probability of long-term survival.

Statement of interest

None declared.

• Received January 5, 2010.
• Accepted March 27, 2010.
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• Navarro J ,
• Rainisio M ,
• Rommens JM ,
• Buchanan JA ,
• ↵ UK Cystic Fibrosis Database . Annual Data Report 2004. University of Dundee 2006 . www.cystic-fibrosis.org.uk/pdfs/annualreport/AuditReport2004.pdf Date last accessed: October 4, 2010. Date last updated: April, 2: 2010 .
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A Case of Cystic Fibrosis (KEY)

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Description.

This is the answer key for the case study on cystic fibrosis where students explore how children are diagnosed with CF, how CF mutations affect transport across the cell membrane, and how two drugs can be used to treat the disease. The activity is used in AP Biology class and requires students to complete a CER (claim, evidence, reasoning) at the end to justify the best course of treatment for patient Zoey.

The student version of this case is available for free at biologycorner.com and includes two versions, in-person and remote learning version.

Download provides the answer key and links to the Google docs for the student worksheets for both in-person and remote learning. Document also includes rubric for CER and additional resources for teaching.

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