UB Contributing to Dramatic Results in CF Care, Research

(EDITOR’S NOTE: This is the first installment in a three-part series recognizing Cystic Fibrosis Awareness Month.)

By Dirk Hoffman

Researchers and clinicians at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo have played key roles in developing game-changing discoveries such as cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies that are designed to correct the malfunctioning protein made by the CFTR gene. Their efforts are continuing on a daily basis as they seek to develop more novel and improved therapies.

Cystic fibrosis is a progressive, genetic disease that affects the lungs, pancreas and other organs.

There are close to 40,000 children and adults living with cystic fibrosis in the United States (and an estimated 105,000 people have been diagnosed with CF across 94 countries), according to the Cystic Fibrosis Foundation.

During the 1950s, a child with CF rarely lived long enough to attend elementary school. Today, many people with CF are achieving their dreams of pursuing careers, getting married and having children, and living into retirement.

Four Jacobs School faculty members involved with CF recently sat for a roundtable discussion on the state of the disease, new therapeutics and clinical guidelines, and some of the new challenges facing the population.

The faculty members are:

• Carla A. Frederick, MD, associate professor of medicine. She is an adult pulmonologist who takes care of individuals with CF at the Cystic Fibrosis Center of Western New York. She co-directs the CF research program at the center through the Cystic Fibrosis Foundation’s Therapeutics Development Network (TDN). She sees patients through UBMD Internal Medicine.
• Danielle M. Goetz, MD, clinical associate professor of pediatrics. She is a pediatric pulmonologist at Oishei Children’s Hospital and UBMD Pediatrics and director of the Cystic Fibrosis Center of Western New York. She co-directs the CF research program at the center through the Cystic Fibrosis Foundation’s TDN. At the national level, she is serving on the position paper for the new CF Care Model for the CF Foundation and is a leader for the Foundation’s Quality Improvement Network’s mental health lab.
  
• Ryan C. Hunter, PhD, associate professor of microbiology and immunology. His lab is a group of microbiologists who focus on the bacterial infections that impact the lungs of individuals with cystic fibrosis. The researchers think about how these bacteria are behaving at the site of infection within the lungs of the patient and try to come up with new therapeutic strategies moving forward that can be used to better combat these infections.
  
• Beth A. Smith, MD, clinical professor of psychiatry and pediatrics and interim chair of psychiatry and division chief for child and adolescent psychiatry. On the national level, she serves as chair of the Cystic Fibrosis Foundation’s Mental Health Advisory Committee, whose goal is the integration of mental health care into routine CF care. Smith also serves on the CF Foundation’s North American Planning Committee as its pyschosocial chair, and on its Clinical Research Advisory Board. Her research is focused on mental health and cystic fibrosis, specifically around anxiety, depression and its effect on disease outcomes, as well as appearance. Smith is also involved in multiple intervention trials, specifically for depression and anxiety, including randomized, controlled trials for CF-specific cognitive behavioral therapy.

Goetz: It is an exciting time because for those of us who have been involved with CF for many years, we have seen a lot of changes such as a lot of treatments that we did not have previously — mostly the CFTR modulators (the most famous one is elexecaftor-tezacaftor-ivacaftor, or Trikafta) approved for people as young as age 2 as of 2021.

These therapies are helping people live longer lives; they help their pulmonary function and their weight gain. Their overall quality of life improves.

Frederick: When I first started in medicine, I saw so many young patients that did not have a very long life expectancy.

Now, it is almost like a mid-career change for me. Earlier in my career, I was caring for adults who were inevitably getting sicker and who were going for lung transplants, on oxygen, and would need to apply for disability.

Now, in addition to routine daily care, the most common issues adults with CF face are things like thinking about careers, figuring out what they are going do with their life that they never thought they would have to do before — having kids, having grandchildren.

In Buffalo, we have a high percentage of people who have access to CFTR modulator therapy. We currently have 116 adult patients and 68 pediatric patients. It has completely flipped from when we started. There used to be more pediatric patients than adult patients.

Smith: As the life expectancy has increased, it has caused some good challenges. Patients with CF did not plan to live that long. They did not plan for college or a career.

Now some of them are old enough to retire so there are a lot of issues around future planning. They are dealing with conditions such as osteoporosis and dementia — comorbidities that people did not live long enough to have.

Hunter: From a research perspective, it is an exciting time as well. We are most interested in the bacterial infections of the lungs and the nature of those are changing. With these modulator therapies, lung function is improving.

The pathogens are still hanging around, but lung function is getting better. It’s interesting to think about what airway infections are going to look like, moving forward. We are shaping our research in that direction, just trying to think about what lung infection might become, but also some of the comorbidities as well.

For instance, there is an increased risk in colorectal cancer in the aging CF population so my lab is also now thinking about gut microbes and what kind of role they might play in gastrointestinal manifestations of the disease.

CF as a disease ties in really well, timing-wise, with UB’s commitment to aging research. I think it is a great case study of what the aging population is facing.

Goetz: I think they are a key to the outcomes we have had, even prior to the modulators. The concept of a multidisciplinary care network idea started in the 1960s. In 1997, it became more standardized as there was a guidebook made by the CF Foundation and others.

Key team members are respiratory therapists, dietitians, social workers/mental health providers, physicians and nurses, along with other subspecialists.

Having that team has helped us in our assessment and treatment of the patients. We are assessing the whole person and making sure we are addressing all aspects of care. Each person focuses on and becomes experts in the area of the daily treatments that patients with CF have to undergo.

It is a collaborative effort. We do a lot of pre-visit planning, prior to the clinic visits and try to include the patients in that.

Frederick: Traditionally, pulmonary disease — and nutritional deficits with the inability to absorb fat nutrients — those two areas have treatments for them that CF centers have provided for a number of years.

Also, more commonly as individuals age, CF-related diabetes is one that over half of individuals with CF have some form of, that might move on a spectrum throughout their life

Some individuals have had many treatments over time, that could be toxic to their kidneys so chronic renal disease can develop in some.

Cancer is another big one that is emerging in understanding, and there is not a way where we can just implement screening like the general population. Some of these cancers in the GI form come faster than you would have predicted.

Also, we are in a culture where we always think of mental health, anxiety and depression as something that comes along with chronic illness, especially this one. This is not something that is simply related to feeling down when their heath is worse off, it can also occur when they are feeling better. There are a lot of people who have guilt associated with surviving longer than siblings or friends with CF, or when someone improved on CFTR modulator therapy some feel like their own identity is lost when this new, healthier person evolves.

Hunter: Chronic sinus infection is another one. About 95 percent of patients with CF have them. Maybe not lethal directly, but it is a risk factor for lower airway infection.

Smith: It depends on where you are on the lifespan. The children that are born now are going to have a much different mental health trajectory than those who were raised thinking they are going to die earlier than they are.

When the life expectancy changed, it also stirred up a lot of trauma. We are doing a study right now, hearing personal narratives from patients with CF across the lifespan. In the over 50 age group, medical traumatic stress and procedure anxiety is ubiquitous.

These are individuals who have had many, many procedures throughout their life and many traumatic medical procedures and the trauma from them has been layered throughout their lifespan. I feel the interventions we are providing now earlier and earlier are going to result in a much different trajectory.

Smith: There is often talk about a lack of understanding. During the COVID-19 pandemic, some positives came out of it in that people understood the idea of isolation, of that worry of getting an infection that can potentially kill you.

We all got a taste of that. In some ways, it gave credibility to everything that patients with CF have been going through across their lifespan.

Frederick: The reasons for these isolation guidelines is because of the fear for cross-contaminating different individuals with CF with different strains of bacteria that could become harmful.

Hopefully, future research will lead to relaxing those guidelines because quality of life is important. Separating people in time and space and touch is kind of cruel in this lifelong illness where finding someone who truly understands one’s point of view is difficult.

Goetz: In children, we are doing observational studies on preschoolers who are on Trikafta, and seeing what happens to their growth parameters and pulmonary function.

We are also doing surveys on personal experience with Trikafta in adolescents. We received a grant from the CF Foundation for all the newborn screening programs at the CF centers in New York state to assure all people with CF and their families have genetic counseling from a genetic counselor trained in CF. This is important due to the increasing complexity of CF genetics and to address unique CF mutations in diverse populations.

Frederick: We are involved in a rollover study from a head-to-head trial between current modulator therapy (elexacaftor/tezacaftor/ivacaftor) versus a once-a day alternative.

It is in the rollover phase where everyone is getting the once-a-day alternative therapy.

Taking a pill twice a day versus once-a-day may seem simple, but it isn’t. There is not a one-size-fits-all. Some people may feel that the current therapy is not good enough because “xyz” side effects happen — weight gain, mental health side effects such as anxiety, etc. Some simply do not have as strong of an improvement as desired.

These therapies are life-changing so more personalized medicine is in the works elsewhere to help make that therapy really great for everybody.

We participated in all the trials coming up to this present modulator therapy.

We dosed the first person with ivacaftor in the world here in Western New York and she just had her second baby a couple of months ago.

We have had a long history of recruiting people with CF to participate and families at first didn’t know what they were getting into, but now enter those trials with hope and excitement.

Smith: In addition to the medication trials, we’ve had a few mental health trials. We worked hard on a randomized, controlled trial of a cystic fibrosis-specific cognitive behavioral intervention for depression and anxiety. We are now in the adolescent pilot phase of the study. Buffalo is also involved in a national randomized, controlled implementation trial. We are implementing different models of how to disseminate this cognitive behavioral therapy that is specific to CF and we are studying it in a randomized way.

Buffalo is also the lead site in a multisite project to develop a CF-specific general mental health screener to pick up on other important and impactful mental health conditions in addition to depression and general anxiety for adults with CF.  

We also have the longest longitudinal database for depression and anxiety screening and are looking at the longitudinal trajectories of depression and anxiety in patients with CF 12 years and older and associations to important health outcomes.

Smith: I am the founding chair of its mental health advisory committee. It came about after the international guidelines for mental health screening and treatment in CF, where I led the screening portion. The Foundation wanted to figure out how to disseminate and implement these guidelines in the care centers across the U.S. With our initiatives, currently over 95% of individuals with CF 12 and older are screened annually across U.S. CF Centers.

We’ve taken that show on the road and worked to help implement the mental health in CF guidelines in Australia and across Europe. We have international membership on our committee and many of the resources we have created have been translated into 50+ languages.

In some countries without a lot of mental health infrastructure, when individuals are screened for depression and anxiety, that may be one of the only resources they are given.

Frederick: We are also involved in the Success With Therapy Research Consortium that is a branch of the Foundation’s research efforts to help partner with people with CF and their families to see how we can help improve health and self-management.

In a randomized, controlled trial, we are measuring everything and all visits are structured. But in the real world, when things like parenting or having a job, or having a friend come into the mix, does using this therapy still work? We perform some observational research to study these things.

We are involved in a lot of survey studies of qualitative research. Nutrition is a huge topic. In the new era of widely available modulator therapy, what does the world of nutrition look like? There is a study where we are learning about attitudes toward nutrition.

It seems like it would be a no-brainer to take this modulator therapy, but there are lots of other variables, so we are participating in a survey study with all sorts of different parameters for people to see what kind of modifiable or non-modifiable factors are affecting the week they take modulator therapy.

These studies are a really nice way we round out our center. We have mental health; we have care, and we have clinical research, and we have this other consortium where we partner with people with CF to see if we are really on the right track to help their lives be better.

Goetz: We are working with the CF Learning Network, which is the Quality Improvement Network for the CF Foundation. At our center, we do QI projects on all sorts of topics.

They asked me to be co-director of the laboratory on mental health to help design QI projects that the whole network can use. I am also serving on the CF Foundation committee, writing a position paper on the new CF Care Model in 2023-2024.

I have also served on the Foundation’s Therapeutics Development Network (TDN) steering committee. We get to look at all the protocols and see what is coming down the pipeline. We get to help shape what TDN is looking at for the sites.

Right now, they are doing gene editing and mRNA studies, so we are in a regional network of the TDN. We meet with other centers like Pittsburgh, West Virginia, Rochester and Syracuse.

They know there may not be a lot of subjects in Buffalo or each individual center who are eligible for genetic therapy, but we may be able to refer people to other centers within the network. The TDN is dividing the centers into geographic regions so people may more easily participate in studies.

Hunter: I serve on the basic science grant review committee. Twice a year, a bunch of mostly basic researchers get together and we review applications. They are mostly U.S.-based, but they do accept international.

About 20-to-30 of us get together to review the science, to help the CF Foundation establish its priorities and decide what to fund. We try to make recommendations on which science is the strongest and which proposals are most worthy of being supported by the Foundation.

Smith: When I first got involved with Drucy (Drucy S. Borowitz, MD, who served as the Cystic Fibrosis Center director at the former Women & Children’s Hospital of Buffalo for more than 25 years) and some of the other pulmonologists, they were excited to have a child and adolescent psychiatrist who was interested in chronic illness and recognized the need for that.

They were doing collaborative care before it was called collaborative care. I was brought in as another specialist and wound up spending my career in CF because of the multidisciplinary nature and the spirit of collaboration.

Goetz: I became the CF center director in 2014, so we did a year where Dr. Borowitz and I were co-directors before that. She mentored me and we transitioned, but then she was still here until she went to the CF Foundation. Even while working at the CF Foundation, Dr. Borowitz was always there as our mentor. She was always in our corner, always available.

Smith: We would be putting in grants or writing a paper that got rejected for the second time, and Drucy would just take her proverbial red pen and very magically make edits. She was such a great mentor.

Goetz: We are trying to carry on the tradition she started.

Smith: Buffalo is a small center and yet we are involved in so many of these groundbreaking CF research projects. We have such a cohort.

I think it is due to Dr. Borowitz and her culture that patients and their families are very giving of themselves to our studies. Our rates of participation in studies are higher than most centers. Although we are small, we are mighty.

And the individuals are a part of this team of researchers. We have patient advisers on every one of our grants. And all of the educational materials are co-written with individuals with CF.

It has been just a great experience because many of them have said “I never thought I was going to be a researcher” or “I never thought I was going to be an author.”

Goetz: We are working on a CF Foundation position paper that I am helping to write in a group that includes patients and parents. It is asking the question if we need to change the care model now that we have modulators.

Patients and families should be a part of those discussions because they are the ones living it.

Smith: Their lived experience puts everything that we do into context. They are able to look at what we are producing and give us that feedback.

There is so much resilience in this population. Their survival stories are now thriving stories.