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• Volume 14, Issue 11
• Cystic fibrosis: a diagnosis in an adolescent
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• http://orcid.org/0000-0001-9674-0879 Monica Bennett 1 ,
• Andreia Filipa Nogueira 1 ,
• Maria Manuel Flores 2 and
• Teresa Reis Silva 1
• 1 Pediatric , Centro Hospitalar e Universitario de Coimbra EPE , Coimbra , Portugal
• 2 Pediatric , Centro Hospitalar do Baixo Vouga EPE , Aveiro , Aveiro , Portugal
• Correspondence to Dr Monica Bennett; acinomaicila{at}gmail.com

Most patients with cystic fibrosis (CF) develop multisystemic clinical manifestations, the minority having mild or atypical symptoms. We describe an adolescent with chronic cough and purulent rhinorrhoea since the first year of life, with diagnoses of asthma, allergic rhinitis and chronic rhinosinusitis. Under therapy with long-acting bronchodilators, antihistamines, inhaled corticosteroids, antileukotrienes and several courses of empirical oral antibiotic therapy, there was no clinical improvement. There was no reference to gastrointestinal symptoms. Due to clinical worsening, extended investigations were initiated, which revealed Pseudomonas aeruginosa in sputum culture, sweat test with a positive result and heterozygosity for F508del and R334W mutations in genetic study which allowed to confirm the diagnosis of CF. In this case, heterozygosity with a class IV mutation can explain the atypical clinical presentation. It is very important to consider this diagnosis when chronic symptoms persist, despite optimised therapy for other respiratory pathologies and in case of isolation of atypical bacterial agents.

• cystic fibrosis
• pneumonia (respiratory medicine)

https://doi.org/10.1136/bcr-2021-245971

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A high degree of diagnostic suspicion is of fundamental importance when chronic symptoms persist, despite optimised therapy for previous diagnoses and in case of isolation of atypical bacterial agents in microbiological studies.

This case describes an adolescent with a chronic cough since the first year of life, adequate weight gain and normal pubertal development, without improvement with optimised therapy for other respiratory pathologies. There was no reference to gastrointestinal symptoms. There was clinical worsening at 13 years of age and isolation of Pseudomonas aeruginosa in sputum culture. After extensive investigation, including sweat test and genetic study, it was possible to confirm the diagnosis of cystic fibrosis (CF).

Case presentation

A 13-year-old female teenager presented with chronic cough and purulent rhinorrhoea with periods of intermittent clinical worsening with associated fever since the first year of life. This was accompanied by various medical specialties, with diagnoses of asthma, allergic rhinitis and chronic rhinosinusitis. She was under therapy with long-acting bronchodilators, antihistamines, inhaled corticosteroids, and antileukotrienes and submitted to several courses of empirical oral antibiotic therapy, without sustained and effective clinical improvement. She presented an adequate height–weight evolution, with a body mass index (BMI) at 50th−85th percentile and normal pubertal development, no reference to gastrointestinal symptoms or previous hospitalisations. Her family background was irrelevant. Due to clinical worsening, with emetising cough associated with intermittent fever and night sweats, a pulmonary CT scan was performed, which revealed parenchymal densification, air bronchogram, thickened bronchi, mucoid impaction and mediastinal adenopathies. Observed in the emergency department, the objective examination highlighted bibasal crackles on pulmonary auscultation, without other alterations. She was treated with clarithromycin, later associated with co-amoxiclav. An extended investigation was initiated, which revealed erythrocyte sedimentation rate of 52 mm/hour, C reactive protein test of 4.10 mg/dL, negative BK and interferon gamma release assay test, and isolation of P. aeruginosa in sputum culture. The antibiotic therapy was changed to ciprofloxacin and sweat tests were performed with positive results on two occasions (102 and 110 mmol/L). Later, a genetic study revealed heterozygosity for the F508del and R334W mutations, which confirmed the diagnosis of CF. Faecal elastase was performed, and the result was normal (>500 µg/g).

After antimicrobial therapy with ciprofloxacin, she maintained P. aeruginosa, and methicillin-sensitive Staphylococcus aureus (MSSA) was now discovered in the sputum. For this reason, she was hospitalised for intravenous eradication. After 2 weeks of antibiotic therapy with meropenem, gentamicin and teicoplanin, P. aeruginosa was eradicated but not MSSA. Linezulide was prescribed for 2 weeks, with a good response, and the microbiological study was negative.

Outcome and follow-up

During the follow-up period (2 years), she continued having frequent respiratory infections, with isolation of P. aeruginosa and MSSA in respiratory secretions intermittently, requiring the need for several courses of antibiotic therapy. The antibiogram of P. aeruginosa has remained sensible. Currently, she continues follow-up in a specialised fibrosis cystic centre, under inhaled therapy with colistin/tobramycin, hypertonic saline, salbutamol, dornase alfa, budesonide/formoterol, chest physiotherapy and oral azithromycin prophylaxis. Her pulmonary function is normal with a currently forced expiratory volume in 1 s of 87% and she shows adequate height−weight evolution, with BMI maintained at P50–85. The sweat chloride test was not repeated after confirmed diagnosis.

CF is one of the most commonly diagnosed genetic disorders 1 and the most common life-shortening autosomal recessive disease among Caucasian populations, with a frequency of 1 in 2000–3000 live births. 2 CF is caused by mutations in a single large gene on chromosome 7 that encodes the cystic fibrosis transmembrane conductance regulator ( CFTR ) protein.

There are more than 2000 mutations/variations of the CFTR gene reported and listed in the CFTR mutation database. A small subset are CF disease-causing mutations, of which the majority are associated with pancreatic insufficiency and a smaller subset are associated with pancreatic sufficiency. Most of the known mutations/variations related to CF are described in the CFTR2 database (Clinical and Functional Translation of CFTR). This website provides information about what is currently known about specific genetic variants or variant combination and is a useful resource to correlate clinical measures to the large number of variants identified to date. 3 4

Clinical disease requires disease-causing mutations in both copies of the CFTR gene. Mutations of the CFTR gene have been divided into five different classes. The most common mutation is F508del which is included in category class II mutations—defective protein processing. Approximately 50% of patients with CF are homozygous for this mutation, and 90% will carry at least one copy of this gene. In general, mutations in classes I−III cause more severe disease than those in classes IV and V. Class IV and V mutations are associated with moderate phenotypes and pancreatic sufficiency. 5 The R334W is a rare mutation included in class IV—defective conduction and associated with pancreatic sufficiency. 5 6 Those with less severe mutations present with pancreatic sufficiency and single organ manifestations of CF. Some of these patients would fulfil the diagnostic criteria for CF and some would be classified as having a CFTR-related disorder if the diagnosis of CF cannot be fulfilled. 7

The phenotypic expression of disease varies widely, based on CFTR-related (genotype-related) and non-CFTR-related factors (environmental and other genetic modifiers). Genotype–phenotype correlations are weak for pulmonary disease in CF and somewhat stronger for the pancreatic insufficiency phenotype. 5

Many studies in different individuals heterozygous for CFTR gene mutation have been performed to find out the association of CFTR gene mutation with asthma. The results are inconclusive, as some of the studies have shown positive association, whereas other could find either protective or no association. 8 Also, at this time, there is no evidence for a specific association between CFTR gene mutation and other allergic manifestations.

Clinical manifestations are multisystemic and heterogeneous. 9 The first symptoms of the disease usually appear in the first years of life, and most patients develop a multisystem disease, with predominantly respiratory and digestive symptoms. 2 5 10 The usual presenting symptoms and signs include persistent pulmonary infection, pancreatic insufficiency and elevated sweat chloride levels. However, many patients demonstrate mild or atypical symptoms, and clinicians should remain alert to the possibility of CF even when only a few of the usual features are present. 2 Progressive pulmonary involvement is the main cause of morbidity and mortality. Clinically significant pancreatic insufficiency eventually develops in approximately 85% of individuals with CF. The remaining 10%–15% of patients with CF remain pancreatic sufficient throughout childhood and early adulthood, but these individuals are at risk of pancreatitis. Pancreatic exocrine function may be evaluated indirectly by measurement of faecal elastase, which is clinically practical but has limited accuracy. Low levels of faecal elastase suggest pancreatic insufficiency and support a diagnosis of CF. 2 5 11–13

The diagnosis of CF is based on compatible clinical findings with biochemical or genetic confirmation. The sweat chloride test is the mainstay of laboratory confirmation, although tests for specific mutations, nasal potential difference (NPD), immunoreactive trypsinogen, stool faecal fat or pancreatic enzyme secretion may also be useful in some cases.

Both of the following criteria must be met to diagnose CF: (1) clinical symptoms consistent with CF in at least one organ system, or positive newborn screen or having a sibling with CF; and (2) evidence of cystic CFTR dysfunction (any of the following): elevated sweat chloride ≥60 mmol/L; presence of two disease-causing mutations in the CFTR gene, one from each parental allele; abnormal NPD.

Sweat chloride test ≥60 mmol/L is considered abnormal. If confirmed on a second occasion, this is sufficient to confirm the diagnosis of CF in patients with clinical symptoms of CF. Positive results of sweat testing should be further evaluated by CFTR sequencing. Determining the CFTR genotype is important because the results may affect treatment choices as well as confirm the diagnosis. For patients with inconclusive results of sweat chloride and DNA testing, measurement of NPD can be used to further evaluate for CFTR dysfunction. 5 14

Newborn screening programmes for CF are now performed routinely in several countries, which contributed to a dramatic increase in the number of CF cases identified before presenting with symptoms. The rationale for this screening is that early detection of CF may lead to earlier intervention and improved outcomes because the affected individuals are diagnosed, referred and treated earlier in life compared with individuals who are diagnosed after presenting with symptomatic CF. In Portugal and some other European countries, this programme was implemented less than 10 years ago, contributing to a late diagnosis in older children.

There are different neonatal screening programmes that include biochemical screening and/or DNA assays with panels to test for the most common CFTR mutations in the local population. Most programmes test for between 23 and 40 mutations, and some programmes even perform adjunctive full gene sequencing. Screening for a greater number of mutations increases the likelihood of identifying infants with CF and also increases the identification of rare or unique sequence mutations, making interpretation of the result more complicated. As only a limited number of mutations are evaluated on the genetic screens, it is possible to miss the diagnosis. Thus, it is important to follow such children closely, with particular attention to weight gain and recurrent respiratory infections. Clinicians should consider CF in individuals with suggestive symptoms, even when results of the newborn screen are negative or equivocal. 5 14

In the case described here, heterozygosity with a class IV mutation, usually associated with an intermediate phenotype and pancreatic sufficiency, may explain the atypical clinical presentation and consequent diagnosis only in adolescents. We also hypothesise that this child’s allergic manifestations may have delayed the diagnosis.

As the spectrum of clinical presentation is very variable, it is very important for clinicians from multiple specialties to be vigilant and suspect this diagnosis in conditions such as recurrent pulmonary infection, male infertility, pancreatitis, nasal polyposis and malabsorption even in patients with negative newborn screening. 2 10 13

Learning points

There is a wide spectrum of manifestations of cystic fibrosis (CF). These variations and wide spectrum are based on cystic fibrosis transmembrane conductance regulator (CFTR)-related (genotype-related) and non-CFTR-related factors (environmental and other genetic modifiers).

Most patients with CF develop multisystemic and heterogeneous clinical manifestations, with predominantly respiratory and digestive symptoms.

A minority have mild or atypical symptoms.

Heterozygosity with a class IV mutation usually is associated with an intermediate phenotype and pancreatic sufficiency and can explain the atypical clinical presentation.

It is very important to consider this diagnosis when chronic symptoms persist, despite optimised therapy for other respiratory pathologies and in case of isolation of atypical bacterial agents in microbiological studies.

Ethics statements

Patient consent for publication.

Consent obtained from parent(s)/guardian(s)

• Dickinson KM ,
• ↵ Cystic fibrosis mutation database . Available: http://www.genet.sickkids.on.ca/Home.html
• ↵ Clinical and functional translation of CFTR . Available: https://cftr2.org/
• Ellis L , et al
• Awasthi S ,
• Gartner S ,
• Salcedo Posadas A ,
• García Hernández G
• Castellani C ,
• Linnane B ,
• Pranke I , et al
• Farrell PM ,
• Ren CL , et al
• Kharrazi M ,
• Bishop T , et al

Contributors MB cared for study patient, planned and wrote the article. AFN collected data. MMF provided and cared for study patient, served as scientific advisors and critically reviewed the study proposal. TRS cared for study patient, served as scientific advisors and critically reviewed the study proposal.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

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Chapter 19:  Case Study: Cystic Fibrosis

Julie M. Skrzat; Carole A. Tucker

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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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The Biology Corner

Biology Teaching Resources

Case Study: Cystic Fibrosis Mutations

This case study is a follow-up to the Cystic Fibrosis Case Study where students explore how changes in transport proteins affects the movement of ions, resulting in a build-up of chloride ions and the symptoms of the disease.

Students were introduced to the idea that different mutations can cause differences in the transport proteins, but in the first version, the origin of these mutations was not discussed.

Eventually, students get to the chapter on DNA, RNA, and protein synthesis, so it’s a good time to circle back to the CF case and explore how mutations in DNA can affect the protein made by the ribosomes.

Students should already have some background in the central dogma, but a review may be in order to remind students how to transcribe DNA to RNA and then use a codon chart to determine the sequence of amino acids. This practice worksheet on using codon charts is something they may have done in freshman biology.

CFTR Mutations

This case explore frameshift mutations, missense mutations, and nonsense mutations. Students are given a section of DNA to transcribe and compare it to mutant DNA. Students should see that changes in DNA can result in changes in the synthesized protein, though some changes are more profound than others.

The link below is a Google Doc designed for remote learning but will work for in-class lessons. An original in-class version is also available, where it doesn’t have the colored text boxes.

Shannan Muskopf

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• Cystic Fibrosis
• Thread starter wanderlost
• Start date Feb 18, 2008
• Feb 18, 2008

A friend of mine is a nursing student and has to do this case study for class, I told her i would help, but there are some things I don't know. If you know any of these answers and have the time to type them, I'd appreciate it! I already did a lot of it, but some of the transplant stuff I didn't know. But anything would help, as I will compare my answers to yours! TIA! <b>Client Profile: Erin is an 8-year-old girl who lives with her parents and two younger sisters, Rachel, who is 5 years old, and Samantha, who is 2 years old. They live in a Midwestern community where Erin's father is a bank manager and her mother is a part-time investment broker who works from home, which allows her to stay at home with the children. Both of Erin's parents are very attentive to the children and are very knowledgeable about Erin's cystic fibrosis, which was diagnosed when Erin was 3 months old. Neither of her sisters has the disease. Erin takes pancreatic enzymes with each meal and snack (six doses per day) and she performs breathing exercises twice a day. Her mother performs postural drainage 1 hour prior to breakfast, again when Erin returns from school in the afternoon, and finally each evening prior to Erin's going to bed. Case Study: During late spring Erin's breathing has become increasing congested over the past week and her parents suspect that she has developed a respiratory infection when she becomes febrile with a temperature of 37.9 0 C (100.2 0 F). They phone her pediatrician, who recommends that she be admitted to the children's hospital 20 miles away.The pediatrician calls the hospital and informs the chief respiratory resident physician of Erin's history, chief complaints at present, and impending arrival. Sputum cultures, complete blood count, serum electrolyte panel, chest x-ray, and pulmonary function diagnostics are prescribed. Erin's last admission for pulmonary clean-out was 6 months ago. Erin is admitted and her diagnostic results include hemoglobin, 18g/dL; hematocrit, 51%; white blood cell count, 15,000 cells/mm3; platelets, 250,000 cells/mm3; red blood cell count, 5.1 million cells/mm3; serum glucose, 130mg/dL; potassium, 4.0 mmol/L; sodium, 130mmol/L; chloride, 90 mmol/L; blood urea nitrogen (BUN), 26mg/dL; and creatinine, 0.7 mg/dL. Her chest x-ray shows consolidation in her right lower and middle lobes, and her oxygen saturation is 89%. Erin's pulmonary function is determined to be 45% and as you are compiling Erin's history, her mother tells you that Erin has been on the lung transplant list for 9 months. Erin weighs 44 lb on admission. Questions 1. Discuss your impressions about Erin's diagnostic values. 2. Discuss what risks Erin has for developing a pulmonary infection. 3. What pertinent information is missing? 4. Identify the common microorganisms that cause respiratory infections in a child with cystic fibrosis. 5. What is the relationship between Erin's condition and her oxygen saturation level? 6. The health care provider prescribes ceftazidime 1 g IV every 8 hours; gentamycin 50mg IV every 8 hours; and vancomycin 265 mg IV every 8 hours. Discuss why these drugs are prescribed for Erin. 7. Discuss the safety and efficacy of the doses of the antimicrobial agents prescribed for Erin. 8. What are the criteria established for lung transplant candidates? 9. Erin's condition worsens, and when no cadaver lungs are available, Erin's mother states that she wants to donate part or all of one of her lungs to Erin. After testing her mother for compatibility, the surgeon decides to proceed with the transplant the following day. Identify the priority client problems for Erin following the transplant. 10. Discuss the common immunosuppressant agents used to prevent organ rejection. 11. Erin receives a single lung transplant. Discuss what the risks are for her cystic fibrosis recurring in her transplant lung. 12. Erin and her mother recover from the surgery. Discuss the teaching priorities you will address with Erin and her parents prior to Erin's discharge. 13. What are the current statistics for successful lung transplants?</b>  

Am I the only one that thinks this is a little unbelievable? 45% lung function on transplant list, at 8 years old? Anyway.. I usually frown on doing someone else's homework for them, but this seems like a fun exercise. I'm sure most of us could do this passably well, never having set foot in nursing school.. sad, eh. 1. Not too familiar with exact blood values but I *think* that hemoglobin is low and white cell count is high.. but don't quote me on that. She is well underweight for an 8 year old, and her height is not listed. 2. Risk factors? Like having CF? Or risks as in exposure to colds/illness at school? 3. Height and BMI information. GI information missing. Medication list missing. DRUG ALLERGIES missing. Any physical exam info missing - breath sounds etc, signs of dehydration, throat/nose exam, etc. 4. Staph, Pseduomonas aeuroginsa and to a lesser extent B. cepacia, Aspergillus, MRSA 5. Her 02 sucks, and she has a respiratory infection, I'm not sure what else they want you to say there. 6. Antibiotics that were shown to be useful according to her last sputum culture, I would hope. 7. That seems a bit high for her age and weight, but your friend can probably look up the specifics of that. (especially the 1g of ceftaz.. I took 2g and I weigh 3x what this imaginary patient does) 8. This is why I said it seems unreasonable. As far as I know, your FEV1 should be more in the 20-30% range.. not 45%. We have tons of people on this site in the 40's that work full time jobs and have families.. and are pre-tx. <skipping the last few since I don't have much tx knowledge> Tell your friend she needs to share the official answers with us when she gets her hw back. <img src="i/expressions/face-icon-small-tongue.gif" border="0">  

• Feb 19, 2008

I too thought that the FEV1 was high for being listed on a transplant list. I am not familiar with the entire transplant procedure...I do know that chest size, blood type, antibodies, etc are significant as far as transplant goes. 1) Erin has an elevated WBC at 15,000 (normal is around 4,500 to 10,800 I think) indicates infection, her Hgb (hemaglobin) is elevated at 18 as is her Hct (hematocrit) at 51. Her RBC's are slightly elevated at 5.1. Maybe she is a bit dehydrated...but perhaps she has polycythemia as a result of chronic hypoxia (just a guess though). The consolidation in her RLL and RML indicates pneumonia. Her sodium and chloride are also low at 130 and 90 respectively also due to her CF. BUN and creat. look okay. Glucose is okay if this is not a fasting sample. She is undeweight at 44 lbs, no height listed. 3.) Alot is missing as SevenStars said: Any CT scan results , GI info (bowels, CFRD?, nutritional screens), definitely drug allergies, what organisms ultimately grew out of the sputum sample, the entire physical exam, meds, were any repeat PFT's ordered?, also..what other meds or interventions were ordered for Erin (such as O2, nutrition assessments, meds, chest physio etc...) I know I forgot other stuff... 6.) Vanco is used mainly for MRSA (and some other creepy bugs), Gent and Ceftaz are great anti pseudomonals. Hopefully this med combo was dependent on the results of her sputum culture. Gent is 3-6mg/kg/day divided equally in 3 doses usually...Erin is about 20kg, so her max dosage in a day is 120mg total. Maybe the gent is a teeny bit too high. The vanco dosage looks okay. I have seen 1g Ceftazadime given q8 in young patients. I am at loss with the xplant questions.. 11.) The transplanted lung won't develop CF in them...rejection maybe, but not CF..the DNA of the new lung does not have CF Wish I could be more helpful...Hugs, Jenn <img src="i/expressions/face-icon-small-smile.gif" border="0">  

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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. For the next two Wednesdays in May, stay tuned for more stories on UB’s research and clinical care efforts in the area of cystic fibrosis.)

By Dirk Hoffman

Published May 8, 2024

One of the most dramatic success stories in modern medicine is the treatment of cystic fibrosis (CF), where therapeutic breakthroughs have dramatically reduced patients’ symptoms and increased their life expectancies.

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.

Danielle M. Goetz, MD, examines Muhammad Rafay at the UBMD Pediatric Outpatient Center at Conventus. The baby’s family resettled in Buffalo from Pakistan. The New York State newborn screening program revealed the baby has two copies of a CF mutation that is more common in Pakistan.

What is the current state of cystic fibrosis and the research and clinical care surrounding it?

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.

Tap infographics to enlarge.

Can you speak to the importance of multidisciplinary teams at the CF centers?

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.

Carla A. Frederick, MD, is an adult pulmonologist who takes cares of individuals with CF at the Cystic Fibrosis Center of Western New York.

What are some of the common comorbidities among patients with CF?

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.

How are new therapies and better outcomes affecting the mental well-being of patients with CF?

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.

Is the isolation that patients with CF often feel still a legitimate concern?

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.

Beth A. Smith, MD, is involved in a number of  mental health clinical trials that involve cystic fibrosis-specific cognitive behavioral intervention for depression and anxiety and the development of a CF-specific general mental health screener.

What are some of the ongoing clinical trials happening at UB?

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.

Ryan C. Hunter, PhD, serves on the Cystic Fibrosis Foundation’s basic science grant review committee, which helps the CF Foundation establish its priorities and decide what to fund.

Can you talk about your roles on a national level within the Cystic Fibrosis Foundation?

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.

Is there something about Buffalo or UB’s collaborative spirit that helps your efforts?

Smith: When I first got involved with Drucy (Drucy S. Borowitz, MD, who served as the Cystic Fibrosis Center director at the former Woman and 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.

( Next Week:  A look at the career of Drucy S. Borowitz, MD, a leader in cystic fibrosis care and research, who changed the course of the disease in Western New York.)

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