Unmasking Cystic Fibrosis in Adulthood,a Case Report

Abstract

Cystic fibrosis (CF) is a genetic disorder typically diagnosed in early childhood, caused by mutations in the cystic fibrosis transmembrane conductance regulator gene, leading to thick mucus accumulation in the lungs, pancreas, and other organs. While most diagnoses occur in childhood, a growing number of cases are being identified in adulthood, presenting unique challenges for recognition and management. This case highlights a 37-year-old patient diagnosed with CF after presenting with chronic respiratory symptoms, and weight loss. Late diagnosis of CF remains rare but can delay appropriate treatment, potentially impacting long-term outcomes.

Introduction

Cystic fibrosis (CF) is a genetic disorder primarily diagnosed in childhood, characterized by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that result in thick mucus accumulation in the lungs, pancreas, and other organs. ¹ Traditionally, CF is identified early in life, with most diagnoses occurring by age 2. However, as medical knowledge has expanded, diagnostic tools have advanced, and a deeper understanding of the relationship between the various mutations and phenotypic presentation, an increasing number of cases are being diagnosed in adulthood. ² For example, changes as small as the commonly seen mutation of the CFTR gene R117H allele, with an alteration of the 5T portion of the allele will phenotypically present with CF, whereas R117H(7T) is associated with male infertility, and pancreatitis. ² While late diagnosis is still considered rare, it presents unique challenges in both recognition and management of the disease, often delaying optimal treatment and potentially affecting long-term outcomes.^1,2 In adults, CF may present with symptoms such as chronic cough, recurrent respiratory infections, unexplained digestive issues, and infertility in men, making the diagnosis challenging. It is particularly difficult to distinguish CF from other chronic respiratory or gastrointestinal conditions, leading to misdiagnosis or delayed diagnosis. Research has highlighted that approximately 12% to 18% of CF patients are diagnosed in adulthood, with a median age of diagnosis around 36 years. ³ The significance of diagnosing CF in adulthood is profound, as early detection enables better management and improves patient outcomes through specialized treatment aimed at alleviating symptoms, slowing disease progression, and improving quality of life. This case report presents the clinical course of a patient who was diagnosed with CF at 37 years old, highlighting the challenges faced in diagnosing the disease in adulthood and emphasizing the importance of considering CF in differential diagnoses for adult patients with chronic respiratory or digestive issues.

Case Presentation

The patient is a 37-year-old male with a past medical history of diabetes mellitus who presented to the emergency department with complaints of a nonproductive cough, and weight loss of about 30 lbs in the last month. Initial computed tomography (CT) of the thorax with contrast demonstrated bilaterally patchy consolidations (Figure 1). Initial laboratory findings were significant for mild leukocytosis and otherwise largely unremarkable. The patient was found to have Staphylococcus aureus pneumonia and bacteremia, as well as Influenza B. The patient was started on Cefepime and Tamiflu. It’s significant to note both human immunodeficiency virus and tuberculosis testing both were negative. Transthoracic echocardiogram was performed to further evaluation and showed an ejection fraction of 55% to 60% as well as a right atrial echogenic density, concerning infective endocarditis. Transesophageal echocardiogram was able to rule out the suspected infective endocarditis. A repeat CT of the thorax was done and indicated fatty infiltration of the pancreas, indicative of a sign of CF, as well as visualization of a 1.1 cm subcarinal lymph node. These findings together prompted screening for CF. The patient improved clinically and was discharged with pulmonology follow-up for further work up of possible CF.

Figure 1.

Computed tomography thorax: multiple small hilar and mediastinal lymph nodes, and patchy consolidation in the bilateral upper lobes, lingula, and lower lobes; tree and bed appearance noted bilaterally.

When followed by pulmonology outpatient pulmonary function test (PFT) was performed and showed mild obstructive and restrictive disease. High resolution CT was also performed and showed bronchiectatic changes most prominently seen in the bilateral upper lungs (Figure 2). The patient was started on Breo Ellipta, fluticasone-vilanterol, inhaler for his symptoms. Sweat chloride was performed, and found to be elevated, 75 mEq/L (norm <59), sweat volume 15. The patient was sent for gene testing and found to have 1949del84 mutation, indicative of the patient being at least a carrier. Gene sequencing was also performed, and the patient was found to have 2 gene mutations: c.346G>A and c. 1820_1903del. Fecal elastase was also tested for and found to be <50 µg elastase/L, for which the patient was started on pancrelipase supplementation at 24 000 lipase units 3 times a day. The patient’s insulin regimen included insulin glargine 18 units nightly, and insulin aspart 6, 6, and 8 units to be taken with breakfast, lunch, and dinner, respectively.

Figure 2.

High-resolution computed tomography: bronchiectatic changes involving the lungs, most prominent in the upper lungs. There is significant improvement in previously noted multifocal pneumonias. In the current study, there are scattered nonspecific reticulonodular opacities in the lungs. There are new cystic changes in the left upper lung.

A pediatric pulmonologist was consulted for further recommendations and was advised to be started on albuterol and 7% hypertonic saline nebulizer twice a day, and Tobramycin 300 mg nebulized twice a day on 28-day cycles. However, due to multiple socioeconomic factors upon revisitation at the clinic the patient was unable to obtain the Tobramycin, for which it was replaced with Aztreonam 75 mg nebulized solution 3 times a day. The patient was also encouraged to begin using a flutter valve following his nebulizer treatments.

Most recently, the patient has also explained instances of erectile dysfunction as well as noted discrepancies in his fertility. Upon further question despite multiple attempts of over 2 years of conception with his partner, he was unable to do so. His partner was evaluated for concern of infertility, and all testing returned as insignificant. This prompted further investigation into the patient’s own fertility, which is currently ongoing.

Discussion

CF is a genetic disorder that primarily affects the respiratory system, pancreas, and digestive system, leading to thick, sticky mucus buildup that causes significant respiratory and gastrointestinal complications. The disease is caused by mutations in the CFTR gene, which encodes a protein responsible for the transport of chloride ions across cell membranes. ⁴ Defects in this gene lead to dysfunctional or absent CFTR protein, resulting in impaired mucociliary clearance, chronic inflammation, and frequent respiratory infections. The most common mutation in the CFTR gene, which encodes the CFTR protein, is deltaF508, which results in a misfolding and is therefore degraded before reaching the cell surface. ⁴

However, CFTR mutations can include over 2000 different mutations, contributing to variability in disease onset, severity, and clinical manifestations.^4,5 Research has shown that mutations in Class III and IV, such as G551D and R117H respectively, are associated with a milder phenotype allowing patients to live well into adulthood before being diagnosed. ⁵ These cases are often misdiagnosed or dismissed as less severe conditions until genetic testing or sweat chloride testing confirms the CF diagnosis. The sweat chloride test is one of the cornerstones of CF diagnosis. ⁴ This test measures the concentration of chloride in sweat, with values greater than 60 mmol/L being indicative of CF, and confirmatory when identified with at least 1 CF related mutation. ⁴ Intermediate values (40-59 mmol/L), and even sometimes negative sweat chloride value (<40 mmol/L), can be seen in those with CF. ¹ This prompts the need for further investigation with genetic testing in those with sweat chloride values >40 mmol/L when clinically indicated. In addition to sweat chloride testing, fecal elastase testing provides valuable insight into the pancreatic function of CF patients. Low levels of fecal elastase (<100 µg/g) suggest exocrine pancreatic insufficiency, a hallmark of CF. ⁶

Genetic testing plays a crucial role in confirming a CF diagnosis, especially in cases with atypical presentations. CFTR gene sequencing allows for the identification of specific mutations that can explain the patient’s symptoms. The patient had the following mutations: c.346G>A, and c.1820_1903del. The c.1820_1903del, also known as the 1949del84 mutation, characterized by a deletion of 84 base pairs in exon 13 of the CFTR gene. Upon review of the Cystic Fibrosis Mutation Database, it has been reported in 5 patients, and of those able to participate in PFTs, were noted to have mild disease. This mutation was also found in combination with other more severe mutations, such as deltaF508, allowing for the possibility of being a carrier or presenting with a less severe CF phenotype. ⁵ The c.346G>A mutation, also known as E116K, is a missense mutation that alters the protein structure by substituting glutamic acid for lysine at position 116, as per the Cystic Fibrosis Mutation Database. Interestingly, the 1949del84 mutation, that is often found with the deltaF508 mutation, was seen to have similar clinical severity as deltaF508 homozygotes. ⁷ In a study assessing the genotype and phenotypic presentation of the deltaF508 allele and other CF associated mutations, it was found that 99% patients that were homozygous for the deltaF508 mutation were found to have pancreatic insufficiency compared to their heterozygote cohort. ⁸ Also, those only carrying 1 copy of the deltaF508 mutation or none at all were found to have what was defined as milder disease, presenting with CF associated symptoms at an older age, lower diagnostic sweat chloride values, and better pulmonary function testing when adjusted for both age and nutritional status. ⁸

Imaging also plays a key role in the consideration of CF. High-resolution computed tomography (HRCT) and chest X-rays are the primary imaging modalities used for identifying CF. HRCT is the most sensitive imaging modality significant for bronchiectasis, air trapping, and mucus plugging, which is often most pronounced in the upper lobes, and characteristic of CF associated lung damage. ⁹ For CF patients with gastrointestinal involvement, abdominal imaging, such as CT, may reveal fatty infiltration of the pancreas, a common sign of exocrine pancreatic insufficiency. ¹⁰

CF is most commonly diagnosed in early childhood, 1 in 3000 live births in the United States, and typically identified at <1 month old. ¹¹ Genetic screening and newborn screening programs have significantly improved early detection, but delayed diagnosis still occurs in approximately 12% to 18% of CF cases. ³ Late diagnosis is becoming increasingly recognized as more adults present with symptoms that are milder or nonspecific, which may often be misattributed to other conditions. Studies of the Canadian CF Registry have found those who received diagnosis as adults had the following distinctions: milder disease than the typical CF population as characterized by the following: a median FEV1 of 81%, lower prevalence of pancreatic insufficiency (15%), less CF-related diabetes (3%), and a lower culture positivity with Pseudomonas aeruginosa (30.4%). ¹² It is also important to note that the abovementioned study also found that US CF Foundation Patient Registry had 7% to 9% of new CF diagnoses in 1995 to 2005, presenting with more respiratory associated symptoms. ¹² Additionally, many adults are diagnosed during evaluations for unexplained infertility, particularly in men, as CF-related male infertility is common due to the absence of the vas deferens, which is a result of CFTR dysfunction. ³

Lung infections are a leading cause of death in CF. A major component of pulmonary therapy for CF is the use of inhaled antibiotics, which aim to control chronic infections, such as P. aeruginosa. The use of inhaled antibiotics is standard of care in CF patients as chronic suppressive therapy. ¹³ CF patients are known to be both colonizers, and chronically infected with P. aeruginosa, which is a major factor in pulmonary disease in CF. ¹³ The goal is for eradication of P. aeruginosa in CF patients; the EPIC study (Early Pseudomonas Infection Control) demonstrated that patients who do not clear the infection after initial identification in cultures had a more significant clinical decline compared to those who did. ¹⁴ Inhaled antibiotics such as Tobramycin and Aztreonam are an important part of CF management and have been shown to reduce pulmonary exacerbations, improve lung function, and enhance quality of life in individuals with CF. ¹³ Tobramycin is an aminoglycoside antibiotic commonly used in the treatment of chronic P. aeruginosa infections in CF patients. ¹⁰ Tobramycin, administered via nebulization, has shown to significantly reduce pulmonary exacerbations, improves lung function, and improve quality of life.^13,14 Aztreonam, a monobactam antibiotic, works by inhibiting bacterial cell wall synthesis, leading to bacterial lysis and death, and is effective against P. aeruginosa. ¹³ Clinical trials have reported that patients using inhaled Aztreonam experience improved FEV1 values, fewer exacerbations, and reduced need for intravenous antibiotics.^13,14 In a comparative efficacy trial, it was found that inhaled Aztreonam was superior to inhaled Tobramycin as seen by a reduction in acute pulmonary exacerbations, and improvement in lung function. ¹⁷ Pulmonary function was seen to improve by improved baseline mean relative FEV1 after 28 days of treatment with Aztreonam with a change of 8.35% and Tobramycin as 0.55%. ¹⁷ Further, CFTR modulators such as Ivacaftor and Lumacaftor, which are designed to correct specific CFTR mutations, offer a targeted therapy that significantly improves the quality of life and lung function in patients. ¹⁵ Preliminary studies by the CF Patient Registry has found that these CFTR modulators can change the course of CF entirely. ¹⁵ These advancements underscore the importance of early diagnosis, as initiating therapy with CFTR modulators at a younger age may delay the onset of severe complications and improve long-term outcomes. Along with inhaled antibiotics, and the new age CFTR modulators, corticosteroids are often used to treat the inflammations that occurs in CF. ¹⁸ A study assessing lung function and the use of prednisone found that corticosteroids as a prednisolone-equivalent dose of 1.0 to 2.0 mg/kg every other day slows progression of lung disease. ¹⁸

A delayed CF diagnosis results in inappropriate disease management, which can significantly impact patient outcomes. Early diagnosis allows for the initiation of airway clearance therapies, inhaled antibiotics, and pancreatic enzyme replacement therapy, all of which are crucial to managing CF’s complications. Delayed diagnosis can result in irreversible lung damage, more frequent hospitalizations, and worse clinical outcomes. Although studies have shown that decline in FEV1 is similar in those that have been diagnosed as an adult compared to those diagnosed in childhood, it’s also important then to make the distinction that the frequency of death from respiratory failure was also equal. ¹⁶ Therefore, it’s imperative to consider CF as a potential diagnosis in such cases, despite its rarity in presentation in this age group.

Conclusion

This case report discusses the presentation and diagnosis of CF in a 37-year-old male patient, highlighting the challenges of recognizing the disease in adulthood. The patient presented with a nonproductive cough, weight loss, and respiratory infections, initially misattributed to other causes. Upon further investigation, including imaging, PFTs, and genetic testing, the diagnosis of CF was confirmed. The patient was found to have 2 CFTR gene mutations and was started on appropriate treatments, including inhaled antibiotics, and pancreatic enzyme replacement. The report emphasizes the importance of considering CF in the differential diagnosis of adult patients with unexplained respiratory or gastrointestinal symptoms and the need for early diagnosis to optimize disease management and improve outcomes.