Cystic Fibrosis (CF) is an autosomal recessive monogenic disorder with an incidence in the USA of approximately 1/4000 births. The incidence varies greatly between ethnic groups and is most prevalent in individuals of European descent.1 In the past, those diagnosed with CF rarely lived beyond childhood. However, advances in disease surveillance and treatments have significantly increased these individuals’ life expectancy, and those born with CF in the present day are predicted to live into their 4th or 5th decade.2 These patients may present to your clinic to be evaluated for corneal refractive surgery.
CF is caused by pathogenic mutations in both alleles of the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7, which produces the CFTR protein located on apical epithelial cell membranes of various organ systems, including the lungs, GI tract, kidneys, pancreas, male and female reproductive systems, and skin.3 It is also expressed in conjunctival epithelium, corneal epithelium, and corneal endothelium.4 The CFTR gene variants can be categorized into several classes depending on the mutation’s effect on the CFTR protein.5 The most common mutation, a class II homozygous deletion of phenylalanine 508 (F508del), impairs CFTR protein folding, processing, and function. More than 2000 mutations within the CFTR gene have been identified.6 Interestingly, some of these CFTR mutations are not associated with disease and do not appear to impact CFTR protein function.7 In all classes of CF-causing CFTR mutations, CFTR proteins cannot adequately pump chloride ions out of epithelial cells into the extracellular space. This disrupts ionic and osmolar gradients and causes hyperviscous mucus formation and decreased surface membrane hydration. This general mechanism underlies the multisystem effects observed in patients with CF.3
Although certain CFTR gene variants may correlate with specific pathologic manifestations, they do not necessarily correlate with clinical severity.5,8 Clinical severity may vary due to the combination of specific gene variants, the presence of modifier genes, environmental influences, and other factors.9 Thus, patients with CF can have a large variance in clinical presentation, disease severity, and progression. They can also be diagnosed between birth and late adulthood. Patients who do not meet the diagnostic criteria for CF but present with milder clinical symptoms may instead be diagnosed with CFTR-related disorder (CFTR-RD).10 These patients may have single organ system involvement, intermediate sweat chloride test measurements, and two or fewer CFTR mutations, one of which is not categorized as a CF-causing mutation.7,11,12 The age of symptom onset and diagnosis of CFTR-RD are generally later than patients with a classic form of CF.13 It is important to note that half of the individuals with CF aged 18 years or older have only mildly reduced lung function, with a quarter having moderately to severely reduced function.14
This article discusses common ocular manifestations of CF/CFTR-RD and proposes a structured approach for assessing and treating such patients seeking refractive surgery (Figure 1), as well as a novel surgical risk scoring system (Table 1). We also report two patients with CF and CFTR-RD, respectively, who presented for refractive surgery and the outcomes of the procedures. This article aims to assist eye care specialists in the care of this population. While this article focuses on patients with CF, the pathophysiology behind CFTR-related disorders is driven by CFTR dysfunction. Therefore, similar assessment and treatment strategies may be applied to these patient populations as well.
Table 1 Risk Stratification and CF Assessment Scoring Table for Corneal Refractive Surgery
Figure 1 Sample structured approach to assessing and treating patients with CF/CFTR-RD before refractive surgery.
Abbreviations: CF, cystic fibrosis. CFTR-RD, cystic fibrosis transmembrane conductance regulator-related disorder.
Note: Data from Shwachman H, Kulczycki LL43.
A 39-year-old Caucasian female with a history of CF presented for a LASIK consultation. She was a very healthy marathon runner who was well-versed in her condition and its management. She had a history of dry eye disease (DED) and minor CF-related pulmonary issues, specifically exercise-induced bronchospasms. She was taking Kalydeco® (Vertex Pharmaceuticals Incorporated, Boston, MA, USA) 150 mg tablets PO BID and using inhaled and nebulized medications. Review of systems (ROS) was unremarkable for skin abnormalities, pancreatic insufficiency, vitamin A deficiency, hepatic issues, GI issues, and COPD. Manifest refraction was −6.25 D OD and −5.75 D OS with a mean corneal thickness of 540 μm OD and 535 μm OS. Upon examination, it was discovered that this patient had conjunctival staining and superficial punctate keratopathy. Her Schirmer’s test was above 10 mm in 5 minutes and her tear break-up time (TBUT) was greater than 7 seconds. Refractive surgery was deferred. Treatment of DED consisted of punctal plugs and Refresh Plus Preservative Free (PF) Lubricant Eye Drops (AbbVie Inc., North Chicago, IL, USA). She showed significant clinical improvement after 6 months. Corneal staining was completely resolved but there was some conjunctival staining. She was started on Restasis® (AbbVie Inc., North Chicago, IL, USA) BID. She presented twice to the clinic with filamentary keratitis (FK) between 7–18 months after the initial visit, during which several corneal filaments were debrided using Jeweler’s forceps. She was cleared for refractive surgery 12 months after starting Restasis®. Due to concern for a high risk of postoperative ocular surface dryness, PRK was selected as the refractive surgery of preference for this patient.
Alcohol-assisted PRK monovision surgery was performed using an EX500 Wavelight Excimer Laser (Alcon Laboratories, Inc., Fort Worth, TX) using a 6.5 mm ablation zone with a transitional zone of 9.0 mm. The right eye was corrected for distance vision, and the left eye was under-corrected by 0.5 D. Mitomycin C was not used to avoid any risk of prolonged postoperative epithelial healing. An ACUVUE OASYS® bandage contact lens (Johnson & Johnson Vision Care, Inc., Jacksonville, FL) with a base curvature of 8.4 was applied postoperatively and removed after 5 days without any epithelial complications. The patient continued aggressive artificial tear treatment, topical moxifloxacin 0.5% QID OU for 8 days, and prednisolone acetate 1% OU QID for 4 weeks. Restasis® was restarted 8 days postoperatively after moxifloxacin was discontinued. Following 4 weeks of prednisolone acetate therapy, fluorometholone 0.1% was prescribed OU with a tapering regimen of TID for 3 weeks, BID for 3 weeks, and QD for 3 weeks.
During the first 6 months postoperatively, she presented twice to the clinic with FK. Several filaments were debrided from each eye using Jeweler’s forceps. The patient was placed on 10% topical N-acetylcysteine made by a compounding pharmacy to be used QID for 2 months, BID for 2 months, and was discontinued after. Treatment resulted in the complete eradication of FK. The patient’s postoperative refractive error was −0.25 D −0.5 D ×170° OD with UDVA of 20/25, and −0.75 D −0.75 D ×10° OS with UDVA of 20/50, correctable to 20/20 binocular vision. Conjunctival staining revealed minimal ocular surface irregularities. Her postoperative care otherwise was completely uneventful, and she continued using PF artificial tears and Restasis®. At 1 year of postoperative care, the patient did not require additional medications. However, she continues to use her existing medications to manage her residual dry eye symptoms.
A 25-year-old Caucasian male contact lens wearer, with a CFTR-RD diagnosis per patient since childhood, presented seeking refractive surgery. He did not complain of any ocular or systemic issues of CFTR-RD. The patient stated he was not taking CF medications and had no family history of CF. Preoperatively, his manifest refraction was −2.75 D OU and his corneal thickness was approximately 585 μm OU. Corneal and conjunctival staining revealed no remarkable findings. His Schirmer’s test was above 10 mm in 5 minutes and his TBUT was greater than 7 seconds. LASIK was performed using an iFS® Advanced Femtosecond IntraLase™ Laser (Johnson & Johnson Surgical Vision Inc., Santa Ana, CA) to create an 8.7 mm diameter flap with a flap thickness of 110 μm. A VISX STAR S3™ (Johnson & Johnson Surgical Vision Inc., Santa Ana, CA) was used to create a 6.0 mm ablation zone with a transitional zone of 8.0 mm.
Postoperatively the patient responded well but developed more dry eye symptoms relative to other LASIK patients, prompting the insertion of punctal plugs superiorly and inferiorly for approximately 6–7 months. Afterward, Refresh Plus PF Lubricant Eye Drops were prescribed for residual dryness. He had no corneal or conjunctival staining. One year postoperatively, the patient presented with 20/20 corrected vision and a refractive error of +0.5 D OD and +0.25 D OS.
We acknowledge that while patients #1 and #2 had successful surgical outcomes and appropriate treatment, it is important to note that both had mild clinical manifestations of CF and CFTR-RD, respectively. The surgeon’s approach at that time was untested due to a lack of guidelines and general knowledge concerning CF/CFTR-RD and their potential multisystem pathophysiology, particularly their effects on the cornea and eye. To our best knowledge, there is no literature discussing refractive surgery considerations in patients with CF/CFTR-RD. We propose a structured approach to assessing and treating this patient population in preparation for refractive surgery (Figure 1). This approach can be applied to mild to severe CF cases, as well as CFTR-RD, and may assist clinicians who encounter this patient population. We also propose a simple novel surgical risk scoring system that may be used in-office with these patients (Table 1).
Ophthalmologists considering refractive surgery for these patients should be familiar with the non-ocular systemic manifestations of CF. These may include pulmonary pathologies such as chronic obstructive pulmonary disease (COPD), bronchiectasis, or recurrent pulmonary infections. Other manifestations include hepatic disease, pancreatic insufficiency, CF-related diabetes, malnutrition, and vitamin A malabsorption and deficiency.3,8,15 In contrast, patients with CFTR-RD generally have single organ system involvement and milder symptoms than those with CF. Typical manifestations include mild pulmonary issues, congenital bilateral absence of the vas deferens, disseminated bronchiectasis, nasal polyps, chronic sinusitis, and acute recurrent or chronic pancreatitis.7,13 Patient #1 and patient #2 both exemplify how these systemic manifestations may be minimal or absent in well-controlled or less severe CF/CFTR-RD cases. Screening for these manifestations during a medical history and coordinating care with these patients’ primary care physicians, pulmonologists, medical geneticists, or other medical professionals will help determine their refractive surgery eligibility. ROS questions for screening CF/CFTR-RD patients are listed in Table 2. Lastly, genetic testing, if not already performed, may also help guide systemic treatment based on specific CFTR variants.16 Although research has shown that certain CFTR gene variants correlate with more severe gastrointestinal manifestations rather than pulmonary ones, further research is indicated to determine which genotypes may correlate with more severe ocular pathology.9
Table 2 ROS Questions to Consider When Taking a CF/CFTR-RD Patient’s History
Hypoxemia and malnutrition, potential systemic manifestations of CF/CFTR-RD, underlie some ocular pathologies. Patients with more severe CF/CFTR-RD phenotypes may experience corneal hypoxia during sleep. Corneal hypoxia can lead to stromal acidosis and stromal thinning.17 A study by Bradley et al found that patients with moderately severe CF can experience hypercapnia and hypoxemia during sleep and exercise.18 Another study showed that obstructive sleep apnea (OSA), a condition for which patients with CF may be predisposed, is significantly correlated with peripapillary retinal nerve fiber layer thinning, increased risk of acute retinal vein occlusion, decreased endothelial cell density, and decreased central corneal thickness due to hypoxia.19–21 Corneal damage may be prevented by ensuring that patients with moderate to severe CF/CFTR-RD are screened for OSA and receive adequate treatment. As CF patients are predisposed to developing OSA, screening them for floppy eyelid syndrome (FES) and keratoconus (KCN) may be indicated as these conditions have been significantly correlated with OSA.21,22 Proposed mechanisms for FES and KCN suggest that inflammatory mediators, such as matrix metalloproteinases (MMPs), may play a role in their pathogenesis, which can be elevated in CF patients.22,23 Regarding malnutrition, vitamin A deficiency can cause xerophthalmia, conjunctival xerosis, and night blindness.15,24 These can be screened for while performing a medical history and physical exam. In-office tests that can screen for possible vitamin A deficiency include dark adaptation and contrast sensitivity. Patients with vitamin A deficiency secondary to CF may have abnormal dark adaptation and reduced contrast sensitivity.25,26 A vitamin A blood test can also be utilized.
CFTR dysfunction can also cause ocular pathologies. CFTR expression and activity have been observed in lacrimal and meibomian glands, and other secretory epithelial cells in the eye.15,20,27,28 The hyperviscous mucus secretions associated with dysfunctional CFTR proteins may obstruct these glands and cells, leading to lacrimal acinar cell degeneration, meibomian gland dysfunction (MGD), and decreased glandular secretions. Reducing lipid, aqueous, and mucosal glandular secretions destabilizes the tear-film, decreases ocular surface nutrient delivery, and decreases ocular surface lubrication, respectively.15 These obstructions may also trigger a pro-inflammatory response, leading to decreased corneal epithelial cell integrity, conjunctival goblet cell loss, and blepharitis.15,20,28
These alterations can cause ocular surface disorders (OSDs), such as concurrent aqueous-deficient DED and evaporative DED, also known as mixed etiology DED, and superficial punctate keratitis, which was found in patient #1.15,20,29 Additionally, patient #1 was noted to have FK before and after PRK surgery. It has been proposed that an increased tear film mucus-to-aqueous ratio precedes FK. This altered ratio can cause a relative increase in tear film mucus viscosity and impaired mucus clearance, thereby damaging epithelial cells and precipitating filament growth in the cornea.30 FK onset is most commonly associated with aqueous-deficient DED, suggesting that patients with CF/CFTR-RD are at a higher risk of developing FK.31 The corneal surface damage sustained during refractive surgery may exacerbate pre-existing OSDs in these patients, which could be a contraindication for surgery.32–34 A meta-analysis on dry eye occurrence after refractive surgery determined that LASIK had significant reductions in both TBUT and tear production while PRK did not. There has also been an increased rate of dry eye in LASIK compared to other refractive surgery methods, including PRK.35 While this meta-analysis indicates that PRK may be preferred over LASIK in CF and CFTR-RD patients due to the decreased risk of post-operative dry eye complications, the procedure of choice is at the discretion of the surgeon on a case-by-case basis.
A structured approach to assessing and managing this patient population in preparation for refractive surgery is presented in Figure 1. Patients with CF/CFTR-RD who are seeking refractive surgery should be screened with a Standard Patient Evaluation of Eye Dryness (SPEED) II or Ocular Surface Disease Index (OSDI) questionnaire to assess for dry eye symptoms. Tear osmolarity tests, Schirmer’s tests, vital dye stains, TBUT measurements, and meibography can be instrumental in revealing ocular pathophysiology.20,36,37 In both patient cases, initial vital dye stains played a key role in the clinical decision-making progress, prompting further treatment for patient #1 and an indication for safe surgical intervention for patient #2. Postoperative dry eye screening in patient #2 also revealed dry eye symptoms which were successfully managed. Lastly, impression cytology can screen for abnormal changes in conjunctival goblet cell number and density.38,39
Markers of ocular surface inflammation should also be assessed, as some are elevated in patients with CF. InflammaDry® (Quidel Corp., San Diego, CA) kits can be used to screen for matrix metalloproteinase 9 (MMP-9) which is elevated in ocular surface inflammation and MGD.23,37 Several studies have also shown that patients with CF have elevated levels of inflammatory mediators interleukin-8 (IL-8), interferon-γ (IFN-γ), macrophage inflammatory protein-1α (MIP-1α), and MIP-1β in their tear films. These may be measured using ELISA assays to further assess the severity of each patient’s ocular surface inflammation.40–42 While ELISA assays are not readily available for clinical use, they may play instrumental roles in diagnosing OSD in the future. Table 3 summarizes relevant screening tools for evaluating patients with CF/CFTR-RD and the possible positive findings.
Table 3 Overview of Ophthalmologic Screening Tools for CF/CFTR-RD Patients
A new potential tool for screening patients with CF/CFTR-RD for refractive surgery is a novel surgical risk scoring system (Table 1). This simple, novel scoring system was adapted from the Shwachman-Kulczycki (SK) score, which was created in 1958 to assess the clinical severity of CF in children.43 Although the SK score was created over 60 years ago, it has remained a useful and simple tool for monitoring the clinical severity of CF in children and adolescents.44 Our modified scoring system is comprised of three categories: general activity, physical examination, and nutrition. The score from each section is summed to obtain a final score, after which the surgical risk of the patient is determined to be low (3), moderate (4–6), or high (7–9). Our scoring system may assist in refractive surgery risk stratification because inflammatory mediators in tears, such as IL-8, IFN-γ, and MIP-1α, have been shown to be elevated with increasing clinical severity and dry eye findings in patients with CF who were assessed using a similar scoring system.41,45 Our scoring system has not yet been validated and may serve as a starting point for others to refine in the future.
Following screening, various treatment strategies may be employed to prepare them for surgery and ensure a rapid and uneventful recovery. While nebulized N-acetylcysteine products, such as Mucomyst® (E.R. Squibb & Sons, LLC, New Brunswick, NJ), are indicated for controlling pulmonary mucus obstructions, topical N-acetylcysteine medications, which were utilized in patient #1, can also be used to manage inflammatory CF/CFTR-RD ocular manifestations by inhibiting MMP-9 and nuclear factor kappa B (NF-κB).23,46,47 Doxycycline also inhibits MMP-9, providing a similar protective effect for the cornea, and may be used preoperatively to treat bacterial blepharitis.37,48,49 Mainstream treatments for various ocular surface disorders should be implemented as first-line treatment in these patients, including artificial tears, topical steroids, cyclosporin A 0.05% (Restasis®), lifitegrast 5% (Novartis Pharmaceuticals Corporation, Xiidra ®, East Hanover, NJ)), punctal plugs, and warm compresses.37
Unlike patients #1 and #2, some may experience unexpectedly severe or recalcitrant perioperative OSDs. Additional treatment options are available in these circumstances, including autologous blood serum drops, platelet-rich plasma (PRP) eye drops, therapeutic contact lens bandages, self-retaining amniotic membranes, amniotic membrane extract eye drops (AMEED), and topical mesenchymal stem cell therapies, such as the commercial product Regener-Eyes® (Regenerative Processing Plant, LLC, Palm Harbor, FL).50–56 AMEED and Regener-Eyes® are not currently FDA approved but have promising therapeutic potential as they leverage their anti-inflammatory, anti-angiogenic, and non-immunogenic properties to promote limbal stem cell proliferation, facilitate corneal epithelial healing, and treat DED.54–56
Further research may identify safer and more effective drugs for treating CF’s ocular manifestations by targeting the CFTR protein, as ivacaftor, for example, has been correlated with cataract development in children and adolescents.57 Multiple novel CFTR-targeting ocular treatments are also undergoing research and may be utilized to treat CF/CFTR-RD in the future. Small molecule CFTR activators treat DED by increasing ocular surface membrane hydration but require further research in patients with CF/CFTR-RD.58
To our knowledge, the two patient cases detailing refractive surgery considerations and outcomes in individuals with CF and CFTR-RD are the first to be reported. Successful completion of PRK and LASIK in these patients offers encouragement that refractive surgery can be completed in other patients with CF/CFTR-RD. However, the lack of knowledge and precedent regarding this topic makes it difficult for ophthalmologists to validate whether patients with CF/CFTR-RD are eligible for these procedures. Therefore, this article proposes a novel structured approach for assessing and treating patients with CF/CFTR-RD in preparation for refractive surgery, based on the most current literature (Figure 1). Further research will hopefully lead to the creation of systematic guidelines to provide the best possible outcomes for these patients. Finally, given the relatively unknown association between CF/CFTR-RD and refractive surgery outcomes, we suggest that ophthalmologists and patients with CF/CFTR-RD discuss the risks and unknown complications of these procedures in detail before proceeding with surgery. We also encourage surgeons who perform refractive surgery on these patients to consider publishing reports on their outcomes to help establish precedent on this topic.
Data Sharing Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Compliance with Ethics Guidelines
The case series was approved by the Hoopes Vision Ethics Board and patients’ consent to publish was acquired.
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
This article is supported by Research to Prevent Blindness, New York, USA.
All authors declare that they have no conflict of interest in this work.
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