Oral guaifenesin for treatment of filamentary keratitis: A pilot study

Oral guaifenesin for treatment of filamentary keratitis: A pilot study

The Ocular Surface 17 (2019) 565–570 Contents lists available at ScienceDirect The Ocular Surface journal homepage: www.elsevier.com/locate/jtos Or...

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The Ocular Surface 17 (2019) 565–570

Contents lists available at ScienceDirect

The Ocular Surface journal homepage: www.elsevier.com/locate/jtos

Original Research

Oral guaifenesin for treatment of filamentary keratitis: A pilot study a,b,1

a,c,1

d,e

a

Giulia Coco , Francisco Amparo , Sangita P. Patel , William Foulsham , Jimena Tatiana Carreno-Galeanoa, Steven G. Stockslagerf, Joseph B. Ciolinoa, Jia Yina, Reza Danaa,∗

T

a

Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA Department of Clinical Science and Translational Medicine, University of Rome Tor Vergata, Rome, Italy c Department of Clinical Sciences, Division of Health Sciences, University of Monterrey, Monterrey, Mexico d Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA e Research and Ophthalmology Services, VA Western NY Healthcare System, Buffalo, NY, USA f The Permanente Medical Group, Department of Ophthalmology, Elk Grove, CA, USA b

ARTICLE INFO

ABSTRACT

Keywords: Filamentary keratitis Refractory filamentary keratitis Filamentary keratitis treatment Corneal filaments Oral guaifenesin Guaifenesin

Purpose: Pilot study to evaluate the safety and efficacy of oral guaifenesin in reducing the signs and symptoms of filamentary keratitis. Methods: Prospective, uncontrolled open-label pilot study. Twelve patients with non-Sjögren dry eye disease (DED) and secondary filamentary keratitis received treatment with oral guaifenesin 600 mg twice a day (total dose of 1.2 g/day) for 4 weeks. Adverse events, change in the number of corneal filaments, corneal fluorescein staining (CFS; NEI grading system), and symptoms (Ocular Surface Disease Index) were assessed. Results: Before starting oral guaifenesin, all patients were on topical medical therapy for their condition. At baseline, the mean number of filaments was 5.8 ± 2.9, CFS score 7.3 ± 3.2, and OSDI score 55.6 ± 25. After 4 weeks of treatment, the number of filaments was 2.1 ± 2.2 (p = 0.04 vs. baseline), CFS score 6.5 ± 3.1 (p = 0.5), and OSDI score 46.1 ± 30.9 (p = 0.2). One patient discontinued the medication due to gastrointestinal side effects. Conclusions: Oral guaifenesin was safe and generally well tolerated, and demonstrated modest efficacy in reducing the severity of filamentary keratitis. These results should be considered preliminary; however, placebocontrolled investigations would be justified to evaluate the therapeutic efficacy of oral guaifenesin as a mucolytic in treatment of filamentary keratitis.

Introduction Filamentary keratitis is a chronic and recurrent eye condition characterized by thread-like mucous filaments that adhere to the corneal surface. Common symptoms include foreign body sensation, grittiness, pain, intense photophobia, tearing, mucoid discharge, increased blink rate and in severe cases blepharospasm [1,2]. The etiology of the disease is not completely understood; yet evidence suggests that corneal surface disorders, tear film abnormalities and anatomical factors may contribute to pathogenesis [2–4]. Notably, aqueous insufficient dry eye disease (DED) is the most commonly associated condition [5,6]. Various ocular surface conditions that may accompany the disease include graftvs-host disease (GVHD), superior limbic keratoconjunctivitis, viral

keratoconjunctivitis, exposure keratopathy, prolonged eye patching after ocular surgery, cataract surgery, penetrating keratoplasty, ptosis, or neurotrophic keratitis, among others [3,7–9]. The management of filamentary keratitis aims to treat both the underlying ocular surface pathology (e.g. dry eye disease), in addition to reducing the mucous filaments on the cornea, which independently of the underlying condition can cause morbidity. Commonly used regimens involve strategies to alleviate symptoms and protect the ocular surface (lubrication, punctal plugs and bandage contact lenses [BCL]), strategies to reduce inflammation (mild local corticosteroids and/or cyclosporine) and strategies to break down the mucous filaments (topical N-acetylcysteine) in addition to physical removal of large filaments [7]. Notably, treatment success is variable and patient-

Corresponding author. 20 Staniford Street, Boston, MA, 02114, USA. E-mail address: [email protected] (R. Dana). 1 These authors equally contributed to this work. ∗

https://doi.org/10.1016/j.jtos.2019.03.008 Received 29 January 2019; Received in revised form 18 March 2019; Accepted 26 March 2019 1542-0124/ © 2019 Elsevier Inc. All rights reserved.

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dependent, with some cases being refractory to standard therapy. As a result, there is substantial interest in finding new treatment options. Oral guaifenesin is a well-tolerated over-the-counter medication that is commonly used as an expectorant for cough management [10]. A variety of mucins, including MUC5AC and MUC16, are present at high levels in the respiratory tract mucus and have an increased expression in pulmonary disease [11,12]. MUC5AC and MUC16 are also highly expressed at the ocular surface and within filaments [3]. Given the overlap in the expression of MUC5AC and MUC16 in respiratory secretions and corneal filaments, we hypothesized that oral guaifenesin therapy would reduce symptoms and filament formation in patients suffering from filamentary keratitis by altering the composition and consistency of mucous.

Table 1 Demographic, diagnostic and therapy details at baseline. Clinical Parameters at Baseline Age (yrs), mean ± SD Gender Male Female Underlyng Diagnosis Non-Sjogren Dry Eye Disease Graft-versus-Host Disease Therapy at baseline Artificial tears Topical corticosteroids Cyclosporine Autologous Serum N-acetylcysteine Antibiotic ointment PROSE lens Oral doxycycline Punctal cautery Punctal plugs

Methods In this prospective, non-randomized, open-label pilot study, a total of 12 patients with a diagnosis of current filamentary keratitis were studied. Eligibility criteria were an age of 18 years or older and the presence of corneal filaments in at least one eye. Patients were excluded from the study if they had Schirmer I test with anesthesia of less than 3 mm in either eye, had an active ocular surface infection of any type, had undergone ocular surgery within 30 days prior to enrollment, or had any other concurrent eye disease requiring immediate initiation of a new treatment. Patients were also excluded if they had a history of hypersensitivity to oral guaifenesin, of if they had a history of nephrolithiasis or any restrictions to their water intake, since guaifenesin has been reported to be associated with the development of kidney stones [13,14]. Patients were instructed to take each dose of oral guaifenesin with a large glass of water (50 cL). The institutional Human Studies Committee approved the study protocol, which adhered to both the tenets of the Declaration of Helsinki and the Health Insurance Portability and Accountability Act. All patients provided written informed consent before participating in the study. Study participants received treatment with oral guaifenesin 600 mg twice a day (total dose of 1.2 g/day) for 4 weeks. We evaluated the following parameters at the baseline visit and at the 4 week follow-up visit: (i) best-corrected visual acuity (BCVA), (ii) average number of filaments of both corneas, (iii) corneal fluorescein staining score (using the National Eye Institute/Industry (NEI) scoring system [15]), and (iv) ocular surface symptoms using the Ocular Surface Disease Index (OSDI) [16]). The primary outcome of the study was the mean reduction in the number of corneal filaments in both eyes after 4 weeks of treatment with oral guaifenesin. The secondary outcome was the mean change in OSDI score from baseline after 4 weeks of treatment with oral guaifenesin.

63.7 ± 8.9 7 (58) 5 (42) 12 (100) 11 (92) 11 (92) 7 (58) 4 (33) 6 (50) 3 (25) 3 (25) 1 (8) 4 (33) 8 (67) 3 (25)

Results This study included 12 patients (5 women and 7 men) with a mean age of 63.7 ± 8.9 years (range, 46–74 years). All patients had a diagnosis of active filamentary keratitis due to dry eye disease. At baseline, all patients were on topical medical therapy for their ocular condition with artificial tears (92%), corticosteroids (58%), cyclosporine (33%), autologous serum (50%), N-acetylcysteine (25%), antibiotic ointment (25%), PROSE (Prosthetic replacement of the ocular surface ecosystem) lens (8%) and oral doxycycline (33%); all patients, except for two, had punctal cautery or plug occlusion at the time of enrollment (83%). The demographics and baseline diagnostic and treatment details of the population are shown in Table 1. Of the 12 patients, one patient discontinued the medication referring mild vomiting and diarrhea and declined to attend the follow-up visit. A second patient did not comply with the treatment regimen and was excluded from the analysis. Among the 10 patients who completed the study, two patients reported symptoms of dry mouth while taking oral guaifenesin (20%). There were no severe adverse events reported during the study. The data from the ten patients who completed the study were analyzed as described in the methods section. The mean baseline measurements were: BCVA 0.24 ± 0.23 LogMAR, number of filaments 5.8 ± 2.9, CFS score 7.3 ± 3.2, Schirmer I test with anesthesia 5.9 ± 4.1, and OSDI score 55.6 ± 25. The measurements after receiving treatment with guaifenesin for an average of 4.4 ± 0.7 weeks, the BCVA maintained without change (0.24 ± 0.20; p = 0.84), there was a reduction in the mean number of corneal filaments of 3.7 filaments (2.1 ± 2.2; p = 0.04), a reduction in the mean OSDI score of 9.5 units (46.1 ± 30.9; p = 0.2) and a mean reduction in CFS of 0.8 units (6.5 ± 3.1; p = 0.5) In six of the ten studied patients, oral guaifenesin was the only new treatment prescribed at the beginning of the study while the other four patients concurrently received an increase in their topical corticosteroid regimen (e.g. loteprednol or fluorometholone from QD to BID or from BID to TID) due to the severity of their disease (see Fig. 1); a summary of patients’ treatments is shown in Table 2. In the patients in whom oral guaifenesin was the only addition to the treatment regimen, there was a mean reduction in the number of filaments of 1.3 (p = 0.5) and a reduction in the mean OSDI score of 4.7 (p = 0.9). In the patients who received a concurrent increase in topical corticosteroids, the mean reduction in the number of filaments was 7.4 (p = 0.07), and the reduction in the mean OSDI score was 16.7 (p = 0.3) (Figs. 2 and 3; Tables 3 and 4).

Statistical analysis We calculated the difference in the mean number of filaments and OSDI score between baseline and follow-up visits and evaluated their change over time. We used the paired-sample Wilcoxon signed-rank test if data did not follow a normal distribution and the paired Student t-test in the case of normally distributed data. For all the analyses we considered the average value of both eyes for all variables with the exception of symptom scores (OSDI), which were considered per patient. Data are presented as the mean ± standard deviation (SD), a range for continuous variables, and percentages for categorical variables. A twotail P value of less than 0.05 was considered statistically significant in all statistical tests. The statistical analysis was performed using STATA 13.0 (StataCorp, College Station, TX). 566

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Fig. 1. Enrollment scheme. Patients included in the study (n = 12). Two patients did not complete the study either due to a non-ocular adverse reaction to oral guaifenesin (n = 1, gastrointestinal side effects) or due to lack of compliance with the prescribed oral guaifenesin regimen (n = 1). Patients who completed the study (n = 10) were prescribed with either oral guaifenesin alone (n = 6) or oral guaifenesin plus an increase in the dose of topical corticosteroids (n = 4), depending on the severity of their disease.

Discussion

diseases [18]. Based on the similarities between the mucus composition of corneal filaments and mucus in the respiratory tract we hypothesized that drugs utilized to clear respiratory mucus could also potentially assist in elimination of corneal filaments by altering their consistency and composition. Oral guaifenesin is an over-the-counter medication frequently used as an expectorant for coughing and bronchitis [10], and it is well tolerated, affordable and accessible. Although its exact mechanism of action has not been fully established, in vitro studies on respiratory epithelial cells that were stimulated to release mucins have shown that guaifenesin decreases MUC5AC production in a dose-dependent manner [10]. Oral guaifenesin is known to hydrate respiratory mucous secretions, thereby facilitating their removal from the respiratory airways [19]. Studies have also established that guaifenesin increases mucociliary transport and alters mucous rheology [10]. Two other agents that are used to treat respiratory secretions, N-acetylcysteine and ambroxol, have been shown to be less effective in reducing MUC5AC secretion compared to guaifenesin [20]. Although topical N-acetylcysteine has been evaluated and used as a therapeutic option for filamentary keratitis [21–23], it is not commercially available and has to be compounded without preservatives from the sterile solution used to treat respiratory conditions and for this reason, it is not always readily available. In addition, many reports show that it can cause adverse effects, including burning sensation and irritation. Based on the

We studied the potential effect of treatment with oral guaifenesin after several reports from patients in our clinical practice that reported improvement of ocular symptoms after using oral guaifenesin for reasons unrelated to their ocular condition—e.g. treatment of mucus secretions of the common cold and bronchitis. The results of this pilot study suggest that oral guaifenesin may contribute to modest reduction of corneal filaments and ocular symptoms in patients with filamentary keratitis (Fig. 2A). Detachment and elevation of the corneal epithelial basement membrane during filamentary keratitis allows accumulation of mucus and epithelial cells in the subbasal space [4]. Histological analyses demonstrate that filaments are composed of a twisted epithelial core wrapped in mucus [3], and immunostaining analyses show that mucin glycoproteins, in particular, MUC5AC and MUC16, are highly expressed in filaments [3]. MUC5AC, a goblet cell-derived mucin expressed on the conjunctival epithelium, is present in the acellular region of filaments [3]. In contrast MUC16, a membrane mucin expressed on both conjunctival and corneal epithelium, is present in almost all parts of the filaments [3]. These two mucins are commonly found in the respiratory tract [11,12], and expression of MUC5AC is increased in diseases of the airways such as chronic bronchitis [17]. Thus, mucolytic agents, such as guaifenesin, are commonly used as adjuvant therapies in respiratory

Table 2 Data on baseline topical therapy, punctal occlusion, PROSE lens and systemic therapy per patient. Corticosteroid regimen and change is highlighted in the right-sided column when applicable. BLL: bilateral lower lid; BUL: bilateral upper lid; RLL: right lower lid; LLL: left lower lid. Subject

Topical Therapy

Punctal occlusion (plugs/cautery)

PROSE lens

Systemic therapy

BLL cautery BLL cautery

– Yes

Prednisolone 10 mg qd





BLL cautery BUL plugs not retained BUL cautery



Doxycycline 100 mg qd

Loteprednolol 0.5% bid



Artificial tears, Cyclosporine, Fluorometholone 0.1%, RLL cautery, LLL plug Autologous serum Patients who received oral guaifenesin + topical corticosteroid increase 7 Artificial tears, Lubricating ointment, BUL and BLL cautery Prednisolone 0.12%, Autologous serum 8 Artificial tears, Lubricating ointment, BUL and LLL cautery Fluorometholone 0.1% 9 Artificial tears, N-acetylcysteine, Cyclosporine, BLL cautery, re-opened Loteprednolol 0.5% 10 Artificial tears, Bacitracin ointment, Prednisolone – 0.12% Patients excluded from the analysis 11 Artificial tears, Lubricating gel RLL plug, LLL plug not retained 12 Autologous serum BUL plugs, BLL plugs not retained



Methotrexate 2.5 mg (7 tablets/week) Doxycycline 100 mg bid

Fluorometholone 0.1% bid



Prednisolone 50 mg qd

Prednisolone 0.12% bid

tid

Fluorometholone 0.1% bid

tid

Patients who received only oral guaifenesin 1 Artificial tears, Erythromycin ointment 2 Artificial tears, N-acetylcysteine, Cyclosporine, Autologous serum 3 Artificial tears, Polysporin ointment, Loteprednolol 0.5%, Autologous serum 4 Artificial tears, N-acetylcysteine, Loteprednolol 0.5% 5 Artificial tears, Cyclosporine, Autologous serum 6

567

Corticosteroid regimen & change

Loteprednolol 0.5% bid

– –

Doxycycline 100 mg qd

Loteprednolol 0.5% bid

tid



Prednisolone 60 mg qd

Prednisolone 0.12% qd

bid



Doxycycline 100 mg bid



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Fig. 3. Graph showing symptoms score (ODSI) at baseline and 4 weeks after the addition of oral guaifenesin. (A) Cumulative OSDI score in all patients who received oral guaifenesin. (B) Separate analysis for patients who only added oral guaifenesin as a new treatment at baseline and patients who received oral guaifenesin and an increase in topical corticosteroids simultaneously.

Fig. 2. Graph showing the number of filaments at baseline and 4 weeks after the addition of oral guaifenesin. (A) Cumulative filament number in all patients who received oral guaifenesin. (B) Separate analysis for patients who only added oral guaifenesin as a new treatment at baseline and patients who received oral guaifenesin and an increase in topical corticosteroids simultaneously.

Our study had several limitations. Identification and recruitment of subjects with homogeneous clinical characteristics or who met the inclusion criteria was not simple, leading to a small sample size for our study. Another factor that complicated the study was the use of multiple therapies (‘polypharmacy’) by participants for the management of their chronic ocular surface disease, making it difficult to draw firmer conclusions. Treatment of refractory filamentary keratitis can be very challenging and a variety of unconventional treatments have been explored with variable results, including hyperosmotic solutions, diclofenac sodium eye drops, eyelid surgery to induce blepharoptosis, botulin toxin injections, or autologous serum tears [2,28,30,31]. Nevertheless, a shortage of effective, readily available or affordable therapies for filamentary keratitis persists. Oral guaifenesin can be a therapeutic option for patients with limited access to compounded topical mucolytic agents or for patients who are intolerant or irresponsive to them; it also can be an alternative for patients in whom topical corticosteroids entail risk or for those already on maximal conventional therapy. Similarly, oral guaifenesin can be considered a convenient and readily available alternative for patients in the initial stages of filamentary keratitis where it could outweigh the burden of limited access to special formulations of topical N-acetylcysteine. This small study suggests that treatment with oral guaifenesin for filamentary keratitis can be safe and generally well tolerated, with most patients experiencing an improvement of their ocular surface condition, especially when guaifenesin is used in conjunction with corticosteroids. Further investigations evaluating the therapeutic efficacy of guaifenesin in larger randomized trials are justified.

evidence of superior in vitro efficacy of guaifenesin over N-acetylcysteine and OTC availability of oral guaifenesin to patients, we evaluated its efficacy in reducing symptoms and number of filaments in filamentary keratitis. In this study, all patients placed on a course of oral guaifenesin demonstrated a reduction of symptoms and number of filaments. Interestingly, patients with severe ocular surface disease that only added oral guaifenesin to their treatment regimen showed symptomatic and clinical improvement; however, the most significant results were observed with the addition of oral guaifenesin and an increase of topical corticosteroids. We can only speculate as to why this association was observed. One possibility is that patients placed on an increased dose of topical corticosteroid tended to have more severe ocular surface disease at baseline (higher staining and OSDI), thereby permitting a greater magnitude in reduction of symptoms and number of filaments in response to therapy. Another explanation is that oral guaifenesin may be more effective when used in combination with corticosteroids. While corticosteroids themselves can suppress mucus production [24–26], evidence from the literature and our own clinical experience suggests that in many patients with severe ocular surface disease, such as ocular GVHD, topical corticosteroids alone do not induce sufficient relief of filamentary keratitis [2,27–30]. Although symptoms improvement was proportionally less pronounced than improvement in the number of filaments, symptoms reduction was more significant than the reduction of punctate epithelial keratitis. We hypothesize that the changes in OSDI scores were driven by a reduction in the number of filaments but the residual symptoms obey to the remaining underlying epithelial disease (CFS). 568

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Table 3 Outcome measures at Baseline and Week 4. Baseline

Week 4

Addition of oral guaifenesin (n = 10) Outcome Measures Filaments (number) Mean ± SD (% 5.8 ± 2.9 change) P value vs. baseline Ocular Surface Disease Index Mean ± SD (% 55.6 ± 25.0 change) P value vs. baseline Corneal Fluorescein Staining (NEI grading Mean ± SD (% 7.3 ± 3.2/15 change) P value vs. baseline -

Oral guaifenesin as only treatment (n = 6)

Oral guaifenesin + topical steroids* (n = 4)

Addition of oral guaifenesin (n = 10)

Oral guaifenasin as only treatment (n = 6)

Oral guaifenesin + topical steroids* (n = 4)

4.1 ± 1.2

8.4 ± 2.9

2.1 ± 2.2 (-64%)

2.8 ± 2.6 (−32%)

1 ± 1.2 (−88%)





0.04

0.5

0.07

42.0 ± 18.9

76.1 ± 18.9

46.1 ± 30.9 (-17%)

59.4 ± 37.5 (−22%)

– system) 6.3 ± 1.9/15



0.2

37.3 ± 25.2 (−11%) 0.9

8.8 ± 4.3/15 –

5.4 ± 3.0/15 (−14%) 0.16

8.0 ± 5.7/15 (−9%)



6.5 ± 3.1/15 (-11%) 0.5

0.3

0.7

Table 4 Data per patient on best-corrected visual acuity (BCVA), corneal fluorescein staining (CFS), number of filaments and symptoms score (OSDI) at baseline and follow-up visit. GVHD: graft-versus-host disease. Baseline Subject

Age

Sex

Diagnosis

Patients who received only oral guaifenesin 1 70 M GVHD 2 69 M GVHD 3 74 F GVHD 4 55 F DED 5 73 F GVHD 6 46 M GVHD Patients who received oral guaifenesin + topical 7 53 M GVHD 8 60 F GVHD 9 69 M GVHD 10 60 M GVHD Patients excluded from the analysis 11 65 M GVHD 12 70 F GVHD

BCVA

Follow-up CFS

Filaments

OSDI

BCVA

CFS

Filaments

OSDI

0.1 7.5 0.05 5 0.6 7 0.0 3 0.6 7 0.1 8 corticosteroid increase 0.2 15 0.4 7 0.3 8 0.0 5

2.5 4.5 4.5 3 4 6

31.3 12.5 56.8 60 35 56.3

0.3 0.05 0.5 0.1 0.5 0.0

5.5 3 6 1 8 9

4 0 2 6 5 0

31.8 22.9 77.5 12.5 20.8 58.3

7 5 10.5 11

54.1 72.7 100 77.5

0.2 0.4 0.3 0.0

6 8 12 6

0 2 2 0

22.9 93.8 89.6 31.3

0.4 0.1

2 2

50 16.7

0.4 3.5 2.5 75 Withdrawn due to gastrointestinal side effects (vomiting, diarrhea)

2 6

Conflicts of interest

Not compliant

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