Laura M Periman, MD completed her medical school, ophthalmology residency and Cornea/Refractive Surgery fellowship at the University of Washington in Seattle, WA. She is the Founder and Director of Dry Eye Services and Clinical Research and the Ocular Surface Disease Fellowship Director at the Periman Eye Institute in Seattle, WA where Sathi Maiti, OD and Natasha Balani OD, are current Fellows.
Every spring, there is one constant we see in our chairs: seasonal allergic conjunctivitis. The incidence of ocular allergy has been on the rise for the past two decades in both developed and developing nations, with some reports suggesting a prevalence of 20-40% of the population.1,2 Why the rise? Some experts suggest a phenomenon called “Season creep” that has caused a lengthening of pollen season due to climate change. Others cite poorer air quality (diesel exhaust, smoke), and coexisting food allergies. Potentially, it is multifactorial.
As a result of ocular allergies, patients may complain of red, itchy, irritated, teary, swollen, sore, dry eyes and/or light sensitivity. Interestingly, only 80% of ocular allergy patients report itching, so clinicians cannot rely on this symptom to aid in the diagnosis.3 On slit lamp examination, clinical findings commonly include swelling of the bulbar conjunctiva (i.e., chemosis), papillae, superficial conjunctival vasodilation (i.e., redness), increased tear meniscus height, and lid edema.4,5 More severe manifestations may include stringy mucus discharge, anterior blepharitis, meibomian gland disease (Figure 1), and corneal epitheliopathy.4,6,7
Commonly, our ocular allergy patients have concomitant dry eye, which adds a layer of complexity that we must be prepared to manage. This link is explored further in the feature article by Katherine Mastrota. Reduced lacrimal output means less tear volume to flush the allergens from the ocular surface, which decreases defences against allergens. The culmination of these factors often results in significant discomfort and can render the ocular surface unfit for contact lens wear. Estimates show that revenue loss from contact lens drop out can range from $160-600 per patient per year, with approximately 16% of contact lens wearers dropping out each year. This loss of revenue certainly adds up over time.8
In addition to its economic impact, ocular allergy affects our patients’ quality of life from an occupational and emotional standpoint. Buchholz et al. found in administering the Eye Allergy Patient Impact Questionnaire (EAPIQ) that 17% of patients were unable to perform necessary tasks on days when eye allergy symptoms were present.9 Al-Diari et al. classified symptomatology by frequency and found itching (79.9%), redness (38.8%) and watery eyes (29%) to be most common and cited these eye allergy symptoms correlated positively (r=0.480; p<0.001) with decreased emotional and psychological health.10
Understanding the systemic and ocular immunomodulatory pathways in an allergic response is paramount in achieving correct diagnosis, treatment and management. An allergic reaction is a response to an offending antigen. Antigens may include pollen, grass, dust, mites (including Demodex), dander, and other chemicals. Allergic reactions may also involve responses to chemicals such as perfumes, makeup, preservatives, and essential oils. The allergic cascade starts when an allergen (Ag) stimulates lymphocytes, or IgE antibodies (Ab) which are attached to mast cells. An adaptive immune response takes place when that same allergen later stimulates mast cells and they degranulate, resulting in the liberation of histamine (H), cytokines, leukotrienes, chemokines and other inflammatory mediators.5 In the eye, the battleground occurs right at the ocular surface in the tear film and within the conjunctival stroma and corneal epithelium. It has been found that there are 50-300 million mast cells in the eye, with the highest concentration found in the substantia propria of the conjunctiva. The impact from the sheer volume of IgE mediated response to antibodies can be profound.
Propagated cellular reactions and downstream events may include:
- Conversion of arachidonic acid to pro-inflammatory prostaglandins and leukotrienes (e.g. LTB4)
- Stimulation of itch and pain receptors, vasodilation of blood vessels and increase in endothelial cell permeability causing tissue edema of the dermis and epidermis
- Late phase infiltration of eosinophils and basophils 8-10 hours following antigen presentation and histamine release
- Recruitment of Polymorphonuclear leukocytes (PMNs)5 and T cells (Th1, Th2, Th17)
- Meibomian gland obstruction: Reyes et al. demonstrated Th17 cells play a central role in MG obstruction through recruitment of PMNs. PMNs are the immunologic bridge between AC and MGD7
- Clinical manifestations include seasonal (SAC) and perennial allergic conjunctivitis (PAC) (most common), acute allergic conjunctivitis (AAC), giant papillary conjunctivitis (GPC), and less commonly, vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC).
Practical Diagnostic Advice
Dr Periman has developed a simple method to help with differential diagnosis. In office, to differentiate between ocular allergy and dry eye, we perform a 3 minute Pataday test: instill one drop of an antihistamine in one eye and a preservative free artificial tear in the other eye. Relief of grittiness and a smoother more comfortable sensation in the antihistamine treated eye is a clue that an allergic component is present. This test is commonly performed in our DED evaluations. Now that we know the link between AC and MGD, even mild allergic conjunctivitis cases need to be treated topically. Formal skin allergy testing (i.e. Allerfocus™) can also serve as a valuable tool in counseling on allergen avoidance
Knowing that allergic conjunctivitis can drive MGD, treating even subtle SAC/PAC can be important in the DED/MGD patient. Helper T cells in the late-stage response of SAC release IFN-γ, which decreases goblet cell density and causes goblet cell apoptosis.5 Furthermore, PMN infiltration is implicated in meibomian gland dysfunction, so patients with allergic conjunctivitis should be treated for their primary disease and assessed for these secondary comorbidities.
Examination should include:
A thorough tear film and lid assessment: MG secretion quality and expressibility using the Pult scale; vital dyes fluorescein and lissamine green, and meibography or retrograde illumination with penlight or transilluminator. Early diagnosis and treatment of plugged terminal ductules, turbid meibum, and meibomian gland inspissation may prevent meibomian gland disease progression (scarring, atrophy, gland dropout).
Slow down on slit lamp examination: A gross papillary reaction and mucus discharge are obvious signs but mild edema, vasodilation, chemosis and increased tear output can be subtle. Look for a rapid FDDT (fluorescein dye disappearance time). Remember to flip the upper eyelids and look for papillary conjunctivitis as well as lid wiper epitheliopathy.
Look at the whole clinical picture: SAC is frequently accompanied by nasal symptoms (rhinitis). Listen to the patient’s voice for signs of sinus congestion. Listen for frequent throat clearing as a sign of post-nasal drip. Inquire about environmental allergies, contact lens hygiene and seasonal intolerance, skincare products, and makeup.
The recommended treatments will vary according to severity. In general, avoidance of offending agents is recommended, through techniques like keeping windows closed, using filters, dust mite covers for bedding, new pillows, and monitoring pollen count; however, these avoidance strategies are ineffective towards ubiquitous allergens. Simple at-home treatment options include cool compresses to elicit vasoconstriction and decrease histamine release and itch signaling from the nerves, and use of chilled, and where needed, preservative free, artificial tears (PFAT) to help reduce itch and dilute allergens and inflammatory mediators.11,14 If these treatments are not adequate, topical pharmacologic options like antihistamines, mast cell stabilizers, dual-activity antihistamine/mast cell stabilizer agents, steroids, and immunomodulators like cyclosporine and lifitegrast can be considered next. These include both over-the-counter (OTC) as well as prescription options. However, 90% of patients who have tried OTC medications stated that these products were only effective “some or none of the time,”2 so it may be preferable to focus on prescription options as our first line pharmacologic recommendations.
Over the Counter Options
|Generic name||Brand names||Availability||Class||Action|
|ketotifen 0.025%, 0.035%||Alaway, Zaditor, Claritin Eye, Refresh Eye Itch Relief, Visine All Day Itch Relief||US and Canada||mast cell stabilizer/ antihistamine||H1 receptor antagonist, inhibits inflammatory mediator release|
|olopatadine HCL 0.2%, 0.1%, 0.7%||Pataday Once Daily Relief, Twice Daily Relief, Extra Strength Once Daily Relief||US and Canada (Rx only)||mast cell stabilizer/ antihistamine||H1 receptor antagonist, inhibits inflammatory mediator release|
|naphazoline 0.025%/ pheniramine 0.3%||Opcon-A, Naphcon-A, Visine-A||US and Canada||antihistamine/ decongestant||naphazoline: vasoconstriction adrenergic agonist, pheniramine: H1 receptor antagonist, anticholingergic|
|Generic name||Brand names||Class||Availability||Action|
|alcaftadine 0.25%||Lastacaft||antihistamine/ mast cell stabilizer||US only||H1, H2, H4 receptor antagonist, mast cell stabilizer. The only Pregnancy category B agent in class. Uniquely beneficial in VKC.|
|bepotastine besilate 1.5%||Bepreve||antihistamine/ mast cell stabilizer||US and Canada||competitive H1 receptor antagonist|
|epinastine HCL 0.05%||Elestat||antihistamine/ mast cell stabilizer||US only||direct H1 receptor antagonist, inflammatory mediator release inhibitor|
|azelastine HCL 0.05%||Optivar||antihistamine/ mast cell stabilizer||US only||relatively selective H1 antagonist, inflammatory mediator release inhibitor|
|cetirizine 0.24%||Zerviate||antihistamine||US only||selective H1 receptor antagonist|
|nedocromil sodium 2.0%||Alocril||mast cell stabilizer||US and Canada||inhibits histamine and leukotriene release, decreases chemotaxis and eosinophil activation.|
|lodoxamide tromethamine 0.1%||Alomide||mast cell stabilizer||US and Canada||mast cell stabilizer, inhibits eosinophil chemotaxis|
|cromolyn sodium||Cromolyn Sodium||mast cell stabilizer||US and Canada||mast cell stabilization via calcium influx inhibition. Inconvenient frequent dosing schedule.|
|loteprednol etabonate 0.2%, 0.5%||Alrex, Lotemax||steroid||US and Canada||anti-inflammatory|
|fluorometholone acetate 0.1%||Flarex||steroid||US and Canada||anti-inflammatory|
|loteprednol etabonate 0.25%||Eyesuvis||steroid||US||anti-inflammatory, approved for treatment of dry eye disease|
|cyclosporine 0.05%, 0.09%||Restasis, Cequa, Klarity-C||immunomodulator||US and Canada||suppresses T lymphocyte proliferation & cytokine activity, mast cell and basophil stabilization, reduces eosinophil recruitment|
Due to their dual-action, combination antihistamine/mast cell stabilizers have become a commonly prescribed first line treatment. Of note is alcaftadine due to its broad spectrum (H1, H2, and H4) histamine receptor blocking; it is uniquely beneficial for treatment of vernal conjunctivitis.12,4
While they may seem like a reasonable option, care needs to be taken when considering oral antihistamines like diphenhydramine and loratadine due to their M3 receptor promiscuity, direct lacrimal gland output inhibition and decreased mucin output from goblet cells, potentially inducing dry eye symptomatology. Cetririzine and fexofenadine have the least M3 receptor affinity of the oral options.13 For patients with concurrent allergic rhinitis an intranasal steroid may be considered instead, however IOP should be monitored.14 Punctal plugs should also be avoided in patients with allergies, as they trap the allergy burden on the ocular surface.
For those where maximum topical medical therapy is inadequate, full allergy testing and allergen specific immunotherapy (AIT) like sublingual immunotherapy (SLIT) or subcutaneous immunotherapy (SCIT) should be considered next. This is the only therapy option that can provide long-term benefit once the therapy has been completed, due to reduced end-organ response to allergen exposure by downregulation of the Th2 response and upregulation of regulatory T cells that produce inhibitory cytokines.13
Newer treatment options include considering drugs previously used for other conditions such as topical immunomodulator calcineurin inhibitors like cyclosporine A and tacrolimus, particularly for severe cases of AKC and VKC, as well as lifitegrast, which has been shown in a murine allergic eye disease model to reduce Th17 cells and polymorphonuclear neutrophils in the conjunctiva.15 Biologics like anti-IgE omalizumab or anti-IL-4Ra/IL-13Ra dupilumab5 are also potential new options, however dupilumab-induced ocular surface disease (DIOSD) has been shown in some patients being treated with dupilumab for atopic dermatitis.20 Intense pulsed light (IPL) has also been shown in a recent study (soon to be published) to decrease allergic keratoconjunctivitis-related ocular itch.19 Targets for new and future pharmaceutical options could be thymic stromal lymphopoietin (TSLP) inhibitors such as the new monoclonal antibody, tezepelumab.21 TSLP is an epithelial cell derived pro-inflammatory cytokine which has been shown to play a role in severe ocular allergy by initiating the allergic inflammatory reaction between epithelial and dendritic cells.16,18 Inhibiting this upstream signal could be beneficial. Other innovations include new drug delivery models such as a ketotifen (dual-action antihistamine/mast cell stabilizer) loaded soft contact lens, which recently underwent clinical trials 17 and has just received its first regulatory approval in Japan.
With increasing prevalence of ocular allergy and ever-expanding contact lens parameters and options, clinicians must remain vigilant in the detection and treatment of ocular allergy for patients. This requires a thorough patient history, a quality exam using appropriate diagnostic tools, and palliative and pharmacologic treatment options. By doing so, this spring, our patients’ eyes will enjoy the beauty and joy the season has to offer.
- Gomes PJ. Trends in prevalence and treatment of ocular allergy. Curr Opin Allergy Clin Immunol 2014; 14:451–6.
- Rosario N, Bielory L. Epidemiology of allergic conjunctivitis. Curr Opin Allergy Clin Immunol. 2011 Oct;11(5):471-6. doi: 10.1097/ACI.0b013e32834a9676. PMID: 21785348.
- Feng Y, Wang X, Wang F, et al. The Prevalence of Ocular Allergy and Comorbidities in Chinese School Children in Shanghai. Biomed Res Int. 2017;2017:7190987. doi:10.1155/2017/7190987
- Leonardi A, Di Stefano A, Vicari C, Motterle L, Brun P. Histamine H4 receptors in normal conjunctiva and in vernal keratoconjunctivitis. Allergy. 2011 Oct;66(10):1360-6. doi: 10.1111/j.1398-9995.2011.02612.x. Epub 2011 May 5. PMID: 21545429.
- Leonardi A, Modugno RL, Salami E. Allergy and Dry Eye Disease. Ocul Immunol Inflamm. 2021 Feb 5:1-9. doi: 10.1080/09273948.2020.1841804. Epub ahead of print. PMID: 33544639.
- Reyes, N, Matthew, R, and Saban, D. “Induction and Characterization of the Allergic Eye Disease Mouse Model.” Type 2 Immunity, edited by R. Lee Reinhardt. Humana Press, 2018, pp. 62-70.
- Reyes NJ, Yu C, Mathew R, et al. Neutrophils cause obstruction of eyelid sebaceous glands in inflammatory eye disease in mice. Sci Transl Med. 2018;10(451):eaas9164. doi:10.1126/scitranslmed.aas9164
- Nguyen, T L. How to Reduce Contact Lens Dropouts. Review of Optometric Business, 28 June 2017.
- P.M. Buchholz, J. Walt, D. Lorenz, C. Burk, J. Lee; Patient Impact of Allergic Conjunctivitis as Measured by the Eye Allergy Patient Impact Questionnaire (EAPIQ) . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3735.
- Al-Dairi W, Al Saeed AA, Al Sowayigh OM. Impact of Quarantine During COVID-19 Pandemic on the Quality of Life of Patients with Allergic Conjunctivitis. Cureus. 2020;12(12):e12240. Published 2020 Dec 23. doi:10.7759/cureus.12240
- La Rosa M, Lionetti E, Reibaldi M, Russo A, Longo A, Leonardi S, Tomarchio S, Avitabile T, Reibaldi A. Allergic conjunctivitis: a comprehensive review of the literature. Ital J Pediatr. 2013 Mar 14;39:18. doi: 10.1186/1824-7288-39-18. PMID: 23497516; PMCID: PMC3640929.
- Chigbu DI, Coyne AM. Update and clinical utility of alcaftadine ophthalmic solution 0.25% in the treatment of allergic conjunctivitis. Clin Ophthalmol. 2015;9:1215-1225. Published 2015 Jul 8. doi:10.2147/OPTH.S63790
- Periman, L. (2015, March 1). Clues to DTS may lurk on meds list. Retrieved March 01, 2021, from https://www.ophthalmologymanagement.com/issues/2015/march-2015/clues-to-dts-may-lurk-on-meds-list
- Dupuis P, Prokopich CL, Hynes A, Kim H. A contemporary look at allergic conjunctivitis. Allergy Asthma Clin Immunol. 2020 Jan 21;16:5. doi: 10.1186/s13223-020-0403-9. PMID: 31993069; PMCID: PMC6975089.
- Periman LM, Perez VL, Saban DR, Lin MC, Neri P. The Immunological Basis of Dry Eye Disease and Current Topical Treatment Options. J Ocul Pharmacol Ther. 2020 Apr;36(3):137-146. doi: 10.1089/jop.2019.0060. Epub 2020 Mar 12. PMID: 32175799; PMCID: PMC7175622.
- Matsuda A, Ebihara N, Yokoi N, Kawasaki S, Tanioka H, Inatomi T, de Waal Malefyt R, Hamuro J, Kinoshita S, Murakami A. Functional role of thymic stromal lymphopoietin in chronic allergic keratoconjunctivitis. Invest Ophthalmol Vis Sci. 2010 Jan;51(1):151-5. doi: 10.1167/iovs.09-4183. Epub 2009 Sep 9. PMID: 19741251.
- Pall, Brian OD, MS*; Gomes, Paul MS†; Yi, Frank MS*; Torkildsen, Gail MD‡ Management of Ocular Allergy Itch With an Antihistamine-Releasing Contact Lens, Cornea: June 2019 – Volume 38 – Issue 6 – p 713-717doi: 10.1097/ICO.0000000000001911
- Guo C, Liu J, Hao P, Wang Y, Sui S, Li L, Ying M, Han R, Wang L, Li X. The Potential Inhibitory Effects of miR-19b on Ocular Inflammation are Mediated Upstream of the JAK/STAT Pathway in a Murine Model of Allergic Conjunctivitis. Invest Ophthalmol Vis Sci. 2020 Mar 9;61(3):8. doi: 10.1167/iovs.61.3.8. PMID: 32150250; PMCID: PMC7401772.
- Dan Li, Shi-Bin Lin, Liu-Hang-Hang Cheng, Ming-Zhi Zhang, and Biao Cheng. Photobiomodulation, Photomedicine, and Laser Surgery. ahead of print http://doi.org/10.1089/photob.2020.4826
- Popiela, M.Z., Barbara, R., Turnbull, A.M.J. et al. Dupilumab-associated ocular surface disease: presentation, management and long-term sequelae. Eye (2021). https://doi.org/10.1038/s41433-020-01379-9
- Matera MG, Rogliani P, Calzetta L, Cazzola M. TSLP Inhibitors for Asthma: Current Status and Future Prospects. Drugs. 2020 Apr;80(5):449-458. doi: 10.1007/s40265-020-01273-4. PMID: 32078149