Perennial Allergic Conjunctivitis

Perennial allergic conjunctivitis (PAC) is an inflammatory response of the conjunctiva triggered by exposure to allergens such as pollens, animal dander (flecks of dead skin cells and hair/feathers) and other environmental antigens. Intermittent (less than 4 weeks in duration) seasonal allergic conjunctivitis (SAC) and persistent (more than 4 weeks in duration) perennial allergic conjunctivitis (PAC), makes up a large number of ocular (eye) allergy cases.

PAC may not be caused exclusively by seasonal allergens, although they may play a role. PAC generally occurs in response to environmental allergens (dust mites, animal dander, moulds, cockroach dust, airborne allergens and cigarette smoke) that are present throughout the year and is generally chronic. About 79% of patients of PAC may still have seasonal exacerbations and is generally worse in the autumn when exposure to house dust mites, animal dander and fungal allergens is greatest. It is less common and tends to be milder than the seasonal form. Most cases of SAC occur during the spring and autumn when the level of seasonal allergens (i.e. pollens) is high.  Majority of PAC and SAC affect both young and middle-aged people of both sexes.

PAC and SAC are the common and sub-acute forms of ocular allergy, usually accompanied by seasonal allergic rhinitis. Although PAC and SAC are relatively mild conditions, rarely causing permanent visual impairment, their effects on the quality of life can be profound, with significant morbidity.

Atopy (a genetic predisposition to develop an allergic reaction) is a genetically determined predisposition to hypersensitivity reaction upon exposure to specific environmental allergens/antigens. It includes allergic conjunctivitis, as well as seasonal allergic rhinitis (hay fever), asthma and eczema. Allergic conjunctivitis is a type I (immediate) hypersensitivity reaction, being mediated by de-granulation of mast cells (MCs) in response to the action of immunoglobulin E (IgE).  

Perennial allergic conjunctivitis (PAC) represents a disease under chronic allergic conjunctivitis (CAC), together with seasonal allergic conjunctivitis (SAC), atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC) and, to a certain extent, giant papillary conjunctivitis (GPC). In perennial and seasonal allergic conjunctivitis, conjunctival inflammation is quite mild and corneal involvement never occurs. In contrast, AKC and VKC are severe inflammatory diseases, which may involve cornea and can cause permanent visual impairment.

PAC and SAC are more frequently associated with rhinitis, while AKC and VKC are more frequently associated with eczema and asthma respectively.

References:

Agarwal Sunita, Agarwal Athiya, Apple David J, Buratto Lucio, Alio Jorge L, Pandey Suresh K and Agarwal Amar.Textbook of Ophthalmology Volume 1.First Edition. Jaypee Brothers Medical Publishers (P) Ltd. 2002. New Delhi. P. 843-844.

 http://www.ejournalofophthalmology.com/ejo/ejo54.html

Bowling Brad, Kanski's Clinical Ophthalmology- A Systematic Approach. Eighth Edition. Elsevier, 2016. P. 144-145.

Holland Edward J, Mannis Mark J, Lee W Barry. Ocular Surface Disease - Cornea, Conjunctiva and Tear Film. Elsevier Saunders. 2013. P. 91-96.

http://emedicine.medscape.com/article/1191467-overview

http://www.medscape.com/viewarticle/831091

http://eyewiki.aao.org/Allergic_conjunctivitis

http://www.ncbi.nlm.nih.gov/pubmed/3467503

Nelson Leonard B., Olitsky Scott E., Harley's Pediatric Ophthalmology. Fifth Edition. Lippincott Williams & Wilkins. 2005. P 211.

http://www.chm.bris.ac.uk/motm/histamine/jm/receptors.htm

Spector S & Raizman M (1994): Conjunctivitis medicamentosa. J Allergy Clin Immunol 94: 134–136.

Barney NP & Graziano FM (2003): Allergic and immunologic diseases of the eye. In: Adkinson NFJ, Yunginger JW, Busse WW, 

Symptoms of PAC and SAC are essentially similar and typically develop on a gradual basis but can also develop suddenly following contact with the offending allergen.

Ocular symptoms associated with PAC may be:

-       Ocular itching.

-       Redness of eyes.

-       Watering or tearing (epiphora).

-       Burning.

-       Stinging or pricking sensation.

-       Mucoid discharge.

-       Chemosis (swelling of conjunctiva).

-       Photophobia (sensitivity to light).

-       Eyelid swelling.

-       Dryness of eyes.

Perennial allergic conjunctivitis is less common than SAC and tends to be milder than the seasonal form.

PAC causes symptoms throughout the year, generally worse in the autumn when exposure to animal dander, house dust mites and fungal allergens is highest. In contrast, Individuals with SAC have symptoms of acute allergic conjunctivitis for a defined period of time, caused by pollens from trees, weeds and grass, although the specific allergen varies in different geographic locations. Persons with SAC are symptom-free in winter/cooler climates because of the decreased airborne transmission of these allergens.

Acute allergy is caused by IgE-mediated MC de-granulation, whereas chronic allergies are also associated with continuous activation of MC but with predominance of mediators, such as eosinophils and T- helper2 (Th2) lymphocyte-generated cytokines.

Pathophysiology:

Both PAC and SAC are type I (immediate) IgE-mediated hypersensitivity reactions, due to environmental airborne allergens, with the mast cell (MC) playing a central role. A reaction occurs when a sensitised individual is exposed to a particular antigen. IgE has strong affinity for MCs triggering its de-granulation.

An allergen reacts with specific IgE antibodies bound to a sensitised MC, triggering cross-linkage of the IgE molecules and an influx of calcium ions into the MC. This causes the MC to de-granulate and release preformed inflammatory mediators, such as histamine, which causes the signs and symptoms associated with the early-phase response in sensitised individuals.

There are two components of MC activation. The first is the release of pre-formed mediators, including histamine. The second is the synthesis of arachidonic acid and the subsequent metabolic cascade, resulting in production of prostaglandins and leukotrienes.

Histamine binds to Histamine1(H1) receptors and results in primary allergic symptoms of itching, burning, tearing and stinging sensation, while binding to the Histamine2(H2) receptor releases leukotrienes and prostaglandins, stimulating mucus production and also increasing vascular permeability. This early phase response is immediate and lasts clinically for about 20-30 minutes. (http://www.chm.bris.ac.uk/motm/histamine/jm/receptors.htm).

MC de-granulation also initiates a series of cellular and extracellular events, which lead to the late-phase response (production of prostaglandins and leukotrienes). MCs also release cytokines and chemotactic factors which induce the production of IgE from B lymphocytes (B cells), enhance the production of T helper lymphocytes, attract eosinophils and activate vascular endothelial corneal and conjunctival cells to release chemokines and adhesion molecules. Chemokines and adhesion molecules mediate the infiltration of eosinophils, basophils, neutrophils and T helper lymphocytes to the site of inflammation.

De-granulating eosinophils release toxic proteins which have cytotoxic effects and further enhance MC de-granulation. These products of eosinophils are toxic to the corneal epithelium and, if present chronically, may result in ulceration. The late phase response is characterised by an influx of multiple inflammatory cells.

Diagnosis of PAC is generally based on clinical history and careful slit-lamp (bio-microscopic) examination by an eye-specialist.

Important features of the history include a personal or family history of atopic disease such as:

-       Allergic rhinitis.

-       Bronchial asthma.

-       Atopic dermatitis.

Patients with PAC are more likely to also have perennial rhinitis with features of sneezing and nasal discharge.

 

Signs and symptoms of PAC (are usually milder and with longer duration) and SAC are essentially similar and typically develop on a gradual basis but can also develop suddenly following contact with the offending allergen. The difference relies on specific allergens to which patients are sensitive and the chronicity of exposure.

PAC remains self-limited without ocular surface damage and is usually bilateral, although it may be asymmetrical. If the allergic insult occurs with a particular allergen entering only one eye, ocular changes may exceptionally be unilateral. The symptoms and signs are recurrent, occurring rapidly following the exposure to allergens.

PAC is less common than SAC and, as patients are chronically exposed to allergen, symptoms and signs occur year-round. The most common triggers are mould spores, animal dander, and dust mites usually found in the household. Patients may also be sensitive to seasonal allergen with a superimposed offender to their symptoms. Because of the prolonged exposure, the conjunctiva may become boggy, chronically red, and irritated. Papillary hypertrophy along the tarsal conjunctival surface may occur with chronic exposure to allergens in PAC. The discharge is whitish but thick, and even stringy.

Moulds, house dust, and animal dander participate in the disease process. The severity of symptoms varies depending on the type of allergen, its concentration, and time of exposure.

Dry eye facilitates allergen contact with the ocular surface since the capability of tears to ‘wash away’ the allergen is usually compromised.

The most significant symptom in allergic conjunctivitis is itching. Patients usually complain of intense itching of the eyes, sometimes along with a burning sensation and tearing. Discharge is usually serous, clear and watery, but with a ropy characteristic.

Without itching, the diagnosis of allergic conjunctivitis is suspect. With intense itching, the diagnosis of allergic conjunctivitis is very likely, but one should also consider ocular conditions like dry eye, toxic conjunctivitis, contact dermatitis, blepharitis, and other forms of allergic conjunctivitis. In these other disorders, itching is usually mild and occasional.

Signs of SAC:

Signs on slit-lamp (bio-microscopy) examination may be:

-       Lid oedema.

-       Mucoid discharge, which may be stringy/ropy.

-       Mild papillary reaction.

-       Conjunctival hyperaemia.

-       Chemosis may be apparent in the bulbar and lower tarsal conjunctiva, giving to it a ‘milky’ or pale pink appearance.

-       Dramatic unilateral bulging of the conjunctiva, frequently described as the acute formation of a ‘bubble’ in the eye, mainly when patients rub their eyes. Conjunctiva balloons, due to intense and acute infiltration of cells and fluids, causing chemosis.

-       Dellen (shallow saucer-shaped excavations in periphery of cornea) of cornea may form due to intense conjunctival chemosis and unstable tear film. Dellen may resolve with the resolution of chemosis.

-       Punctate keratitis may be present rarely.

 Diagnostic procedures:

Investigations are generally not required.

-       Intra-dermal skin test: Intra-dermal skin test is the standard clinical test for the diagnosis of type I hypersensitivity reaction. Cutaneous tests, such as the scratch or prick, and more rarely, the intra-cutaneous injections, may be utilised to determine the antigens causing hypersensitivity. The prick test is the preferred method because it is more sensitive, less variable, and more comfortable to patients than the intra-cutaneous test.

Normally, skin test for particular allergens is rarely needed.

-       Superficial conjunctival scrapings: Superficial conjunctival scrapings in more active cases may help to establish the diagnosis by revealing characteristic eosinophils which are not normally present on the conjunctiva. However, eosinophils are observed in the most severe cases, but are generally present in the deep layers of the substantia propria of the conjunctiva. For this reason, the absence of eosinophils on conjunctival scrapings does not rule out the diagnosis of allergic conjunctivitis. Even the presence of one eosinophil or eosinophilic granules is consistent with a diagnosis of allergy.

-       Radio-allergo-sorbent test (RAST): Radio-allergo-sorbent test (RAST), a blood test, may also help to define the allergens. Elevated IgE levels in serum (RAST, ELISA) and in tear fluid are present in almost all patients with PAC.

-       Conjunctival provocation test: Conjunctival provocation test consist of instilling offending allergen into the conjunctival sac, producing the typical symptoms of PAC. Conjunctival provocation tests are rarely necessary for the diagnosis of PAC and it has rather proven to be a reliable method to evaluate ocular therapeutics.

-       Nasal allergy test: There is also a possible involvement of nasal allergy in some patients with allergic conjunctivitis, such as PAC, and therefore, there may be value to a nasal challenge with allergen combined with registration of ocular features.

PAC should be differentiated from conditions like:

-       Keratoconjunctivitis sicca (dry eye syndrome).

-       Contact dermatitis.

-       Toxic conjunctivitis.

-       Blepharitis.

-       Other forms of allergic conjunctivitis.

-       Superior limbic keratoconjunctivitis.

-       Bacterial conjunctivitis.

-       Viral conjunctivitis.

Management should be carried out under medical supervision.

General measures:

Management of PAC includes reducing the amount of allergen exposure.

-       Keeping household clean: Allergens in PAC are usually mould spores, animal dander, dust mites, and are predominantly found in the household. Therefore, carpets must be cleaned, changed or removed, as well as children’s stuffed animals, soft toys, and curtains. The mattress top and sides must also be cleaned and enclosed in plastic bags or other dust mite proof cover. Sheets, pillows and blankets should be washed in hot water (54 degree Celsius). Pillows and the base of the bed must be vacuumed regularly. Pets should be kept out of the bedroom, and the bathroom should be kept clean and dry to inhibit mould growth.

-       Air purifiers: While it is better to stop dust mites at the source, reducing the dust levels in the air could be an adequate strategy. Air purifiers that use high-efficiency particulate arrestance or high-efficiency particulate air (HEPA) filtration are more effective and safer (remove up to 99% of the material like dust mite faeces, all allergens, such as animal dander, dust, pollen, or cockroach faeces).

Supportive measures:

Supportive measures include:

-       Cold compresses: Cold compresses decrease ocular inflammation.

-       Saline solutions: Irrigation of ocular surface with saline solution facilitates removal of allergens, and thus achieves the primary principle of allergy management by minimising exposure of the ocular surface to allergens.

-       Artificial tears: Preservative-free artificial tears may be used to wash or dilute allergens and inflammatory mediators away from the ocular surface. In addition, some types of artificial tears provide relief through the lubrication of the ocular surface. Ointments or time-released tear replacements, used at night, provide a longer-lasting measure, delivering ocular surface lubrication during sleep. These agents are used for mild PAC only since they neither treat the underlying allergic response nor modify the activity of any of the mediators of inflammation. Artificial tear solutions should be kept in refrigerator, since the use of cold drops produces vasoconstriction, ameliorating symptoms and signs.

-       Avoidance of eye rubbing.

Medical therapy:

It is important to note that in the treatment of acute or chronic forms of allergic eye diseases, patient compliance may not be ideal, giving the false impression of poor efficacy of medical therapy.

Medical therapy includes:

-       Topical vasoconstrictors: Topical vasoconstrictors may provide short-term relief. Decongestant reduces chemosis, eyelid oedema, and redness by inducing vasoconstriction. There is also some amelioration of ocular itching with the use of topical vasoconstrictors. Like artificial tears, topical vasoconstrictors do not reduce the allergic response, because they do not antagonise any of the mediators of allergic inflammation. However, prolonged use of vasoconstrictors may cause rebound conjunctival redness and inflammation (‘conjunctivitis medicamentosa’) (Spector S & Raizman M (1994): Conjunctivitis medicamentosa. J Allergy Clin Immunol 94: 134–136.), and they are ineffective in severe ocular allergy. To minimise this potential side-effect, exposure to medicine should be limited through less frequent dosing or shorter treatment durations.  Examples include naphazoline, and oxymetazoline.

-       Topical antihistamine: Antihistamine eye drops are prescribed for the relief of acute signs and symptoms of PAC by blocking the histamine receptors in the conjunctiva. The antihistamine is effective for the acute onset and reduces pruritus. For allergic complaints limited to eyes, topical anti-histamines are prescribed and are free of untoward side-effects of systemic oral anti-histamines. Topical anti-histamines provide faster relief than systemic anti-histamines and have longer duration of action than topical vasoconstrictors, non-steroidal anti-inflammatory drugs, pure mast cell stabilisers and corticosteroids, the drugs commonly used in the treatment of ocular allergy. These medications do not affect other pro-inflammatory mediators, such as prostaglandins and leukotrienes, which remain uninhibited. Examples include pyrilamine and pheniramine.

-       Combined topical vasoconstrictor and antihistamine: Combined topical vasoconstrictor and antihistamine like antazoline (antihistamine) with xylometazoline (vasoconstrictor), may provide short term relief. Decongestant reduces chemosis, eyelid oedema, and redness by inducing vasoconstriction. The antihistamine is effective for the acute onset and reduces pruritus.

-       Systemic antihistamines: Systemic antihistamines may also relieve signs and symptoms of allergy. Oral antihistamines may be indicated for severe symptoms of allergy involving eyes, pharynx and nose simultaneously. Some, such as diphenhydramine, cause significant drowsiness and may be useful in aiding sleep.

-       Topical second-generation H1 antihistamines: Topical selective H1 receptor blockers are better than vasoconstrictors alone or in combination with non-specific anti-histamine eye-drops, in controlling signs and symptoms of PAC. The group contains drugs like emedastine and levocabastine. The enhanced clinical efficacy of these medicines over first-generation anti-histamines like pheniramine may be due to inhibitory effects of new-generation anti-histamines on the pro-inflammatory cytokines. Topical second-generation H1 antihistamines are much more selective for peripheral H1 receptors, as opposed to the central nervous system H1 receptors, cholinergic receptors, and some H2 receptors that cause cardiac arrhythmia. This selectivity significantly reduces the occurrence of adverse drug reactions, such as drowsiness/ sedative action, dry eye and dry mouth.

-       Topical mast cell stabilisers: Topical mast cell stabilisers decrease the de-granulation of conjunctival MCs, preventing the release of histamine and other chemotactic factors. However, the drug does not relieve existing symptoms and has no role in the treatment of the acute phase of PAC; mast cell stabilisers should be used on a prophylactic basis. They need to be used long term (treatment effect usually requires continued use over 5-7 days) or in conjunction with other classes of medications, such as antihistamines. Examples are cromolyn sodium, Iodoxamide, nedocromil, and pemirolast.

-       H1 receptor blocker and mast-cell stabiliser (Dual-acting agents): Dual-acting agents exert multiple pharmacological effects, such as histamine receptor antagonist action, stabilisation of MC de-granulation and, subsequently, suppression of activation and infiltration of eosinophils. Examples are oloptadine, azelastine, epinastine and ketotifen. Drugs also exert anti-inflammatory effects through other mechanisms e.g. olopatadine affects release of cytokines. 

-       Non-steroidal anti-inflammatory Drugs (NSAIDs): Non-steroidal anti-inflammatory Drugs (NSAIDs) inhibit production of prostaglandins and have no role in blocking mediator such as leukotrienes. Example is ketorolac tromethamine and diclofenac.

-       Topical corticosteroids: Corticosteroid eye drops are very effective in treating PAC, but the numerous adverse effects, such as secondary infections, elevated intraocular pressure, and formation of cataract, make their use selective. Patients using corticosteroids should be closely monitored.  Anti-inflammatory and immunosuppressive effects of corticosteroids are broad and non-specific. Topical steroids must be prescribed only for a short period of time and for severe cases that do not respond to other therapy. Pulse dosing of topical steroids may be employed, followed by maintenance with an MC stabiliser. Modified steroids such as loteprednol etabonate and rimexolone may be used, and loteprednol has superior safety profile.

-       Immune-modulators: Immune-modulators such as cyclosporine drops and tacrolimus ointment have demonstrated efficacy in the treatment of ocular allergy. Cyclosporine A is an immunosuppressant that acts by inhibiting eosinophilic infiltration by interfering with type IV allergic reactions in the conjunctiva. Tacrolimus acts mainly by inhibiting the action of T cells. Both agents are associated with fewer side effects and are preferred over chronic use of corticosteroids in the treatment of allergic conjunctivitis. Immune-modulator agents are reserved for more severe forms of allergic conjunctivitis (such as VKC and AKC) and have limited indications in cases of PAC.

-       Allergen-specific immunotherapy: Allergen-specific immunotherapy is an effective treatment used to induce immunologic tolerance when the allergen is well known. The primary objectives of allergen-specific immunotherapy are to decrease the symptoms triggered by allergens and to prevent recurrence of the disease in the long term. It is indicated in patients who have evidence of specific IgE antibodies to clinically relevant allergens. Skin prick testing is the preferred method of testing for specific IgE antibodies and identification of allergen for the immunotherapy. Candidates for immunotherapy include those who:

(1)    Have symptoms that are not well controlled by pharmacological therapy or avoidance measures.

(2)    Require high doses of medication, multiple medications, or both to maintain control of their disease.

(3)    Experience adverse effects of medications, or

(4)    Wish to avoid the long-term use of pharmacological therapy.

 

Prognosis:

Prognosis of PAC is good despite significant discomfort and undesirable cosmetic appearance. Allergic conjunctivitis generally clears up readily. Although, allergic conjunctivitis may commonly reoccur, it rarely causes complications or visual loss.

For prevention of PAC, avoidance of the offending allergen is the primary behavioural modification. Specific testing will identify the responsible allergen and help a person to ensure ways to avoid it.

Contact reactions caused by medications or cosmetics may be prevented by avoidance.

Reduce amount of allergen exposure by:

-       Keeping household clean: Allergens in PAC are usually mould spores, animal dander, dust mites, and are predominantly found in the household. Therefore, carpets must be cleaned, changed or removed, as well as children’s stuffed animals, soft toys, and curtains. The mattress top and sides must also be cleaned and enclosed in plastic bags or other dust mite proof cover. Sheets, pillows and blankets should be washed in hot water (54 degree Celsius). Pillows and the base of the bed must be vacuumed regularly. Pets should be kept out of the bedroom, and the bathroom should be kept clean and dry to inhibit mould growth.

-       Using air purifiers: Air purifiers that use High-efficiency particulate arrestance or high-efficiency particulate air (HEPA) filtration are more effective and safer (remove up to 99% of the material like dust mite faeces, all allergens, such as animal dander, dust, pollen, or cockroach faeces).

 

While it is better to stop dust mites at the source, reducing the dust levels in the air could be an adequate strategy.

  • PUBLISHED DATE : Mar 23, 2016
  • PUBLISHED BY : Zahid
  • CREATED / VALIDATED BY : Dr. S. C. Gupta
  • LAST UPDATED ON : Mar 23, 2016

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