Description of the condition
Blepharokeratoconjunctivitis (BKC) is a type of inflammation of the surface of the eye and eyelids. The diagnosis is clinical and based on changes of the lid margin (fine blood vessels on the lid margin = telangiectasia, thickening, scarring), meibomian gland dysfunction (MGD), redness of the eye (= conjunctival hyperaemia), conjunctival chemosis and inflammation of the cornea (dry spots = punctate epithelial keratitis, corneal opacities, ulceration, thinning, vascularisation and scarring) (Farpour 2001; Viswalingam 2005). Inflammation of the ocular surface causes symptoms such as watering, itching, foreign body sensation, burning sensation, eye rubbing and sensitivity to light (photophobia) (Viswalingam 2005).
The incidence and prevalence of BKC in children are unknown. In paediatric eye clinics, BKC is a common diagnosis and is estimated to be the reason for referral in 12% to 15% of cases (Gupta 2010; Hammersmith 2005). The gender distribution differs between published case series; there appears not to be a definite male or female predilection. Children of Asian descent may be more frequently affected. In a UK case series of 44 children, 50% were of Indian or Sri Lankan descent, 45.5% were White and 4.5% were of Middle Eastern origin (Viswalingam 2005); in another UK case series of 27 children, 63% were White, 30% were of Indian or Pakistani origin, 4% were of Middle Eastern and 4% were of Chinese origin (Jones 2007). The age of onset is in early childhood, and case series studies report a mean age of onset of 3.2 to 4.5 years, with a range of five months to 13 years (Farpour 2001; Hammersmith 2005; Jones 2007). The young age of onset means that children are at risk of developing secondary amblyopia ('lazy eye'), which is a loss of vision due to the brain not learning how to process high-resolution visual information. Indeed, one paediatric case series recorded reduced visual acuity despite treatment in 70% of affected eyes, with a rate of amblyopia of 56% (Jones 2007); this report derived from a tertiary referral centre and all included children had severe disease with corneal involvement in at least one eye, which may have led to selection bias. Refractive error (both spherical and cylindrical) is common (Gupta 2010; Jones 2007). A particularly severe phenotype with prolonged duration of the condition into adulthood, a systemic association of rosacea and a high risk of corneal complications, such as thinning, vascularisation and perforation, has been observed in a proportion of White patients (Hamada 2012). Whilst this Cochrane review is concerned with the medical management of BKC, surgical interventions are occasionally indicated, such as the injection of antivascular epithelial growth factor for corneal vascularisation, corneal gluing for corneal perforation and corneal transplantation for severe scarring; the latter being associated with a high risk of rejection because of corneal vascularisation.
Early features of BKC are lid margin disease and chalazia (cysts within the eyelid) (Jones 2007). Qualitative and quantitative tear film lipid deficiency and the activation of inflammatory pathways may be underlying factors which lead to the conjunctival and corneal signs and symptoms that distinguish BKC from blepharitis (Foulks 2003; Hamada 2012). BKC is a chronic condition and early intervention may help prevent severe corneal disease with loss of vision (Hamada 2012; Jones 2007).
Meibomian gland dysfunction
The meibomian glands, located in the eyelids, secrete a layer of lipids and proteins that protect the tear film against evaporation; dysfunction of these glands can result in a sensation of dryness or grittiness. Much has been suggested about the mechanisms underlying MGD and how to manage it, mainly in adults. We have presented a summary of the recent literature on this in Appendix 1.
Bacterial flora on lid margin and conjunctiva
Bacteria may secrete enzymes such as lipases which further destabilise the tear film (Farpour 2001; Gupta 2010; Nichols 2011; Viswalingam 2005).
Conjunctival cultures from healthy children frequently grow staphylococcal species pluralis (spp.) (42%) and diphtheroids (30%) and, occasionally, streptococcal spp. (13%), Propionibacterium acnes (11%) and Corynebacterium spp. (2%) (Singer 1988). In children with BKC, a case series of four children reported low numbers of coagulase-negative staphylococci in three children and P. acnes in one child (Farpour 2001). Another case series of 44 children with BKC reported culture-positive lid margin and conjunctival swabs in 34.1%, with 12 of 15 showing a moderate or heavy growth of Staphylococcus aureus, one of 15 Staphylococcus epidermidis and two of 15 mixed S. aureus/S. epidermidis (Viswalingam 2005). A large case series from a centre in India found positive cultures in 52 of 290 children with BKC (17.9%), and 34 of 52 grew S. aureus, 13 of 52 P. acnes and five of 52 grew both (Gupta 2010).
Diagnosis of BKC is based on symptoms and clinical signs, as described above. Lid margin and conjunctival swabs for bacterial culture are not performed routinely in clinical practice. Similarly, lid margin changes are not routinely quantified in paediatric practice. However, grading and scoring systems, adapted from systems used in adults, have been proposed (Nichols 2011).
The examination of children is often limited by patient co-operation, particularly when ocular surface inflammation is severe, and photophobia and discomfort are intense. However, some subscales used in the MGD staging system have been used to develop a staging system for childhood BKC. Viswalingam 2005 introduced a classification for BKC severity based on bulbar and tarsal conjunctival signs (hyperaemia, infiltration, obscuration of tarsal conjunctival vessels, and papillary and follicular changes) and the extent of corneal involvement in degrees (less than 120, 180 to 240, 240 to 360). This system was expanded to include elements of the conjunctival active inflammation score (Elder 1997), the Chronic Stevens Johnson Syndrome/Toxic Epidermal Necrolysis score (Sotozono 2007) and the abbreviated MGD grading system (Bron 2003; Foulks 2003). The resulting grading system has four grades (none, mild, moderate, severe) with separate grading for disease activity (A) and damage (D) (Hamada 2012). Activity scoring is based on conjunctival hyperaemia/oedema, corneal vascularisation (involving 90 degrees of the corneal periphery or less, more than 90 degrees, peripheral/to pupil margin/into central zone), and conjunctival or corneal ulceration or perforation. Damage scoring is based on lid distortion, subconjunctival fibrosis (fornix shortening), the presence and extent of established vessels/fibrovascular pannus and peripheral/central corneal thinning (Hamada 2012). The latest addition to this system includes the Oxford scoring system of corneal staining (Bron 2003; Hamada 2013). This scoring system can be used to evaluate treatment efficacy, such as complete success, signified by a reduction in activity scores from any grade to A0 ('no activity'), partial success, signified by a reduction in activity scoring not reaching grade A0, and treatment failure, signified by no change in or a worsening of activity scoring (Hamada 2012; Hamada 2013).
A functional measure of activity and damage is visual acuity; this may also indicate the presence of secondary amblyopia (Jones 2007).
Description of the intervention
Akin to the treatment of adult MGD and blepharitis, the treatment of childhood BKC targets the obstruction of meibomian gland openings (melting, expression and removal of meibomian gland secretions and debris from the lid margin by daily warm lid compresses and lid margin cleaning), the bacterial flora of lid margin and conjunctiva (topical and systemic antibiotics) and ocular surface inflammation (topical immunosuppressants and topical/systemic antibiotics inhibiting bacterial lipases, topical lubricants diluting inflammatory mediators in the tear film and compensating for tear film deficiency). Dietary modifications, particularly an increased intake in essential fatty acids (EFAs), may also be of benefit (Hamada 2012; Jones 2007). Rarely, systemic immunosuppression with prednisolone, azathioprine or mycophenolate mofetil may be required to treat sight-threatening corneal involvement (Hamada 2012).
This Cochrane review focused on systemic treatments.
How the intervention might work
There is no absolute indication for the use of systemic antibiotics in childhood BKC. Most study authors use systemic antibiotics for moderately severe or severe BKC (Viswalingam 2005) for both their antibiotic and anti-inflammatory effect. In contrast to adults, compliance with oral medication in children may be better than with topical treatment. Whilst some study authors describe the use of a systemic antibiotic instead of topical treatment (Meisler 2000), most use systemic antibiotics in addition to topical agents (Gupta 2010; Hamada 2012; Hammersmith 2005; Jones 2007; Viswalingam 2005).
The use of tetracyclines is contraindicated in children under the age of 12 years; adverse effects observed with their use include phototoxicity, gastrointestinal disturbance, oesophageal irritation and effects on secondary dentition (Paediatric Formulary Committee 2013). The overall tolerance of side effects is reported as good in adults (Geerling 2011). Doses of tetracyclines used for the treatment of MGD range from 250 mg once to four times a day (tetracycline and oxytetracycline) to 50 mg to 100 mg once or twice a day (doxycycline and minocycline). Geerling 2011 reported the use 40 mg doxycycline daily for rosacea. Jones 2007 reported the use of 100 mg doxycycline daily for BKC in a child over the age of 12 years in whom secondary dentition was complete.
In adults with MGD, oral tetracycline derivatives such as doxycycline and minocycline are used for mild and moderate symptoms and signs (Nichols 2011). In MGD, tetracyclines are mainly used for their anti-inflammatory and lipid-regulating properties (inhibition of bacterial lipase production and reduction of proinflammatory chemokines) rather than for their antimicrobial effects (Geerling 2011). Minocycline, which reduces the population of bacterial lid flora in individuals with rosacea, has an additional antimicrobial effect (Geerling 2011). Tetracyclines exert their anti-inflammatory effects by targeting multiple cell types involved in the production and release of proinflammatory chemokines, such as neutrophils (migration and chemotaxis), lymphocytes (proliferation, transmigration and activation), and corneal and conjunctival epithelial cells (Geerling 2011). They also have antioxidative effects, inhibit phospholipase A2, proinflammatory interleukins (ILs) and matrix metalloproteinases (MMPs), and have antiangiogenic properties (Geerling 2011; Krakauer 2003; Li 2006; Solomon 2000; Tamargo 1991).
Erythromycin is the most commonly used systemic antibiotic in childhood BKC (Gupta 2010; Hammersmith 2005; Jones 2007; Meisler 2000). The prescribed dose in childhood BKC ranges from 660 mg to 500 mg/day, or from 12.5 mg to 40 mg/kg body weight, divided into two or three doses, with a treatment duration of seven weeks to 12 months (Farpour 2001; Hammersmith 2005; Meisler 2000; Viswalingam 2005). Newer macrolide antibiotics, such as azithromycin and clarithromycin, are more stable and better absorbed than erythromycin (Klein 1997). Azithromycin has been used in childhood BKC (Choi 2013). Similar to tetracyclines, macrolide antibiotics have antibacterial and anti-inflammatory properties. They inhibit bacterial protein synthesis by binding to the 50S subunit of bacterial 70S ribosomes (Klein 1997). The effect can be bactericidal or bacteriostatic, depending on the bacterial species, drug concentration, growth phase of the organism and inoculum size (Klein 1997). In vitro, macrolide antibiotics reduce the release of proinflammatory cytokines, particularly IL-1beta, -6, -8 and -12, tumour necrosis factor-alpha (TNF-alpha), and MMP-1, -3 and -9, and affect neurophil chemotaxis and phagocytosis (Geerling 2011; Li 2010; Murphy 2008). In an animal model of corneal inflammation, azithromycin reduced leucocyte migration into the cornea and decreased mRNA expression levels of IL-1beta, TNF-alpha and intercellular adhesion molecule (ICAM)-1 (Sadrai 2011). The risk of adverse effects is low, though gastrointestinal complains such as diarrhoea/loose stools, abdominal pain, vomiting and nausea may occur. Erythromycin can interact with theophylline, carbamazepine, warfarin, cyclosporine, terfenadine and digoxin (Klein 1997). Allergic reactions, such as skin rash, fever, eosinophilia and joint pain, are unusual (Klein 1997). Gastrointestinal side effects and interactions with other drugs may be less frequent with azithromycin and clarithromycin (Klein 1997). If used for prolonged periods, both azithromycin and clarithromycin can cause reversible hearing impairment (Klein 1997).
Amoxicillin in combination with clavulanic acid has been used in one case series of childhood BKC, with the aim of targeting the bacterial flora on the lid margin and conjunctiva (Cehajic-Kapetanovic 2010). In most Gram-positive bacteria, amoxicillin inhibits cell wall synthesis. Clavulanic acid inhibits beta-lactamase enzymes, thereby preventing bacterial resistance to amoxicillin.
Dietary modification/supplements: essential fatty acids
Dietary modification, particularly an increased intake of omega-3 and -6 EFAs, has recently been proposed as an additional treatment component in childhood BKC (Hamada 2012; Jones 2007). In adult women, higher intake of EFA is associated with a reduced incidence of dry eye syndrome (Miljanović 2005). EFA intake affects the polar lipid profiles of meibomian gland secretions, lowers the levels of IL-1beta, -6 and -10, and reduces symptoms of ocular discomfort and dryness (Geerling 2011; Pinazo-Durán 2013; Sheppard 2013; Sullivan 2002). In human corneal epithelial cells in vitro, alpha-linolenic acid reduces the expression of the proinflammatory chemokines IL-1beta, -6 and -8, and TNF-alpha (Erdinest 2012). In endothelial cells in vitro, cyclo-oxygenase converts omega-3 and -6 EFAs to prostanoid derivatives, which inhibit angiogenesis by augmenting prostaglandin E2 and reducing angiopoietin-2 levels, resulting in an antiangiogenic effect (Szymczak 2008). Dietary EFAs are primarily derived from seafood, such as tuna, mackerel, salmon, sardines, bluefish, swordfish, light flesh fish, shrimp, lobster and scallops, and from margarine, butter, mayonnaise or other creamy salad dressings, peanuts, and other nuts and plant oils used in cooking (e.g. corn, sunflower, rapeseed oil) (Miljanović 2005). A supplement used in childhood BKC is flaxseed oil (alpha-linolenic acid, an omega-3 EFA) (Jones 2007). Adverse effects have not been described in the context of blepharitis/BKC treatment, although EFAs may have anticoagulant and undesired immunomodulatory effects (Royal Pharmaceutical Society 2013; Fenton 2013)
Prednisolone, azathioprine and mycophenolate mofetil have been used in isolated, severe cases of BKC. Only one case series has reported their use in children and young adults (Hamada 2012).
Prednisolone is an oral glucocorticoid with a potent anti-inflammatory action. It acts by binding with a cytoplasmic glucocorticoid steroid receptor and then translocates to the nucleus of the cell where it results in the increased transcription of proteins involved in inhibiting the production of inflammatory mediators (e.g. lipocortin). It also results in the inhibition of the transcription of proinflammatory cytokines (Ritter 2008). Adverse effects of systemic steroid therapy can include: adrenal suppression, Cushing's syndrome, diabetes mellitus, hypertension, increased susceptibility to infection, osteoporosis, gastric ulceration, cataracts and psychiatric disturbances (Paediatric Formulary Committee 2013).
Azathioprine is an antiproliferative immunosuppressant administered orally. It is a prodrug of 6-mercaptopurine, a purine antimetabolite, and is converted to the active form of the drug in the liver (Ritter 2008). Adverse effects include bone marrow suppression, mucositis, gastrointestinal disturbance and cholestatic jaundice. The deactivation of azathioprine is catalysed by thiopurine-S-methyltransferase (TPMT). Individuals deficient in this enzyme are at high risk of haematopoietic suppression with normal doses of the drug; hence, consideration should be given to checking TPMT levels before commencing the drug treatment (Paediatric Formulary Committee 2013).
Mycophenolate mofetil is a prodrug ester of mycophenolic acid and is administered orally. It suppresses the proliferation of T and B lymphocytes through the inhibition of purine synthesis (Ritter 2008). It also inhibits the production of proinflammatory cytokines. Adverse effects include gastrointestinal disturbances, bone marrow suppression, cytomegalovirus infection and lymphoma (Paediatric Formulary Committee 2013).
Why it is important to do this review
In paediatric eye clinics, BKC is a common and sometimes sight-threatening condition that can affect a child’s quality of life. New treatments, such as topical and systemic azithromycin and systemic immunosuppressants, are emerging. Children, their families and clinicians need accurate and unbiased data on the benefits and potential harms of the different management options available so as to inform treatment choice, particularly as medication is often required for prolonged periods of time.