Systemic treatment for blepharokeratoconjunctivitis in children

  • Review
  • Intervention

Authors


Abstract

Background

Blepharokeratoconjunctivitis (BKC) is a type of inflammation of the surface of the eye and eyelids which can affect children and adults. BKC involves changes of the eyelids, dysfunction of the meibomian glands, and inflammation of the conjunctiva and cornea. Chronic inflammation of the cornea can lead to scarring, vascularisation and opacity. BKC in children can cause significant symptoms which include irritation, watering, photophobia and loss of vision. Loss of vision in children with BKC may be due to corneal opacity, refractive error or amblyopia.

BKC treatment is directed towards the obstruction of meibomian gland openings, the bacterial flora of lid margin and conjunctiva, and ocular surface inflammation. Dietary modifications that involve increased intake in essential fatty acids (EFAs) may also be beneficial. Both topical and systemic treatments are used; this Cochrane review focuses on systemic treatments.

Objectives

To assess and compare data on the efficacy and safety of systemic treatments (including antibiotics, nutritional supplements and immunosuppressants), alone or in combination, for BKC in children aged between zero to 16 years.

Search methods

We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to April 2016), EMBASE (January 1980 to April 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 21 April 2016.

Selection criteria

We searched for randomised controlled trials that involved systemic treatments in children aged between zero to 16 years with a clinical diagnosis of BKC. We planned to include studies that evaluated a single systemic medication versus placebo, and studies that compared two or multiple active treatments. We planned to include studies in which participants receive additional treatments, such as topical antibiotics, anti-inflammatories and lubricants, warm lid compresses and lid margin cleaning.

Data collection and analysis

Two review authors independently screened the literature search results (titles and abstracts) to identify studies that possibly met the inclusion criteria of the review. We divided studies into 'definitely include', 'definitely exclude' and 'possibly include' categories. We made a final judgement as to the inclusion or exclusion of studies in the 'possibly include' category after we obtained the full text of each article.

Main results

No report or trial met the inclusion criteria of this Cochrane review; no randomised controlled trials have been carried out on this topic. There is a lack of standardised outcome measures.

Authors' conclusions

There is currently no evidence from clinical trials regarding the safety and efficacy of systemic treatments for BKC. Trials are required to test efficacy and safety of current and future treatments. Outcome measures need to be developed which can capture both objective clinical and patient-reported aspects of the condition and treatments.

Resumen

Tratamiento sistémico para la blefaroqueratoconjuntivitis en niños

Antecedentes

La blefaroqueratoconjuntivitis (BQC) es un tipo de inflamación de la superficie del ojo y los párpados que puede afectar a niños y adultos. La BQC incluye cambios en los párpados, disfunción de las glándulas de Meibomio e inflamación de la conjuntiva y la córnea. La inflamación crónica de la córnea puede dar lugar a la formación de cicatrices, vascularización y opacidad. La BQC en los niños puede provocar síntomas significativos que incluyen irritación, lagrimeo, fotofobia y pérdida de la visión. La pérdida de la visión en los niños con BQC se puede deber a la opacidad corneal, a un defecto de refracción o a la ambliopía.

El tratamiento de la BQC está dirigido a la obstrucción de las aberturas de la glándula de Meibomio, la flora bacteriana del margen del párpado y la conjuntiva y la inflamación de la superficie ocular. Las modificaciones dietéticas que incluyen una mayor ingesta de ácidos grasos esenciales (AGE) también pueden tener efectos beneficiosos. Se utilizan tratamientos tópicos y sistémicos; esta revisión Cochrane se centra en los tratamientos sistémicos.

Objetivos

Evaluar y comparar los datos sobre la eficacia y la seguridad de los tratamientos sistémicos (que incluyen antibióticos, suplementos nutricionales e inmunodepresores), solos o en combinación, para la BQC en niños entre cero y 16 años de edad.

Métodos de búsqueda

Se realizaron búsquedas en CENTRAL (que contiene el registro de ensayos del Grupo Cochrane de Trastornos de los Ojos y la Visión [Cochrane Eyes and Vision Group]) (2016, número 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (enero 1946 hasta abril 2016), EMBASE (enero 1980 hasta abril 2016), en el ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) y en la World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). No se aplicó ninguna restricción de fecha ni idioma en las búsquedas electrónicas de ensayos. La última búsqueda en las bases de datos electrónicas se realizó el 21 de abril de 2016.

Criterios de selección

Se realizaron búsquedas de ensayos controlados aleatorios que incluían tratamientos sistémicos en niños entre cero y 16 años de edad con un diagnóstico clínico de BQC. Se planificó incluir estudios que evaluaran una medicación sistémica única versus placebo, y estudios que compararan dos o múltiples tratamientos activos. Se planificó incluir estudios en los cuales los participantes recibieron tratamientos adicionales como antibióticos tópicos, antiinflamatorios y lubricantes, compresas calientes en el párpado y limpieza de los márgenes del párpado.

Obtención y análisis de los datos

Dos autores de la revisión, de forma independiente, examinaron los resultados de la búsqueda en la literatura(títulos y resúmenes) para identificar los estudios que posiblemente cumplían con los criterios de inclusión de la revisión. Los estudios se dividieron en las categorías "incluir definitivamente", "excluir definitivamente" e "incluir posiblemente". Se emitió un juicio final en cuanto a la inclusión o la exclusión de los estudios en la categoría "incluir posiblemente" después de obtener el texto completo de cada artículo.

Resultados principales

Ningún informe de ensayo cumplió los criterios de inclusión de esta revisión Cochrane; no se han realizado ensayos controlados aleatorios sobre este tema. Hay una falta de medidas de resultado estandarizadas.

Conclusiones de los autores

Actualmente no hay pruebas de ensayos clínicos con respecto a la seguridad y la eficacia de los tratamientos sistémicos para la BQC. Se requieren ensayos para analizar la eficacia y seguridad de los tratamientos actuales y futuros. Se deben desarrollar medidas de resultado que puedan captar los aspectos clínicos objetivos y los informados por los pacientes en cuanto al trastorno y los tratamientos.

Plain language summary

Systemic treatment for blepharokeratoconjunctivitis in children

Blepharokeratoconjunctivitis (BKC) is a condition that involves inflammation of the eyelids and the front of the eye. It occurs in children and adults. Children with BKC have watering, itching, red eyes that are painful in bright light. They may develop loss of vision due to scarring of the cornea, which can be described as the front windscreen of the eye. Various treatments are given for BKC, including antibiotics, anti-inflammatory agents and dietary supplements. Sometimes these treatments are given as eye drops and ointment while in severe cases they may be given systemically (usually orally). It can also be easier to administer medication to children orally than giving eye drops or ointment.

This Cochrane review aimed to assess the effects of systemic treatments for BKC in children aged between zero to 16 years. We searched the published literature and registers of clinical trials for studies. We did not find any high quality research studies in this subject area. No report or trial met the inclusion criteria of this Cochrane review. The studies we found did not compare the treatment against another treatment or placebo in a randomised way, so we cannot be certain that the effects of treatment seen are not due to other factors. Doctors also used many different ways to measure the effects of treatments. The searches are current to April 2016.

We recommend further research into the effects of systemic treatment for BKC. We also recommend developing new ways of measuring the effects of treatments taking into account clinical measurements and children’s and families’ opinions on their condition.

Laički sažetak

Sustavno liječenje blefarokeratokonjunktivitisa u djece

Blefarokeratokonjunktivitis (engleska kratica: BKC) je stanje koje uključuje upalu očnoga kapka i vjeđe. Pojavljuje se u djece i odraslih. Djeci koja imaju BKC oči suze, svrbe ih, crvene su i bolne na jako svjetlo. Mogu izgubiti vid zbog oštećenja rožnice, koja se opisuje kao prednje očno vjetrobransko staklo. Brojni su pristupi liječenju BKC, uključujući antibiotike, protuupalna sredstva i dodatke prehrani. Nekad se ta sredstva daju u obliku kapi i masti za oči, dok se u težim slučajevima mogu dati sustavno (najčešće oralno). Djeci je lakše dati lijek na usta (oralno) nego u obliku kapi i masti za oči.

Cilj ovog Cochrane pregleda je procjena učinaka sistemskog liječenja BKC u djece u dobi između nula do 16 godina. Pretražena je objavljena literatura i registri kliničkih ispitivanja za studije. Nije pronađena ni jedna istraživačka studija visoke kvalitete u tom području. Nema istraživanja koja bi zadovoljila kriterije za uključivanje u ovaj Cochrane pregled. Istraživanja koja jesu pronađena u literaturi nisu usporedila liječenje s drugim tretmanom ili placebom na randomizirani način, pa se ne može sa sigurnošću tvrditi da rezultati liječenja nisu takvi zbog drugih čimbenika Liječnici su također rabili i različite vrste mjerenja rezultata liječenja. Dokazi se odnose na istraživanja objavljena do travnja 2016.

Preporučuju se daljnja istraživanja učinaka sustavnog liječenja BKC-a u djece. Preporučuje se također i razvoj novih načina mjerenja učinaka liječenja uzimajući u obzir klinička mjerenja i mišljenje djeteta i obitelji o njihovu stanju.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Maja Bilić
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Резюме на простом языке

Системное лечение блефарокератоконъюнктивита у детей

Блефарокератоконъюнктивит (БКК) - это состояние, которое включает воспаление век и передней части глаза. Это заболевание встречается у детей и у взрослых. У детей с БКК возникает слезотечение, зуд, покраснение глаз, болезненность при ярком свете. У них может развиться потеря зрения из-за рубцевания роговицы, которую можно охарактеризовать как переднюю часть оболочки глаза. Для лечения БКК предлагаются различные виды лечения, включающие антибиотики, противовоспалительные средства и пищевые добавки. Иногда это лечение предоставляется в виде глазных капель и мазей, а в тяжелых случаях их можно вводить системно (обычно перорально). Также, возможно, детям легче давать лекарство внутрь, чем применять глазные капли или мази.

Целью этого Кокрейновского обзора было оценить эффекты системного лечения БКК у детей в возрасте от нуля до 16 лет. Мы провели поиск в опубликованной литературе и в регистрах клинических испытаний. Мы не нашли исследований высокого качества в этой области. Ни один отчет или клиническое испытание не соответствовали критериям включения этого Кокрейновского обзора. В исследованиях, которые мы нашли, не сравнивали варианты лечения друг с другом или с плацебо рандомизированным способом, поэтому мы не можем быть уверены, что обнаруженные эффекты лечения не обусловлены другими факторами. Врачи также использовали множество различных способов оценки эффектов лечения. Поиск актуален по состоянию на апрель 2016 года.

Мы рекомендуем дальнейшие исследования эффектов системного лечения БКК. Мы также рекомендуем разрабатывать новые способы оценки эффектов лечения с учетом клинических данных и мнения детей и их семей об их состоянии.

Заметки по переводу

Перевод: Укина Анастасия Олеговна. Редактирование: Александрова Эльвира Григорьевна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: cochrane.russia.kpfu@gmail.com; cochranerussia@kpfu.ru

Resumen en términos sencillos

Tratamiento sistémico para la blefaroqueratoconjuntivitis en los niños

La blefaroqueratoconjuntivitis (BQC) es un trastorno que incluye la inflamación de los párpados y la parte delantera del ojo. Se presenta en niños y adultos. Los niños con BQC presentan lagrimeo, picazón, enrojecimiento en los ojos y dolor causado por la luz brillante. Pueden desarrollar pérdida de la visión debido a la formación de cicatrices en la córnea, que se puede describir como el parabrisas frontal del ojo. Para la BQC se administran diversos tratamientos que incluyen antibióticos, agentes antiinflamatorios y suplementos dietéticos. En ocasiones estos tratamientos se administran en forma de gotas y pomadas para los ojos, mientras que en los casos graves se pueden administrar de forma sistémica (generalmente por vía oral). También puede ser más fácil administrar la medicación a los niños por vía oral que administrar gotas o pomadas para los ojos.

Esta revisión Cochrane intentó evaluar los efectos de los tratamientos sistémicos para la BQC en niños entre cero y 16 años de edad. Se realizaron búsquedas de estudios en la literatura publicada y en registros de ensayos clínicos. No se encontraron estudios de investigación de alta calidad sobre este tema. Ningún informe o ensayo cumplió los criterios de inclusión de esta revisión Cochrane. Los estudios que se encontraron no compararon el tratamiento versus otro tratamiento o placebo de forma aleatoria, de manera que no es posible estar seguro de que los efectos observados del tratamiento no se deben a otros factores. Los médicos también utilizaron muchas maneras diferentes de medir los efectos de los tratamientos. Las búsquedas están actualizadas hasta abril 2016.

Se recomiendan estudios de investigación adicionales sobre los efectos del tratamiento sistémico para la BQC. También se recomienda el desarrollo de nuevas formas de medir los efectos de los tratamientos que tengan en cuenta las mediciones clínicas y las opiniones de los niños y las familias sobre su trastorno.

Notas de traducción

La traducción y edición de las revisiones Cochrane han sido realizadas bajo la responsabilidad del Centro Cochrane Iberoamericano, gracias a la suscripción efectuada por el Ministerio de Sanidad, Servicios Sociales e Igualdad del Gobierno español. Si detecta algún problema con la traducción, por favor, contacte con Infoglobal Suport, cochrane@infoglobal-suport.com.

Background

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).

Diagnostic tests

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

Systemic antibiotics

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).

Tetracyclines

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).

Macrolides

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).

Beta-lactam antibiotics

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)

Immunosuppressants

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

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

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

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.

Objectives

To assess and compare data on the efficacy and safety of systemic treatments (including antibiotics, nutritional supplements and immunosuppressants), alone or in combination, for BKC in children aged zero to 16 years.

Methods

Criteria for considering studies for this review

Types of studies

We planned to include randomised controlled trials (RCTs) in the review. We excluded quasi-RCTs (e.g. those that allocated participants to treatment groups in alternating order of presentation or based on client identification number or date of presentation).

Types of participants

We planned to include children aged zero to 16 years with a clinical diagnosis of blepharokeratoconjunctivitis (BKC).

Types of interventions

We planned to evaluate systemic treatments, including tetracycline derivatives, macrolides, beta-lactam antibiotics, essential fatty acids (EFAs), prednisolone, azathioprine and mycophenolate mofetil. We planned to include studies that evaluated a single systemic medication versus placebo, and those that compared two or multiple active treatments. We planned to include studies in which participants received additional treatments such as topical antibiotics, anti-inflammatories and lubricants, warm lid compresses and lid margin cleaning.

Types of outcome measures

BKC is defined by both subjective symptoms and objective clinical changes. Improvement of symptoms is the major goal of treatment and is usually associated with a reduction in clinical signs.

There is no validated patient- or parent-/carer-reported evaluation tool by which to quantify the symptoms of BKC. The Quality of Life in Children with Keratoconjunctivitis (QUICK) questionnaire, a tool to assess the impact of a different inflammatory eye surface condition, allergic keratoconjunctivitis, on children’s well-being (Sacchetti 2007), has not been evaluated in children with BKC. In adults, the Ocular Surface Disease Index (OSDI) is a commonly used symptom measure, though recently Rasch analysis has demonstrated multidimensionality and poor targeting (Dougherty 2011).

As for clinical signs, the grading system based on BKC activity and damage allows an evaluation of treatment efficacy (Hamada 2012; Hamada 2013; Viswalingam 2005). Treatment success is reflected in a reduction of the activity score, which ranges from zero to three. Outcomes can be defined either as a change in activity score as an ordinal numerical value or, as proposed by Hamada 2013, as complete success (reduction in activity score to zero), partial success (exit value smaller than the baseline value) and no change (lack of treatment effect).

A composite scoring system such as the BKC activity/damage grading system may overcome the problem of inconsistent reporting in clinical trials, as observed in adult MGD trials (Asbell 2011; Nichols 2011).

Primary outcomes
  • Percentage of children who experience an improvement in symptoms, reported by the child or by their parents/carers, preferably measured by a validated tool or published grading system, at three months (± one month) after start of treatment.

Secondary outcomes
  • Percentage of children with elimination of all clinical signs of ocular surface inflammation ('complete success'), preferably measured by a composite grading system.

  • Percentage of children with an improvement in clinical signs of ocular surface inflammation ('partial success'), preferably measured by a composite grading system.

  • Change from baseline in best corrected visual acuity in affected eye(s) in logMAR measured using an Early Treatment of Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 m or, in younger children, with a Keeler crowded logMAR chart at 3 m.

  • Percentage of participants suffering from uncontrolled or poorly controlled disease progression due to treatment failure.

  • Percentage of participants suffering adverse effects of medication.

  • Adherence to treatment, as a percentage of (study medication issued minus residual study medication returned at end of trial)/(study medication issued).

  • Total amount of topical steroids (total number of drops) and systemic immunosuppressants (total dose) used during the trial duration.

  • Cost-effectiveness or cost-utility of treatments.

We planned to evaluate all outcomes at three months (± one month) after the start of treatment.

Search methods for identification of studies

Electronic searches

We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to April 2016), EMBASE (January 1980 to April 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 21 April 2016.

See appendices for details of search strategies for CENTRAL (Appendix 2), MEDLINE (Appendix 3), EMBASE (Appendix 4), ISRCTN (Appendix 5), ClinicalTrials.gov (Appendix 6) and the ICTRP (Appendix 7).

Searching other resources

We planned to manually search the reference lists of the trials included in the review for additional trials. We also planned to use the Science Citation Index to identify reports that have cited the studies included in this review. With both of these strategies we were aiming to identify any other relevant reports or trials that have not been identified by the electronic searches. We did not handsearch journals or conference proceedings.

Data collection and analysis

Selection of studies

Two review authors (ADN and MOG) independently screened the results of the search (titles and abstracts) to identify studies that loosely met the inclusion criteria of the review. We did not mask the review authors to the study authors, institution or journal. We divided studies into 'definitely include', 'definitely exclude' and 'possibly include' categories. We planned to make a final judgement regarding the inclusion/exclusion of those in the 'possibly include' category after we obtained the full-text copy of each article. We obtained translations of abstracts and, where necessary, full-text articles into English, where necessary, before we made a final decision regarding inclusion/exclusion. We took care to identify multiple reports of the same study and, where we identified these, we linked them together. We independently examined full-text reports for compliance with inclusion criteria. We planned to resolve any disagreements over which studies to include by discussion or through consultation with a third review author. We planned to list studies that we excluded after we obtained the full-text article in a 'Characteristics of excluded studies' table and we aimed to provide the reason(s) for exclusion.

Data extraction and management

Two review authors (ADN and MOG) planned to independently extract data using a data extraction form (Appendix 8), which we developed in conjunction with the Cochrane Eyes and Vision Group (CEVG) using Chapter 7 of the Cochrane Handbook for Systematic Reviews of Interventions for guidance (Higgins 2011a). Where data were missing or unclear, one review author would have attempted to contact the trial authors for unpublished data or clarification. We planned to make initial contact via email and if there was no response we planned to send a second email. If there was still no response we would have attempted to contact study authors by phone, and if this was unsuccessful we would have documented this. We planned to enter data into Review Manager (RevMan) (RevMan 2014); one review author would have entered the data and the second review author would then have checked for any errors.

We planned to collect the following information on study characteristics.

  • Study design: parallel group RCT, with either one or both eyes of each participant reported.

  • Participants: country, total number of participants, age, sex, inclusion and exclusion criteria.

  • Intervention and comparator details: including number of people (eyes) randomised to each group.

  • Primary and secondary outcomes as measured and reported in the trials, adverse events.

  • Length of follow-up.

  • Date study conducted.

  • Funding and conflicts of interest.

Also we planned to collect the following data for our predefined outcomes separately for intervention and comparator groups.

  • Dichotomous outcomes: number of participants followed up and number of events.

  • Continuous outcomes: number of participants followed up, mean and standard deviation.

Assessment of risk of bias in included studies

Two review authors were to work independently to review the risk of bias in included studies using the Cochrane 'Risk of bias' assessment tool, detailed in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b), as guidance. We planned to grade each parameter of trial quality as at either 'low risk' of bias, 'high risk' of bias or 'unclear risk' of bias.

The six main domains of the Cochrane 'Risk of bias' tool include the following.

Selection bias

We intended to grade studies as either at 'high risk', 'low risk' or 'unclear risk' based on the method of randomisation (sequence generation) and allocation concealment. If we had made an assessment of 'unclear risk', we planned to ask the study authors to provide further information to enable us to make a more detailed risk assessment. Examples indicative of a 'low risk' would be randomisation using computer-generated sequences or a random number table, the central allocation of treatments and concealment of allocation. We would have classified a description of "randomised controlled trial" without details of the allocation schedule as at 'unclear risk', and we planned to contact the study authors for more details. We would have classified lack of allocation concealment as 'high risk'.

Performance bias

Performance bias can occur if participants/carers or staff know which treatment group the participant has been allocated to. In this review, both objective/physician-reported outcomes and self-report of symptoms could be affected by performance bias. We were, therefore, to make a judgement regarding performance bias for individual studies.

Attrition bias

Attrition (e.g. following withdrawal or loss from follow-up) can cause bias. We planned to record incomplete outcome data. We intended to document the rate of withdrawal from each treatment group. Should study authors not have taken missing data into consideration, we planned to classify the risk of bias as 'high risk'. We also planned to classify the risk of bias as 'high risk' if the reason for missing outcome data was likely to be related to the true outcome, if the proportion of missing outcomes compared with observed event might have induced clinically relevant bias in intervention effect estimate (dichotomous data), if plausible effect size (difference in means or standardized difference in means) among missing outcomes might have induced clinically relevant bias in observed effect size (continuous data), if the study authors performed an "as treated" analysis with substantial departure of the intervention received from that assigned at randomisation, and if there was inappropriate application of simple imputation.

Detection bias

We planned to judge studies on their use of masking strategies. Detection bias can occur if outcome assessors know which treatment participants have received.

Reporting bias

Where a study protocol was available, we intended to compare the published protocol with the final outcomes to assess the risk of selective outcome reporting as 'high risk', 'low risk' or 'unclear risk'. Where no protocol was available, we planned to study the full-text article to make this judgement.

Other bias

We intended to judge whether the design of each study was subject to any risk of other bias not detailed above.

We planned to grade this as at 'unclear risk' if a publication contained insufficient information to allow us to make a judgement, and our attempts to contact study authors to clarify were unsuccessful.

The review authors were not to be masked to any aspect of the study design and we planned to resolve any disagreement by discussion or by consultation with a designated third review author.

Measures of treatment effect

Our primary outcome is dichotomous as are the first two secondary outcomes. We planned to use the risk ratio as the measure of treatment effect. LogMAR visual acuity values tend to be normally distributed, and we planned to use the mean difference with 95% confidence intervals (CIs) as a measure of treatment effect. However, we would have noted whether or not study authors assessed the symmetry of their data and also how investigators assessed the logMAR scores, as different charts may yield different values. We planned to use odds ratios for adverse events, as these are relatively good approximations when risks are rare (less than 10%). However, if the included studies reported a variety of adverse events and only one trial reported each type, we planned to simply collate this information. We also intended to collate information on adherence to treatment, simultaneous use of topical steroids and systemic immunosuppressants, and economic data.

Unit of analysis issues

Each child may have one or two affected eyes, and both disease severity and activity may differ between eyes. Systemic treatment should be effective in both eyes. We planned to include studies in which participants had either one or both eyes affected. The primary outcome (i.e. whether or not the child or parent/carer reports an improvement) could be measured at the eye level or at participant level; there is therefore potential for a unit of analysis issue. We planned to review articles to ensure that if the study included both eyes of the participant, the study authors had dealt with this appropriately by defining the "study eye" (e.g. the worse affected eye). Since treatment is systemic, a trial that uses fellow eyes as controls would be inappropriate.

Dealing with missing data

For each outcome we planned to assess whether study authors conducted an 'intention-to-treat' analysis. One review author was to attempt to retrieve any missing data by contacting the authors of the relevant papers. If we had failed to obtain the missing data but the study authors had adequately examined reasons for loss to follow-up and found that they were similar between treatment groups, we planned to use available case analyses. We planned to document whether the original studies stated that they compared the characteristics of participants with complete data with those of participants with no missing data and whether they provided any information about the possible effects of missing data.

Assessment of heterogeneity

We planned to examine studies for sources of methodological and clinical heterogeneity. We then intended to assess clinical, methodological and statistical heterogeneity by performing the following.

  1. We planned to examine the characteristics of the included studies.

  2. We intended to look for different directions of effects and poor overlap of the CIs on the forest plot.

  3. We aimed to assess the results of the Chi² test and the I² statistic with CIs. We planned to interpret values of the I² statistic as advised in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We did not plan to adopt strict thresholds for the I² statistic but typically we would be concerned if values were 50% or higher.

Assessment of reporting biases

If we had a sufficient number of included trials (more than 10) we would have constructed a funnel plot to assess evidence of publication bias, although we acknowledge that asymmetry in such a plot does not always indicate publication bias.

Data synthesis

Regarding data analysis, we planned to follow the guidelines in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011).

We planned to attempt to collate all data relevant to our primary and secondary outcomes. We intended to perform a meta-analysis on our primary outcome and the first two secondary outcomes. Some studies may report composite scores for signs and symptoms, and others may report individual scores for signs and symptoms. We planned to perform meta-analyses on the proportion of participants categorised into each of the three outcome groups based on composite scores.

We intended to collate the results of studies that reported only individual scores for signs and symptoms; we would not have included them in a meta-analysis. We planned to collate the data for other secondary outcomes, but to avoid any multiplicity issues and for review clarity, we would not have meta-analysed these data but would have provided a summary in tabulated form.

We aimed to use a random-effects model unless there was a very small number of studies (fewer than three), in which case we planned to use a fixed-effect model. Had we detected substantial heterogeneity, either methodological (by review of studies) or by large values of the I² statistic (as outlined in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b)), we might not conduct a meta-analysis.

Subgroup analysis and investigation of heterogeneity

We intended to conduct subgroup analyses based on the following.

  • Participant age (less than eight years versus greater than or equal to eight years), as adherence to treatment may increase with age. We selected eight years as the cut-off based on clinical experience, at around this age children are often more co-operative with assessments and treatments.

Sensitivity analysis

We planned to conduct a sensitivity analysis to assess how robust our review results are to the inclusion of studies at high risk of bias (by which we mean those that we judged to be at high risk of bias in any of the domains assessed).

Summary of findings

We planned to prepare a 'Summary of findings' table (Higgins 2011b). We planned to describe populations, interventions and outcomes as outlined above. We would not distinguish between low-, medium-, or high-risk populations. We present the proposed outline for a 'Summary of findings' table in Appendix 9. We planned to use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (see below) to assess the quality of the evidence (GRADEpro 2015).

The GRADE Working Group grades of evidence are listed below.

  • High quality: further research is very unlikely to change our confidence in the estimate of effect.

  • Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

  • Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

  • Very low quality: we are very uncertain about the estimate.

Results

Description of studies

Results of the search

The electronic searches yielded a total of 440 references (Figure 1). The Cochrane Information Specialist scanned the search results, removed 196 duplicates and then removed 199 references which were irrelevant to the scope of the review. Two review authors (ADN and MOG) independently screened the remaining 45 reports, but none met the inclusion criteria of this review.

Figure 1.

Study flow diagram.

Included studies

No study met the eligibility criteria.

Excluded studies

We did not review any study in full.

Risk of bias in included studies

No study met the eligibility criteria.

Effects of interventions

No study met the eligibility criteria.

Discussion

Summary of main results

No publications met the inclusion criteria of this Cochrane review. This means that there is no high-quality evidence of the safety and efficacy of systemic treatments for blepharokeratoconjunctivitis (BKC).

Overall completeness and applicability of evidence

As we could not include any studies, we were unable to address the objectives of this review. Some studies included children with this condition, but all were retrospective and none were randomised.

Quality of the evidence

The current body of evidence is limited to case series without control groups. This approach is restricted by a number of methodological limitations and bias. The quality of the evidence is therefore insufficient to make recommendations on treatment.

Potential biases in the review process

We based our approach to this Cochrane review on a broad search, including any reports on this condition. It is therefore unlikely that the search would have overlooked any relevant studies.

Agreements and disagreements with other studies or reviews

We are unaware of any other systematic review of high-quality evidence on this topic. Existing reviews did not grade the quality of the evidence, but are narrative summaries about BKC and its treatment.

Authors' conclusions

Implications for practice

In the absence of high-quality evidence about efficacy and safety of different treatment regimes, there is uncertainty about indications and effectiveness of systemic treatment. All published work consists of case series, without control groups. Outcome measures vary greatly and make comparisons between studies difficult. At present, it is not possible to make a recommendation to use systemic erythromycin or comparable agents, or essential fatty acids (EFAs).

Implications for research

Clinical trials are required to test efficacy and safety of current and any future treatments, such as systemic antibiotics (erythromycin, azithromycin and others), immunosuppressants and dietary supplements (EFAs). The first such trial should evaluate the most commonly used systemic treatments, oral erythromycin versus dietary supplements of essential fatty acids. There is a need for standardised outcome measures to be developed aiming to capture both objective clinical and patient-reported aspects of the condition and treatments.

Acknowledgements

The Cochrane Eyes and Vision Group (CEVG) created and executed the electronic search strategies. We thank Jennifer Evans and Samer Hamada for their comments on the published protocol and Anupa Shah for her assistance throughout the editorial process.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. Meibomian gland dysfunction

An international workshop defined meibomian gland dysfunction (MGD) in adults as “a chronic, diffuse abnormality of the meibomian glands, commonly characterized by terminal duct obstruction and/or qualitative/quantitative changes in the glandular secretion. It may result in alteration of the tear film, symptoms of eye irritation, clinically apparent inflammation, and ocular surface disease” (Nichols 2011). MGD is one cause of posterior blepharitis, an inflammatory change of the posterior lid margin. MGD may initially be asymptomatic; as it progresses, lid margin signs such as the expressibility and quality of meibomian gland secretions and telangiectasia of the lid margin may develop — then called posterior blepharitis (Nelson 2011; Nichols 2011; Tomlinson 2011).

Located within the tarsal plate of the eyelids, the meibomian glands produce and secrete lipids and proteins that spread onto the tear film, making it more stable and resistant to evaporation (Nichols 2011). Most commonly, MGD is caused by obstruction of the opening of the gland onto the posterior lid margin; this obstruction is often caused by thickened secretions and keratinised cellular debris (Nichols 2011). Age, gender, hormonal factors and medication can all contribute to the viscosity and quality of meibomian gland secretions and may be involved in the obstruction of the meibomian gland opening (Nichols 2011).

With MGD, the tear film becomes unstable and hyperosmolar, and evaporates more quickly, which leads to signs and symptoms of dry eye syndrome (Nichols 2011; Suzuki 2011). In human corneal epithelial cells in vitro, hyperosmolarity increases the expression and production of proinflammatory cytokines and chemokines such as interleukins 81 and 21, and matrix metalloproteinase inhibitors 1, 9 and 13, in a process mediated by a group of key signalling molecules called mitogen-activated protein kinases (Li 2006; Luo 2004).

The altered microenvironment associated with MGD may also allow increased bacterial growth on the lid margin (Nichols 2011).

Appendix 2. CENTRAL search strategy

#1 blepharokeratoconjunctivitis or blepharokeratitis or blepharoconjunctivitis or BKC

Appendix 3. MEDLINE (Ovid) search strategy

(blepharokeratoconjunctivitis or blepharokeratitis or blepharoconjunctivitis or BKC).tw.

Appendix 4. EMBASE (Ovid) search strategy

(blepharokeratoconjunctivitis or blepharokeratitis or blepharoconjunctivitis or BKC).tw.

Appendix 5. ISRCTN search strategy

blepharokeratoconjunctivitis OR blepharokeratitis OR blepharoconjunctivitis OR BKC

Appendix 6. ClinicalTrials.gov search strategy

blepharokeratoconjunctivitis OR blepharokeratitis OR blepharoconjunctivitis OR BKC

Appendix 7. ICTRP search strategy

blepharokeratoconjunctivitis OR blepharokeratitis OR blepharoconjunctivitis OR BKC

Appendix 8. Data extraction form

Review author      
Study ID      
Dates when study was conductedIf not available, comment 'dates not available'
Funding source(s)      
Declarations of interest by researchers      
Methods

Study design

  • Parallel group randomised controlled trial (RCT).

  • Paired eye or intraindividual RCT.

  • Cross-over RCT.

  • Other, specify.

Eyes

  • One eye included in study.

  • Two eyes included in study.

Risk of biasSelection bias
Performance bias
Attrition bias
Detection bias
Reporting bias
Other bias
ParticipantsCountry
Setting
Number of participants
Number of boys
Number of girls
Average age
Age range
Ethnic group
Inclusion criteria
Exclusion criteria
InterventionsIntervention 1 = active intervention 1
Intervention 2 = placebo or active intervention 2

Outcomes (as defined in study)

Please specify which

Primary outcome

  • Number of children who experience an improvement in symptoms.

Secondary outcomes

  • Number of children with elimination of all clinical signs of ocular surface inflammation ('complete success'), preferably measured by a composite grading system.

  • Number of children with an improvement in clinical signs of ocular surface inflammation ('partial success'), preferably measured by a composite grading system.

  • Change from baseline in best corrected visual acuity in affected eye(s) in logMAR.

  • Percentage of participants suffering from uncontrolled or poorly controlled disease progression due to treatment failure.

  • Percentage of participants suffering from adverse effects of medication.

  • Adherence to treatment, as a percentage of (study medication issued minus residual study medication returned at end of trial)/(study medication issued).

  • Total amount of topical steroids and systemic immunosuppressants used during the trial duration.

  • Cost-effectiveness or cost-utility of treatments.

PRIMARY OUTCOME
Improvement in symptoms
Intervention 1Intervention 2
Time pointTotal number of participants% with improvement of symptomsTotal number of participants% with improvement of symptoms
3 months      
       
       
SECONDARY OUTCOMES
Elimination of all clinical signs of ocular surface inflammation ('complete success')
Intervention 1Intervention 2
Time pointTotal number of participants% with complete successTotal number of participants% with complete success
3 months      
SECONDARY OUTCOMES:
Improvement in clinical signs of ocular surface inflammation ('partial success')
Intervention 1Intervention 2
Time pointTotal number of participants% with partial successTotal number of participants% with partial success
3 months      
SECONDARY OUTCOMES
Change from baseline in best corrected visual acuity in affected eye(s) in logMAR
Intervention 1Intervention 3
Time pointTotal number of participantsMeanStandard deviation*Total number of participantsMeanStandard deviation*
3 months      
SECONDARY OUTCOMES
Adverse events from uncontrolled disease progression
Intervention 1Intervention 2
Time pointTotal number of participants% with adverse eventsTotal number of participants% with adverse events
3 months      
SECONDARY OUTCOMES
Adverse events from interventions
Intervention 1Intervention 2
Time pointTotal number of participants% with adverse eventsTotal number of participants% with adverse events
3 months      
SECONDARY OUTCOMES
Adherence to treatment, as a percentage of (study medication issued minus residual study medication returned at end of trial)/(study medication issued)
Intervention 1Intervention 2
Time pointTotal number of participants% of issued medication usedTotal number of participants% of issued medication used
3 months      
SECONDARY OUTCOMES
Total amount of topical steroids and systemic immunosuppressants used during the duration of the trial
Intervention 1Intervention 2
Time pointTotal number of participantsTotal amount of co-medication used (specify)Total number of participantsTotal amount of co-medication used (specify)
3 months      
SECONDARY OUTCOMES
Cost-effectiveness/cost-utility
Intervention 1Intervention 2
Time pointTotal number of participantsTreatment cost, utility dataTotal number of participantsTreatment cost, utility data
3 months      
       

Appendix 9. Proposed outline for 'Summary of findings' table

Treatment A compared with Treatment B for children with blepharokeratoconjunctivitis (BKC)

Population: children aged 0 to 16 years with a clinical diagnosis of BKC

Settings: hospital eye clinics, ophthalmologists’ offices/clinics

Intervention: systemic antibiotics, anti-inflammatories, immunosuppressants and immunomodulators, dietary supplements

Comparison: placebo or other active intervention

Outcomes Illustrative comparative risks* (95% CI)

Relative

effect

(95% CI)

Number of
participants

(studies)

Quality

of the

evidence

(GRADE)

Comments
Assumed riskCorresponding risk
Intervention A Intervention B
Percentage of children who experience an improvement in symptoms, reported by the child or by their parents/carers, preferably measured by a validated tool, at three months (± one month) after start of treatment      
Percentage of children with elimination of all clinical signs of ocular surface inflammation ('complete success'), preferably measured by a composite grading system      
Percentage of children with improvement of clinical signs of ocular surface inflammation ('partial success'), preferably measured by a composite grading system      
Percentage of participants suffering from uncontrolled or poorly controlled disease progression due to treatment failure      
Percentage of participants suffering from adverse effects of medication      
Adherence to treatment, as a percentage of (study medication issued minus residual study medication returned at end of trial)/(study medication issued)      
Total amount of topical steroids and systemic immunosuppressants used during the duration of the trial      

*The basis for the assumed risk is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the intervention group and the relative effect of the intervention (and its 95% CI).

Abbreviations: CI: confidence interval; RR: risk ratio. GRADE: GRADE Working Group grades of evidence (see section 12.2.1, Cochrane Handbook for Systematic Reviews of Interventions)

Contributions of authors

MB, MOG and ADN developed the protocol. MOG and ADN screened studies against the inclusion criteria and wrote the Results and Discussion. FL and ST critically reviewed the clinical sections of the review. CB reviewed the statistical sections and MB reviewed drafts of the review.

Declarations of interest

ST, FL, CB, MB and MOG have no financial interests to declare. ADN is the lead investigator on research grants from Moorfields Eye Charity and Thea Pharmaceuticals, paid to Moorfields Eye Hospital and the UCL Institute of Ophthalmology, to develop outcome measures and study molecular pathways in BKC. She has no personal financial interest to declare.

Sources of support

Internal sources

  • National Institute for Health Research (NIHR), UK.

    The review authors acknowledge financial support from the Department of Health through the award made by the NIHR to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology. The views expressed in this publication are those of the review authors and not necessarily those of the NIHR, the NHS, or the Department of Health.

External sources

  • NIHR, UK.

    • Richard Wormald, Co-ordinating Editor for Cochrane Eyes and Vision (CEV) acknowledges financial support for his CEV research sessions from the Department of Health through the award made by the NIHR to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology.

    • The NIHR also funds the CEV editorial base in London.

    The views expressed in this publication are those of the review authors and not necessarily those of the NIHR, the NHS, or the Department of Health.

Differences between protocol and review

None

Ancillary