© Journal of Ophthalmic Inflammation and Infection pings COS Cres Corneal cross linking and infectious keratitis: a systematic review with a meta-analysis of reported cases serge LAlo™, Aksar Aboud, Dvd Dia Val oe Beer del Casio? and Jose A GegundezFernandez* Abaract Backgrounds Calagen cos Inking (CA) of the comnea has been developed recent 36a new teat for ‘rutrug resistant infectious keratts, The im of this study ito sumone he reviosypublened dota and ‘eluate the efectvenss of i texment Rests: The seach ident 12 ates. The numberof ees was 108. the fects Kas was assoc wth tuetera 58 eyes (57: Gram postive bate in 44 44 of which wore feed wih Mjecbartenum (78) a Gran-negetive cra 4 ees (1390, fang 13 eye (1 abd Acorthamoda 87 eyes) Ih 256 28, the ieebesogial culture was negate or nat peforned. The meantime of repthelzin ater CAL as 207 281 cays ito of 3, nmr of 149), Sten eyes underwer dec cx anlar kertoDus The Dood aa gered tht CXL Pa a faverble eet che lock of comes ming in 8 5 C1077 dan efees Conclusion: Atbough andomzed contol as 6 neaded, the aalable evidence sypeos the use of La she westment of inecious bre Keywords: Colage cos intng Infctous karat WN, Comes meting Background “Microb ert can incton of the cornea hat i sociated witha risk permanent val impaent [5 Jean be cated by bacterin ang, prtenea 2nd rast. The common ek for fo netous Keratiis Inch cclae trims. conta lens wet recent ols Surgery, pressing ocular surfce dese, dry eyes ‘orm comme sensation mpirment. hrc wa of topial sures and system immunosuppresion (6-8, The treniment sally cans of tier administered snubs If dagnoss and untaton of appropate ant ‘rerbil resent are delet as bee estimated that ‘nly 50% of the eyes wil ea with good visual aut 9). The emergence of mulidug-resstant bacteria a concen ha might copleate the ueatmant and cut of ct rn gt Aa @ Springer Infectious Keats considerably. Microbes develop rei her to antibiotic remit of chromo motion, Inductive expeesion of Latent chromosomal gees, oF fecha of ene mate ws trasdormation baer ‘hogetansdacton, or plasmid conjugation [10-12] Some Incr ket restart ta the newest ais ane ‘own eee esrb [1213 The high cont fs dog. ih freqency of ressance to antic, and rk of ‘comeal ling and canal sas make the choir of new Sppmaches very desabe. Clgen tos inking (CXL) {Garg ukravoke-A (UV"A) and rbodavin i a weatnest that was developed to erase the menial strength ef the com thus ging I posses 1o Block the pro- farsion of eratocon (415) The procedure is bast fn wng rion as 2 photosensitizer which generates reactive oxygen species when acted by UY-A 3 65 0 ‘roam. By way of photochemical eats, hse ge fae to coment bonds or cro inks in the comeat roma ibolavn, or viamia 2, sa naurlly occuringcompound and an extol human nutrient apance Scltss demonseated i the 1860 ha en when expo to visible o UV ight, could be used to inctate the RNA containing tobacco mosaic vrs (16. Resench has oon ners since 2000 in wing awn 363 photosnsizrto inactivate phages n psn, platelet nde ol procs [17-19] The potoetation of nio ‘awn damages the BNA and DNA of mlcooreanisns By ovation proceses. causing lions in chroma Sands [17-20 boa has planar ing stuture hat Interests between brses of DNA and RNA, stich re sults inthe endaton of ckie aids when Dunne Ribotvinindcss a change in properties ofthe ealgen tnd has 4 alflning eect on he corneal za, whch ties and ners is rstance to emote bacteria degradaon avoiding the progesion of corneal smelting (2122) Lintatons ef te apptation of UV are ‘mau he lac of penton an a stong dependence fon the distance fom the UV source, which mayest hhonbomegencous microbial imcsatin. The comple tions ated to UY lit should be careflly considered in patents yh cornea ules Usual, only 10% of UV Tighe pencrats the ator chamber and ira with ‘he ayers that contain anal concentration of bl vin In these patent, the penetration would be grester {nd would canoe endl el low A re of pal ations [2329 hare deserbed. that CXL was able 0 impeone healing in patie wh coil eat rd back the pogesn of comeal meting In tro experiments [3032 have mappte the view that thre fv bctrcdl fst of chi combination by ‘smonstration of bacterial slnination wing 365 am light photo activation of eboain, We analy the stud ies published on severe infectious bert tested th the core rss linking procedure The results nde that this could bea new toe inthe management of Infections Hert resistant to antibiaietestment In 2000, Schaar [3 Bet dered the ase of CXL to four patents suferng ftom matting uler ofthe cornea fof vaboas ergs. After the tentment of thece of the four paint, the melting peocess was Hock there fe, saver cates [252527 2931 38] are eseribed, bet {ystematic smal thee data ng Methods Published journal aries wore considered asthe ele ments of study and a specie Merstue search, was performed in for stage Stage 1 (Unique citations) - A Madne (Nationa! Library af Mediene Bethesda, Maryland, USA) search From January 200 [anary 2013 was performed dental aces describing the eatment of CXL a teem ero inking «erat it 0 2000 9 205 and [Ue or ‘Mrobi + Tet + ros, inking tit to 20000 2018 Sage 2 (Artie reel) ~ Al asrats frm the ‘Modine sexches were stint erty ares that reported cn results We excadd 70 or ‘mma states. Oi jurnal ates poised in “English were nuded. Copies af the artis were obtained, nd the ilogaphies were searched ‘mana fr sda artes pubsed ia poe evened journal Sage 3 (Artie mcson) - Compete articles were reviewed to ety toe that reported orga lina daa oe competion) of CXL uetment As the ‘numbers of articles were soe, we dood to nce a Stage 4 (Artie exlsion)- We exude al ares, that described the use of CXL bv reo ial. ate abstractions and analysis ‘A mytcaous and systeatic review of the complete Srtces war performed. All appro. information regarding expects of CXL teauent as analyzed The fpamaryouteome was the Healing of corneal usr, de ‘eds eithelizaton, with ao progessve ifiteaton, ‘lok of corneal meling al secondary ed pt ecoy cy of visual acuity. We evaluated the total pal and Invomplse relations of cme ules ae the proce ture: Adverse outcomes ae the progesion of melting, ‘corneal transplants, comeal decompenstion ad com pheatons teted to the procedure All data were razed using Micooit fae! (Miroslt Corporation, ‘Washington, USA) Patent popultion charetenscs ‘were recorded. Complstions and thee testment were hoted. To dxtermine the incidence of Bock comme tcking ater CXL, the sm of block comme meng was vided bythe total umber of patents foreach stay. ‘here were 12 aries on CXL eeatnent in infections oft [23 293438, Accoeing to the protcal forthe Cochrane sjtematic mete analy [9] all the articee Inded in the sty were csifed a evel 3 endence (Pom anahil stadia case reports, ene src). TO sues the validity ofeach study we evahatd the sink Tasty of groups a the burline the description of pi mary and secondary outores andthe presentation of the Fens Furteemire, the adequacy of reporting data ‘was ealated and the missing fallow up was taken int> ecoont. Thee parameter were cau at adequate arta inadequate and unknown, The ek of Bas was (Sahin. When al te erin were adequate, the sy ‘was dase as having low tsk of is. Within ths group we found three ste [26.3437] When ane ot Tote ceria were pataly met we dase the stl i howng 2 taerte rick of bine Fur stains wereTable Summary of published sud pes Goren rena (res a em 2oHK ‘ea i in eer) x ‘sn it sncaiem) wow eee7 sanseR az isa Unt ence ron le i at Alona el ra SC ere 10s van Sato nO‘nc in this category [2527293 i ve ston (232524358) one oF more cetera id not met the viene and thew stdes wore clase 3 Fuving 9 high rskebas- Results and discussion esate ‘tol of 12 articles wore selected, able 1 summarizes daa items from each popes Il papers were case repos for case series. "The total numberof eyes treated with CXL was 104 AS nove of the stds was anata, comparative satsical methods could not be apple Price im his ate [34], suggests tat 200 paiepanss would be requ t adequately test the hypothe of the eflcct of CXL om infetious keratitis and the enrol tent ofthe paints in hs atudy bal ia pogre A UVX lamp (PESCIIKE Meditrade GmbIt, Hucneberg Switzerland) vas dhe useument used ia most ase, Nine tudes [23-272436-38] pesformed the procadre sing ths estan A Vega CBM X linker (CSO, Florence, Italy was used in one study [28], and in ewo studies [29.5], the models of the iemtraments were not Specified Standard treatment ard parameters were used ial cases A 365-am wavelength of LV-A ight see eas used to leradlte the wee, carey avoiding the Timbal are Corneal surf radiance’ wax appre rmatly 3 mea” foe period of 30 la In al cases (32527-29438), dung the induction pein, 01% ibflavin and 20% dextran TOO drope were topically sdministered to the corsa for 3 poiod of 20 to 30 min {intervals of? to'3 min, Dring the ivadance, the ‘ministration of ibollrin was continued with ene fiop at Sin intervals In one study (971, hypotonic Tiber aw gued wen corse thickness wat lest than 400 yn, and only in one ate [34,36 patients tree randomized to diferent UV'A durations sing ‘eb ased random number generator. The fst 12 pa ‘eipane were rndomized to 15 or 30min. The proto cal was amended, and subsequent participants (1 = 28) tress sendomized to 30- or 45 mun treatments ater ‘Theo Seller, MD, PhD, suggested that duration sould pethap be lengthened for infections heratiti (personal fommuniation, Apel 12, 2010), Forty one subjects sere male and femal in some ats, the gender war hot specified. The average age was 528219. Ie was imple o extract deta dat of visual acuity fom Some studs. AE the fest vis, the average best erected vrul aesty (BCVA) wae O54 005 and at the end of flow up was 0.16 017. The best ests of CVA. are obtained in one patient infected sith Moraslla and two with Saurews. The worst were in patients infected with fang ane Myenbaceriar The Infectious Keratiis was associated wth bactera In 5 yer G7 Gram poutive bacterin 48 (43 of which were ince with Mycobacterium (361) and Gram-negative bacteria in 1 eyes (3), fangs i 3 ‘jes (128). and Acathamota in 7 eyes 8). I 2 {es (25), the mirobinigia clare was negative ot tot performed. The eof the infilete range Between (01 and 5 mm with an average of 27 mm. A the fist ‘st, I ees presented hypopyon. The mean time of piezo after CXL wae 207 #281 days (nnn ‘of 3: maxim of 195) Te possible to detect 3 ong period of epithelzation in elder patents (Pearson -O1. <0) and in patients infected ith Acanthamoeba nd Auprplus (60 t9 140 das) and Mjcabacterumt {20 days). We observed faster epihelization in Gram posite octet followed by Gram-negative bate, ‘Acenthameebs ane fargs. The duration of epithelia tion divided by each group of pathogens are summa Fed in Table 2. We observed very few completions after the EXL procedure: One eye developed comes! ‘loma and one hada severe dent sion, The fist je was afected with Candia and the second had egitive culture. The aniblotic and the antifungal teat sent were continued afer CXL fv 291269 day: The patients (16 eyes) fom the Makdoumt (28) study old bot have antibiotic drops. Acanthamoce teetnent was Toowed fr £0 day after CXL Sbten eyes underwent expo lamellar keratoplasty, Corel transplantation was Imote frequent in fungus followed by Acenthanceba sd Gram: postive and Gram-negative bacteria Table 3 ‘escribes the Incidence of taneplantation in cach {rowp. Eleven patents needed cores! transplantation for tectonie easons heather five patents aly neede Mul rchobiltation due to residual cornea sare, We ‘timated that the overall probably of Blocking cor teal melting and promoting eptheliation in patents ‘listed by lafectiour Kents teated wth CXL wae {5 (65% C1027, 091). The estimate of response was -guite sila Beewcen the tule (Table) Dicusion iboats deradton products ave boos stad for a longtime and have very high salty profes [7.15 Wil the caren applications and pepe ofthe UV A nd 22 dherapy in mind, we ventured explore ts poten til ue for tenting infections Kera Marinet [22) ‘Table 2 Tne of epithelzaton in days among diferent Patosers indo st sien o05 Come wansolant rated to iterentpathonens oil pathogens une of apd among ope ite pape 33) comaagunetsons MT (eaten ported in viroawide specu of izoonganis ra ‘ton Tere sens to be song evident the process auld ao be eet inact keri, According 0 Devious studies [23-2527-293438), the ueatment ems more fective to block corned! mln ia the folowing ord: in Gram-negative Bacteria (13/14 92%) followed by Gram-postive buctera (7/84 848), Acanthamoeba (517, 71%), and finaly fangus (8/3; 61%). Inthe Gram postive groups, the bacteria ih the worst outcome’ was Mfjeoucterium. All patienss Infected with this underwent corneal transplan ln Acanthamoeba the fce rakes generated by eatin, 52, combined vith Iydiogen pereatehned oxdation, seem t be succes n newtaizing Acanthamoeba gst [29] At the moment the dation of thi resent i ‘only fr Infcteus hte not rexponsve to antatic teste, but we cn eto think boat wang sean ternative treatment especialy for Acanthamoeba The ‘how inprtat ents terion the depth of nes thon Ife more than 250-um dep, the ek of endo fallos rtd to UNA bln i igher. urtherors, the efetivenes of thi teste ie lower the exp the Table Propetion of ey responding to XL in each stady Popuran oper ai OH Felons a ee 19S) ern Ome Mcafee a coe) soot OMA 9, ew 15 Soe 00ien 5) inflate. Fungal infection pene decper tan baci an ths partern can explain wby the teste i esse ect and more dangerous In the study of Miler [37] 8 tent iced wh Candid and teat by CXL devel {pot a camel edema de to nde fare, Pans 135] dscrbed rine mectansms faction i the healing of ‘oma ker ach a (I) ataton of pathogens bye ct damage to baer DNA [40 (2) neesel resstance to enzymatic deren (21 initiate by the inerese ‘valent bands inthe come toms cusng egreson ‘in ler morplogy. (3) inereased stromal tense strength nd ity of cornea cokagen, which may prevent mel ing (41, (4) wound healing by induction of apoptosis {ilowed by repopultion retring the arma catch tectre of the conc 15) (5) reduced suscep ofthe sue wo Us nani due to wivastuctrl ange [2 (6) cxnealeptelsrce reformation de to the ailey ef rbolvin in the devdopment and malauenee of the Saraesrctures ofthe epithelial ells (3), (7) ceria Steraton of function groups of nude acids Ia the ‘ceri, making repation impssible (4), (8) educon in inllarunatry so immune le), reduced no ‘elie reponse of corneal nerves tht decease pal 44] Si reduced tendency to generate vancalariation 83, “Another advantage of CXL I wo avd exergy erate ‘pln. This minnie eink adsl provide the ‘pportunity to pesform lamelc gratis 1 would so Be ‘cl to relact the rai of rection he retin rate ater emergency hertoplasty is much higher than standard Jeatoplay [5], There ae only «smal numberof tc Jes mvalble duc to the ethical problem of sdecting po tiets to tat with CXL without atin thom alfecing the result Inthe maou ofthese stdes this treatment was choven fo recurset and unreponsive atta Only the ptt fm the say of ako se csmeo%eoctal ura of otic tonto ain 20 347 tpn uconceanent 87 (24) wore nt at» severe tage: This the only sty in Thick the patent dl nat have anebotc drops Conclusion | In concosen, our cbverations show that corneal CXL coud be anew interesting way of handing Infectious erate CXL treatment supported by idence af effec in the cont of infectious ert stopping the progres of cornea ting, bt he absence a on tool groups in the studies published to date does ot low ts to inde this tretment ae mediately feasible. The tetment seems to be more effective blocking corneal melting in bacteria ard Acanthamneba than in gus, but the dine grades of severity of eats and the shure of standardization f0 vase this do not allow us to provide a clear al suggestion Furthermore a recent arte (46) showed 2 conritory outcome nthe appetion of CXL a bis neta wth ‘Acamhumocha Rerats, stating that this treatment was not efecte. On the other hand, another autor [7] pr Dossd @ combined treatment with amphoterin Band CXL in fang inecon In this may, the dag interacts ‘eth eh ing membrane tol forming tansmerbrane ‘nels and allows the ann ta eter ita the cll andthe destroy ts acti. We ave to bea in mind so that CXL with UY-A and tof ces core pe meaty (48) apd how tis sue ean afet postoperative leeatment. The expected complains of CXL tt ine tio Reais ae endothe cl lose reed to ung ‘ee indtation and entation of previ expe Det With the intention of avoiding these completions, tne propene the follwing ft to ala al patents wie {presi history of Hepes Herts second, 19 se Iyponmaty effin hen 2 deep intra ob served At present, CXL shouldbe consdeed in cases of Deere unrenponaeinkctous heat bore underakg tmergncy Ketopasty. Astudy to compare CXL vith encard opel ania eaten in which the ewerty ‘of heats and the infecting organism are homogenous regu occa poe dapper, Sere omorton ees SER Say nero amps re ‘Shines ion tAScaps ty rae mc pod cao ad en ea gear ‘Seon sno edn ed el re conitpment Semi apenn tye tom i roy (hf yh ve eo Sahn ad RONEN Nit natin taetgc, ame 0 pu ont (ican nt omer ae sa ‘Sra eters nanan Gas Seve Oto ‘Rg Ce UCase he os ‘on seman mance on See eee eet rreine ito een Seema Se enaieons Shovoeneeteartatere ere erin iar, akan nen dre 2 Seen iegieetoratore ee ee Seer tee cnr ed i meson eeio cti Seecesas ee smc sane gronae dra Bae a on acne eetessgemenentorsn » BEE macanmornentes innoctal ura of otic tonto ain 20 347 tpn uconceanent 87 » See creer ne Sone 0 ES er wearer, So cet nas, 1 EE tenuis incessant apes re EER a oes > Rel ec ere aoe eee cen eco or ‘Syren es Gorara em tector csr ats al Sri Pod ec ve a deer 2 Mtn ur atone se ena Ra ye Saco et A 93 Calg vee yar Suan ers tame € 2 Co out ‘sorcery acme mary uns ieameichssa oe a Sara etn OD Rd Resantemsey (ection Sen ey ‘inn ea ay rie >» Mame Scene cto hetanaoen, 10 (en amy te aoe then ge 20 10 Sh ia oma (scp utara et S708 co Kear coe ntetoensa-eon mr om eran 0 Tl an i DR yn cr tites may yumi ha as “4 Siocon net ‘ec ours Beetle ee! = RGR Se tomers 47, Bing B19 Cn gate mest ea Submit your manuscript to a SpringerOpen® journal nd benefit from: Pave ere| tne pen once Opn ase eo eee hey ita heater ese Sint eur nxt manic ae pingwopen com