Cross Linking Related Infections
Crosslinking (CXL) is a procedure where the cornea is exposed to UV light to promote a strengthening of the collagen fibrils. As with all medical procedures, there is a risk of infection.
Cross-linking is considered relatively safe because it has been shown to inhibit bacterial replication by oxidative damage to the DNA and RNA of bacteria, performing a tougher environment for bacteria to proliferate, reduction of inflammatory cells, and several other beneficial properties. CXL has actually been used in cases of microbial keratitis that does not respond to medical treatment. 
The rate of infection with the procedure is not known because it occurs so infrequently. In the multi-center clinical trial in the United States, one patient out of 102 enrolled developed an infection, which resolved after appropriate treatment.  There are also several case reports reporting infections. It may be that the epithelium- off CXL technique is associated with a slightly higher risk of infection because of the loss of the external barrier of the cornea, as well as the use of a bandage contact lenses in the postoperative period.
There are several bacteria that have been correlated with this condition,  and are often found in other infectious keratitis. They include Staphylococcus aureus, Streptococcus pneumonie and Pseudomonas aeruginosa. The process of infection has been studied in animal models.
- Pseudomonas aeruginosa: these infections are related to the use of contact lenses. The bacteria is a gram negative rod, found in the environment, often in moist places. P. aeruginosa is capable of secreting at least seven proteases: elastase A, elastase B, modified elastase, alkaline protease, protease IV, pseudomona aeruginosa small protease, and large exoprotease. These enzymes, especially elastase B, can produce severe corneal damage. Elastase A can cleave a host transmembrane protein, designated the protease-activated receptor, which, when cleaved, can start the production of cytokines. Small protease is able to cleave collagens, suggesting that this enzyme could be important in the destruction of the cornea.
- Streptococcus pneumoniae: these infections are often related to trauma and eye surgery. The outer capsule of Pneumococcus is formed of polysaccharides and is the most studied virulence factor. Besides its capsule, the pneumococcus has pneumolysin, a protein that is a toxin that is related to cell wall lysis.
- Staphylococcus aureus: S. aureus is the most common cause of bacterial keratitis. S. aureus has been shown to bind to human corneal cells in culture due to a fibronectin-binding protein on the bacterial surface, but this process may be aided by a collagen-binding adhesin on the bacterial surface. Despite this binding ability and the coccus, and the presence of the bacteria in the eyelid skin, infections rarely occurs. Perhaps the most important factor and protecting barrier is the phospolipase A2 enzyme found in the tear film, which may be compromised in people using contact lenses for long periods of time.
Pollhammer et al  reported a case of a 42 year old patient in which epithelium-off crosslinking was performed due to keratoconus. Three days after the procedure the patient had decreased vision (20/400), diffuse conjunctival injection, corneal edema, and multiple paracentral infiltrations in the corneal stroma with a moderate anterior chamber inflammation without epithelial defect. A corneal scrape and culture were performed where Escherichia coli was found. Treatment with toprabymicin 14 mg/mL and cephazolin 50 mg/mL was started. After 10 weeks, an avascularized stromal scar was left with a BCVA of 20/63.
Rana et al reported 2 cases of bacterial keratitis with subsequent corneal perforation after crosslinking. The first case was of a 19 year-old female with a past medical history of atopy with allergic eye disease, and a history of keratoconus referred with a painful red eye 3 days after transepithelial CXL. A large central cornea abscess was found with a 3 mm hypopyon. Corneal scrapings were taken and Staphylococcus aureus was isolated. Treatment was given initially with cefuroxime 5% and gentamycin 1.5 % at half hour intervals, as ciprofloxacin 750 mg PO. Seven days after CXL treatment a corneal perforation formed and cyanocrylate glue was needed. The infection could be controlled but left a large central vascularized scar, with a counting fingers visual acuity. The second case was of an 18 year old male referred with a corneal abscess in his right eye 5 days after CXL performed for keratoconus. Corneal cultures were taken and methicillin resistant Staphylococcus aureus was isolated. At 48 hrs, the cornea perforated and cyanocrylate glue was needed as well. The infection was controlled but the vision remained severely limited.
Perez-Santoja et al also reported a case of microbial keratitis after CXL. The case was of a 29 year-old woman with no systemic disease, and a diagnosis of progressive keratoconus. The patient was scheduled for intra-corneal ring segment implantation in the left eye, which was performed without complications. Later on, the patient was scheduled for CXL in the right eye, which was performed with the epi-off technique. In the first 2 follow-up visits, a well defined white nodules surrounded by small satellite lesions and hazy stromal infiltrate in the upper midperipheral cornea was found. Cultures were taken and Staphylococcus epidermidis was isolated. After control of the infection, topical fluorometholone 0.10% tid was added. Five months after treatment, the BSCVA was 20/22.
Sharma et al reported a case of a Pseudomonas keratitis after a CXL. This case presents a 19 year old woman with a 3 day history of pain, redness and decreased vision after one day after epi-off CXL for keratoconus. Of note, the author mentions that the bandage contact lens that was inserted after the procedure had fallen off 1 day prior to office visit due to excessive eye rubbing. At presentation, the visual acuity was hand motion. The cornea was scraped and Pseudomona aeruginosa was isolated. Following treatment, the infiltrates decreased in size and the hypopyon gradually disappeared, leaving a leucomatous corneal opacification. At 2 months the CDVA was 20/200.
Rama et al reported a case of a bilateral keratoconus in a 32 year-old man. He underwent an epi-off CXL and was treated postoperatively with a bandage contact lens, ofloxacin tid, lurbiprofen qid and artificial tears tid. On the following day, the patient noticed a conjunctival discharge and eye redness, so he instilled the medications and rinsed his eyelids with tap water. An ophthalmologist diagnosed acute catarrhal conjunctivitis and added levofloxacin drops qid. On the third day, there was progressive corneal opacification and a descemetocele. Despite aggressive therapy, the patient got worse and on the fifth day, a conjunctival flap was performed due to the descemetocele. Cultures were positive for Acanthamoeba. On the11th day, the cornea perforated and a therapeutic penetrating keratoplasty was performed. The postoperative follow-up was uneventful and the patient eventually achieved 20/40 vision with pinhole.
Kymionis et al reported a case of a 21 year-old woman who developed HSV keratitis after epi-off CXL for keratoconus. On the fifth day postoperatively the patient presented with a geographic epithelial defect, stromal edema and 2+ cells in the anterior chamber. PCR analysis was positive for HSV DNA detection. Topical coritocsteroids were discontinued and oral aciclovir 400 mg qid, methylprednisolone 32 mg qd and topical cyclopentolate tid was started. After 2 days the geographic ulcer had reepithelized and topical steroids were added. Two months later, a mild central corneal opacity remained, but the UCVA recovered to 20/25.
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