OSN Cornea Health Round Table: Infection detection, prevention and treatment

At OSN New York 2014, Terry Kim, MD, OSN Cornea/External Disease Board Member, led a panel of experts in a discussion on detection, prevention and treatment of adenovirus, TASS, MRSA and MRSE, and endophthalmitis. Off-label uses were discussed.

Red eye protocol

Terry Kim, MD: Here is the case: A 39-year-old ophthalmologist complains of unilateral red eye and photophobia with watery discharge of 2 days’ duration. The eye is inflamed with some follicular response and acute conjunctivitis that may be viral, allergic or bacterial. How are you diagnosing patients such as this?

Jodi Luchs, MD: An accurate diagnosis is made only 27% to 50% of the time; even cornea specialists get it wrong half the time because the clinical picture can be confusing. There is a diagnostic tool that can help increase the accuracy of the diagnosis, at least to rule out adenoviral conjunctivitis, and that is the RPS Adeno Detector Plus, which is a simple test. Technicians can use it as kind of a red eye protocol when a patient comes in with those findings. The limit of detection is low — 6 ng/mL — so these tests are extremely sensitive and specific for epidemic keratoconjunctivitis (EKC). If you get the diagnosis wrong and you tell this patient that he has EKC when he does not, then he is going to be out of work for 2 weeks so he does not spread it around. There is a huge economic impact, not only for the individual but also for the system. Diagnostic accuracy is important.

Kim: A lot of these patients are treated with antibiotics because of the possibility that there is a bacterial component to the infection.

Terrence P. O’Brien, MD: That is a major problem. Prescribing unnecessary antibiotic not only adds costs to the whole health care pool, but also promotes increased selection pressure and increasing antimicrobial resistance. Adenovirus is an occupational hazard for all of us, so it is something that we want to watch out for and diagnose accurately with high sensitivity and specificity.

Penny A. Asbell, MD, FACS, MBA: One thing we have not mentioned is how contagious this is, and that is true in your office as well. You can train your staff to note a patient with a red eye and begin to evaluate him, instead of bringing him from room to room, from the auto-keratometer to some other machines, contaminating a lot of space and equipment. That impacts not just you as the treating physician, but also your other patients who will be seen thereafter. Those patients will remember if they came to your office for a cataract check and a couple of days later have a red eye. So if somebody comes in with red eyes, we right away begin this protocol to try to determine more specifically what is going on.

O’Brien: At Bascom Palmer Eye Institute in Florida, certain strains of adenovirus are always present in the community, and then at certain times of the year we may have appearance of the more virulent strains that can cause EKC. We have a red eye room where patients who are triaged initially in a Checkpoint Charlie-type system are put in the room, but they must be triaged correctly.

Kim: As far as viral shedding is concerned, if the patient has a positive test, how long do you tell him to stay out of work?

O’Brien: Two weeks. There are interesting data that show the virus can shed for even beyond 14 days. The virus can survive on surfaces outside of the body for up to 21 days, so as Dr. Asbell said, we have to be careful in our environment to make sure we are treating the environment as well as the patient.

Luchs: We can also use the Adeno Detector Plus to help guide whether or not the patients are still shedding. We can bring them back and retest them, and we can see if they are still shedding.

Kim: How are you going to treat this patient: with topical antiviral therapy, artificial tears, topical Betadine (Purdue Products), topical corticosteroids or topical antibiotics?

O’Brien: For years we have been searching for an effective anti-adenoviral medication, yet to date there is no commercially available FDA approved agent. I would be cautious with topical corticosteroids because there are studies that indicate that the use of topical corticosteroids can prolong the shedding of adenovirus, so corticosteroids are a double-edged sword here. Sometimes we would use them later in the course for a significant subepithelial infiltrate stage 4 and stage 5 adenoviral keratoconjunctivitis, but in the early stage, you may actually prolong the course.

The use of povidone-iodine antiseptic has been also suggested because povidone-iodine is rapidly microbicidal, also for adenovirus and even HIV, so if you catch the patient early, povidone-iodine might be effective in reducing the viral load.

Kim: What concentration of povidone-iodine do you use, and how do you dose it?

O’Brien: We use the same 5% povidone-iodine that we typically use in the operating room perioperatively. We have the patient apply it twice a day to both eyes in the earliest stages of infection.

Richard L. Lindstrom, MD: I do not see many of these patients, and I will probably be controversial here, but I have been putting these patients on Zirgan (ganciclovir, Bausch + Lomb). They probably will not shed for as long. Depending on the patient, I may even be a little bit more aggressive than that. I even discuss with the patient the possibility of having their significant other take it prophylactically.

Asbell: We did one in vivo rabbit study that showed the shedding for the adenovirus was down to 1 week, so we were kind of pleased about that. It did not change the clinical course in the rabbit, and it did not seem to shorten the redness that we noticed, but the shedding in viral cultures was decreased by 50% from 2 weeks down to 1 week. So I might treat both eyes, even the one that is not involved, and I sometimes suggest family members do so as well, but I do point out that it is not FDA approved for that particular use. We are about to start another study looking at the combination of an antiviral and a steroid together to see how that works out.

Tal Raviv, MD, FACS: That is a great point. A lot of us do use the steroid because the patient desires and needs something. Tears are not going to cut it. Steroids alleviate the symptoms, and the immune response is a big part of the redness, but using it with an antiviral, that could change how we treat this condition.

Douglas A. Katsev, MD: In 25 years, I have seen more aggressive EKC this year than I have ever seen. I am pretty quick to use a steroid and Zirgan to prevent some of the inflammatory complications that can happen with this disease. EKC is thought to be a self-limiting disease, but punctal stenosis and corneal opacity can cause long-term issues if inflammation is not controlled.

O’Brien: I agree with Dr. Lindstrom. You have to be very aggressive with this type of severe presentation. We use topical anesthetic and a nonsteroidal and then peel these membranes because permanent architectural damage to the conjunctiva can result that will lead to a permanent dry eye state, loss of goblet cells and even cicatricial changes with symblepharon.

What about when you get the subepithelial infiltrate (stage IV), these viral footprints that can linger for a long time, how do we treat them? We know they respond to topical corticosteroids, but the moment you taper or back off, they come back.

Asbell: I do not think there is all that much data on nonsteroidals and these infiltrates. First, I treat if there is a visual component. If the vision is good, I would not continue to treat with anything. There are a fair number of papers published on using topical cyclosporine, and it can work. It is not as effective as steroids, but you can taper one to use the other, to use less steroid over time.

Kim: My indications for using a topical corticosteroid in these severe EKC cases include severe pain, decreased vision from subepithelial infiltrates, and conjunctival membrane or pseudomembrane formation. After the acute infection, some of these EKC patients become visually symptomatic from these residual subepithelial scars in the cornea. Any suggestions as to what we can do with them?

O’Brien: We published an article about this and the potential role for phototherapeutic keratectomy, or excimer PTK. That certainly is something you do not want to use if it is the subepithelial/anterior stromal changes after herpes simplex virus because the wavelength 198 nm is in the ultraviolet range and that could reactivate herpes. But for adenovirus, we have had some success with using excimer PTK in select cases. We treat with ganciclovir 0.15% gel while using the corticosteroid as well.

Lindstrom: I have treated quite a few, usually just with PTK. Maybe I should have used an antiviral, but I thought of these as not infectious eyes that had adenoviral EKC years ago, when I did not really think there was going to be any chance of causing any recurrence. I did not think of it like herpes. So I never have used an antiviral.

O’Brien: You are correct that there is not the viral latency in the nerve as with herpes. So not reactivation in the sense of active virus, but reoccurrence of inflammation. It is rare, but there can be reactivation of adenovirus related inflammation. It has been reported.

Lindstrom: Well, what antiviral works, an oral acyclovir?

O’Brien: No, the topical ganciclovir 0.15% gel. Also, worry about possible HSV in this setting.

Lindstrom: I have not used either, and I have never seen a recurrence, but that does not mean I shouldn’t have been.

Kim: How long would you all wait then to do a PTK treatment?

Lindstrom: Out 2 years after an EKC if they have not responded to anything else. To me, they are a bunch of scars. I have not thought there was any active infiltrate; I actually had not thought there was a chance of reactivating it. I have never seen a recurrence, and they respond like any other superficial scar.

O’Brien: The tragedy is that some of these patients are using prolonged corticosteroids, and every year we have a case at grand rounds that has resulted in permanent steroid-induced severe glaucoma.

Kim: Back to the Adeno Detector Plus. How much does it cost, and is it reimbursable?

Luchs: The test itself is reimbursable. Cost depends on the volume ordered, but on average about $10 a test and reimbursement is slightly higher. You are not making a lot of money doing the test, but you are not losing money, and certainly what you are gaining in terms of the clinical information and the value to the patient is huge.

Lindstrom: I am just going to throw this out. A lot of people are promoting the idea of having a “red eye room,” and I am kind of talking to the comprehensive ophthalmologist now, who maybe does not really come at these kinds of cases. Perhaps the red eye room should be in a different doctor’s office. These are miserable patients to take care of. You might get it. Everyone in your office might get it. You really do not want these patients in your office, I don’t think.

O’Brien: Maybe they should be sent to the Red Planet – Mars.

Recognizing, managing TASS

Kim: Let’s change gears. Here is a new case: A 71-year-old woman undergoes uneventful cataract surgery, postoperatively receives a topical fourth-generation fluoroquinolone, an NSAID and a corticosteroid, and presents 1 day postoperatively without much pain or injection, but with edema, hypopyon and decreased vision. Is this endophthalmitis?

Luchs: You have to think about endophthalmitis, but one of the key things that does not fit with that presentation is that the patient has no pain.

O’Brien: And the timing, too. I don’t know if the patient was patched overnight, but you might expect that this would have started the day of the surgery.

Lindstrom: In real deal endophthalmitis, at least the ones that I have seen, patients would have pain, lid edema and a severely injected eye; they do not come in with a quiet eye. However, the toxic anterior segment syndrome (TASS) cases that I have seen do not have any pain; they just have blurry vision. Often they do not have hypopyon.

Kim: In this case, the surgeon found out that the surgery center had a TASS epidemic a day earlier, so obviously a concern here. How do you manage these cases of TASS?

Raviv: It is helpful to know that there are two or three other cases. Now your differential goes more toward TASS; maybe the other two cases did not have hypopyon and were more classic TASS. But just because you have three, it could also be endophthalmitis. If there is hypopyon in all three, I think endophthalmitis. I think 100% of retina surgeons who referred this patient would do a tap and inject at a minimum; then, if it is TASS, we would want to attack with steroids. When you are not sure and you have a compliant patient in the morning, I would try high-dose difluprednate in the office as sort of a differentiating factor of what to do next.

O’Brien: Regarding management, you are obliged to rule out infection. Once you have ruled that out, you want to be aggressive. I bring up the timing because with a pre-formed toxin, the insult occurs immediately. If I can catch a patient early, I would take him immediately back to the operating room and try copious irrigation with an anterior chamber washout because the solution to pollution is dilution. At day 1, though, the damage is probably already done.

Kim: You as the surgeon are going to be the key person to identify TASS, and you are going to be the key person who lets the operating room staff know because you are the only one from the OR who is going to see these patients postoperatively.

Some recommendations that have been listed are to examine your cleaning and processing instruments, document the lot numbers of all these products, keep a record of all the equipment that was used, and communicate this to your operating room staff and certainly your clinic staff. The American Society of Cataract and Refractive Surgery has a TASS Task Force that will do a site evaluation to help investigate and address the cause of TASS. You want to identify these cases as soon as you can and, as mentioned, possibly even bring them to the operating room and irrigate them to remove or dilute that toxic substance.

Lindstrom: I have never done that because they seem to respond rapidly to topical steroids, so I don’t know if I would bring the patient back to the operating room if they did not have hypopyon and just had a little more of the average corneal edema.

O’Brien: They can also have a variant of TASS called toxic endothelial cytotoxicity damage, and these are going to require an endothelial keratoplasty surgery. The pupils and iris are affected by these toxins as well, so the patient has a permanent mydriatic pupil in some of the more severe cases. So if you can get them early, which is the problem because typically we don’t, it might be reasonable to bring them back to the operating room, and I have had some success doing that.

Katsev: I tend to send all TASS cases to my retina colleagues right away. They tend to inject almost all of my TASS cases as if they were infectious cause. I cannot say that I have had that many in the last several years, but when they do come, they come in waves until you find the source.

O’Brien: Do they inject antibiotic and steroid or antibiotic alone?

Katsev: I know they inject antibiotic; I don’t know about the steroid.

MRSA, MRSE

Kim: Let’s talk a little bit about MRSA and MRSE, which we all know are major health care concerns, specifically for us in ophthalmology. We have seen an increase in this organism in our post-refractive as well as our post-cataract cases. All patients are at risk, not just health care workers and patients with exposure to long-term care facilities. There has been an increase in both nosocomial as well as community-acquired staph infections, and we all are currently doing what we can in terms of prophylactic measures, including povidone-iodine, antibiotics, treating the lid disease, paying more attention to the wound, and now we have wound sealants available as well.

Here is the case: A 61-year-old internist presents for routine cataract surgery. This is an internist who is exposed to the health care environment, who probably has a higher chance of having colonization with MRSA or MRSE, not documented. Would you change your management?

Luchs: Your concern is that this is someone who may be colonized with MRSA or MRSE. This might be a good case in which we can inject an intracameral vancomycin compound that we have available now that might give that individual that extra edge of protection.

Kim: For argument’s sake, let’s say this patient is colonized with MRSA. Now, are you going to do something different, and if so, what are you going to do?

Raviv: I use intracameral moxifloxacin, and I would continue to do that here if vancomycin was available. But recently I have started using ReSure ocular sealant (Ocular Therapeutix) in a few patients at high risk who come in with MRSA stamped on their chart, or they are monocular, or they have severe immune deficiency from oncology treatment. This produces a nice watertight closure. Even by applying pressure to the wound lip, I cannot get that eye to leak.

Kim: That is a good point. In terms of intracameral antibiotic options, there is a formulation of intracameral cefuroxime that is commercially available in Europe. Can you share your thoughts on the ESCRS study and if you think this is the right agent to use?

O’Brien: That was an ambitious landmark study in Europe that was conducted to compare the use of topical antibiotics vs. intracameral. In that case, it was levofloxacin vs. intracameral cefuroxime and advanced generation cephalosporin. Like in any trial, there were some issues with the design, like not starting topical antibiotic until postop day 1, but at least one question was answered: Intracameral antibiotics work, and cefuroxime has become the standard of care in Europe.

The problem with cefuroxime, though, is just what you have pointed out. Its spectrum of activity is limited and does not include MRSE or MRSA. I think we would use an intracameral antibiotic if it were FDA approved and commercially available, but we would want to have one that has better coverage against the organisms that we are concerned about in the United States.

Originally Published on Ocular Surgery News U.S. Edition