Lecture: Microbial Keratitis in the Developing World

DR. ROY: Thank you. So, hello, everybody. And thank you for joining in for today’s discussion on microbial keratitis. I’m Aravind Roy. I’m faculty at L V Prasad Eye Institute in India. Microbial keratitis, especially so in the developing world continues to pose numerous challenges to the clinical ophthalmologist. This is not only a cornea emergency, but potentially sight-threatening and organ-threatening as well. And therefore, as ophthalmologists, we need to understand not only the nuances in managing microbial keratitis. But also understand what would be a rational way in going forward in treating and saving the vision in these patients. So, we’ll start with a couple of cases just to give a perspective of how microbial keratitis presents in our part of the world. So, this was a young patient. In the third decade of life. And he sustained a minor trauma in his eye. And this eye was having a blurred vision and then there was some faint corneal edema in the eye. This picture is very typical of probably a stromal keratitis which is mediated. Nevertheless, it is important to scrape and see if there are any organism there is. At this visit, what we see was an epithelial defect and a small singularity. And this patient eventually developed a more dense kind of stromal edema in the cornea. So, we started them, and almost a week later, he started worsening. So, these are signs that perhaps underlying organism is very different from the virus. And then we start the scraping. And we found that this was a patient who had cysts. This is something very common in our scenario. It starts as a very early corneal edema and then goes. This is typical of keratitis. And this patient will need drugs. This patient was started on PHMB and chlorhexidine. And eventually, they healed with a scar and subsequently there was a plan for an optical PK done.
This is where the patient presented with a epithelial defect. There was a central corneal similarity. There was a melt in the cornea. The margins were feathery and ill-defined. And this was fungus. And the hypopyon was blurred. There was the hypopyon in the interior chamber. And they had scrapings and fungus, and then the patient was started on antifungals. It turned out to be a Acremonium species. Then the patient was following up and at one visit presented with a bilateral loss of vision. What we saw was very shocking. There was almost a complete corneal melt with the corneal infiltration. That was in the other eye. The eye we were treating, which was the left eye, this patient had a operation with the pseudocornea. Very dense and very unhealthy-appearing cornea. Extending right up to the superior limbus. So, the patient was planned for a corneal scraping, the TA+ BCL + AC reformation in the left eye. So, somebody is asking what is PHMB? This is an antiparasitic medication. This medication is standard treatment. So, this was the patient — the second patient and then he was accordingly plans for a parasitic — in the left eye and a large corneal perforation in the right eye. When we performed the microscopy, there was a gram-negative bacteria. And sensitive to only gentamicin. But resistant to other antibiotics. And the patient was started on 45 gentamicin in both eyes. And we saw that with the infections, it helped to control the inflammation. So, this was the patient after the tissue and the contact lens in the right eye. In the left eye, the keratoplasty was done. We continued to treat with antibiotics in the left eye. But there was a resistance of the hypopyon in the antechamber. And possibly with the occurrence in such a scenario, we wait for the steroid. And accordingly, we withdrew the steroid, because it was fungus to start with, and that could have been a possible secondary infection. There was a large graft mismatch with the graft override. That could be again added to the poor health of the graft on the surface and could have led to the possible non-healing of the epithelial on the graft in the left eye. So, this patient, again, the scraping was performed and we thought perhaps this was a time we should continue not only with the antibiotics, but also continue to treat subjunctively this eye. And this was a repeat of the keratoplasty in the left eye. So, this patient, again, the particular keratoplasty was done for this eye. And in the right eye, performed the TA again because the tissue had been lost and it was also lost. The right eye also because of persistent loss of the tissue. Again, it was done in the left eye, the right eye, two times TPK has been done, and it was negative. We could not ascertain whether it was the fungus to start with, whether it was the secondary infection with gram-negative bacilli, or something else. In such a scenario, it is not only difficult to salvage the eye, but is an extensive workup in microbiology to understand what could be the challenges and the possible organisms and how can we effectively direct our therapy against such organisms. This is another case where the patient, a 52 year male who sustained injury with a foreign body could be an insect or something. This eye developed a whitish black of the interior temporal paracentral cornea. And there was the condition. And it was involving the mid to deep stroma. When we scraped with the 10 potassium hydroxide, we found there was a branching fungal elements and hyaline. We started this patient on natamycin and also tablets. Eventually the epithelial defect started to reduce. But the plaque continued to persist and it was much more well-defined. And there was also a continued melting of the corneal stroma. There were the fibrinous membranes and continued the medication. Sometimes debriding can be — as a standard measure, it’s always been described that debridement is required to de-bulk the fungal load in the cornea. But sometimes debridement can expose the stroma to the inflammatory cells that are — or the inflammatory cytokines and actually accelerate the corneal melting that can happen in this microbial keratitis. This patient was requiring a plan because of the continued melt. But considering that this was a small-sized defect and there was some amount of cornea, and with descemetocele, we decided to continue with the contact lens tissue. And that was what was done. And eventually the patient resolved with this patient. If they had not, we definitely would have considered a therapeutic keratoplasty for this patient.
So, these patients illustrate that since many of the cases the incidence of microbial keratitis in Nepal, India, Myanmar, Bhutan is considerably higher than the United States. In a publication about 20, 25 years ago, they projected the rate of new ulcers that occur every year in India was 840,000 new cases of microbial keratitis. We are dealing with a high load and need to understand the changing demographics of this condition and also change the approach to such a condition so we are much well-prepared in handling this entity. So, just about a year ago we were analyzing the outcomes of microbial keratitis using the information from the pandemic lockdown and we found that during the lockdown, the primary examination with the local ophthalmologist was way more than it was seen before the lockdown. And the prior medications are also appropriate. There was much more severe keratitis presenting as compared to the type of cases which we used to see before the COVID-19 pandemic. So what it means is that if we compare a publication from our institute, about 15 years ago about 40% of the treatment that was done in the community was either indiscriminate combination therapy compared to operate antimicrobial therapy that is currently being prescribed. What this means with this study and the previous study is that the level of wellness in the community is much better. Which is a very welcome sign. Number two is that there is a lot of — there is a lot of awareness amongst the patients and also among the prescribing. When the community is treated well, is treated appropriately. And our care is a referral for those cases which do not resolve or those patients who continue to worsen with the local treatment. So, this could be because of the better understanding. Would be the better ability of drugs or the seeking behavior. There’s always been a dynamism between the tertiary and the community about whether to have an empirical approach, give a prod-spectrum antibiotic? Or chase the bug and get the microbiology? What should we do? Because sometimes the cases are very difficult. We understand the clinical picture write-up. And always we will not be able to perform a good scraping primarily because of the lack of the microbiologist service.
So, this was another paper which suggested that when the clinical picture is very obvious, that whether we are dealing with a particular type of organism, should we do microbiology? Is there a role of microbiology? Well, definitely the conclusion was that it is important to understand that not two ulcers are alike. Many organisms may have a final problem and corneal melting. But we should understand what is the underlying organism and treat that appropriately. So, management should definitely be based on a good laboratory workup. But the limitation obviously is that there is a need for well-equipped laboratory, cost of trained staff, cost and logistics. This is an example of how it is prepared. These are not commercially variable so the PHMB is prepared as a component in the pharmacy. And typically in centers like in India. Or a couple of other centers in India which when they get the request, we compound that and send it to the concerned physician.
So, as I was mentioning that most ophthalmologists cannot afford to — or do not have access to microbiology. But nevertheless, it’s important to understand microbiology and the leaps and bounds with which microbiology has progressed in handling ocular samples. And it’s also important to understand that ocular samples have extremely small in the quantity and they need to be handled with care unless that is not done, it’s easy to miss an organism. So, some of the new advances that’s happening in microbial keratitis, what has been getting involved now is the VITEK 2 Compact system forking looking at them. And it consists of a compact workstation. And then an analysis that happens and the barcode is generated. The codes tell us the type of organism right up to the genus and species. And then based on that, the final output tells us that what is the organism? What kind of drug this is organism is then resistant to. And how and where — how do we classify this organism? So, this is a reagent card which is one for every strip that we use. And for every sample, we use one card and the card is read by the machine and there is a normative database within the machine which classifies this into the type of organism that we might be dealing with over here. So, there is some — there are a couple of more questions also that, we yes, microbial keratitis can be cured. If scraping does not reveal anything, there are principles of imperial treatment. Sorry, there are methods in which we should perform empirical treatment. Typically starting with a broad spectrum antibiotic. Why start with that? Because most seen in our part of the world, they are primarily bacterial and not fungal. When we start with antibiotics, we cover them for a week and then we start to assess whether there is a response. If there is no response, then we should definitely stop for three days and then re-scrape again. I’ll be covering again in my subsequent slides about the principles of management of microbial keratitis. Coming back in microbiology, immunofluorescence assay is very important. Especially when we are performing a test whether there is an infection. For example, HSV which is a very common cause of microbial keratitis or viral keratitis. This is tagging and usually — it has a good sensitivity and specificity. When it is positive, it was usually suggestive of HSV infection. PCR again is a very sensitive technique. It has the sensitivity of 100%, but it’s not very specific. Meaning that while it can easily catch minute quantities of DNA. But it may not be able to definitely rule out a disease. So, again in this, the DNA is taken from the scraping samples. It is extracted and then it is amplified and in the system, the type of — the amplified DNA is subject to electrolysis. And they can help us decipher the type of organisms. And they’re recognized by the tag, what is over there. So, when we compared HSV-1 in a recent study and we found that both the combined IFA with PCR. IFA, immunofluorescence assay with germ staining, then it increases. If we have the PCR, we can easily catch the DNA. But having an ancillary test in addition to that will help us improve our diagnostic capability. Meaning we can rule out the disease in a better way. Meaning the specificity also increases. Then what has now evolved is the user for the real time PCR. What it does, it not only tells us that there is a presence of DNA, but it also tells us how many copy numbers exist for this DNA. This was a recent paper from our group which showed that if we have a type of say HSV infection, now HSV — and the population, anybody about 35 years of age would have HSV. But just having the DNA is not enough. Should we have the particular type of copy numbers or particular load of coupe numbers? When we see particularly high copy numbers, that means there’s an active virus. And the real time PCR which can tell us whether the numbers are low or high. Tells us whether there’s active replication of the viral particles or the viral DNA. So, this is an active infection. What’s next is the monitor of the user electroscopey. And that helps in identifying organisms. And next is the NGS, the next generation sequencing. This is analysis of the ocular microbiome. This tells us what is the different types of the genus and species that are presented on the surface. And it is a very sensitive test. It catches many organisms and the DNA that populate. There are many common cells on the ocular surface. And not necessarily the pathologic bacteria or the fungi that may be there. But the NGS helps in sequencing the entire microbiome or the microbiota of the ocular surface. It is important because there is a ratio of the common cell versus the pathogenic organisms. Whether there is infection, then the issue of the pathogenic organisms are much more compared to the normal cells that normally occupy the ocular surface. So, these are some photographs of the next generation sequencing performed from the ocular surface and the type of phylum, the classified, the unclassified fungi that may be there on the ocular surface. And they can always be presented as heatmaps where it tells us that what are the predominant types of genus that are there, or species that are there in each sample that we analyze.
So, in addition there are certain ancillary diagnostics that we can perform in microbial keratitis. And one such is the anterior segment OCT. This is important to understand necrosis, cystic spaces, areas of stromal perforation and presence of retro corneal plaques. This should be planned for surgical intervention such as kind of a deep laminar, with — we can document it. This is another case, there is a foreign body and the tissues that have been there. And this is beautifully captured by the, and this is optically clear part is the foreign body with the back shadowing. And there’s a lot of stromal edema and stromal in the edema. Confocal is primarily a research tool. And very few people have access to it actually. And those who need a fair amount of operator skill. And what it shows is that — yeah. And what it shows is that every organism will have a particular — it will have a particular morphology. For example, what we see on the screen is the fungal filaments. So, fungal filaments would be typically be highly reflective. And usually sized within 3 to 8 microns. They have irregular branching, but a very uniform width. That helps us distinguish that a deep-seated fungal infection can be easily seen on the confocal. Whereas just a scraping would definitely miss this organism. Similarly — typically, it’s highly reflective double wall around particles. And they are within the epithelial — the epithelial or the stroma.
So, what should be protocol in our laboratory workup and is it necessary? When should we do the empirical treatment? What would be the treatment if microbiology is not available? This is an important and interesting document recommended by the WHO. And it was also recommended by a grouch experts from Southeast Asia. And this document is freely available online. And I would urge all of you to go through this document to understand what can be treated at a primary level and what should be referred. So, a basic workup that anybody can do, even without access to microbiology is to perform a microscopic — with a simple slide and this is a very specific test. Meaning that it has a specificity of 92%. It easily rules out fungal infection. Second, if we see a lesion. But this is involving the full thickness of the cornea. It doesn’t appear to be very severe. It is paracentral. Not involving the visual axis. It’s unlikely that this infection will be fungal. And if it is smear negative, then one can start empirical treatment and start with broad spectrum antibiotics. I would like to understand what are the types of empirical treatment that you use in your clinical practice. So, we are launching a poll question and I request you to vote about your practices.
Okay.
So, the majority seem to use commercially available newer generation fluoroquinolones as you can see on the screen. There are merits of doing that. And in many countries, it’s available over the counter, especially in Southeast Asia. And there are I would say administering to the patient is. They may not be broad spectrum because many don’t have adequate gram-negative coverage. And secondly, there’s — the systems as well. Probably what would be best to use is one of the combination therapy with say Cefazolin and ofloxacin gentamicin. So, coming forth with the management scenario, why should we use the combination? Because it gives you the broadest possible coverage for the antimicrobial therapy. It provides coverage for gram-positive, gram-negative. And in case there’s a possibility that someone has missed in the smear. And until culture reports are available, sometimes the culture may not be possible. We can still cover against a lot of microorganisms across the spectrum. Second, suppose the ulcer is appearing to be non-severe. But it has a dry appearance, ill-defined margins. There is a plaque, it’s likely to be fungal. And we also get fungus. Then the likelihood of this being a fungus is high. I mentioned a couple of slides ago, you perform the simple microscopic, and we find out whether we are dealing with a fungus. We can start on the community level treatment with antifungal drugs. Now when we start the treatment with antifungal drugs and the patient is not suffering from a severe ulcer. Then there’s the priority that we can still treat and heal this ulcer at the community level. And if it doesn’t respond, if it continues, if the ulcer looks like fungal, but the smear is negative. Then this is a case where one should refer this patient to tertiary eye care. So, treatment with antifungal and anti-Acanthamoeba drugs should only be started after the guidance. Number one, all severe cases should be referred. What do you mean by severe cases? Severe cases are those where there is a keratitis. Number two, where there is an ulcers that threatening to perforate the cornea. Or an ulcer that is approaching the corneal limbus. All where there is possibility of associated keratitis. When there is a need for a keratoplasty. All is involvement of the ocular structures adjacent to the cornea. In those cases, one should consider referring to a tertiary cells. Then is there a role of fluoroquinolones, cortical steroids? Should we do monotherapy or combined? This was on the poll. We noted that fortified antibiotics are not commercially available. There is a limited shelf-life. There is issues in storing these drugs. The pH may change. And when we use them, there is usually the cost of toxicity. So, fluoroquinolones are easily available, easily prescribed, do not need to be stored under very specific conditions. And they can be very easily used by the patient and they are commercial formulations. And they are comparatively less toxic. But there are issues. So, when we look at the study, we found that gradually over the last decade or two decades, continuously there’s been the problem of drug resistance. And more and more isolates tend to be resistant to fluoroquinolones. So, what was susceptible is different. We need to shift to a different class of antibiotics. If we are looking at an ulcer which is smaller, less than 2 millimeter, non-severe and probably involving the stroma. It’s good to start with the fluoroquinolone or a cephalosporin. How long to treat? Typically as long as the you willer has completely healed. And we should not pay for an antibiotic. And rather when there is a scarring, then we should stop abruptly. Tapering is never done in prescribing antibiotics. Is there a role of corticosteroids? There’s been studies that shows that corticosteroids reduce the inflammation and the scarring. But sometimes they may accentuate the secondary infection as well. There have been numerous studies, good quality evidence that’s shown that there is very little impact of using antibiotics in connection with corticosteroids. This role is very limited and the treatment is at best avoiding corneal ulcers. Treatment — core treatment with corticosteroids is to be avoided. This is a 37-year-old male, there’s a dry-appearing lesion on the cornea. When we scraped, we found filamentous object. And there was the white microscopy, again showing the same patterns. This patient required antifungals. Now, antifungals come with different classes of drugs and there is a lot of change in the prescribing patterns that has been happening. And there are many anecdotal reports, the polyenes, imidazole and others are helping with it. Should we shift? And is there a role for the newer drugs such as voriconazole. The study published almost a decade ago, more than a decade ago, we found that still natamycin is the best possible drug we have in treatment of fungal keratitis. It has been found sob effective in specialist, voriconazole, but it’s found that the natamycin is a better drug and it helps to treat the filamentous fungi in a Bart way compared to, say, voriconazole.
In addition, there’s within a lot of interest in the use of intrastromal injections. The procedure is very simple to perform. In those deep-seated ulcers, it is important to insert the needle. This is a 29-gauge needle which is inserted into the mid-level of the stroma. The drug is typically divided into five doses and it is injected into the main stroma. We create an area of whitening around the area of the infiltrate. And I will be using this drug 360 degrees all across the area of singularity. And this helps to create a barrage of the drug around the lesion. Typically two injections have given 72-hours apart. And we try not to give more than that. The dose is 50 micrograms per ml. And this has to be fractionated and created.
So, the other thing that we look for is a collagen cross-linking in the setting of microbial keratitis. But again, collagen cross-linking has been designed for arresting progression, and not particularly for the treatment of microbial keratitis. But nevertheless, it’s found an interesting application in intractable ulcers. But there is no definitive protocol for applying collagen cross-linking. It might be more than the standard protocol that is used for collagen cross-linking might not be recommended for microbial keratitis. And a recent study also showed that there is no improvement in microbiological cure, no improvement in scar size. And there was no increase in the percentage of — and no difference in adverse events. And the need for TPK in the eyes for fungal keratitis. In bacterial keratitis, it’s still used. But it’s very variable. And while it can be used for small ulcers, but for large users, it may have very little implications. What also is being increasingly studied is the use of dynamic treatment. So, PDT is something that is interesting because photodynamic treatment helps in creating reactive oxygen species which has a killing power. And it helps to kill the bugs and help in ancillary treatment of microbial keratitis. In this, rose Bengal has been tried in different combinations and found to be much more effective in killing the bugs compared to others. So, this was a pilot study. And it was with a lot of enthusiasm about treatment of photodynamic therapy in patients that had accompanied — but again, these are also plagued by the same drug therapy. How many times we use what should be a standard application? And what should be the — so, in summary, it’s important to be familiar with the signs of managing corneal ulcers. The art of making a diagnosis definitely have a good microbiology support, refer to the guidelines. And understand that the role of fluoroquinolones, corticosteroids, newer antifungals, there are advantages and limitations and one should make decisions based on these limitations. So, thank you so much for your patient hearing. We can take a few questions before we end the session. So, there are some questions in the chat box. I’m going to start one after the other. One is that is there a role of biofilm? Biofilm is extremely important because that has been found to be one of the reasons of non-response to medications. And biofilm-forming bacteria have been extremely resistant to treatment. And that’s one mechanism by which bacteria develop resistance. Then in the case of small perforation of using groupless VCL so, groupless VCL is easy to do. And it doesn’t really require any surgical expertise. It can be a very simple way of intervening without performing the graft. But the limitation is that we can only perform this of a 2 millimeter perforation and not beyond that. But if it is 2 to 3, we may need other procedures like the graft. tectonic graft is the go-to if there is a large perforation. Corneal ulcers are caused but microorganisms. It could be because of a trauma. Usually in the developing world it is trauma during agricultural work or labors. Workers may get injured.
And due to some occupational hazard and may get infected. Could be bacteria or fungi or any other parasite. Fluoroquinolones are typically started in a loading dose. Meaning hourly it for the first 48 hours. Following which they are given in a maintenance dose of eight times a day until resolution. Following which they are abruptly stopped. So, these drugs are four times a day. It is given four times a day with the cataract surgery where we give these antibiotics as a profile active measure. There is no infection mere. We give the drugs to prevent any possible infection. Okay. Next question. So, yeah, frequency of topical. We have answered this. Okay. Next. Are there specific drugs for the use of intrastromal injections? So, typically we give intrastromal injections for fungal ulcers. And both and in this all, it can be given. Antibiotic the are typically not referred because they have had — the antibiotics are good. Penetration is very good. And usually the antibiotics reach the aqueous well. So, there is very less requirement of giving antibiotics with stromal injections. Metaherpetic keratitis is because of the excessive use of antivirals. There one needs to want therapy and allow the healing to occur. So, steroids, again, I would not use, or rather I would use lubricants and observe this case. And can ASOCT be the first line? Yes. Definitely it can be the first line investigations. But what we also need to understand that we may need to find out the delaying organism and start treatment accordingly. A major cause of microbial keratitis is a abrasion which gets contaminated because microorganisms are available everywhere. And in the bridge of the epithelium, one can have a secondary infection. And the role of photo coagulation, the studies show there is very limited role of photo cross-linking. All are being investigated. It’s found to have some promise for fungal keratitis. But it’s counter-effective. There is a role of doxycycline, yes. Because empirically, it reduces the amount of the corneal stroma. It is subjective. Many experts use it, many do not. Primary line of treatment of microbial keratitis is to use these drugs primarily as a combination therapy of fluoroquinolone with a cephalosporin. So, that we get maximum coverage for gram-positive and gram-negative. There’s a good drug, natamycin is a very good molecule and it is the first-line treatment for many types of filamentous fungus. That includes both — and also — so, definitely it can be a good choice of drug for filamentous fungus. The guideline on WHO, this is — you can Google this by WHO guideline for referral of antibiotics. So, sorry, not referral. Referral of microbial keratitis. So, this is how the WHO guidelines, microbial keratitis is some of the words. It’s freely available online. You may select and download it at your convenience. How to deal with adenoviral conjunctivitis? It needs only supportive treatment with lubricant eye drops. If there is a bacterial keratitis, just consider adding lubricants. Topical lubricants. Autologous serum I’ve never used in this. I feel it’s more useful in dry eyes. So, not sure about that. For bacterial, we use the combination antifungal — the broad spectrum therapy which is cephalosporin and — and the first line treatment is natamycin. In stromal inflection, those are for program, and we give about 0.1 to 0.2ml to this. And typically we use it, but you can also use natamycin. crystalline keratopathy, there’s an antibiotic.
Hypopyon could be infectious in fungal keratitis. May yield fungal. So, paracentesis is not required. Is there a role for sub conjunctival and antifungal? They are very toxic. It may lead to local necrosis and a lot of pain. Antifungal drops from capsules. I have no experience. It is the drug, if it is, yes. But I have no experience of antifungal drops. Compounding antifungal drops. Then a combination of gentamicin with moxifloxacin, yes, you can do that. And how to encounter keratitis from Pasteurella? I’m not sure if we have seen this organism. But you can have the microbiology to the sensitivity profile for this organism and do that. Stromal infections are contraindicated when there’s a — definitely we avoid giving stromal injections because that may need to perforation of the cornea. In pregnant woman, again, very difficult. One should use either azithromycin, or probably those that are having least systemic absorption so there’s no toxicity in the growing fetus. sensitivity and specificity of corneal scrapings are very different depending on how the study is designed. For example, in bacterial keratitis, the sensitivity is 80 to 85%, and specificity will be 68 to 72%. But it all depends on the number of samples we are taking from that study and how many positives we are getting. But the large rule of thumb is sensitivity and specificity are in the ranges of 60 to 70% and 80 to 90%. Contact lens can definitely cause keratitis. In such cases also in addition to microbiology culture, the solution, culture the lens. And find out the causative organisms. It can be caused by pseudomonas or fungi. It can stay in the eye and they can get blocked. Sub conjunctival injection, I don’t use them. They cause a lot of pain to the patient. Better is to use the topical preparation. And if you feel that the patient is non-compliant, then in those cases we can admit the patient and observe for a couple of days. Vitamin C, again, it’s just — it helps in collagen — preventing collagen breakdown. Common risk factor is typically trauma. Diabetes. Maybe corticosteroid use indiscriminately. All of these are risk factors. Intrastromal injections. Again, a lot of information is available on the Internet. But to simplify it, typically this is used in deep stromal keratitis, intrastromal injections. It can be given. 50 microgram per ml is the recommended dose. And it is given five divided by this to form it. You can look up publications on the web and also to the video that I showed. I think this video will also be presented on the Cybersight library. You can consider revisiting it should you need to refer to it. Fortified — we don’t make fortified antifungal. I’m not sure how to make that. But it comes as an injection. So, if we can have a pharmacy which can compound it for us, we can make drops. Steroids, I typically do not use steroids in the management of microbial keratitis. In severe keratitis, we try to refer to a cornea service. In those cases, we need to perform emergency corneal transplants. It’s important to send it immediately. If we cannot do, or we do not have the availability of the service, then try using a tissue additive. If not — if nothing is available and you are no a community where there is no cornea service available, try to do a conjunctival flap. That’s the last resort somebody can do. At least it will help heal the ulcer and reduce the pain. A new patient of MK has imminent perforation. Keep doing it in the theater, and keep the tissue additives or the cornea for transplant in case there’s a large perforation. But yes, scraping, we commonly do this procedure, but we do it in the operating room. Role of — I’m not sure about this. Antioxidants, yes, the supplements can be used. Can we be given intrastromal steroids? No, I have never tried. Usually given in ocular allergy, but not in the setting of users. Hypopyon has little role. It collects within the next 6 hours. The role is very limited. Sometimes fungal ulcers may have fungus in the deep-seated ulcers. It can be send for microbiology analysis and get a diagnosis. And NSAIDs are required for treatment of the ulcer. And the pain that is with them. In severe fungal keratitis if there is involvement of the sclera, yes we do evisceration. If antifungals are available, then we can prepare them from the systemic — and we can add an oral antifungal. Steroids in SPK. Probably not required. One can give. But SPK is beneficial for the microbial keratitis. It can be a variety of causes. So, it’s kind of a — it’s kind of a generic diagnosis. So, unless we do not know the cause, giving a steroid can be tricky. A cost of penetrating keratoplasty? Probably not much in any society. But what is important is the follow-up of the patient and the compliance to steroids after the keratoplasty. So, if a patient is not able to come, then the keratoplasty may not be very helpful in such a setting. And NSAIDs causing melt — I’m not sure about that. Usually it does not. But I’m not sure. Would you mean a topical NSAID, probably? But systemic NSAIDs, no. Okay, then. So, I think we have covered more than 50 questions and that’s amazing. All of you have been a very, very interactive audience. So, thank you.