Rhino-orbital-cerebral mucormycosis has emerged as an epidemic within the COVID-19 pandemic. Its treatment requires a multi-disciplinary approach, and therefore there is a need for consensus among clinicians for a common management protocol. During this lecture, the doctors discuss different clinical manifestations observed in different specialties and their treatment approach. This will help us reach a common ground for a treatment protocol and, thereby, manage the disease effectively.
[Umang] Good morning, good afternoon, good evening to all my friends across the world. A lot of you know that India went through a crippling second wave of COVID just a few weeks back. We’re in a relative state of calm. While India continues to achieve stability over the existing COVID situation, mucormycosis, that is often wrongly also called as the black fungus, has emerged as a new challenge to India. Within months from being a rare condition caused by a ubiquitous largely innocuous fungi, it has been declared into an epidemic. The incidence of mucormycosis has risen more rapidly during the second wave and reports suggest that by the end of May we had over 15,000 mucormycosis cases in India. Various states have quickly undertaken measures, there are task forces, guidelines, arranging separate wards in hospitals for management, as well as procurement of drugs.
Why suddenly has this situation happened? It should actually inspire a lot of epidemiological investigation to identify the responsible causes. Some of the risk factors we know are high blood sugar, excessive use of steroids. And then things like potential role of industrial oxygen, impure water in skin and halos, unclean oxygen cylinders. Indiscriminate use of antibiotics, and some topical local higher grade medications also, some people implicate. None of these have been explored yet and I think it’s important to identify the cause so that we can correct it.
A lot of these patients have had hospitalizations and one wonders whether proper infection control measures need to be instituted in hospitals. And so that’s another area of importance of standardizing treatment guidelines and having good hospital infection control measures. We know since this is a platform through which a lot of eye hospitals and ophthalmologists would be participating, a lot of eye hospitals work in isolation. And ophthalmologists may not be the right doctor for the initial treatment, but then a lot of patients come to ophthalmologists because the symptoms start somewhere close to the eye. And yes, very quickly you can lose your sight. It is important that ophthalmologists learn to recognize the problem, what investigations are required, and what kind of a team is required to manage it.
We’re thankful for Orbis and Cybersight platform to discuss mucormycosis today. I think all of us as ophthalmologists need to know the disease today. And it’s a multidisciplinary approach to treatment of this disease.
And today we have a wonderful panel of doctors. We have Dr. A.K. Grover, the chairman of Department of Ophthalmology at Sir Ganga Ram Hospital. A very renowned oculoplastic surgeon, a teacher to many, and is a great prolific surgeon. Dr. Shaloo Bageja, a senior consultant in Oculoplasty Unit from Sir Ganga Ram Hospital. Dr. Manish Munjal, senior consultant in the ENT Department at Sir Ganga Ram Hospital, New Delhi. Dr. Shweta Gogia, again, a consultant in the Department of ENT. Dr. Atul Gogia is a senior consultant in Internal Medicine and Infectious Diseases at Sir Ganga Ram Hospital. Dr. Salil Bhargav, consultant radiologist, Dr. Chand Watal, chairman of Department of Microbiology at Sir Ganga Ram Hospital. We are very thankful to the entire team from Sir Ganga Ram Hospital who have had a lot of experience in managing these patients. I’m sure by now they are exhausted in dealing with these cases across, and it’s not just patients from Delhi, it’s from across North India that they get patients for management.
To moderate are my colleagues, Dr. Nishi Gupta, she’s the head of ENT at Dr. Shroff’s Charity Eye Hospital and my colleague, Dr. Sima Das, head of Oculoplasty. And they will be introducing the speakers. Over to Dr. Sima and Dr. Nishi.
[Nishi] Dr. Shaloo Bageja, can we request you to please start your talk?
[Shaloo] Good evening, everyone. I am thankful to Orbis and Dr. A.K. Glover and Dr. Sima and Dr. Nishi, for giving me the opportunity to participate in this webinar. It is a hot topic these days.
Mucormycosis, I will be basically discussing the clinical manifestation and diagnosis of mucormycosis, the opthalmic perspective.
It is a very known entity to us and we all know it’s a ubiquitous and opportunistic infection caused by fungi of the order Mucorales. Rhizopus being the most common. And because of the angioinvasive nature of the disease and the delay in diagnosis, the mortality rate has been reported as high as 80%.
In tropical countries like India, the environment is quite favorable for fungi to grow. And the prevalence in India has been reported about 80 times than in the developed countries. And diabetes is considered to be the most important risk factor in India and India has been called the diabetes capital of the world. While in the Western world, the hematological malignancy and the organ transplantation are the risk factors for mucormycosis.
Before the COVID era, we used to see on not more than two or three cases per year. But we have seen the sudden surge in mucormycosis cases, especially in the COVID wave two. This has been proposed that this virus is creating a favorable environment in which helps this opportunistic infection to grow. There’s a decrease in oxygen, the hypoxic state, increased glucose level due to the induced hyperglycemia or diabetes, and the acidic environment is created due to the diabetic ketoacidosis and the metabolic acidosis which decreases the vigorous activity of the WBC.
And the drugs prolong the mechanical ventilation and the drugs like corticosteroids and tocilizumab, which are used to save the life of COVID-19 instead affect the immune system of the host. And thus the COVID-19 virus is still also causes endophthalmitis and do cellular damage from both of these leading to lymphopenia and decrease in CD4 and CD8 T cell count. They increase the cytokines, especially the interleukin 6 and increases the ferritin level. And because of the availability of the free iron in the blood, it’s a fertile medium for the fungus to grow. And all these factors promote the growth of mucormycosis.
The big hallmark of mucormycosis is angioinvasion leading to thrombosis, infarction, and extensive necrosis in the tissue. We all know that spores are present all around us. We inhale it from the nasal cavity and immunocompromised patients they grow rapidly to the PNS and from there they spread to orbit. Either directly through the minor or through the eye and throat because either perineural/perivascular spread has also been seen. From orbit through orbital apex direct through the cavernous sinus or directly through the cribriform plate it may go through the portion of the cerebrum or in the perineural spread.
These patients have a wide spectrum of presentation and we should have a high aim of efficient. And we should be well aware with symptoms. They could have general symptoms like headache, fever, malaise, facial swelling, numbness, or jaw pain. And among the nasal they can present with nasal blockage or purulent or blood and discharge. One should peep into the nostril whenever there’s a high suspicion of the infection. Among the ocular finding they can present with the symptoms of bulging of eye, droopy eyelid, blurring vision or double vision.
The clinical signs as an ophthalmologist, which we see, are eyelid edema or periorbital edema, chemosis, proptosis, which is due to the increased inflammation and a decrease in the orbit. And the skin discoloration which is due to the thrombosis and necrosis. Significant necrosis of the tissue is present as a black eschar. Ptosis and ophthalmoplegia are both indications when the disease has extended to the orbital apex or the superior orbital fissure in wall. The patient may present with loss of vision or as a CRAO because of the retinal vessel thrombosis or the optic nerve involvement. We should not forget to see the corneal sensation because of the tri general involvement, the patient may have non-healing effect on trophic ulcer. And beyond the eye we should also examine the nose because both of the necrosis we may see the palatal eschar. These clinical signs we should also keep in this mind whenever the patient presents to us with sudden ptosis, or proptosis, or ophthalmoplegia.
Whenever there is the clinical suspicions of mucormycosis we should look with an endoscopy in the clinic or we can take the help of ENT colleagues and tend the deep nasal swab. And with the direct microscopy using a red KOH mount, we could have a rapid presumptive diagnosis. Showing the characteristic aseptate hyphae with wide branching and the specimen can also be sent for culture. The molecular method has now evolved and is a useful tool and shows the positivity rate of 70-75% and it also identify the strain of the fungi.
Whenever the sinus debridement is done, the specimen is sent for histopathology which in addition to the aseptate hyphae classify, we can also see the angioinvasion and the tissue infarction which is diagnostic of these.
Coming to imaging, MRI is the first contrast of the imaging of choice. CT scan can be done in those cases in which there is a contraindication for MRI. This imaging not only helps in the localization of the nasosinus limited or if it involves the orbit or if it has extended to the cranium. It also helps to know the extent of the disease so we can plan our management accordingly. This is the image showing the bilateral ethmoid sinus the T2 coronal image and showing the maxillary sinus of the left eye involvement with the inferior extraconal masking.
This coronal image showing the posts contraction, the non enhancement of all the muscles just indicating that there’s extensive disease. In this T1 image we can see the non enhancing medial rectus muscle with the orbital disease.
This is the diffusion image showing the bilateral involvement with the destruction of the optic nerve and tenting of the globe suggesting the extensive disease and we have to prognosticate the patient accordingly.
Some of the examples of showing the apical lesion and the extension into the pterygopalatine fossa.
Depending upon this clinical spectrum, these disease have to be as accurate as possible. Possible or proven ROCM. Possible is when we have typical signs and symptoms of the mucormycosis with a typical history and risk factor. Probable is called when they have supportive evidence of endoscopy or imagining. And we call it proven when we have confirmed it on direct microscopy or histopathology.
Depending upon our clinical examination and diagnostic modality, the disease can be staged. Initially it was divided into three stages by Nithyanandam S et. al. But now a more proposed elaborative staging has been proposed by Dr. Honavar who has clubbed up symptoms and signs including the diagnostic tool depending on the stage of involvement, and which help us reprise the patient and customize their care accordingly.
Here are some of the clinical examples of how the patient has presented to us. He’s a 47-year-old male who’s diabetic, vaccinated, one dose. He was home quarantined, he had no history of steroid but he developed symptoms four days after the symptom of nasal blockage and infraorbital hypoaesthesia. Presented to our ENT colleague. Ocular examination was within normal limits and the imaging showed the pansinusitis and he was managed accordingly.
Another patient, a 39-year-old male, was non diabetic, non vaccinated. He recovered from COVID but was readmitted because of the drop in oxygen saturation. He had received one cylinder of industrial oxygen and omnacortil for five days. He reported to have hyperglycemia but his HbA1C was 10.9, so he was a pre diabetic. He presented to us with the symptom of headache, discharge, facial swelling, double vision and diminution of vision.
On ocular examination, he had left side fullness, mild ptosis, ophthalmic grade of -1 to -2 and slight diminution of vision. On imaging he has sinusitis, along with a localized epsis in the lateral quadrant, a localized epsis averting the lateral rectus extending in the corneal intracorneal compartment.
Another patient who was non diabetic, not vaccinated. And he had received Medrol for six days only for persistent fever. And after two weeks he developed symptoms of facial swelling, headache and jaw pain. These non-specific symptoms should be kept in mind whenever we are seeing any patient. However, his ocular examination was within normal limits.
He had sinusitis with extension into the NLD and was well managed with an ENT colleague.
The fourth case is a 60-year-old female who had comorbidities. She was hospitalized due to low oxygen saturation, discharged, but she developed facial swelling. ENT colleague elsewhere had done a sinus debridement with partial maxillectomy. And after two weeks she presented to us with a sudden drooping of eyelid.
On ocular examination she had total ptosis, ophthalmoplegia, and drop in vision. And on CT scan, on MRI imaging, she had sinus debridement was done, but she had apical lesion with the sinus involvement.
Day two of admission, she developed a sudden stroke and we can see that there is a small growth in the ICA narrowing along with a multiple infarct in her training.
We can have a wide spectrum of the manifestation, presentation, and we should have a high amount of suspicion in these cases. The management, we have four critical factors we should keep in mind. Early and rapid diagnosis, reversal of the predisposing factor, good metabolic control. Administration of appropriate antifungal therapy and extensive surgical debridement is the key, especially the sinus debridement. Which not only decreases the load, gives us a specimen for histopathology, and improves the drug action on the affected tissue. Thus a multidisciplinary collaboration is a must for managing these cases.
Among the antifungal agent, liposomal amphotericin B is the drug of choice as it has lesser side effects and better survival rate. Triazole is almost available to use which can be used on day one and also in this present scenario when there is a huge shortage of this liposomal amphotericin B.
Coming to the oculoplastic perspective. We have three things in our area. Transcutaneous Retrobulbar Amphotericin, orbital debridement which can be done endoscopically or transconjunctivally depending upon the location of the lesion, and exenteration. Aim of the debridement is to remove the necrotic and the devitalized tissue so that we can reduce the fungal flow and the drug can have a better diffusion into the affected tissue.
Transcutaneous Retrobulbar Amphotericin B has been used in titration earlier for aspergillus mainly. Now there are a few case reports which show that there has been promising results and some have also used a catheter to irrigate the amphotericin B. And we can consider one of the first line option for the treating and salvaging the globe if the disease is not so extensive in the orbit.
This injection of amphotericin B is used for the limited or localized disease in the orbit. It can also be used in bilateral disease or with patients who have poor prognosis where the intraocular extension is severe. It has an off label use, it should be reconstituted with sterile water to prevent the precipitation of the drug. Dosage I prefer is one milligram per ml, the patient who have good vision, restored vision, for seven day. And 3.5 milligram per ml I use who have a gross diminution of vision or no perception of light for five days.
The injection of site we should choose depending upon the imaging where is the localized disease. If it’s medial, we can use the superomedial transcutaneous or transparent meripose or if you want to approach the intracorneal, or we want to use the intra, we should go through the lateral retrobulbar inferior orbit. We do have the complication, we can see the inflammation is there after the injection, but it goes in a day or two. And a compartment syndrome has been reported in the literature, but personally I don’t have seen any such episode in my practice. And before injecting the injection, we should also give lidocaine, depending on how sensitive is the patient. Sometimes the patient can tolerate it, sometimes we have to give lidocaine before injecting amphotericin B.
This is a patient who presented to us with no perception of light and we tried to salvage the globe. And you can see the disease in the orbit. This is the ADC was showing the hyper intense necrotic tissue. But post pre injection, they have shown a slight resolution of the disease. And so this is a promising modality of treatment and we should keep in mind if the disease is not so extensive.
Orbital debridement, as all you said, if there’s a localized necrotic tissue and we know that we cannot go with that and we have to debride all this and if not possible endoscopically, then we have to go through the transconjunctival route.
Another patient who had an abscess and then we had debride it transconjunctivally and post operatively the resolution was pending and improving moments.
Coming to the exenteration, this is the most destructive surgery. And there are no such guidance available with us for the exenteration. Basically in the clinic, judgment of each surgeon went to exenterate and literature has said that exenteration does not affect the patient’s survival because there are multiple factors involved in the survival of the patient. However, ophthalmoplegia and loss of vision and not the clear indications of exenteration. We have other modalities available to us so we should, if there is a localized disease we should go for amphotericin B injection or we could do the localized debridement if there’s necrotic tissue.
The clear indication of what I prefer in my practice for exenteration is the extensive disease, the patient presenting with a skin eschar or MRI is tenting of globe, extensive orbital disease, and there’s a stretched optic nerve, severe proptosis. These patients and these globes are not salvageable and we should go ahead with exenteration early.
This is another patient who presented with no PL and there are no enhancing muscles seen on MRI. These types of patients should be taken early for exenteration.
The apical involvement and the bulky cavernous sinus and the restriction of the optic nerve, so this patient was taken for exenteration. If you’re trying for a transcutaneous info, we should go for sequential MRI and every four days, four to five days at interval we should procedure MRI. And if we see the progression of the disease then we should plan for exenteration.
Our in burst of the head, at first we sometimes can’t save these patients, the patient had extensive debridement but still had the intraocular involvement.
I’d like to share my series and my experience at Ganga Ram Hospital. In COVID wave one we had only 31 patients. And 29 were diabetic and we exenterated six patients. However, in COVID wave two, we had 131 patients arrive with ocular disease. 102 were diabetics, 128 received steroids. And we had to exenterate 25 patients and bilateral disease was seen in 11 cases. There’s a huge number of patients with mucormycosis and the mortality was also high, especially in the active COVID patient.
Just to summarize, we should have awareness among the COVID care teams and they should have a high index of suspicion for Rhino-Orbital-Cerebral Mucormycosis. We should educate the patient on the time of discharge of the warning symptoms and signs. And the key to good outcome is early diagnosis, rapid initiation of medical therapy, and extensive and aggressive surgical debridement.
Prevention is always better than cure. Judicious and supervised use of systemic steroids, aggressive metabolic control, educating the patients, and to consider if there’s any role of prophylactic posaconazole in high-risk patients.
At the end I’d like to acknowledge Dr. A.K. Grover who’s been a guidance source throughout this COVID period and always in my life. Dr. Chand Wattal who is heading the microbiology department, Dr. Shashi Dhawan’s who’s the pathologist, Dr. Gogia has always been managing our patients and listening to our queries. Dr. Salil Bhargav, day in and day he’s teaching us about the MRIs and the progression and disease pattern. We have worked as a team with our ENT surgeons. And at the last and not my resident who has worked day in and day out with my toughest patients. Thank you.
[Sima] Thank you, Dr. Shaloo for that comprehensive talk. And we have a couple of questions from the participants. I’ll just take one of them which is related to the retrobulbar ampho B injection. You use lidocaine before giving the amphotericin injection. And if you use lidocaine, how much amount do you use?
[Shaloo] I use lidocaine, about .5 ml normally before giving the injection and wait for two, three minutes and then I inject the amphotericin. Of course, patients are already so apprehensive I have not tested them without lidocaine. But some people say they do use it without lidocaine and patients are comfortable. But I have not tried without lidocaine. I give them lidocaine before injecting the amphotericin.
[Sima] In your experience, what has been the success rate with this injection? How effective do you find that injection?
[Shaloo] In our 40 cases of this injection, six cases we had to exenterate. The rest were milder forms we were able to manage. But in those, also, in five cases it was mild to moderate. But they have progressed faster so we had to exenterate them. And the key is the sinus debridement along with a medial extraconal debride. Because they do the endoscopic debridement so most of the necrotic tissue they remove. So the load is reduced and thus the action of the injection is also more. But the days of progression in the sequential MRI, then we give the injection. But we do keep a close watch in these patients and we have to do it every fourth and fifth day, MRI scanning, to see the progression.
[Nishi] That was an excellent talk and I’d like to invite the next speaker, Dr. Manish Munjal. Dr. Manish Munjal is a senior surgeon in Otolaryngology Department of Ganga Ram Hospital and he’ll be talking on mucormycosis diagnosis and management, the ENT perspective.
[Manish] At the outset, Dr. Shaloo, I just don’t know these days, it’s more like a family than being colleagues. We are seeing each other day in and out. And not to talk about Dr. Shweta, Dr. Varun, all the eye and ENT residents, it’s that kind of situation which we are facing. As she has said, 131 cases treated so far. And even today, as of today, we have more than 60 cases admitted in the hospital. We are facing new problems every day. And through this forum, also I hope to have some light on that.
Being a very common disease, there is bound to be some slides which will be the same. But I’ll run through one of them. And as we have mentioned, we talk about fungal sinusitis because the basis of this fungal infection is the sinus and the nose mucosa. Out of them, but most of them are benign. And around 50 of them are the ones which cause systemic or CNS infections. And based on all these things they can be categorized into invasive as well as non-invasive sinusitis.
We very well see the incidence of non-invasive sinusitis all throughout the years in the form of allergies, in the forms of mycetomas. But whenever the fungal hyphae which where the spores they break into the mucosa, submucosa, bone, or blood vessels, they become invasive.
And based on that, there is a classification where allergic and fungal balls, they are, in fact, are mentioned under the category of allergies. And along with that the invasive ones, which are most dangerous, and in that also, the acute invasive fungal sinusitis infection which are broadly we’re to talk about, that’s mucormycosis, is the most dangerous. But of course there are some chronic variations that chronic invasive fungal sinusitis and chronic granulomatous also, which we see much during our clinical practice otherwise.
Why is acute invasive fungal sinusitis most lethal? Because the mortality rates are described in the range of 50-80%. Thankfully it is rare in immunocompetent patients. And basically it has two types of clinical populations in India that are involved and because one of them are the diabetics, which are heavily numbered in India. And the other ones are the immunocompromised ones with severe neutropenia as Dr. Shaloo had mentioned. That may include chemotherapy patients, bone marrow transplant, organ transplants, AIDS. And now not to mention about the post COVID convalescence patients. This is a new category in this.
The species, especially the mucormycosis species, we’re talking about the Phycomycetes class of the order Mucorales, also known as rhizophore mucous. And these are the ones which are the most commonly involved with this kind of a problem.
These species have an active ketone reductase system that enables them to thrive in a glucose-rich medium where the acid pH is also low. And basically it has been seen that the hyperglycemia leads to impaired neutrophil chemotaxis. And individuals with imparied Glutathione pathway are the most commonly affected. The Rhizopus species also favors an iron-rich environment and are frequently isolated in patients receiving deferoxamine, iron-chelation therapy.
The next thing is talking about these symptoms of such patients. We do have whenever there is an occurrence of patients, as Dr. Shaloo had mentioned the occurrence of headache, nausea, fever, lethargy, sometimes you will not find too much of symptoms other than this. But then, of course, one would like to see symptoms of nose, purulent discharge, stuffiness, a little bit of thick discharge coming out, a little bit of bleeding. And one symptom that we have found much infrequent and very specific symptoms is this intraorbital hypoesthesia. There are orbital symptoms that are beautifully described by Dr. Shaloo, where there is periorbital or retro-orbital pain, sometimes leading to ophthalmoplegia symptoms like diplopia, blurred vision. And of course we don’t want symptoms like these where there is convalescence, this convulsion issues, dizziness, unsteady, that means we have a brain involvement.
When we have a look at these patients you will also find sometimes a nasal and palatal findings. Where you find this gray or erythematous appearance in the initial part which can later on progress to black, necrotic masses. That’s black eschars. And from there we all know the name black fungus has found its place. Of course one has to do a very thorough clinical examination through neurology where we have to check whether there are any palsies, not to even talk about cranial nerve I, we always look at that. But other nerve palsies like II, III, IV, V, VI, and VII nerve also not infrequently as seen.
Smell sensation is usually a confusing thing, as I said, because in COVID patients that thing is sometimes invariably gone and it’s wrong to ask them whether they can smell the thing and it doesn’t lead to anything. But of course, ocular findings of cellulitis, proptosis, fixed pupil, or dilated pupil. And if the lid is not rising, III nerve involvement, also sometimes nystagmus and blindness that is seen commonly with these things.
We don’t want to see a patient in this situation where there’s already swelling coming in and both the eyes are involved and therefore early detection is the key. And we must recognize the symptoms before it is too late.
What are the keystones to management of mucormycosis? The first step is not uncommon these days, where there are panic video calls and all those things, but we must insist that the patient must come in for an ENT or an opthalmological examination. The second step would probably be radiological imaging if required. And if it is present not on the first meeting, there is a role of, as Dr. Shaloo also said, a very good role of nose endoscopy and subsequent biopsy or culture. There is, of course, a role of surgery, I’ll place the role of surgery a little bit above and over the medical management. But they go synergistically hand-in-hand, of course.
Even for radiology, as we mentioned, even small sinister examinations, just a little bit of thickening in this sinus. But if you don’t miss it, the amount it’s showing is a little bit of fat suppression and all is to be taken seriously and has to be correlated with the symptoms that the patient is giving.
Of course, some people do believe in a CT finding and there are many patients who do not like to get an MRI done initially because of various issues. Where good CT examinations also may reveal soft tissue thickening, hypoattenuating mucosa with aggravation, rapidly aggressive bone destruction of sinus walls. And also sometimes an isolated never before happening unilateral involvement of ethmoids and sphenoids also should give us a little bit of insight into the possibility of disease.
If one does an MRI which I think a contrast MRI is the investigation of choice. T1 fat suppressed image and T2 images are ideal. And we are learning them day by day where you do get a beautiful idea of the thickening around the cavernous sinuses and the optic nerves and everything. And investigating is very well possible.
There are some things I’ll run, I’ll not discuss them because Dr. Shaloo has already discussed, but this is one slide where this is an invasion in the cavernous sinus along with the vitreous and the intra cavernous part of IC getting engulfed around with the disease. Of course, there is suppression of image in the sphenoid which shows active disease in that part. And there could be small satellite infarcts also in the parietal in the temporal lobes which could be indicative of possibly thrombosis in the internal carotid artery happening on that side.
As I said, it is important that an MRI, whenever there is a definitively or a serial requirement for examination, an MRI is one of the best investigations of choice. And out of that, we have found that in early diseases obliteration of periantral fat around the sinuses is a good subtle sign of extension and needs a more urgent attention than just a sinus involvement.
The sample collection is one of the most, most sensitive and important part of treatment of mucormycosis and it should be really prompt. We must use peripheral tissue samples which encompass disease as well as healthy areas. Middle turbinate samples are great for biopsies, but one must take samples from these areas also sometimes where there’s not possible to do punch biopsies like this example. I think it just happened in the morning today, we sent it for a pus culture curate smear and it came out positive. These subtle areas of discharge from the antrum are very important.
We cannot miss, of course, these black eschars and with fungal mycelia as can be seen in this slide so easily. And such cases are very easy to diagnose.
But even then once we have done the sample, it is important to use too much of saline and these samples must be sent right to the microbiologist without any crushing or freezing. And they must be put for the best results within 15-20 minutes without any preservatives.
It’s always a challenge and only then you will get these beautiful, courtesy of Dr. Watal’s department, these slides where they have seen these beautiful acute branching aseptate hyphae along with these thickened ones. And a beautiful growth coming in later on.
What do we do when we have acute fungal sinusitis or a mucormycosis situation? The first thing which we have learned and especially in the era of diminishing availability of the vital drug amphotericin, is aggressive surgical debridement. That is one of the most important thing which we have learned in this wave and it has helped save many lives. And, of course, whenever we can we must start the antifungal therapy if possible, reversal of the underlying cause of immunosuppression. That is why we must, Dr. Atul Gogia will probably talk about it. How to schedule the dosage of steroids and stopping them. Recovery from neutropenia is one of the most predictive form of survivors and of course, the death rate is largely defined by the intracranial spread.
It cannot be treated alone as we have found out very well. We always had ophthalmologists along with us, but we have realized that this is much, much important to have an infectious disease physicians around us all the time. Because these are severely immunosuppressed individuals. Sometimes because of the nephrotoxic effects of drugs we need nephrologists, we have to frequently send patients to intensive care units. And intensivists, neurologists, and among us, both of us, we are required in these cases.
We must prognosticate early to all patients because we have a fulminantly fatal clinical pattern. And patients without sinus involvement also in higher stages may have mortality rates up to 50-80%. And of course, with intracranial invasion, mortality can exceed that also.
Important from the surgical point of view, as a surgeon we must realize that there are basically the most common three points of entry of this infection into the body, into the paranasal system, and into the skull. One is the most common which is the trans nasal group. The other one, which is opening up and we are showing an increased number is the trans oral route where it comes through the foramina, of the dental foramina. And the third one is the trans orbital.
From the nasal cavity, the fungus is seen invading the lateral wall mucosa, then from the turbinates, through the maxillary sinus, to the pterygomaxillary space and deep neck spaces. This is the infero lateral spread, it may reach the intracranium or the middle cranial fossa through the forum ovale placed laterally in the skull base.
From the superior, which is also sometimes very dangerous from the ethmoids, it can lead to the inferior skull basin, to the low and that is the superior spread.
From the ethmoids it can even go supero lateral and through the orbit apex, it can through the cavernous sinus, and then the supero lateral spread. And the posterior spread through the foramen rotundum, sphenoid, clivus, it can go to the middle, and various ways it can go into the brain.
From the dental foraminas, we can see the necrosis of the hard palate, maxilla and the premaxillary space. And of course the least common which is the direct orbital spread, can be through the conjunctival presence of disease. We have seen a few cases of this where there’s a pan global involvement and then subsequently the orbital apex and cavernous sinus get involved.
But the focus of our infection is this little space behind the maxillary sinus and this is called the pterygopalatine fossa. The disease then takes a route either superior laterally, superior, posterior, inferior. And this crucial reservoir of disease exploration must be included in all infections.
First of all, the team will decide the exclusion criteria for the management if the patient is very poor GC, there’s significant intracranial involvement, severely immunocompromised, all the other factors one should take a decision. Whether one can treat this person. But once you take the decision, the first thing you must really evaluate is whether you can do a widespread endoscopic debridement in this case. We have to stage these cases early for that. And later on things like orbital exenteration and multiple stages of surgeries and also check endoscopies form a part of treatment.
Although we have other classifications, we have commonly we will share later on our mucormycosis study group has staged them into five stages. We are trying to build a consensus on these stage where there’s subunit one side of the nose as category one, and then more than one subunit where there’s no lamina papyracea involvement and no skull base involvement. Then of course there is a stage three where there’s further lamina papyracea but not frank eye involvement. And then there’s involvement of the medial compartment or lateral spread into the pterygopalatine space. Then stage five is of course significant extranasal spread that includes the brain and all. It helps in prognosticating the disease.
One small clip for those who want to see how the fungus looks like. This poor man who already has orbital involvement. One can go in and see these disease processes, a necrotic mixed up middle turbinate. And going from there, we enter laterally into the space, the sinus called the maxillary sinus. We use these beautiful debrider machines which we use in normal face surgeries also and try to remove as much as the diseased part as possible. Along with that, you can see that so much devascularization of the sinus mucosa that when you are removing it these purplish patches of devascularized mucosa filled with pus pockets of the fungus, they come out in the thing and slowly, slowly you try to attain the areas of clearance.
Going forward sometimes you have to enter the maxillary sinus directly and this is called the Denker’s approach where we approach the inside of the cheek and go directly into the sinuses to break the free maxillary space and into the area which is the invertible force on the posterior wall. Furthermore, you have a situation like this. This is the pterygomaxillary space which we were talking about. It’s behind a very tough bone and later on we opened this space. After opening, these are the lateral pterygoid muscles and once you put in your instruments and try to take out the fat, one can see a lot of pus trickling out.
This is all endoscopic. Then, of course, once you’re sure the maxillary artery and all the severe vital structures are preserved, then you enter the space. And with a debrider you remove all the necrotic material which may include, unfortunately, the maxillary artery lumps. And here you can see the IV nerve vito segment, that’s the maxillary nerve reaching up to the foramen rotundum. Sometimes you have to do painful decisions like removing the vito nerve and have to reach up to the phenomena.
One little thing that I do sometimes is the decompression of the orbit. This is the lamina preparatia where there was significant orbital disease in the area of the medial compartment of the eye. And once you remove the lamina and you open up the periosteum, you see the pus trickling out. And this person, we could save the eye. One of the eyes that Dr. Shaloo showed, and with this we can really get some time to treat such patients.
Of course, I’ll not talk too much about, but the definitive therapy is usage of amphotericin B. I think Dr. Gogia will be talking a lot about that. We, as surgeons, do use this topical application through an atomizer spray of this amphotericin B in saline solution. It has been recommended at many centers, they are not clinical trials talking about its efficacy.
But in the end after a few weeks, this is the kind of mucosa you need to be looking at after surgery. And one little small endoscopy that you do once in a while that gives you joy that this person is not going to die of the disease.
As said, results pre COVID we used to have a survival rate of only 50%. And that was probably because the systemic manifestations of the mucormycosis came into it because of very serious diseases like renal transplants, bone marrow transplants, and things that you would see in a tertiary care center. In those cases, we used to still do surgeries, more than one surgery per patient. But we still used to have slightly higher mortality rate. But after the coming of the wave one of mucormycosis which we saw in December 2020, as Dr. Shaloo said, we saw about 30-40 cases. We were very, very disturbed with the amount of incidence, but we could save up to 60-70% of those cases. And that primarily probably was because of the immoreversal of the patient as soon as the steroids and everything was done. And we had only five mortalities on that post COVID group out of the 30-40 cases. This was the mucor in COVID time data at that time.
In the end, I would say that key points in COVID times is that a multidisciplinary team is even more important because the immunosuppression is often a different kind, people are coming out of COVID with all those complications and there is a steroidopathy, there is a multiorgan stress, there is also possibility of sepsis in these cases. Secondly because of amphotericin being less and less in amount, a wide surgical debridement is more required in even earlier times available. You get high dose amphotericin lipid complexes, one must do, but thankfully post COVID survivors are still better than in early times.
We are doing many projects on this. Hopefully we’ll have more data on this coming in.
Thank to everybody who was mentioned in Dr. Shaloo’s slide and also our young doctors, all over, not only Ganga Ram, but all over the place who have come forward and helped to bring this COVID menace to the minimum and hopefully for the disease itself. Thank you so much.
[Nishi] Thank you Dr. Manish. That was really a very informative talk. There are many questions in the chat box. We can take just one that says, what are the reports and incidence of mucormycosis outside of India?
[Manish] This comes out of a very interesting webinar which I had with Dr. Chakrabarti from PGI, he’s a very renowned microbiologist and authority on mucormycosis. And we were always discussing that, why do we have so many cases and the West has so many little? Because we had extensive talks and our hospitals are attached academically to Harvard School also. And they reported in the whole wave of mucormycosis, Boston Medical School could only report one case of mucormycosis. Largely said, 80-85% of mucormycosis population, rhino-cerebral mucormycosis is an Indian subcontinent. One of the things which our microbiologist, who I’d like to commend on that, is probably the presence of more fungus spores in the environment of the Indian subcontinent which might be one of the reasons.
But other than that, clinically speaking, there’s no doubt about the fact that in various use of steroids where it was not required in even mild to moderate COVID infections. Giving very high dose of steroids which was required for treatment, but without any monitoring of sugar in the houses and also in some medical treatment centers. Along with the fact that the steroids were tapered in a very, very long duration, that could be one of those factors. Then we all know that this fungus, it loves iron-rich environments and also probably heavy metals like zinc may have helped in the progression. These are the causes which were we can say definitely for sure that there’s some amalgamation of truth in higher incidence of mucormycosis in India. That I would definitely say. These studies have to be done in a larger level in more detailed level.
[Nishi] I think that answers the question. To add a little more to it. We can say the mucor was always there in India. But the cases reported in the literature are that we saw only one case in 1,000. And right now we are seeing five cases per 1,000.
[Manish] Yes, ma’am.
[Nishi] If we talk about one case per 1,000, so that means that incidence was also 80% more than the other countries, simply because of the causes that you have explained. I think that answers the question. Now Dr. Sima, we can invite the next speaker.
[Sima] Thank you, Dr. Manish. Thank you, Dr. Nishi. We will move onto the talk by Dr. Atul Gogia now. He’s a senior consultant in the Internal Medicine and Infectious Disease Department at Sir Ganga Ram Hospital. We know we do infections together which has a lot of systemic implications, the role of infectious disease physician is so, so important. I look forward to listening to your perspective, Dr. Goglia.
[Atul] Thank you, Dr. Sima. Thank you Dr. Grover and the Orbis team for having me onboard today. Actually everything has been so well covered, there’s hardly anything for me to tell. Actually, Dr. Manish only recently has told me that he has learned how to manage all the comorbidities on his own, so probably now our role goes down. Because with the current pandemic and the surge in all the cases of mucormycosis and this whole data, we all have been working as a team. We have seen that everybody has now seen the other side of the story.
My ophthal and ENT colleagues have already described all these symptoms and the focus, generally, of my colleagues is on these areas. It is the orbital, periorbital, nasal. This already has been discussed. We have to go beyond this as an internist or infection control.
We have seen so many weird pictures, so I wanted to make it a little prettier. This is the bird eye view of the whole story I would like to give you. This is how we would like. We, as internal medicine doctors, our job is more like a detective. We discuss that it’s mucor, we’ve discussed that it’s Rhizopus species. All these species are there which lead to this.
How does this patient get to predisposed to this disease? We’ve had enough discussion about the risk of COVID-19 person triggering, use of steroids, comorbidities like transplant, malignancies. But from time and whatever literare we have seen and whatever cases of mucor we have seen in pre-COVID times also, the major risk factor which I believe today also remains, uncontrolled diabetes mellitus. If you see all the literature, more than 80% of the cases would be having uncontrolled diabetes. And the newer trend which we have seen in recent times is use of voriconazole therapy and the azoles which are used as a major pre action by most of us clinicians. And that also has led to a surge in mucor. But it is not just steroids, it’s the other therapies also which are being used which are precipitating predisposing conditions for mucor to invade. The fungus is already lying there, it is ubiquitous, and it is just the invasion which is required and that could happen once there is immunosuppressed status. Long ICU stays happening in these patients, all these are adding up to an increased risk of mucormycosis which was a disease as was already highlighted by Dr. Shaloo and Dr. Manish, that we have been seeing cases earlier also. But the surgeons because the number of cases which have defected right now is large, the COVID-19 patients are large, a lot of patients are getting diagnosed or getting diabetes, so that is what is happening.
We all have already discussed about rhino-orbital, rhino-cerebral mucormycosis. But as internists we have to keep our mind and ears open because we have to see for other signs of mucor because that is something which is sinister. We’ve had pulmonary mucor, we’ve had GI mucor, we’ve had recent GI mucor presenting with perforation, we have disseminated mucor. Those things also have to be kept in mind while we are managing such cases. Although rhino-orbital and rhino-orbital-cerebral remains the most common where ID. But we have to keep our eyes and ears open to the rest of the systemic or other organ involvement which we may see in such patients.
As the diagnostic modalities have already been discussed. The most important part is a microbiological examination. No infection disease can be controlled by an apt microbiological sampling and by the apt department we have of microbiology headed by Dr. Watal, where we are directly informed of these kinds of things. It is very, very important to send in their sample whether it is a nasal sample or from the eye or from the bronchoalveolar lavage. And as soon as you hear that there are non-septate hyphae, you should start immediately thinking of mucormycosis, or zygomycosis as it was known as. And culture should be attempted to be sent. Culture should always be sent for speciating and later on also for us to be able to get good data from the microbiology lab for susceptibility to various antifungals. Because in the current scenario, we are already running short of the antifungal therapy.
This is just a pictorial representation. If you see the one on the left, the A, is how a typical hyphae mucor would look like. And the C is something which is like, see the aspergillus is how it looks like, the D one again, is a mucor. They are broad aseptate, so that is how.
This is where I have adapted some of the guidelines, which is the global guidelines for the diagnosis and management of mucor. It was a European group study where there are a lot of Indians also involved in this study. And as we already discussed, that we are having the maximum number of mucor cases across the globe.
If you see as currently we are talking about COVID-19 but other conditions like neutropenia, diabetes, trauma, or seeing not other symptoms have also been predisposing factors for developing mucor. And radiological investigation is the modality wherever there is. Whenever such a patient is presenting with high clinical suspicion, should be their facial pains, sinusitis, proptosis, imaging is to be done. MR preferably, or a CT depending on, CT would probably tell you the bone destruction better. And sampling, as we’ve discussed, a biopsy, histopathology, along with microbiology would help us.
Going on to the treatment. As we discussed, the most important aspect is multisystemic approach. It is just not only surgical debridement because surgical debridement along with medical management both have to go hand in hand. As soon as you are able to find out that there is a strong suspicion of mucor it should be treated like an emergency. Rapid action is to be taken. The purpose of surgical debridement should be threefold: disease control, histopathology, and microbiological diagnosis. Plus immediate treatment.
Initiation, all of us are aware that liposomal amphotericin B is the drug of choice. We should not wait for it to be started. As soon as we’re able to get hands on the drug it should be started. Full dose needs to be started on the very first day. Slow escalation is not to be done, that we’ll give a lower dose today and see how the patient reacts and increase the dose gradually, that is not to be done. Five milligram per kilogram on day one is the treatment. If there is CNS involvement, 10 milligram per kilogram is the dose which is to be given. If there is pre-existing renal compromise then we have to involve our renal colleagues, some patients. Or there are other drugs which can be given although they are second in line drugs. Drugs like isavuconazole or posaconazole which are both available in IV formulation as well as oral formulation.
The question always arises, how long do you treat these patients? How much amphotericin do you give these patients? The response has to be a clinical response as well as an imaging response. If you are able to establish a stable disease or a partial response, then that is a time you can think of switching over from intravenous therapy to oral therapy by way of posaconazole or isavuconazole.
Posaconazole is available in two oral preparations. One is a suspension and other are 100 milligram tablets. The thing is that if you are using a suspension, the thing is that you have to ensure that it is taken along with food, especially a fatty meal for adequate absorption. Whereas in the tablet formulation, this problem is less. It is 300 milligram twice a day for first days because I see people giving various doses in various formulations. It’s 300 milligram twice a day for day one and 300 milligram once a day from second day onwards, that is posaconazole.
If you go over to isavuconazole, again, the dosage is 200 milligram three times a day for the first two days and then 200 milligram per day from day three onwards. That is the schedule which you should follow. If you’re using an oral suspension of posaconazole it is 200 milligrams four times a day.
Surgical debridement along with this therapy. This just sums up what you have to do. Clinical findings and underlying features consistent, do an imaging, taper off, reversal of underlying disease which Dr. Manish highlighted. Most important is to get the steroids to as minimum or off. There is a lot of controversy as to how much steroid to give, who long to give. All patients who are moderate to severely ill only are to be given steroids. Mild patients, non-hypoxic patients steroid should completely be avoided. Blood sugar level control is very, very important. We have to ensure blood sugar levels target of less than 180 milligrams per deciliter which is, I am telling you, very, very difficult. We have been managing COVID patients for over a year now and the kind of steroid and the diabetes which is there, is very difficult to manage this hyperglycemia. And most of the patients sometime would require insulin infusions. But we have to do it, it is very important.
Immunosuppression therapy, if any other immunosuppressive drugs a lot of patients who are renal transplant patient getting COVID, high risk for mucor, getting steroids, they’re already on other immunosuppressive drugs, so we have to discuss this with our colleagues and get the immunosuppression to bare minimum, which we can do. Surgical consultation. Obviously we already know that without extensive resection/debridement, we cannot achieve a stable or remission in the disease. And as I’ve discussed in the previous slides that amphotericin for an initial three weeks, see their response and then switch over to oral drugs.
And when we are talking about salvage therapy, when we’ve done all this, still the patient is not improving, we can raise the dose to 10 milligram, add on the other drugs along with that. A combination therapy may be used. There are various other therapies which do not have any standardization/guidelines of use like hyperbaric oxygen, iron chelator, GCSF, interferon, and sodium bicarb for reducing acidosis. But these are all anecdotal and have been used in small cases. But not very, very substantial.
Just a brief overview of these drugs that I give before I wind up. Because we are using these drugs left, right, and center, we should have just a view of what these drugs. This is just a word about amphotericin B. We have only read about various formulations. With the current shortage, I am sure all my colleagues and myself are seeing all the variety of amphotericin coming. Someday patient is getting one variant and someday the other. We have to deoxycholate the conventional amphotericin B, we have the liposomal, we have the lipid complex, and we have the colloid dispersion. We have all the varieties are there. Their dosage is a little different in the sense that the deoxycholate, the dosage is 1 to 1.5 milligrams per kilogram. Whereas the liposomal and the lipid complex, the role as we’ve discussed is around five milligram per kg. And for the colloid dose it is four milligram per kg.
These are the various formulations which are available. These are the various structures. I’m not going to detail of these because of scarcity of time.
This is just a pneumonic for all those and we are aware of these side effects of amphotericin B. It’s anemia, muscle spasms, phlebitis, headache, hypotension, hypokalemia, thrombocytopenia, emesis, encephalopathy, respiratory stridor, increased temperature – that is fever, chills, immediate hypersensitivity, nephrotoxicity, and bronchospasm. You can all. And there are other rare side effects. As we have been using this drug extensively and in high numbers. We have seen rare side effects like conduction defects, cardiac defects. We have seen long term side effects of hearing loss as well. That is also from my ENT colleagues, we have to be aware that when we are giving high doses of amphotericin, we have seen patients losing their hearing.
Just a word about posaconazole. There is a lot of confusion I was telling you earlier, that various formulations are there. So as the preparation is 100 milligram, you should get that 300 milligram twice a day for one day, that is two doses. And then 300 milligram once a day. It is not 100 milligram three times a day or something. 300 milligram once or twice a day depending on the day. And if you’re giving this oral, enhanced bioavailability is there. IV obviously whenever there’s a pricing concern.
What are the common side effects which we see with posaconazole? Well, we can have neutropenia, we have anorexia, electrolyte disbalances, hypokalemia can also be there with posaconazole. There are neurological side effects of headache, paresthesias. Abdominal discomfort, diarrhea, flatulence, raised liver enzymes. So we have to monitor the liver enzymes and a lot of these patients already have raised liver enzymes so we have to monitor and very closely follow this. Rash and pruritus can be there and fatigue and fever are also some of the other side effects.
This slide is especially important because a lot of these patients are already on different drugs, so we have to be aware of drug interactions. You will be seeing transplant patients. Posaconazole has a lot of interaction with all these: sirolimus, cyclosporine, tacrolimus and steroids. If the patient’s on ART protease inhibitors there are interactions, cardiac patients, statins patients are getting, patients are getting calcium channel blockers, digoxin, and chemotherapy patients. We have to be aware of all these things whenever we are using these drugs because no harm is what is taught to us as clinicians. Do no harm is a primary aim, so we have to be aware.
This is, again, isavuconazole. We’ve already discussed the dosage. 200 milligrams Q8 hourly and for 2 days and then once a day.
Side effects. Important side effects being cardiac also, hypokalemia. And drug interaction. Again, it is very important to know the drug interactions there are a whole lot of other drug interactions which are happening. There is an increase or decrease in the levels of the isavuconazole drugs.
Just to sum up. We have to have a team approach, do and don’ts we’ve already discussed. Control hyperglycemia, we have to monitor blood glucose level post COVID discharge and in diabetics. Steroids have to be used judiciously. Use of clear, sterile water for humidifiers during oxygen therapy. Use of antibiotics and antifungals judiciously. This is most important which we have to do.
And what we don’t have to do is don’t miss warning signs and symptoms. Don’t consider all cases of blocked nose as cases of bacterial sinusitis, especially when the setting is there. And do not hesitate in seeking aggressive investigation as appropriate for detecting fungal etiology. And don’t lose crucial time to initiate treatment for mucormycosis.
Thank you, stay safe and strong. Thank you so much.
[Sima] Thank you, very much Dr. Atul for summarizing. I know it’s a never ending topic, but in the interest of timing we have to move on.
Dr. Nishi, would you like to open the panel discussion?
[Nishi] I would like to welcome you all on this interesting topic. We’ve heard a lot of interesting talks. And there are some of the panelists who have not put up their views. I would like to ask these questions first to Dr. Salil. I think as a radiologist you are the most important person in this era who actually guides us, what to remove and what to preserve. We all know that MRI is the investigation of choice, but there is a question from the audience also. And it would be good to touch that part also for you. If the MRI is not available, what is the significance of CT? Would you order CT and what are the things that we can see on the CT scan?
[Salil] Coming to the question, I would definitely order a CT, without any hesitation, in a patient who either cannot tolerate being in the MR cabinetry for that long or who is too unstable and is moving too much. And on a CT scan itself, there are about seven signs that are very specific for invasive fungal disease in the paranasal sinuses. A score of two or three or more of those signs is enough to be more than 95% specific. The difference between MR and CT comes only in the ability of MR to demonstrate which areas have a larger burden of disease. In CT we might see everything as an increased attenuation, in MR I am able to pick up more clearly that this specific area has a lot of fungal load and has necrotic tissue and is probably in need of surgical debridement because your drug won’t reach that. On CT that call might be a little difficult but saying that this invasive fungal is not difficult. In short, I would order a CT without any hesitation.
[Nishi] Okay, I think that answers the question. This was one audience who asked that and I would also like to add that there is an article by Madrid group et al that gives you seven specific signs that we can look at the CT scan. Like you can orbital invasion without any bony breach. And there are other little signs of subtle ulceration et cetera. Those who do not have access to MRI can go for CT scan but yes, we all agree? Yeah?
[Salil] I would like to add a small point. As ENT surgeons, generally when you order a CT, the scan center or the hospital is used to printing films in bone window. But when you’re expecting mucor a soft tissue window is very important. Just as you described, finding tissue on either side of the sinus, whether it’s the maxillary sinus and you see tissue and in front of the sinus in the premaxillary space, or behind in the retroantral or pterygopalatine fossa. Just seeing that soft tissue’s enough, on both sides of the bone without significant bony destruction, or even some rare infraction is enough to say this is probably invasive.
[Sima] Question. How reliably we can predict necrosis on MRI? I know we are relying a lot on MRI to tell us which are the vital and devitalized area. So how predictable is that?
[Salil] Necrosis in mucor is of two types. One is necrosis because an area of soft tissue has been replaced by fungus. That can occur in the premaxillary area of the retroantral pterygopalatine fossa or the medial orbit. The other kind of necrosis that happens is necrosis distal to the site of an arterial involvement. You can have involvement of the palatine artery and then in front of the palate without actual mucor disease in the palate.
Both of these types of disease will show low enhancement on the post contrast study. The T2 weighted images and the diffusion weighted images tend to show T2 high point density in areas where there is fungus. And not if it is just an area of infarct which has varied other signals. But the characteristic signal of fungal tissue is they’re replacing a particular area is very characteristic. Using T2 diffusion and contrast, you can pretty much characterize an area of being a reactive edema, inflammation, infection with inflammation, infection with obvious devitalized tissue and necrosis, an infarct as in BOLD infarcts.
[Sima] I would like to move to Dr. Watal for a couple of common queries related to the microbiology. We know that some of the guidelines do ask for a positive microbiology report even for initiation of the treatment in some situations. Especially in these days when we have a large state and some of the medicines sometimes are in scarcity. What is the sensitivity of the KOH or how reliably we can just find it out on KOH and what is the sensitivity of doing a blind nasal as well in case when endoscopy is not possible in the location?
[Chand] This is basically an unscientific question because this is guided from the guidelines from the government that we wouldn’t give you the medicine. Having said that, you see the limitations of the microscopies have with whatever you may say. It depends on the eyes behind the microscope that is actually looking at the slide and trying to give you the diagnosis. If you look at the literature that the KOH has the sensitivity of around 73-80%. But unfortunately the specificity is relatively poor, it drops down to 35-45%. Whereas if you look at the cultures it’s the other way around. But unfortunately cultures our sensitivity’s around 46%. This is the KOH and it depends suddenly its sensitivity can go as high as 80-85% depending on the experience of the viewer who’s trying to process and look at it.
It also depends on the type of sample that you are giving, how good the sample is. You refer to a swab, but the swabs are actually not the good samples except when we said that some samples we took a chance and we found hyphae in that. But you would not know the region as it is. Many times unless you take a biopsy or the tissue and the margins, you will not be able to get the diagnosis as in a confirmed manner at all. You may get on a swab, just aspergillus which is maybe misleading because these are very common cells as well. And when you do the biopsy you can see actually it is a mixed infection or you discover mucor there.
These are the things when Manish said that you do a histopathology oblique culture, it does not have to be the oblique. It has to be done both because for sure the invasion, the histopathology will tell you, whereas we will tell you KOH culture primarily in the KOH, which is the quickest way of knowing once the sample is there. In another 30 minutes we can reach back to the clinician and tell him that we are faced with a mucormycosis.
Because it’s so classical. Any microbiologist who has seen it once will never forget it all his life. These have a very characteristic appearance and it’s very difficult to get a wrong diagnosis by a lot. The guy has to go totally off, or the sample is not good, to get into the negative results. More often than not you will be able to procure the work, but always in fungal infections, the super most important thing is the clinical diagnosis. It’s sad that due to the shortage of drugs that you are guarding you have ot sure you have to show a report before you get a drug. That’s actually not the science. Basically in fungal infections, I will repeat, primarily it is a clinical diagnosis which works. And first, all these studies have taken the gold standard as the clinical suspicion and the clinical diagnosis. They are taking that as the gold standard.
[Nishi] Dr. Grover, can I ask you the next question on how do you decide on exenteration? And what is the role of conservative management?
[A.K.] Thank you, Dr. Nishi. I think first of all let me thank Orbis and thank Shroff’s Eye Center, you and Dr. Sima and Dr. Umang, for the opportunity to have this multidisciplinary team from Ganga Ram present all the aspects of the disease. I think what they have highlighted is how a multidisciplinary team is critical to the management of this condition and it is the team that has to do the management of this condition. The diagnosis critically depends on the support of the microbiologist, the pathologist, and the radiologist. I think that is the first take home message from this.
You asked about the management based on the clinical and the radiological features which helps us decide between conservative treatment and going in for a surgical exenteration. One important thing to realize is that medical management is critical, along with nasal debridement or sinus debridement which has to be complete. As well as the debridement of all the areas including the pterygopalatine fossa, including the premaxillary area, wherever the spread may be. But deburdening is the first critical essential part of the therapy combined with appropriate full dose medical therapy as stressed by Dr. Atul Gogia.
Then comes the question of orbital management. In the orbit there are several factors that weigh in. When we looked at the picture in wave one and we looked at the picture in wave two, we have seen some changes which have been very important in decision making. What we do realize is that there are a lot of younger patients that have gotten involved in this pandemic, they’ve gotten involved in the active stage of the disease, and bilaterally has been almost 10%. And we’ve had exenteration in 24 cases, which is almost 20% of our 131 cases. This is because the disease severity and the initial presentation was quite severe in the beginning of this wave.
There has been some change in the picture as the wave has progressed. The precise point that may help you make the diagnosis are whether the disease is localized or whether it is a diffused disease and what radiologically you see as dead areas, areas with fungus, as Salil has so beautifully pointed out. Or areas which are still enhancing on contrast. If you have inflammation you can very well manage medically combined with debridement. And wherever there is a localized disease you can use well-directed, appropriately positioned retrobulbar therapy to augment that. But whenever the disease burden is severe involving the entire orbit, you have proptosis, you have positive pressure on pressure on the orbit, then you need to think of exenteration to debulk, to reduce the burden of the orbit.
However, there are cases who have an associated active COVID disease and have problems with being given any kind of anesthesia. They can’t be taken out for debridement and will be only taken out for retrobulbar injections. Similarly those with very bad prognosis like bilateral disease, extensive intracranial extension, we will not be able to take up for exenteration and they may do with just the retrobulbar injections to decrease the burden of the disease.
[Nishi] Thank you, sir, that was very informative and Dr. Sima if you can hear me, I think we all agree that if the orbital effects is involved and the disease is going towards the sinus. As the one case shown by Dr. Shaloo also, who later on went on to have those patchy involvement of the brain. I think those are probably the definite indications of orbital exenteration. What do you say, Dr. Sima?
[Dr. Sima] Dr. Grover, just a quick question. Have you seen patients with fully eye involvement without sinus involvement?
[A.K.] No, we haven’t. The portal is through the sinuses. There have been a couple of reports which I’ve seen from some of the presentations from all over the country. We have a huge pool from all over the country now, where people have presented without any prior known disease of COVID. And they had just the eye presentation with some apical involvement because of a sphenoid sinus pathology. And then they picked up to be COVID positive. But those are very much the exception. In our series of 131 cases, we do not have any without the sinus involvement. And in fact, the earliest patients presenting to us are sent to the ENT surgeon to confirm the diagnosis to look at the possible pathology on endoscopy. And that, in fact, is the best way of diagnosing early cases.
[Sima] Thank you, thank you, sir. Dr. Atul, a couple of questions in the message box regarding the systemic management part. Specifically on the use of steroid. What is typically safe or rational steroid, say in a non hyperglycemic patient who has COVID and has fever for more than seven days? What should be the protocol of steroid use, what do you say?
[Atul] There’s a lot of debate as to this. If you see the international or now the Indian latest, COVID India Guidelines, if you see the use of steroid is clearly for people who are moderately to severely ill, that is people who are hypoxic. If you see the use of steroid came in from the RECOVERY trial which was done in the UK and that was the only drug apart from mechanical oxygen and other treatment which have shown definite benefit. The dosage which is recommended is six milligrams of dexamethasone once a day, is what is recommended usage. In most of the guidelines that is recommendation.
But people are using varied amount of dosage and obviously if the fever is persisting beyond seven days in non-hypoxic patients also there was this guideline to use these steroids. And most of the guidelines if you say they would say that steroids should be stopped within 7-10 days. But sometimes in the clinical setting it becomes very, very difficult but that’s what the guidelines say.
[Nishi] Dr. Shweta, you have been doing a lot of cases, I know. And depending on the extent of debridement, in your experience as Dr. Sima said, the threshold of possible exenteration is going down now. Because we have been doing a lot of endoscopic orbital debridement and other things. What is your experience of those cases done endoscopically versus the orbital exenteration, how do you see them?
As a follow up, I would specifically like to ask you, those cases who have undergone endoscopic orbital decompression, or debridement, we have a lot of questions, a lot of us, because none of us has actually seen the post op patients. We’ve received some of the photographs, some of the patients have done very well and some have really worsened. What is your experience with your cases?
[Shweta] We did a lot of learning from the experience, learning from the MRI teams that this area needs to be addressed. The medial part of the orbit especially. Because that is one of the earliest areas to be involved. And if we are doing an endoscopic orbital decompression and if we are able to decompress up to the orbital apex, normally we get very good results and it alleviates the patients from going into an orbital exenteration.
Taking up a patient who has involvement of the nose and we see that there is involvement of the pterygopalatine fossa. It becomes very important, I think, now we have learned from the cases that we’ve done that it is important to address these areas. Especially the pterygopalatine fossa which is a large reservoir for the disease. Though the bone might look healthy once we’ve done, we’ve opened the maxillary sinus, sometimes we just see a healthy bone there. But once we remove that bone and see the contents in the pterygopalatine fossa then we’re actually astonished to see that there is a lot of disease which is residing in that area.
If the disease remains there, obviously, it will serve as a conduit to go into various other regions. That is just like a highway and it’s going to go into many other regions of the head and neck. This region and the region of the medial compartment of the eye, I think this is very, very important to address while we’re taking up the patients for a surgical debridement. If I just bored these regions in the first surgery, in the first initial surgery once we’re seeing the patients, I think we can avoid many repeated surgeries also. Because once we take these patients up for MRI scans or radiological scans, then we very often find disease still lingering in those areas. It is very important to address these areas.
And in the post operative period also, all these patients who we did an orbital decompression or we did the medial compartment in these patients, they responded really, really well to the treatment. And we could discharge them fast, the requirement for amphotericin was quite less. And I think we could avoid the more disfiguring surgeries in these patients. It is of vital importance to address the medial compartment of the eye and also we can, if we are suspecting something which would be residing in the inferior compartment that can be addressed at the same time. If we take up the floor of the orbit through the maxillar approach, we do a Denker’s and then we can address the entire medial wall, the inferior wall, and even to some extent the lateral wall of the orbit, which goes a long way in the recovery of the patient.
[Nisha] Thank you, Dr. Shweta. I think we would like to, I know I have, and I would like to say thank you to all these panelists and all the speakers.
[Prachi] In these challenging times of pandemic, discussions like these are very critical in understanding the new challenges that come along, like that of mucormycosis. We thank Dr. Umung Mathur, executive director at Dr. Shroff’s Charity Eye Hospital for spearheading this entire initiative. Our sincere thanks to the entire team of Sir Ganga Ram Hospital, led by Dr. Ashok Kumar Grover, chairman, Department of Ophthalmology at Ganga Ram Hospital and Vision Eye Center. The discussion led by you, sir, they have been very enriching and will guide all the participants to understand the epidemic of mucormycosis.
We thank all the esteemed speakers, Dr. Shaloo Bageja, Dr. Manish Munjal, and Dr. Atul Gogia for taking out time from your busy schedule and sharing clinical manifestations, diagnosis, and management from an ophthalmologist, ENT, as well as an internist perspective on mucormycosis. We are really grateful to all the panelists, Dr. Shweta Gogia, Dr. Salil Bhargav, and Dr. Chand Watal for such thought-provoking discussion on management of the disease.
And a big thanks to Dr. Sima and Dr. Nishi for being such an excellent moderators and facilitating all discussions. And finally, thanks to all the wonderful participants for your presence and valuable questions. Thank you, everyone, have a good day ahead. Stay safe and stay healthy.