What is Mucormycosis?
Mucormycosis is a fungus that is ubiquitous. This organism is present in the soil and all around us and is also a commensal that is present in the nose and oropharynx. It is an opportunistic organism – this means that it invades and causes infection only when the host’s immune system is compromised. A normal healthy person’s immune system would easily be able to fight a fungal infection like mucormycosis. It invades the nose and the paranasal sinuses. It then gradually spreads to the neighboring structures which is the orbit-it then affects the extraocular muscles, the optic nerve and the orbital apex beyond which it then spreads intracranially involving the cavernous sinus, the leptomeninges, and the brain. This form of invasive mucormycosis which is the commonest clinical manifestation is called Rhino-Orbital-Cerebral Mucormycosis (ROCM).
Why are we seeing so much of it now?
Typically one would come across fewer than a handful of cases of mucormycosis in an entire year. And most of these patients would be poorly controlled diabetics, Organ transplant patients, or those on long-term immunosuppressive medication. Recently following the second wave of the COVID-19 pandemic there has been a sudden surge in the number of ROCM cases. It is believed that the COVID-19 infection itself leads to a rise in their blood sugar level. This obviously affects both those who are not previously diabetic as well as diabetics, who have been on medication to control the blood sugar levels. The increased blood sugar levels that persist even after recovery from Covid 19 make them susceptible to opportunistic infections such as mucormycosis. In addition, many Covid 19 patients who undergo treatment in the hospital receive intravenous steroids to control the pulmonary complications of COVID-19. Apart from having an immunosuppressive effect of its own, steroids further cause a rise in the blood sugar level, as a side effect. This cumulative effect of COVID-19, diabetes mellitus and steroids put vulnerable patients at an extremely high risk of developing mucormycosis. India as of now is reporting over 400,000 cases of COVID-19 every day. As a result, the total number of patients suffering from this disease is extremely high, and therefore even if a small fraction of those end of developing this form of ROCM it adds up to a significantly high number of cases that are being seen all across the country.
How is this disease recognized?
Most of our patients who present to us have advanced symptoms such as complete ptosis or drooping of the eyelid; proptosis or outward protrusion of the eyeball; ophthalmoplegia and loss of vision. Early signs and symptoms include stuffiness of the nose, pain around the nose the cheek and behind the eye; Swelling of any one side of the face, Blackish discoloration of the skin around the cheek or the nose or eyelids; Dull headache; As it progresses, patients complain of blurred vision, diplopia/double vision or complete loss of vision. Once it involves the brain, patients may have seizures, loss of consciousness, focal neurological deficits, altered sensorium. In some patients, it also can involve the hard palate or the upper part of the mouth where a blackish discoloration or a necrotic patch of the mucosa can be seen which is also diagnostic of Mucormycosis. Typically a swab is taken from the nose or the palate which is then examined and on KOH mount. The presence of aseptate hyphae confirms the diagnosis of mucormycosis.
What happens next? how is this disease managed?
ROCM requires a multidisciplinary approach. This involves a physician or an intensivist taking care of the underlying immunosuppressive condition or the metabolic status of the patient. An ENT surgeon is at the forefront of the battle against ROCM. Since the focus of the disease is almost always the sinuses this requires aggressive surgical debridement of the sinuses in order to prevent the progression of the disease. In this surgery known as functional endoscopic sinus surgery or FESS, All the infected material and necrotic tissue debris are thoroughly debrided and removed from the sinuses. The aim of this surgery is to reduce the fungal load of the disease. This is because Mucormycosis causes angioinvasion: the organism invades the small and medium-size vessels inciting inflammation and causing occlusion of these blood vessels. This in turn leads to rapid necrosis and tissue damage. Also because the blood vessels are occluded and there is necrosis any systemically administered medication is unable to reach the actual focus of infection. Therefore it is extremely important to remove all necrotic, devitalized tissue from the sinuses. If the disease involves the orbit the ophthalmologist or the oculoplastic surgeon is then called in to help in the management of this disease. There is very little anecdotal evidence about the effect of retrobulbar injections of amphotericin B In mucormycosis. The surgical management of the orbit is based on radiological evidence of the amount of tissue involved and the invasion of the orbital apex. Some surgeons advocate aggressive debridement and removal of all necrotic tissue within the orbit but spare the globe. Other surgeons advocate early and aggressive orbital exenteration in order to remove the fungal load from the orbit and prevent further progression and involvement of the cavernous sinus. The management of mucormycosis is effective only if the underlying immunosuppressive condition is reversed, long-term antifungal medication is administered and early aggressive sinus debridement is performed.
Is Exenteration needed in all cases?
This is the most important question that needs to be addressed in these cases. There have been previous reports that have mentioned that exenteration did not affect the patients’ survival. But in those reports, exenteration was performed in patients with progression of disease into the intracranial fossa. However, the subset of patients that we are interested in, are those with sinus and orbital involvement. This organism directly invades the lumen of the blood vessels and causes extensive endothelial damage, resulting in thrombus formation and ischemia to the surrounding tissues. The infarcted tissue creates an environment that promotes fungal proliferation, and the resultant poor vascular supply prevents systemic medical therapy from eradicating the fungus. This infarcted tissue soon becomes necrosed.
In our clinical experience, the factors that help in deciding if the orbit should be exenterated or not are:
- The amount of orbital involvement by the fungus / the extent of necrosis in the orbit: Extensive necrosis within the orbit are signs of poor viability and with fewer drugs reaching in, exenteration will help in clearing all infected material.
- The involvement of the orbital apex: Impending involvement of the orbital extension is an urgent indication for exenteration. This is because the intracranial extension takes place through the cribriform plate or the orbital apex only. Therefore, at this stage, exenteration has a role in preventing intracranial extension of the disease.
- Intracranial extension of the disease: Once the disease has reached the intracranial space, the role of exenteration is limited. Some advocate that since at this stage, exenteration will not affect the eventual outcome, it should not be performed. Others advocate that exenteration would still reduce the infective load of the disease and should be done.
The factors that are not a direct indication for exenteration are:
- Loss of vision
This data is however not clinically validated, but based on clinical trends that have been observed in practice.
What is the medical management of Mucormycosis?
Amphotericin B is the gold standard for the treatment of Mucormycosis. It is available as amphotericin B deoxycholate in a lyophilized form. While it is effective it is accompanied by dose-limited toxicity, is infusion-related reactions and nephrotoxicity. There are lipid association formulations of amphotericin B available. The most commonly used is liposomal Amphotericin B. This reportedly has fewer side effects; lesser nephrotoxicity and better blood-brain barrier penetration. It is however more expensive. Other options that can be added as adjunct drugs include posaconazole and isuvaconazole. Voriconazole is not recommended in mucormycosis.
The medical management begins with the induction of therapy of liposomal AMB (L-AMB) ranging from 5 to 10 mg/kg / day for two weeks. This is followed by a phase of dual therapy: L-AMB + Oral Posaconazole (300 mg BD) for day 1 and 300 mg OD for 2 weeks. Based on the radiological monitoring, oral posaconazole may be continued for a further 2-3 weeks.
Do retrobulbar injections of Amphotericin B help?
We need to look at the evidence before we decide whether it works or not ; as of now there are only four reported cases of effectively managing orbital mucormycosis with retrobulbar amphotericin B injection. Most of these cases that were diagnosed and treated had vision that was largely intact which is unlike what we are seeing where most cases patients are presenting to us have loss of vision. Furthermore, it is difficult to say whether retrobulbar amphotericin B alone is effective because in all patients all other modalities of management such as sinus debridement and administering amphotericin B are also being done. The kind of cases where one can consider retrobulbar amphotericin B or in cases of mucormycosis with minimal orbital involvement on radiology. Or in bilateral cases where one orbit is extensively involved and the clinically better orbit needs to be conservatively managed; so in addition to aggressive debridement, local administration of amphotericin B may be considered. Retrobulbar injections of amphotericin B as the sole therapy for the treatment of orbital mucormycosis may not be effective as there are no guidelines for the dosage or the frequency of injections. Orbital injections of amphotericin B is an off-label usage of amphotericin B and therefore must be done with caution.
At the end of the day, management of the disease is a team effort – it involves the intensivist, the ENT surgeon, the oculoplastic surgeon and the neurologist.