COVID-associated cerebral mucormycosis – Not actually a black fungus!

Fungi are the interface organisms between life and death – Paul Stamets

CAM (covid-associated mucormycosis) is wrongly addressed as black fungus in Covid-19 pandemic by surgeons/physicians/policy makers in our country.

What is black fungus? Black fungus is actually dermatiaceous fungus. It is darkly pigmented because of presence of melanin in its cell wall. Infections with this fungus may remain localized at the site of traumatic inoculation, or within the nasal sinuses. This fungus is not causing outbreak of fungal infections noted in current covid pandemic in India/elsewhere.

Black fungus term probably originated from black eschars/black discharge/black pigmentation noted in patients affected with mucor fungal infec­tions. There is no microbiology text­book description/scientific publication, mentioning mucor infections as black fungus infections. One ENT surgeon somewhere in Western India wrongly used this word in his interview to BBC at the onset of the second covid wave, and rest is history, thanks to electronic and print media! So, which fungus is causing CAM and cerebral mucormycosis infections (brain fungal infections in covid pandemic) then? Present outbreak is caused by Rhizopus mucorales fungi and not by black fungi.

Rhizopus mucorales grows rapidly over a few days in the hyperglycemic environment (high blood glucose). The iron-rich state caused by deferoxamine, an iron-chelating agent, also favors the fungal growth. Spread to the frontal lobes may happen via ethmoid sinuses/transorbital route. Infection spreading along the sphenoid sinuses to the nearby cavernous sinus results in cranial nerve palsies. This may be followed by extensive thrombosis of the cavernous sinus, jugular veins, and carotid artery.

Where are mucor spores found around us? Mucor fungi are ubiquitous molds occurring in the soil, compost, animal dung, rotting wood and plant material, fruits, vegetables, and even in the nose and mucus of healthy people.

Who can be affected with mucor fungal infection? Elderly diabetics, history of high-dose long-duration steroid therapy, recent recovery from covid infection (2–4 weeks prior), malignancy, immunosuppressants, long-term ventilator/oxygen therapy, tocilizumab/immuno­modulator usage, or hemochro­matosis.

However, a few cases of cerebral mucor infection have been seen in young non-diabetics also.

When to suspect CAM? Facial – pain/discoloration/swelling; eye – drooping of eyelid/eye bulge (ptosis/proptosis/EOM restricted, decreased vision); Nose – stuffiness, foul smelling, nasal discharge, discoloration on nose, bleeding from nose (epistaxis); pain – headache, dental pain; fever, altered sensorium, paralysis. When in doubt – take opinion. Cerebral mucor can manifest as acute or subacute rapidly progressive infection, and have high morbidity and mortality in uncontrolled diabetics/immunocompromised by angiotropic invasive fungus manifesting as ROCM (>40% cases). High index of suspicion and early diagnosis is the key.

Check list for early sentinel signs and symptoms Since most covid centers are managed by young residents/interns/junior doctors, it is imperative that they are apprised of twice daily check list for third/fourth/sixth cranial nerve paresis/limb weakness or drowsiness in all patients affected with covid illness.

Major complications, which can happen in cerebral mucor, include cavernous sinus thrombosis, carotid artery obstruction, central nervous system infarction secondary to mycotic intravascular thrombosis, manifesting with hemiparesis, hemiplegia, coma, and death, CNS hemorrhage, abscess, inflammation, and blindness

How to diagnose CAM? Nasal endoscopy, deep nasal swab, CT, and MRI imaging. It commonly manifests 7–14 days after recovery from covid infection; however, one can still have RT-PCR viral antigen positivity with active cerebral mucor infection.

Who treats it? Show to your local doctor, who will refer you to an ENT surgeon/eye surgeon or neurologists/neurosurgeon/referral center.

How is it treated?

• Medical manage­ment. Liposomal Amphotericin B for four weeks followed by oral Posaconazole for four weeks (based on clinical response) or Isovucanazole. Approximate total cost of Lyophilized Amphotericin B (₹25000)/Liposomal Amphotericin B (₹300,000) for a four-week course.
• Surgical management. Early extensive debridement of sinuses and nasal irrigation by ENT surgeon, orbital exenteration, if indicated, neurosurgical if intracranial spread. If patient has intracranial spread of disease, one needs to do excision/drainage of abscess and debridement/removal of bone flaps at times to relieve life-threatening raised intracranial pressure.
• Cerebral mucormycosis is a treatable illness with timely and aggressive multidisciplinary team approach (ENT, eye, and neurosurgeons with neurologists). Uncontrolled diabetics are especially predisposed to get brain mucor infections with its associated risks and complications. If untreated, it is a universally fatal illness.

Once Diagnosed, can it be treated at home? No. It requires hospital admission to confirm diagnosis and early medical/surgical treatment. I am aware of a couple of patients who were administered antifungals at home due to lack of beds in hospitals. Outcomes were bad in all of them.

Is it an emergency? Yes.
If treated early – good outcome. If untreated – 50 percent of patients can become blind/die. Of nine cases with brain mucor treated (personal communication), only one patient could not be saved as she presented in altered sensorium late in the course of disease. Cerebral mucor infection can be treated if antifungals and neurosurgical intervention is offered timely to such patients.

Is CAM unique to Covid-19 pandemic? No. Mucormycosis was noted even in pre-covid period with an incidence of 28 percent in Asia c.f. 34 percent incidence in Europe. However, the number of cases in covid pandemic have increased to >5 times owing to high-dose irrational steroid/oxygen therapies in undiagnosed diabetics and immunocompromised individuals.

Is CAM due to industrial oxygen supply? Covid first wave did not have so many cases of mucormycosis. Surge in ROCM in the second wave and association with high dose steroids and industrial oxygen usage association contemplated. Data is being studied. However, the disease is also noted in those who were not on oxygen therapies.

How to prevent CAM? Avoid indi­scriminate use of steroids/tocilizumab. Betadine mouth gargles. No nasal drops. Sterile asepsis during oxygen therapy, sterile water for humidifier. and daily change of humidifier tubing. Barrier mask. Aggressive monitoring and control of DM. Optional use of oral Posaconazole in high-risk groups (>3 weeks of ventilation or oxygen therapy >3 weeks of steroids, uncontrolled DM).

Acute shortage of beds in hospitals for cerebral mucor and other mucor infections were noted during the second wave in India. Crises of Amphotericin still persists despite claims for adequate supply being made available. Large number of patients are still getting under-dose of the said therapy due to lack of adequate medicine supply.

Take home. Prevention and early diagnosis is the key to improve outcomes in cerebral mucor and other mucor infections; and please remember these are not black fungus infections.