MUCORMYCOSIS in the Era of Covid-19.pptx

In this presentation, we discuss the presentation of Mucormycosis in Covid-19 epidemic

1. Mucorales - where are they ? Mucoral e s are everywhere Particularly in soil and in decaying organic matte r , such as leaves, compost pile s , or rotten wood. Optimum con d i tions for the growth - 2 7 °C, high humidity and low pH Around 1 5000 spores are inhaled over a 24-h period by an adult person -7 but we don't get infected why?- b ec a use we are immunocompetent Surprisingly and importantly , members of the Mucorales are very rarely found in nasal mucus - NOT A COLONISER Richardson MD et a l ; Journal of Fungi 2019 Clin M i c rbio / i nf e c t 2009,

2. Who are a risk ? Quantitat i ve or qualitative decrease i n neutrophils and phagocytes l. Hematologic malignancies 2.Hematopoietic stem cell transplantation (HSTC) 3.Solid organ malignancies 4.Solid organ transplantation 5. High dose corticosteroids/immuno­suppression 6.Rheumatologic diseases 7.Uncontrolled diabetes mellitus with ketoacidosis 8 . Metabolic acidosis 9.Deferoxamine therapy Multiple transfusions Malnutrition,neonatal prematurity 12 . Prophylaxis with voriconazole . 1.Skin injuries, burns, trauma 2.Natural calamities like tornadoes, tsunami,volcanic eruption 3.Combat-related injuries 4.Contaminated bandages, tongue depressors 5 . lnjection drug use 6.Prolonged hospital stay lmmunosuppressed lmmunocompetent

3. Sometimes no cause is found – undiagnosed primary immunodeficiency ?

4. Differentia I Di a gnosis Bacter i al S i nus i t i s and Allergic Fun g al S i nusit i s Aspergillosis Nasal and Paranasal Malignancies Cavernous Sinus Thrombosis Migraine Headache Brain Tumor and Pseudotumor Cerebri Orbital tumor , and cellulitis

5. Mucormycosis : what is special with diabetes? D M a n d ketoac i dosis → pha g oc y tic c e ll s d y sfunctional ; with impair e d chemota x is and defect i ve kill i ng DKA pat i ents have an ac i d i c blood pH with e levated levels of free iron , → major nutrient e l ement Mucorales Acidic environment → impaired chelating ability of transferri n and hemoglobin making fr ee iron available E l evate d leve l s of g l ucose an d i ron , incr e ase the cell surface expr e ssion of GRP-78 , a major h ost receptor for Mucorales High glucose , iron and beta - hydoxybutyrate (BHB) induce the e x pr es sion of C otH on fungal germ li ngs

6. Mucormycosis : A result of defective phagocytosis

7. Pathogenesis

8. HOS T - P A TH O G E N I NTERA C TIONS Mucormycosis → extensive angioinvasion → vessel thrombosis and tissue necrosis → BLACK FUNGUS ↓ lschemic necrosis → prevent delivery of leukocytes and antifungal agents to the foci of infection and therefore the poor outcome with just ant i fun g als

9. Hea l thy host Intact skin/mucosal barrier Innate immunity Mucus layer of sinus- anti microbiol property Essential nutrient iron firmly bound to the serum proteins- NUTRIENT IMMUNITY Tissue macrophages phagocytose the inhaled spores and kill them Neutrophils produce reactive oxygen metabolites kill the spores and hyphae Entry : Sk i n/mucosa! trauma- swabs ? Spores i n ai r COVID --> increased iron availability, Diabetes causing phagocyte dysfunction 7 MUCORMYCOSIS Mucormycos i s

10. COVID-19 and Mucormycosis : Some missing links? Contamination of swabs sticks at the production or packaging sites - sampling by a contaminated swab, minor mucosa! trauma at the time of sampling and loss of epithelial barrier due to SARS-CoV-2 infection Genetic predisposition ? B . 1.617 variant causing immunosuppression ? The dose of steroids/ Population/ Virus/Geography was similar in the first wave ,then what has changed in this wave ??

11. What i s M u c or my c o s i s ? R a re fungal infection Present n a tura l l y in environment - soil

12. Usually 40 cases per year – a major center – now … 40 per month or more ‘Prevalence of mucormycosis in India in nearly 70 times higher than global data ’

13. W h o i s at r i s k ? Steroids - Very high doses Hyperglycemic - sugar persistently high Cancer patients Transplant patients Trauma patients

14. Treatment options

15. Clinical characteristics and outcomes of 16 c ases with COVID-19 and Mucormycosis ; experience f r om a tertiary care center i n I ndia and review of li t e rature Mar 201 9 - J an2020 6250 pati e nts treated w i th C ov i d- 1 9 2/ 6250 Covid -19 -7 Rh i no-Orb i to-Cerebral Mucormyco s is 9-28 days follo w ing r e so l u t i on of Cov i d-19 1 Post Renal Transp l ant ; lmm u nos u ppressants / Stero i ds 1 End Stage Renal D i sease 1 4 pres e nted with M u cormycosis & concurr e nt/ asy m ptomat i c Covid 19 13 ROCM, 1 P u lmonary As y pmtomatic 5; Mild 6 ; Moderate 6 ; S evere 2 12/14 - Co-morbi d i t ies 2/1 4 - No co-mor b i dities 11 - D i a b ete s ; 1 new l y discovered at a d missi o n 1 2 / 1 4 Lymphopenia

16. I ntr o duction Rhinocerebral mucormycosis , also called zygomycosis . It is a acute fungal infection (progresses with in days),few cases may be chronic (weeks) Commonly associated diseases include diabetic ketoacidosis, severe burns, steroid therapy, solid organ transplantation, prolonged corticosteroid therapy, hemochromatosis, patients with HIV, neutropenia, malnutrition, hematologic malignancies. Some research demonstrated that about 9% of Rhinocerebral mucormycosis was found in patients without any predisposing factors. Number of cases are increasing in COVID -19 patients, maybe due to prolonged steroid use, ?immunodeficiency following COVID-19

17. C a se 42 years old male Known diabetic Covid-19 positive on 22/4/2021,treated for covid pneumonia elsewhere and discharged on 11/5/2021 c/o Holocranial headache, insidious in onset gradually progressive, not associated with vomiting, visual disturbance and generalised weakness since past 2 weeks. O/E Conscious, oriented; abulia+, apathy +, speech and language normal. Vision and other cranial nerves normal by bedside examination. Power 5/5 in all limbs.

18. Im a g i ng - T l W - MRI

19. F LA I R

20. DWI

21. Post OP Post op CT brain- Pneumochepalus in anterior skull base. Patient underwent Endoscopic anterior skull base repair. Patient is stable, no fresh neurological deficits

22. P a thogenesis of R hinocerebra l mucormycosis Invasion of blood vessels by fungal hyphae damages the endothelium causing blood clots that occlude the blood vessels leading to ischemia and necrosis of surrounding tissue. In Rhinocerebral mucormycosis , invasion of brain and orbit is through the involvement of sphenopalatine and internal maxillary arteries The involvement of the internal carotid artery and cavernous sinus thrombosis is common only in long-standing cases.

23. Sympt o ms Unilateral retro-orbital headache and lethargy are the earlier presentation. Other general presentation includes nausea, fever, nasal congestion and rhinorrhea, epistaxis, nasal hypoesthesia, facial pain and numbness, history of black nasal discharge and sinusitis. Common eye complaints are retro­-orbital or periorbital pain, amaurosis, diplopia, blurring of visions. CNS involvement presents with convulsions, dizziness, altered mental status and gait. o ·

24. C l i n ic a l exa m i n a tion Nasal and orbital cellulitis. reddened and swelling of nasal bridge and skin of cheek- later blackening Black eschar visible on nasal mucosa or palatine mucosa. palatal ulceration Proptosis, ophthlmoplegia , loss of vision. Multiple cranial nerve palsies

25. Ev a l u ation Evaluate for risk factors- Diabetes mellitus, steroid use, haematological malignancies, immunosuppressants ,etc... Investigation of choice in early fungal ball detection is a CT scan. MRI helps to visualize the soft tissue changes Biopsy of antral necrotic tissue for histopathological study to confirm the diagnosis. Nasal scrapings and fine-needle aspiration cytology- shows fungal hyphae .

26. C T CT-scan thickening of mucosa with hyperdense areas. The invasive sinusitis phase shows the opacification of sinuses with bone erosion. CT brain may show intracranial masses, brain abscesses , and ischaemic infarcts with perilesional edema

27. M R I T1 : iso i ntense lesions T2: variable with around 20% of patients showing high T2 signal T1 C+ (Gd): the devitalised mucosa appears as contiguous foci of non­ enhancing tissue, leading to the black turbinate sign Brain- T1 hypo,T2/FLAR E hyper Abscess- rim contrast enhancement with diffusion restriction .

28. H P E Microscopic examination shows fungal hyphae, which are aseptate, branching with 90 degrees, irregularly wide. Brain tissue: necrosis, infiltration of polymorphonuclear and multinucleated giant cells along with aseptate hyphae. H&E stain showing focal brain tissue necrosis and infiltration by thin walled broad, non­ septated hyphae (black arrow) PAS stain showing multiple broad hyphae (black arrows).

29. Cu l t u re s Culture media: Sabouraud Dextrose Agar. Staining: Lactophenol cotton blue Rhizopus Morphology Rhizopus G rowing on SD

30. T re a tment Mucormycosis is a medical emergency, early diagnosis and initiation of vigorous surgical and medical therapy is the key. Control of diabetes mellitus and treatment of DKA Stop steroids and other immunosuppressive drugs( eg ., toclizumab , baricitinib , tofacitin i b) Extensive surgical debridement of all necrotic tissue. Antifungal treatment.

31. Surgery Extensive surgical debridement to remove necrotic tissue and establish sinus drainage is essential. multiple surgeries are often necessary for cure Endoscopic sinus surgery and topical administration of antifungal in the debrided area is also useful Maxillectomy or ethmoidectomy is performed according to the site involved Proper clearance of involved tissue and, (>1cm) excision of healthy tissue is required to eradicate the disease. lntracranial involvement necessitates craniotomy and debridement

32. I ntr a c r a n i a I extension Brain abscesses required burr-hole and aspiration frontal lobe mass requires craniotomy and debulking

33. Other thera pies Other experimental therapies for RCM have been reported with varying success. These include- hyperbaric oxygen nebulized or local irrigation with amphotericin B topical hydrogen peroxide the combination of amphotericin B with flucytosine, rifampin or fluconazole None of these additional agents has shown consistent in vivo or in vitro activity

34. H yper b a ric oxygen T h era py Hyperbaric oxygen exerts a fungistatic effect. it aids neovascularization, with subsequent healing in poorly perfused acidotic and hypoxic but viable areas of tissue. Exposure to 100% oxygen for 90 minutes to 2 hours at pressures from 2.0 to 2.5 atmospheres with 1or 2 exposures daily for a total of 40 treatments. Reported toxicities of hyperbaric oxygen include teratogenicity and rarely pulmonary or central nervous system side effects.

35. Summary Steroids should not be given indiscriminately Good glycemic control while managing COVID-19 Suspect the disease early, patients need to be advised with early signs & symptoms Mask to be used even at home after discharge from hospital (at least for 1month post-Covid) Training of all microbiologists for mucormycosis diagnosis Education, Education, & Education for doctors on managing mucormycosis Unknown areas to be explored Cost of treatment is a serious challenge in India; considerable number of patients cannot afford therapy Stark inequities in the distribution of resources to weather the storm Universal vaccination Research in fungal diseases, especially those that disproportionately affect the world's poor