Mucormycosis in Covid-19 Pandemic

1. Rhinoorbitocerebral Mucormycosis
(ROCM)
Dr. M. D. Mohire (MD, DM)
Neurology Centre & Research
Kolhapur, Maharashtra, India

2. Overview
Introduction, History & Epidemology
Sources of infection
Predisposing factors
Clinical features
Diagnosis
Treatment
Prognosis & mortality

3. Introduction
Highly serious fungal infection in low immunity host
Caused by fungus of Mucorales, species Rhizopus
Incidence is 0.6 to 3 /1 million in Western countries.
India 14 cases / 100,000 Persons, (Precovid)
Males & Females are equally affected
Incubation period for mucor is 3 to 15 days

4. Predisposing conditions
Diabetes (T1DM & T2DM), with high sugar with/without ketoacidosis
Cancer patients on chemotherapy
Transplant cases on immunosupressants
Autoimmune disorders on DMTs
Leukemias & Lymphomas
Covid-19 patients on steroids (CAM)
IV Drug abusers

5. Mucormycosis [History]
1885 - CNS infection first described in man
1943 - Triad of T2DM, Ketoacidosis, nasoorbital necrosis, ketoacidosis,
1955 - First survival in 14 years girl with Diabetes treated with iodides.
1958 - Efficacy of Amphotericin established
1962 - Survival has improved with Amphotericin-B.
1980 - Liposomal Amphotericin B available

6. Classification of Mucormycosis
Rhinoorbitocerebral mucormycosis (ROCM) : 50%
Pumonary mucormycosis : 20%
Gastrointestinal mucormycosis : 5%
Cutaneous mucormycosis & other : 10%
Disseminated mucormycosis 15%
Covid-19 steroid induced mucormycosis (CAM)

7. Source of Infection
Bread mold Dung
Damp soil
Rotten Fruits & Vegetables

8. Susceptibility for Mucormycosis
Diabetes with/without ketoacidosis,
Bad oral hygiene
Transplant patients on immunosupressants,
Cancer patients on chemotherapy
ROCM frequent in Covid-19 Diabetics on steroids
ROCM is slow in Nondiabetics

9. Covid Associated Mucormycosis (CAM) in india
End of May 2021, over 10,000 cases are reported
From Dec to Feb 2021 the infection rate is scorging rapidly
Recorded from almost every state of India
Diabetes in over 95 % of cases
It is now declared to be National Emergency & Notifiable disease.

10. Covid Associated Mucormycosis (CAM) in India
Dexamethasone reduce lung inflammation in Covid-19 pneumonia
Steroids leads to shooting of blood sugar in diabetics
Steroids impairs immunity
Covid Diabetics requiring long admission
Covid Diabetics requiring O2 for many days to weeks & ventilators
Suboptimal hygiene of Industrial O2, Oxygen tank regulators &
humidifier for O2 use are possible reasons for surge of mucormycosis

11. Covid Associated Mucor (CAM) Majority in India
CAM is typically observed 10 to 20 days after discharge
In India about 80 million people are diabetic
Diabetes seen in 95 % of cases
More than 70 % of all World cases cases in India

12. Symptoms of ROCM Mucormycosis
Fulminating symptoms
Aggressive spread is characteristic of CAM
Nasal stuffiness, epistaxis, fever, diplopia,
Blindness one or both sides, swollen face, Proptosis, red eyes
Black/Bloody discharge from nostrils,
Drowsiness, stroke on one side, seizures

13. Warning signs in Mucormycosis
Redness around eyes, red eyes, epistaxis, severe headache,
Uni or bilateral proptosis, toxic patient with fever

14. Mucormycosis (CAM)
Typical Case.
ESCHAR
Swollen face, bilateral ptosis & Eschar

15. 62 Yrs.M, T2DM 30 years, Covid RT-PCR positive, HRCT Score 20, D-dimer, CRP high,
treated with dexamethasone, Blood sugar 300 to 510 mgs during adm, oxygen for 10
days, . Discharged on day 15.
Day 10 of discharge : Watering nose with cough
Day 13 of discharge : Mild fever, severe headache without vomiting
Day 14 of discharge : Sudden R eye visual loss
Day 17 of discharge : R eye ptosis, R ext phthalmoplegia, R pupil dilated, R eye
blind, & swollen face with proptosis
Day 20 of discharge : L eye blindness, L ophthalmoplegia, R Proptosis
Day 21 of discharge : Diagnosis ROCM on scrapings from nose, MRI showed
Pansinusitis,
Day 21 Liposomal Amphotericin B started, Died on 27 the day
ROCM ‘Typical Case’

16. MRI scan showing sinusitis
ROCM ‘Typical Case’ MRI head
Sphenoid
sinusitis
Ethmoid & Maxillary
sinusitis

17. Signs in ROCM
Swollen face, ptosis one or both sides, black eschar at nostrils
Sometimes black eschar on palate & pharyngeal walls
Conjunctival oedema with chemosis & Proptosis Panophthalmitis
One or both sides 2nd, 3rd, 4th, 5th 6th, 7th cranial nerves,
(Cavernous sinus thrombosis uni or bilateral)

18. Typical Lesion of ROCM
Eschar ( black necrotic tissue)
Necrotic tissue is Black

19. Cavernous Sinus Thrombosis in ROCM
Proptosis with loss of Vision is typical
Cavernous Sinus Thrombosis one or both sides is frequently
asscociated with Proptosis

20. ROCM lesions on Palate

21. Nasal Endoscopic Pictures of ROCM

22. Mucormycosis (ROCM)
(Diagnosis)
 High suspicion in a diabetic or immune-compromised
 Neuro + ENT, Eye signs, MRI Head, Orbits , Angio & Veno
 Neuro + ENT + Eye signs + MRI = Certain
 Confirmed Tissue Diagnosis after Nasal Endoscopy

23. Mucormycosis (CNS Signs)
Commonly involved is Optic Nerve
Other Nerves involved : Cr Ns 3, 4, 5, 6, 7 & rarely 9, 10, & 11.
Hemiparesis, Hemiplegia, seizures
Altered sensorium
Cavernous sinus thrombosis leads to 2, 3, 4, 6 Cr Ns dysfunction
Cr Ns are invaded by angioinvasiveness & perineural spread

24. Clinical Staging of Rhinocerebral Mucormycosis
First Stage : Blocked Nose, Congestion of Eyes, Swelling & numbness of Face
Second Stage : Spread to Orbits, Headache & Orbital pain, Blindness, in one or both eyes
Third Stage : Involvement of Jaw & Mouth, Fever, UC, Black Nose
In 3rd Stage Brain is involved, Brain is involved in 20%.

25. Investigations
Routine, RFT, LFT, Electrolytes, HbA1C, Urine & blood ketones
Baseline MRI Head & Orbits with Angio & Veno
Nasal scraping for KOH, & special Fungal stains
Fungal culture on blood agar & special fungal media
Diagnostic Nasal endoscopy (FESS) for Tissue diagnosis

26. Lab diagnosis
Often difficult
Scraping from nasal cavity mostly negative on microscopy
Tissue biopsy on endoscopic aspiration is Positive
Frozen tissue sections with special fungal stains are diagnostic
Fungal cultures are diagnostic

27. ROCM Orbital Imaging
T2-weighted MRI shows
hyperintense sinuses & orbital
hyperintense signal lesion
displacing eyeball
T2-MRI shows hyperintense
ethmoid cells. Soft tissue
swelling seen anterior to eyeball.
orbital hyperintense signal along
orbital apex into left cavernous
sinus & internal carotid artery
T1-weighted MRI shows hypointense
mucosal thickening of left ethmoid
cells.Soft tissue swelling seen anterior
to eyeball,.orbital isointense along
orbital apex into cavernous sinus.
Lone et al, Ind J Otology,2015,21, 215-218.

28. Imaging Characters of Sinuses, Orbit, Face, Skull and Brain
Showing Swollen Ext Ocular Muscles, Mass in sinuses & Bone Erosion
Structures Involved
Ethmoid sinus : 85 %
Maxillary sinus : 80%
Orbit : 76 %
Face : 60%
Brain : 15 %
Skull base : 15 %
Sphenoid sinus : Least common
Frontal Sinus : Least common
Multiple regions are involved in most cases

29. Brain involvement in ROCM
Dissiminated mucormycosis (hematogenous)
Diect extension in Frontal lobe Leptomeningeal
Stroke
Mass lesion
Mass lesion
Brain Abscess

30. Brain arterial & Venous involvement
Int Carotid A Thrombosis
R-Cavernous Sinus Thrombosis
ROCM

31. Mechanism of Spread in between two cavernous sinuses
Spread of Mucormycosis is very fast. Spread is ascending Angioinvasiveness.
Spread is also ascending perineural through 3rd, 4th, 5th, 6th, & 7th Cranial nerves
Dissiminated Hematogenous spread is also important.

32. Orbital Pathology in ROCM
Congestion, Proptosis, Chemosis,
Hemorrhage, abscess formation, Extensive necrosis
Central tissue necrosis, with acute inflammatory exudate
Invasion of Subcutaneous fat, orbital fat and fascial layers
Thrombosing Arteritis, Veins less involved
Superior Orbital Syndrome

33. Tissue Biopsies from nasal endoscopy & Orbit
Nonseptate hyphae in Eosin and Hematoxylin

34. Ribes, J. A. et al. 2000. Clin. Microbiol. Rev. 13(2):236-301
Morphologic structures seen in the sporangium-producing Mucorales

35. Branching at right angles
Lactophenol cotton blue
On microscopy on KOH Preparation & Sabaroud medium
KOH Preparation
Nonseptate hypae
Growth on Sabauroud medium
Courtesy to Dr Shishir Vanjare, GSMC & KEMH, Mumbai

36. Mucor growth culture on Agar Plate

37. Immunology of Mucormycosis
In healthy state resting spores are resistant to phagocytic
killing. So spores are susceptible to degradation by
macrophages.
The case of immune suppression, and ability of
macrophage against Mucorales is compromised.
On penetration of the endothelial lining, mucorales
attack platelets.
Platelets adhere to mucormycete spores, and favour
germination & destruction. Dendritic cells are activated
in response to Mucorales, inducing adaptive immunity.

38. Mucormycosis
[Pathogenesis]
 Mucorales involve arteries causing thrombosis & infarction.
 Mold spread quickly along lamina properia of small and
medium sized arteries and extend beyond Cr Ns into brain.
 Infection involve all structures in the path, orbit, eye, bone
and brain.
 ICA thrombosed in 1/3 of autopsies.
 Carvenous sinus thrombosis frequent.
 Perineural ascending spread thr Cr Ns to Brain
 (Thrombosis of arteries and veins due to angioinvasiveness)

39. Management of Mucormycosis “Time is LIFE”
Guidelines
Early diagnosis of Rhinocerebral Mucormycosis
Baseline MRI Head, MR Head-Orbit, Angio-Veno
URGENT Diagnostic Nasal Endoscopic for biopsy
Diagnosis confirmed on Biopsy, Correct Metabolic Parameters
Start Inj Amphotericin B, Oral Posaconazole,
Early Surgical Debridment by nasal Endoscopy & Orbital & Facial debridment.
Stop Anticoagulation 12 hrs before 1st debridment,
(Cont. next Page)

40. Most of CAM Diabetics are on Rivoroxaban OR Dabigatran on discharge
If Second Debridment needed,
Consider 2nd Debridment based on Clinical & Repeat Imaging
Stop Rivaroxaban for 12 hours before second Debridment
Restart Rivaroxaban 12 hours after Second Debridment
After 15 days of Antifungal Treatment, review for continuing therapy for 1 to 2
Weeks
Always monitor Carefully Neurological signs
Management of Mucormycosis “Time is LIFE”
Cont. from last slide

41. Medical Management
Blood sugar control, daily monitoring of RFT, LFT, Hemogram, Electrolytes
Liposomal Amphotericin B, 1.5 to 5 mg/kg/day, for 2 weels for all, watch Toxicity
Dual therapy of Amphotericin B & Posaconazole, 300 mg BD, on day 1,
From day 2, 300 mg once a day for all patients.
Oral Posaconazole 300 mg BD, for next 2 to 4 weeks or more monitoring clinical &
radiological recovery.
(Tissue diagnosis is must before starting treatment)

42. Inj. Amphotericin B Preparations
Conventional Preparations
Liposomal Amphotericin B
Colloid Dispersion
Lipid Complex
Inj Amphotericin B is to be administered by slow IV infusion
Premedication : 1) 1 liter of Nacl to avoid renal toxicity
Antihistaminics and Glucocorticoids to prevent Anaphylaxis
Amphotericin B need dilution in Dexrous for administration & slow infusion
Costly, Less Renal toxicity

43. Liposomal Amphopericin B Injection
Broad spectrum Antifungicidal
Adverse effects : Fever, Headache, Renal toxicity,
Hypokalemia, hypomagnesimia
Anorexia, Nausea, Vomitng, Hepatic toxicity, cardiac
arrythmias, Liposomal Preparationhas
Drug Interactions : Flucytosine, Cisplastin, Foscarnet,
Aminoglycosides
Start with low dose, gradually increase to Therapeutic levels

44. Liposomal Pharmacodynamics of Amphotericin B
Bioavailability : 100% for intravenous infusion.
Protein Binding : 90 % to plasma proteins
Metabolism : Exclusively renal
Half life : 15 days
LD 50 : > 5 mg / kg, can result in Cardiorespiratory arrest

45. Tab Amphotericin B : IIT- Hyderabad
Oral Amphotericin –B : 60 mg Tab
Nanotechology
Less Kidney toxicity
Cost Rs 200 / day
Great Promise

46. Oral Posaconazole
Antifungal drug superior to Flucanozole
Hepatic Toxicity : Mild to severe
Absorption decreased by proton pump inhibitors
Can be used as salvage treatment in those intolerant to Amphotericin B
IV & Liquid formulation also available
Can also used as stepdown treatment after administration of Amphotericin B
Caution needed with other drugs with potent CYP450 inhibitors

47. Surgical Management of CAM
Early surgical debridment of sinuses for all (Escharotomy)
Transcutaneous retrobulbar Amphotericin B, 3.5 mg in 1 ml, in selected cases
Orbital exentrationfor those with extensive orbital involment
Facial surgical debridment
Follow up of patient ofter discharge to check recurrence
Aggressive Medical treatment & Surgical intervention

48. Management of Cavernous Sinus & Arterial occlusion in Mucormycosis
Aggressive Treatment with Amphotericin B & Prosaconazole is the KEY
Use of Anticoagulation & Antiplatelets
It is better to do Early Surgical debridment to prevent stroke
Mannitol can be used only if needed to reduce ICT
Craniotomy with Decompressive surgery is sometimes Life Saving

49. Complications & Prognosis
Blindness, stroke, facial disfiguration, organ damade & death
Mortality is over 50 % despite prompt diagnosis & treatmen
Delay in Diagnosis is culprit for higher deaths

50. Why Epidemic of Mucormycosis in India
There are few cases of Mucormycosis in rest of the World
India had no cases of of Mucormycosis in 1st Covid 19 Wave
In 2nd Wave we have 3 times more cases than 1st Wave
Maharashtra produce 1500 metric tons of Medical O2 per Day
O2 requirement of Maharashtra in 2nd Wave jumped to 300%
Suboptimal hyegine of Industrial O2, and water used in O2 therapy humidifier
Suboptimal hyegine in Hospitals, due to workload beyond human capacity

51. Prevention of Mucormycosis
Personal hygiene of body with attention to nose and oral cavity
Environmental cleanliness
Early diagnosis of mucormycosis by mass awareness campaign
Early institution of therapy
Adequate contrpl of blood sugar levels in diabetics
Personal awareness in Diabetics & immunocompromised

52. DD of Rhinocerebral Mucormycosis
Orbital Tuberculosis
B-Cell Lymphoma
IgG-4 related disease
Orbital Sarcoid
Malignancy-Meastasis
Wegener’s granulomatosis
Tolosa Hunt Syn
Vascular Malformation of Orbit

53. Summary & Conclusions
Rhinoorbitocerebral Mucormycosis is highly fatal disease
Early diagnosis is most crucial
New Symptom in Diabetic (Post-Covid) should be investigated URGENTLY.
Severe Headache out of proportion to common cold in Diabeti consider Mucormycosis
Early MRI Imaging of Orbits & Brain should be done
ENT & Eye Consultation for New symptoms need consideration
Early Diagnosis of Mucormycosis is warrante
Aggressive Medical & Surgical Treatment carries good outcome.