Webinar on mucormycosis

1. Dr Anjana Mohite
Associate Professor
Dept of Otorhinolaryngology
D.Y.Patil Medical College,
Kolhapur, Maharashtra
INDIA

2. Intended learning outcomes
 To be aware of the epidemiology of mucormycosis.
 To understand the pathophysiology of RCM.
 To be familiar with different clinical manifestations.
 To be aware of available management options for
mucormycosis.
 To be aware of complications and prognosis of
mucormycosis.

3. Introduction
 Paltauf first identified rhinocerebral mycosis in 1885.
 Mucormycosis is a life threatening invasive infection .
caused by fungi belonging to the order Mucorales.
 It is mostly seen in patients who are immune compromised
due to various reasons.
 Rhizopus oryzae is the most common organism isolated
and is responsible for more than 70% of all cases of RCM.
 Uncontrolled metabolic conditions especially DM in
ketoacidosis is the main risk factor and core determinant
of the world wide incidence of mucormycosis.
 2 Types-Acute Fulminant and Chronic Indolent.
 Fatality is more than 30 to 85%.

4. Epidemiology
Life
threatening
• One of the deadliest among communicable
diseases, along with lower respiratory infections,
tuberculosis and diarrheal diseases
Incidence
• Worldwide Incidence of 6/100 000 cases/year
increasing incidence every year along with
increased mortality*
Impact
8-15% of nosocomial blood stream infections
Fourth most common isolate of patients of the
intensive care unit
Mortality
• Kills up to 1.5 million people each year,
• Mortality rate around 50% but early diagnosis and
appropriate treatment save 80% of these patients
on Lilienfeld-Toal M, Wagener J, Einsele H, Cornely OA, Kurzai O. Invasive Fungal Infection. Dtsch Arztebl Int.

5.  Mode of spread- Humans acquire the infection
predominantly by inhalation of sporangiospores.
 Occasionally by ingestion of contaminated food or
traumatic inoculation of sporangiospores through skin or
mucosa.
 Mucormyces is ubiquitous.
 Seasonal- autumn / summer.
 Developed countries- immunocompromised.
 Developing countries- uncontrolled DM.
 Despite advances in diagnosis and treatment, mortality
remains high .

6. Mucormycosis in India
 A review of several Indian studies has revealed a
prevalence rate of 0.14 cases/1000 population of
mucormycosis, which is 70 times the worldwide rate.
 Uncontrolled diabetes is a strong risk factor; however in
India this association is overwhelming.
 Data shows that 16-23% of patients were unaware of
underlying DM and mucormycosis was in fact a diabetes-
defining illness in these patients.
 At places where there is poor access to healthcare and
diagnostic facilities, most patients present with advanced
orbital and intracranial extension.

7. Global versus Indian Incidence
 Disease burden is higher in Europe than in Asia, as they reported
34% in Europe, followed by Asia (31%) and North or South
America (28%), Africa (3%), Australia and New Zealand (3%).
 The contrary data may be due to under-reporting during this
period from Asian countries. In reality, a rising number of cases
are reported from India.
 Prevalence of Mucormycosis at 140 cases per million population
in India,
 Ranging between 137,807 cases to 208,177 cases.
Mean of 171,504 cases.
Mean attributable mortality at 65,500 cases (38.2%) per year.
Prakash et al J. Fungi 2019, 5, 26

8. Clinical spectrum of mucormycosis
 Rhino cerebral mucormycosis- most common.
 Pulmonary
 Cutaneous
 Gastrointestinal
 Disseminated
 Isolated renal

9. Risk Factors
 Poorly controlled DM, Diabetic ketoacidosis.
 Haematological malignancies.
 Solid organ transplant, stem cell transplant.
 Penetrating trauma, burns.
 Prolonged steroid therapy.
 Chelation therapy with defuroxamine.
 IV drug users.
 Neutropenia.
 Malnutrition.

10. Diabetes a major risk factor
 Diabetes mellitus as predisposing factor varies from 17% to
88% globally.
 Three major case series from India reported diabetes as a risk
factor over 50% cases(74%) with mucormycosis and in 43%
DM was diagnosed for the first time.
 Recent multi-centre study from India documented that 57% of
their patients had uncontrolled diabetes mellitus with 10%
diabetic ketoacidosis.
 Diabetes as a risk factor was significantly higher in North India
compared to South India.

11. Pathogenesis
 Agents of mucormycosis are ubiquitous and
frequently air borne.
 Infections mainly involve the lungs, sinuses and brain.
 Invasion of major blood vessels with consequent
ischaemia,necrosis and infarction of tissues.
 Neutrophils play a central role in host defence
mechanism.
 Ketoacidosis, hyperglycemia and hypoxia are
excellent growth conditions for these fungi.
 Ketoacidosis decreases inflamatory responses and
delays local aggregation of granulocytes and
fibroblasts.

12. Clinical manifestations of
mucormycosis
 Nose-Blackish necrotic turbinates “eschar” is the
hallmark.Most frequent sites – near middle turbinates,
septum and inferior turbinates.
Discolouration, granulation, ulceration, crusts.
 PNS – Headache,sinusitis - maxillary followed by
sphenoid, ethmoid.
 Oral cavity and oropharynx – Palatal ulceration,
palatal necrosis respecting the midline.

13. Clinical manifestations
 Eye – peri orbital odema, eye pain, orbital
odema,ophthalmoplegia, blepharoptosis, blurred vision,
acute vision loss.
 Facial- pain, facial numbness, facial cellulitis, skin
discoloration.
 CNS-Multiple cranial nerve palsies.(2nd to 7th), coma
stroke.
 Fever is variable.

14. CLINICAL PHOTOGRAPHS

15. Staging of RCM
 Stage I - Infection of nasal mucosa and sinuses.
 Stage II - Orbital invovement (orbital apex
syndrome, superior orbital fissure syndrome).
 Stage III - Cerebral involvement in which
intracranial spread occurs via:
Ophthalmic artery
Superior orbital fissure
Cribriform plate

16. Diagnosis
Diagnostic nasal endoscopy KOH mount

17. Diagnosis: Imaging studies
 Both CT and MRI can be used. MRI provides better
delineation of blood vessels, peri neural spread and intra
cranial extension.
 Roles
1. Detects fungal angioinvasion.
2. Bone destruction and necrosis.
3. Soft tissue involvement.
4. Intra cranial involvement.
 Sinus imaging
1. Mucosal thickening,opacification.
2. Changes in air fluid level
3. Cavernous sinus involvement

18. Diagnosis confirmed: Histopathology
 Mucormycosis -non septate hyphae with right angle
branching.
 H & E stain GMS stain

19. Management of mucormycosis
 Early surgical debridement + antifungal therapy + control
of underlying risk factor is recommended.
 Aggressive and repeated debridement of necrotic tissue in
nose, sinuses, orbit.
 Antifungal therapy – Amphotericin B, Posaconazole,
Isavuconazole.
 Hyperbaric oxygen therapy –High oxygen pressure
increases the ability of neutrophils to phagocytose agents
of mucormycosis.
 CONTROL OF DIABETES.

20. Early diagnosis & Rx benefit
 A recent study by Chamelos et al. quantified the early
initiation of polyene anti-fungal therapy.
 They reported that if treatment was initiated within 5
days of diagnosis of mucormycosis the survival rate
drastically improved from 49% to 83%.
EARLY DIAGNOSIS & Rx
α
GOOD PROGNOSIS

21. Successful treatment of
Mucormycosis
Four steps:
1. Early and prompt diagnosis.
2. Reversal of underlying predisposing factor.
3. Prompt anti fungal therapy.
4. Aggressive surgical debridement where applicable.

22. Stage Nomenclature Symptoms Signs
Stage 1 Sino- nasal disease Headache Eschar on turbinate
Nasal discharge Nasal crusting
Facial pain & swelling Palate necrosis /
perforation
Skin erythema of
maxillary area
Stage 2 Rhino-orbital disease Loss of vision Chemosis
Diplopia Proptosis
Ptosis
Opthalmoplegia
Stage 3 Orbito-cerebral disease Facial/ multiple Altered mental functions
cranial nerve palsy Hemiplegia
Cavernous sinus
thrombosis
Staging

23. Treatment Protocol
Three distinct treatment groups were created based on
the nature of surgery that the patients underwent.
 Group A - Medical treatment with amphotericin B +
sinonasal debridement only.
 Group B - Medical treatment with amphotericin B +
sinonasal debridement with orbital exenteration and /or
palatal excision.
Group C-Only medical treatment with amphotericin B.

24. IFI
Antifungal
Oral
Diazoles Triazoles
Posaconaz
ole
I.V.
Azole
s
Voriconaz
ole
Flucona
zole
Polyene
s
Conv
AmB
Lipid
Formulatio
ns
Liposomal AmB
AmB Lipid
Complex
Echinocandin
s
Caspofung
in
Anidulafu
ngin
Antifungal therapy in IFI
Patrick T. McKeny; Trevor A. Nessel; Patrick M. Zit Antifungal Antibiotics. https://www.ncbi.nlm.nih.gov/books/NBK538168/ updated on September 2020

25. Anti fungal treatment
 Primary anti fungal is a polyene.
 Conventional amphotericin is cost effective but
nephrotoxic and needs RFT monitoring.
 Liposomal amphotericin is less nephrotoxic and can
be used in higher dosage .
 Associated with 67% survival rate in comparison with
39% in non liposomal preparations.
 Liposomal amphotericin is found to be more effective
in Diabetes mellitus, intra cranial spread and
neutropenic patients.

26. Optimal Dosage of Polyenes
 Conventional Amphotericin B - 1mg/kg/day.
 Liposomal Amphotericin B - 5 to 7.5mg/kg/day.

27. Posaconazole and azoles
 MIC- 1microgram/ml.
 Dosage is 400mg BID with variable bioavailability.
 In pre clinical animal models ineffective in
mucormycosis.
 Fluconazole, Iatroconazole and Voriconazole do not
have reliable activity against mucormycosis.(Sun QN
et al).

28. Combination therapy
 Recent studies have shown that combination therapy
with polyene- capsofungin has shown good results in
Rhino - ocular and Rhino cerebral mucormycosis.
 Combination therapy of posaconazole with
amphotericin B did not show any added benefit.
 It is demonstrated that the survival rate on
combination of surgical debridement and antifungal
therapy is greater (70%) than the surgery (57%) and
therapy alone (61%).

29. Surgical management: Debridement
 As blood vessel thrombosis and tissue necrosis
results in poor penetration of drugs at the site
of infection,surgical debridement plays a key
role.
 Surgical debridement was independantly found
to be associated with good prognosis.
 Recent studies support the use of frozen section
for the clearance of margins.
 Use of calcofluor fluroscence has shown to
increase the sensitivity.

30. Complications of RCM
 Neurological deficits.
 Blindness
 Cerebral thrombosis, infarction and stroke
 Anosmia
 Cavernous sinus thrombosis
 ICA thrombosis
 Garcin syndrome
 Facial and nasal deformity.

31. Prognosis
Prognosis is generally variable.
 Good- in early diagnosis and prompt management.
 Poor- in late diagnosis and extensive spread.
Mortality rate depends on :
clinical form, type of fungus, severity, underlying risk
factors and use of surgical intervention.

32. Mortality in Types
Clinical form Mortality
Mucormycosis in HIV/AIDS 100%
Disseminated mucormycosis 90%
Rhinocerebral mucormycosis 30 - 85%
Sinus mucormycosis 46%
Pulmonary mucormycosis 76%
Cutaneous mucormycosis 4 -10%
Isolated renal mucormycosis 35%

33. COVID-19 and RCM
 India bears the dubious distinction of being both the
diabetes, as well as the mucormycosis, ‘capital’ of the
world. COVID-19 and its treatment, against this
backdrop, amounts to a recipe for disaster.
 As well said “Post COVID-19 Mucormycosis - from
the Frying Pan into the Fire”.
 Post COVID-19 sepsis has had a rampage in the human
body and we are literally left picking up the pieces.

34. .
 dysregulated innate immune response
 ciliary dysfunction
 cytokine storm
 thrombo-inflammation
 microvascular coagulation
This cascade of immune exhausting events facilitates
secondary bacterial and fungal infections especially in
critically ill patients subjected to emergency invasive
procedures, mechanical ventilation, poor nursing ratios,
prolonged hospital stays and breaches in asepsis.
Further, the use of corticosteroid treatment and anti-IL-6-
directed strategies in these highly susceptible hosts along
with high fungal spore counts in the environment creates
the perfect setting for mould infections in COVID
patients.

35. Multifaceted approach
 The interprofessional approach to rhinocerebral
mucormycosis with medical intensivists,
otolaryngologists, physicians, ophthalmologists,
radiologists, pathologists, microbiologist,
neurosurgeons, neurologists and pharmacists escalate
the diagnosis and treatment which may reduce
mortality and morbidity.

36. Patient Education
 Control of diabetes.
 .Regular follow up visits to hospitals.
 Diagnostic nasal endoscopy as a rule in all diabetics
presenting with sinusitis.
 Knowledge of warning symptoms.
 Merits, demerits and necessity of various interventions.
 Possible complications in the absence of interventions.
 Post COVID 19 diabetics should have regular follow ups.

37. Summary
 Mucormycosis is an uncommon aggressive infection
affecting 10,000 individuals globally each year.
 RCM is the most common and aggressive form of
mucormycosis.
 Prompt radical surgical debridement, anti fungal
therapy, correction of underlying metabolic or
impaired immunological status and control of other
concomitant infections are necessary for improved
survival.
 Mortality is high in RCM.
 Mucormycosis developing in the post COVID-19
setting ‘breaks the back’ of a patient’s family who is
barely recovering from a traitorous viral infection.

38. Take home message
 Patient education.
 High index of clinical suspicion in presence of risk
factors.
 We reinforce the necessity for careful nasal endoscopic
evaluation and biopsy in “at risk patients”.
 More weightage for aggressive surgical debridement with
prompt anti fungal therapy till histopathology specimen is
negative for fungus.
 To have meticulous follow up of post COVID diabetic
patients to catch mucor at an early stage.
 Coordinated efforts from multidisciplinary team for a
successful outcome.

39.  References
 Prenissl J, Jaacks LM, Mohan V,et al. Variation in health system performance for
managing diabetes among states in India: a cross-sectional study of individuals aged 15 to
49 years. BMC Med 2019; 17:92.
 Lim S, Bae JH, Kwon HS,et al. COVID-19 and diabetes mellitus: from pathophysiology to
clinical management. Nat Rev Endocrinol 2021; 17:11–30.
 Prakash H, Chakrabarti A. Global Epidemiology of Mucormycosis. J Fungi (Basel) 2019;
5:26.
 Chakrabarti A, Kaur H, Savio J, et al. Epidemiology and clinical outcomes of invasive
mould infections in Indian intensive care units (FISF study). J Crit Care 2019; 51:64-70.
 Rudramurthy SM, Singh G, Hallur V et al. High fungal spore burden with predominance
of Aspergillus in hospital air of a tertiary care hospital in Chandigarh. Indian J Med
Microbiol2016; 34:529-532.
 Ibrahim AS, Spellberg B, Walsh TJ, et al. Pathogenesis of mucormycosis. Clin Infect Dis
2012; 54 (Suppl 1):S16-22.
 Kathy H, Tony A, Matthew J, et al. A case of invasive pulmonary mucormycosis resulting
from short courses of corticosteroids in a well-controlled diabetic patient. Medical
Mycology Case Reports 2020; 29:22-24,
 ASA and APSF Joint Statement on Elective Surgery and Anesthesia for Patients after
COVID-19 Infection
 Patel A, Kaur H, Xess I, et al. Clin Micro Inf 2020; 944.e15

40. Thank you