mucormycosis and its management in OMFS

1. MUCORMYCOSIS
PRESENTED BY - S MAHIMA

2. CONTENTS
• INTRODUCTION
• MICROBIOLOGY
• PATHOGENESIS
• ROUTES OF SPREAD
• PREDISPOSING CONDITIONS
• TYPES
• PULMONARY MUCORMYCOSIS
• CUTANEOUS MUCORMYCOSIS
• GASTROINTESTINAL MUCORMYCOSIS
• DISSEMINATED MUCORMYCOSIS
• UNCOMMON FORMS
• RHINOCEREBRAL MUCORMYCOSIS
• DIAGNOSIS
• MUCOR AND COVID-19
• TREATMENT

3. INTRODUCTION
• Fulminant fungal infection occurring in debilitated patients with an underlying pathologic condition
• Third invasive mycosis in order of importance - after candidiasis and aspergillosis - caused by fungi of class
Zygomycetes, order Mucorales
• First documented report of human mucormycosis - Paltauf, 1885 - reported a disseminated infection in a
patient with rhinocerebral involvement caused by angioinvasive, ribbon-like hyphae that was termed -
Mycosis mucorina

4. MICROBIOLOGY
Macroscopic appearance of a
positive culture for Mucorales
Microscopic details of Mucorales

6. • Commonly found in soil than in air - exist in form of spores (protect themselves, assist in dispersal)
• Primary mode of acquisition - inhalation of spores from environmental sources
• Occurrence - more prevalent in tropical areas
• Dispersal and occurrence - more common during summer than in winter - fungal spores thrive in dry, arid
conditions
• Can also occur in decaying matter - decaying vegetables, fruits
• Mucoralean fungi - reproduce anamorphically via non-motile sporangiospores released from different
sporangia

7. PATHOGENESIS

8. ROUTES OF SPREAD

9. PREDISPOSING CONDITIONS
• Malignant hematological disease with or without stem cell transplantation
• Prolonged and severe neutropenia
• Poorly controlled diabetes mellitus with or without diabetic ketoacidosis
• Iron overload
• Major trauma
• Prolonged use of corticosteroids
• Illicit intravenous drug use
• Neonatal prematurity and malnourishment
• Antifungal agents - with no activity against zygomycetes -voriconazole, caspofungin
• Hospital environment - nosocomial mucormycosis -exposure to heavy air fungal loads because of construction work,
contaminated air filters, variety of healthcare-associated procedures, device, contaminated wound dressings,
transdermal nitrate patches, intravenous catheters, tongue depressors, allopurinol pills
• Iatrogenic

11. TYPES
• Rhino-orbito-cerebral mucormycosis (ROCM)
• Pulmonary mucormycosis
• Gastrointestinal mucormycosis
• Cutaneous mucormycosis
• Disseminated mucormycosis
• Uncommon rare forms - endocarditis, osteomyelitis, peritonitis,
renal infection

12. PULMONARY MUCORMYCOSIS
• Occurs most often in neutropenic patients with cancer undergoing induction
chemotherapy, those who have undergone HSCT, have graft-versus-host disease
• Overall mortality rate - high (76%), even higher in severely immunosuppressed
• Clinical features - non-specific, cannot be easily distinguished from those of pulmonary
aspergillosis
• Patients usually present with prolonged high-grade fever unresponsive to broad-spectrum
antibiotics, Non-productive cough, hemoptysis, pleuritic chest pain, dyspnea
• In rare circumstances - endobronchial or tracheal lesion, especially in diabetics - can cause
airway obstruction, results in lung collapse, invasion of hilar blood vessel, subsequent
massive hemoptysis
• May invade lung-adjacent organs - mediastinum, pericardium, chest wall

13. • On chest images - non-specific, indistinguishable from pulmonary aspergillosis
• Most frequent findings - infiltration, consolidation, nodules, cavitations,
atelectasis, effusion, posterior tracheal band thickening, hilar or mediastinal
lymphadenopathy
• Air crescent sign may be observed, similar to that seen with pulmonary
aspergillosis
• Researchers have observed - CT finding of reversed halo sign, focal round area of
ground-glass attenuation surrounded by ring of consolidation

14. CUTANEOUS MUCORMYCOSIS
• Direct inoculation of fungal spores in skin - may lead to disseminated disease
• The reverse (dissemination from internal organs to the skin) is very rare
• Depending on extent of infection - classified as localized (affects only skin or
subcutaneous tissue), deep extension (invades muscle, tendons, bone),
disseminated (involves other noncontiguous organs)
• Onset gradual, may progress slowly or fulminant - leading to gangrene,
hematogenous dissemination
• Typical presentation - necrotic eschar accompanied by surrounding
erythema, induration
• Non-specific erythematous macule - small, apparently insignificant -
cutaneous manifestation of disseminated disease in immunosuppressed
patient
• Less common presentations - superficial lesions, only slightly elevated
circinate, squamous borders, targetoid plaques with outer erythematous
rims, ecchymotic or blackened necrotic centers
• In patients with open wounds - lesions with a cotton-like appearance
resembling that of bread mold

15. GASTROINTESTINAL MUCORMYCOSIS
• Uncommon, seldom diagnosed in living patients - such cases - diagnosis is delayed - mortality rate is as high as 85%
• Only 25% of gastrointestinal mucormycosis cases - diagnosed antemortem
• Reported - mainly in premature neonates, malnourished children, individuals with HMs, diabetes mellitus, history of corticosteroid use
• Acquired - ingestion of pathogens in foods such as fermented milk, dried bread products, consumption of fermented porridges,
alcoholic drinks derived from corn
• Use of spore-contaminated herbal, homeopathic remedies
• One group of authors - series of cases of gastrointestinal mucormycosis presumably transmitted orally with sporangiospore
contaminated tongue depressors used for oropharyngeal examinations in a hematology-oncology clinic
• Can occur in any part of the alimentary system - stomach is most commonly affected, followed by colon, ileum
• Infection usually presents with an appendiceal, cecal, ileac mass or gastric perforation - may be associated with massive upper
gastrointestinal tract bleeding

16. • Premature neonates - necrotizing enterocolitis
• Neutropenic patients - mass-like appendiceal or ileal lesion, neutropenic fever, typhlitis, hematochezia
• Diagnosis - usually delayed - non-specific presentation requires a high degree of suspicion, leading to early use of
endoscopic biopsy analysis
• Can also involve liver, spleen, pancreas
• Fungus can invade bowel walls, blood vessels - bowel perforation, peritonitis, sepsis, massive gastrointestinal
hemorrhage - most common cause of death

17. DISSEMINATED MUCORMYCOSIS
• Mucormycosis in one organ can spread hematogenously to
other organs - most commonly associated with dissemination -
lung
• Also occurs from - alimentary tract, burns, extensive cutaneous
lesions
• Brain - common site of spread, metastatic lesions may also be
found in liver, spleen, heart, other organs
• Patients with iron overload (especially deferoxamine),
profound immunosuppression (recipients of allogeneic stem
cell transplants - graft versus host disease treated with
corticosteroids), profound neutropenia, active leukemia -
classic groups at risk
• Symptoms, evolution - vary widely, reflecting host as well as
location, degree of vascular invasion, tissue infarction in
affected organs
• Postmortem diagnosis - quite common
• Metastatic skin lesion - important hallmark in early diagnosis
• Without appropriate treatment - always fatal

18. UNCOMMON FORMS
• Endocarditis, osteomyelitis, peritonitis, pyelonephritis, rare cause of prosthetic or native valve endocarditis Intravenous drug use -
typical risk factor
• Endocarditis occurs principally on, around prosthetic valves - can cause aortic thrombosis
• Osteomyelitis - occurs after traumatic inoculation, surgical intervention (eg- tibial pin placement, anterior cruciate ligament repair)
• Rare - involvement of peritoneal cavity by Zygomycetes - patients undergoing continuous ambulatory peritoneal dialysis
• Peritonitis - slowly progressive, attributable mortality rate in patients receiving delayed, inappropriate treatment - high as 60%
• Catheter-related mucormycosis - prompt removal of catheter, use of systemic antifungal therapy for several weeks are essential
• Renal mucormycosis - immunocompromised patient who presents with hematuria, flank pain, unexplained anuric renal failure
• Isolated renal mucormycosis - intravenous drug users, renal transplant recipients in developing countries with warm climates such as
India, Egypt, Saudi Arabia, Kuwait, Singapore
• Another rare manifestation - brain involvement (typically in basal ganglia) - without rhino-orbital involvement in patients with
leukemia, intravenous drug abusers
• Isolated mucormycosis - mastoid, oral mucosa, bone, bladder, trachea, mediastinum, ear - rare
Osteomyelitis, a rare form of mucormycosis

19. RHINOCEREBRAL MUCORMYCOSIS
• Most common form - in patients with diabetes mellitus
• May also occur in - underlying malignancies, recipients of hematopoietic stem cell or solid organ transplants, individuals
with other risk factors
• Infection develops after inhalation of fungal sporangiospores into paranasal sinuses
• Infection may then rapidly extend into adjacent tissues
• Upon germination - invading fungus may spread inferiorly to invade palate, posteriorly to invade sphenoid sinus,
laterally into cavernous sinus to involve orbits, cranially to invade brain
• Invades cranium through either orbital apex or cribriform plate of ethmoid bone, ultimately kills host
• Occasionally - cerebral vascular invasion can lead to hematogenous dissemination of infection with or without
development of mycotic aneurysms

20. Clinical presentation
Rhino-sinusitis, Rhino-orbital, Rhino-maxillary, Rhino-cerebral
Facial findings
• Facial swelling
• Black eschar - results from necrosis of tissues after vascular invasion by fungus - may be visible in nasal
mucosa, palate, skin overlying orbit
• Excrutiating pain
• Paresthesia
• Sinus tract opening
• Infection in dangerous area of face

21. Intraoral findings
• Halitosis
• Intraoral pus discharge
• Palatal eschar
• Exposed palatal bone
• Sinus tract
• Unexplained loosening of
teeth
• Unhealed tooth socket
• Mobility of maxilla

22. Nasal findings
• Perinasal swelling
• Foul smelling nasal discharge
• Nasal congestion
• Sinusitis
• Destruction of the turbinates
• Black necrotic eschar in nasal cavity

24. Orbital findings
• Invasion of orbit - unilateral
• Peri-orbital cellulitis
• Chemosis
• Exophthalmos (Proptosis)
• Opthalmoplegia
• Erythema, cyanosis of facial skin overlying the involved sinuses
and/or orbit
• Orbital apex syndrome
• Pain, blurring, loss of vision - invasion of globe or optic nerve
Acute orbital apex syndrome

29. DIAGNOSIS
Blood tests
• CBC (Look for neutropenia / monocytopenia, Raised ESR)
• FBS, PPBS, HBA1C
• LFT, RFT with electrolytes
• HIV, HBsAg
Nasal Endoscopic Examination
• Black necrotic tissue, eschar
• Spongy appearance

30. Radiographic imaging
• X-Ray PNS (Para Nasal Sinuses) and OPG (Ortho-Pantomogram) - can be normal
• CECT of PNS and Orbit - Erosion and thinning of hard tissues, mucosal thickening of sinuses, enlargement of
masticatory muscles
• Contrast MRI - Optic neuritis, intracranial involvement, CST, infratemporal fossa involvement
• HRCT Chest - Reverse halo sign: nodule (≤3 cm)/ mass (>3 cm) or consolidation with surrounding ground-glass opacity
halo, central necrosis, air-crescent sign

31. Biopsy
• Nasal cavity for ROCM
• Palatal involvement - from oral cavity
• Transbronchial biopsy, BAL (for Pulmonary)
• CT guided FNAC - considered in some cases of Pulmonary Mucormycosis

32. Histopathology
• To confirm the diagnosis - biopsy samples can be cultured
• All Mucorales grow rapidly (3-5 days) on most fungal culture media - Sabouraud agar, potato dextrose agar incubated
at 25–30°C
• Broad ribbon-like, thin-walled, primarily aseptate or pauci septate hyphae, irregular diameters, non-dichotomous
irregular branching, accompanying tissue necrosis, fungal angioinvasion
• Grocott Methenamine Silver GMS and periodic Acid-Schiff PAS stains

33. Direct microscopy
KOH mount (or fluorescent wet mount) - an inexpensive, invaluable method to rapidly give presumptive diagnosis
Culture and sensitivity testing
• Mucorales grow on any carbohydrate substrate
• Colonies appear usually within 24–48 hrs
• Identification is based on colonial/ microscopic morphology, growth temperature
• Major concern about culture - low sensitivity - can be falsely negative in up to 50% of mucormycosis cases
• Hence - combination of clinical, laboratory work up essential

34. Molecular methods
• Molecular techniques - PCR - identify fungus directly from infected tissues or from bronchalveolar lavage
• These tests - require invasive sampling (biopsy, bronchalveolar lavage)
• Mucorales DNA detection in non-invasive specimens like serum - effective for early diagnosis
Serology
• There are no commercially available antigen markers to detect Mucorales
• β-Dglucan test does not detect antigen components of Mucorales cell wall - can help to
• rule out invasive aspergillosis, most frequent differential diagnosis, combined Aspergillus and Mucorales infections

35. MUCOR AND COVID-19
• Increase in ferritin level - commonly seen in COVID–19 patients - Iron overload can lead to increased susceptibility to
Mucormycosis
• Prolonged use of higher end antibiotics - kill the bacterial commensals - proliferation of fungal commensal such as
Rhizopus or Mucor - susceptible environment
• Excessive use of steroids – aggravate hyperglycaemia - create conducive environment for proliferation
• Intubation, Mechanical ventilation, Chronic respiratory disease - damaged epithelial and endothelial tissues - site for
fungal angioinvasion
• Diffuse alveolar damage with severe inflammatory exudation - COVID-19 patients - immunosuppression with decrease
CD4 +T and CD8 +T cells
• Severe form of COVID-19 illness - reduce level of lymphocytes, neutrophils - increase chances of getting Mucormycosis
infection

36. BURDEN
• India - the second largest Covid affected population in the world with more than 2.65 crore cases as on 24th May 2021
• India - diabetes capital of the world - nearly 7.7% of adult population being diabetic
• Recent times - witnessed increased cases of Mucormycosis in India
• Mostly seen in post covid diabetic population
• According to - Central government – total of 40824 mucormycosis cases have been reported - out of which nearly 3229
patients have succumbed to the disease
• Nealry 28186 patients - still under treatment for same - 31% patients have been cured
• Karnataka declared mucormycosis as a notified disease - after registering 97 cases - 4 patients lost their lives till 17 May
2021

37. PREVENTION
• Proper usage of masks (universal)
• Avoid activities - involve contact with soil or dust - dusting or yard work or gardening
• Hand-hygiene - good way to avoid transferring infection from hands to respiratory mucosa
• Proper wound care (Surgical dressing, usage of antiseptic, debridement)
• Strict glycaemic control, regular blood glucose monitoring
• Strict adherence to Anti-Diabetic medications
• Post COVID follow up, daily blood glucose monitoring in previously non-diabetics as well
• Diet, Lifestyle modifications for preventing Diabetes
• Cessation of smoking and alcohol
• Avoidance of self-medication
• Compulsory Health education - patients suffering from Covid-19, those who have been discharged from either home
isolation or facility-based treatment
• Information dissemination, Risk communication, Health education to public on early warning signs, symptoms
• Judicious use of antibodies/ antifungals and steroids

38. Advisory from ICMR
regarding COVID-19
associated
Mucormycosis

40. TREATMENT
General Principles
• Four factors are critical for eradicating mucormycosis -
1. Rapidity of diagnosis
2. Reversal of the underlying predisposing factors (if possible)
3. Appropriate surgical debridement of infected tissue
4. Appropriate antifungal therapy
• Early diagnosis - important because small, focal lesions can often be surgically excised before they
progress to involve critical structures or disseminate
• Unfortunately - no serologic or PCR-based tests to allow rapid diagnosis
• Autopsy series have reported that up to half the cases of mucormycosis are diagnosed postmortem

42. Antifungal treatment

44. Iron chelation with deferasirox
• Host iron availability is fundamental to the
pathogenesis of mucormycosis
• Predisposition of patients with diabetic ketoacidosis
(DKA) - developing mucormycosis is caused in part by
increased free serum iron in the setting of acidemia
• In 2005 - new iron chelator - deferasirox - approved by
US FDA
• As effective as liposomal amphotericin B (LAmB)
therapy
• Combination deferasirox/LAmB therapy -
synergistically improves survival rates

45. Hyperbaric oxygen
• Improves the flow of oxygen to ischemic tissues, alleviates acidosis, inhibiting fungal growth
• Boosts killing capacity of leukocytes by providing optimal oxygen tensions for oxidative bursts
• Beneficial addition to standard surgical and antifungal therapy to treat infection – particularly in diabetic patients who
have rhinocerebral disease
• Increased oxygen pressure that can be achieved with hyperbaric oxygen treatment seems to improve the organism-
killing ability that neutrophils possess
• By correcting lactic acidosis - treatment with hyperbaric oxygen promotes oxidative action of AmB

46. FESS
The purpose of functional endoscopic sinus surgery (FESS) is to restore normal paranasal air sinuses mucociliary function

47. SURGERY
SURGICAL DEBRIDEMENT
• In rhinosinusitis surgical - debridement of infected tissue - crucial component of therapy, should be urgently performed
to limit aggressive spread of infection to contiguous structures
• Repeated removal of necrotic tissue or radical surgical resection (e.g - exenteration of orbit) with subsequent
reconstructive surgeries may be required for lifesaving control of rapidly evolving infection
• Extraction of tooth , thorough debridement, curettage

49. MAXILLECTOMY
A maxillectomy is a procedure to remove a primary tumor in the maxilla
The procedure involves surgical removal of some of the bone, part of roof of mouth possibly some of the teeth

53. ORBITAL EXENTRATION
Based on the scoring system, it was observed that those patients who crossed a score of 23 were eligible candidates for
orbital exenteration as agreed upon by the Otorhinolaryngologist and Ophthalmologists

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