Mucormycosis is a fatal disease. Involves many organs. This presentation shows extensive discussion including diagnostic and treatment controversies

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Mucormycosis
DR.S.SESHA SAI
SENIOR RESIDENT
ST.JOHN’S NATIONAL ACADEMY OF HEALTH SCIENCES

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Overview
 Introduction
 Causes
 Clinical features
 Diagnosis
 Treatment
 Prophylaxis
 Prognosis
 Conclusion

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Introduction
 Mucormycosis (formerly Zygomycosis) – Ubiquitous in
soil and forms Sporangiospores.
 Important opportunistic mycosis in severely
immunocompromised with Hematological
malignancies and HSCT or SOT
 Necrotising Pneumonia is predominant feature of
pulmonary mucormycosis

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Types
 Rhino-cerebral
 Pulmonary
 Disseminated
 Cutaneous/Soft tissue
 Gastro Intestinal
 Uncommon (like Renal)
Rhinocerebral>Pulmonary Jeong et al.,Fishman’s
Pulmonary>Rhinocerbral European Study of Working Group
on Zygomycoses

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Causes

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Causes
 Immunocompetent
 Cause not known
 A chronic insult of a well-defined and
localized body area might have resulted in a local
immunocompromise
 Pulmonary type is uncommon

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Causes
Patients on Anti-aspergillus drugs
 Increasing trend in pulmonary mucormycosis in
patients receiving antifungal agents with activity
against aspergillosis but not mucormycosis.
 Animal studies - increased virulence of Mucorales spp.
following voriconazole pre-exposure.
 Difficult to establish a causal relationship between
voriconazole use and development of mucormycosis

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Diagnosis – Clinical features
 Immunocompromised
 Indistinguishable from aspergillus
 Non productive Cough, fever, pleuritic chest pain, hemoptysis
 Favorable factors
 Severe sinusitis
 Rhino-orbital extension
 On Aspergillus-active antifungals
 Repeated absence of Asp GM/ ß-D glucan in serum

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Diagnosis-Radiology
 Endobronchial lesions in Diabetics
 Infiltrate, wedge-shaped consolidation, multiple
nodules (>10) , cavitation, mycetoma, lobar collapse
and, rarely pleural effusion
 Halo sign & Air Crescent sign (McAdams et al-12%)
 Reverse Halo Sign

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Reverse Halo Sign
 Focal area of GGO surrounded by ring of consolidation
 ~20 to 90 % of pulmonary mucormycosis
 Legouge C et al- 15 of 16 pts leukemia with neutropenia
 Lee et al- 54% with mucor and 6% with IPA
 Even though these findings are not conclusive, they may be used as
indicators to start aggressive diagnostic laboratory tests

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Reverse Halo Sign

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Diagnosis
 Immunocompetent
 Pulmonary involvement is uncommon
 If occurs, chronic symptoms up to 4 months
 Uncommon
 Asymptomatic Mycetoma
 Multiple mycotic pulmonary artery aneurysms
 Pseudoaneurysms
 Asymptomatic solitary nodules
 Normal chest radiographs
 Ulcerative tracheobronchitis in lung transplants
 Hypersensitivity pneumonitis in farm workers & Scandinavian sawmill
workers (wood trimmer’s disease)

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Diagnosis
Microscopy
 Direct microscopy – optical brighteners like
Blankophor and Calcofluor White
 Hyphae are of variable width, non septate, irregular
ribbon like with wide angle bifurcations (90˚)
 Periodic acid-Schiff or Grocott Gomori’s methenamine
silver staining - highlight
fungal hyphae

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Microscopy

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Diagnosis
Culture
 Tissue swabs, sputum, or BAL cultures are usually nondiagnostic
 Direct microscopy of bronchoalveolar lavage & transbronchial
biopsy may increase the yield
 Rapid growth (3 to 7 days) on Sabouraud agar
and potato dextrose agar incubated at 25◦C to 30◦C
 Aggressive vertical growth toward the lid of the Petri dish – Lid
lifters
 Specimens should be chopped not grounded

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Culture

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Diagnosis
Histopathology
 Hyphae will be seen
 Neutrophilic or granulomatous inflammation
 Absent in a few cases - immunosuppressed patients.
 Invasive disease is characterized by prominent infarcts
and angioinvasion.
 Perineural invasion may be present.
 Angioinvasion - extensive in neutropenic patients

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Diagnosis
Molecular based methods
 PCR, RFLP, DNA sequencing that targets the 18S
ribosomal DNA of Mucorales
European Society of Clinical Microbiology and Infectious
Diseases(ESCMID) & European Confederation of Medical
Mycology(ECMM) 2013
Recommendation

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Diagnosis
Antigen Detection & Specific T cells
 Galactomannan and ß-D Glucan – If negative likely
invasive mucormycosis than IPA.
 Mucorales-specific T cells - enzyme-linked
immunospot (ELISpot) assay
Recommendation

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Diagnosis
Genus & Species Identification
 No strong evidence that identification to the genus/species level
may be important to
guide treatment.
 Better epidemiological knowledge and investigation of outbreaks
 Sequencing of Internal Transcribed Spacer (ITS) of rRNA is the best
technique

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Genus &
Species
Identificatio
n
 Carbon assimilation
profiles – ID32C and API
50CH commercial kits
 DNA targets – 18s, 28s,
cyt b, FTR1 gene
 Matrix-assisted laser
desorption/ ionization
time-of-flight (MALDI-
TOF) mass spectrometry

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Diagnosis
Hamilos G, Samonis G, Kontoyiannis DP. Pulmonary
mucormycosis. Semin Respir Crit Care Med. 2011;32:693–702
Three-step analysis approach of CT guided biopsy specimens
of lung lesions to differentate pulmonary mucor and IPA:
1. Calcofluor-white staining - septated versus aseptae
hyphae
2. Aspergillus Galactomannan and PCR testing for rapid
identification
3. PCR testing of DNA in specimens where aseptate
hyphae were observed or Aspergillus markers were
negative

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Treatment
General principles
 Early diagnosis (Chamilos et al.)
 Early administration of active antifungal agents
 Reversal of underlying factors
 Complete removal of all infected tissues
 Use of various adjunctive therapies

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Treatment
Primary Antifungal Therapy
 Liposomal Amphotericin-B first line recommended
agent
 Fluconazole, Voriconazole – No reliable activity,
Itraconazole – Absidia species
 Posaconazole, Isuvaconazole can also be used as first
line therapy

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Treatment
Liposomal Amphotericin B
 2016 ECIL & ESCMID/ECMM liposomal form as first line
 Can be given as 5mg/kg/day to 10mg/kg/day, if CNS involved
 Surgery + Lip Amp B increases survival rates and cure rates

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 Use of Amphotericin Deoxycholate is discouraged
(ESCMID/ECMM)
 ABLC can also be used- if no CNS involvement (B)
 Alternate routes – ABLC aerolised with Respigard II
nebulizer, Direct instillation of Amphotericin B into
pulmonary cavities or pleural space

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Treatment
Azoles
 Posaconazole 800mg/day in 2 or 4 divided doses – first
line (ESCMID/ECMM), Salvage therapy (ECIL-6)
 Isuvaconazole (Cornely OA et al) – 200mg OD. But
VITAL study showed higher mortality rates and poor
response

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Treatment
Duration of Treatment
 Highly individualized
 Near normalization of radiograph, negative biopsy
specimens and cultures, recovery from
immunosuppression

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Treatment - Surgery
 Removal of necrotic tissue – Increases penetration of
antifungals
 Lobectomy, Pneumonectomy or wedge resection
 Surrounding infected healthy-looking tissues should
be removed
 Groll A et al. – Mortality reduced by 79%

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Treatment - Salvage Therapy
 If disease is refractory or intolerance towards previous
antifungal therapy.
 Posaconazole(A)
 Polyenes + Posaconazole(B)
 Lipid complex, liposomal, Colloidal dispersion (B)
 Polyenes + Caspofungin(C)
ESCMID/ECMM 2013

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Treatment – Adjunctive
Therapies
 Hyperbaric Oxygen – 100% O2 at 2atm pressure for 90
min twice a day (C)
 Cytokine therapy in hematological malignancy –
GCSF(A), Granulocyte transfusion +/- IFNγ (C)
 Lovastatin
 VT-1161(otesaconazole) – Inhibits fungal CYP51
 Nivolumumab and IFNγ

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Treatment – Adjunctive
Therapies
Iron chelators – Deferasirox
 Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor)
study
 First randomized trial for any treatment of mucormycosis
 45%(5) mortality at 30 days, 82%(9) mortality at 90 days
 Deferasirox cannot be recommended as part of an initial
combination regimen for the
treatment of mucormycosis.

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Iron chelators – Deferasirox
 Hematological malignancy – ECIL-6 and
ESCMID/ECMM recommended against its use.
 Other than hematological malignancy –
ESCMID/ECMM marginally supports its use(C)

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Prophylaxis
ESCMID/ECMM
 Neutropenic or GvHD with immunosuppressive
outbreaks – Posaconazole 600mg/day (C)
 Surgery and Past h/o mucormycosis – Strong
recommendation

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Prognosis
 Overall mortality in pulmonary mucormycosis – 50-70
%, if disseminated >90%

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Conclusion
 More common in immunocompromised
 Suspected in patients already on anti-aspergillus
treatment
 No specific clinical or radiological features making
diagnosis more difficult and challenging
 Diagnostic options are limited with variable results
 Invasive diagnostics have more yield which is not
possible in some patients

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Conclusion
 Early diagnosis means early treatment and leading to less mortality
rates
 Reversal of underlying factors, Surgery and Liposomal amphotericin
B increases cure rates
 Duration of treatment is highly individualized
 Posaconazole, Isuvaconazole can also be tried
 Salvage therapy in refractory or intolerant pts
 Adjunctive therapies need to proved in large trials and standardized

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References
 Fishman's Pulmonary Diseases and Disorders, 5th edition
 Pilmis B, Lanternier F. Recent advances in understanding and management of
mucormycosis 2018, F1000 research
 Challenges in the diagnosis and treatment of mucormycosis
A. Skiada. Medical Mycology, 2018
 ESCMID and ECMM joint clinical guidelines for the diagnosis and management
of mucormycosis 2013, Clin Microbiol Infect 2014
 Mucormycosis and entomophthoramycosis: a review of the clinical
manifestations, diagnosis and treatment, R. M. Prabhu and R. Patel,Mayo clinic of
medicine, Clin Microbiol Infect 2004