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Mucormycosis
The document provides a comprehensive overview of mucormycosis, an opportunistic infection primarily affecting immunocompromised individuals. It details the causes, clinical features, diagnostic methods, treatment options, and prognosis of the disease, emphasizing the importance of early diagnosis and intervention. The document also highlights various antifungal therapies, the role of surgery, and challenges in management, particularly in patients with hematological malignancies.
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Mucormycosis
- 1. ©drseshasai Mucormycosis DR.S.SESHA SAI SENIOR RESIDENT ST.JOHN’SNATIONAL ACADEMY OF HEALTH SCIENCES
- 2. ©drseshasai Overview Introduction Causes Clinical features Diagnosis Treatment Prophylaxis Prognosis Conclusion
- 3. ©drseshasai Introduction Mucormycosis (formerlyZygomycosis) – 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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- 5. ©drseshasai 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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- 7. ©drseshasai Causes Immunocompetent Causenot 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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- 10. ©drseshasai Causes Patients on Anti-aspergillusdrugs 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
- 11. ©drseshasai Diagnosis – Clinicalfeatures 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
- 12. ©drseshasai Diagnosis-Radiology Endobronchial lesionsin 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
- 13. ©drseshasai 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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- 15. ©drseshasai Diagnosis Immunocompetent Pulmonaryinvolvement 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)
- 16. ©drseshasai 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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- 18. ©drseshasai 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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- 20. ©drseshasai Diagnosis Histopathology Hyphae willbe 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
- 21. ©drseshasai 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
- 22. ©drseshasai 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
- 23. ©drseshasai Diagnosis Genus & SpeciesIdentification 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
- 24. ©drseshasai Genus & Species Identificatio n Carbonassimilation 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
- 25. ©drseshasai Diagnosis Hamilos G, SamonisG, 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
- 26. ©drseshasai Treatment General principles Earlydiagnosis (Chamilos et al.) Early administration of active antifungal agents Reversal of underlying factors Complete removal of all infected tissues Use of various adjunctive therapies
- 27. ©drseshasai 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
- 28. ©drseshasai 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
- 29. ©drseshasai Use ofAmphotericin 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
- 30. ©drseshasai Treatment Azoles Posaconazole 800mg/dayin 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
- 31. ©drseshasai Treatment Duration of Treatment Highly individualized Near normalization of radiograph, negative biopsy specimens and cultures, recovery from immunosuppression
- 32. ©drseshasai 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%
- 33. ©drseshasai Treatment - SalvageTherapy 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
- 34. ©drseshasai 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
- 35. ©drseshasai Treatment – Adjunctive Therapies Ironchelators – 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.
- 36. ©drseshasai 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)
- 37. ©drseshasai Prophylaxis ESCMID/ECMM Neutropenic orGvHD with immunosuppressive outbreaks – Posaconazole 600mg/day (C) Surgery and Past h/o mucormycosis – Strong recommendation
- 38. ©drseshasai Prognosis Overall mortalityin pulmonary mucormycosis – 50-70 %, if disseminated >90%
- 39. ©drseshasai Conclusion More commonin 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
- 40. ©drseshasai Conclusion Early diagnosismeans 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
- 41. ©drseshasai References Fishman's PulmonaryDiseases 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
Editor's Notes
- #4 Grow on carbohydrate substrate…inhalation of fungal sporangiospores that have been released in the air or from direct inoculation of organisms into disrupted skin or gastrointestinal tract mucosa and causes different forms of disease
- #5 Mucorales family is divided into 6 genus..Rhizopus oryzae is most common. Common organisms different across diff countries. Most common is Rhizopus even in india. 70-85%
- #6 Decreasing order of frequency
- #7 frequent blood transfusions in HM-iron overload-treat with Deferoxamine. Bcz of its siderophore property it can be used by mucor for utilization of iron for its growth DM/DKA- Rhinocerebral, HM,HSCT,SOT severe immunocomp-Pulmonary
- #9 1978 to 2009, 212 from 35 countries. India(94)>usa>Australia climatic, socio-economic, scarce hygienic conditions, diagnostic delay – diabetics, malnourished Their 5 cases-chronic sinusitis-can be assumed that local insult Pulmonary less common in immunocompetent
- #10 1885 to 2005-929 immunocomromised
- #11 vori,echino active against asp but not mucor suspect mucor- fungal sinusitis if immunosupresed pts on antifungal drugs like Other studies increased mucor prior to voriconazole and recent RCT did not find higher incidence.
- #12 Timely diag is crucial-as first line anti asp-vori not effecrive for mucor Hyphal invasion of blood vessels-necrosis of adj parenchyma Tissue necrosis is the hallmark of mucormycosis –but not specific asp, fusarium, tb
- #14 24 mucor ct scans – 96 ipa Cop, Ipa, gpa, infarction, tb, pcp
- #15 54 m aml allogenic stem cell transplant
- #19 Sputum/BAL 25%, tissue specimens with abundant growth yield 50% in cultures Tblb hemaogolocal malignancies thrombocytopenic Hyphae are friable in nature and hence may be damaged during tissue manipulation
- #20 Fullfy gray or brownish and later becomes pepper speckled appearance due to formation of sporangiospores
- #21 No genus or species identification 60-100%
- #22 Fresh tissue and paraffin Fresh-resp specimens & ct guided biopsy 61 of 61 culture neg 5 Formalin fixed Paraffin less yield recommended as valuable add on tools that complement conventional diagnostic procedures
- #23 in three haematological patients developing invasive mucormycosis at diagnosis and throughout the entire course of the invasive disease but not for long after resolution of the infection
- #24 varies from taxa to taxa, but stable in general in the same genus… set a similarity cutoff for identifying species Clsi-clinical & lab standard institute isham internat society for human & animal mycology
- #25 Strips containing carbohydrate substrates and findings are compared to database. Drawback-new fungus cannot be detected which is not in database
- #26 require validation in a wider range of patients before PCR becomes a standardized adjunctive diagnostic test for mucormycosis
- #27 delay in rx for >5days in HM two fold rise in mortality 82vs48 Immunosuppressive medications, particularly corticosteroids , treatment of DKA Blood vessel thrombosis and resulting tissue necrosis –poor penetration of antifungals
- #28 Polyenes, Azoles
- #29 Europ confere infections in leukemia,
- #31 steady-state plasma concentrations 1 week. Drug interactions RIF, PPI. Preferable to receive initial amb for several days Outcomes in the two groups were similar, and isavuconazole was thus deemed to be an alternative to amphotericin B, as first-line treatment of mucormycosis Limitatins-small study hence large trails are necessary to prove the same
- #32 Indicatoors that pt is candisate for stopping antifungals
- #33 as the speed of the extension of the infection by hyphae is enormous 230 cases Many studies surgical rx with medicl rx decreased mortality enormously
- #35 promoting wound healing, phagocytic cell function, and ampb oxidative killing mechanisms, direct antifungal activity Vt1161 investigational drug proven benefit in animal model Lovastatin-inhibits mucor in vitro and animal models don’t know clinically menaingful Case report immunostimulating drug-benefit in unresponsive to conventional rx
- #36 Iron utilized by fungus with help of deferoxamine which have siderophore activity Phase II, Improved survival in diabetic mice, to prove clinically. 20pts lamb+deferasriox, lamb+placebo Lamb thrice weekly,deferasirox 20mg/kg/day 14 days N=11, n=9, 5 withdrew within 3 days
- #37 Several limitations to defeat mucor-more sick pts in deferasirox arm, mortality due to progression of infection and progression of underlying disease Diabetes-isolated risk factor-many case reports shown benefit
- #38 Same drug and same dose used for treatment
- #39 Shows how fatal is disease. even though mortality has come down from 100 to 47% in 1970 after introduction of amphb and almost unchanged since then