Mucormycosis - Fusariosis

Anna Skiada, MD

University of Athens, Greece © by author ESCMID Online Lecture Library Mucormycosis (zygomycosis)

Mucormycosis has emerged as an increasingly important infection with a high mortality It is the third© invasive by author fungal infection in order of importance after Candidiasis ESCMIDand Aspergillosis Online Lecture Library Mucormycosis (zygomycosis)

 A group of infections caused by the fungi of the order Mucorales

 Most common genera:  Lichtheimia  Rhizopus © by author  Mucor ESCMID Rhizomucor Online Lecture Library  Cunninghamella  Apophysomyces

Epidemiology

 Ubiquitous in nature  Found in soil, as well as in decaying organic material (fruit, bread, etc)  The human pathogens grow fast in any carbohydrate substrate© by author  Many agents of mucormycosis can grow ESCMIDin temperatures Online above Lecture Library 37ºC

Modes of transmission

 Inhalation

 Direct inoculation (trauma)

 Ingestion

 Mucormycosis usually occurs in immunocompromised patients

 Immunocompetent hosts may develop mucormycosis of soft tissues as a result of trauma

 The fungi show a© predilection by author for vessel wall invasion resulting in thrombosis and necrosis of surrounding tissue

ESCMID Infections areOnline typically acuteLecture and fulminant Library

 Diabetes mellitus  Hematologic malignancies (neutropenia)  Other malignancies  Transplantation  Corticosteroids  AIDS © by author  Iron overload ESCMIDBurns, trauma, Online iv drug Lecture use Library

Clinical Presentation

 Sinusitis - Rhinocerebral  Pulmonary  Cutaneous  Disseminated© by author  Gastrointestinal ESCMID CNS Online Lecture Library  Renal  Bones, heart, mediastinum, etc.  Necrotic eschars

© by author ESCMID Online Lecture Library  Rapidly progressive; hyphae invade the internal elastic lamina of blood vessels, infarcting sinonasal tissue and creating an acidotic environment of tissue necrosis that is ideal for continued fungal proliferation.  “Acute necrotizing© by FRS author”  May lead to thrombosis of carotid arteries and cavernous sinuses, invade the orbits or ESCMIDthe brain: rhinocerebral Online Lecture disease Library.

 Fever (50 to 90% of patients)  Proptosis, facial swelling, palatal ulcer, coma.  In an immunocompromised patient, a sign or symptom of sinonasal inflammation should initiate imaging studies and nasal endoscopy.  Anesthetic regions© by of theauthor face and oral cavity may precede the development of objective ESCMIDchanges in the Online sinonasal Lecture mucosa. Library

Ferguson B J Otolaryngol Clin North Am 2000;33:349-65.  Mucosal pallor is the earliest and most reliable manifestation of fungal angioinvasion and can be missed if physicians are attempting to locate the classically described necrotic eschars of advanced diseased  Nasal endoscopy with directed biopsies is indicated in all immunocompromised patients with altered facial© sensationby author or signs and symptoms of acute bacterial RS refractory to ESCMID72 hours of medical Online therapy. Lecture Library Gillespie MB, O'Malley BW. Otolaryngol Clin North Am 2000;33:323-34. © by author ESCMID Online Lecture Library Pulmonary mucormycosis

. It occurs most frequently among neutropenic patients.

. It presents with nonspecific symptoms such as fever, cough and dyspnea; hemoptysis may occur with vascular invasion. © by author

. Radiological presentation includes segmental ESCMIDconsolidation thatOnline progresses Lecture to contiguous Library areas of the lung, with occasional cavitation.

Chest x-ray: mucormycosis

Bigby et al. Chest 1986 5 days later A rapidly progressing Pancoast syndrome due to pulmonary mucormycosis: a case report

© by author ESCMID Online Lecture Library Extensive edematous changes of the left chest wall and axilla, left pleural effusion, J Med Case Reports. 2011; 5: 388. and pulmonary parenchymal consolidation. Pulmonary mucormycosis

 Reversed halo sign: focus of ground-glass attenuation surrounded by a solid ring.  Infarcted lung, with greater amount of hemorrhage at the periphery.  189 pts with fungal pneumonia:© by author 132 with IPA, 37 with mucormycosis, 20 fusariosis.  RHSESCMID in 7 (19%) of mucormycosis Online Lecture Library and 1 (<1%) in aspergillosis.

Wahba et al. Clin Inf Dis 2008;46:1733 Georgiadou et al. Clin Inf Dis 2011;52 Cutaneous mucormycosis

 In normal hosts, the traumatic inoculation of a high load of sporangiospores under the skin leads to cutaneous mucormycosis.

 Extension to the subcutaneous tissue or bone is common in patients who have© delayed by author or ineffectively treated cutaneous mucormycosis.

 In immunocompromised patients the infection may ESCMIDdisseminate. Online Lecture Library  Cutaneous mucormycosis can manifest as a superficial or deep infection.

 It can appear as pustules, blisters, nodules, necrotic ulcerations, echthyma gangrenosum-like lesions or necrotizing cellulitis © by author ESCMID Online Lecture Library Insulin site wound in a renal allograft recipient

© by author ESCMID Online Lecture Library The abdominal wall ulcer with necrotic margin and floor showing white, cottony filamentous growth. Gupta A, et al. Saudi J Kidney Dis Transpl 2011;22:134-5 Cutaneous mucormycosis Cunninghamella bertholletiae

Chronic myelogenous leukemia in blast crisis

NecroticESCMID lesion with surrounding Online erythema Lecture Library

 The lesion was a location with elasticized tape after the puncture for pleural effusion Motohashi et al. Am J Hematol 2009 Mucormycosis of the scalp after a car accident

Premature neonates Gastrointestinal bleeding Often diagnosed post-mortem © by author ESCMID Online Lecture Library Disseminated mucormycosis

May affect any organ Initial lesion may be the lung, the sinus or the skin Most common© bypresentation author in patients treated with deferroxamine, inESCMID IVDUs andOnline in patients Lecture with Library hematological malignancies Disseminated mucormycosis

Computed tomography of chest showing Cerebral magnetic resonance pulmonaryESCMID infiltrates and Onlinecavitary lesions. Lectureimaging showingLibrary a ring enhancing lesion consistent with brain abscess  Patient received chemotherapy for AML Renal mucormycosis

. The clinical signs and symptoms are non-specific

. Imaging signs are non-specific

. Various non-invasive tests (PCR, antigens etc) are not yet standardized© by author . Biopsy cannot always be performed due to severe ESCMIDthrombocytopenia Online Lecture Library . Definite diagnosis is usually made in an advanced stage of the disease Direct examination: Broad hyphae, non- septate, branching in 90o angles

Culture

Rhizopus oryzae on Sabouraud’s dextrose agar Lichtheimia (Absidia), with a Rhizopus oryzae characteristic conical shaped columella © by author ESCMID Online Lecture Library

Mucor sp. Saksenae vasiformis Histology

. Tissue reaction is minimal

Rickerts et al. CID 2007 Treatment

 Reversal of underlying risk factors, if possible.  Ketoacidosis  Immunosuppression

 Antifungal drugs  Liposomal amphotericin B (AmbiSome) and lipid ampho B (Abelcet) are the© drugs by of choiceauthor  Dose of AmBisome: 5-7mg/kg/BW  Duration of treatment: At least 6 weeks, but longer may be ESCMIDnecessary. Online Lecture Library  Posaconazole is also active. Second line treatment. A.Skiada et al. Diagnosis and treatment of mucormycosis in patients with haematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3) Surgical treatment

 Surgical debridement of all necrotic tissue must be performed, especially in soft tissue infection.

 In rhinocerebral disease, prompt surgical debridement, repeated if necessary, is considered a© crucial by authorcomponent of successful therapy ESCMID Online Lecture Library  In lung disease, the lesion may be removed if it is single. Surgical treatment

• Fusarium spp.

• Pseudallescheria boydii / Scedosporium

• Acremonium spp. © by author ESCMID Online Lecture Library • Paecilomyces spp. Fusarium spp.

 Important plant pathogens

 Widely distributed in soil, organic matter and in water worldwide, as part of water structure biofilms © by author ESCMID Online Lecture Library Fusariosis

In humans they cause a broad spectrum of infections:  Superficial (keratitis, onychomycosis)  Locally invasive  Disseminated© (immunocompromised) by author ESCMID Online Lecture Library Other disease caused by Fusarium spp.

 Fusarium spp. may also cause allergic disease (sinusitis) in immunocompetent patients, and  Mycotoxicosis in humans and animals following ingestion of food contaminated by toxin-producing Fusarium spp. © by author

Nucci, M., and E. Anaissie. 2007. Clin. Microbiol. Rev. 20:695-704 ESCMIDBennett, Online JW and M. Lecture Klich. 2003. Clin. Microbiol. Library Rev. 16:497- 516

Fusarium spp.

F. solani 50% of fusariosis F. oxysporum 20% F. verticillioides 10% (F. moniliforme) F. proliferatum F. chlamydosporium F. anthrophilum F. dimerum F. sacchari © by author ESCMID Online Lecture Library

Nucci, M., and E. Anaissie. 2007. Fusarium infections in immunocompromised patients. Clin. Microbiol. Rev. 20:695-704 Portals of entry: sinuses, lung, skin Direct inoculation (trauma, contact lenses, conidia onychomycosis)

inhalation

May be recovered from hospital water system samples Risk factors in immunocompetent

 Foreign bodies (contact lens)

 Continuous ambulatory peritoneal dialysis (peritonitis)  Burns, trauma © by author ESCMID Online Lecture Library

JAMA. 2006. 296:953–963. Risk factors in immunocompromised

 Hematological malignancies / prolonged and profound neutropenia (>90% of cases)  Hematopoietic stem cell transplant (HSCT) recipients/ GVHD  Severe T-cell immunodeficiency  Prolonged treatment© by with author corticosteroids

ESCMID Online Lecture Library

Cancer. 2003; 98:315–319 Fusariosis in immunocompetent patients

Keratitis or more rarely, endophthalmitis Onychomycosis Cellulitis after trauma Peritonitis in© CAPD by author Septic arthritis, after trauma ESCMID Online Lecture Library Fusariosis in immunocompromised • Neutropenia and prolonged fever • In patients with HSCT – GVHD and treatment with steroids

Cellulitis Nucci & Anaissie. Clin Infect Dis 2002; 35: 909 Disseminated fusariosis

Acute myelogenous leukemia

Tezcan et al. J Clin Microb, 2009;47:278–281 Skin lesions due to Fusarium sp.

Ecthyma gangrenosum

Multiple, painfulβλάβες

Nucci & Anaissie. Clin Infect Dis 2002; 35: 909 Invasive lung fusariosis

RightESCMID upper lobe mass with intervalOnline development Lecture of peripheral cavitation Library (arrow) or air-crescent sign.

Marom et al. AJR:190, June 2008 Differences between aspergillosis and fusariosis

Skin is affected much more commonly in fusariosis Fusarium spp. is often found in blood cultures, in contrast to aspergillus© by author ESCMID Online Lecture Library Histology

 In tissue, the hyphae are similar to those of Aspergillus spp., with hyaline and septate filaments that typically dichotomize in acute and right angles.  However, adventitious sporulation may be present in tissue,© by and author the finding of hyphae and yeast-like structures together is highly suggestiveESCMID of fusariosis Online in the Lecture high- Library risk population.

Direct examination With KOH 20% (or + blancophore, or calco fluor-white)

• Hyaline hyphae with septate filaments in acute angles • These characteristics are also found in other fungal ©infections by author (Aspergillus, Acremonium, Paecilomyces, Scedosporium) ESCMID Online Lecture Library

Very helpful!!! Culture

Molecular methods

 For identification of Fusarium spp.

 For determination of species

1. Antifungal agents . amphotericin B, voriconazole 2. Immunotherapy . Growth factors for neutropenics, IFN-γ and/or GM-CSF for patients with adequate neutrophils 3. Surgery © by author . debridement of necrotic tissue 4. Removal of central venous lines if there is fungemia ESCMID Online Lecture Library Treatment of localized infection

 Keratitis is usually treated with topical antifungal agents

 Natamycin is the drug of choice

ESCMID OnlineClin. Lecture Microbiol. Infect. Library 2004;10:773– 776 Arch Ophthalmol. 2006;124:941 Prevention

 Before the initiation of immunosuppressive therapy patients should be carefully examined for possible lesions on the skin or nails.

 If lesions are found they should be treated before initiating chemotherapy.© by author ESCMID Online Lecture Library Conclusions

 Fusariosis, like mucormycosis, usually affects immunosuppressed patients and leads to high mortality rates.

 Successful outcome is largely determined by the degree and persistence© of immunosuppressionby author and the extent of the infection.

ESCMID Early diagnosis Online and prompt Lecture initiation ofLibrary treatment are very important

Thank you!