Current Epidemiology,Diagnostic and Treatment Approaches of Invasive Zygomycosis (Mucormycosis) George Petrikkos, MD, Professor of Internal Medicine and Infectious Diseases [email protected]© by author National and Kapodistrian University of Athens State-of-the-art in Emerging Fungal Infections, ESCMIDESCMID Online Postgraduate Lecture Education LibraryCourse 8 - 9 September 2011, Cluj-Napoca, Romania Zygomycosis Zygomycosis is the third invasive mycosis in order of importance after candidiasis and aspergillosis, but its frequency is rising and its fatality remains high. © by author ESCMID Online Lecture Library Zygomycetes • Everywhere in nature – Decaying vegetation and in soil • Common genera: Rhizopus, Absidia, Cunninghamella, Rhizomucor, Syncephalastrum, Saksenaea, Apophysomyces and Mucor • Hyphae are broad, irregularly branched and have rare septations© by author – Opposite of Aspergillus difficult to culture ESCMID Online Lecture Library Zygomycosis: Epidemiology • The incidence of Zygomycosis is approximately 1.7 cases per 1 000 000 inhabitants per year,which means 500 patients per year in the USA.1 • Post-mortem evaluation shows that zygomycosis is ten- to 50-fold less frequent than candidiasis or aspergillosis, and it appears one to five cases per 10 000 autopsies.2-4 • In patients undergoing allogenic bone marrow transplantation the© incidence by author may be 2-3%.5,6 1. Ree JR et al. Clin Infect Dis ; 27:1138-1147;1998. 2. Hotchi M et al. Am J Clin Pathol ;74:410-416;1980. 3. Tietz HJ et al. Mycosis (suppl 2); 81-85;1998. 4.Yamazaki T et al. J Clin Microbiol ; 37: 1732-1738;1999. 5. Maertens J et al. Bone Marrow Transplant ; 24:307- ESCMID312;1999. Online Lecture Library 6. Marty FM et al . N Eng J Med ; 350:950-952 Percentages of Zygomycosis Cases 100% 80% 60% culture 40% 20% © by author Percentage of zygomycosis cases documentedbycases zygomycosis of Percentage 0% 1940s 1950s 1960s 1970s 1980s 1990s 2000s ESCMID Online Lecture Library Roden M, et al. Clinical Infectious Diseases 2005; 41:634–53 Changing Spectrum of Invasive Molds Incidence per 1000 Patient Days 0,7 0,21 Fusariosis Aspergillus 16% 0,6 Zygomycetes 0,18 0,5 0,15 0,4 0,12 0,3 0,09 0,2 0,06 Rate of aspergillosis of Rate Rate of Zygomycosis of Rate Zygomycosis 0,1 0,03 Invasive 20%© by author 0 0 Aspergillosis 2000 2001 2002 2003 200 64% Year ESCMID Online Lecture Library Kontoyiannis DP, et al. J Infect Dis. 2005;191:1350-1360. TRANSNET IFI Incidence July 2001-Dec 2005 45 40 Apergillosis Fusariosis 35 Zygomycosis 30 25 20 15 10 © by author 5 0 Jul-Dec Jan-Jun Jul-Dec Jan-Jun Jul-Dec Jan-Jun Jul-Dec Jan-Jun Jul-Dec ESCMID2001 2002 Online2002 2003 Lecture2003 2004 Library2004 2005 2005 •Cases/1000 transplants Incidence of invasive fungal infections after stem cell transplant, in USA, 2001-2006 (TransNet) 1,8 1,6 1,6 1,4 1,2 1,1 © by1 author 0,8 0,6 incidence incidence (%) 0,3 -month cumulative -month 0,4 0,2 12 0 ESCMID Online LectureAspergillosis Library Candidiasis Zygomycosis Kontoyiannis et al. 2009 Zygomycosis • Increasing incidence • Vulnerable populations: – Diabetes mellitus (association with ketoacidosis) – Malignancy (mostly haematological) – Bone marrow transplantation – Solid organ transplantation – Intra-venous drug use – Deferroxamine therapy – Trauma/Critical illness© by author • Voriconazole? Roden, et al. Clin Inf Dis 2005;41:634-53. ESCMID OnlineKauffman, Lecture CID editorial 2004.Library Zygomycosis Underlying Diseases Other 6% Diabetes 13% Burn Hema 3% malignancy 46% Trauma 17% SO © by author transplantation Immunocompetent: 2 4% Other malignancies BMT 4% 7% G.Petrikkos, A.Skiada, L.Pagano, A.H.Groll, A.Mitroussia-Ziouva, B.Dupont, C.Lass- Floerl, E.BouzaESCMID ,E Roilides, J Meis, Online and the Lecture Library ECMM Zygomycosis Working Group, ICAAC, 2008. Risk factors and most common clinical presentation of zygomycosis Predisposing conditions Clinical presentation Immunosuppression (malignancy) Respiratory tract infection, disseminated infection Metabolic (diabetes) Respiratory tract infection, rhinocerebral infection Deferoxamine therapy Disseminated infection Skin and soft tissue breakdown Primary cutaneous and soft tissue infection Intravenous illicit drug use Endocarditis, cerebral infection Neonatal prematurity © byGastrointestinal author infection, disseminated infection Malnourishment Gastrointestinal infection ESCMID Online Lecture Library Mortality Due to Mold Infections 80 100% 70 60 80% 50 64,0% 40 60% 52,0% 30 42,0% 40% Underlying 20 patientsof % 10 20% Mortality 0 © by author 0% Aspergillus spp Zygomycetes Fusarium spp 11,802 patients (18 centers) ESCMID OnlinePagano Lecture L et al. Haematologica Library 2006;91:1068- 1075. CLINICAL MANIFESTATIONS © by author ESCMID Online Lecture Library Zygomycosis The most frequenly observed clinical manifestations Rhinocerebral and pulmonary zygomycosis While cases have been described gastrointestinal cutaneous disseminated © by author and miscellaneous ESCMID Online Lecture Library Zygomycosis Site of infection Heart 1% Disseminated Lung 15% 24% Sinusitis 11% Bone 1% © by author Soft tissue Rhinocerebral 26% 22% G.Petrikkos, A.Skiada, L.Pagano, A.H.Groll, A.Mitroussia-Ziouva1, B.Dupont,ESCMID C.Lass-Floerl, Online E.Bouza ,E Lecture Roilides, J Meis, Library and the ECMM Zygomycosis Working Group, ICAAC, 2008. Rhino-cerebral zygomycosis © by author ESCMID Online Lecture Library Rhino-cerebral Zygomycosis It is the most frequent presentation overall and classically affects diabetics with ketoacidosis. Usually presents with facial and/or eye pain, proptosis and progressive signs of involvement of orbital structures (muscles, nerves and vessels). Common complications© byinclude author cavernous sinus and internal carotid artery thrombosis. ESCMID FatalityOnline 40%-50% Lecture Library Rhino-cerebral Zygomycosis Pathogenesis • Acquired by the inhalation of spores • Infection starts in the nasal turbinates then spreads to involve the orbits and the brain • Mucor is angioinvasive and can lead to infarction of infected tissues © by author ESCMID Online Lecture Library Rhinocerebral Zygomycosis Presentation • Acute – Fever – Facial pain – Nasal congestion – Epistaxis – Changes in vision – Changes in mentation • Spreads to palate, orbits and brain • Can lead to tissue © by author necrosis and eschar formation ESCMID Online Lecture Library Rhinocerebral Zygomycosis Presentation • Exam findings – Tissue necrosis – Changes in sensation – Vision loss – Proptosis and globe© byfixation author – Bony erosions on CT – Maxillary and ethmoid sinuses most common ESCMID Online Lecture Library Rhinocerebral Zygomycosis Presentation • Chronic – Visual changes – Neurological complaints – Proptosis and globe fixation – Mass lesions and bony erosions on CT © by author ESCMID Online Lecture Library Rhinocerebral Zygomycosis Definitive diagnosis • CT is suggestive but not sensitive of specific • Histopathology • Cultures confirmation • Direct PCR is being investigated © by author ESCMID Online Lecture Library Fungal invasive sinusitis DD • Multiple species in invasive sinusitis for DD – Aspergillus (acute / chronic) – Fusarium – Dematiaceous molds (chronic) – Candida in AIDS and marrow transplant patients © by author ESCMID Online Lecture Library Pulmonary Zygomycosis © by author Anteroposterior chest radiograph showing bilateral ESCMIDnodules and Online a worsening Lecture lingular infiltrateLibrary Juliette L. Wohlrab,et all CHEST / 120 / 3 / SEPTEMBER, 2001 Pulmonary Zygomycosis . It occurs most frequently among neutropenic patients. It presents with nonspecific symptoms such as fever, cough and dyspnea; hemoptysis may occur with vascular invasion. Radiological presentation includes segmental consolidation© that by author progresses to contiguous areas of the lung, with occasional cavitation. ESCMID Fatality Online 80% Lecture Library Pulmonary Zygomycosis Clinical manifestations *Very similar to invasive bronchopulmonary aspergillosis - results in pulmonary infarction & necrosis • Patients with hematological malignancies (lymphoma, leukemia) are particularly at high risk © by author ESCMID Online Lecture Library Pulmonary Zygomycosis in a Diabetic Patient © by author Chest roentgenogram showing CECT chest showing cavitary consolidation consolidation in left lingular lobe in left lung and fresh infiltrates in right lung AnuradhaESCMID et al Indian Online Journal of Medical Lecture Microbiology, Library (2006) 24 (3):222-4 Pulmonary Zygomycosis © by author CT scan of the chest with a cavitary infiltrate in the left upper lobe with interstitial changes and effusions bilaterally ESCMID(nodules Onlinenot demonstrated Lecture in thisLibrary image Juliette L. Wohlrab,et all CHEST / 120 / 3 / SEPTEMBER, 2001 Diagnosis: Pulmonary mucormycosis, BOOP © by author Vascular invasion and hemorrhagic Nonseptated hyphae with wide-angle infarct with fungal overgrowth within branching consistent with Mucor vessels. Areas of BOOP are also seen (Gomori’s methenamine- silver, original (hematoxylin-eosin,ESCMID original 20). Online 40).Lecture Library Juliette L. Wohlrab,et all CHEST / 120 / 3 / SEPTEMBER, 2001 Cutaneous Zygomycosis © by author ESCMID Online Lecture Library Cutaneous Zygomycosis It has been reported with minor trauma, insect bites, contaminated dressings and patches, wounds, and burns. The necrotic lesions progressively evolve from the© by epidermis author into dermis and even muscle and bone. ESCMID Online Lecture Library Cutaneous and subcutaneous Zygomycosis * Clinical manifestations Local