Cryptococcus gattii in Humans and Animals

Transcription

1 Cryptococcus gattii in Humans and Animals Emilio DeBess, DVM, MPVM Oregon Health Authority Portland, OR

2 Fun with Fungus

3 C.gattii in the News

4 History 1970 First clinical case of Cryptococcus gattii 1984 Epidemiology of C.gattii versus C.neoformans published C.gattii isolated to tropical/subtropical regions Australia, Brazil, Cambodia, Hawaii, southern California, Mexico, Paraguay, Thailand, Vietnam, Nepal, and countries in central Africa 1999 C.gattii diagnosed in a group of human and animal cases from Vancouver Island, British Columbia 2004 C.gattii isolated in Oregon Steady rise in number of cases since C.gattii cases reported in Oregon to date

5 Cryptococcus Taxonomy A grubii C. neoformans variet y AD serotypes neoformans D AD Vs. C. gattii gattii B B or C VNIV VNI VNII VNB VNIII molecular types (genotypes) VGI VGII VGIII VGIV subtypes VGIIa VGIIb VGIIc others Courtesy of Dr Julie Harris /CDC

6 Clinical Data from Australia Speed and Dunt: all cases of Cryptococcus from a population-based registry ( ) analyzed for differences between C.gattii and C. neoformans with regards to clinical and host immune status 71 cases were typed 51 C.neoformans 46 had immunosuppression (23 HIV positive, 23 with another unspecified immunosuppressing condition) and only 5 described as healthy hosts 20 C.gattii all 20 were HIV seronegative and none with immunosuppressing conditions Clinical presentations C.gattii more likely to have pulmonary involvement Both had high rates of meningeal disease (85% and 70%) intra-cerebral lesions and focal symptomology more common with C.gattii Outcomes No deaths in C.gattii group versus 30% mortality in C.neoformans group C.gattii patients more likely to suffer neurologic sequelae (39% versus 3%) and to require either CNS or thoracic surgery

7 Clinical Data from Australia (2) Mitchell et al: A retrospective review of 118 cases of cryptococcal CNS disease presenting to Australian teaching hospitals between 1985 and 1992 (all routinely typed as gattii or neoformans) Immune deficiencies 60 patients with AIDS only 1 C.gattii case 23 patients with other immune deficiencies (13 heme malignancies, 10 on immunosuppressing meds) Only 1 C.gattii case 35 patients without AIDS or other immune deficiencies 26 (74%) C.gattii 9 (26%) C.neoformans Outcomes C. gattii had mortality rate of 15%

8 C.gattii in Australia Summary Host risk factors and clinical features of cryptococcosis dependent on the infecting species healthy hosts were primary target of C.gattii infection C.gattii (vs. C.neoformans) was associated with lower mortality a higher incidence of complications increased long-term sequelae focal lesions What about C.gattii infection in BC and the Pacific NW US?

9 Environmental Sampling- BC, Canada C.gattii found in environmental sampling on Vancouver Island Increasing diagnoses between 1999 and 2004 in patients on the mainland and in Pacific NW US (without travel exposure) MacDougal et al: Large scale environmental sampling from mainland BC and Washington State ( ) 3% of environmental samples (soil, air, water, swabs from non- Eucalyptus trees and other structures) positive for C.gattii

10 Clinical Epidemiology from BC Galanis and MacDougal: 218 cases (124 confirmed by culture and 94 probable with positive CrAg, histopathology, or microscopy and HIV seronegative) from lab reporting to BC public health authorities ( ) Rise in incidence of infection in British Columbia over study period 6 cases in 1999 to 38 cases in 2006 Average age was 58 years, 55% were male 38% immunocompromised (HIV, transplant, cancer, steroids) Presenting clinical features respiratory syndrome in 76.6% CNS syndrome in 7.8% both in 10%

11 Clinical Epidemiology from BC #2 Lung nodules (single or multiple) were most common radiographic findings 19 total deaths CFR 8.7% (confirmed and probable) and CFR 12.1% (confirmed) Mortality associated with older age (p=0.019) and CNS syndrome (p=0.014) 74% of those who died had underlying medical conditions cancer, COPD, asthma, liver disease, diabetes, HIV infection, lung transplant, CHF and congenital cardiac disease. 47% of those who died were immunocompromised (p=0.267)

12 Clinical Epidemiology in Oregon DeBess et al: 60 cases of C.gattii reported in Pacific NW US (WA, OR, CA, ID) through July % male, and 45% of cases were aged years 81% (of 47 patients for whom data was available) had a clinically recognized predisposing condition 29% either HIV or transplant Mortality of 33% (of 45 patients with known outcomes) 20% of patients died due to C.gattii 13% of patients died with C.gattii (higher than the reported case fatality rates in both BC and in Australia)

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14 Background Summary Unique strain in a novel environment Epidemiology suggests unique clinical features compared to the previously published data Scarcity of large clinical series of C.gattii infection, therefore lack of detailed clinical and outcome information The large number of cases reported recently in Oregon provides opportunity to improve our understanding of this infection and the clinical care of these patients

15 Cryptococcus gattii Human Infection in Oregon

16 Culture-confirmed C.gattii in Oregon, between November 2004 and November 2010 Gender and Age 27 female, 19 male Median age 58 years Range No difference by gender Number (%) of Cases by Site of Infection 21 (46) Pulmonary 12 (26) CNS 9 (20) CNS & Pulmonary 1 (2) Bloodstream alone 3 (6) Other Number of Cases by Year n=46 cases

17 Clinical Presentations Major Sites of Infection Symptom onset to diagnosis Median # days (range) Presenting Complaint(s) & # of patients CNS 22 (7-180) Pulmonary 37 (12-180) CNS & Pulmonary 33 (6-51) Headache 7 Confusion 4 Seizure 1 Visual field deficit 1 Dyspnea 8 Cough 5 Asymptomatic 4 Fever 2 Weakness 1 Confusion 1 Headache 3 Cough 3 Hemoptysis 2 Dyspnea 1 Confusion 1 Syncope 1

18 Predisposing Conditions: Totals** Predisposing Conditions Number of patients (%) At least one immune-suppressing condition (Solid organ transplant, autoimmune disease, active malignancy, HIV) No immune-suppressing conditions but at least one chronic medical condition (Chronic renal, liver or lung disease, or diabetes) No immune-suppressing or chronic medical conditions 24 (52%) 10 (22%) 12 (26%) **each patient represented only once

19 CNS Cases 21 patients had CNS infection 9 of 21 also had pulmonary infection 4 of 21 had focal cryptococcomas Initial CSF results for 17 patients with meningitis: (non-focal CNS infection) CSF Feature (n) Median Range Opening Pressure in cm H2O (n=8) WBC /mm3 (n=17) Percent mononuclear cells (n=17) Protein mg/dl (n=17) Glucose mg/dl (n=16)

20 Predisposing Conditions Condition # (%) Patients Details Autoimmune Disease 12 (26%) SLE (2), Autoimmune hepatitis, Psoriatic Arthritis, Polymyositis, Sarcoidosis, CNS vasculitis, Giant cell arteritis, Microscopic colitis, HSP, Eosinophilic fasciitis Solid Organ Transplant 9 (20%) 4 Renal, 2 Lung, 1 Cardiac, 1 Liver Cancer 7 (15%) 3 active (acute leukemia, NHL, CLL) 4 in past (SCC, testicular, uterine, melanoma) HIV 3 (7%) 2 AIDS (CD4 16, 27) 1 on ART (CD4 290) Steroids (prior to diagnosis) 24 (52%) 14 on steroids for >3 months prior to diagnosis Chronic Lung Disease 12 (26%) 4 COPD, 4 asthma, 2 transplant (1 CF), 1 bronchiectasis, 1 sarcoid Chronic Liver Disease 7 (15%) 5 HCV, 2 HBV, 1 autoimmune hepatitis Chronic Renal Disease 10 (22%) 4 on HD, 4 transplant, 2 lupus nephritis Diabetes 17 (37%)

21 Predisposing Conditions: Totals** Predisposing Conditions Number of patients (%) At least one immune-suppressing condition (Solid organ transplant, autoimmune disease, active malignancy, HIV) No immune-suppressing conditions but at least one chronic medical condition (Chronic renal, liver or lung disease, or diabetes) No immune-suppressing or chronic medical conditions 24 (52%) 10 (22%) 12 (26%) **each patient represented only once

22 Predisposing Conditions and Disease Manifestations Predisposing Condition Solid Organ Transplant Autoimmune Disease Hematologic Malignancy Lung (n=21) CNS (n=12) Lung and CNS (n=9) HIV ESRD on HD Chronic Lung Disease Chronic Liver Disease Diabetes None 1 7 3

23 Type C gattii VG Subtype Number of Cases (n= 46) Died Survived VGIIa (40%) 15 (60%) VGIIb 3 2 (66%) 1 (33%) VGIIc 15 5 (33%) 10 (66%) VGI 3 1(33%) 2 (66%) Type Immune Suppressed Chronic Medical Conditions No Predisposing Conditions VGIIa VGIIb VGIIc VGI 1 0 2

24 Typing by Clinical Syndrome Primary Site of Infection VGIIa (n=25) VGIIb (n=3) VGIIc (n=15) VGI (n=3) Lungs* CNS CNS and Lungs Blood 1 Other 2 1 *4 pts with lung infection had asymptomatic nodules: 2 VGIIa and 2 VGIIc

25 Mortality by Infection Manifestation Manifestation # Patients (%) Death (n= 18) Survival (n= 28) Pulmonary (n=21) 12 (57) 9 (43) - Asymptomatic pulmonary nodules 0 4 (100) CNS (n=12) 1 (8) 11 (92) - Solitary CNS lesion 0 4 (100) Pulmonary and CNS (n=9) 4 (44) 5 (56) Bloodstream only (n=1) 1 (100) 0 Other (urine, throat, toenail) (n=3) 0 3 (100)

26 Mortality by Predisposing Condition Predisposing Condition # Patients (%) Death (n= 18) Survival (n= 28) Solid Organ Transplant (n= 9) 5 (56) 4 (44) Autoimmune Disease (n=12) 7 (58) 5 (42) Hematologic Malignancy (n=3) 2 (67) 1 (33) HIV (n=3) 0 3 (100) Chronic Lung Disease (n=8) 5 (63) 3 (37) Chronic Liver Disease (n=9) 6 (67) 3 (33) Diabetes (n=16) 10 (69) 6 (31) No underlying medical conditions (n=12) 0 12 (100)

27 Summary of Mortality Feature # patients (%) P-value Death (n= 18) Survival (n= 28) Mean age in years Male 8/18 11/ Predisposing Conditions Immune-suppressing Conditions Chronic Medical Conditions Only No Predisposing Conditions Site of Infection Pulmonary CNS CNS and Pulmonary Bloodstream (only site) Other Positive C.gattii Blood Cultures (n=23)

28 Conclusions and Discussion Increasing number of diagnosed cases of C.gattii in Oregon over past 6 years Increased proportion of patients with C.gattii had underlying comorbidities than previously reported (74%) Serum cryptococcal antigen only 68% sensitive for pulmonary infection and 94% sensitive for CNS infection in this series (culture as gold standard) Both site of infection and mortality correlated strongly with host immune/medical status Mortality occurred exclusively in patients with underlying conditions CNS disease more likely in patients without underlying conditions Relative good baseline health of those with CNS disease may explain why CNS disease associated with better outcomes than pulmonary disease Fungemia was a particularly poor prognostic indicator

29 Cryptococcosis in Animals Port of entry = respiratory tract via inhalation of spores Yeast generally precipitate into the upper respiratory tract, as they are too large to be immediately delivered into the lungs Based on presentation- oral exposure may be a factor in animals Predisposing factors to infection: Commercial environmental disturbances Immunosuppression FeLV/FIV in cats Chronic immunosuppressive therapy

30 Cryptococcosis Clinical signs in Cats Nasal/Pharyngeal/Sinus involvement Sneezing Mucoid nasal discharge Proliferative soft tissue mass on nasal planum Cutaneous ulceration

31 Cryptococcosis CNS involvement For brain signs Depression, seizures, altered mentation, circling, ataxia, head-pressing Ocular signs Blindness Chorioretinitis Retinal detachment Anterior uveitis

32 Cryptococcosis Lower Respiratory Disease Smaller desiccated yeast inhaled directly into the lungs Dyspnea, tachypnea, cough *Skin/subcutaneous involvement* Present in 40-50% of cases Papules Nodules Ulceration and drainage Regional lymphadenopathy Anorexia, lethargy, fever (uncommon)

33 Cryptococcosis Canine Cryptococcosis: Dogs < 4 years CNS involvement (50-80%) Upper respiratory tract (50%) Ocular disease (20-40%) Cutaneous disease (10-20%) Head, feet, nail beds, oral mucous membranes

34 Cryptococcus gattii Animal Data, Oregon Subtypes Isolated (N=40) Animal Type VGIIa VGIIb VGIIc VGIII Canine Feline Elk Goat Sheep Dolphin Ferret 2 Alpaca Horse - 1** - - Total 27 (68%) 4 (10%) 8 (20%) 1(2%)

35 Site of initial infection at presentation in Animals Tissue/sample lung nasal discharge brain skin abscess oral cavity swelling fecal liver renal mass n n Tissue/sample 11 head swelling 1 8 periorbital swelling

36 Laboratory Identification Culture on CGB agar distinguishes species C. gattii stains blue Molecular analysis identifies genotype and subtypes by Dr Lockhart) India ink preparation showing capsules of Cryptococcus Color reaction on CGB agar RFLP or MLST distinguishes subtypes

37 Treatment of Cryptococcosis Treatment Fluconazole = treatment of choice Good CNS penetration 50mg/cat PO q 12 hrs 5mg/kg PO q 12-24hrs (dogs) Itraconazole = good second choice Effective in cats and dogs Despite lack of CNS penetration, has been used to successfully treat CNS cryptococcus (BBB not intact due to inflammation) 10mg/kg PO q 24 hrs Ketoconazole = variably effective, ineffective in CNS dz Lipid complex amphotericin B for severe or refractory cases

38 Susceptibilities.

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40 Location Location Location Cases by geographical location

41 Geographic location of Cryptococcus gattii, Oregon COLUMBIA CLATSOP TILLAMOOK WASHINGTON MULTNOMAH HOOD RIVER SHER- MAN UMATILLA WALLOWA YAMHILL CLACKAMAS WASCO GILLIAM MORROW UNION POLK MARION LINCOLN WHEELER BAKER BENTON LINN JEFFERSON GRANT CROOK LANE DESCHUTES COOS DOUGLAS LAKE HARNEY MALHEUR CURRY JOSEPHINE JACKSON KLAMATH

42 Ecological Niche Modeling of Cryptococcus gattii in the Pacific Northwest % 81-90% 71-80% 61-70% 51-60% 41-50% 31-40% 21-30% 11-20% 1-10% 0% Model based on 32 domestic veterinary cases in the US, The data were split into 50% training and 50% testing subsets and applied against seven environmental layers: January minimum and maximum temperatures, temperature seasonality, minimum temperature of coldest month, annual temperature range, and mean temperature of coldest quarter. The mean training and testing accuracy of the model were 82% and 78%, respectively. Map created November 23, 2010 by Julie Harris, CDC, with assistance from Sunny Mak, BC CDC.

43 Acknowledgments Centers for Disease Control and prevention Dr Chiller, Dr Harris and Dr Lockhart Oregon Health Authority and the OSPHL Dr Paul Cieslak, Dr Lynn Fitzgibbons, Rob Vega Oregon State University Veterinary Diagnostics laboratory

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