Cryptococcus gattii in Humans and Animals DeB… · Speed and Dunt: all cases of Cryptococcus from...
Transcript of Cryptococcus gattii in Humans and Animals DeB… · Speed and Dunt: all cases of Cryptococcus from...
Emilio DeBess, DVM, MPVM
Cryptococcus gattii in Humans and Animals
Oregon Health Authority Portland, OR 97232 [email protected]
Fun with Fungus
C.gattii in the News
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 2004 56 C.gattii cases reported in Oregon to date
C. gattii
gattii
B B or C
VGI VGII VGIII VGIV
VGIIa VGIIb VGIIc otherssubtypes
Cryptococcus Taxonomy
Vs.
C. neoformans
grubii neoformansvariety
A DAD ADserotypes
VNI VNII VNBmolecular types (genotypes)
VNIII VNIV
Courtesy of Dr Julie Harris /CDC
Clinical Data from Australia Speed and Dunt: all cases of Cryptococcus from a population-based
registry (1980-1990) 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
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%
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?
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 (2001-2005) 3% of environmental samples (soil, air, water, swabs from non-
Eucalyptus trees and other structures) positive for C.gattii
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 (1999-2006) 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%
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)
Clinical Epidemiology in Oregon
DeBess et al: 60 cases of C.gattii reported in Pacific NW US (WA, OR, CA, ID) through July 2010 54% male, and 45% of cases were aged 50-69 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)
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
Cryptococcus gattii Human Infection in Oregon
Culture-confirmed C.gattii in Oregon, between November 2004 and November 2010
02468
101214161820
2004 2005 2006 2007 2008 2009 2010
Number of Cases by Year
n=46 cases
Gender and Age
27 female, 19 male
Median age 58 years Range 15-96 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
Clinical Presentations Major Sites of
Infection Symptom onset to diagnosis
Median # days (range) Presenting Complaint(s) &
# of patients
CNS 22 (7-180)
Headache 7
Confusion 4
Seizure 1
Visual field deficit 1
Pulmonary 37 (12-180)
Dyspnea 8
Cough 5
Asymptomatic 4
Fever 2
Weakness 1
Confusion 1
CNS & Pulmonary 33 (6-51)
Headache 3
Cough 3
Hemoptysis 2
Dyspnea 1
Confusion 1
Syncope 1
Predisposing Conditions: Totals**
Predisposing Conditions Number of patients (%)
At least one immune-suppressing condition (Solid organ transplant, autoimmune disease, active malignancy, HIV)
24 (52%)
No immune-suppressing conditions but at least one chronic medical condition (Chronic renal, liver or lung disease, or diabetes)
10 (22%)
No immune-suppressing or chronic medical conditions 12 (26%)
**each patient represented only once
CNS Cases
CSF Feature (n) Median Range
Opening Pressure in cm H2O (n=8)
41 17-55
WBC /mm3 (n=17) 172 1-1090
Percent mononuclear cells (n=17)
73 26-100
Protein mg/dL (n=17) 115 30-571
Glucose mg/dL (n=16) 38 2-100
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)
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%)
Predisposing Conditions: Totals**
Predisposing Conditions Number of patients (%)
At least one immune-suppressing condition (Solid organ transplant, autoimmune disease, active malignancy, HIV)
24 (52%)
No immune-suppressing conditions but at least one chronic medical condition (Chronic renal, liver or lung disease, or diabetes)
10 (22%)
No immune-suppressing or chronic medical conditions 12 (26%)
**each patient represented only once
Predisposing Conditions and Disease Manifestations
Predisposing Condition
Lung (n=21)
CNS (n=12)
Lung and CNS (n=9)
Solid Organ Transplant 3 2 4
Autoimmune Disease 9 0 2
Hematologic Malignancy 2 1 0
HIV 2 1 0
ESRD on HD 3 0 1
Chronic Lung Disease 6 1 1
Chronic Liver Disease 4 0 0
Diabetes 9 1 5
None 1 7 3
Type Number of Cases (n= 46)
Died Survived
VGIIa 25 10 (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 11 6 8 VGIIb 1 2 0 VGIIc 11 2 2 VGI 1 0 2
C gattii VG Subtype
Typing by Clinical Syndrome
Primary Site of Infection VGIIa (n=25)
VGIIb (n=3)
VGIIc (n=15)
VGI (n=3)
Lungs* 12 2 7
CNS 7 1 3 1
CNS and Lungs 3 4 2
Blood 1
Other 2 1
*4 pts with lung infection had asymptomatic nodules: 2 VGIIa and 2 VGIIc
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)
Mortality by Predisposing Condition
# Patients (%)
Predisposing Condition 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)
Summary of Mortality Feature # patients (%) P-value
Death (n= 18)
Survival (n= 28)
Mean age in years 62 56
Male 8/18 11/28 0.77
Predisposing Conditions
Immune-suppressing Conditions 12 12 0.14
Chronic Medical Conditions Only 6 4 0.16
No Predisposing Conditions 0 12 0.0012
Site of Infection
Pulmonary 12 9 0.034
CNS 1 11 0.015
CNS and Pulmonary 4 5 0.72
Bloodstream (only site) 1 0 0.39
Other 0 3 0.27
Positive C.gattii Blood Cultures (n=23) 5 0 0.046
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
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
Cryptococcosis
Clinical signs in Cats
Nasal/Pharyngeal/Sinus
involvement
Sneezing
Mucoid nasal discharge
Proliferative soft tissue
mass on nasal planum
Cutaneous ulceration
Cryptococcosis CNS involvement
For brain signs
Depression, seizures, altered mentation, circling,
ataxia, head-pressing
Ocular signs
Blindness
Chorioretinitis
Retinal detachment
Anterior uveitis
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)
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
Cryptococcus gattii Animal Data, Oregon 2007-2011 Subtypes Isolated (N=40)
Animal Type VGIIa VGIIb VGIIc VGIII
Canine 7 1 2 -
Feline 4 1 5 1
Elk 1 1 - -
Goat 5 - - -
Sheep - - 1 -
Dolphin 1 - - -
Ferret 2
Alpaca 7 - - -
Horse - 1** - -
Total 27 (68%) 4 (10%) 8 (20%) 1(2%)
Site of initial infection at presentation in Animals
Tissue/sample n
Tissue/sample n
lung 11 head swelling 1
nasal discharge 8 periorbital swelling 1
brain 7
skin abscess 6
oral cavity swelling 4
fecal 2
liver 2
renal mass 2
Laboratory Identification
Culture on CGB agar distinguishes species • C. gattii stains blue
Molecular analysis identifies genotype and subtypes (@CDC by Dr Lockhart)
India ink preparation showing capsules of
Cryptococcus Color reaction on CGB agar RFLP or MLST distinguishes
subtypes
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
Susceptibilities…….
Location Location Location
Cases by geographical location
Geographic location of Cryptococcus gattii, Oregon 2008-2010
GILLIAM
MAN
WASCO
CLATSOP
BAKER
CROOK
DESCHUTES
DOUGLAS
GRANT
LAKE
MALHEUR
MORROW
UMATILLA
UNION
WALLOWA
WHEELER
SHER-
COLUMBIA
CURRY
POLK
TILLAMOOK
LINCOLN
WASHINGTON
CLACKAMAS
JACKSON
LANE
BENTON
JOSEPHINE
HARNEY
JEFFERSON
MULTNOMAH
MARION
KLAMATH
LINN
HOOD RIVER
COOS
YAMHILL
Model based on 32 domestic veterinary cases in the US, 2004-2010. 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.
Ecological Niche Modeling of Cryptococcus gattii in the Pacific Northwest
91-100%81-90%71-80%61-70%51-60%41-50%31-40%21-30%11-20%1-10%0%
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