No thing to Disc lo se F un with F ung us C.g a ttii in the Ne - - PowerPoint PPT Presentation

E milio De Be ss, DVM, MPVM

Crypto c o c c us g attii in Huma ns a nd Anima ls

Ore g o n He a lth Autho rity Po rtla nd, OR 97232 e milio .de b e ss@ sta te .o r.us

No thing to Disc lo se

F un with F ung us

C.g a ttii in the Ne ws

Histo ry

 1970



F irst c linic a l c a se o f Crypto c o c c us g a ttii

 1984



E pid e mio lo g y o f C.g attii ve rsus C.ne o fo rmans pub lishe d



C.g attii iso la te d to tro pic a l/ sub tro pic a l re g io ns



Austra lia , Bra zil, Ca mb o d ia , Ha wa ii, so uthe rn Ca lifo rnia , Me xic o , Pa ra g ua y, T ha ila nd , Vie tna m, Ne pa l, a nd c o untrie s in c e ntra l Afric a

 1999



C.g attii d ia g no se d in a g ro up o f huma n a nd a nima l c a se s fro m Va nc o uve r Isla nd , British Co lumb ia

 2004



C.g attii iso la te d in Ore g o n



Ste a d y rise in numb e r o f c a se s sinc e 2004



56 C.g attii c a se s re po rte d in Ore g o n to d a te

• C. gattii

gattii

B B or C VGI

VGI I

VGI I I

VGI V VGI I a VGI I b

VGI I c

• thers

subtypes

Crypto c o c c us T a xo no my

Vs.

• C. neoformans

grubii neoformans

variet y

A D AD AD

serotypes VNI

VNII VNB

molecular types (genotypes) VNIII

VNIV

Co urte sy o f Dr Julie Ha rris / CDC

Clinic a l Da ta fro m Austra lia

 Spe e d a nd Dunt: a ll c a se s o f Crypto c o c c us fro m a po pula tio n-b a se d

re g istry (1980-1990) a na lyze d fo r diffe re nc e s b e twe e n C.g attii a nd C. ne o fo rmans with re g a rds to c linic a l a nd ho st immune sta tus



71 c a se s we re type d



51 C.ne o fo rmans



46 ha d immuno suppre ssio n (23 HIV positive , 23 with a no the r unspe c ifie d immuno suppre ssing c o nd itio n) a nd o nly 5 d e sc rib e d a s he a lthy ho sts



20 C.g attii



a ll 20 we r

e HIV se r

• ne g a tive a nd no ne with immuno suppre ssing

c o nd itio ns



Clinic a l pre se nta tio ns



C.g attii mo re like ly to ha ve pulmo na ry invo lve me nt



Bo th ha d hig h ra te s o f me ning e a l d ise a se (85% a nd 70%)



intra -c e re b ra l le sio ns a nd fo c a l sympto mo lo g y mo re c o mmo n with C.g attii



Outc o me s



No d e a ths in C.g attii g ro up ve rsus 30% mo rta lity in C.ne o fo rmans g ro up



C.g attii pa tie nts mo re like ly to suffe r ne uro lo g ic se q ue la e (39% ve rsus 3%) a nd to re q uire e ithe r CNS o r tho ra c ic surg e ry

Clinic a l Da ta fro m Austra lia (2)

 Mitc he ll e t a l: A re tro spe c tive re vie w o f 118 c a se s o f c rypto c o c c a l CNS

dise a se pre se nting to Austra lia n te a c hing ho spita ls b e twe e n 1985 a nd 1992 (a ll ro utine ly type d a s g a ttii o r ne o fo rma ns)

 Immune de fic ie nc ie s



60 pa tie nts with AIDS



• nly 1 C.g attii c a se



23 pa tie nts with o the r immune d e fic ie nc ie s (13 he me ma lig na nc ie s, 10 o n immuno suppre ssing me d s)



Only 1 C.g attii c a se



35 pa tie nts witho ut AIDS o r o the r immune d e fic ie nc ie s



26 (74%) C.g attii



9 (26%) C.ne o fo rmans

 Outc o me s



• C. g attii ha d mo rta lity ra te o f 15%

C.g attii in Austra lia Summa ry

 Ho st risk fa c to rs a nd c linic a l fe a ture s o f c rypto c o c c o sis

de pe nde nt o n the infe c ting spe c ie s

 he althy hosts we re prima ry ta rg e t o f C.g attii infe c tio n

 C.g attii (vs. C.ne o fo rmans) wa s a sso c ia te d with

 lo we r mo rta lity  a hig he r inc ide nc e o f c o mplic a tio ns  inc re a se d lo ng -te rm se q ue la e  fo c a l le sio ns

 Wha t a b o ut C.g attii infe c tio n in BC a nd the Pa c ific NW US?

E nviro nme nta l Sa mpling - BC, Ca na da

 C.g attii fo und in e nviro nme nta l sa mpling o n Va nc o uve r

I sla nd

 I

nc re a sing dia g no se s b e twe e n 1999 a nd 2004 in pa tie nts o n the ma inla nd a nd in Pa c ific NW US (witho ut tra ve l e xpo sure )

 Ma c Do ug a l e t a l: L

a rg e sc a le e nviro nme nta l sa mpling fro m ma inla nd BC a nd Wa shing to n Sta te (2001-2005)

 3% o f e nviro nme nta l sa mple s (so il, a ir, wa te r, swa b s fro m no n-

E uc a lyptus tre e s a nd o the r struc ture s) po sitive fo r C.g attii

Clinic a l E pide mio lo g y fro m BC

 Ga la nis a nd Ma c Do ug a l: 218 c a se s (124 c o nfirme d b y

c ulture a nd 94 pro b a b le with po sitive CrAg , histo pa tho lo g y,

• r mic ro sc o py a nd HI

V se ro ne g a tive ) fro m la b re po rting to BC pub lic he a lth a utho ritie s (1999-2006)

 Rise in inc ide nc e o f infe c tio n in British Co lumb ia o ve r study

pe rio d

 6 c a se s in 1999 to 38 c a se s in 2006  Ave ra g e a g e wa s 58 ye a rs, 55% we re ma le  38% immuno c o mpro mise d (HI

V, tra nspla nt, c a nc e r, ste ro ids)

 Pre se nting c linic a l fe a ture s  re spira to ry syndro me in 76.6%  CNS syndro me in 7.8%  b o th in 10%

Clinic a l E pide mio lo g y fro m BC # 2

 L

ung no dule s (sing le o r multiple ) we re mo st c o mmo n ra dio g ra phic finding s

 19 to ta l de a ths  CF

R 8.7% (c o nfirme d a nd pro b a b le ) a nd CF R 12.1% (c o nfirme d)

 Mo rta lity a sso c ia te d with o lde r a g e (p=0.019) a nd CNS

syndro me (p=0.014)

 74% o f tho se who die d ha d unde rlying me dic a l c o nditio ns  c a nc e r, COPD, a sthma , live r dise a se , dia b e te s, HIV

infe c tio n, lung tra nspla nt, CHF a nd c o ng e nita l c a rdia c dise a se .

 47% o f tho se who die d we re immuno c o mpro mise d (p=0.267)

Clinic a l E pide mio lo g y in Ore g o n

 De Be ss e t a l: 60 c a se s o f C.g attii re po rte d in Pa c ific NW US

(WA, OR, CA, I D) thro ug h July 2010

 54% ma le , a nd 45% o f c a se s we re a g e d 50-69 ye a rs  81% (o f 47 pa tie nts fo r who m da ta wa s a va ila b le ) ha d a

c linic a lly re c o g nize d pre dispo sing c o nditio n

 29% e ithe r HI

V o r tra nspla nt

 Mo rta lity o f 33% (o f 45 pa tie nts with kno wn o utc o me s)  20% o f pa tie nts die d due to C.g attii  13% o f pa tie nts die d with C.g attii  (hig he r tha n the re po rte d c a se fa ta lity ra te s in b o th BC a nd

in Austra lia )

Ba c kg ro und Summa ry

 Uniq ue stra in in a no ve l e nviro nme nt  E

pide mio lo g y sug g e sts uniq ue c linic a l fe a ture s c o mpa re d to the pre vio usly pub lishe d da ta

 Sc a rc ity o f la rg e c linic a l se rie s o f C.g attii infe c tio n, the re fo re

la c k o f de ta ile d c linic a l a nd o utc o me info rma tio n

 T

he la rg e numb e r o f c a se s re po rte d re c e ntly in Ore g o n pro vide s o ppo rtunity to impro ve o ur unde rsta nding o f this infe c tio n a nd the c linic a l c a re o f the se pa tie nts

Crypto c o c c us g attii Huma n I nfe c tio n in Ore g o n

Culture -c o nfirme d C.g attii in Ore g o n, b e twe e n No ve mb e r 2004 a nd No ve mb e r 2010

2 4 6 8 10 12 14 16 18 20

2004 2005 2006 2007 2008 2009 2010

Numbe r of Ca se s by Ye a r

n=46 c a se s

Ge nde r a nd Ag e

 27 fe ma le , 19 ma le  Me dia n a g e 58 ye a rs  Ra ng e 15-96  No diffe re nc e b y g e nde r

Numb e r (%) o f Ca se s b y Site o f I nfe c tio n 21 (46) Pulmo na ry

12 (26) CNS 9 (20) CNS & Pulmo na ry 1 (2) Blo o dstre a m a lo ne 3 (6) Othe r

Clinic a l Pre se nta tio ns

Ma jor Site s of Infe c tion Symptom onse t to dia g nosis Me dia n # da ys (r a ng e ) Pr e se nting Compla int(s) & # of pa tie nts

CNS 22 (7-180)

He a da c he 7 Co nfusio n 4 Se izure 1 Visua l fie ld de fic it 1

Pulmo na ry 37 (12-180)

Dyspne a 8 Co ug h 5 Asympto ma tic 4 F e ve r 2 We a kne ss 1 Co nfusio n 1

CNS & Pulmo na ry 33 (6-51)

He a da c he 3 Co ug h 3 He mo ptysis 2 Dyspne a 1 Co nfusio n 1 Sync o pe 1

Pre dispo sing Co nditio ns: T

• ta ls**

Pr e disposing Conditions Numbe r

• f patie nts (% )

At le a st o ne immune - suppr

e ssing c ondition

(So lid o rg a n tra nspla nt, a uto immune dise a se , a c tive ma lig na nc y, HI V) 24 (52%) No immune -suppre ssing c o nditio ns b ut a t le a st o ne c hr

• nic me dic al

c ondition

(Chro nic re na l, live r o r lung dise a se , o r dia b e te s) 10 (22%) No immune -suppre ssing o r c hro nic me dic a l c o nditio ns 12 (26%)

**e a c h pa tie nt re pre se nte d o nly o nc e

CNS Ca se s

CSF F e a ture (n) Me dia n Ra ng e

Ope ning Pre ssure in c m H2O (n=8) 41 17-55 WBC / mm3 (n=17) 172 1-1090 Pe rc e nt mo no nuc le a r c e lls (n=17) 73 26-100 Pro te in mg / dL (n=17) 115 30-571 Gluc o se mg / dL (n=16) 38 2-100

 21 pa tie nts ha d CNS infe c tio n



9 o f 21 a lso ha d pulmo na ry infe c tio n



4 o f 21 ha d fo c a l c rypto c o c c o ma s

 Initia l CSF

re sults fo r 17 pa tie nts with me ning itis: (no n-fo c a l CNS infe c tio n)

Pre dispo sing Co nditio ns

Condition # (% ) Patie nts De tails

Auto immune Dise a se 12 (26%) SL E (2), Auto immune he pa titis, Pso ria tic Arthritis, Po lymyo sitis, Sa rc o ido sis, CNS va sc ulitis, Gia nt c e ll a rte ritis, Mic ro sc o pic c o litis, HSP, E

• sino philic

fa sc iitis So lid Org a n T ra nspla nt 9 (20%) 4 Re na l, 2 L ung , 1 Ca rdia c , 1 L ive r Ca nc e r 7 (15%) 3 a c tive (a c ute le uke mia , NHL , CL L ) 4 in pa st (SCC, te stic ula r, ute rine , me la no ma ) HI V 3 (7%) 2 AI DS (CD4 16, 27) 1 o n ART (CD4 290) Ste ro ids (prio r to dia g no sis) 24 (52%) 14 o n ste ro ids fo r >3 mo nths prio r to dia g no sis Chro nic L ung Dise a se 12 (26%) 4 COPD, 4 a sthma , 2 tra nspla nt (1 CF ), 1 b ro nc hie c ta sis, 1 sa rc o id Chro nic L ive r Dise a se 7 (15%) 5 HCV, 2 HBV, 1 a uto immune he pa titis Chro nic Re na l Dise a se 10 (22%) 4 o n HD, 4 tra nspla nt, 2 lupus ne phritis Dia b e te s 17 (37%)

Pre dispo sing Co nditio ns: T

• ta ls**

Pr e disposing Conditions Numbe r

• f patie nts (% )

At le a st o ne immune - suppr

e ssing c ondition

(So lid o rg a n tra nspla nt, a uto immune dise a se , a c tive ma lig na nc y, HI V) 24 (52%) No immune -suppre ssing c o nditio ns b ut a t le a st o ne c hr

• nic me dic al

c ondition

(Chro nic re na l, live r o r lung dise a se , o r dia b e te s) 10 (22%) No immune -suppre ssing o r c hro nic me dic a l c o nditio ns 12 (26%)

**e a c h pa tie nt re pre se nte d o nly o nc e

Pre dispo sing Co nditio ns a nd Dise a se Ma nife sta tio ns

Pre disposing Condition L ung (n=21) CNS (n=12) L ung a nd CNS (n=9)

So lid Org a n T ra nspla nt 3 2 4 Auto immune Dise a se 9 2 He ma to lo g ic Ma lig na nc y 2 1 HI V 2 1 E SRD o n HD 3 1 Chro nic L ung Dise a se 6 1 1 Chro nic L ive r Dise a se 4 Dia b e te s 9 1 5 No ne 1 7 3

T ype Numbe r

• f

Case s (n= 46) Die d Sur vive d

VGI I a 25 10 (40%) 15 (60%) VGI I b 3 2 (66%) 1 (33%) VGI I c 15 5 (33%) 10 (66%) VGI 3 1(33%) 2 (66%)

T ype Immune Suppr e sse d Chr

• nic Me dic al

Conditions No Pr e disposing Conditions

VGI I a 11 6 8 VGI I b 1 2 VGI I c 11 2 2 VGI 1 2

C g attii VG Sub type

T yping b y Clinic a l Syndro me

Primary Site of Infe c tion VGIIa (n=25) VGIIb (n=3) VGIIc (n=15) VGI (n=3) L ungs*

12 2 7

CNS

7 1 3 1

CNS and L ungs

3 4 2

Blood

1

Othe r

2 1

*4 pts with lung infe c tio n ha d a sympto ma tic no dule s: 2 VGI I a a nd 2 VGI I c

Mo rta lity b y I nfe c tio n Ma nife sta tio n

Ma nife sta tio n

# Patie nts (% )

De a th (n= 18) Surviva l (n= 28) Pulmo na ry (n=21)

12 (57)

9 (43)

• Asympto ma tic pulmo na ry no dule s

4 (100) CNS (n=12) 1 (8)

11 (92)

• So lita ry CNS le sio n

4 (100) Pulmo na ry a nd CNS (n=9) 4 (44) 5 (56) Blo o dstre a m o nly (n=1) 1 (100) Othe r (urine , thro a t, to e na il) (n=3) 3 (100)

Mo rta lity b y Pre dispo sing Co nditio n

# Patie nts (% ) Pre disposing Condition

De a th (n= 18) Surviva l (n= 28) So lid Org a n T ra nspla nt (n= 9) 5 (56) 4 (44) Auto immune Dise a se (n=12) 7 (58) 5 (42) He ma to lo g ic Ma lig na nc y (n=3) 2 (67) 1 (33) HI V (n=3)

3 (100)

Chro nic L ung Dise a se (n=8)

5 (63)

3 (37) Chro nic L ive r Dise a se (n=9)

6 (67)

3 (33) Dia b e te s (n=16)

10 (69)

6 (31) No unde rlying me dic a l c o nditio ns (n=12)

12 (100)

Summa ry o f Mo rta lity

F e atur e # patie nts (% ) P- value

De a th (n= 18) Surviva l (n= 28) Me a n a g e in ye a rs 62 56 Ma le 8/ 18 11/ 28 0.77 Pre dispo sing Co nditio ns Immune -suppre ssing Co nditio ns 12 12 0.14 Chro nic Me dic a l Co nditio ns Only 6 4 0.16 No Pre dispo sing Co nditio ns 12

0.0012

Site o f Infe c tio n Pulmo na ry

12

9

0.034

CNS 1

11 0.015

CNS a nd Pulmo na ry 4 5 0.72 Blo o dstre a m (o nly site ) 1 0.39 Othe r 3 0.27 Po sitive C.g a ttii Blo o d Culture s (n=23)

5 0.046

Co nc lusio ns a nd Disc ussio n



I nc re a sing numb e r o f dia g no se d c a se s o f C.g a ttii in Ore g o n o ve r pa st 6 ye a rs



I nc re a se d pro po rtio n o f pa tie nts with C.g a ttii ha d unde rlying c o mo rb iditie s tha n pre vio usly re po rte d (74%)



Se rum c rypto c o c c a l a ntig e n o nly 68% se nsitive fo r pulmo na ry infe c tio n a nd 94% se nsitive fo r CNS infe c tio n in this se rie s (c ulture a s g o ld sta nda rd)



Bo th site o f infe c tio n a nd mo rta lity c o rre la te d stro ng ly with ho st immune / me dic a l sta tus 

Mo rta lity o c c urre d e xc lusive ly in pa tie nts with unde rlying c o nditio ns



CNS dise a se mo re like ly in pa tie nts witho ut unde rlying c o nditio ns



Re la tive g o o d b a se line he a lth o f tho se with CNS dise a se ma y e xpla in why CNS dise a se a sso c ia te d with b e tte r o utc o me s tha n pulmo na ry dise a se



F ung e mia wa s a pa rtic ula rly po o r pro g no stic indic a to r

Crypto c o c c o sis in Anima ls

 Po rt o f e ntry = re spira to ry tra c t via inha la tio n o f spo re s  Ye a st g e ne ra lly pre c ipita te into the uppe r re spira to ry tra c t,

a s the y a re to o la rg e to b e imme dia te ly de live re d into the lung s

 Ba se d o n pre se nta tio n- o ra l e xpo sure ma y b e a fa c to r in

a nima ls

 Pre dispo sing fa c to rs to infe c tio n:

 Co mme rc ia l e nviro nme nta l disturb a nc e s  I

mmuno suppre ssio n

 F

e L V/ F I V in c a ts

 Chro nic immuno suppre ssive the ra py

Crypto c o c c o sis

 Clinic a l sig ns in Ca ts

 Na sa l/ Pha ryng e a l/ Sinus

invo lve me nt

 Sne e zing  Muc o id na sa l disc ha rg e  Pro life ra tive so ft tissue

ma ss o n na sa l pla num

 Cuta ne o us ulc e ra tio n

Crypto c o c c o sis

 CNS invo lve me nt  F

• r b ra in sig ns

 De pre ssio n, se izure s, a lte re d me nta tio n, c irc ling ,

a ta xia , he a d-pre ssing

 Oc ula r sig ns  Blindne ss  Cho rio re tinitis  Re tina l de ta c hme nt  Ante rio r uve itis

Crypto c o c c o sis

 L

• we r Re spira to ry Dise a se

 Sma lle r de sic c a te d ye a st inha le d dire c tly into the lung s  Dyspne a , ta c hypne a , c o ug h  *Skin/ sub c uta ne o us invo lve me nt*  Pre se nt in 40-50% o f c a se s  Pa pule s  No dule s  Ulc e ra tio n a nd dra ina g e  Re g io na l lympha de no pa thy  Ano re xia , le tha rg y, fe ve r (unc o mmo n)

Crypto c o c c o sis

Ca nine Crypto c o c c o sis:

 Do g s < 4 ye a rs  CNS invo lve me nt (50-80%)  Uppe r re spira to ry tra c t (50%)  Oc ula r dise a se (20-40%)  Cuta ne o us dise a se (10-20%)  He a d, fe e t, na il b e ds, o ra l

muc o us me mb ra ne s

Crypto c o c c us g attii Anima l Da ta , Ore g o n 2007-2011

Sub type s I so la te d (N=40)

Anima l T ype VGI I a VGI I b VGI I c VGI I I Ca nine 7 1 2

• F

e line 4 1 5 1 E lk 1 1

• Go a t

5

• She e p
• 1
• Do lphin

1

• F

e rre t 2 Alpa c a 7

• Ho rse
• 1**
• T
• ta l

27 (68%)

4 (10%)

8 (20%) 1(2%)

Site o f initia l infe c tio n a t pre se nta tio n in Anima ls

Tissue/sample

n

Tissue/sample

n

lung

11

head swelling

1

nasal discharge

8

periorbital swelling

1

brain

7

skin abscess

6

• ral cavity swelling

4

fecal

2

liver

2

renal mass

2

L a b o ra to ry I de ntific a tio n

 Culture o n CGB a g a r disting uishe s spe c ie s

• C. g attii sta ins b lue

 Mo le c ula r a na lysis ide ntifie s g e no type a nd sub type s

(@ CDC b y Dr L

• c kha rt)

I ndia ink pre pa ra tio n sho wing c a psule s o f Crypto c o c c us Co lo r re a c tio n o n CGB a g a r RF L P o r ML ST disting uishe s sub type s

T re a tme nt o f Crypto c o c c o sis

 T

re a tme nt

 F

luc o na zo le = tre a tme nt o f c ho ic e



Go o d CNS pe ne tra tio n



50mg / c a t PO q 12 hrs



5mg / kg PO q 12-24hrs (do g s)

 Itra c o na zo le = g o o d se c o nd c ho ic e



E ffe c tive in c a ts a nd do g s



De spite la c k o f CNS pe ne tra tio n, ha s b e e n use d to suc c e ssfully tre a t CNS c rypto c o c c us (BBB no t inta c t due to infla mma tio n)



10mg / kg PO q 24 hrs

 K

e to c o na zo le = va ria b ly e ffe c tive , ine ffe c tive in CNS dz

 L

ipid c o mple x a mpho te ric in B fo r se ve re o r re fra c to ry c a se s

Susc e ptib ilitie s…….

L

• c a tio n

L

• c a tio n

L

• c a tio n

Case s by ge ogr aphic al loc ation

Ge o g ra phic lo c a tio n o f Crypto c o c c us g a ttii, Ore g o n 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 dom estic veterinary cases in the US, 2004-2010. The data were split into 50% training and 50% testing subsets and applied against seven environm ental layers: January m inim um and m axim um tem peratures, tem perature seasonality, m inim um tem perature of coldest m onth, annual tem perature range, and m ean tem perature of coldest quarter. The m ean training and testing accuracy of the m odel were 82% and 78% , respectively. Map created Novem ber 23, 2010 by Julie Harris, CDC, w ith assistance from Sunny Mak, BC CDC.

E c o lo g ic a l Nic he Mo de ling o f Crypto c o c c us g attii in the Pa c ific No rthwe st

91-100% 81-90% 71-80% 61-70% 51-60% 41-50% 31-40% 21-30% 11-20% 1-10% 0%

Ac kno wle dg me nts

 Ce nte rs fo r Dise a se Co ntro l a nd pre ve ntio n

 Dr Chille r, Dr Ha rris a nd Dr L

• c kha rt

 Ore g o n He a lth Autho rity – a nd the OSPHL

 Dr Pa ul Cie sla k , Dr L

ynn F itzg ib b o ns, Ro b Ve g a

 Ore g o n Sta te Unive rsity –

 Ve te rina ry Dia g no stic s la b o ra to ry