cryptococcus neoformans 1992

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linical

Microb io logy

News l e t t e r

Vol. 14, No. 23

De cem ber 1, 1992

ryptococcus neoformans

Mark La Rocco Ph.D.

Department of Pathology and Laboratory

Medicine

University of Texas Medical School

Houston TX 77225

There is , perhaps, no other fungal

pathogen in rece nt times that has had as

dramatic an impact on cl in ical med icine

and public heal th as

C r y p t o c o c c u s

n eo fo rma n s . Long rega rded as an oppor-

tunistic pathogen in patients with Hodg-

kin 's d isease, leukem ia, d iabetes , and

prolonged s teroid therapy, the morbid-

i ty and mortal i ty of

C . n e o f o r m a n s

d isease has exp loded wi th the adven t o f

acqu i red imm unodef ic iencysyndrome

(AIDS). C ryptococca l meningit is is the

mos t comm on f i fe- th rea ten ing oppor-

tunistic fu ngal diseas e in patients

in fec ted wi th the hum an imm uno-

deficienc y virus (HIV) ty pe 1 . In the

United States , the prev alence of the

disease in th is pat ient populat ion is

be tween 7 and 12% (1 -3 ) and i s as h igh

as 20% in A IDS pat ients in t ropical

Africa (4).

The pu rpose of th is art icle is to re-

view the cri t ical features of the mycol-

ogy , eco logy , and ep idem io logy o f C .

n e o f o r m a n s

and to sum marize cu rren t

information on the pathophysiology,

diagnosis , an d treatmen t of cryptocoe-

cal disease.

M y c o l o g i c F e a t u r e s

C . n e o f o r m a n s

is an encapsulated,

monomorph ic yeas t. Tw o var ie t ies and

four serotypes have been described: C.

n eo fo rma n s va r . n eo fo rma n s ,

which co r-

responds to serotypes A a nd D; and C.

n eo fo rma n s va r . g a t ti i ,

which co rre-

sponds to serotypes B a nd C. The de -

scription o f the teleomorphic form of

the o rgan ism by Kw on-Chung e t a l . (5 )

led to i ts classificat ion as the b asidiomy-

ce te Fi io b a s id i e l l a n eo fo rm a n s F . n eo -

f o r m a n s v a r. n e o f o r m a n s a n d F .

n eo fo rma n s va r . b a c i l li sp o ra ) ,

al though

these fo rms are ra re ly encoun tered un-

der laboratory condit ions. Species of

Cryp to co ccu s produc e ovoid to globose

vegetat ive cel ls with mult ipolar b lasto-

con id ia a tt ached by a narrow neck . The

cel ls are usual ly surrounded by a poly-

sacchar ide capsu le and may ra re ly fo rm

rudime ntary pseudohyphae. All species

o f

Cryp to co ccu s a re

non-fermentat ive

but wil l ass imilate a variety of carbohy-

&a te substrates . Prod uction of urease,

inositol assimilation, and microscopic

morp hology are ke y features that d is tin-

guish

Cryp to co ccu s

from othe r yeasts .

At least seven species have been de-

scribed but i t is gen eral ly bel ieved that

C . n e o f o r m a ~

is the only human patho-

gen. Separat ion of species is readily

ach ieve d by assimilation studies and

pigm ent production. The lat ter relates

to the abi l i ty of C.

n e o f o r m a n s t o f o r m

melan in p igmen ts f rom o - and p -d iphe-

nol com pounds through the production

of pheno l ox idase enzymes . The sub-

strate for p igment production was origi-

nal ly a m edium containing an exWact

f rom pu lver ized seeds o f

Gu izo t i a

a b yss in i ca b i rd seed ) .

More recen t ly ,

b i rd seed agar has been rep laced by

caffe ic ac id med ium , wh ich con ta ins

the d ipheno l compounds necessary fo r

pigmentat ion (6). The fo ur serotypes of

C. n eo fo rma n s a re

recogn ized on the ba-

sis of the ant igenic specifici ty of the

capsular polysaccharide. Although

most cl in ical m icrobiology laboratories

do not sero type isolates , d ifferent iat ion

of the two spec ies varian t s may be occa-

sional ly useful for epidem iologic pur-

poses. A s imple agar med ium

containing L-canavan ine, g lycine, and

bromthym ol b lue has been shown to re -

l iably dis t inguish the A and D sero-

t yp es C . n eo fo rm a n s va r . n eo fo rma n s )

from the B an d C serotypes (C.

neofor-

ma n s va t . g a t t i i )

by the abi l i ty of only

the lat ter to cause blueing o f the me dia

around c olonies (7).

The curren t taxonom ic classification

of C . n e o f o r m a n s has been supported

(so fa r ) by recen t molecu lar ap -

proaches. Gene tic analyses can circum-

I n T h i s I s su e

C r y pt oc o c cu s n eo f o rm a n s . . . . . . .

77

An overview o f the eco logy,

epidemiology, mycology, and diagnostic

and therapeu tic aspects of this

important opportunistic pathogen

A c t i n o m y c e s n a e s l u n d ii

Bacteremia . . . . . . . . . . . . . . . . . . . 1 8 1

A case report

F a t a l I n f e c t i o n d u e t o

A l c a l i g e n e s

x y l o s o x i d a n s

subsp ,

x y l o s o x i d a n s

in a N e u t r op e n k H o s t . . . . . . . . . . 82

case report

C M N E E I 1 4 ( 2 3 ) 1 7 7 - 1 8 4 , 1 9 9 2 E i a e v i e r

0 1 9 6 4 3 9 9 / 9 2 / 0 . 0 0 + 0 3 . 0 0



ven t the confus ion o f ten genera ted by

the plast ici ty of phenotyp ic t raits , par-

t icularly whe n deal ing with the anamo r-

ph ic s tages o f fung i. New ly deve loped

techniques that have been succe ssful ly

applied to the taxonom ic s tudy of

cryptococci include rapid restrict ion

mapping using the polyme rase chain re-

act ion (8), res trict ion frag men t polym or-

ph ism ana lys i s o f mi tochondr ia l DNA

(9), and electrophoret ic karyotyping by

pulsed field gel e lectrophoresis (10).

Such s tudies wil l undoubted ly enha nce

our unders tand ing o f the phy logenet ic

relationship between

Cryptococcus and

othe r fungi. Wh ethe r these sophisti-

cated techniques will imp rove our cur-

rent level of proficiency in the

diagnosis and trealm ent of cryptoc occal

disease remains to be determ ined.

E c o l o g y D i s t r i b u t i o n a n d

E p i d e m i o l o g y

The w or ldwide occurrence o f c ryp to -

coccal d isease s tands as evide nce for

the environmen tal ubiquity of

C. neofor-

marts.

As o r ig ina l ly descr ibed by E m-

mons (11), the organism thrives in the

alkaline, high-nitrogen and high-salt

content of dried pigeon feces . Pigeons

are rarely infected, perhaps beca use of

an unsuitably h igh body tem perature of

42°C. Studies have reported the recov -

ery f rom dr ied o r mois t p igeon feces o f

large numbers of v iable organisms w ith

an abi li ty to remain viable for up to 2 yr

(12). This well-described ecologic

niche is val id only

for C. neoform ans

var. neoform ans

and, unt i l recently , the

natural habitat of C. neoform ans var.

gatt i i

was unknow n. Austral ian invest i-

gators , howeve r, have provided com pel-

l ing eviden ce for a b iotrophic

association between C. neoform ans var.

gatt i i

and the r iver red gum t ree

Euca-

lyptus camaldulensis

(13). Their studies

have dem ons t ra ted the env i ronmen ta l

p resence o f C. neoforma ns vat . gat t i i

only during the flowering periods of E.

camaldulensis in late spring (14). They

postulate that the organism m ay be a

smut-L~ke fungu s tha t ov er-w inters in

the deve lop ing buds o f the euca lyp t

with release o f basidiospores in to the

env i ronmen t when the hos t p lan t f low-

ers (13). The y further speculate that the

basidiospores serv e as infectious propa -

gules . Hum an infect ion ma y be direct

or through a vecto r such as (in Austra-

l ia) the koala, wh ich favors the eucalypt

as a foo d source. In support of their hy-

pothesis is the finding of C. neo formans

vat. gatt i i

in the feces o f the koa la and

an endem ic focus o f d i sease caused by

C. neoform ans var. gatt i i

in the rural

aboriginal populat ion of the A ustral ian

Northern Terri tory , a natural habitat for

E. camaldulensis

(14).

These rec ent and fascinat ing find-

ings on the eco logy o f C. neo formans

are in ag reemen t wi th cu rren t ep idemi-

ological d atao The restricted niche o f C.

neoform ans var. gat t ii to E. camaldulen-

sis

may exp lain the p reva lence o f the

varian t in patient isolates from tropical

and subtropical reg ions (15). Similarly,

serotypes A and D C. neoform ans vat .

neo formans)

predom inate in isolates re-

covered from pat ients with and without

AIDS in the United States (16). Of in-

terest is the rec ent report of

C. neofor-

man s vat . gat t i i in an

AIDS pat ient

living in So uthern Californ ia (17) fol-

lowed by ano ther communica t ion an -

nouncing the isolation of the variant

f rom E. camaldulensis

t rees growing in

San F rancisco (18).

H o s t - P a r a s i t e

I n t e r a c t i o n s

The po lysacchar ide capsule o f C .

neo formans

consis ts mainly of g lucu-

ronoxy lomannan and ga lac toxy lman-

nan. I t is considered a v irulence factor

in that s tudies have demo nstrated the

antiphagocytic and imm unosuppressive

effects of ca psular polysacch aride (19,

20). Phen ol oxidase-m ediated synthesis

of me lanin has also been l inked to viru-

lence in a mur ine mod el o f in fec t ion

(21), al though the mecha nism has not

bee n established.

Hos t -defense mechan isms aga ins t C .

neo formans have been s tud ied by sev -

eral investigators. In supp ort of strong

natural huma n resis tance to

C. neofor-

mans ,

immu ni ty appears ac t ive on sev -

eral levels . Neutrophils , macrophages,

ant ibody, sensi t ized T cel ls , and n atural

ki l ler cel ls have al l been shown to have

anti-cryptoeocca l act iv i ty (22). C ell-me-

diated immu nity is probably the most

important protect ive mecha nism against

sys temic c ryp tococca l d isease and re -

cent s tudies have foc used at tent ion on

the imm unomodula to ry e f fec t o f C. neo-

f o r m a n s

on the T-cel l network. Crypto-

cocca l an t igens have been shown to

induce T-suppressor cel ls in mice,

wh ich then b lun ts de layed- type hyper-

sensitivity (23). Induc tion of T-suppres-

sor cel ls in HIV -infected pat ients with

cryp tococcos is ma y fu r ther aggrava te

an a l ready dow n-regu la ted ce l lu la r re -

sponse, perhaps explaining the high in-

c idence and severe symptom ato logy o f

the dise ase in th ese patients.

C r y p t o c o c c a l I n f e c t i o n :

C u r r e n t S t a t u s

In their monogra ph published in

1956 , L i t tman and Z im merm an re -

corde d 151 fatal cases of cryptococco-

sis in the U nited States during the

period from 1949 to 1956 (24). The y

quite correct ly conclude d that the figure

underes t imated the t rue inc idence o f

disease in this country s ince manda tory

repor ting was no t requ i red . The CD C

reported 788 fatal cases in the period

from 1952 to 1963 (an average of 66

cases per ye ar) (25), and 1 ,040 fatal

cases f rom 1965 to 1975 (average o f

104 cases per year) (26). Beginning in

1965 , the Fungus Im munology Branch

of the CD C offered na t ionwide tes ting

of serum and cerebrospinal f lu id for C.

neo formans

antige ns and /or antibodies.

By correla ting their f mdings with avail-

able cl in ical , my cologic, and histologic

data, they docu me nted 1 ,264 proven

N O T E :

N o r e s p o n s ib i l i ty i s a s s u m e d b y t h e P u b l i s h e r

f or an y

i n j u r y a n d / o r d a m a g e t o p e r s o n s o r

p m p e ~ y a s

a m a t t e r o f p r o d u c t s l i a b il i ty , n e g l i g e n c e o r o t h e r w i s e , o r f r o m a n y u s e o r

o p e r a t io n o f a n y m e t h o d s , p r o d u c t s , i n s t r u c ti o n s o r i d e a s c o n t a i n e d i n t h e m a t e r i a l h er e i n . N o s u g g e s t e d t e s t o r p r o c e d u r e s h o u l d b e c a r r i e d o u t u n l e s s , i n t h e r e a d e r ' s j u d g m e n t , i t s r i s k i s

j u s t i f i e d . Be c a u se o f r a p i d a d v a n c e s i n m e d i c a l

s c i e n c e s w e

r e c o m m e n d t h a t t h e i n d e p e n d e n t v e r if i c a t io n o f d i a g n o s e s a n d d r a g d o s a g e s s h o u l d h e m a d e . D i s c u s s i o n s , v i e w s a n d

r e c o m m e n d a t i o n s a s t o m e d i c a l p r o c e d u r e s , c h o i c e o f d r u g s

an d d rag d os ages are

t h e r e sp o n s i b i l i t y o f t h e a u t h o r s .

Clinical Microbiology Ne wsletter

f l S S N 0 1 9 6 - 4 3 9 9 ) i s

i s s u ed t w i ce

m o n t h l y i n

on e i n d exed vo l u me p er year

b y E l s e v i e r S c ie n c e P u b l i s h i n g C o . , I n c. , 6 5 5 A v e n u e o f t h e A m e r i c a s , N e w

Y o r k , N Y 1 0 0 1 0 . S u b s c r ip t i o n p r ic e p er year . 1 3 5 . 0 0 i n c l u d i n g p os t age an d h a n d l i n g i n t h e U n i t e d S t at e s , C a n a d a , e n d M e x i c o . A d d 5 2 . 0 0 f o r p o s t a g e i n t h e r e s t o f th e w o r l d . S e c o n d - c la s s

pc~tage

p a i d a t N e w Y o r k , N Y a n d a t a d d i t io n a l m a i l i n g o f fi c e s . P o s tm a s t e r . S e n d a r k h e s s c h a n g e s t o Clinical Microbiology Newsletter E l s e v i e r S c i e n c e P u b l i s h i n g C o . , I n c ., 6 5 5 A v e n u e

o f t h e A m e r i c a s , N e w Y o r k , N Y 1 0 0 1 0 .

78

0 1 9 6 - 4 3 9 9 / 9 2 / 0 . 0 0 + 0 3 . 0 0 © 1 9 9 2 E l s e v i e r S c i e n c e P u b l i s h i n g C o . , I n c . C l i n i c a l M i c r o b i o l o g y N e w s l e t t e r 1 4 : 2 3 , 1 9 9 2



l.)

c~ 5

r j

u .w

0 4

Z.-

Z 2

Y E R

o o o o o o o o o ° ° O

940 197 1980

1990

Figure 1. Incidence of cryptococcal disease in the United States 1960-1991.

cases of cryptococ cosis dur ing a 1 2-yr

per iod cover ing 1965 to 1977 and est i -

mat ed an i nc idence o f 500 cases per

year by 1978 (27) . A 450% increase

over a 20 -y r per iod wa s cons idered , fo r

good reason, a s tar tl ing med ical revela-

t ion. The expanding ro le of C . n eo fo r

m a n s a s a n

opportunist ic pathogen in

the imm unocomp romised pa ti en t was

appreciated 3 y r before the in i tial re-

po r t s o f an acqu i r ed imm unodef i c iency -

l ike syndrome in homosexual men .

Figure 1 depicts the exp losive r i se in

the es t imat ed i nc idence o f c ryp tocooca l

disease in the Uni ted Slates s ince 1981.

Cal cu la t ions a re based on year -by -year

repor ting of AIDS cases in th is count ry

and an es t imat ed 10% p reva l ence o f

cryptoco ccal meningi t i s in th is pat ient

populat ion, a figure wel l supported by

recen t s tud i es (1 -4 ) . Wi th now over

200 ,000 cases o f AIDS repor t ed t o t he

CDC (28 ), po ten t ia l l y 20 ,000 new cases

o f c ryp tococcos i s have occu r red i n t he

last decade , an approximate increase of

1 ,500% as com pared to the previous

decade . In 1991 , 43 ,389 ne w cases o f

AIDS w ere r eco rded by t he CD C, co r re-

iating to potent ial ly ove r 4 ,300 n ew

cases o f c ryp tococcos i s i n t ha t year

a lone , over t h ree t imes t he nu mber o f

cases docum ented during the ent i re pe-

r iod f rom 1965 to 1977 Cryp tococ cal

meningi ti s i s the mo st comm on l i fe-

threatening fung al infection in the pa-

t ient wi th A IDS , and of ten i s the f i rs t

manifestation of the diseas e (1--4).

The c l in ical presentat ion of crypto-

coccos i s i s dependen t upon t he imman-

ocom peten ce of the infec ted patient .

Infect ion may b e superf icial or deep, lo-

cal ized or d i f fuse, and can select ively

involve speci f ic organs or d isseminate

to mul t ip le organ system s. The por tal of

ent ry for the organism is the lung; h ow-

ever , pulmon ary infect ion i s usual ly as-

ymptomat ic. Cent ral nervous system

involvem ent i s the mo st f requent ly d iag-

nosed fo rm o f c ryp tococcos i s , a lt hough

the predi lect ion of C . n e o f o r m a n s fo r

t he CNS has no t been conclus ive ly ex -

plained. Abn ormal i t ies in the cerebro-

spinal f lu id (CS F) are general ly found.

Opening p ressure i s of ten elevated, g lu-

cose i s dep ressed i n ha l f t he cases , p ro -

tein concen t rat ion i s almo st always

e l eva t ed, ce l l coun t s r ange f rom 40 t o

400 l eukocy t es per m m 3 and have a

lymphocy t i c p redominance.

Several recen t repor ts on the cl in ical

presentat ion of cryp tococc al meningi ti s

in HIV-infec ted pat ients have detai led

important d i f feren ces in the cl in ical

f indings as compa red to pat ients wi th-

ou t HIV (1 -4 ) . H IV pa t ien t s o f t en p re-

sent wi th minimal s igns of meningeal

inf lammat ion and m inimal or no abnor-

mal i ti es o f t he CSF. The l ack o f CS F

abnorm al i t ies m ay exist despi te the

p resence o f l a rge numbers o f yeas t s i n

the f lu id . Addi t ional d iagnost ic features

characteristic of this patient popula tion

are l i s ted in Table 1 and are d iscuss ed

fur ther below.

Pr ior to the ad ven t of ant ifungal ther-

apy , symptom at i c c ryp tococcos i s was

invar iably fata . Th e m ortal i ty of the

disease wa s great ly d iminished wi th the

avai labi l i ty of amph oter icin B. A l-

t hough t he usefu lness o f 5 - f l uo rocy to -

s ine a lone i s l imi t ed by deve lopmen t o f

resis tance dur ing therapy, Bennet t and

co l l eagues show ed t he benef i t o f combi -

nat ion therapy wi th amphoter icin B and

5-f luorocy tosine for the t reatment o f

cryptoc occa l meningi t i s (29) . The regi -

men a l l ows a l ow er dose o f ampho-

tericin B to b e use d, thus alleviating

some o f t he t ox i c it y p rob l ems assoc i -

ated wi th the drug. Co mbina t ion ther-

apy wi th ampho ter i c in B and

5-f luorocytosin e for the t reatment of

cryptoc occa l meningi t i s in HIV -in-

fecte d patients has b een disappointing.

Rel apse i s commo n and , m ore impor -

tant ly , m any pat ients ca nnot to lerate the

bone m ar row suppress ion i nduced by 5 -

f luorocytosine. Toxic i ty i s further am -

pf i f ied in pat ients t reated w i th

azidothymidine, a drug wi th a propen-

si ty for causing leukopenia. As a resul t,

an in tensive search for al ternat ive thera-

p i es i s underway . Much o f t he focus

has been on f l uconazo l e , the new o ra l

triazole antifungal. Althou gh optimal

therapy for cryp tococc al meningi ti s in

the HIV-infec ted pat ient remains unde-

fined, a recent, large multicenter trial

determined f luconaz ole to be a suitable

al ternative to am photer icin B a s a

pr imary thera py (30) . Addi t ional

ev idence sugges t s t ha t f l uconazo l e may

also be a usefu l suppressive therapy in

chronical ly infected individuals (31) .

L a b o r a t o r y D i a g n o si s

Defini t ive d iagnosis , based on the

morp hologic an d physiolo gic features

des crib ed earl ier in this article, is read-

i ly accompl i shed by r ec overy o f

C . n eo

f o r m a n s f rom CS F, b lood , o ther body

fluids, or t i ssue. The organism is non-

fast id ious, wi l l grow at 25°C or 37°C,

and can be cu l ti va t ed on m os t rou ti ne

fungal media. B eca use the organism is

var iably sensi t ive to cyclohexim ide, se-

lect ive med ia should be avoided. Pr i-

ma ry growth usua l ly occu rs within 48

to 72 h; c onsequ ent ly , the organisms

ma y be detec ted dur ing rout ine bacter io-

l og ic wo rkup o f spec imens . Recov ery

f rom b lood can be ach i eved wi th mos t

0196-4399/92/ 0.00 + 03.00 179

linical MicrobiologyNewsletter 14:23,1992 © 1992 Elsevier Science Publishing Co., Inc.



T A B L E 1 . C o m p a r i s o n o f l a b o r a t o r y f e a t u r e s o f c r y p t o c o c c a l m e n i n g i t i s i n

p a t ie n t s w i t h a n d w i t h o u t A I D S

Patients

CSF With AIDS Without AIDS

High opening pressure >65% >65%

Low glucose < 25% -50%

High protein ~50% >90%

White-cell count >20hnm 3 <30% >70%

Pleoeytosis mild or absent present

India -ink positiv e >80% <_.50%

Number of yeasts +++ +

Antigen-positive 90--100% (high titer ) >9 0%

Blood culturo--positive -50% <50%

Serum antigen-positive 98-100% ~_50%

aMo dified from referen ce 4.

ava i l ab le b lood cu l tu re me thodo log ie s ,

bu t s ome s tud ie s have s how n the s upe -

r io r pe r fo rm ance o f ly s i s -cen t r i fuga t ion

( 32 ). T h e B A C T E C 4 6 0 a n d 6 6 0 s y s -

t ems (B ec ton-Dick ins on Diagnos t i c

I n s t ru m e n t S y s t e m s , T o w s o n , M D ) ,

w h i c h m e a s u r e g r o w t h r a d io m e t r ic a U y

and by in f ra red s pec t ros copy , re spec -

t ive ly , m ay oc cas iona l ly fa i l t o de tec t

the p re s ence o f C . n e o f o r m a n s in the

b lood cu l tu re bo t t l e de s p i t e g rowth o f

the o rgan i s m in the m ed ia (33 ) .

T h e m i c r o sc o p i c e x a m i n a t i o n o f

C S F mixed w i th Ind ia ink i s a t r ad i-

t i on a l m e t h o d f o r r a p i d , p r e s u m p t i v e

iden t i f i c a t ion o f C . n e o f o r m a n s . T h e

te s t s u f fe r s f rom a l a ck o f s ens i t iv i ty

a n d s p e c i f ic i t y a n d t h e n e e d t o e x a m i n e

l a r ge v o l u m e s o f C S F . E v e n w h e n e x -

a m i n e d b y e x p e r i e n c e d p e r so n n e l , t h e

te s t is pos i t ive in on ly 50% of pa t i en t s

wi th c ryp toc occa l men in g i t i s (22 ).

T he de ve lopm en t o f l a tex pa r t i c l e

agg lu t ina t ion (L PA) fo r the de tec t ion o f

C . n e o f o r m a n s caps u la r po lys accha r ide

i n C S F a n d s e r u m o f f e r e d a s i g n i fi c a n t

i m p r o v e m e n t f o r t h e r a p id d i a g n o s i s o f

c ryp tococca l men ing i t i s . In i t i a l s pec i f i c -

i ty p rob lems , pa r t i cu la r ly in s e rum , due

to in t e r fe r ing s ubs tances s uch a s rheu-

m a t o i d f a c t o r, h a v e b e e n r e s o l v e d b y

p r e t re a t m e n t o f s p e c i m e n s w i t h p r o n a s e

(34) . C ur ren t ly , L P A i s e s t ima ted to

have a s ens i t iv i ty g rea te r than 90% fo r

the d iagnos i s o f c ryp tococc a l men ing i -

t is (22). Fa lse pos i t ives are un usual . Re-

cen t ly , how eve r , L PA c ros s - reac t iv i ty

has been repor t ed in pa t i en t s w i th d i s -

s emina ted in fec t ions w i th T r i c h o s p o r o n

b e i g e l i i

(35) . A no the r repor t de s c r ibed

a fa l s e -pos i t ive re s u l t l i nked to con tami -

na t ion o f C SF wi th s yne re s i s f lu id (36 ) .

Ove ra l l , howeve r , c ryp tococca l L PA i s

cons ide red the m os t r e l i ab le s e ro log ic

t e s t fo r the d iagnos i s o f a funga l d i s ea s e .

C e reb ros p ina l f lu id s tud ie s in HIV-

in fec ted pa t i en ts w i th c ryp tococca l

men ing i t i s o f t en revea l the p re s ence o f

l a rge numbers o f yea s t s in the abs ence

o f a n i n f l a m m a t o r y r e sp o n s e a n d I n d i a

ink p repa ra t ions ma y be pos i t ive in

ove r 80% of cu l tu re -pos i tive ca s e s

(1 -4 , 22 ) . E x t rem e ly h igh L PA t i t e r s ,

pa r t i cu la r ly in s e rum, ma y occur . T he

labora to ry s hou ld be a l e r t ed to the pos -

s ib i l it y o f a p rozone reac t ion an d the

need to inc lud e appropr i a te d i lu t ions o f

the s pec im en . Pe rs i s t en t ly e l eva ted s e -

rum an t igen t i t e rs a re com m on (2 , 4 ,

22 ) , a l thoug h the c l in i ca l s ign i f i c ance i s

unc lea r . F ina l ly , t he inc lus ion o f s e r i a l

L P A s e r u m a n d C S F t it e rs i n t h e e v a l u -

a t ion o f pa t i en t s s ub jec ted to nove l

t rea tmen t p ro toco l s w i l l p robab ly c l a r-

i fy any p rognos t i c va lue a s s oc ia t ed

with the tes t .

S u n n n a r y

In the i r z ea l t o en l igh ten c l in i ca l

c o l l e a g u e s o n t h e i m p o r t a n c e o f f u n g a l

p a t h o g e n s i n t o d a y ' s p a n t h e o n o f i n f e c-

t ious d i s ea se , med ica l my co log i s t s a re

s om e t imes d r iven to a f l a i r fo r the d ra -

mat ic . In 1970, Aje l lo (37) suspected

tha t the p reva lence o f c ryp tococcos i s

w a s m u c h h i g h e r t h a n t h e c u r r e n t in f o r -

mar ion ind ica ted . He de s c r ibed c ryp to -

c o c c o s i s a s t h e s l e e p in g g i a n t a m o n g

s y s t e m i c m y c o s e s. I n 1 9 78 , K a u f m a n n

a n d B l u m e r (2 7 ) o f t h e C D C c o m p i l e d

s e ro log ic da ta on the d i s ea s e and p ro -

c l a i m e d c r y p t o c o c c o s is t h e a w a k e n i n g

g i a n t . T h e p r o p h e c y o f th e m e t a p h o r,

f rom a 1992 pe rs pec t ive , is unne rv ing .

T h e g i a n t i s i n d e e d w i d e a w a k e a n d a

f e a r s o m e c o n t e m p o r a r y o f s y s t em i c m y -

coses .

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ctinomyces naeslundii

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Division of Infectious Diseases

Department of Internal Medicine and

Microbiology Laboratory

Department of Pathology

Maimonides Medical C enter

Brooklyn NY 11219

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n e n t o f n o r m a l h u m a n m o u t h f l o r a. I t

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porte

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C a s e R e p o r t

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t o m y , s p l e n e c t o m y , a n d R o u x - e n - Y

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d i f f e r e n t i a t e d a d e n o c a r e i n o m a a r i s i n g

f r o m t h e p r o x i m a l s t o m a c h a n d e x t e n d -

i n g t o t h e e s o p h a g e a l m a r g i n a n d p e r i -

g a s t r i c f a t .

T h e p a t i e n t d i d w e l l u n t i l t h e p o s t o p -

e r a ti v e d a y 1 4 , w h e n h e d e v e l o p e d v o m -

i t in g a n d a t e m p e r a t u r e o f 1 0 2 ° a n d w a s

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