cryptococcus neoformans 1992
TRANSCRIPT
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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
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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
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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.
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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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Brooklyn NY 11219
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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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