Coccidioidal Meningitis - Dr. Aaron Shelub

34 Pages·2010·0.34 MB·English

Coccidioidal Meningitis
Clinical Presentation and Management in the Fluconazole Era
Glenn Mathisen, MD, Aaron Shelub, MD, Jonathan Truong, MD, and Christine Wigen, MD, MPH
Abstract: Despite the advent of newantifungal agents, coccidioidal Abbreviations: AIDS = acquired immunodeficiency syndrome,
meningitis (CM) remains a difficult-to-treat condition with significant AmBD=amphotericinBdesoxycholate,CF=complementfixation,
morbidityandmortality.Inthisstudywedirectlycomparetheclinical CM = coccidioidal meningitis, CSF = cerebrospinal fluid, CT =
presentation and management of patients with Coccidioides immitis computerizedtomography,ELISA=enzyme-linkedimmunoserolo-
meningitisintheazoleera(after1980)tothatofacohortofpatientsfrom gic assay, HAART = highly active antiretroviral therapy, HIV =
the pre-azole era. We reviewed 30 CM cases seen at 3 Los Angeles human immunodeficiency virus, IRB = institutional review board,
hospitalsbetweentheyears1993to2008(B2008cohort[)andcompared LAmB = liposomal amphotericin B, MRI = magnetic resonance
themto31patients(B1980cohort[)describedbyBouzaetalinapre- imaging,po=orally,VP=ventriculoperitoneal.
viousstudy.Thedemographicsandclinicalpresentationofpatientsin
the2008cohortweresimilartothoseofthe1980cohortexceptfora
higherincidenceofHispanicpatients(2008:53%vs.1980:6%)anda
greater percentage of patients with underlying, predisposing clinical INTRODUCTION
conditions(2008:66%vs.1980:32%).Tenpatientsinthe2008cohort
Despite the advent of new antifungal agents, coccidioidal
had human immunodeficiency virus/acquired immunodeficiency syn-
meningitis(CM)remainsadifficult-to-treatconditionwith
drome(HIV/AIDS),aconditionnotreportedintheearlierstudy.Lab-
significant morbidity and mortality. Up until the 1980s, intra-
oratoryfindingsweresimilarbetweenthe2groupsexceptforalower
thecal amphotericin B was the mainstay of treatment for this
incidenceofperipheralleukocytosisandeosinophiliainthe2008group. condition.32Althoughthedrugofferedthefirsteffectivetherapy
Thereweremarkeddifferencesindrugtreatmentbetweenthe2eras.
for the condition, administration of amphotericin B via the in-
Inthe2008cohort,29patientsreceivedfluconazoletherapy:13were
trathecal route is difficult and is associated with significant
treated withfluconazole monotherapy,and 16received a combination toxicity.30Theadventofazoleagentsintheearly1980soffered
of fluconazole and intravenous amphotericin B. Although almost all
thehopethatanewclassofantifungaldrugswouldprovemore
patients(29/31)inthe1980cohortreceivedintrathecalamphotericinB,
effectiveandlesstoxicthanpreviousdrugregimens.Subsequent
only3patientsinthe2008studyreceivedamphotericinBviathisroute.
studiesestablishedtheutilityoffluconazoleinthemanagement
WithrespecttocomplicationsofCM,asimilarpercentageofpatientsin of CM,25 and the drug has now become the accepted first-line
eachcohortdevelopedcomplicationssuchasstrokeandhydrocephalus. agent in the treatment of the condition.24,30,67 In addition to
The2008cohort(40%)hadsimilarmortalitycomparedtopatientsinthe
fluconazole,otherazolessuchasitraconazoleandvoriconazole
1980 study (39%); survivors in both groups experienced significant
appear tohaveactivityinCMandhavebeenusedtotreatthis
impairmentofactivitiesofdailyliving.Althoughrecommendedasfirst- condition.17,49,63 Unfortunately, a major drawback of azole
linetherapyforCM,azole-basedtherapiesarenotcurativeanddonot therapy is the need to continue treatment indefinitelyVin
necessarilypreventcomplicationsassociatedwiththedisease.
patients with clinically proven CM, suspension of therapy is
CM remains a serious illness with a high rate of morbidity and
usuallyassociatedwithrelapseofthecondition,sometimeswith
mortality. Immunocompromised individuals, especially those with seriouscomplications.21
HIV/AIDS,areatspecialriskforCMandrepresentagreatershareof
We conducted the current study to compare the present
theoverallpopulationwiththiscondition.Despitetheclearadvantages
management of CM with management of the condition in the
of azole treatment in CM, new therapeutic approaches are needed to
pre-fluconazole era (before 1990). Our study is a retrospective
provide definitive cure and to reduce the need for long-term sup-
analysisofarecentcohortof30patientsinLosAngelescom-
pressive therapy.
pared to a similar cohort of patients from the pre-azole era,
(Medicine2010;89:251Y284) describedbyBouzaandcolleaguesin1981.8
History
CoccidioidomycosiswasfirstdescribedbytheArgentinian
FromCedarsSinai-UCLAAffilialtedMulticampusInfectiousDiseasePro- physician Alejandro Posadas in 1892.47 The initial casewas a
gram(GM,AS,JT,CW),LosAngeles;CedarsSinaiMedicalCenter,Los soldier who presented with progressive, destructive verrucous
Angeles;OliveView-UCLAMedicalCenter(GM,JT,CW),Sylmar;VAWest
lesions of the face. A skin biopsy demonstrated a spherical,
Los Angeles Medical Center, Los Angeles; Los Angeles County Depart-
mentofPublicHealth(CW),LosAngeles;andSouthernCaliforniaKaiser nonmotileorganismwithahighlyrefractiledoublewall.Despite
PermanenteMedicalGroup(JT),LosAngeles,California. thepresenceoftheBparasite[onbiopsy,Posadas(andhismentor
ThisworkwassupportedbyanunrestrictededucationalgrantfromPfizer Wernicke) did not believe this was the cause of the condition,
Pharmaceuticals.
and thought the patient actually had mycoses fungoides. Four
Reprints:GlennMathisen,MD,Chief,InfectiousDiseaseService,
OliveView-UCLAMedicalCenter,DepartmentofMedicine, years later,RixfordandGilchristdescribedasimilar condition
Rm2B182,14445OliveViewDrive,Sylmar,CA91342 in2patientsresidingintheSanJoaquinValleyofcentralCali-
(e-mail:gmathisen)ladhs.org). fornia.52Again,anorganismwaspresentonskinbiopsy;how-
Copyright*2010byLippincottWilliams&Wilkins
ever,theseinvestigatorsbelievedtheconditionwascausedbyan
ISSN:0025-7974
DOI:10.1097/MD.0b013e3181f378a8 underlyingparasiticinfection.Theparasiteresembledprotozoa
& 251
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Mathisenetal Medicine Volume89,Number5,September2010
from the genus Coccidia and, upon the suggestion of the used to treat CM.16 While ketoconazole had activity against
noted parasitologist G. W. Stiles, they named the organism C immitis, its poor CSF penetration and high rate of nausea/
Coccidioidesimmitis.TheappellationBimmitis[meansBsevere[ vomiting(associatedwithhigherdosing)madeitanineffective
andreferstothesevere,progressiveclinicalcourseobservedin agentforlong-termtherapy.
theaffectedpatients. In1990,Tuckeretal63reportedthefirstuseofatriazole-
The next major advance in understanding the disease itraconazole in the treatment of CM. Compared to the imida-
occurredin1900whenWilliamOphu¨ls,aprofessorofpathology zoles,triazolesgenerallyhavemorefavorablepharmacokinetics
at Cooper Medical College (which became Stanford Medical including improved absorption, greater tissue penetration, and
Schoolin1921),identifiedthefungalnatureoftheorganismand lessinhibitionofthehumancytochromeP450system.Although
succeeded in transmitting it to mice.20 He later described the itraconazolehadsomedemonstrableclinicalbenefit,itsvariable
clinicalspectrumofthediseaseinacaseseriesthatdocuments oral absorption and poor CSF penetration limited its use as a
CM in a patient who died from disseminated coccidioidomy- first-line agent for CM. In 1990, the triazole fluconazole was
cosis.43ThisispresumablythefirstdescribedcaseofCM.Over introducedintheUnitedStates.Comparedtopreviousagentsit
the next several decades, clinicians and researchers delineated hasalmostcompleteoralabsorption,goodCSFpenetration,and
theclinicalpresentationandcourseofCMinaseriesofpapers. excellent in vitro activity against C immitis. Similar to other
In1924MorrisreportedthefirstcaseofCMasthesolesiteof members of the azole family, it is fungistatic to C immitis at
extrapulmonary dissemination.40 In 1936, Abbott and Cutler1 clinically achievable concentrations. Animal studies in the late
reviewed14casesanddescribedthetypicalcerebrospinalfluid 1980sdemonstratedpotentialefficacyoffluconazoleinmurine
(CSF) findings in the condition. A subsequent pathological CM.27,57Subsequentcasereportsandstudiesoutlinedtheuseof
report demonstrated the prime role of meningeal involvement fluconazoleinhumanswithCM.14,64Areportof18patientsby
withcoccidioidalcentralnervoussysteminfection.18 Tucker et al64 delineated the pharmacokinetics of fluconazole
EarlytherapiesforCMwereineffective,andpatientsalmost andreportedaclinicalresponsein15ofthepatientstreatedwith
alwaysdiedwithinafewyearsofdiagnosis.TheVeteransAffairs the drug. The drug was well tolerated when given in doses
(VA)-Armed Forces Cooperative Studyof Coccidioidomycosis rangingfrom50to400mg/day.Theinvestigatorscommentedon
tracked over 700 patients with coccidioidomycosis during a relapseofCM(whenthedrugwasdiscontinued)andsuggested
period (1955Y1958) before the advent of effective antifungal thatthehigherdosesmightbeusefulinnonrespondingpatients.
therapies.Vincentetal65reviewedthesedataandidentified21 In 1993, the results of a National Institute of Allergy and In-
patientswhodevelopedCMwhileunderobservation;17ofthese fectious Diseases (NIAID)-Mycoses Study Group trial further
individualsdiedwithin31monthsofsymptomonset.Therewere supportedtheuseoffluconazoleinthetreatmentofCM.25Inthis
a few patients with more prolonged survival (55Y146 mo); study, 50 patients with CM were treated with fluconazole at a
however, lacking effective antifungal therapy, CM was almost doseof400mgperdayforupto4years;37of47patientswho
always a serious illness with a high mortalityVthere was sig- could be evaluated (79%) responded to therapy, regardless of
nificant neurologic disability, and most patients died within previous treatment with other antifungal agents (amphotericin
2yearsofdiagnosis. B).Althoughdiscontinuanceoffluconazolewasassociatedwith
The outlook for coccidioidomycosis began to change clinicalrelapse,thisstudyfurtherestablishedtheprominentrole
withtheintroductionofamphotericinBin1957.Thisdrugisa offluconazoleinthemoderneraofCMmanagement.Published
lipophilic molecule that exerts its action by binding to ergos- reports34ofexcellentinvitroactivityofvoriconazoleagainstC
terolsinthefungalcell;thesubsequentalteredmembraneper- immitisledtosubsequentuseofthedruginpatientswithCM.17
meabilityandintracellularpotassiumlossleadstodecreasedcell
viability.ParenteralamphotericinBwasthefirsteffectivedrug
PATIENTSANDMETHODS
treatment for coccidioidomycosis, and quickly became the
treatment of choice for severe and disseminated coccidioido- PatientSelection
mycosis. Unfortunately, parenteral amphotericin B had poor We retrospectively reviewed the medical records of all
CSFpenetrationandwaslargelyineffectiveintreatmentofCM.
patientswithadiagnosisofCMat3LosAngeles-areahospitals
Intheearly1960s,WilliamWinn(andotherinvestigators)pio-
(VAWest Los Angeles Hospital, Olive View Medical Center,
neeredtheuseofintrathecalamphotericinBformanagementof
andCedarsSinaiMedicalCenter)fromtheyears1993to2008.
CM.22,69 Although there was still a significant morbidity and Institutional review board approval for chart review was
mortalityassociatedwiththecondition,intrathecalamphotericin
obtained. CM was defined by a) positive CSF cultures or de-
BbecamethemainstayofmanagementforCMuntiltheadvent
tectionofcomplement-fixingantibodytoCoccidioidesantigen
oftheazoletherapiesinthe1980s.8 intheCSFinthepresenceofotherCSFabnormalitiestypicalof
Miconazole, a substituted imidazole, was the first azole
CM, or b) illness plus CSF abnormalities compatible with
used to treat coccidioidomycosis.61 Imidazoles and related
chronicmeningitisandeitherdetectionofserumcomplement-
agents (triazoles) bind to fungal cytochrome P-450 enzymes
fixing type antibodies or isolation of Coccidioides species
and inhibit C-14> demethylation of lanosterol, a key step in from an extraneural site.24 CSF abnormalities compatible
productionofergosterol,animportantcomponentofthefungal
with meningitis included CSF pleocytosis (CSF cell count
cellmembrane.MiconazoleisfungistaticagainstCimmitisand 94 cells/mm3), elevated total protein, and/or decreased CSF
requiresparenteraladministration.Althoughthedrughadsome
glucose(hypoglycorrhachia)accordingtolaboratorystandards
degree of CSF penetration, patients with CM often required at each facility. Lumbar arachnoiditis was defined as nerve
intrathecal therapy for a clinical response. Early studies of
root/back pain with evidence of lumbar nerve root enhance-
miconazole(ofteninpatientswhohadfailedorhaddifficulty
ment on gadolinium-enhanced lumbosacral magnetic reso-
tolerating amphotericin B) provided mixed results. The high
nanceimaging(MRI).
rates of relapse, due to its lack of fungicidal activity and the
necessityforparenteraladministration,madeitanimpractical ConductofStudy
agent for long-term therapy.Ketoconazole,a closerelativeof We obtained baseline information for patients at time of
miconazole, was introduced in 1976 and was subsequently initial presentation with CM at the aforementioned hospitals.
252
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Medicine Volume89,Number5,September2010 CoccidioidalMeningitis
Wereviewedpatientadmissiondata,hospitalcourse,treatment,
andfollow-up.Themajorityofpatientswerefollowedforover TABLE1. DemographicsandClinicalPresentationofPatients
2 years. We compiled data regarding patient age, predisposing WithCoccidioidalMeningitis:2008vs.1980Cohort*
risk factors, initial presentation symptoms and signs, evidence
2008 1980
ofneurologicdeficits,generalserumandCSFlaboratorypara-
meters, serum and CSF serologies, imaging procedures, evi- No.ofPts(%) No.ofPts(%)
denceofdissemination,disseminationinterval,therapyreceived, No.ofpatients 30 31
neurosurgical interventions, and response to therapy including Ageinyr:mean(range) 42.9(27Y72) 41.3(18Y65)
the ability to perform activities of daily living. Response
Sex
to therapy was determined by clinical improvement including
Male 25†(83) 27(87)
improved function/symptoms, CSF parameters, and decrease
Female 5(17) 4(13)
in CSF coccidioidal titer. We compared the data for this
Race
group (B2008 cohort[) to data for a group of 31 patients with
Asian 2(7)
CM treated between 1964 and 1976 in the pre-fluconazole era
Black 4(13) 10(32)
described in a retrospective study by Bouza et al (B1980
Hispanic 16(53) 2(6)
cohort[).8
White 8(27) 19(61)
DataAnalysis Predisposingfactors‡ 20/30(66) 10/31(32)
Patient clinical presentation and predisposing conditions None 10 22
in the present cohort (2008 cohort) were compared with those Alcoholabuse 3 8
in the 1980 cohort. We compared the diagnostic modalities Diabetes 4 3
(forexample,serology,CSFanalysis,radiographicprocedures) Corticosteroids 2
between the 2 groups when appropriate. Patient response to Postpartum 1 1
therapy in the 2008 cohort and subgroups was compared with Carcinoma 1
thatinthe1980cohort.Specialattentionwasplacedonwhether Pulmonarytuberculosis 2
patients received azole alone or azole therapy in some combi- Statusposttransplant 1
nationwithamphotericin.Inaddition,theneedforVPshuntor HIV/AIDS 10
Ommaya reservoir was contrasted with the need in the 1980 Hypertension 3
cohort.WealsocomparedCMmorbidity(forexample,activities CMasinitialmanifestation 18/30(60) 20/31(65)
of daily living;employmentstatus)andmortality amongcases Extra-CNSbeforeCM 12/30(40) 10/31(35)
inthe2cohorts. Interval(initialSxtoCNSSx)§ 6.9mo 17/24G3mo
Extra-CNSinvolvement
RESULTS Lung 17/30(57) 15/31(48)
We compared 30 patients with CM from 1993 to 2008 Skin 3/30(10) 13/31(42)
(2008 cohort) to 31 cases from the pre-1980 period (1980 Bones 2/30(7) 8/30(26)
cohort)(Tables1Y4).Moreextensiveinformationonthecurrent Prostate 1/30(3) 1/30(3)
cohort (2008), including clinical presentation, laboratory stud- ClinicalSx/signs
ies,radiologicprocedures,therapyandoutcomeispresentedin Headache 23/30(77) 23/31(79)
Tables 5Y12. Instructive cases from the current study are pre- Nausea/vomiting 17/27(63) 15/31(48)
sentedintheAppendixattheendofthepaper.Similardatafrom Fever(onadmission) 20/30(66) 24/31(77)
the 1980 cohort can be obtained from the original paper by Mentalchanges 22/30(73) 14/31(45)
Bouzaetal.8 VisualSx 9/30(30) 10/31(32)
BackgroundInformation Papilledema 1/9(11) 5/31(16)
Weightloss 13/23(56) 18/31(58)
Theageofour patientsvariedfrom27to72years(mean
Focalneurologicsigns 7/30(23) 5/31(16)
age, 42.9 yr). Men outnumbered women (24 male patients
E80%^;6femalesE20%^).Sixteen(53%)patientswereHispanic, None 17(57) 26(84)
8(27%)werewhite,4(13%)wereblack,and2(7%)wereAsian. Focal 7(23) 5(16)
All patients had lived in California for at least 2 months, and Non-focal 4(13)
(Generalizedweakness)
many came from endemic areas within the state. In the 1980
NA 2(7)
cohort,19(61%)patientswerewhite,10(32%)wereblack,and
Meningealirritation 11/28(39) 10/31(32)
only2(6%)patientswereHispanic.
Lumbararachnoiditis 3/30(10) 11/31(35)
PredisposingFactorsandUnderlyingDisease Abbreviations:CNS=centralnervoussystem,NA=notavailable,
Sx=symptoms.
Of the 30 patients in the present cohort, 20 (66%) had
predisposing conditions, including human immunodeficiency *The2008cohortreferstoacollectionof31patientsseenbetween
1993and2008;the1980cohortreferstotheretrospectiveanalysisof
virus/acquired immunodeficiency syndrome (HIV/AIDS) (10
31patientsseenbetween1964and1976.8
patients; 33%), diabetes mellitus (4 patients; 13%), alcohol
†For purposes of tabulation, the female transsexual patient was
abuse(3patients;10%)andpregnancy(1patient;3%).IfAsian/
reportedasamale.
black/Hispanicracewerealsoconsideredasriskfactors,then
‡In2008cohort,thefollowingconditionswereseenin1patienteach:
97%(29/30)ofthepatientsinthe2008cohortwouldbecon-
seizuredisorder(preexisting),idiopathicpulmonaryfibrosis,intravenous
sideredtohaveatleast1predisposingfactor.Inthe1980cohort,
druguser,asthma,hepatitis.
32% of patients (10/31) had predisposing factors; of these
§For 2008 cohort, information available in 12 patients; 1 outlier
individuals,8(26%)hadarecenthistoryofalcoholabuseand
(Pt#28:15yr)excluded.
3(10%)hadunderlyingdiabetesmellitus.
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Mathisenetal Medicine Volume89,Number5,September2010
clinicalsignofmeningealinvolvementcouldbeestimatedin12
TABLE2. LaboratoryDataofPatientsWithCM:2008vs. patients.Themeanintervalwas6.9monthswithamaximumof
1980Cohort 19 months (Patient 21). This compares with the 1980 cohort
wheretheintervalwaslessthan3monthsin17of24patients.
2008 1980
No.ofPts(%) No.ofPts(%) ClinicalData
Leukocytosis(WBC910,000 1/30(3) 10/27(37) Headache
cells/mm3)
Peripheraleosinophilcount 5/28(18) 13/27(48) HeadacheisacommonpresentingclinicalsymptomofCM
Q350cells/mm3* andisoftendescribedasBbilateral,intenseandthrobbing.[8In
Abnormalhemoglobin/hematocrit 12/30(40) NA the2008cohort,77%(23/30)ofpatientshadaninitialpresen-
LowserumNa+(G135mEq/dL) 18/30(60) NA tationwithheadache;thiswassimilartothe1980cohort,where
CSF the symptom was recorded in 74% (23/31) of patients. With
OPQ250mmH O 10/12(83) 7/23(30) respecttoothersignsofintracranialhypertension,55%(15/27)
2
WBC(94cells) 25/28(89) 23/30(77) of patients in the 2008 cohort presented with nausea and
Lymphocytepredominance 18/27(67) 20/22(91) vomitingonadmission,afigurethatwascomparabletothe1980
(950%lymphocytes) cohort(48%:15/31patients).Only1patient(Patient19)inthe
LowCSFglucose(e40mEq/dL) 19/27(70) 17/28(61) current study had documentation of the triad of intracranial
IncreasedTP(Q45mg/dL)† 23/27(85) 22/29(76) hypertension (headache, vomiting, and papilledema). Menin-
+CSFculture 9/28(32) 8/29(28) gismus was equally common on physical examination in both
Spherulesonwetmount None 2/29(7) groups(2008:39%;1980:32%).
Serology
+SerumELISAIgG 25/27(93) NA
+SerumELISAIgM 15/27(56) NA TABLE3. RadiologyinPatientsWithCM:2008vs.1980Cohort
+SerumCFtiterQ1:2 22/23(96) 25/30(83)
+SerumCFtiterQ1:16 20/23(87) 2008 1980
+CSFELISAIgG 15/21(71) NA No.ofPts(%) No.ofPts(%)
+CSFELISAIgM 8/22(36) NA
Chestradiograph
CSFCF 18(60) 30(97)
Normal 9/30(30) 8/30(27)
Positive 10(59) 25(83)
Abnormal 19/28(68) 22/30(73)
Negative 7(41) 5(17)
Diffusebilateralinfiltrates 9(30) 4(13)
ACNS‡ 1(3)
Mediastinal/hilarnodes 8(27) 5(17)
Notdone 11(37)
Cavity* 4(13)
NegativeCSFCFtiter 7/17‡(40) 5/30(17)
Miliarynodules 11(37) 3(10)
Abbreviations: ACNS = anticomplementary nonspecific CF titer, Focalpneumonitis 7(23) 14(47)
OP=openingpressure,TP=totalprotein,WBC=whitebloodcells.
Pleuraleffusion 3(10)
*Maximum counts/percentage of eosinophilia in an individual
Cardiomegaly 1(3)
patient: 2008: 783 cells/mm3;16%;1980:14,840cells/mm3;53%.
CThead 29/30(97) 6(19)
†CSF total protein: 2008: mean = 155.7 mg/dL (8Y453 mg/dL)
Normal 8(28) 1(17)
excluding single pt with 4932 mg/dL; 1980: mean = 165.5 mg/dL
(15Y545mg/dL). Abnormal 21(70) 5(83)
Intraventricularhemorrhage 1(17)
‡OnepatientwithACNSCFtiter.
Infarct 9(30)
Hydrocephalus 10(33) 5(83)
Basilarmeningitis 5(17)
HistoryofNon-MeningealCoccidioidomycosis Atrophy 3(10)
Background information on both patient cohorts is sum- Herniation 1(3)
marized in Table1. Meningitiswas part of the initial manifes- Notdone 1(3) 25(81)
tationofdiseasein60%(18/30)ofpatientsinthecurrentcohort MRIhead 20/30(66) NA
andin65%ofpatientsinthe1980cohort.Diagnosisofextra- Normal 1(5)
CNS coccidioidomycosis before the clinical presentation of Abnormal 19/20(95)
meningitiswassimilarinbothgroups(2008:40%;1980:35%). Infarcts 4(20)
With regard to extra-CNS disease, rates of lung involvement Hydrocephalus 6(30)
(2008:57%;1980:48%)weresimilarinbothgroups;however, Basilarmeningitis 9(45)
the 2008 cohort hadlower rates of both skin disease (10% vs. Atrophy 2(10)
42%)andboneinvolvement(7%vs.27%)comparedtothe1980 Herniation
cohort,respectively.Forthe2008cohort,pathologicalevidence Notdone 10(33)
of involvementoutsidethecentralnervoussystemistabulated Otherstudies
inTable8anddiscussedinthepathologysection. EEG
Abnormal† 2/2(100) 9/15(60)
IntervalBetweenFirstSymptom(orExposure)
Abbreviations:EEG=electroencephalogram.
andMeningitis
*1980:Twopatientswithconcomitantpulmonarytuberculosis.
Inthecurrentstudy,theintervalbetweenthefirstsymptom
†AbnormalEEG:2008:1diffuseslowing;1980:1focal.
suggestive of any form of coccidioidomycosis and the first
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Constitutional SignsandSymptoms
TABLE4. TreatmentandOutcomeinPatientsWithCM:
Constitutionalsymptomssuchasfever(2008:66%;1980:
2008vs.1980Cohort
77%)andweightloss(2008:56%;1980:53%)weresimilarin
2008 1980 bothgroups.
No.ofPts(%) No.ofPts(%)
OtherPhysicalFindings
Antifungaltherapy
At clinical presentation, coccidioidal skin lesions were
Fluconazolemonotherapy 13(43) N/A
noted in 3 patients (10%) in the 2008 cohort compared to 13
Fluconazole+IVamphotericinB* 16(53) N/A
patients(42%)inthe1980cohort.
IVAmphotericinBalone 1(3)
IVAmphotericinB+IT 29/31(94) LaboratoryData
amphotericinB
A comparison of admission laboratory data between the
IVAmphotericinB 9(30)
2008and1980cohortispresentedinTable2,anddetailedlabo-
(lipidproduct)
ratorydata(serumandCSF)fromthe2008cohortareoutlinedin
ITamphotericinB‡ 3(10) 29/31(94)
Table 6. In the present cohort, the peripheral white cell count
Itraconazole 1(3) N/A
(leukocyte count Q10,000 cells/mm3) was elevated in only 1 of
Voriconazole 6(20) N/A
30patients(3%)comparedto10of27cases(37%)fromthe1980
Neurosurgicalprocedures
cohort. Peripheral eosinophilia (for example, eosinophil count
Intraventricularreservoir 2/30(7) 15/31† Q350 cells/mm3) was less common in the current patient popu-
Ventriculostomy
lation (5/28; 18%) compared to the 1980 cohort (13/27; 48%).
VPshunt 9/30(30) 9/31(29)
Significant anemia (hemoglobin G12.0 g/dL) was equally com-
Shuntcomplications 2/7(29) 4/9(44)
moninbothstudies(2008:40%;1980:38%).
Follow-up
Survival
SerumSerology
Alive 17(57) 19(62)
Dead 12(40) 12(39) Theserumenzyme-linkedimmunoserologicassay(ELISA)
Losttofollow-up 1(3) ? testwasnotavailableinthe1970satthetimeoftheinitialstudy,
Activitiesofdailyliving(ADL)§ butwasusedforpatientsinthecurrentprotocol.Inthepresent
ADLable 14/17(82) 11(35) study, ELISA IgG was positive in 93% of patients (25/27) at
ADLunable 3/17(18) ? sometimeduringtheirclinicalillness,andtheELISAIgMwas
Working 2(7) 10(32) positivein56%(15/27).In1patient(Patient30)bothtiterswere
negativeearlyinthediseasebutsubsequentlyturnedpositive.In
Uncertain 1(3)
thepresentcohort,theserumcoccidioidalcomplementfixation
Abbreviations: ADL = activities of daily living, IV = intravenous, (CF)testwaselevatedin22of28patients(range,1:4to1:512);
IT=intrathecal,N/A:notapplicable,?=unknown.
mostofthesepatients(20/23;87%)hadtitersof1:16orgreater.
*Includes amphotericin B deoxycholate or lipid amphotericin B
preparation.
CerebrospinalFluid
†1980study:total27reservoirs;2/15patientsfreeofcomplications.
MoredetaileddataonCSFfindingsatclinicalpresentation
‡RouteofITamphotericinBadministration:2008study:lumbar:1;
reservoir: 2; 1980 study: cisternal: 11; lumbar: 17; reservoir: 21; VP fromthe2008studyarepresentedinTable6.Inpatientswhere
shunt: 5; lumbar hyperbaric: 4; lateral cervical: 2; ventriculo-jugular: an opening pressurewas recorded, 9 of 11 cases (82%) had an
3.(SomepatientshadITamphotericinBadministrationbymorethan opening pressurethat wasQ250mmH O. In the current study,
2
1route). otherCSFparametersassociatedwithCMincludeelevatedCSF
§Referstosurvivorsatlastknownfollow-up. leukocytecount(25/28;89%),lymphocytepredominance(18/27;
67%),hypoglycorrhachia(19/27;70%),andincreasedtotalpro-
tein(23/27;85%).Theseparametersweresimilartothoseseenin
NeurologicComplications the1980cohort(seeTable2).Inasubsetanalysisofthecurrent
Inthe2008cohort,73%(22/30)ofpatientspresentedwith cohort, therewas a slight trend toward polymorphonuclear pre-
mental status changes (for example, lethargy, obtundation/ dominanceinpatientswithHIV(4/10;40%)comparedwithnon-
confusion,dizziness,bizarrebehavior,anddisorientation)com- HIVpatients(4/17;24%).Approximatelyone-thirdofpatientsin
paredto45%(14/31)inthe1980cohort(seeTable1).Neuro- bothstudies(2008:32%;1980:28%)hadapositiveCSFculture
logicsignsandsymptomswerecommoninour patientcohort; forCimmitissometimeduringtheirclinicalcourse.
24of30(80%)patientspresentedwithfocal(7/30)ornonfocal
(17/30) neurologic findings; these abnormalities included gen- CSFSerology
eralizedweakness,ataxia,diplopia,focalweakness,andconfu-
Inthe2008study,theCSFELISAIgGwaspositivein11
sion (see Table 5). Patients 8 (facial weakness), 13 (pupillary
of 21 cases (52%); the CSF ELISA IgM was positive in 8 of
dilatation)and27(diplopia)hadevidenceofcranialnervedys-
22cases(36%).Inthepresentcohort,theCSFcoccidioidalCF
function.Focalfindingsinthe1980studywereseenin16%of
testwaspositivein10of17patients(58%)comparedto25of
patients (5/31). Hydrocephalus (based on computerized tomog-
30patients(83%)inthe1980study.
raphy ECT^ scan or MRI) was seen in 12 of 30 (40%) patients
inthe2008cohort;only 6casesunderwentCTscanning inthe
1980study,and 5patients(5/31;16%) haddocumentedhydro- OtherLaboratoryandClinicalStudies
cephalus.Lumbararachnoiditisultimatelydevelopedin10% of Although not recorded in the 1980 study, a significant
patients (3/30) in the 2008 cohort compared to 35% (11/31) of percentageofpatientsinthecurrentcohorthadhyponatremiaat
individuals in the 1980 study. thetimeofclinicalpresentation(18/30;60%).Thistendedtobe
255
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Mathisenetal Medicine Volume89,Number5,September2010
ClinicalCourse Respondedtofluconazolebutdiedin2006fromperforatedduodenalulcer,seeminglyunrelatedtoCM. Developedsevereheadache3dafteradmissionwithabnormalLP(elevatedOP).PtbecamecomatosedespiteIVAmbanddied1moafteradmission.Patientdied5dlaterofcerebralherniation. HadelevatedCSFpressureandremainedobtunded.Died2dlaterdespitefluconazole.Diagnosisofcoccidioidomycosisonlymphnodebiopsy. Treatedwithfluconazoleandimproved;dischargedfromhospitalandlosttofollow-up.Improvedwithshunt,fluconazole,andamphotericinB;long-termtreatmentwithfluconazole. DeterioratedfollowingfluconazoleandITamphotericinB.Laterdevelopedhydrocephalusbutdieddespiteshuntingprocedure.Subsequentlydevelopedhydrocephalusrequiringshunt.Latertreatedwithoralfluconazolebutdiedfromunclearreasonsin2005.PatientwithsuspectedCMbutsubsequentlydiscontinuedfluconazoleseveralyrlaterwithnoapparentrecurrence.TreatedsuccessfullywithIVamphotericinandfluconazole.Dischargedtonursinghomebutlaterdiedfromunclearcause.
n
PresumedsseminatioInterval 1yr NA NA NA 6wk NA NA NA 1.5yr 4wk NA
Di
e
r
DxBefoningitis Yes No No No Yes No No No Yes Yes No
yMe
x
o
C
e
d
o
n E
PhysicalExamFindings FeverLEweaknessBilateralLEedemaDisorientation Fever/lethargyDystonictonguemovementsLsupraclav(2.2cm)RLLcracklesLethargy ObtundationMeningismus FeverCachexia FeverLethargy Bizarrebehavior BizarrebehaviorRsidedweaknessUrinaryincontinence FeverConfusionBlurryvisionRsidedfacialdroop FeverFallstoRside FeverDiplopiaAtaxiaDecreasedtouchinL
z)
n
e
WithCM:2008Cohort PredisposingorUnderlyingCondition MildrenalinsufficiencyS/PAVRandpacemakerDiabetesmellitusHypertension HIV/AIDS(CD4=109):Drugabuse:Meth,MJ PreviousAIDS/HIV(CD4=273;VL400)onHAART(stavudine/Glamivudinenelfinavir) PreviousAIDS/HIV(CD4=171)onHAART(abacavir/lamivudine/efavirHistoryofmigraineAIDS/HIV(newdiagnosis)(CD4=162;VL299K) AIDS/HIV(previousdiagnosis)(CD4=17) HistoryofETOHabuse Preexistingseizuredisorder+Hypertension None HistoryofIVDU;ETOHabuseTruckdriver;RecentjailinSanJoaquinValley HIV/AIDS(CD4=24;VL330K)Substanceabuse(MJ;ETOH)+Truckdriver
groundInformationon30Patients ClinicalPresentation 72-yr-oldwhitemalewithpreviousdiagnosisofCM(1998)presentedwith2mohistoryoffever,headache,weightloss(20lb)andperiodicdisorientation.27-yr-oldwhitemalewithhistoryofdruguseandnewlydiagnosedHIV/AIDSpresentedwith3mohistoryoffever,weightloss(25lb.)andlethargy.32-yr-oldHIV+AAtranssexualfemalepresentedwith3mohistoryoffever,headacheandlethargy(historyofLOC).32-yr-oldHIV+whitemalepresentedwith2wkhistoryofheadache,N/V,andobtundation.40-yr-oldHIV+Hispanicmalewith6wkhistoryoffever,weightloss(30lb)andSOB(+pneumonitis).33-yr-oldHIV+Hispanicmalewith1wkhistoryoffever,lethargy,andN/V.53-yr-oldHispanicmalepresentedwithfever,headache,weightloss(20lbin3mo),alteredmentalstatus,andhydrocephalus.42-yr-oldAAmalepresentedwith1.5mohistoryofHAandalteredmentalstatus. 54-yr-oldAAmalewithpreviousdiagnosisofpulmonarycoxypresentedwith3mohistoryofheadache,fever,andconfusionafterfluconazolenoncompliance.44-yr-oldwhitemalewithdiagnosisofcoxypneumoniapresentedseveralwklaterwithfeverandfallingtoRside.B[50-yr-oldHIV+whitemalepresentedwith3mohistoryofheadacheanddizziness.
LE5.Back AdmissionDate 8/29/01 11/8/93 1/26/98 5/20/02 3/22/02 4/8/96 5/7/99 11/17/98 1/3/02 5/24/96 10/24/00
B
TA Pt 1 2 3 4 5 6 7 8 9 10 11
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Medicine Volume89,Number5,September2010 CoccidioidalMeningitis
PtwithHIV/AIDSwassuccessfullytreatedwithhigh-dosefluconazolebutsubsequentlylosttofollow-up.TreatedwithIVfluconazoleandamphotericinB;however,subsequentlydiedfollowingboutofARDSandCdifficilediarrhea.Treatedwithfluconazolebutdied6wklaterwithprogressiverespiratoryfailure. ImprovedfollowingfluconazoleandamphotericinB;however,developedhydrocephalusrequiringaVPshunt.PtcurrentlystableonHAARTandoralfluconazole.Respondedtofluconazoleandcurrentlystableonhigh-dose(1gQd)oralfluconazole. Stableonhighdose(1gQd)fluconazole. TreatedwithamphotericinBandfluconazolewithsubsequentrelapses.Mostrecently,developedlumbosacralarachnoiditisandiscurrentlystableonpovoriconazole.Treatedwithhigh-dosefluconazole(1600mgQd).SubsequentlyrequiredVPshuntforhydrocephalus.Currentlystableonfluconazole.Died1wkafteradmissionwithARDSandhypotension.FoundtohaveCMonpostmortemexamination.InitiallytreatedwithLamBbuthadseveralrelapsesonazoles.Subsequentlydevelopedlumbosacralarachnoiditis.Currentlystableonoralfluconazoleandposaconazole. (Continuedonnextpage)
A A A mo A A yr A wk mo
N N N 5 N N 1 N 3 19
No No No Yes No No Yes No No Yes
s
BlurryvisionAbnormalgait FeverObtundationBilateral+BabinskiLpupilreaction, FeverLung:bibasilarralesErythemanodosum FeverwithlethargyMeningismus+Skinlesions(facialnodules/pustules) FeverConfusionMeningismus Blurryvision FeverMeningismusVisualfielddeficitBilateralUEweaknes ObtundationMeningismusPapilledema Fever+Skinlesion(Leyebrow,Lear)Lung:ralesFeverLethargyMeningismus
n;
o
si
n
e
HIV/AIDS None IdiopathicpulmonaryfibrosisChronicosteoarthritisS/PBillrothIIpyloroplastyCoronaryarterydisease;hyperthyperlipidemiaHIV/AIDS(CD4=98) FactorVLeidendeficiency None Pregnancy None Diabetesmellitus2yr(cid:1) Pregnancy
3-yr-oldHIV+Hispanicmalewith4dhistoryofheadache,dizzinessandblurryvision. 9-yr-oldHispanicfemalewithpreviousdiagnosisofCM(1991)presentedagainin2000withfever,N/V,andalteredmentalstatus. 8-yr-oldwhitemalewithhistoryofpulmonaryfibrosispresentedwith1wkhistoryoffeverandrash.Foundtohavepulmonaryinfiltrates,erythemanodosum,andCM.4-yr-oldHIV+HispanicmalewithprevioushistoryofHIV/AIDS(offHAARTx2yr)presentedwith6wkoffever,headache,skinlesions,andcough.2-yr-oldwhitemalewith2mohistoryoffever,headacheassociatedwithepisodeoftransientlossofconsciousness.2-yr-oldHispanicmalewithprevioushistoryofcoxypneumonia(1999)presented6yrlaterwith5dhistoryofheadacheandblurryvision.7-yr-oldHispanicfemalepresentedwithcoxypneumoniaduringpregnancyandsubsequentlydevelopedheadache,fever,andnausea/vomitingfollowingdelivery.1-yr-oldHispanicmalepresentedwith3wkhistoryofheadache,N/V,andalteredmentalstatus(confusion). 5-yr-oldAAmalepresentedwith3wkhistoryoffever,cough,headache,andweightlossY(1020lb).0-yr-oldwhitefemaledevelopeddisseminatedcoxy(lung,bone)duringthirdtrimesterofpregnancy.19molaterpresentedwithrecurrentfeverandheadache;CMwassubsequentlydiagnosed.
6 3 6 4 5 5 3 4 4 3
5/4/99 7/29/00 9/6/00 11/9/06 5/12/98 7/6/05 6/19/06 3/12/04 4/22/02 4/1/04
2 3 4 5 6 7 8 9 0 1
1 1 1 1 1 1 1 1 2 2
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Mathisenetal Medicine Volume89,Number5,September2010
d
e
ClinicalCourse Symptomsresolvedandpatientcurrentlystableonfluconazole. Diagnosedwith‘‘carcinomatousmeningitis’’andstartedoncorticosteroidsandITmethotrexate.SubsequentlydiedandwasfoundtohaveCM. Ptrespondedtovoriconazoleandcurrentlyremainsstableonthatdrug.SubsequentlydevelopedhydrocephalusandrequiredVPshunt.Pthassevereneurologicimpairmentsbutthenstableonoralvoriconazole. TreatedwithIVfluconazolefollowingdiagnosisofCM.Pthadrecurrencebutiscurrentlystableonvoriconazole.PatientsubsequentlypresentedwithasepticmeningitisanddiagnosisofCM.PatienttreatedwithIVfluconazoleandsuccessfullytransitionedtooralfluconazole.Subsequentlyreadmittedwithseizureandclinicalrelapse;OmmayareservoirplacedandptreceivedITamphotericinB.Ptdevelopedlumbosacralarachnoiditis.Mostrecentlytreatwithhigh-dose(1200mgQd)oralfluconazole.
n
PresumedsseminatioInterval 8mo NA 8mo 5mo NA NA 15yr
Di
e
r
DxBefoningitis Yes No Yes Yes No No Yes
yMe
x
o
C
s h
n c
PhysicalExamFindings FeverMeningismusBlurryvisionMultipleskinulceratioAtaxia MeningismusConfusionBizarrebehaviorAnterogradeamnesiaLUEweakness MeningismusConfusion/alteredspeeGeneralizedweaknessFeverSomnolenceConfusionGeneralizedweaknessUnabletowalkLankleskinlesionFeverMeningismusBlurryvisionPhotophobiaDrowsinessDiplopia FeverRLEweakness
PredisposingorUnderlyingCondition Diabetes None None Diabetesmellitus None HIV/AIDS;(CD4=182)Primarysyphilis HIV/AIDS(CD4=34)Coxypneumonia(1994)
ntinued) ClinicalPresentation 38-yr-oldHispanicmalewithdiabetesmellituspresentedwithdisseminatedcoxy(lung,skin)andtreatedwithfluconazole.8molaterpresentedwithfever,HA,weightloss(10lb).42-yr-oldAAmalepresentedwithalteredmentalstatusandpulmonaryinfiltrates.DiagnosedwithcarcinomatousmeningitisB[butpatientdiedshortlyafterwardandwasfoundtohaveCMatpostmortemexamination.22-yr-oldHispanicmalewithhistoryofpulmonarycoxypresented9molaterwithHA,andconfusion.44-yr-oldHispanicmalewithdisseminatedcoxy(pneumonia,prostate)presented2yrlater(afterstoppingfluconazole)withY12moheadache,weightloss(50lb),seizures,andalteredmentalstatus.25-yr-oldHispanicfemalepresentedYwith12wkhistoryoffever,headache,nausea/vomiting,photophobia,andweightloss(8lb).37-yr-oldHIV+Hispanicmalewithhistoryofcoxypneumoniapresentedwithheadache,alteredmentalstatus,andcough. 33-yr-oldHIV+Hispanicmalewithremotehistoryofpulmonarycoxy(1994)presentedwithfever,headache,nausea/vomiting,anddizziness.
o n
E5.(C dmissioDate 4/5/08 1/4/01 1/25/07 4/13/07 6/28/04 9/7/07 9/29/06
L A
B
TA Pt 22 23 24 25 26 27 28
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Medicine Volume89,Number5,September2010 CoccidioidalMeningitis
ol, apoorprognosticsign:11ofthesepatientsultimatelydied.Liver
n chemistries were not reported in the 1980 cohort; however,
DiagnosedwithCMandsubsequentlytreatedwithpofluconazole.Thepatientremainsstableonpofluconazole(400mgpoQd).CMdiagnosed2molaterwhenCimmitisgrewfromCSFspecimen.PatientinitiallyrespondedtoIVamphotericinBandpofluconazole;however,developedhydrocephalusandrequiredVPshunt.Died1molaterfromshuntmalfunctionandcerebralherniation. osis,Dx=diagnosis,ETOH=ethamity,R=right,S/P=statuspost. TahtpRChpaeaaehpdrbfderloa1eosiRIrb9oxntm3na8il,Rmtdo0eohairdaaeognmctldide2ioonacli0ghlydot0iolSahgci8artvetratfie,ucat2rhfnodtp0rifhdhor0uhieiodmen8nrsgctCos,ttsfhtiocuoewchtdnhce2iyeitts.0dhet0icsironta8asisddtceahiiostonehcgiol2nrsiarkntpctiihnochaeahrseltoewcprdsutertesrertresa(eae1inraln:eetb1tdan0cstoto0iiuonrm)dmnTypw.aaaUla(br3seinlne0dlni%1k7ion9e.)t
omycextre ofufs2e8bpilaattieernatlsi(n6fi8l%tra)t,edse(m30o%ns)t,ramtiendgiafisntidnianlgasdtehnaotpinacthluyd(e2d7d%if)-,
oidper miliary nodules (37%), and focal pneumonitis (23%). In the
No NA CoccidiUE=up 1rpa9adt8iie0ongtrcsaopihnhostr,ht,ew21it29h8a0ofscpo3eh0cotrrputam(tcioesnmimtspial(ar7erd3t%oto)th2ehpacadutirearenbntnstoisrntmutdahlye.c2Fh0oe0us8rt
y=ve, cohort) had evidence of pulmonary cavities; 2 of these indivi-
oxati dualshadconcurrentpulmonarytuberculosis,afindingnotseen
cg
s,ne inthe2008study.
No No hocyteneg= BoneInvolvement
n LE T-celllympotavailable, csbeooehnnoerBost;cnoahnanoeswrosweuuvertervinere,eypasertarlfwdeoiaerosrmgetre1andppohiatnt(ir1seo3enuetoti(TfnPae3abl0tylieepnpa7tet)ir2.ef1noIn)trsmht(hae4edd3%2ai0nl)y0;tt8ahicteclloee2has0soit0ort8n2,
FeverMeningismus/confusioGeneralizedweaknessBilateralreflexesinj(negBabinski)FeverMeningismus placement,CD4=CD4MJ=marijuana,NA=n vpsdsmBiiooaesgotmsltnivneteeionelnfiyomnttcmsswaedtynr(nioaPetttnht.lae(ietIt4doi,inesspn[ntwteathosotiienitnmeh2scn1p2ylt9ue8,es8cd)l2ii.0io5tfinif)scgc,os1uhhfh7pooootcwwraaptkee,lavdebtleiyoetarht,nnrieactetshatselsdeu(ois4rrdeif7vome%mnnyaosu)sitnlatwahdinppaeedvlprreiee(vnau1egmrp1rttoceasplrbikiaegnretnaiiceclcsonaomiltnnolsy--)-f
ree, Neuroradiology
s cvalvehetamin agnosCisTabnrdaimnasncaagnesmheanvteobfeCcoMm.eInanthiem2p0o0rt8anctothooorlt,in21thoefd2i9-
mellituC =aortiethamp pfiantdieinngtsso(7f2b%as)ilahradmeanninagbintiosr(m1a7l%C),Tcebrreabirnalsicnafnarcthta(t31in%c)lu,danedd
DiabetesHepatitis None an,AVRMeth=m htsicymadner;oo1cfeotphfhetah1leu9ss8e0(p3sa4ttu%iedny).t,saChnTaddowananlsyina6tnrpaaevtmeienentrrtgsiciunungladrteehrcwehmennootlroarhgCaygTeab,tratanhidne
c all 6 eventually were found to have hydrocephalus. Other ra-
merimity, diologicstudiesperformedinthe1980cohort,includingcerebral
36-yr-oldHispanicmalewithpulmonarymass(+Cimmitisspherules)presentedwithfever,headache,nausea/vomiting,andmildconfusion.49-yr-oldAsianfemalepresentingwithfever,cough(pneumonia),headache,andconfusion. Seeprevioustables.AA=AfricanAusdruguse,L=left,LE=lowerextre awupBdaippcnnnhnsauaeeegtdtrnoariisddiloereeicosmennsiMenegdltittiraexonssrinRetlnattci[ebwemtI(slparnPushbaMteo,sdaciloarinntaepfvRciigondneuneklIrunnfnle;mbyatmitpudhnsraaameec(ebsgbid2rt1inonowlw0(8pasioe2/ena,raarn3r0nnecsmmc0a2%stdrnen1eaaeappoy)nl,wlnn.ahtcMiofi2eMtaaenMirf8nvleRgeoR)dntaoRihgIitfitIf.liinseIoransoa;gubbsppf(s6nplrta3hteha6dith1iyniie%nfene,%atonolcl)rrts)uthauc,sthicmdhernahaofrienvrboyercto,1eenanhdcmmo9rtuiercdon8scaasi2tcpl0loituhyie0nuididecnp0ddd1eoaeh28oeyhaorw0meboclfqd0ruoaryoaue82tssfchivib0nohcno(eiu3onsearlhstiot0lhdsa.cpawp%oi;dafvrOerauani)td3as-f-l.,,
7/1/06 6/6/96 breviations:=intraveno gMeaelnbIininogtpheseiae1ls9Bd8oi0onpceosahytotrimtietwofaesxnpoltoerdattohraytc2rapnaitoietonmtsyhtaodrmuleenoinu-t
AbDU tumor. Although meningeal involvement was discovered post-
9 0 V mortem in 2 patients (Patients 20, 23), none of the patients in
2 3 I
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Mathisenetal Medicine Volume89,Number5,September2010
TABLE6. LaboratoryDatafor30PatientsWithCM:2008Cohort
Absolute
WBC Eosinophil SerumNa SerumELISA SerumCF LPOP/CP CSFWBC
Pt ((cid:1)103/uL) Count(cells/uL) Hb/Hct (mEq/dL) (IgM/IgG) Titer (mmH O) (cells/mm3)Diff(%)
2
1 10.9 109 13.9/41 131 Neg/Pos 1:4,then1:64 NR ND
2 3.9 ND 9.3/27.5 126 Pos/Pos 1:128 300 1(100P)
3 7 0 10.7/32 129 ND ND NR 128(7L;91P;2M)
4 10.3 0 11.9/34.1 126 Neg/Neg ND 500 793(18L;79P)
5 7.7 462 5.9/17.5 142 Neg/Pos 1:256 NR 4(100L)
6 5.3 0 11.0/34 127 ND ND NR 145(47L;49P)
7 6.5 390 13.2/38.3 132 Pos/Pos 1:512(5/20) NR 33(78L;4P;18M)
8 7.1 213 14.6/42.5 133 Neg/Pos 1:32(10/28/98) 420 944(54L;43P)
9 5.4 162 12.9/39.2 125 Neg/Pos 1:128 NR 290(52L;6P;5M;37U)
10 10.6 191 16.4/48.4 139 Pos/Pos 1:8 NR 7(98L;2M)
11 7.2 65 12.1/33.7 130 Neg/Pos 1:4 350 374(40L;59P;1M)
12 5.8 116 13.6/40.6 135 Neg/Pos ND NR 1100(83L;15P;2M)
13 9.5 0 7.6/25 134 Pos/Pos Neg NR 7(65L;35M)
14 9 270 10.5/32 132 Pos/Pos 1:16 NR 63(100L)
15 4.7 423 9.9/28.1 126 Pos/Pos 1:16 NR 40(83L;13E;4M)
16 9 126 15.7/46.4 140 Neg/Pos 1:256 NR 271(84L;14P;1E)
17 4.4 62 15.3/49.8 144 Neg/Pos 1:258(10/14/04) NR 270(91L;3P;6M)
18 7.9 47 11.1/33.1 140 Pos/Pos 1:32 NR 186(42L;57P;1M)
19 8.3 91 13.4/37.7 126 Pos/Pos 1:64 NR 840DiffNA
20 14.9 298 14.3/42.7 117 Pos/Pos 1:16 NR ND
21 10 20 14.5/41.4 135 Neg/Pos 1:32 280 144(35L;57P;1E;7M)
22 10.4 333 14.6/43.5 125 Pos/Pos 1:32 290 378(21L;60P;15M)
23 5 ND 13/40 136 ND ND 150 460(92L;8P)
24 12 120 15.21/46 140 Pos/Pos 1:512 NR 569(98L;1P;1E)
25 6.4 403 13.4/38.7 134 Neg/Pos ACNS NR 4(97L;3P)
26 6.2 744 12.9/40 145 Pos/Pos 1:16 200 700(92L;8M)
27 8.7 783 11.1/31.6 132 Pos/Pos 91:512 NR 8(95L;5M)
28 4.2 168 12.5/36.7 146 Neg/Pos 1:32 220 240(61L;1P;3E;34M)
29 8.9 71 13.5/39.8 130 Pos/Pos 1:16 NR 47(90L;4P;3M)
30 11.9 0 44/14.7 130 Neg/Neg(Later+/+) G1:2 380 580(65L;10P;16E;9M)
Abbreviations: See previous tables. BAL = bronchoalveolar lavage, CP = closing pressure, CRAG = cryptococcal antigen, E = eosinphils,
Hb/Hct = hemoglobin/hematocrit, IDCF = immunodiffusion complement fixation, Glu = glucose; L = lymphocytes, M = monocytes, NA =
notavailable,ND=notdone,NR=notrecorded,OP=openingpressure,P=polymorphonuclearleukocytes,Pos=positive,RBC=redblood
cells,TP=totalprotein,U=unidentified,probablyplasmacells.
the 2008 cohort had a diagnosis of CM made by premorbid 23) had meningeal involvement; Patient 23 had parenchymal
meningealbiopsy. involvementofthelumbarspinalcordinadditiontomeningeal
findings.
Pathology
We compared extra-CNS coccidioidal involvement in the Treatment
2008 cohort with that in the 1980 cohort (Table 8). In both Antifungal therapy in the 2008 cohort is compared to
groups, the respiratory tract was the most common site for in- that in the 1980 cohort in Table 4; more detailed information
volvement (2008: 17 patients; 1980: 15 patients). Skin in- aboutthe2008cohortisoutlinedinTable9.Inthe2008cohort,a
volvementwasthenextmostfrequentextra-CNSsite,although total of 29 patients received fluconazole therapy; 10 of these
itwasmorecommoninthe1980cohort(13patients)thaninthe patients were treated with fluconazole monotherapy, and 16
2008 cohort (5 patients). In the current study, 7 patients had patients received a combination of fluconazole and intravenous
either biopsy or zautopsy specimens sent for pathological ex- amphotericin B. Of the patients receiving combination azole/
amination,includinglungbiopsy(2patients),skin(3patients), amphotericinBtherapy,8patients(Patients5,7,10,11,13,15,20,
lymphnode(2patients),andprostate(1patient).Autopsieswere 21)hadpolyeneandazoletherapystartedconcurrentlyorwithin
performedin3patientsinthe2008cohort,andalldemonstrated several days of each other. In this group, various forms of
multipleorganinvolvement.Allautopsypatients(Patients4,20, amphotericinBwereused,including6patients(Patients2,8,10,
260
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