Cryptococcosis after renal transplantation: Report of ten cases

Gerhard P. J. Schroter, ~I.D., Donald R. Temple, .M.D., Bo S. Husberg, M.D., Richard Weil, III, M.D., and Thomas E. Starzt, M.D., Ph.D., Dcm'er, Colo.

Tm cases of CI")Ploco((osis hat'e hem identified ill a 1; ;ear expr'lifllce u'ith more than 650 rmaltrall.-,plalltJ. Eight paticilts had 71I!'11illgitiJ, 0111' patil'llt had a cerebral gJ'allllloma, alld ill olle patimt Ihl! infalioll appeared to be limited to flU' lungs. The (t'lItrallll.'nJollS 5)'stCI11 illfection often /1/G5queradl!d as brain tumar and was not suspected illitiall),. The most us/fill diagllostic test ;cas cerebrospinal fluid examination including India illk preparation. f'ariollS thn-apeutic regimens u'ith ol11phOli/icin B and '-jluorocytosille u.'ere effective ill suppressi11g the infection. A combil/atioll of low doses of amphotericin B, not affecting kidneyfunction, with 5-jlUOTOcyto.,ine Jor at least J 1I10nths u'as associated v.'ith remissioll of disease in five patil!lI1s "J.·ho still are alive, including three patifllts u'ithout recurre11ce for longer than one yar. Five deaths J weeks to 4 Jears after the bCgi1illillg of treatllll'llt were not due to CT)'P!ococcosis; death resulted from vascular disease and septicemia ill three of the four patief/Is with knou'n causes of death. Central/tel'Jous S)stem cl)·pto(occosis, with the exception of the Tare cerebral granuloma, is associatcd ".L'ith little illftammation. If cad)' death from increased intracranial pressure or cerebral edema is prevented, prolollged thera/')' with amphotericin Band 5-jluorocJtosillc ma)' be expected to colltrolthe infectioll, eren in immunosuppressed patients. .

From the Departme1lts of Pediatrics al!d Surgery. Unil.'mity of Colorado Medical Cn;:t'T, and tht 11et/ran's Admil1;"'lration Hospital, Drlll'tlr, Colo.

AT THE University of Colorado ~fedical Center and the Denver Veteran's Administration Hospital, more than 650 kidney transplants haye been done from 1962 through 1974. Prednisone and azathioprine ha\'e been the main drugs used for immunosuppression, al­though initially prednisone was reserved for rejection crises. AJ:'!tilymphocytic globulin was added in 1966, and cyclophosphamide has been substituted for azathioprine in some patients since 1971.. Rejection episodes have been treated by temporary increase~ of

the daily prednisone dose, usually to 200 mg. follo\\'ed by 10 to 20 mg. daily reductions and/or b}' imravenous infusions of 1 Gm .. of methylprednis()lone .. In addition, some rejection episodes have been treated by graft irradiation (150 r x 3) or by actinomycin D .. 37

Supported by research grants from the "eterans Administra .. tion; by grants 1'\OS. AI ... nl .. Oi'898 and .-\~I .. Oiii2 from the National Institute, of Health: b, grants Nos. RR·00051 and RR .. 000G9 from the wnerdl Clinical ResealCh C"nters Program of the Di,i,ion of R~seaHh Resources. :\ational Imlitules of Health.

Prt"senh.:d ~t Ihe Fir~t Annual :\It .. ~ting of the Ameritan Socic!)· of Trans pI am Surgeon •. Chicago. III .. ~13) 23. I !J75.

Reprinl re<jut'sl>: G. P. J. Schroter. ~I.D .. Deportment of Surger),. P. O. Box C .. 3l15. L·ni\,er.il) of Colorado ~It'dical Center, 4200 E. :-';il1th .\\e .. Den'· .. r, Colo. S02:?0.

268 SURGERY .\tarch,1976

.... '.' ~ .. :", .'"

CASE MATERIAL

During the past 13 years, including the first 2 months of 1975, ten cryptococcal infections have been identified and treated in eight men and one woman (B. ~.), ages 2i to 51 years, and in one 12-year-old girl (C. S .. ) (Table I). Three of these patients (E. T.,

. R. 1\.., C. S.) had received more than one renal trans­plant before the diagnosis of cryptococcosis.

In eight patients the infection appeared after long-term immunosuppression during the third to tenth year after transplanration. In the other u\·o patients the diagnosis was made during the fourth (B .. K) and tenth months U. H.) after transplantation.

Immunosuppression. At the time of diagnosis of

Vol. 79, No. J. pp. 268 .. 277

""'II''':~ i9 .\·!;t!~"(r J

ill fectioi1. all patieJlts were receiving maiJlten:1Ilce prc:dnisone and azathioprine. Olle patient (B. X.) still \,as receivillg alltilymphocytic globulin injectiolls. In three patients (E. T., W. S., C. S.). a temporary increase of the daily prednisone dose preceded exacerbation of symptoms. In another patient (L. 0.), the onset of symptor:\s fullowed 3 months of "'eeldy infusions of meth}'lprednisolone (I Gm.) in addition to mainte­nance immunosuppression.

Organ involvement. The central nen'ous system was affected in nine parients; there was meningitis in eight and a brain granuloma in one patient (Table II). The lungs were simultaneously involved in thl'ee patients (E. T., L. 0., J. H.); Cryptococci were found in the urine of two of the three parients (M. La., C. S.) whose urines were cultured for fungi. The infection appeared to be confilled to the lungs in one patienr (~1. Li.). Fever was detected in only three patients (B. ~., W. S.,

C. S.). Pulmollary CI}ptococcosis. The pulmonary infection

was recognized as indistinct nodular infiltrates in three patients (E. T., J. B., M. Li.), two of whom had positive sputum cultures (E. T.. ~1. Li.). The infiltrates were detected on chest x-rays taken for suspected pulmo­nary embolus ill one patient (1\1. Li.) and in the other two patients on routine films taken 2 months before and one month after the detection of cryptococcal meningitis.

Ct'lllralllervOllJ sJStem CI)"ptococcosis. The most common symptom of central nervous system infection was headache, "hich occulTed in eight of the nine patients. The headaches antedated additional symptoms by weeks or months in four patient!> (E. T., W. S., C. S., J. H.). Other manifestations included memory loss, disorientation, confusion, dyscalculia, dysphasia, mus­cle weakness, unsteadiness, tremor, urinary inconti­nence, behavioral and emotional disturbances. Focal neurological signs included hemiparesis, truncal and limb ataxia. nystagmus. intermittent diplopia, dysar­thria, and right-left disorientation. Four patients (B. ::'\ .. L 0 .. W. S., J. H.) had seizures. Bizarre beha\'ior, hallucinations. and disorientation were so prominent in one p;)tient (R. K.) that he \,'as thought to have a steIoic\·induced ps~chosis hefore the correct diagnosis was made about 4 weeks after the onset of symptoms. Another patient (L. 0.) \\as evaluated for two episodes of transient hemiparesis or p:tresthesias and aphasia and had abnormal ct"rt'brospinal fluid;) months before tlat' ,'iagnosis \,'as made.

Papilledema was Hoted in four patients (B. X., E. T., W. S., J. 1-1.). Acute neurological deterioration and

C~pl(/(()((Osi.\ nJtn ulla/transplalltation 269

Table I

11l1~r.·(l' bfl-a'un tramplontalion

Case .-Igt and diagrwlis of So. Patifllt (yr.) s .. x Donor inji-clion

1 J. H. 27 ~! Sister 10 mo. 2 B. ~. 29 F Sister 3Vt mo. 3 R. K. 48 M Son 2 yr., 6 mo.

Cadaver 1 yr., S mo. Cadaver 1 yr., 3 mo.

4 ~L La. 42 M Unrelated 6 yr., 9 mo. living

5 L. O. 33 M Brother 4 yr. 6 W.S. 34 1\1 COllsin 9 yr., 7 mo. 7 E. T. 43 ~f Brother 5 yr.

Cada\er 8 mo. S C. S. 12 F Mother 4 yr.

Cada\'er 7 mo. 9 r.. W. 49 M Cadaver 5 yr., 5 mo.

10 M. Li. 51 M Cadaver 3 yr., 7 mo.

appearance of papilledema wel'e observed in two patients ,\"ith chronic headaches (E. T., W. S.) after temporary increases of corticosteroid for rejection episodes.

Two other patients (J. H., B. N.) developed progres­sively increased intracranial pressure; in one patient (B. ::'\.) partial loss of vision was due to thrombosis of branches ofthe retinal veins, in the other patient (J. H.) ventriculoperitoneal shunt was required and \\'as complicated by cardiorespiratory anest.

Laboratory studies. Skull x-rays showed an erosion of the sella turcica of one patient (E. T.). a 7 111m. shift of the pineal gland to the right in another patient (E.

\\'.). and c2.lcifzcations in the area of the choroid plexus in a third patient (B. X.).

Eight patients had brain scans done \,·ith technitium pertechnetate. In one patient (Eo W.), a space-oc­cupying le;ion with increased isotope uptake and cold center ,,'as found in the left frontal lobe. Brain scans of other patients showed a diffuse increase of isotope uptake O\'er the brain surface (B. K) and a localilc:d i!lCl"ea;;e of isotope upt:lke over the left occipital lobe \ R. K.).

Electroencephalograms of all nine patients with central nen'ous system cryptococcosis sho\\'ed some slO\\ing and di,organizarion of electrical acthity \,ith focal predominance in fOllr and paroxysmal activity in two p:uienb.

CerdJra! al1giograms \,ere done 011 six patients. Tht.' angil.graIn (onfirmed the one focal lesion detected by scali (E. \\'.j. Angiographic abnormalities in other patients here dcla~'ecl filling of the left rhobndic win

~~tt',~ :::~~::-.-:~.~.

27(} SchruIl" l'1 al. Sur,. ,', ,'I,f/Jrch. 19;~

Table 11. Organ im·ohemellt. duration of s~ mptoms, outcome of treatment, and major complications in ten renal tr.lIlSplant recipients with cnptococcosis

Duratiun o{'ymprulI/s Cast 640'-1' di'l;nosis .\'0. Paliml Orgal/ i1l1:0""'1/11'111 and trfalml'II!

J. H. ~Ieninges, lungs 6 ,,-I;..

2 B. ~. ~Ieninges 7 wk.

3 R. K. Meninges -I wk.

-l ~1. La. ~Ieninges 3 ,,'k.

5 L.O. !lleninges. :> mo. mediastinal lymph nodes

6 \\'.S. Meninges 2 mo.

i E. T. Meninges. lungs Sel'eral mo.

8 C.S. :\Ieninges Sel'eral mo.

9 E.\\'. Cerebral 6 wk. granuloma

10 !II. Li. Lungs Se\eral mo.

and adjacent sagittal sinus (W. S.) and irregularities in an erial outlines (;\1. L.).

Two patients were subjected to pneumoencephalog­r.:lphy. In one patient studied \'ia lumbar puncture, a mild dilatation of the fourth \'entricle \,'as seen (B. ~ .). The other patient was studied by \'entricular puncture \\'ith the finding of mild dilatation of the lateral \'entricles and obstruction of the basilar cystern (j. H.).

Lumbar punctures were performed in all but one patient (E. \V.) (Table III). The cerebrospinal fluid pressure usually was increased. and most patients \dlh c~ptococcal meningitis had a mild lymphocytic pleocytosis. elevated protein, and decreased glucose concentration. A borderline protein concentration of 4~ mg. per 100 ml. (R. K.) or a decreased glucose concentration of 30 mg. per 100' ml. (B. :\.) \,ere the only abnormalities founel in t,,'o patients with c~p­tococcal meningitis. CrJPforo(cuJ lll'oJonl/GI/S was isolated from cultures of the cerebrospinal fluid of eight patients \,·ith meningitis. India ink preparations dem­onstrated encapsulated yeasts in all six patients with meningitis in whom this cerebrospinal fluid examina-

Ca 11.11' of deatli or Oulcollll' of Irralmpnl major complications

Died afler 2 yr. of Unknown. Renal and congesli\e , treatment. heart failure

Died 1 yr., i mo. after Posloperati\'e pulmonary emboli, treatment Staphylococcal septicemia.

Died after 3 "k. of Pulmonary emboli. pneumonia trealment. and Klebsiella septicemia.

Died after 5 mo. of !lIesenleric I'ein thrombosis. treatment. pulmonary emh:>Ii, ..

pneumonIa, perItonitis. bacteroides and klebsiella septicemia

Died 3 yr., 9 mo. after M)'ocardial infarction trealment.

Alive> 1 ~r. after Renal failure due to chronic treatment. rejection. Pneumonitis,

pneumocystis carinii? Alive> 1 yr. afler Recurrent pulmonary embolus.

treatment. Alive 2 mo. after Renal failure due to chronic

treatment. rejection. l"ocardia asteroides abscess.

Alive, on treatment Cardiac an·h>thmia. for2mo.

Alive> 1 }T. after Recurrent pulmonary embolus. treatment.

tion was done. The infection was identified by needle biopsy in the patient wilh a granuloma of the left frontal lobe (E. \V.) (Fig. i), who was not subjected to

lumbar puncture. Cerebrospinal fluid protein also "as eleyated in the patient I,·jlh cr}ptococcosis limited to the lungs (\1. Li.).

Results of therapy. The cryptococcal infections \\-ere treated \,'ith amphotericin Band 5-fiuorocytosine alone or in simultaneous or sequential combination (Table IV). Immunosuppression was continued as considered necessary to avoid rejection of the graft. The duration of treatment was variable.

The first two patients U. H., B. No) recei\'ed standard doses of intrayenous amphotericin B and additional amphotericin B intrathecally: J. H. received a total

'dose of6.47 Gm. intravenously oyer a period of2 years and 5.25 mg. intrathecally gi\'en during the first 2 months of treatment. The cerebrospinal fluid became normal during the fifth month of treatment. Cryp· tococci were found in India ink preparations and in cultures of cerebrospinal fluid onl)' during the firsl week of treatment and on one isolated occasion one year and 7 months after the beginning of treatment.

j

I ~'

Sur;:,'", .fflrrh, 19;6

'1.'11 rt.>nal

. uT

iO lls

'aryemboli. icemia. Cleumonia cemia. ;)bo~is.

lids. h~iella

·hronic ius, i? y embolus.

hronic asteroides

\. embolus.

by needle f the left ~jected to , aI!'o \,'as :imited to

Ions ,,'ere

ocytosine nbination inued as the graft.

standard ldditional d a total of2 years 1e fir~t 2 .:i became iH. Cryp-1S and in

I he first ,~ion one 'eatment.

•

1 ~ r

,'.,/Il"'! 79 SUlflb." J

CT)'PIU(u((osis aJler rmal Ira 1/5plalltation 2.1

T ble III Initial cerebro'pinal Auid findings in renal transplant recipients with CTvptococcosis a ,

Opmil/glcll),il1g I nit .. blood ails Cast pr .. ,;urt Red blood (fils

.\'n . Patiellt (11111/. Hi)) (pa 1/1111.3) (per mm.')

J. H. 1501- 185 247 158* 34*

2 B. N. 700/480 0 4 3 R, K. 300!200 0 2 4 M. La, -/- 0 -9

I-

S L.O. 280/- 14 29 6 \V.S. 400/340 3 SO 7 E.T. 240'170 0 140 8 C.S. 190/- 0 14 9 E. W. Not done. positive needle biopsy of brain

10 M. Li. -/- 0 0

-\'enlril-ulaT fluid.

t:\O = nol done.

\"hich was 3 months after temporary discontinuation of treatment. The major complication of the meningitis was increased intracranial pressure with signs of brain stem compression and diabetes insipidus. Twelye dap after drainage of "elltricubr fluid through a Rickham reservoir. a ventriculoperitoneal shunt \,·ith a low pressure Holter "ah'e was created, but it had to be removed 3Y2 months later because of Staph),lococcus

rpidermidis infection. One month later a new ,'en­triculoperitoneal shunt was implanted because of persistent increased illtracranial pressure which had resulted in cardiorespiratory arrest. The new shunt appeared to function for the rest of t he patient's life.' Severe low back pain and persistently high spinal fluid protein concentration in comparison to "entricular fluid suggested that the illtrathecal administration of amphotericin B might haye caused arachnoiditis. The high doses of intr.l\'enOHs amphotericin B ,,'ere followed by renal failure 11'2 years after the beginning of treatment. after '5 Gm. had been g1\'en. Hemodialysis became necessary one month later. The patient died 2 years after the detection of cryptococ­cosis and 2 years and 10 rr:onths after transplantation. An autopsy was not performed, bur. renal failure with congestive heart failure \\'as the clinical cause of death, I

Additional problems before he died included un­explained fe\'er. malnutrition. \'omiting, diarrhea. and intermittent gastrointestinal hemorrhage.

B. N. recei\'ed 1 Cm. of amphotericin B intra,'en­ously and 17.5 mg. imrathecally oyer a period of i weeks. The India ink preparations of cerebrospinal fluid consistently demomtrated Cryptococci for 2 months but the organi,m could be isolated in culture

P.\lS Lyf/ph Prutein Glucose India ink (per min, 3) (pa ",m,3) (mg.ldl) (mg.ldl) pTt})aratiun Cu/tur'

105 145 32 55 + + 15* 18* 15* 105* ~ot +* 0 4 3!l 30 + + 0 2 42 55 + +

23 49 145 44 ~O + i) 29 74 20 NO +

10 70 83 6 + + 7 133 60 29 + + 3 11 16 51 + +

0 0 86 83 Nega- !\ega· tive ti'·e

only during the first 3 weeks oftreatment. Cerebrospi­nal fluid findings became normal 5 months after treatment. Initially her condition deteriorated, ,,·ith signs of increased intracranial pressure, but she gradually improved after amphotericin B was discon­tinued and replaced by 5-fluorocytosine (4 Gm. per day). which she continued to take for 5 months. She remained asymptomatic until her death from staphylococcal septicemia shortly after total hip ar­throplasty for steroid arthropathy of the right hip .. -\t

the time of death she also had chronic osteomyelitis. acute bronchopneumonia, acute purulent bacterial meningitis and cerebritis, and pulmonary emboli. She died 2 years and 4 months after transplantation. OiCe

year and i months after treatment for cryptococcal meningitis. Autopsy revealed residual cryptococcal organisms in the basal ganglia.

I n eight other patients subsequently treated for cryptococcosis. amphotericin B was used intravenously in smaller doses. starting with one to 3 mg. on the first day followed by increases of one to 2 mg, per day until a maimenance dose of 10 to 20 mg. per day \,as reached. After evidence of impro"ement, usually at the time \,'hen the maintenance dose was reached, it \,'as administered only every other day or less frequently. The total dose of amphotericin B was 385 to 8,10 mg. for fi'-e patients effectively treated with this regimer., No significant deterioration of renal function \,'as seell wit h these 10'" doses.

One patient (L. 0.) was treated cffecth'ely with S-IO mg. of amphotericin B alone during 4 months. He sub~eqllently remained asymptomatic until death fro:Tl recurrent myocardial infarction 7* years after trans·

2;2 Stl r;~lt"- f'( al.

-o~ ~~

C", ... ()

io

8 t'j ¥

o v O. 0 0-'

-.J !

,~

eo ';

\..'

-

Surg. '! .\Iarch. 1976

, ~ '00-) <-A

, :>,l})

'0

, ':J

~~ ;;~ '~9

:3

Fig. 1. ~cedle biopsy of the cerebral granuloma of Patient 9 (E. W,J sho',ing the yeasts s[2i ned by methenamine silver. (Original magnification. x280,)

plantation or 3 years and 2 months after treatment. Ho\\e\'er. the protein concentration of his cerebrospi­nal fluid remained elevated and at autopsy residual cryptococcal meningitis and infected mediastinal lymph nodes were found.

Seven patients also received 5-fluoroqtosine with the amphotericin B. 'The usual dose was 150 mg. per kilogram daily divided into four oral doses. Three patients (W. S .• C. S .• E, W.) also taking azathioprine. including two patients with impaired renal function (W. S .. C. S,). developed reversible leukopenia neces­sitating reduction or discontinuation of the 5-Auorocytosine and the azathioprine. Two patients complained of loss of appetite and had diarrhea \"hile taking full doses of 5-fluoroc}tosine.

The cell: ral nervous system infection of one patient (~1. La.) cleared under treatment with 5-AuorocYlOsine alone. but 2 months afta the beginning of treatment persistent urinary excretion of cryptococci. still sensi­ti"e to 5-A lIorocytosine. subsided onl} after the aclcli-

tion of small doses ( 15 mg, per day) of am photericin B. This patient died after 5 months of treatment. 7 years and 2 nlOnths after transplantation, from mesenteric vein thrombo:;is. bowel gangrene. septicemia. and pulmonary emboli. ~o residual cryptococcal illfection was found at autopsy.

One patient (R. K.) died 3 weeks after the beginning of 5-Auoroc} tosine treatment and one week after addition of amphotericin B, one year and 4 months after his third, transpbnr. His death was caused by massive pulrllonar} embc,li and infection. but residual cryptococcal meningitis sti!! \,'as present at autopsy.

The five patients treated most recently-four I"ith central nenOllS system infection (E_ T_. \\'. So. C. S,. E. \\'.) a nd one with pulmonary cr~ prococcosis (\1.

Li.)-all were treated from the beginning I\'ith a combination of amphC1teriLin Band 5-flllorocytosine in the doses olltlincd for a period of 12 weeks. In all patients the infection responded promptly to (rea't­ment. Threc patielJts (E. T. W_ S .• M_ Li,) h:ne

, 1

] J

J'Q[ump i9 Sumo,., J

Table IV. T re::

Cau .vo_ PrJi"l!

J. H_

2 B. ~.

3 R_ K_

4 ~r. La.

5 L.O_ 6 W_5_

7 E, T_

8 C.S_

9 LK

10 ~L Li.

remained <1;:-1>

over a year :Jftt completed [rt' treatment. ~::H I,ith a large eel.

is undetermint Associated p:

patient; hale i To). renal bilul multiple sqU.lll

herpetic srom, canllll pneuI isethionatc •. \ \ asMoides (c. s. and cardiac ar:

Olle patient 1\'

C'1ptococcal 11

administr;n:, III

DISCUSSIO:,\

CryptoLtltci , nature. C'-:.JI"

Sur;:('T"f

.\Iarch. /976

• tl

otericill B. nt, i ~'ears

nesenteric ~mia. and I infection

beginning eek after -I months caused by It re~idual

utopsy. ·four \\ith " .. C.S .. E. cosis . (~r. g with a \tosine in ·h. In all

to treat­Li.) have

{

l

Volwn~ 79 SUIIII>"1)

Cryplo(Occo"is after Tt'llallmn.<plullfaliun .,-.. _IJ

Table IV Treatment of cnptococcosis in ten transplant patients . . ,-llllphfOlrricil1 B

C(lJt Dflily d{.sl'

I Total do,e

I Dllraliull of

.\'0. Pa/ifnt tmg.) (mg.) treotment

J. H. 1 to -10 6.-170 2 yr.

2 B. N. 1 to -10 1.000 7 wk.

3 R.K. 1106 21 6days

4 M. La. I to 15 195 4 wk.

5 L.O. 3 to 20 840 4 mo. 6 \V.S. 1 to 15 565 12 wk.

7 E. T. 1 to 20 810 12 wk.

8 C. S. 1 to 10 385 3 mo.

g E.W. I to 20 428 >2mo.

10 M. U. 1 to 20 450 12 wk.

remained asymptomatic and \dthout recurrence for oyer a year after treatment. One patiel1l (c. S.) has just; completed treatment. The Outcome of continuous treatment. started 2 months ago in the patient (E. W.) \,-ith a large cerebral granuloma in the left frontal lobe. is undetermined at present.

Associated problems idelllified in these fi\-e suniving patients have included pulmonary emboli 1~I. Li., E. T.). renal failure due to chronic rejection (\\'. S .. e. S.). multiple squamous cell carcinoma of the skin (W. S.), herpetic stomatitis (\\'. S.), possible pneumocystis carlnll pneumOllltIs (treated \,·ith Pentamidine isethionate) (W. S.). abscess of the thigh dut'" toSocGrdia

aJieroides (C. S.), unexplained li\'er dysfunction (e. S.). I

and cardiac arrhythmia \,·ith atrial fibrillation (E. W.). One patient (W. S.I aho has residual ataxia follt)\"il1g cryptococcal meningitis but also follo\"ing gentamicin administration.

DISCUSSION

Cryptococci are Yt:'astlike fungi widcl~ di5tribuled in natu\"e. CI),P'OCO(CUS 1/('(10 rma JlS is the onh' ~peCles

5-jlIlOr('(j/osil1t

Dail. dOl~ I Dllratiall of (Cm.1 tTfatmerll

none none

-I 5 mo.

12 3 wk.

8 to 12 18 wk.

0 0 4 to 8 12 wk.

12 12 wk.

1.5 1 mo.

10-4-8 >2 mo.

8-12 12 wk.

Remarks

- - .. +.:>.2.:> mg, AmphotenclIl B

intr;Jthecally Amphotericin B replaced by

5·AuorOcYtosine. + ) 7.5 mg. Amphotericin B intrathecally

Amphotericin B added 2 \\L

after beginning of 5-AuoTOC)10si ne

Amphotericin B added 2 mo. after beginning of 5-fluorOC\'losine

Amphoteri~in B alone Amphotericin B + 5-

fluoroqtosine simultaneously

Amphotericin B + 5-Auorocytosine simultaneously

Amphotericin B + 5·fluoroc)'tosine simultaneously

Amphotericin B + 5-Auorocytosine simultaneously

Amphotericin B + 5-fluoroc),!osine simultaneously

knO\,",l to cause disease in man. Cryptococci have been found in soil. especially in soil containing bird drop­pings: but they also bave been identified in man as a saprophyte 011 the skin. in the respiratory tract, and in the gasrroimestinal tractY· 29 C1)'PIOCOCCUS Ill?oJon!lGIU

has a capsule of polysaccharides which contributes to its pathogenicity by protecting the organism from being phagocytosed by leukocytes and macrophages.'· 10 This capsule may prevent an acute infiammalOl'Y response, usually absent with cryptococcal infections! especially of the central nervous srstem,~8 by co\'ering other fungal antigens and pre"enting host sensitization to the~e more potent fungal antigensl9•

The capacity to form this capsule is determined not onl~ genetically but also by the ellvironment.!S Capsule formation requires available free water and is an cn~rg\'-consuming metabolic process. Dnder certain gro\\th conditions. such as in soil with high mineral content or in culture medium "'ith high osmolal·ity. the fungus is unable to produce a capsule. IS Because of the smaller size of nonencapsulated \'ariallls, these can be expected to h3\'e a greater chance of passing through

the:' hlllll.1II UI'p'-'r ropil ;lton tr:tct and reaching the lun~s afler inh;d:llion.' Inh:tialion of tht: smaller nO~t:ncapsllble:d fOIlIl~ ;ltlll;til~ may be the most com mon lIlode: "f ill fl'l I iOIl. III I he Illngs the orga nisms find ,\II t'll\irOl1l11e:nt 1';\, ".-ahle for cap,ule formation; hO\\·C'\c:r.lhe: high nalllr;t! inllllullity orman against the nOIlC'llcotp,ulatccl fortll. \\ hi, It ~til1l11\;rtt:S an inflam­m:llur~ rcspPII:>ei" ami i~ readil~ phagocytosed,9. 10 may account fur Ihe: illfre:(llII .. ·ltl IllTlIlTence of cryptococcal disease despite the lIIan~ opportunities for exposure. The incidC'ntal autopsy finding of primary pulmonary cryptococcal cumplexes. with subpleural pulmonary granuloma and hilar Iyrnphnodes containing Cr;;Plococ­(lIS 11 1'0/0 rma liS. is COnSi!ilcnt with the hypothesis that inhalation is a common route ofinfection.:tl Inhalation of organisms can n:slllt in colonization or disease of the respiratory trac!.:!3· ~O. U Following dissemination. the infc!Ction has a tendellc~ to localize in the central nervous system. II. H. 17 although ct:ntral nenous system in\'ol\'ement may not become apparent until pulmo­nary imolvement no longer is detectable. Pulmonary infection was evident in onl)" two of ollr nine patients

with central nervous system in fection (E. T.. J.. H.); in one other patient (L.. 0.) infected mediastinal Iymph­nodes were found at autopsy yeal's later.

Compromise of host defense mechanisms due to immunosuppressive therapy or malignancy can be found in a significant number of patients with cryp­tocoecal infections. 13• 21. ~~ HO\\·ever. only a fel\' cases of this complication after renal transplantation have been reported.33. 3lI. 39

I n our experience cryptococca I in fections usually occur late after transplantation and therefore this ~nfection might not ha\'e been included in an earlier publication from this center concerning fungal infec­tions after transplantalion. 31 The late appearance of this disease suggests acquisition of this infection under immunosuppression rather than exacerbation of a pre-existing. inapparent infection. which might be expected to reveal itself earlier after initial intensi\'e immunosuppression. However. the time of acquisition remains uncertain because of the insidious nature of this infection. III three of our patients. an exacerbation of symptoms was obsen'ed after a temporary increase of cnrticosteroid therapy. In rats and guinea pigs. reactivation of experimental cryptococcal infection under the influence of corticosteroids has been oh­sened.zo and the possibilit~ of autogenous reinfection from an inapparent fuCtI' call not be ruled out.

The clinical manifestations of cryptocoecal infection of the central nervous sy~tent were mainly signs of

SlIrgl'ry March. 19i6

disturbed brain function and increased intracranial pressure. frequently creating a suspicion of brain tumor and directing initial studies to seal'ch for a space-occll p~ i ng lesions: ho\\·e\'er. such a lesion was detected in onl~ one patient (E. W.). Fever and meningeal signs freqllentl~ were absent. Spi nal fluid analyses indicated only mild inflammation.

'. ' In the majorit)" of patients the central nen-ous

system infection remains limited to the meninges .. Cerebral granulomata were found in onl}' one of our patients and are rare; onl~' 26 cases ha\'e been described in the English language medical literature, compared to several hundred cases of cryptococcal meningitis.7 . 12. -12 The majority of patients with cryptococcal granulomata of the brain or spinal cord have an as,ociated meningitis. The development of granulomata can be considered a late complication of a meningeal infection with extension into the gray matter from an adjacent meningeal focus.

In mice it has been 5hO\\I1 that the reaction of the host to the presence of encapsulated CI)plococcus neofol'mam is organ dependent.26 The encapsulated yeast or capsular polysaccharides evoke almost no inflammation and the organisms tend to persist if directly inoculated into the brain of the animal. On the other hand intraetitaneous or intraperitoneal inocula­tion is follO\\ed by inflammation and elimination of the yeast by phagocytosis.

Lack of an exudative inflammation also is charac­teristic of human cryptococcosis of the central nervous system. 2• 2. The inflammation found at autopsy after death from cryptococcal meningiti~ frequently is nor extensive enough to explain death. Increased intracra­nial pressure due to cerebral edema. impaired cere­brospinal fluid circulation. and metabolic effects ap­pears to p1a~ an important role in the morbidity and mortality rates of patients \dth cryptococcal menin­gitis. The effect of increa:;ed intracranial pressure is well illustrated by our patient who required ven­triculoperitoaeal shunting. as \\'ell as by reported cases benefiting fr\.~m interlllittem or cOlI!inuulIs remo\'al of cerebrospinal fluid. 3• U Immunosuppressive therapy. including corticosteroids. can be expected to deIa~

elimination of the fungu, from the respiratory tract following inh:1lalion. to acri\"3Ie a d,xJlIant focus. and to increase Ihe risk of dissemination. The cuntI"ihution of curticosteroids to the modification uf an established central nenotl, system infection is less certain. Cor­ticostt:roids at least might be expected to alle\'iate temporali" the increased illlracrani:ll pressure and the papilledema \\'hich rapidly appeared in t\\'O of OUI'

•. ____ ---r~' ---:-.~ ~~ --',;..r."-- .. ----.~ ---~ ""-.. -.-.-~- ---.--'-.------ ----...-- ---..----~------. - - -~-

"·oluw. i9 Surn~n- J

patients after doses.

Therapy \\·i, prognosis of c approach to tl based on (he \,"orkers.tr. 1.0\\

out irre\'ersiblt . total amount o!

of cryptorocca: after treatment

Amphoterici membranes ar; interruption 0

Amphotericin I it disappear5 1

tra\,enous infll kno\\'n sites or of the administ persistence of : tion in the uriI' storage fol1o\\-, rather than rJ binding sites .. responsible fOI amphotericin J

foIlo""ing "hie. fluid concemra response to th, dose appro::;cl. creased int:ac ministration 0

important, 2,.

combination ( associates. !~

Five-fiuoroC\ for the tream interferes \\i:h n lIcleus. It h:1> including gOOl

tract afler o:;:d

and much Ie" human bod\ a;

necessitaling c\ failure.3-I In sp~ 5-fluoruc~ rosin the treatn,ent percent of p.lt: therapeut:c f':'

These disapp<-' tendency of Cr

S"'g''J ,farch, 1976

ltracranial of brain

reh for a lesion was '-e\'cr and pinal fluid

11 ner"ous meninges. Jlle of our lave been literature. ~ptococcal

ients with pinal cord ;pment of cation ofa the gray

ion of the :ryPtO(O(CUS

=apsubted almost no

persist if lal. On the al inocula­.ion of the

is charac­al nen'ous opsyafter ntly is not d intracra­ired cere­~ffects ap­bidityand :.a1 menin­lressure is • ired ,'en­'rted cases emo\'alof e therapy, ~ to delay Hory tract rocus, and ntribution '~tablished

tain. Cor­) alle\;ate rc and the ,0 of our

",./I//1/,f 79 Sumber J

patients after withdra\\'al of high corticost~roid doses.

Therapy "'ith all1pholcl'icin B has improved the progno~is of cryptococcal meningitis. II. H. 17. 3l Our approach to therapy ,\'ith .lmphotcricin B doses was based on the recommendation of Drut.l and co· \\'orkers,16 Lo\\' doses permit prolonged therap\' with­out irrcversible renal damage. \"hich is rebted to the total amollnt of amphotericin B receiyed.-H The nature of crrptococcal infection and the tendency to relapse after treatment makes prolonged trefltmellt ad\'isable.

Amphotericin B attache~ to the sterols of cell membranes and its acti\'it~, against fungi is due to interruption of the integrity of cell membranes,ls Amphotericin B has unusual phannacokinetics4 in that it disappears rapidly from the circulation after in­travenous infusion because of either storage at un­known sites or rapid inacti\'ation; only a small amount of the administered dose is detectable in the urine. The persistence of low serum le\'cIs and continuous excre­tion in the urine for weeks after therapy suggests early storage foUowed by slow return to the circulation, rather than rapid inacti\'ation. Satur,)-tion of cellular binding sites, including those of fungi. may be responsible for the therapeutic effect of low doses of amphotericin B given oyer a prolonged period of time, following which therapeutic serum and cerebrospinal fluid concentrations cannot be expected. An immediate response to therapy cannot be expected with this low dose approach. Early in therapy, l>rc\'ention of in­creased intracranial pressure by corticosteroid ad­ministration or by temo\'al of spinal fluid may be ' important, as illustrated by a patient treated with a combination of these measures by Ikemoto and associates. If

Five-fluorocytosine is a newer antifungal agent used for the treatment of cryptococcal infections.22• 41 It interferes with nucleic acid synthesis in the yeast cell nucleus. It has many ad\'antages over amphotericin B • including good absorption from the gastrointestinal tract after oral administration. good tissue penetration, and much less toxicity. IL is not metabolized in the human body and 90 percent is excreted by the kidney, necessitating dose adjustme~t in the presence of renal failure. 34 In spite of these phar'macological ad\'antages, 5-fluorocytosine has not replaced amphotericin B for the treatment of cryptococcal meningitis. Only 50 percent of patients primarily treated ha\'c had a good therapeUlic rcsponse and the relapse rate was high.' Thesc disappointing results may be explained by the tendency of Cryptococcus strains to become resistant to

C')ptlJ(o((()sis aftrr rmol trQI!Splulltatioll 2i5

5-fluorocytosine' during treatment and by the need for prul"nged treatmcnt. \\'e treated only one patient primarily ,\,ith 5-fluorocytosine alone, and there was remission of his meningitis. although persistent fun­guria sub~ided only after the addition of small do~es of amphotericin B. In our other patients 5-fluorocytosine was used in combination with amphotericin B. A syner­gistic effect has been demonstrated for these two agems,30 possibly based on the increased penetration of,5-fluorocytosine into yeast cells with membranes damaged by exposure to amphotericin B.3S .-\mphoteri­cin B also has shown to delay de\'e!opment of 5-fluorocytosine resistance in experimental crypto­coccal infection in mice.s Better results with 5-fluoroc}'tosine have been obtained in patients failing to respond to initial amphotericin B therapy.! The available information about the pharmacokinetics of amphotericin B suggests that residual amphotericin B may enhance the 5-fluorocytosine effect.

The final outcome of the treated cryptococcal meningitis is known in five of the ten transplant patients who died after treatment (Table II). One patient died early in the course of treatment for cryptococcal meningitis and the' other four patients died 5 months to four years after detection of the infection. No dcath could be attributed to the cryp­tococcal infection. Four patients died of vascular or septic complications or both. The cause of death of one patient is uncertain. Although therapy appeared clinically to havc been effective in all five patients who died. residual organisms were found years after treatment in two patients. Three of the fi"e lil'ing patients have been obsen'ed for oyer one lear after treatment. All five of these patients have no clinical signs of cryptococcosis.

ADDENDUM

Since this paper was completed, an additional patient (C. S.) died from multiple organ failure. unrelated to the pre\10us cryptococcal meningitis. At autopsy. 7 weeks after completion of therapy. slight fibrosis of the leptomeninges. wilh scattered macrophages, was observed. but no cryptococci were iden­tified in the brain.

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.;.~:~:; ·~A:'~-/~1H>: .. 'j.-r~-

Volu"'~ 79 Numb!T J

42. Vij3)an. ~ .. tricubr gt':

re\·ie,,· of t~ 43. W3rr, \'; .. E

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Cryptococrosis aftfT renal trampla1l/a/ion' 211

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