Cryptococcus meningitis in a child successfully treated with amphotericin B, with a review of the pediatric literature

The Journal of P E D I A T R I C S

577

Cryptococcus meningitis in treated Mtb amplootericin B, vitb a review of the pediatric literature B. Emanuel, M.D., ~ E. Ching, M.D., A. D. Lieberman, M.D., and M. Goldin, M.S. CHICAGO~

ILL.

also known a s torulosis or European blastomycosis, is a mycotic disease of m a n and animals caused by Cryptococcus neoformans (Torula histoIytica or Cryptococcus hom{nis). T h e first case reported was by Zenker 1 in 1861 in a m a n dying from a fungous infection involving the central nervous system, and it is most probable that the organism was C. neoformans. Biisse 2 and Buschke S independently recovered yeastlike organisms f r o m a w o m a n with bone lesions who died from generalized involvement. Tile organisms w e r e referred to as Saccharomyces neoformans. Vuillemin 4 recognized the lack of ascospores, thus differentiating it from true yeast, and called it C. homlnls. T h e generic term Cryptococcus was used or given by KiltC R Y P T O C O C C O S I S ~

From the Departments o[ Pediatrics and Microbiology, Chicago Medical School, and Mount Sinai Hospital, Chicago, Ill. e'Address, Department o[ Ped{atr{cs, Mount S{nai Hospital, Cali[ornla Avenue at 15th Street, Chicago 8, Ill.

zing2 I n 1902, Frothingham G recovered the organism from a pulmonary lesion in a horse, and Von H a n s e m a n n 7 in 1905 recovered the organism for the first time from a m a n dying of meningitis. I n 1916, Stoddard and Cutler s recorded the clinical and pathologic features of the disease, described the morphologic and cultural characteristics of C. neoformans, and proved it to be a true yeast, reproduced by budding only. Because it fails to produce 'mycelium or ascospores, it is now classified with the anascosporogenous yeasts. I n Lodder's '~ classification Cryptococcus has 25 species, all saprophytic except C. neoformans. Saprophytic strains are Widespread in nature, 1~ and are found in soil, 11 food, and the skin and gastrointestinal tract of m a n ~2 and animals. 1~ Pathogenic strains have been recovered from peachesff 3 milk, and from the oropharynx, gastrointestinal and vaginal tracts of apparently healthy carriers? 4 Some relation seems to exist to pigeon manure. 10 T h e yeasts are thought to enter the body

5 78

Eraanuel et al.

F i g . 1. R i g h t m i t t i n g film.

middle

lobe i n f i l t r a t e s e e n o n a d -

through the respiratory tract, which explains the frequency of lung involvement, 14 although the tonsils and skin are considered the portal of entry by Freeman? 5 Cryptococcosis is world wide in distribution but the largest number of cases has been reported in the United States, where approximately 450 cases have been recorded in adults. The actual incidence of the disease cannot be estimated accurately by the number of published cases. Alteration of the host-parasite relationship, disturbance in the reticuloendothelial system, and debilitating disease contribute to the lowering of resistance to the organisms. Coexistence of cryptococcosis with Hodgkin's disease, 2~ leukemia, reticulum cell sarcoma,2~, 27 histoplasmosis,2S tuberculosis,2S moniliasis, 2~ and diabetes 2~ have been previously described. The organism most likely reaches the central nervous system by way of the blood stream, 16 producing 3 varied types of pathologic pictures: (1) meningitis, where the subarachnoid space of the base of the brain is most frequently involved; (2) meningoencephalitis, where the gray matter is mostly

October 1961

affected with a honeycomb appearance of the cortex, basal ganglia, brain stem, thalamus, or cerebellum; and (3) cryptococcal granuloma, which is frequently found in the cerebellum and cerebrum. Other organl~ such as the lung, liver, spleen, skin, and lymph nodes are less frequently involved. 14 In 1937 Levin ~7 reviewed the literature and since then numerous other reviews have been published,14, 18, 19 but none in the pediatric literature. The prognosis, except for the localized, cutaneous type, is grave, especially when the central nervous system is involved. Until the advent of amphotericin B, ~ these cases were nearly always fatal. We have recently encountered in a child a case of C. neoformans meningitis associated with tuberculosis of the lung. To our knowledge, this is the first child with cryptocoecal meningitis to have apparently recovered completely when treated with amphotericin B. Certain aspects of this case will be discussed and the review of the pediatric literature on cryptococeal meningitis is included. CASE

REPORT

G. H.,t an 18-month-old Negro boy, was brought in a comatose condition to the emergency room of the Mount Sinai Hospital, Chicago, on Aug. 21, 1960, with tonic and clonic convulsions and a temperature of 104 ~ F. For about one month prior to admission, the child had had frequent colds, a cough, and fever but improved when given penicillin by a local physician. Three days prior to admission, the child again developed a dry cough, rhinorrhea, and fever. On the day of admission, shortness of breath was also noted. In the emergency room, the child was comatose; the pupils were equal, dilated, and unresponsive to light. There was a slight ptosis of the left eyelid, the neck was supple,

"X'The trade-mark of E. R, Squibb & Sons for amphoterlcln B is Fungizone. tFrom the service of Dr. H. S. Go/don.

Volume 59 Number 4

Amphotericin B in cryptococcus meningitis

and Kernig's, Brudzinski's, and Babinski's signs could not be elicited. The throat was slightly reddened, the ears clear, and no significant Iymphadenopathy could be found. The breath sounds were harsh, but with no r~les or dullness to percussion. The heart was normal, but there was a tachycardia. The abdomen was soft, and no organs or masses could be felt. Phenobarbital, intramuscularly, and aspirin suppositories were given, but convulsions continued for another half hour. A roentgenogram of the chest was immediately taken and a moderate pneumonia of the right middle lobe of the Iung was visualized (Fig. 1). The fundi showed no papilledema, and a lumbar puncture was performed. The pressure was slightly elevated, and the clear fluid obtained included 217 cells per cubic millimeter, predominantly neutrop.hils. T h e protein was elevated, and the P a n @ test was positive. Glucose and chloride concentrations were normal. Organisms resembling Cryptococcus were seen in this specimen, but, unfortunately, no cultures were made on it. Examination of the blood showed a hemoglobin of 8.1 Gm. per 100 ml., hematocrit 28, red blood ceils 3.75 million per cubic millimeter, and color index 0.69. T h e leukocyte count was 8,100 per cubic millimeter with 3 per cent bands, 55 per cent neutrophils, 34 per cent tymphocytes, 5 per cent eosinophils, 2 per cent monocytes, and 1 per cent basophils. The sedimentation rate was 30 mm. per hour. '* The blood urea nitrogen was 18.5 rag. per cent. The child was given 1,000,000 units of penicillin, intravenously, twice a day; 250 mg. sulfadiazine, intravenously, every 6 hours; and 50 rag. per kilogram chloramphenicol, intramuscularly, every 6 hours. On the second hospital day, his neck become slightly rigid. A Mantoux test (t:10,000 OT.) was markedly positive after 24 hours. The child was then immediately placed on

*Wintrobe method.

579

para-amin0salicylic acid, 750 rag., 3 times a day; isoniazid, 100 mg., 3 times a day; streptomycin, 50 rag., intramuscularly, twice a day; and prednisone, 10 mg., twice a day. One the third hospital day, the patient was alert and free of convulsions. The lumbar puncture was repeated, the cell count was 207 per cubic millimeter; 90 per cent of them, however, were lymphocytes in this specimen. India ink preparations showed numerous encapsulated ceils morphologically typical of C. neoformans. A direct count of the organisms showed them to be greater than 10,000 per cubic millimeter. A diagnosis of cryptococcal meningitis was m a d e and amphotericin B, 15 mg. given intravenously in 500 ml. of dextrose in water with addition of 0.5 ml. heparin as a precaution against thrombophlebitis, was added to the therapeutic regimen. Potassium iodide was also given, starting at 3 drops twice a day and increased by 1 drop per day until a dose of 12 drops twice a day was reached. This was stopped on the sixty-second day of hospitalization when the lung lesion was felt to be a tuberculous rather than a cryptococcal granuloma. T h e history from the child's parents revealed that the patient was in close contact with an uncle who had been treated for tuberculosis since February, 1960. It was also learned that the child had been playing around pigeon excreta. The course of the disease and the treatment are shown in Fig. 2. The prednisone, chloramphenicol, and penicillin were discontinued after the third hospital day. The amphotericin B was given every other day or 3 times weekly when the blood urea nitrogen became abnormally elevated. This dosage was found to be best. During the last 2 weeks of therapy, amphotericin B was given once a week in a dose of 30 mg. Despite intensive drug therapy, liver function tests remained normal, and the drug was well tolerated. Throughout the long hospital course, every effort was made to isolate the tubercle bacillus from gastric washings, spinal fluids, and bronchial aspirations. All smears, cultures, and guinea pig inoculations were negative for acid-fast bacilli. Skin and serologic tests

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Volume 59 Number 4

Amphotericin B in cryptococcus meningitis

for blastomycosis, coccidioidomycosis, and histoplasmosis were all negative. The cryptococci were seen in large numbers in the first 5 specimens of spinal fluid, but none in the succeeding 4 specimens. The number of organisms, the size of the capsule, and the amount of budding diminished strikingly with each succeeding specimen. Every effort to culture the organism, however, failed. All animal inoculations were also negative. I t is probable that the intensive therapy with the antibiotics and amphotericin B were responsible for the negative cultures. Ordinarily, this organism grows with ease on ordinary laboratory media, either at room or incubator temperature.l~, 14 T h e child progressively improved during his hospitalization, although the lung lesion did not diminish in size (Figs. 3, 4, and 5). The child was discharged from the hospital after the spinal fluid findings returned to normal on his eighty-seventh hospital day. He was continued, however, on antituberculosis therapy. Five months after discharge, the child has remained in good health, is gaining weight, and is mentally normal, with a normal electroencephalogram. The pulmonary lesion has decreased in size on the continued antituberculosis therapy (Figs. 6A and 6B). REVIEW

OF THE

58 1

liver in 8, the spleen in 7, the kidney in 5, the eyes in 4, the skin in 3, the bones, adrenals, and thyroid in 2, and the pancreas, heart, and lymph nodes in 1. In the pediatric age group, cryptococcosis is also frequently associated with other diseases such as histoplasmosis, a9 moniliasis, 4a Hodgkin's disease, 37 sarcoidosis, ~6 and tuberculosis. 49 Cryptococcosis is a subacute or chronic

Fig. 3. Persisting lung lesion, 1 month later.

LITERATURE

T o date, including the report of the prcsent case, we have been able to find only 23 cases of cryptococcus meningitis in children less than 15 years of age. Table I summarizes the significant data on these cases. The ages of the patients ranged from 20 minutes post partum to 15 years of age. The presence of the disease in a 20-minute-old newborn ~s is definite evidence of the existence of a congenital cryptococcal infection. Of the 23 cases, 3 definite cases and 3 equivocal cases appeared in the neonatal period. The sex distribution, as in the adults, favors the males, although such a distribution is difficult to explain. The disease is not limited to the white race; 5 of the patients were Negroes. The brain and the meninges were involved in 23 cases, the lungs in 9, the

Fig. 4. Persistance of lung lesion, 2 months later,

58 2

E m a n u e l et al.

October 1961

T a b l e I. R e v i e w of tile w o r l d p e d i a t r i c l i t e r a t u r e

Duration

of

A g e , sex, race

symptoms be[ore Cerebrospinal Physical findings and admission presenting symptoms findings 4 weeks Diarrhea, irritability, drowsiness, No definite number and signs of meningeal irritacells, all lymphocytes tion 1'Pressure

Author Barlow 2~

Country Year Australia 1923

Carton and Mount 30

United States

1933

12, F, W

6 weeks

Reeves, Butt, and Hammack al

India

1938

15, F, W

9 months Headache, vomiting, stiff neck, 97 cells, mostly polymorphonublurred vision, cough, fever, clear leukocytes, emaciation, and optic atrophy lymphocytes later "]'Pressure at first, normal later Protein1'

Longmire and Goodwin a2

United States

1939

4, F, W

3 months Fever, dyspnea, convulsions, stu- 100 to 400 cells, por, deafness and blindness, polymorphonuemaciation, cyanosis, stiff neck, clear leukocytes and papilledema 75, lymphocytes 25 "]'Pressure Protein~" Glucose 35

D'Aunoy and Lafferty sa

United States

1939

7, M, N

Sudden

Stiff neck, semicoma, and acute 100 to 250 ceils illness ~'Pressure

Marshall and Teed 3~

United States

1942

9, F, W

6 weeks

Fever, headache, nausea, irritabil- 8 to 15 Cells ity, vomiting, much rigidity, 1"Pressure Kcrnig +, papilledema, and retinal hemorrhage

Dormer, et al. 3~ South Africa

1945

12, M, N

Hamilton and United Thompson aG States

1946

6, M, N

2 weeks

Debre, et a l Y

1946

12, M, W

Unknown

France

3, F, W

Headache, vomiting, poor vision, hyporeflexia, Babinski and Kernig +, left ptosis, sixth nerve palsy, papilledema, retinal hemorrhage and exudation, coma, and death

88 cells, 90% lymphocytes 1'Pressure Protein 100 Glucose 40

4 months Cough, headaches, anorexia, Many polymorphoweight loss, clubbing of fingers, nuclear leukocytes fever, and dullness in right upper chest

Malaise, anorexia, fever, head- 320 cells, mostly ache, vomiting, generalized conpolymorphonuvulsion, papilledema, stiff neck, clear Ieukocytes Brudzinski +, and hyporeflexia ~'Pressure Protein 180 Glucose ) I0

Headache, vomiting, fever, con- Not done vulsions, photophobia, opisthotonos, papilledema, hepatosplenomegaly, ulcer on neck, and mass over clavicle

Volume 59

Number 4

A m p h o t e r i c i n B in cryptococcus meningitis

5 83

Antimot-

Direct smear

tern diagnosis Yes

Duration of illness Organs involved 3 months Brain

Autopsy Treatment Yes None

Yes

5 weeks

Brain

No

Positive chest abscess aspiration

Yes

2 years

Brain

_

Positive from CSF

Positive from CSF

Yes

3 months Brain, meninges, lung, thyroid, liver spleen, and kidney

Positive from CSF

Positive from CSF

No

48 hours

Positive from CSF

Positive from CSF

Yes

5 months Brain

Sulfadiazine

Living, well, subnormal intelligence 4 years later

Positive from CSF

Positive in guinea pig

Yes

5 months Lung and brain

Sulfadiazine, KI

Postoperative meningitis following right upper pulmonary lobectomy Patient survived, no follow-up

Positive from CSF Positive from sputum

Positive from cisternal puncture; positive from sputum

Yes

Sulfadiazine

Chest x-ray--nonspecific lung infiltration Pneumoencephalogram--enlargement of one ventricle and other not visualized

Positive from CSF

Yes

KI

Coexisting Hodgkin's disease

of cryptocoeeus -Positive from CSF

Culture

Positive from CSF

Positive from CSF

Positive from CSF and chest abscess

aspiration

72 days

2 weeks

Brain

Skull x-ray showed signs of increased intracranial pressure

Sulfadiazine Skull x-ray--inTorula creased marking antigen, K I Chest x-ray--interlobar empyema CSF still positive 2 years later Reported to be well 9 years later, but with sequelae

Yes

Yes

Lungs

Skin, lungs, heart, spleen, liver, and brain

K I orally, NaI intravenously, 5 % NaI, and acriflavine intrathecally

Remarks Optic atrophy prior to death

Yes

584

E m a n u e l et al.

October 1961

Table I. Cont'd Duration

of Country

Year

Age, sex, race

symptoms before admission

Cox and Tolhurst ss

Australia

1946

7, M, W

5 weeks

Mider, Smith, and Bray a9

United States

1947

12, M, N

Greening and Menville 40

United States

1947

6, M, N

2 weeks

Upper respiratory infection, head- 300 cells, lymphoache, vomiting, convulsion, and cytes 30% stiff neck ]'Pressure ++Pandy Protein]` Glucose, normal

Cloward ~1

Hawaii

1948

51,/.~, M, Chinese

1 week

Septic temperature, headache, ir- 450 cells, lympho-. ritability, convulsions, paralysis, cytes 33 % retinal hemorrhages, and papiI- ?Pressure ledema Protein 114 to 140

Neuhauser and United Tucker ~42 States

1948

7 weeks, M, W

7 weeks

Vomiting, twitching, rigidity, hy- 27 to 36 cells, 75% drocephalus, cataract and cholymphocytes rioretinitis, ankle clonus, and Protein 1,400 Babinski + Glucose 69

Neuhauser and United Tucker ~ 2 States

1948

19 days, M, W

19 days

Jaundice since birth, hepatosplenomegaly, dark urine and clay stool, hydrocephalus, and malnourishment

Neuhauser and United Tucker *.42 States

1948

17 days, M, W

4 days

Irritability, convulsions, hypertonieity, frequent clonic motions of extremities, hepatosplenomegaly and chorioretinitis

Spicer, Hiatt, United and Kessel~3 States

1948

4 years

Headache and lethargy, repeated Cloudy episodes of pulmonary infiltra- "]'Pressure tion with chronic cough, and septic temperature

Nassau and WeinbergHeiruti 44

Israel

1948

12 days, M, W

5 days

Cyanosis and generalized convul- 5,000, later 263 sion, no nuchal rigidity, hypocells reflexia, Kernig +, splenomeg- Protein 238 to 240 aly, skin macular and papular Glucose 14 my. lesions, and hydrocephalus

Health 4~

United States

I950

27 days, IV[, W

Lepau, et al. ~6 United States

1953

10, F, N

Author

8, M, W

Physical findings and presenting symptoms

Cerebrospinal findings

Headache, vomiting, leg pain, 41 to 50 cells, 40 to semicoma, active deep reflex, 46% lymphoeytes paralysis of right leg and arm, ]`Pressure stiff neck, and papilledema Protein]"

3 months Weakness, weight loss, anorexia, fever, and red swollen sternoclavicular region which drained, generalized lymphadenopathy

Endophthalmitls with separation of retina

massive

_

3 months Anorexia, weakness and general- 2,720 cells, 95% ized lymphadenopathy, later polymorphonuheadache, fever, vomiting, clear leukocytes, coma, and death later 16,000 cells Protein 70 to 200 o GlUcose 10 to 20 C1 110 to 121

Volume 59

Number 4

Amphotericin B in cryptococcus meningitis

5 85

AntimOT-

Direct smear

of cryptoeoeeus

Culture

Positive from CSF

Positive from CSF

Positive from blood and bone marrow

Positive from CSF

_

Duration of illness

Yes

289

Au-

Organs involved

topsy

Treatment

Remarks

Lungs and brain

Yes

_

Chest x-ray--fibrosis and small nodules

Brain, liver, kidney, and bones

Yes

months

No

11 days

Yes

Positive from CSF

Yes

28 days

No

23 days

Associated with generalized histoplasmosis

No

KI, sulfadiazinc, and penicillin intrathecally

Died

Brain

Yes

Penicillin, sulfadiazine

Pneumoencephalogram performed Exploratory trephination for brain abscess-negative

Brain, eyes, and lungs

Yes

Skull x-ray---calcification of frontal region Punctate and calcification along ventricles

2 months Brain

Positive from CSF

_

Positive from CSF

tern diagnosis

Positive postmortem from CSF

No

4 days

Spleen, liver, brain, and bone

Yes

Skull x - r a y - - p u n c t a t e calcification of the brain

Positive postmortem from CSF

No

10 days

Brain, liver, spleen, kidney, lungs, and eyes

Yes

Skull x-ray calcifications of cortex and brain substance

Positive from CSF and urine

No

35 days

Brain, lungs, kidney, spleen, pancreas, adrenal, and liver

Yes

Sulfadiazine

Positive from CSF after death

No

Brain and skin

Yes

Penicillin, sulfadiazinc

Positive from CSF

No

27 days

Many organs including eyes and brain

Yes

Positive fl'om CSF, nose and throat

Yes

61 days

Brain

Yes

6 weeks

_

Associated with generalized candidiasis

Congenital origin Combined lesion with toxoplasmosis

Polymyxin B, Coexisting Boeck's intramussarco{d cularly, and nystatin intrathecally

586

October 1961

E m a n u e l et al.

T a b l e I. Cont'd Duration

of Year

.Age~ sex~ race

Soysal, Unat, Turkey and Tahsinglu 47

1954

7, M, W

Oliviera Campos 4s

Portugal

1955 32 weeks, premature, F, W

Nanda, et al. ~9 United States

1956 10, M, W

Author

Country

symptoms be[ore admission

Physical findings and presenting symptoms

Cerebrospinal findings

3 months Ulcerative crusting skin lesions, 'acute illness, cough, fever, lymphadenopathy, membranous tonsils, papilledema, and hepatosplenomegaly At birth

3 weeks

"Xpersonal communication with the authors indicates that the

infection. Cases with pulmonary involvement are usually asymptomatic or m a y have a slight cough, scanty mueoid sputum, and infrequent hemoptysis. There is rarely fever, malaise, and weight loss. Clinical symptoms and physical signs become evident when meningitis supervenes. Fever, headache, vertigo, nausea, irritability, vomiting, stupor, confusion, lethargy, and convulsions are noted. Nuchal rigidity, positive Brudzinski's and Kernig's signs, as seen in other meningitides, appear. Later, increasing intracranial pressure develops with its associated signs of papilledema, ophthalmoplegia, and cranial nerve involvement. Fever is seldom above 101 ~ F., the leukocyte count is variable, and the erythrocyte sedimentation rate is usually normal. The spinal fluid is under increased pressure. It m a y be clear but is generally turbid, and, on rare occasions, x a n t h o chromic. The cell count is usually between 40 and 1,000 cells with an average of 200 to 300 per cubic millimetera; the cells are mostly lymphocytes, although at an early stage they m a y be polymorphonuelear ieuko-

Cyanosis, brachycardia, weak respiration, anasarca, hydrocephalus, and hepatosplenomegaly Headache, nausea and vomiting, 84 cells, 80% emaciation, lethargy and weaklymphocytes ness, bilateral papilledema and ~'Pressure nuchal rigidity, ankle clonus, and Babinski +

3 cases quoted had toxoplasmosis and the cryptococcosis was not

cytes. Total protein is increased and glucose and chlorides are slightly decreased. In the neonatal period, cryptococcosis presents itself with different symptoms than in older children. Cyanosis, convulsions, failure to thrive, jaundice, hepatosplenomegaly, chorioretinitis, skin rash, and punctate calcifications in the brain m a y be noted. Thus cryptococcal meningitis must be differentiated from other diseases, especially congenital toxoplasmosis and cytomegalic inclusion disease. 56-5s Cryptococcosis, or other fungous invaders of the central nervo~as system, should be considered in the differential diagnosis of meningitis or expanding intracranial lesions. This will be frequently suggested by pleocytosis of the cerebrospinal fluid, reduced glucose and chloride levels, and increase in protein and pressure. Specimens of fluid should be cultured for fungi on Sabouraud's and other media and India ink preparations should be examined. The pathogenicity of strains of C. neo[orraans is determined by Iaboratory methods such as those described by Benham. 12 The

Volume 59

Number 4

f

Araphotericin B in cryptococcus meningitis

58 7

Antimottern

pirect smear

o~ cryptococeus

Culture

diag- Duration nosis o[ illness No 10 days

No

positive from Positive from CSF CSF

Yes

Organs involved

Autopsy

Brain, skin, lymph Yes nodes, thyroid, tonsils, liver, spleen, kidney, adrenal, and eyes

20 minutes Brain, liver, and spleen

6 months Brain

Treatment Remarks Penicillin and Chest x-ray--normal sulfadiazinc

Lived for 20 minutes

Yes

_

Ethyl vanillate

Coexisting tuberculous meningitis Living with residual spasticity of left hand and wrist, and hyperkinetic behavior EEG--diffuse organic dysrhythmia

I etinitely proved.

characteristic features are f e r m e n t a t i o n of all sugars, e x c e p t lactose, good g r o w t h on most c u l t u r e media, a n d p a t h o g e n i c i t y to mice. Staining of the capsule with m u c i c a r mine a n d the a p p e a r a n c e in I n d i a ink p r e p a rations are p a t h o g n o m o n i c of this o r g a n ism. 14 T r e a t m e n t of cryptococcosis was a challenge until a m p h o t e r i c i n B was introduced. Previous t r e a t m e n t consisted of roentgen therapy,40 sulfonamides,S~, Sl diamidines,~2 iodides, 1~ penicillin, tetracycline, ethyl vanillate,49, s4 nystatln,S3 a n d c y c l o h e x i m i d e ? ~ T h e prognosis was p o o r a n d most p e d i a t r i c patients died. O u t of the g r o u p reviewed, only 5 survived, b u t with neurological sequelae in 3; 2 h a d no follow-up. DISCUSSION

T h e r e are three interesting features in our case: the association of tuberculosis a n d cryptococcosis; the failure to c u l t u r e the fungus despite the n u m e r o u s organisms seen; and the uneventful recovery with a m p h o t e r i cin B.

Fig. 5. Lung lesion still present 3 months later.

588

Emanuel

et al.

Fig. 6A. Lung lesion decreasing in size on antituberculosis therapy, 5 months later.

The diagnosis of pulmonary tuberculosis in the child was supported by the history of contact with the disease, the positive tuberculin test, and the resolution of the persisting pulmonary lesion during prolonged antituberculosis therapy. Additional evidence for the diagnosis was the location of the lung lesion. In cryptococcosis, the lesion is twice as common in the lower lobe as in the upper and middle lobes. In 50 per cent of reported cases, there is involvement of 2 or more lobes and in about one third there is diffuse involvement of both lungs26' 60-62 This is in contrast to our case, where the lesion was in the right middle lobe. The failure to recover tubercle bacilli on culture and animal inoculation could be attributed to the intensive antituberculous therapy instituted prior to bacteriologic examination. The failure to culture Cryptococcus despite the numerous organisms repeatedly seen on smear, may likewise be due to the intense antibiotic and amphotericin B therapy. On administration of the drug, the capsule of the fungus decreased very strikingly in size. The uneventfuI recovery from this usually fatal disease, we feel, is due to the very intense therapy with the antifungaI antibiotic amphotericin B.

October 1961

It is recommended that therapy with amphotericin B be started with 0.25 my. per kilogram daily and that the dose be gradually increased until an optimum level is attained; this is generally achieved with 1.0 mg. per kilogram. A dose exceeding 1.5 rag. per kilogram is cautioned against. We instituted therapy with a dose of 1.25 mg. per kilogram and maintained this dose despite the azotemia. There were rare occasions when symptoms of nausea, vomiting, and irritability were manifested. When the drug was administered every other day or 3 times weekly, the azotemia disappeared. During the last 3 weeks of hospitalization the dose was doubled to 2.5 mg. per kilogram, but was given only once a week. This did cause, once again, an elevation of the blood urea nitrogen but was otherwise well tolerated. The patient received a total of 490 mg. of the drug during a 12-week course. Liver function studies were within normal limits.

Fig. 6B. Lateral film showing regression of middle lobe lesion.

Volume 59 Number 4

Amphotericin B in cryptococcus meningitis

5 89

and tuberculosis manifesting m e n i n g e a l s y m p t o m s should be w a t c h e d for s u p e r i m posed c r y p t o c o c c a l infection. T h e a l m o s t 100 p e r cent m o r t a l i t y rate of the 23 cases reviewed before the use of a m p h o t e r i c i n B stresses the p a r a m o u n t role the d r u g plays in the m a n a g e m e n t a n d t r e a t m e n t of this fungal disease. ADDENDUM

Fig. 7. X-ray 7 months after patient was discharged from the hospital The chest x-ray revealed further resolution of the right middle lobe lesion. The patient is still being maintained on antituberculosis therapy as indicated in our paper.

A n o t h e r side effect of the d r u g is anemia. This m a y h a v e been the cause of the slight d r o p n o t e d in o u r p a t i e n t ' s h e m o g l o b i n level despite s u p p l e m e n t a l iron t h e r a p y , b u t this was only t r a n s i e n t and soon r e t u r n e d to its previous level. SUMMARY

A case of c r y p t o c o c c a l meningitis associated w i t h p u h n o n a r y tuberculosis is reported. T h e t r e a t m e n t of the disease with a m p h o tericin B is discussed; the drug was effective a n d well tolerated. A review of cryptococcosis in the p e d i a t r i c age group f r o m the world l i t e r a t u r e is presented a n d the differences in the clinical manifestations of the disease in the n e o n a t e and the o l d e r child are stressed. Evidence is presented for the occurrence of congenital c r y p t o c o c c a l meningitis. I n the p e d i a t r i c age group, patients with histoplasmosis, moniliasis, H o d g k i n ' s disease, leukemia, sarcoidosis,

Since this article was submitted for publication a paper has appeared in the British Medical fournaI (vol. 2, pp. 91-93, 1961) entitled "Cryptocoecal Meningo-Encephalitis," by W. F. Twining McMath and K. K. Hussain. This article deals with a case of cryptococcal meningoencephalitis in a 4-year-old boy. The child was treated with steroid therapy, 5 mg. doses of prednisolone, tetracycline, 250 mg. every 6 hours, amphotericin B, 0.5 mg. in 5 ml. of water intrathecally and 20 mg. in 250 ml. of 5 per cent dextrose by intravenous drip. He died 3 days following institution of therapy. We wish to thank Dr. H. S. Gordon and the pediatric staff, and the nursing staff, headed by Miss D. Melchior, at Mount Sinai Hospital, Chicago, Ill., for their help. REFERENCES

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