Trzchosporon SEPSIS AND LEUKEMIA ROBERT RIVERA, MD,* AND AYTEN CANGIR, MD+

TnchosDoron cutaneum is a fungus known to cause superficial nodules over the distal third of hair shafts, mainly scalp hair, and to produce a clinical entity known as piedra. This superficial mycosis occurs mostly in temperate and tropical regions and is rarely seen in North America. W s p o r on CU- sepsis is described here in a 12-year-old boy with acute lymphocytic leukemia in relapse. To our knowledge this is the first case reported in the literature. Emphasis is made of the increasing rate of fungal diseases as well as of "oppor- tunistic" infections in this type of immunosuppressed patient.

Cunc.9 36:1106-1110, 1975.

richosporon cutaneum IS A YEAST KNOWN TO T produce superficial nodules on t h e distal portion of the hair , causing a disease called white piedra.This superficial mycosis is present mostly in temperate a n d tropical regions of t h e world; very few cases have been reported in Nor th America.' T h i s disease is limited t o t h e hair shafts; only one case of b r a i n abscess has been reported, i n a patient with primary bronchial carcinoma.'

?'his report describes the occurrence of Trichosporon culaneum sepsis in a 1 2-year-old boy with acute lymphocytic leukemia in relapse. To our knowledge, this is the first case in t h e literature in which sepsis was produced by this "opportunistic" fungal organism.

CASE REPORT

The diagnosis of acute lymphocytic leukemia was established in this 12-year-old Caucasian boy in February, 1969. He had been treated at M. D. Anderson Hospital since June, 1970, and had become resistant to all conventional antileukemic chemotherapy. Four weeks prior to his last hospital admission, the patient received a combination of in-

From the Department of Pediatrics, 'rhe University of I ' r xas System Cancer Center h l . D. Anderson Hospital and 'I'umor Institute, Houston, 'IX.

* Pediatric Oncology Fellow. ' Assistant Professor of Pediatrics. Address for reprints: Ayten Cangir, A l l ) , Dept. of

Pediatrics, l ' h e Llniversity of Texas System Cancer Center XI . L). Anderson Hospital and 'I'umor Institute, 'Texas hledical Center, Houston, ' I X 7702.5.

l 'he authors thank hlrs. L. Corona from hlycology Laboratory. Section of Llicrobiology, .\I. D. Anderson Hospital, for technical assistance.

Keccived for publication July 25, 1974.

termittent cytosine arabinoside with vincristine and bleomycin for remission induction. During this time, a progressive granulocytopenia developed to the point that, on admission, the white blood cell count showed 400 cells/mrn3, with 80% lymphocytes and 20% blast cells. At the time the above chemotherapy was started, the patient also received radiotherapy to a dose of 2400 K to the sacral and coccigeal areas because of severe pain over that area, presumably secondary to leukemic infiltration. A bone marrow study showed a hypocellular specimen with 94% blast cells.

On admission, the patient was febrile and lethargic with a "toxic" appearance. 'The clinical and laboratory findings did not clarify the etiology of fever. Because of severe neutropenia and fever, the possibility of bacterial sepsis was strongly considered. The patient was treated with gentamicin, carbenicil- lin, and cephalothin using conventional doses. Dex- amet hasone, added because of persistent hypoten- sion, was administered on a daily basis during all of his hospitalization.

l'wenty-four hours after admission, blood cultures showed gram-negative rods which later were iden- tified as Enterobacter cloacae. Disc sensitivities indicated resistance to cephalothin and sensitivity to gen- tamicin. chloramphenicol, and carbenicillin. Cephalothin was discontinued and chloramphenicol was added to therapy. 'I'he patient received a total of 1 1 days of parenteral antibiotic therapy. Twenty-four hours after antibiotics were started, the patient became afebrile; however, by the 8th day of antibiotic therapy, the temperature went up to 10ZDF and remained around that level until antibiotics were dis- continued on the I Ith day. During this period, the patient's peripheral white blood count remained below 1000 cells/mm3 with a predominance of lymphocytes; there were I-5% polymorphonuclear leukocytes and 3-10% blast cells. About the time that antibiotics were discontinued, the patient presented clinical evidence of hepatitis including icteric sclerae,

1106

No. 3 TrichosForon SEPSIS AND LEUKEMIA Rivera and Cangir 1107

FIG I . Trichorporon mtanrurn iso- lated from blood culture on Sabou- raud's media (X51, reduced from 57).

'. / . f

palpable liver 4 cm below the right costal margin, and a total serum bilirubin of 6 mg/ 100 ml initially (direct bilirubin 2 mg/100 ml), increasing to a total serum bilirubin of 14 mg/100 ml (direct fraction of 6.6 mg/100 ml). A positive test for Australia antigen was noticed from the beginning of jaundice.

When antibiotics were discontinued, blood cultures on two occasions were negative for bacterial growth but positive for fungi. The patient was then started on amphotericin €3 daily. However, the antifungal agent was given only for 2 days because of the onset of acute renal failure. Because of the severe renal insufficiency and positive blood cultures for fungi, the patient was started on fluorocytosine a dose of 1000 mg/m'/day

for a total of 5 days. In the meantime, the fungus in the blood cultures was identified as Trichoskoron cutaneurn (Fig. I ) .

The identification was made following the Central- Disease Control (Atlanta, Ga) charts for yeast iden- tification.

The yeast colony initially grew in blood agar media and subsequently was subcultured to Sabouraud's media, at 25°C and at 37OC. In these two instances growth was fast and vigorous.

Macroscopic appearance was of a cream-colored, yeast-like colony, wrinkled and solid in appearance. Microscopically, hyphae, arthrospore, and blasto- spore were seen.

1108 CANCER September 1975 Vol. 36

DAY

F

104'

102'

100'

96'

Positive Serum Positive Acute Positive Blood.culture Blood- cul t utes Hepatitis Blood- cultures Renal failure for: Trichosporon

for. Enterobacter Cloacae IAus A + I (2 ) : Yeast Cutonsum I N@polirc lor b o t l t r i o I

FK;. 2. Patient's temperature record with antifungal agents and antibiotics used. Bottom part shows clinical events in progressive order

All fermentations for this particular fungus were negative; positive assimilation for all carbohydrates was noted. I t was also urease active and positive for pseudo-hyphae.

Trirhosporon cutaneum was also present in the urine, tracheal aspirate, throat, and stools. From this time, detailed examination of hair failed to reveal any findings suggestive of Trichosporon cutaneum. Later, two more blood cultures were positive for the same fungus. The patient developed severe anemia and manifestations of' congestive heart failure, suffered cardiorespiratory arrest, and died (Fig. 2).

Necropsy showed systemic Trichosporon cutanatm in- festation including myocardium (Fig. 3), kidneys (Fig. 4), liver, spleen, bone marrow, wall of es- ophagus, and lungs. Renal failure was attributed to extensive infarction of the parenchyma secondary to obstruction of the blood supply by balls of fungus. Lungs also showed uremic pneumonitis. A section from the liver showed the histologic features of early posthepatic cirrhosis. Bone marrow sections showed extensive areas of infarction. I n the few areas where the bone marrow could be evaluated, there were about 15% blast cells.

DISCUSSION

I t is well known that infection is the most common complication of leukemia.' Simone et al.' point out that, in their series, fatal infec- tions in patients in remission were mainly the result of Pneumocystis carini i , herpes virus, cytomegalovirus, and fungi. In patients with bone marrow relapse, the most common cause of infection is b a ~ t e r i a l . ~ These patients are likely to develop infections, not only because of the neutropenia per se, but also because of im-

munosuppression caused by chemotherapeutic agents.'

With the significantly improved survival rate of the leukemic patient because of new chemotherapeutic agents, as well a s the use of new regimens, there has been a n increasing number of patients with extramedullary disease, mainly central nervous system leukemia. a There has also been a n increase in infection, and, as pointed out by Hersh et aI., 'there has been an increase of fungal infection in this type of patient. hlirsky and Cuttner, ' in their series, found that 28% of their patients with acute leukemia died with systemic fungal infections, and concluded that in their experience, Aspergil- /us was a more common invading agent than Candida.

We concur with most authors that predisposi- tion to fungal infections in patients with acute leukemia is induced by immunosuppressive cytotoxic drugs, steroid therapy, and the use of broad spectrum antibiotics.

Trichosporon cutaneum is a member of the sub- family Trichosporoideae in the family of Cryp- tococcaceae. This fungus, which is a normal in- habitant of the soil and is occasionally seen on the human skin as normal flora, is found predominantly in the temperate and tropical zones. 'I'he organism causes white piedra, which is a disease characterized by superficial nodules on the distal portion of the hair, mainly the scalp hair. Another member of this subfamily of fungi, Trichosporon capitatum, can cause death in rabbits when injected intravenously.

As indicated in the case report, our patient at

No. 3 Trichosporon SEPSIS AND LEUKEMIA Rivera and Cangir 1109

FIG. 3. h tus. Notice Trichosporon

,lyocardium of proposi- pustular lesions where cutaneum was isolated.

w - 'a ' =

the time of admission presented with a bacterial sepsis plus immunosuppression secondary to chemotherapy he had received prior to his ad- mission to the hospital. Unfortunately, because of the onset of acute renal failure in this par- ticular patient, i t was impossible to evaluate the therapeutic response of Trichosporon cutaneum to amphotericin B. To our knowledge no reports of sensitivity to any known antifungal agents of this particular fungus have been published.

We believe that "opportunistic" organisms, especially fungi, are playing a very important role as infectious agents, not only in patients with acute leukemia but also in patients that are going through a n immunosuppressive stage.

Over a recent period of 3 months, there were 4 patients in this institution with throat cultures and 16 patients with urine cultures positive for Trichosporon cutaneum; all of these patients were on chemotherapy, radiotherapy, or had had sur- gical treatment in combination with one or the other as part of the treatment for their basic dis- ease. However, in none of these patients did the finding of these fungi result in a clinical disease. This relative frequency was not noticed in the past and probably reflects more aggressive treat- ment of patients with neoplastic disease. Hughes' has pointed out that bone marrow cultures may be a helpful tool in establishing diagnosis of fungal infections early in the course of the disease.

We would like to emphasize the possible role

F~ti . 4. Photomicrograph of kidney showing fungi, morphologically suggestive of 'Trzchosporon (PAS, X252, reduced from 290).

1110 CANCER Sgtember 1975 Vol. 36

of opportunistic fungus as a cause of systemic in- fections in the leukemic patient; the early to longer survivals.

diagnosis of these complications may contribute

K EF E RENC ES

1. Blair. J . E., Lennette, E. H., and Truant, J . P.: hlanual 0 1 Clinical hlicrobiology. Baltimore, Williams and Wilkins, 1970; pp. 362-363.

2. Evans. A. E., Gilbert, E. S., and Zandstra, R.: The in- creasing incidence of central nervous system leukemia in children. Canrer 26:404-409, 1970.

3. Hcrsh. E. hl., Bodey, G. P., Boyd, A. N. , and Friereich. E. J . : Causes of death in acute leukemia. J A M A l93:1U5-l09. 1965.

4. Hughes. M‘. T.: Leukemia monitoring with fungal bone marrow cultures. J A M . 4 218:441-443, 1971.

5. hlirsky. H. S., and Cuttner, J . : Fungal infection in acute leukemia. Cancer 30:348-352. 1972.

6. Scott, h l . J.: Piedra. Arch . Dermofol. Syphilol. 64:767-773, I 9 S l .

7. Simone, J . \,’., Holland, E., and Johnson, W.: Fatalities during remission of childhood leukemia. Blood 39:759-770, 1072.

8. Watson. K. C.. and Kallichurum, S.: Brain abscess due to l’richosporon cutaneum. J . Med. Microbial. 3 : 191-193, 1970.