hepatic candidosis in a patient with acute leukemia leber-candidose bei einem patienten mit akuter...

mycoses 32 (8) 421 -426 . accepted/angenommen: January 12,1989 * 0 Grosse Verlag Berlin 1989

Hepatic Candidosis in a Patient with Acute Leukemia Leber-Candidose bei einem Patienten mit akuter Leukamie Frangoise Meunier', M. GCrard', V. Richard', L. Debusscher', H. Bleiberg' and A. Malengrau' 'Service de MBdecine Interne et Laboratoire d'hvestigation Clinique, HJ. Tagnon, Institut Jules Bordet, Centre des Tumeurs de l'Universit8 Libre de Bruxelles, Bruxelles, Belgium 2Service dAnatomopathologie, Universite Libre de Bruxelles, Bruxelles, Belgium

Key words: Hepatic candidosis - leukemia Schlusselworter: Candidose - Leber - Leukamie

Summary: Isolated hepatic candidosis has been described more frequently in patients with leukemia and consists in a particular clinical entity which remains difficult to control. We report here the case of a patient treated for acute nonlymphoblastic who developed hepatic candidosis two months after the end of intensive consolidation therapy.

Zusammenfassung: Isolierte Leber-Candi- dose ist bereits haufiger an Leukamie- Patienten beschrieben worden und stellt eine besondere klinische Entitat dar, die schwierig zu behandeln ist. Wir berichten uber einen Patienten, der wegen akuter nicht-Iymphoblastischer Leukiimie behan- delt wurde und der 2 Monate nach Beendi- gung einer Intensiv-Konsolidie- rungstherapie eine Leber-Candidose ent- wickelte.

Introduction

The frequency of focal hepatic candidosis (previously considered as an unusual event) seems to have increased during the last

decade. While disseminated candidosis constitutes a well known entity in immunocompromised hosts and particularly among granulocytopenicpatients (2,3,7,11,12,14, 19), invasive candidosis localized to the liver has only been recognized more recently, especially in patients recovering from granulocytopenia after induction and/or consofidation therapy for acute leukemia (1, 6, 8, 9, 13, 15, 16, 18). Focal hepatic candidosis has been occasionally described after documented fungemia but in most instances the source of this complication remains unknown. The case described here is characteristic of this syndrome and emphasizes the various prob- lems encountered in the management of hepatic candidosis.

Case Report

A 58 years old man with acute myelomono- blastic leukemia diagnosed in August 1986 received daunomycin and cytosine arabino- side (ARA-C) as induction treatment, fol- lowed by a high dose of ARA-C and

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F. Meunier et al.: Hepatic Candidosis with Acute Leukemia

m-AMSA as consolidation. During neu- tropenia, the patient was receiving oral pefloxacin (400 mg/12 hrs) and amphotericin B (administered as 10mg tablet/8 hrs) as gastrointestinal prophylaxis.

Secondary to the ARA-C administration, the patient presented severe oral mucositis and disseminated nodular skin lesions which were biopsied and diagnosed as necrotising vasculitis, probably in relation to ARA-C. A fever (> 38.5 "C) was documented during granulocytopenia and the patient received empirical broad spectrum antibiotic therapy including cefta- zidime, amikacin and vancomycin for two weeks, but no pathogen was isolated from the multiple samples obtained. Complete remission of leukemia was achieved on Sep- tember 10, 1986 and the patient was discharged.

Fifteen days later, at home, the patient who was no longer granulocytopenic, com- plained of fever (38 "C), watery diarrhoea and abdominal pain. The patient was treated symptomatically but was re- admitted to the hospital after two weeks for persistence of these gastrointestinal symptoms. A physical examination on admission showed hepatomegaly and elective tender- ness in the right abdominal lower quadrant. Laboratory findings showed elevated neu- trophils count OySC: 18.200/mm3), sedimentation rate (152 m / h ) and a mild elevation of alkaline phosphatases (274 mU/ml, normal value up to 115 mU/ml). All other liver function tests were normal. The gastrograffin enema, hepatic ultra- sound examination, computerized tomographic scan of the liver, stools cultures and Indium labelled leucocytes scintigraphy were all non-contributive. Diverticulitis of the colon was suspected and the patient was treated with ampicillin, metronidazole and gentamicin. Diarrhoea and abdominal pain disappeared and the patient was discharged 15 d after admission, however, mild temperature (38 "C) persisted. Re-admission was again necessary one week later due to identical signs and symptoms. Clinical

examination was as previously described. Temperature on admission was 38.5 "C. Laboratory findings showed a worsening of cholestasis (alkaline phosphatases: 344 mU/ml). On colonoscopy, micro-ulcera- tions of the rectosigmoid mucosa were observed. Biopsy of these lesions showed aspecific chronic rectitis. Culture of the specimen yielded Tomlopsis glabrata. Hepatic ultrasonogram was compatible with multiple microabcesses or hepatic granuloma, and the computerized tomographic scan showed multiple nodular hypodensities not enhanced by contrast (Figure 1). A laparoscopy was performed and showed an enlarged liver with multiple nodules which were biopsied. A direct smear of the specimen stained with calcofluor white (5) was positive for yeast like organisms. Histologi- cal examination of the specimen stained with hematoxylin eosine showed mild stea- tosis and infiltration of portal spaces by numerous polymorphonuclear cells for- ming micro-abscesses. Granuloma were also occasionally seen. Budding yeasts were demonstrated on PAS and Gomorimethen- amine silver stains (Figure 2). Culture of the biopsied specimen failed to grow any fungal pathogen. Further investigations did not reveal evidence of disseminated candidosis : eye ground examinations, multiple blood cultures and urine cultures remained nega- tive. Intravenous amphotericin B therapy was initiated (1.2 mg/kg/48 h) until a total dose of 1600 mg was administered. The fever, abdominal pain and diarrhoea disappeared promptly.

After discontinuation of this antifungal treatment, hypodensities persisted on computerized tomographic scan of the liver but cholestasis slowly decreased (alkaline phosphatases 240 mU/ml). Six weeks after diagnosis of hepatic candidosis, the patient remained asymptomatic and alkaline phosphatases continued to decrease (170 mU/ml). A second hepatic biopsy (transcu- taneous punction) was obtained and showed no interstitial infiltration by inflam- matory cells but persistence of poorly

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Figure 1 : Nodular hypodensities on computerized tomographic scan (D 10).

nuloma. No more yeasts or pseudomyce- lium could be identified.

Three months later, a relapse of leukemia occurred. At this point, liver enzymes were normal despite persistence of hypodensities on computed tomographic scan of the liver. Re-induction chemotherapy with A M - C and m-AMSA was administered.Duringthe following episode of granulocytopenia, septicemia caused by Streptococcus faecalisand Staphylococcus epidermidis was documented and could be controlled with intravenous antimicrobial therapy. Candida krusei septicemia with multiple cutaneous septic emboli also occurred one week after the initiation of broad spectrum antibiotics. At this point, antifungal therapy was rein- stated but 3 weeks later the patient was discharged without specific treatment because of uncontrolled leukemia. He died at home one and a half months after fungemia and no autopsy was performed.

Discussion

Candidu species are isolated from 20 to 50 '/o of healthy subjects and are considered to be part of the normal gastrointestinal flora. This commensal organisms may cause colonisation or numerous infectious com- plications, either locahzed or disseminated. In particular in immunocompromised hosts, various types of candidosis have been documented ranging from mild oropharyn- geal candidosis to rapidly fatal deep-seated candidosis.

Overgrowth of yeasts is enhanced by broad spectrum antibiotics. Mucosal lesions secondary to antineoplastic chemotherapy allow invasion and dissemina- tion of the gastrointestinal microorganisms. This phenomenon seems to constitute the major source for disseminated candidosis. Widespread invasive candidosis involving numerous organs, including the liver, is a

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Figure 2: Gomori methenamine silver stain of specimen obtained by liver biopsy (x 500).

life-threatening condition well documented in granulocytopenic cancer patients (2,3,7, 11, 12,14,19).

Focal hepatic candidosis, however, is a rare opportunistic complication reported mostly in patients with leukemia (1 ,6 ,8 ,9 , 13, 15, 16, 18). A large majority of these patients had acute leukemia and most of them were in complete remission when hepatic candidosis occurred. Nearly all of these patients had received broad spectrum antibiotics, antineoplastic chemotherapy and had documented fungal colonisation of the gastrointestinal tract. They showed a fever refractory to broad spectrum antibiotics, hepatomegaly, non-specific gastrointestinal symptoms such as diarrhoea (in 80 "/o) and laboratory signs of liver involvement with mild to severe elevation of alkaline phosphatases. The etiology of diarrhoea in these patients remains unclear; in particular, there has been no report of histo-

logically proven gastrointestinal candidosis in association with this clinical entity. It is worth noting that most patients were not granulocytopenic at the time of diagnosis of hepatic candidosis. In addition, Candida species were seldom isolated in culture from hepatic biopsies despite histological dem- onstration of yeasts. Most patients received antifungal therapy with amphotericin B alone or in association with 5-fluorocyto- sine. Somes patients received ketoconazole.

Success of therapy appears quite variable and is difficult to interpret from data available in the literature (18). Recovery from this fungal complication only seems to be observed in patients with persistent complete remission of their underlying disease. In patients suffering a relapse of leukemia, re-evolution of hepatic candidosis and/or fungemia often occurred concomitantly.

Our patient is particularly representative of this entity with regard to his clinical pres-

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entation and laboratory findings, in the con- text of prolonged granulocytopenia requir- ing the administration of broad spectrum antibiotics. Hepatic imaging and histologic findings are also characteristic.

The significance of the isolation of ?: gla- bratu from the biopsy of the intestinal mucosais unclear. However, a case report of hepatic abscesses caused by T glabrata has been recently published (4). Another unsolved question is whether the fungemia caused by C. krusei was due to a new episode of candidosis or to endogenous re-infection from persistent focus of hepatic candidosis. Relapse of fungemia or evolution of hepatic candidosis are frequently observed in those patients suggesting a failure of antifungal therapy to eradicate deep-seated foci of infection. Therefore, the management of this entity is frustrating unless the control of leukemia ia achieved. Some investigators have reported the potential value of therapy with ampholiposomes in such circumstan- ces (10,16) but unfortunately this approach remains anecdotical and experimental. Ampholiposomes are not yet commercially available and furthermore, there is a need to perform controlled studies comparing this galenic preparation with conventional therapy consisting of amphotericin B.

In conclusion, severe opportunistic fungal infections may also occur inpatients with leukemia in complete remission and after recovery from granulocytopenia. A patient with fever not responding to broad spectrum antibiotics, with gastrointestinal symptoms and biological signs of liver involvement must be suspected of hepatic candidosis. In this situation, intensive investigations should be performed to confirm this possi- bility.

There are no studies suggesting that a patient who suffered previously Gom hepatic candidosis and relapsing leukemia will benefit from “prophylactic” intravenous arnphotericin B administration during re-induction therapy for the leukemia; however, this approach should be considered, taking into account the lack of control of this

fungal infection. Further studies should be initiated to improve the management of such patients and to establish the potential risk of further antineoplasic chemotherapy, with or without antifungal therapy.

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logy 159,349-j53. 17. Tasihiian. L.S.. J.S. Abramson. J.E. Peacock CorresDondence: Dr. Francoise Meunier.

(1 $84): Focal hepatic candidiasis: a distinct c h i - cal variant of candidiasis inimmunocompromised patients. Rev. Infect. Dis. 6,689-703.

Microdiology and Infectiois Diseases Uht, Institut Jules Bordet, rue Higer Bordet 1, B-1000 Bruxelles, Belgium.

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hepatic candidosis in a patient with acute leukemia leber-candidose bei einem patienten mit akuter...

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