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HEPATOSPLENIC CANDIDIASIS
INFECTIONS OF THE LIVER
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HEPATOSPLENIC CANDIDIASIS A Manifestation of Chronic Disseminated Candidiasis D. P. Kontoyiannis, MD, ScD, M. A. Luna, MD, B. I. Samuels, MD, and G.P. Bodey, MD
Invasive candidiasis is a major cause of morbidity and mortality in patients with hematologic malignancies a d a frequent cause of failure of the initial remission induction chemotherapy in this patient PO ulation.1z,25 Candidemia in neutropenic patients with leukemia is associated wi disseminated organ infection in most cases.lZ,53 The syndrome of acute disseminated candidiasis (ADC) in patients with acute leukemia, increasingly recognized since the 195Os,l1*45 has a predictable prognosis that depends on the recovery of the neutrophil count: If the patients achieve remission of their underlying leukemia and their neutrophil counts recover, then they usually recover with therapy unless the infection is overwhelming. If the neutropenia remains refractory, then the outcome, despite treatment with antifungals, is fatal.lZDuring the last three decades, a chronic form of disseminated candidiasis has been recognized with increasing frequency." 3z*74 Bodey et a1 first reported chronic hepatosplenic candidiasis with hypersplenism in a patient with leukemia who had achieved a complete remission after chemotherapy.1° The patient developed a refractory fever of unknown cause associated with persistent pancytopenia despite normal findings on bone marrow biopsy.1° The patient's spleen was removed and was found to contain multiple abscesses containing Candida spp. After treatment with amphotericin B, the patient fully recovered.1° This syndrome subsequently was described in more detail in the early 1980s1,32 36, 46* 49, so, 73, 74 and is often referred as hepatosplenic candidiasi~,6~ chronic systemic candidiasis: or chronic disseminated candidiasis (CDC). We believe that the last is the most appropriate term, because it describes
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From the Section of Infectious Diseases, Department of Internal Medicine Specialties(DPK, GPB); and the Departments of Pathology (MAL), and Diagnostic Radiology (BIS), University of Texas h4D Anderson Cancer Center, Houston, Texas INFECTIOUS DISEASE CLINICS OF NORTH AMERICA VOLUME 14 NUMBER 3 SEPTEMBER Zoo0
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a chronic infection that may involve other organs in addition to the liver and spleen. PATHOGENESIS
The pathogenesis of CDC is unclear and controversial?,67 The risk factors for the disease are similar to those for the acute form of disseminated candidiasis: the presence of acute leukemia, prolonged neutropenia, intravascular catheters, disruption of mucosal barriers, and the administration of broad-spectrum antibiotics?,lo,32, sf46* 49, so* 67, 73, 74 CDC in nonleukemic patients is rare. Kapur et a1 described such a case involving predominantly the spleen in a patient with diabetes mellitus and sickle cell Recognition of CDC has increased since arabinosyl cytosine (ara-C), especially in high doses, began to be combined with anthracycline as standard remission induction chemotherapy for acute myelogenous leukemia.@The most likely sequence of events leading to the development of CDC in that setting is prolonged neutropenia and mucosal damage of the gastrointestinal tract followed by local invasion and subsequent entry of the Candida spp into the hepatosplenic circulation, resulting in liver infecti011.l~ Because inflammatory reaction is absent, however, the infection most commonly manifests itself only as fever until the patient's neutrophil count recovers, when other symptoms begin to appear. Bosch et al reported the occurrence'of CDC following typhlitis by Candida albicans in a patient with acute lymphocytic leukemia receiving cytotoxic chem~therapy.'~ The above model of pathophysiology of the disease has been replicated in ara-C or cyclosphosphamide-treated neutropenic animal models of subacute disseminated candidiasis.2Or79 Based on studies in a granulocytopenic rabbit model of experimental disseminated candidiasis, Walsh et a1 proposed that the likelihood of a patient developing CDC or ADC following chemotherapy depends on the infecting fungal inoculum; the rabbits receiving the highest Candida inoculum developed ADC, whereas the rabbits receiving the lowest Candida inoculum developed CDC.79. Other theories of the pathogenesis of the syndrome have been proposed. We believe that CDC is a distinct entity from ADC? Typically, neutropenic patients with ADC follow one of three courses: (1)their neutrophil counts do not recover and they die of rapidly progressive infection despite appropriate therapy; (2) their neutrophil counts return to normal, and they respond to therapy and recover; or (3) their neutrophil counts recover after the infection becomes widespread, and the influx of neutrophils to the numerous infected sites causes organ failure and death. Although CDC is assumed to follow an acute infectious episode, most cases of CDC do not follow a recognizable episode of ADC and typically are diagnosed only after the patient's neutrophil count has returned to This suggests that the host inflammatory response is pivotal in defining the lesions that are characteristic of CDC.7* Furthermore, gryuloma formation is the typical response seen in the non-neutropenic patients with CDC, in contrast to the abscess formation with adequate neutrophil count and coagulative necrosis seen in neutropenic patients with ADC." CDC often persists for prolonged periods (as long as 12 months) after resolution of neutropenia, which suggests that this infection could be the result of a specific, as-yet-unknown immune dysfunction in some patients with leukemia, most likely as a result of antileukemic chemotherapy. Because granuloma formation is the characteristic response in patients with chronic mucocutaneous candidiasis, many of whom have defects in lymphocytic or monocyte function,"
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it is possible that patients who develop CDC also have defects in lymphocyte function.62Roilides et al found that patients with hepatosplenic candidiasis have increased serum levels of the anti-inflammatory cytokine IL-lO,& suggesting that a Thl-Th2 imbalance or other selective immunologic defects may underlie the pathogenesis of the syndrome.62 Surprising long-term remission of leukemia recently was reported in three patients with CDC who received minimal chemotherapy." The authors of the report speculated that an infection-associated cytokine release exerted an antileukemic effect." INCIDENCE
The true incidence of CDC is unclear15 because establishing a definite diagnosis is difficult5 and the disease occurs so infrequently that no institution has accumulated a large number of cases. Even though multiple studies in the 1980s2,7, 32, 36* 49, 74 reported a significant increase in the frequency of CDC, some of those case series did not include a denominator.32,49, n,74 Furthermore, it is unclear whether some of the reported increase simply reflected better overall survival in patients with ADC owing to improved supportive care and the routine early use of empiric antifungal therapy, or better detection of CDC owing to the increased awareness of this disease and the introduction of more sensitive imaging techniques such as ultrasonography (US) and computed to69 To complicate matters further, the mography (CT) in routine clinical antemortem incidence of CDC might underestimate its true incidence, because it is well known that Candida dissemination in visceral organs can go undetected 54 A Finnish in almost half of the cases in neutropenic patients with le~kemia.4~. study covering the period 1980 to 1993 found a CDC rate of 6.8%(38/562) in a large cohort of patients with acute leukemia? Similarly, a Spanish study covering the period 1985 to 1990 found a CDC rate of 3.2% (10/305) in patients with leukemia.7In those series, 30% and 29% of cases, respectively, had diagnosed CDC only at autopsy3, The frequency of CDC has decreased dramatically during the last decade. This decrease has been noted at large leukemia and bone marrow transplant centers, such as M. D. Anderson Cancer Center and Fred Hutchinson Cancer Center, where fluconazole prophylaxis has been used e x t e n s i ~ e l yThis ~ ~ trend is well illustrated by a recent large autopsy study of bone marrow transplant (BMT) patients at high risk for CDC; that study clearly showed that the frequency of visceral candidiasis has decreased precipitously since the introduction of fluconazole pro phyla xi^^^ (Table 1). The activity of fluconazole in the prevention of CDC also has been demonstrated in a persistently granulocytopenic rabbit model of infection.8o CLINICAL PRESENTATION
Even though CDC and ADC are believed to represent two points on the same infectious spectrum, CDC as a disease process is distinctly different from ADC (Table 2). The clinical presentation of CDC is unique and is the basis for the definition of the syndrome.13 The infection is seen typically in patients with leukemia who have received cytotoxic chemotherapy. It presents initially as neutropenic fever with no focal signs or symptoms and fails to respond to broad-spectrum antibiotics. Liver function tests and US or CT scans of the abdomen are generally normal at this
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Table 1. SIGNIFICANCE OF HEPATIC CANDlDA ORGANISMS IDENTIFIED AT AUTOPSY ~
~
Fungal Organism
Any Candida species Candida albicans Non-albicans Candida* Histology only
No Fluconazole Fluconazole Relative NO.(%) No. (%) Risk 23/161 (14) 11 3 9
2/168 (1.2) 0 1 1
12 3.1 9.4
95% CI (2.9, 50.1) (0.33, 29.8) (1.2, 73.7)
~
PValue
<0.001
<0.001 0.36 0.009
‘One isolate each of T.glabratu, C. krusei, C. tropicalis, and C. guillimondii. Adaptedfrom van Burik J-AH, Leisenring W, Myerson D, et al: The effect of prophylactic fluconazole on the clinical spectrum of fungal diseases in bone marrow transplant reapients with speaal attention to hepatic candidiasis.Medicine P.246,1998; with permission.
time (Fig. 1).Subsequently the patient‘s leukemia goes into remission, and the neutrophil count returns to normal. However, the patient continues to experience high fever, anorexia, weight loss, and debilitation. Right upper quadrant pain or right-sided pleuritic chest pain may be present. Hepatomegaly or splenomegaly or both are present in half of the cases. At this point, substantial elevation of alkaline phosphatase is noted, an abnormality that can persist for months. Other liver function tests also can produce abnormal results, but these abnormalities are usually less impressive. Other less typical presentations can be encountered. Moseby et a1 have described two patients with acufe leukemia in remission who presented with the triad of abdominal pain, respiratory alkalosis, and abnormal liver function tests and were found to have Cundidu hepatitis.” Similarly, predominant involvement of the spleen with little or no involvement of the liver by Cundidu abscesses has been described in patients with hematologic malignan3
Table 2. FORMS OF DISSEMINATED CANDlDlASlS IN PATIENTS WITH ACUTE LEUKEMIA.
Evaluation
Acute Disseminated Candidlasis (ADC)
Neutropenic fever unresponsive to antibacterials, multiple skin lesions, pneumonia, shock Positive for Candida spp. Blood cultures (30%-70%) Imaging studies (CT, US) Typically negative Course Acute (days-weeks) Clinical presentation
Host response Site of involvement Response to antifungal therapy ‘Overlap may occur.
Chronic Disseminated Candidiasis (CDC)
Non-neutropenic fever, unresponsive to antibacterials, abnormal liver function test results Typically negative Positive for focal lesions Subacute-chronic (weeks-month) Granuloma formulation
Coagulation and hemorrhagic necrosis, abscess formation Predominantly spleen and liver Skin, lungs, GI tract, kidneys, liver, spleen High mortality in absence of Better response neutrophil recovery
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Alkaline Phosphatase
Normal
Elevated
>I000
PUN
Imaging Liver
0
0
+
cies.=,35Some of those patients had predominant signs and symptoms of hypersplenism.l0,=, =* Radiologic Features of Hepatosplenic Candidiasis
In CDC, characteristic lesions are detected in the liver and spleen, and sometimes in other organs, by using US, CT or magnetic resonance imaging (MRI) studies.'z 31* 38, ss, 57, m, These studies are useful once the patient has an adequate neutrophil count. Typically, lesions cannot be detected by US or CT examination when the patient is neutropenic because the patient is unable to produce an inflammatory reaction. Similarly, the known lesions of CDC can disappear transiently during subsequent chemotherapy-induced neutropenia, and reappear after neutmphil recovery? In most centers, the initial diagnosis is made with unenhanced or enhanced CT. MRI and CT scans are the most reliable diagnostic procedures, revealing lesions in about 90% of patients; US identifies lesions in 70% to 75% of patients.@Several patterns of organ involvement can be discerned. In about 63% of patients, lesions can be detected in the liver and spleen; in 22%, only in the liver; and in 15%, only in the spleen.69 Four dominant patterns of hepatosplenic candidiasis have been described using US studies.57Early in the disease, the "wheel within a wheel" pattern develops (Fig. 2). Histologically, it consists of a peripheral hypoechoic zone that correlates with a ring of fibrosis. h i d e the outer hypoechoic wheel is a second hyperechoic wheel composed of inflammatory cells. The central hypoechoic nidus relates to necrotic fungal elements. The second pattern, typical of a bull's eye, evolves from the primary lesion (Fig. 3). These hepatic lesions are usually 1 to 4 an in diameter. The third and most common pattern is a uniform hypoechoic lesion and can be seen in conjunction with the other three patterns (Fig. 4). The fourth pattern, consisting of echogenic foci, usually is seen late in the disease and correlates microscopically with central fibrosis or calcifications or both.
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Figure 2. Transverse sonograrn of the liver in a 28-year-old patient with acute lyrnphocytic leukemia. A wheel within a wheel microabscess (arrow) is demonstrated at the right portal vein. (Modified from Sarnuels 61, Pagani JJ, Libshitz HI: .Radiologic features of Candida infections, In Bodey GP (ed): Candidiasis: Pathogenesis, Diagnosis and Treatment. New York, Raven Press, 1993, pp 137-1516: with permission.)
Figure 3. Transverse hepatic sonograrn in a leukemic patient with chronic, disseminated hepatosplenic candidiasis with characteristic bull’s-eye microabscesses (arrow). (Modified from Sarnuels BI. Pagani JJ. Libshitz HI: Radiologic features of Candida infections. In Bodey GP (ed): Candidiasis: Pathogenesis, Diagnosis and Treatment. New York, Raven Press, 1993, pp 137-156; with permission.)
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Figure 4. Transverse sonogram in a patient with acute lymphocytic leukemia and several typical hypoechoic Candida microabscesses (arrows) anterior to the right kidney. (Modified from Samuels Bi, Pagani JJ, Libshitz HI: Radiologic features of candida infections. In Bodey GP (ed): Candidiasis: Pathogenesis, Diagnosis and Treatment. New York, Raven Press, 1993, pp 137-156; with permission.)
Typically, fungal hepatic candidiasis on CT scans is characterized by multiple small, round, low-attenuation lesions scattered throughout the liver and spleen (Fig. 5). Sometimes peripheral enhancement is seen. Infrequently, tiny central densities presumed to represent hyphae are seen. The appearance on CT scans is not pathognomonic and can be mimicked by metastatic disease and bacterial abscesses. In a three-university collaborative study, MR imaging was reported to be superior to CT in demonstrating chronic, disseminated, hepatosplenic candidiasis in the acute, subacute, and chronic healed phases based on their MR imaging appearances.” 69 Patients with persistent fever or no response to antibiotics were included and grouped as acute, subacute treated, and chronic treated, depending on the duration of their symptoms. Patients with 2 weeks or less of possible infection were considered to have an acute presentation; those receiving antifungal therapy for 3 months and who had a history of hepatosplenic fungal disease were considered to have a chronic treated presentation. Image presence, size, signal intensity, borders, and perilesional changes were recorded for all MR image sequences, and enhancement patterns were determined after the administration of gadolinium. Although the authors concluded that MR imaging has high diagnostic accuracy, they did point out that the initial MR imaging study may be unremarkable in the neutropenic patient. US, CT, and MR imaging studies have been used to determine the patient’s response to thera~y.6~.Studies should be repeated every 3 to 4 weeks initially. Response is indicated by reduction in the size and number of the lesions without the appearance of new lesions. US is an ideal modality for following the patient‘s response because it involves no ionizing radiation and costs significantly less than CT or MR imaging. One alternative approach is to obtain a CT or MRI
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KONTOYIANNJSetal
Figure 5. Unenhanced (A) and enhanced (B) abdominal CT scans in a 34-year-old man with acute myelocytic leukemia demonstrate low attenuation foci microabscesses (anow, A), in the liver and spleen. The fungal lesions are seen better before the administrationof intravenous contrast material. (Modifiedfrom Samuels BI, Pagani JJ, Libshitz HI: Radiologic features of Candida infections. In Bodey GP (ed):Candidiasis: Pathogenesis, Diagnosis and Treatment. New York, Raven Press, 1993, pp 137-156; with permission.)
scan first, because either is more sensitive than US and then, if lesions are detected, conduct an US study immediately thereafter. US then can be used for follow-up; when no more lesions can be detected on US scans, a repeat CT or MR scan is obtained. Multiple scattered low-attenuation foci can persist despite successful treatment, because focal scarring and chronic inactive granulomatous
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Figure 6. Calcified residue (arrows) typical of healed hepatosplenic candidiasis are demonstrated in a child with acute myelocytic leukemia. (Modified from Samuels BI, Pagani JJ, Libshitz HI: Radiologic features of Candida infections. In Bodey GP (ed): Candidiasis: Pathogenesis, Diagnosis and Treatment. New York, Raven Press, 1993, pp 137-156; with permission.) changes mimic active lesions. Over time, calcifications develop in areas of scarring (Fig. 6). Pathologic Patterns of Hepatosplenic Candidiasis Depending on the status of host defenses or rate of recovery of immune competence, hepatosplenic Candida infections have three histologic patterns: (1) necrosis with minimal inflammatory reaction, (2) microabscesses with severe inflammation, and (3) granuloma^.^^ The first two patterns are associated with ADC.@The common denominator in patients with ADC is prolonged severe neutropenia. Histologically, necrotic lesions with minimal inflammatory reaction are characterized by coagulative necrosis associated with hemorrhage without or with minimal inflammation (Fig. 7). The histologic appearance of the lesions reflects the lack of inflammatory cells, and patients with this lesion seldom recover from their neutropenic state. Candida organisms are numerous and easily demonstrated with the help of special stains. Microabscesses, on the other hand, are seen in patients whose bone marrow is recovering and peripheral blood counts are increasing, or in patients who have never been neutropenic. Histologically, in addition to coagulative necrosis, these lesions show a mixture of polymorphonuclear neutrophils, lymphocytes, plasma cells, and monocytes (Fig. 8). The thud pattern, granulomatous tissue reaction to Candida organisms, is less frequent and usually is seen in the liver and spleen. Occasionally, other organs such as the kidney are involved. Histologically, the lesions are characterized by areas of central necrosis or fibrosis, surrounded by granulation tissue,
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Figure 7. Liver tissue showing coagulative necrosis. Note lack of inflammatory cells (hematoxylin-eosin stain, original magnification x 60).
Figure 8. Candida lesion with severe inflammatory reaction (hematoxylin-eosin stain, original magnification x 100).
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Figure 9. Candida granuloma. Note giant cells and fibroblast arranged in a palisade pattern (hematoxylin-eosin stain, original magnification x 100).
macrophages, or fibroblasts arranged in palisades and giant cells (Fig. 9). These are the lesions typically observed in CDC. Grossly and radiologically, the granulomas resemble metastatic carcinoma. DIAGNOSIS
The diagnosis of CDC requires a high degree of suspicion and recognition of the characteristic setting of CDC. No single noninvasive study with enough sensitivity specificity, and positive and negative predictive value is available to establish the diagnosis. A combination of studies often is required, and repeated examinations are warranted if the studies are negative initially but the suspicion of CDC remains high. As previously discussed, modern imaging techniques are increasingly important in the early identification and management of the syndrome.lZ,38, 56, 57, sf G9, 70, 71, If the patient can tolerate the procedure, however, it is desirable to obtain a biopsy to establish the diagnosis. Other disseminated granulomatous disease processes, such as miliary tuberculosis, disseminated fungal disease caused by other fungi such as the invasive molds," Trichosporum beigeliP or Blastoschizomyces capitatus,5* or even malignancyz6can mimic CDC. Because of the size of the lesions, percutaneous CT-guided needle biopsy is sufficient in some patients5,74 but can fail to reveal fungal organisms.5 Because the Cundidu organisms are less numerous in the granulomas than in the lesions seen in ADC, the diagnosis of hepatic candidiasis is established most reliably by open liver biopsy?, 74 Although fungal elements can be identified histopathologically, Candidu spp. can be isolated from tissue culture in only about 50% of cases. Most cases have been caused by C . albicans, but C . tropicalis, C. glabrata, C . krusei, and other Candida spp. are responsible for a few cases." 4, 66, 74 There is evidence that
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the routine use of fluconazole resulted in the increased isolation of the nonulbicans Candida spp. as causes of both candidemiaS9and CDC.76Satisfactory results have been obtained in selected patients by laparoscopic liver biopsy.* 5, 74 Cundida spp. infrequently are isolated from cultures of blood from patients with CDC.9.32 74 Early diagnosis of CDC before the lesions are large enough to be detected by imaging techniques is desirable. Considerable effort has been invested in developing nonculture methods for diagnosing disseminated candidiasis. Promising methods include detection of serum Candida enolase, serum D-arabhitol, and serum c-reactive protein by detection of Cundida mannan by radioimmunoassay; and detection of polymerase chain reaction (PCR)using Candidu speciesspecific probes?* =, = Unfortunately, none of these approaches has proven to be entirely satisfactory. More work is needed in this important area for early and specific diagnosis of the syndrome. TREATMENT
The optimal management of CDC is not yet well established. The most appropriate therapeutic regimens and the end points of treatment are not adequately defined; therefore, a relapse of the infection could occur owing to either premature discontinuation of antifungal therapy or inadequate antifungal therapy in patients with chemotherapy-inducedneutropenia. Because CDC is an uncommon disease, comparative controlled studies are difficult to conduct. Historically, the usual therapy for CDC has been the antifungal agent amphotericin B deoxycholate, yet, in almost 50% of cases, administration for periods up to 6 months and up to a total dose of 6 g is still not enough to stop the infection from progressing.&42The frequent failure of this therapy may be due to the pharmacokinetic properties of amphotericin B. It has been demonstrated that Candida infection can persist in the livers of patients despite the presence of concentrations of amphotericin B that exceed by a hundredfold the minimal inhibitory concentration (MIC) for Cundidu.17 In addition, prolonged treatment with amphotericin B of a chronic infection such as CDC frequently causes considerable toxicity, especially renal.& a Some investigators have advocated using a combination of amphotericin B and 5-fluorocytosine on the basis of an experimental model of hepatosplenic candidiasis in rabbits with prolonged neutropenia." Whether this combination offers sigruficant advantages, however, is not clear." 75 The 1990s saw the introduction of promising agents such as the triazoles and the liposomal formulations of amphotericin B." The liposomal formulations of amphotericin B and fluconazole have a more favorable therapeutic index and 78 A ll of the commercially available parenmore favorable pharmacokinetic~.~~~ teral liposomal formulations of amphotericin B (Amphotericin B Lipid Complex, Liposomal Amphotericin B, Amphotericin B Colloidal Dispersion) permit the administration of the drug at much higher dosesm They also are targeted naturally to the liver and spleen (to different degrees), which promotes their selective interactions with the Cundida membrane?7,78 No extensive experience with the liposomal formulation of amphotericin B, however, has been published.30,s,= A limited series using a liposomal formulation of amphotericin B suggests a response rate of about 85% to 90%." Fluconazole, an azole antifungal, is tolerated well, readily absorbed from the gastrointestinal tract, and distributed widely in body tissues including the liver, spleen, and kidneysz9Fluconazole has a response rate of about 80% and
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is effective even among patients who failed to respond to previous amphotericin B treatment?,21, Some investigators have suggested that the high response to fluconazole is due in part to the previously administered amphotericin B. This conclusion is incorrect, however, because the patients who were given fluconazole after amphotericin B were given the fluconazole because they showed no evidence of response or had progression of disease while receiving amphotericin B therapy.” As noted earlier, the high hepatic concentrations of amphotericin B do not result in the clinical activity of this drug.17It is believed that fluconazole should be the drug of choice for CDC because it is at least as effective as amphotericin B, is less toxic (especially important because of the need for prolonged therapy), can be given orally, and is less expensive than lipid formulations of amphotericin B.= Fluconazole should be administered at a dose of 600 to 800 mg/day, starting on the intravenous route and switching to the oral route, once the patient stabilizes (typically in about 1 to 2 weeks). Usually it takes 2 to 3 weeks to see a measurable response. Fluconazole plus 5-fluorocytosine at lower-than-conventional doses (8 to 10 mg/kg/day) may be superior, but no experience with this combination has been reported. Finally, surgery might be useful in selected cases. Case reports and small series suggest a beneficial role of splenectomy or percutaneous drainage in conjunction with antifungal therapy in immunosuppressed patients with Candida splenic abscesses.34,35, CDC can be a debilitating and persisting chronic infection. It has the potential to interfere with the administration of subsequent antileukemic therapy. During periods of intensification of chemotherapy, the risk of early relapse of CDC and its conversion to acute disseminated candidiasis exists, especially when the infection has shown signs of progression before the onset of chemotherapy. On the other hand, as Walsh et a1 showed, adequately treated CDC seldom progresses to ADC or breakthrough candidemia, especially when antifungal therapy continues though the n e ~ t r o p e n i aWalsh . ~ ~ et a1 recommend that stable infection (defined as no further development of new lesions, no expansion in size of existing lesions, and no further clinical deterioration) be the initial goal of management of CDC before continuation of chern~therapy.~~ Therefore, the duration of therapy should be highly individualized and typically should last for about 6 months. Some patients have been cured with only 1 to 2 months of therapy. Evidence of a response to therapy includes improvement in clinical signs and symptoms, along with decreasing number and size of hepatic and splenic lesions. Residual lesions can remain, even after successful therapy, due to scarring or calcification. Such radiologic findings in a patient who also has no signs and symptoms of the infection and has been in hematologic remission should be reasonable end points for cessation of antifungal therapy. Prognostic factors associated with unfavorable outcome are the development of leukemic relapse during therapy2 recurrent neutropenia, delayed antifungal therapy, and lack of adequate secondary prophylaxis during neutropenia.
PROPHYLAXIS AND FUTURE THERAPEUTIC APPROACHES TO CDC
Although less common now, CDC still occurs despite prophylaxis or preemptive therapy with azoles. Leukemia relapse and Candida colonization of the gastrointestinal tract are risk factors.18 This is not surprising, because we and
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others have found that azoles have no decolonizing effect in at least one mouse model of persistent gastrointestinal colonization by C . albicuns.60, Future therapeutic approaches to CDC should focus on the availability of more effective and safer antifungals that preferably are given orally and once daily, for both therapy and prophylaxis. The deficiencies in the antifungal spectrum of fluconazole limit its use against fluconazole-resistant Candida infections, whose incidence has increased during the last decade.%In light of the preclinical data, the newer generation of triazoles (e.g., voriconazole, SCH 56592, and D0870) and other novel classes of antifungals (e.g., the lipopeptides) show considerable promise in addressing those shortcomings while avoiding the wellknown toxicities of polyenes.28Therefore, the use of these agents alone or in combination with the current antifungal agents for the treatment of CDC should be explored. On the other hand, in the only prospective study of the prevention of CDC reported so fx, Karthaus reported that intensive low-dose intravenous amphotericin (1 mg/kg every other day) was a highly effective and welltolerated prophylactic approach.39The optimal secondary prophylaxis for preventing recurrence in patients with CDC during subsequent chemotherapy is still unclear." It is also likely that cytokine modulation can enhance the therapeutic response in Rfractory cases of CDC.27,* 61 Interferon gamma showed a convincing effect in clearing hepatosplenic lesions in two patients with leukemia and biopsy-proven hepatosplenic candidiasis, whose disease still persisted after 6 weeks of treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) and liposomal amphotericin B (AmBisome).61 @
CDC IN SPECIAL GROUPS Pediatric Patients
CDC has been described in pediatric leukemia patients.16The clinical manifestations and the diagnostic yield of CT in these patients appear to be similar to those in adults." 16, 26 Walsh et a1 studied the pharmacokinetics, tolerability, and clinical efficacy of amphotericin B lipid complex (ABLC) given at a dose of 2.5 mg/kg for 6 weeks in six children with CDC. ABLC levels reached a steady state in the liver within 1 week of therapy, and the drug was well tolerated and efficacious in all patients.86 Bone Marrow Transplant Recipients
The diagnosis of hepatic involvement by Candida could be challenging in bone marrow recipients, who often have other causes of elevation of liver function tests, such as veno-occlusive disease and liver graft-versus-host disease.@Rossetti et a1 reported a disappointingly low sensitivity of the routine imaging studies, even during the last week of life in BMT recipients with autopsy-proven hepatic candidiasis." Fortunately, the syndrome appears to have decreased dramatically in frequency since the introduction of fluconazole as routine prophylaxis in these patients76(see Table 2). Small studies of and pediatric BMT recipient^*^ have provided reassurances that CDC complicating chemotherapy for the treatment of leukemia is not an absolute contraindication to subsequent BMT, provided that the infection is well controlled before the
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transplant and that antifungal therapy (amphotericin B) is continued at least throughout the preengraftment period. SUMMARY
Much progress has been made over the last decade in diagnosing and treating CDC, a chronic and debilitating infection that interferes with the delivery of intensive cytotoxic chemotherapy in patients with leukemia. The use of fluconazole prophylaxis in these patients has decreased the incidence of CDC dramatically. The greatest future challenges are gaining a better understanding of its pathophysiology, and the continued development of effective diagnostic and therapeutic strategies to treat this unusual manifestation of systemic candidiasis.
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(ed): Candidiasis: Pathogenesis, Diagnosis and Treatment, New York, Raven Press, 1993, p 407 Bosch F, Urbano-Ispizua A, Blade J, et al: Systemic chronic candidiasis following typhilitis caused by Candida albicans. Med Clin (Barcelona) 99:581, 1992 Bow EJ, Loewen R, Cheang MS, et ak Invasive fungal disease in adults undergoing remission-inductiontherapy for acute myeloid leukemia: The pathogenetic role of the antileukemicregimen. Clin Infect Dis 21:361, 1995 Carstensen H, Widding E, Storm K, et ak Hepatosplenic candidiasis in children with cancer. Three cases in leukemic children and a literature review. Pediatr Hematol Oncol 7:3, 1990 Christiansen KR, Bernard EM, Gold JWM, et al: Distribution and activity of amphotericin B in humans. J Infect Dis 1521037, 1985 Chubachi A, Miura I, Ohshima A, et al: Risk factors for hepatosplenic abscesses
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in patients with acute leukemia receiving empiric azole treatment. Am J Med Sci 308309,1994 19. Cole GT, Halawa AA, Anaissie EJ: The role of the gastrointestinal tract in hematogenous candidiasis: From the laboratory to the bedside [review]. CIin Infect Dis Z(supp1 2):S73, 1996 20. Cole GT, Lynn KT, Seshan KR, et al: Gastrointestinal and systemic candidosis in immunocompromised mice. Journal of Medical and Veterinary Mycology 27363, 1989 21. de Pauw BE, Raemaekers JM, Donnelly JP, et al: An open study on the safety and efficacy of 5uconazole in the treatment of disseminated Candidu infections in patients treated for hematological malignancy. Ann Hematol 7083, 1995 22. Dear A Hepatosplenic candidiasis in patients with acute leukemia: What is the optimum prophylaxis following subsequent chemotherapy. Eur J Haematol 52184, 1994 23. Edwards JE Jr, Bodey GP, Bowden RA, et al: International conference for the development of a consensus on the management and prevention of severe candidal infections [review]. Clin Infect Dis 25:43, 1997 24. Einsele H, Hebart H, Roller G, et al: Detection and identification of fungal pathogens in blood by using molecular probes. J Clin Microbiol35:1353, 1997 25. Estey EH, Keating MJ, McCredie KB, et al: Causes of remission induction failure in acute myelogenous leukemia. Blood 60309,1982 26. Flynn PM, Shenep JL, Crawford R, et al: Use of abdominal computed tomography for identifying disseminated fungal infection in pediatric cancer patients. Clin Infect Dis 20:964,1995 Dale DC, et al: Comparison of interferon?, granulocyte 27. Gaviria JM, van Burik J-AH, colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor for priming leukocyte-mediated hyphal damage of opportu&ic fungal pathogens. J Infect Dis 179:1038, 1999 28. Georgopapadakou NH, Walsh TJ:Antifungal agents: Chemotherapeutic targets and immunologic strategies. Antimicrob Agents Chemother 40:279, 1996 29. Goa KL, Barradell L B Fluconazole. An update of its pharmacodynamicand phannacokinetic properties and therapeutic use in major superficial and systemic mycoses in immunocompromised patients. Drugs 50658,1995 30. Gokhale PC, Barapatre RJ, Advani SH, et ak Successful treatment of disseminated candidiasis resistant to amphotericin B by liposomal amphotericin B: A case report. J Cancer Res CIin Oncol 119:569, 1993 31. Gorg C, Weide R, Schwerk WB, et al: Ultrasound evaluation of hepatic and splenic microabscesses in the immunocompromisedpatient: Sonographicpatterns, differential diagnosis, and follow-up. J CIin Ultrasound 22525,1994 32. Haron E, Feld R, Tuffnell P, et ak Hepatic candidiasis: An increasing problem in immucompromised patients. Am J Med 8317,1987 33. Hasegawa T, Hiyoshi M, Aoyama Y, et al: Treatment of hepatosplenic candidiasis with liposomal amphotericin B in a patient with acute leukemia: A case report of the experience of use of liposomal amphotericin B. Kansenshogaku Zasshi 72635, 1998 34. Helton WS, Carrico CJ,Zaveruha PA, et al: Diagnosis and treatment of splenic fungal abscesses in the immune-suppressed patient. Arch Surg 121:580,1986 35. Johnson JD,Raff MJ: Fungal splenic abscess. Arch Intern Med 144A987, 1984 36. Johnson TL, Barnett JL,Appleman HD, et al: Cundidu hepatitis: Histopathologicdiagnosis. Am J Surg Pathol 12:716, 1988 37. Kapur A, Vasudeva R, Howden CW:Candida splenic abscess in the absence of obvious immunodeficiency [review]. Am J Gastroenterol92:509, 1997 38. Karthaus M, Huebner G, Elser C, et al: Early detection of chronic disseminated Candida infection in leukemia patients with febrile neutropenia: Value of computer assisted serial ultrasound documentation. Ann Hematolm41, 1998 39. Karthaus M Safe and effective prophylaxis of chronic disseminated candidiasis (CDC) and pulmonary infiltrations in acute leukemia patients (AL) with intensive low-dose I.V. amphotericin B (Id AMB)--a prospective trial [abstract 14221. In Programs and Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). San Francisco, 1999, p 568
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40. Karthaus M Surprising long-term, leukemia-& survival in patients with hepatosplenic candidiasis receiving minimal antileukemictherapy [abstract 16451. Is Programs and Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). San Francisco, 1999, p 575 41. Katayama K, Koizumi S, Yamagami M, et al: Successful peritransplant therapy in children with active hepatosplenic candidiasis. Int J Hematol59125, 1994 42. Kauffman CA, Bradley SF, Ross SC, et al: Hepatosplenic candidiasis: Successful treatment with fluconazole. Am J Med 91:137,1991 43. Kirkpatrick CH: Chronic mucocutaneous candidiasis. In Bodey GP (ed): Candidiasis: Pathogenesis, Diagnosis and Treatment. New York, Raven Press, 1993, p 167 44. Kullberg B-J, van ‘t Wout JW, Hoogstraten C, et a1 Recombinant interferon-y enhances resistance to acute disseminated Cundidu ulbicuns infection in mice. J Infect Dis 168:436, 1993 45. Lanigan R, Meynell MJ: Moniliasis in acute leukemia. J Clin Pathol 12:157, 1959 46. Lewis JH,Pate1 HR, Zimmerman HJ: The spectrum of hepatic candidiasis. Hepatology 2479, 1982 47. Lopez-Berestein G, Bodey GP, Frankel LS, et al: Treatment of hepatosplenic candidiasis with liposomal-amphotericin B. J Clin Oncol5:310, 1987 48. Luna MA, Tortoledo ME: Histologic identification and pathologic patterns of disease caused by Cundidu. In Bodey GP (ed): Candidiasis: Pathogenesis, Diagnosis and Treatment. New York, Raven Press, 1993, p 21 49. Maksymiuk AW, Thongprasert S, Hopfer R, et al: Systemic candidiasis in cancer patients. Am J Med 77(suppl40):20,1984 50. Marcus SG,Walsh TJ, Pizzo PA, et al: Hepatic abscess in cancer patients. Characterization and management. Arch Surg 1281358, 1993 51. Martino P, Venditti M, Micozzi A, et al: Blustoschizomyces cupitatus: An emerging cause of invasive fungal disease in leukemia patients. Rev Infect Dis 12570,1990 52. Martino R, Nomdedeu J, Altes A, et al: Successful bone marrow transplantation in patients with previous invasive fungal infections: report of four cases. Bone Marrow Transplant 13265, 1994 53. Meunier-CarpenterF, Kiehn TE, Armstrong D: Fungemia in the immunocompromised host. Am J Med 71:363, 1981 54. Mirsky HS, Cuttner J: Fungal infection in acute leukemia. Cancer 2 3 8 , 1972 55. Moseby RH, Mark GK, Avi E, et ak Respiratory alkalosis with abdominal pain heralding Candida hepatitis. Occurrence in patients with acute leukemia in remission. Arch Intern Med 142:1495, 1982 56. Moss h4A, Ganso G, Genant HK Fungal abscess. In Moss AA (ed): Computed tomography of the body with magnetic resonance imaging. Philadelphia, WB Saunders, 1992, p 800 57. Pastakia B, Shawker TH, Thaler H, et al: Hepatosplenic candidiasis: Wheels within wheels. Radiology 166:417, 1988 58. Pestalozzi BC, Krestin GP, Schanz U Hepatic lesions of chronic disseminated candidiasis may become invisible during neutropenia. Blood 903858, 1997 59. Pfaller JAM,Wenzel R: The impact of changing epidemiology of fungal infections in the 1990’s. Eur J Clin Microbiol Infect Dis 11:287, 1992 60.Philpott-Howard JN, Wade JJ, Mufti GJ, et al: Randomized comparison of oral fluconazole versus oral polyenes for the prevention of fungal infection in patients at risk of neutropenia. Multicentre Study Group. J Antimicrob Chemother 31:973,1993 61. Poynton CH, Barnes RA, Rees J: Interferon gamma and granulocyte-macrophage colony-stimulating factor for the treatment of hepatosplenic candidosis in patients with acute leukemia. Clin Infect Dis 26239, 1998 62. Prandi G, Lasagni A, Stefani B Clinical and immunological study of 2 cases of systemic candidiasis. Bollettino dell Istituto Sieroterapico Milanese 5565, 1976 63. Puccetti P, Romani L, Bistoni F: A Thl-Th2-like switch in candidiasis: New perspectives for therapy. Trends Microbiol3237, 1995 64. Raina V, Young IT,Foulis AK, et ak Hypersplenism due to fungal infection of spleen in a successfully treated patient with Hodgkin’s disease. Postgrad Med J 65:83, 1989
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65. Roilides E, Sein T, Schaufele R, et al: Increased serum concentrations of interleukin-10 in patients with hepatosplenic candidiasis. J Infect Dis 178:589, 1998 66. Rossetti F, Brawner DL, Bowden R, et a1 Fungal liver infection in marrow transplant recipients: Prevalence at autopsy, predisposing factors, and clinical features. Clii Infect Dis 20801, 1995 67. Sallah S: Hepatosplenic candidiasis in patients with acute leukemia: Increasingly encountered complication. Anticancer Res 19757,1999 68. Samonis G, Maraki S, Hijiioannou I, et a1 Effect of ketaconazole, itraconazole, and fluconazole on the gastrointestinal colonization of mice by C. ulbicuns. Chemotherapy, in press, 1999 69. Samuels BI, Pagani JJ, Libshitz HI: Radiologic features of Cundidu infections. In Bodey GP (ed): Candidiasis: Pathogenesis, Diagnosis and Treatment. New York, Raven Press, 1993, p 137 70. Semelka RC, Kelekis NL, Sallah S, et a1 Hepatosplenic fungal disease: Diagnostic accuracy and spectrum of appearances on MR imaging. AJR Am J Roentgen01 1691311, 1997 71. Semelka RC, Shoenut JP,Greenberg HM, et al: Detection of acute and treated lesions of hepatosplenic candidiasis: Comparison of dynamic contrast-enhanced CT and MR imaging. J M a p Reson Imaging 2341,1992 72. Shirkhoda A, Lopez-Berestein G, Holbert JM, et al. Hepatosplenic fungal infection: CT and pathologic evaluation after treatment with liposomal amphotericin B. Radiology -_ 159&9, 1986' 73. Tashiian LS. Abramson IS. Peacock TE Tr: Focal heuatic candidiasis: a distinct clinical varikt of chdidiasis in~&unocomp&mised paGents. Rev Infect Dis 6:689, 1984 74. Thaler M, Pastakia B, Shwker TH, et ak Hepatic candidiasis in cancer patients: The evolving picture of the syndrome. Ann Intern Med 10888, 1988 75. Thaler M, Backer J, O'Leary T, et ak Evaluation of single drug and combination antifungal therapy in an experimental model of candidiasis in rabbits with prolonged neutropenia. J Infect Dis 158:80, 1988 Leisenring W, Myerson D, et ak The effect of prophylactic fluconazole 76. van Burik J-AH, on the clinical spectrum of fungal diseases in bone marrow transplant recipients with special attention to hepatic candidiasis. Medicine 77.246, 1998 77. Wald BR, Ortega JA, Ross L, et al: Candidal splenic abscesses complicating acute leukemia of childhood treated by splenedomy. Pediatrics 67296, 1981 78. Walsh TJ,Hiemenz J: Lipid formulations of amphotericin 8: Recent developments in improving the therapeutic index of a gold standard. Infect Dis Clin Pract 7(suppl 1):S16, 1998 79. Walsh TJ, Pizzo PA Experimental gastrointestinal and disseminated candidiasis in immunocompromised animals. Eur J Epidemiol8:477, 1992 80. Walsh TJ, Aoki S, Mechinaud F, et ak Effects of preventive, early and late antifungal chemotherapy with fluconazole in different granulocytopenic models of experimental disseminated candidiasis. J Infect Dis 161:755, 1990 81. Walsh TJ, Lee J, Aoki S, et al: Experimental basis for use of fluconazole for preventive or early treatment of disseminated candidiasis in granulocytopenic hosts. Reviews of Infectious Diseases 12(suppl3):307-317,1990 82. Walsh TJ, Hiemenz JW, Anaissie E: Recent progress and current problems in treatment of invasive fungal infections in neutropenic patients. Infect Dis Clin North Am 10:365, 1996 83. Walsh TJ, Hiemenz JW, Seibel NL, et a1 Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases. Uin Infect Dis 261383, 1998 84. Walsh TJ, Merz WG, Lee JW, et al: Diagnosis and therapeutic monitoring of invasive candidiasisby rapid enzymatic detection of serum D-arabinitol. Am J Med 99164,1995 85. Walsh TJ, Pizzo PA Laboratory diagnosis of candidiasis.In Bodey GP (ed): Candidiasis: Pathogenesis, Diagnosis and Treatment. New York, Raven Press, 1993, p 109 86. Walsh TJ, Whitcomb P, Piscitelli S, et al: Safety, tolerance, and pharmacokinetics of amphotericin B lipid complex in children with hepatosplenic candidiasis. Antknicrob Agents Chemother 41:1944,1997
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87. Walsh TJ,Whitcomb PO, Revankar SG, et al: Successful treatment of hepatosplenic candidiasis through repeated cycles of chemotherapy and neutropenia. Cancer 762357, 1995 88. Woolley I, Curtis D, Szer J, et ak High dose cytosine arabinoside is a major risk factor for the development of hepatosplenic candidiasis in patients with leukemia. Leuk Lymphoma 27:469,1997 Address reprint requests to D. P. Kontoyiannis, MD The University of Texas M. D. Anderson Cancer Center Department of Internal Medicine Speaalties Section of Infectious Diseases 1515 Holcombe Blvd., Box 47 Houston, TX 77030
0891-5520/00 $15.00
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HEPATOSPLENIC CANDIDIASIS A Manifestation of Chronic Disseminated Candidiasis D. P. Kontoyiannis, MD, ScD, M. A. Luna, MD, B. I. Samuels, MD, and G.P. Bodey, MD
Invasive candidiasis is a major cause of morbidity and mortality in patients with hematologic malignancies a d a frequent cause of failure of the initial remission induction chemotherapy in this patient PO ulation.1z,25 Candidemia in neutropenic patients with leukemia is associated wi disseminated organ infection in most cases.lZ,53 The syndrome of acute disseminated candidiasis (ADC) in patients with acute leukemia, increasingly recognized since the 195Os,l1*45 has a predictable prognosis that depends on the recovery of the neutrophil count: If the patients achieve remission of their underlying leukemia and their neutrophil counts recover, then they usually recover with therapy unless the infection is overwhelming. If the neutropenia remains refractory, then the outcome, despite treatment with antifungals, is fatal.lZDuring the last three decades, a chronic form of disseminated candidiasis has been recognized with increasing frequency." 3z*74 Bodey et a1 first reported chronic hepatosplenic candidiasis with hypersplenism in a patient with leukemia who had achieved a complete remission after chemotherapy.1° The patient developed a refractory fever of unknown cause associated with persistent pancytopenia despite normal findings on bone marrow biopsy.1° The patient's spleen was removed and was found to contain multiple abscesses containing Candida spp. After treatment with amphotericin B, the patient fully recovered.1° This syndrome subsequently was described in more detail in the early 1980s1,32 36, 46* 49, so, 73, 74 and is often referred as hepatosplenic candidiasi~,6~ chronic systemic candidiasis: or chronic disseminated candidiasis (CDC). We believe that the last is the most appropriate term, because it describes
8
From the Section of Infectious Diseases, Department of Internal Medicine Specialties(DPK, GPB); and the Departments of Pathology (MAL), and Diagnostic Radiology (BIS), University of Texas h4D Anderson Cancer Center, Houston, Texas INFECTIOUS DISEASE CLINICS OF NORTH AMERICA VOLUME 14 NUMBER 3 SEPTEMBER Zoo0
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a chronic infection that may involve other organs in addition to the liver and spleen. PATHOGENESIS
The pathogenesis of CDC is unclear and controversial?,67 The risk factors for the disease are similar to those for the acute form of disseminated candidiasis: the presence of acute leukemia, prolonged neutropenia, intravascular catheters, disruption of mucosal barriers, and the administration of broad-spectrum antibiotics?,lo,32, sf46* 49, so* 67, 73, 74 CDC in nonleukemic patients is rare. Kapur et a1 described such a case involving predominantly the spleen in a patient with diabetes mellitus and sickle cell Recognition of CDC has increased since arabinosyl cytosine (ara-C), especially in high doses, began to be combined with anthracycline as standard remission induction chemotherapy for acute myelogenous leukemia.@The most likely sequence of events leading to the development of CDC in that setting is prolonged neutropenia and mucosal damage of the gastrointestinal tract followed by local invasion and subsequent entry of the Candida spp into the hepatosplenic circulation, resulting in liver infecti011.l~ Because inflammatory reaction is absent, however, the infection most commonly manifests itself only as fever until the patient's neutrophil count recovers, when other symptoms begin to appear. Bosch et al reported the occurrence'of CDC following typhlitis by Candida albicans in a patient with acute lymphocytic leukemia receiving cytotoxic chem~therapy.'~ The above model of pathophysiology of the disease has been replicated in ara-C or cyclosphosphamide-treated neutropenic animal models of subacute disseminated candidiasis.2Or79 Based on studies in a granulocytopenic rabbit model of experimental disseminated candidiasis, Walsh et a1 proposed that the likelihood of a patient developing CDC or ADC following chemotherapy depends on the infecting fungal inoculum; the rabbits receiving the highest Candida inoculum developed ADC, whereas the rabbits receiving the lowest Candida inoculum developed CDC.79. Other theories of the pathogenesis of the syndrome have been proposed. We believe that CDC is a distinct entity from ADC? Typically, neutropenic patients with ADC follow one of three courses: (1)their neutrophil counts do not recover and they die of rapidly progressive infection despite appropriate therapy; (2) their neutrophil counts return to normal, and they respond to therapy and recover; or (3) their neutrophil counts recover after the infection becomes widespread, and the influx of neutrophils to the numerous infected sites causes organ failure and death. Although CDC is assumed to follow an acute infectious episode, most cases of CDC do not follow a recognizable episode of ADC and typically are diagnosed only after the patient's neutrophil count has returned to This suggests that the host inflammatory response is pivotal in defining the lesions that are characteristic of CDC.7* Furthermore, gryuloma formation is the typical response seen in the non-neutropenic patients with CDC, in contrast to the abscess formation with adequate neutrophil count and coagulative necrosis seen in neutropenic patients with ADC." CDC often persists for prolonged periods (as long as 12 months) after resolution of neutropenia, which suggests that this infection could be the result of a specific, as-yet-unknown immune dysfunction in some patients with leukemia, most likely as a result of antileukemic chemotherapy. Because granuloma formation is the characteristic response in patients with chronic mucocutaneous candidiasis, many of whom have defects in lymphocytic or monocyte function,"
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it is possible that patients who develop CDC also have defects in lymphocyte function.62Roilides et al found that patients with hepatosplenic candidiasis have increased serum levels of the anti-inflammatory cytokine IL-lO,& suggesting that a Thl-Th2 imbalance or other selective immunologic defects may underlie the pathogenesis of the syndrome.62 Surprising long-term remission of leukemia recently was reported in three patients with CDC who received minimal chemotherapy." The authors of the report speculated that an infection-associated cytokine release exerted an antileukemic effect." INCIDENCE
The true incidence of CDC is unclear15 because establishing a definite diagnosis is difficult5 and the disease occurs so infrequently that no institution has accumulated a large number of cases. Even though multiple studies in the 1980s2,7, 32, 36* 49, 74 reported a significant increase in the frequency of CDC, some of those case series did not include a denominator.32,49, n,74 Furthermore, it is unclear whether some of the reported increase simply reflected better overall survival in patients with ADC owing to improved supportive care and the routine early use of empiric antifungal therapy, or better detection of CDC owing to the increased awareness of this disease and the introduction of more sensitive imaging techniques such as ultrasonography (US) and computed to69 To complicate matters further, the mography (CT) in routine clinical antemortem incidence of CDC might underestimate its true incidence, because it is well known that Candida dissemination in visceral organs can go undetected 54 A Finnish in almost half of the cases in neutropenic patients with le~kemia.4~. study covering the period 1980 to 1993 found a CDC rate of 6.8%(38/562) in a large cohort of patients with acute leukemia? Similarly, a Spanish study covering the period 1985 to 1990 found a CDC rate of 3.2% (10/305) in patients with leukemia.7In those series, 30% and 29% of cases, respectively, had diagnosed CDC only at autopsy3, The frequency of CDC has decreased dramatically during the last decade. This decrease has been noted at large leukemia and bone marrow transplant centers, such as M. D. Anderson Cancer Center and Fred Hutchinson Cancer Center, where fluconazole prophylaxis has been used e x t e n s i ~ e l yThis ~ ~ trend is well illustrated by a recent large autopsy study of bone marrow transplant (BMT) patients at high risk for CDC; that study clearly showed that the frequency of visceral candidiasis has decreased precipitously since the introduction of fluconazole pro phyla xi^^^ (Table 1). The activity of fluconazole in the prevention of CDC also has been demonstrated in a persistently granulocytopenic rabbit model of infection.8o CLINICAL PRESENTATION
Even though CDC and ADC are believed to represent two points on the same infectious spectrum, CDC as a disease process is distinctly different from ADC (Table 2). The clinical presentation of CDC is unique and is the basis for the definition of the syndrome.13 The infection is seen typically in patients with leukemia who have received cytotoxic chemotherapy. It presents initially as neutropenic fever with no focal signs or symptoms and fails to respond to broad-spectrum antibiotics. Liver function tests and US or CT scans of the abdomen are generally normal at this
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Table 1. SIGNIFICANCE OF HEPATIC CANDlDA ORGANISMS IDENTIFIED AT AUTOPSY ~
~
Fungal Organism
Any Candida species Candida albicans Non-albicans Candida* Histology only
No Fluconazole Fluconazole Relative NO.(%) No. (%) Risk 23/161 (14) 11 3 9
2/168 (1.2) 0 1 1
12 3.1 9.4
95% CI (2.9, 50.1) (0.33, 29.8) (1.2, 73.7)
~
PValue
<0.001
<0.001 0.36 0.009
‘One isolate each of T.glabratu, C. krusei, C. tropicalis, and C. guillimondii. Adaptedfrom van Burik J-AH, Leisenring W, Myerson D, et al: The effect of prophylactic fluconazole on the clinical spectrum of fungal diseases in bone marrow transplant reapients with speaal attention to hepatic candidiasis.Medicine P.246,1998; with permission.
time (Fig. 1).Subsequently the patient‘s leukemia goes into remission, and the neutrophil count returns to normal. However, the patient continues to experience high fever, anorexia, weight loss, and debilitation. Right upper quadrant pain or right-sided pleuritic chest pain may be present. Hepatomegaly or splenomegaly or both are present in half of the cases. At this point, substantial elevation of alkaline phosphatase is noted, an abnormality that can persist for months. Other liver function tests also can produce abnormal results, but these abnormalities are usually less impressive. Other less typical presentations can be encountered. Moseby et a1 have described two patients with acufe leukemia in remission who presented with the triad of abdominal pain, respiratory alkalosis, and abnormal liver function tests and were found to have Cundidu hepatitis.” Similarly, predominant involvement of the spleen with little or no involvement of the liver by Cundidu abscesses has been described in patients with hematologic malignan3
Table 2. FORMS OF DISSEMINATED CANDlDlASlS IN PATIENTS WITH ACUTE LEUKEMIA.
Evaluation
Acute Disseminated Candidlasis (ADC)
Neutropenic fever unresponsive to antibacterials, multiple skin lesions, pneumonia, shock Positive for Candida spp. Blood cultures (30%-70%) Imaging studies (CT, US) Typically negative Course Acute (days-weeks) Clinical presentation
Host response Site of involvement Response to antifungal therapy ‘Overlap may occur.
Chronic Disseminated Candidiasis (CDC)
Non-neutropenic fever, unresponsive to antibacterials, abnormal liver function test results Typically negative Positive for focal lesions Subacute-chronic (weeks-month) Granuloma formulation
Coagulation and hemorrhagic necrosis, abscess formation Predominantly spleen and liver Skin, lungs, GI tract, kidneys, liver, spleen High mortality in absence of Better response neutrophil recovery
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Alkaline Phosphatase
Normal
Elevated
>I000
PUN
Imaging Liver
0
0
+
cies.=,35Some of those patients had predominant signs and symptoms of hypersplenism.l0,=, =* Radiologic Features of Hepatosplenic Candidiasis
In CDC, characteristic lesions are detected in the liver and spleen, and sometimes in other organs, by using US, CT or magnetic resonance imaging (MRI) studies.'z 31* 38, ss, 57, m, These studies are useful once the patient has an adequate neutrophil count. Typically, lesions cannot be detected by US or CT examination when the patient is neutropenic because the patient is unable to produce an inflammatory reaction. Similarly, the known lesions of CDC can disappear transiently during subsequent chemotherapy-induced neutropenia, and reappear after neutmphil recovery? In most centers, the initial diagnosis is made with unenhanced or enhanced CT. MRI and CT scans are the most reliable diagnostic procedures, revealing lesions in about 90% of patients; US identifies lesions in 70% to 75% of patients.@Several patterns of organ involvement can be discerned. In about 63% of patients, lesions can be detected in the liver and spleen; in 22%, only in the liver; and in 15%, only in the spleen.69 Four dominant patterns of hepatosplenic candidiasis have been described using US studies.57Early in the disease, the "wheel within a wheel" pattern develops (Fig. 2). Histologically, it consists of a peripheral hypoechoic zone that correlates with a ring of fibrosis. h i d e the outer hypoechoic wheel is a second hyperechoic wheel composed of inflammatory cells. The central hypoechoic nidus relates to necrotic fungal elements. The second pattern, typical of a bull's eye, evolves from the primary lesion (Fig. 3). These hepatic lesions are usually 1 to 4 an in diameter. The third and most common pattern is a uniform hypoechoic lesion and can be seen in conjunction with the other three patterns (Fig. 4). The fourth pattern, consisting of echogenic foci, usually is seen late in the disease and correlates microscopically with central fibrosis or calcifications or both.
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Figure 2. Transverse sonograrn of the liver in a 28-year-old patient with acute lyrnphocytic leukemia. A wheel within a wheel microabscess (arrow) is demonstrated at the right portal vein. (Modified from Sarnuels 61, Pagani JJ, Libshitz HI: .Radiologic features of Candida infections, In Bodey GP (ed): Candidiasis: Pathogenesis, Diagnosis and Treatment. New York, Raven Press, 1993, pp 137-1516: with permission.)
Figure 3. Transverse hepatic sonograrn in a leukemic patient with chronic, disseminated hepatosplenic candidiasis with characteristic bull’s-eye microabscesses (arrow). (Modified from Sarnuels BI. Pagani JJ. Libshitz HI: Radiologic features of Candida infections. In Bodey GP (ed): Candidiasis: Pathogenesis, Diagnosis and Treatment. New York, Raven Press, 1993, pp 137-156; with permission.)
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Figure 4. Transverse sonogram in a patient with acute lymphocytic leukemia and several typical hypoechoic Candida microabscesses (arrows) anterior to the right kidney. (Modified from Samuels Bi, Pagani JJ, Libshitz HI: Radiologic features of candida infections. In Bodey GP (ed): Candidiasis: Pathogenesis, Diagnosis and Treatment. New York, Raven Press, 1993, pp 137-156; with permission.)
Typically, fungal hepatic candidiasis on CT scans is characterized by multiple small, round, low-attenuation lesions scattered throughout the liver and spleen (Fig. 5). Sometimes peripheral enhancement is seen. Infrequently, tiny central densities presumed to represent hyphae are seen. The appearance on CT scans is not pathognomonic and can be mimicked by metastatic disease and bacterial abscesses. In a three-university collaborative study, MR imaging was reported to be superior to CT in demonstrating chronic, disseminated, hepatosplenic candidiasis in the acute, subacute, and chronic healed phases based on their MR imaging appearances.” 69 Patients with persistent fever or no response to antibiotics were included and grouped as acute, subacute treated, and chronic treated, depending on the duration of their symptoms. Patients with 2 weeks or less of possible infection were considered to have an acute presentation; those receiving antifungal therapy for 3 months and who had a history of hepatosplenic fungal disease were considered to have a chronic treated presentation. Image presence, size, signal intensity, borders, and perilesional changes were recorded for all MR image sequences, and enhancement patterns were determined after the administration of gadolinium. Although the authors concluded that MR imaging has high diagnostic accuracy, they did point out that the initial MR imaging study may be unremarkable in the neutropenic patient. US, CT, and MR imaging studies have been used to determine the patient’s response to thera~y.6~.Studies should be repeated every 3 to 4 weeks initially. Response is indicated by reduction in the size and number of the lesions without the appearance of new lesions. US is an ideal modality for following the patient‘s response because it involves no ionizing radiation and costs significantly less than CT or MR imaging. One alternative approach is to obtain a CT or MRI
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KONTOYIANNJSetal
Figure 5. Unenhanced (A) and enhanced (B) abdominal CT scans in a 34-year-old man with acute myelocytic leukemia demonstrate low attenuation foci microabscesses (anow, A), in the liver and spleen. The fungal lesions are seen better before the administrationof intravenous contrast material. (Modifiedfrom Samuels BI, Pagani JJ, Libshitz HI: Radiologic features of Candida infections. In Bodey GP (ed):Candidiasis: Pathogenesis, Diagnosis and Treatment. New York, Raven Press, 1993, pp 137-156; with permission.)
scan first, because either is more sensitive than US and then, if lesions are detected, conduct an US study immediately thereafter. US then can be used for follow-up; when no more lesions can be detected on US scans, a repeat CT or MR scan is obtained. Multiple scattered low-attenuation foci can persist despite successful treatment, because focal scarring and chronic inactive granulomatous
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Figure 6. Calcified residue (arrows) typical of healed hepatosplenic candidiasis are demonstrated in a child with acute myelocytic leukemia. (Modified from Samuels BI, Pagani JJ, Libshitz HI: Radiologic features of Candida infections. In Bodey GP (ed): Candidiasis: Pathogenesis, Diagnosis and Treatment. New York, Raven Press, 1993, pp 137-156; with permission.) changes mimic active lesions. Over time, calcifications develop in areas of scarring (Fig. 6). Pathologic Patterns of Hepatosplenic Candidiasis Depending on the status of host defenses or rate of recovery of immune competence, hepatosplenic Candida infections have three histologic patterns: (1) necrosis with minimal inflammatory reaction, (2) microabscesses with severe inflammation, and (3) granuloma^.^^ The first two patterns are associated with ADC.@The common denominator in patients with ADC is prolonged severe neutropenia. Histologically, necrotic lesions with minimal inflammatory reaction are characterized by coagulative necrosis associated with hemorrhage without or with minimal inflammation (Fig. 7). The histologic appearance of the lesions reflects the lack of inflammatory cells, and patients with this lesion seldom recover from their neutropenic state. Candida organisms are numerous and easily demonstrated with the help of special stains. Microabscesses, on the other hand, are seen in patients whose bone marrow is recovering and peripheral blood counts are increasing, or in patients who have never been neutropenic. Histologically, in addition to coagulative necrosis, these lesions show a mixture of polymorphonuclear neutrophils, lymphocytes, plasma cells, and monocytes (Fig. 8). The thud pattern, granulomatous tissue reaction to Candida organisms, is less frequent and usually is seen in the liver and spleen. Occasionally, other organs such as the kidney are involved. Histologically, the lesions are characterized by areas of central necrosis or fibrosis, surrounded by granulation tissue,
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KONTOYIANNISetal
Figure 7. Liver tissue showing coagulative necrosis. Note lack of inflammatory cells (hematoxylin-eosin stain, original magnification x 60).
Figure 8. Candida lesion with severe inflammatory reaction (hematoxylin-eosin stain, original magnification x 100).
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Figure 9. Candida granuloma. Note giant cells and fibroblast arranged in a palisade pattern (hematoxylin-eosin stain, original magnification x 100).
macrophages, or fibroblasts arranged in palisades and giant cells (Fig. 9). These are the lesions typically observed in CDC. Grossly and radiologically, the granulomas resemble metastatic carcinoma. DIAGNOSIS
The diagnosis of CDC requires a high degree of suspicion and recognition of the characteristic setting of CDC. No single noninvasive study with enough sensitivity specificity, and positive and negative predictive value is available to establish the diagnosis. A combination of studies often is required, and repeated examinations are warranted if the studies are negative initially but the suspicion of CDC remains high. As previously discussed, modern imaging techniques are increasingly important in the early identification and management of the syndrome.lZ,38, 56, 57, sf G9, 70, 71, If the patient can tolerate the procedure, however, it is desirable to obtain a biopsy to establish the diagnosis. Other disseminated granulomatous disease processes, such as miliary tuberculosis, disseminated fungal disease caused by other fungi such as the invasive molds," Trichosporum beigeliP or Blastoschizomyces capitatus,5* or even malignancyz6can mimic CDC. Because of the size of the lesions, percutaneous CT-guided needle biopsy is sufficient in some patients5,74 but can fail to reveal fungal organisms.5 Because the Cundidu organisms are less numerous in the granulomas than in the lesions seen in ADC, the diagnosis of hepatic candidiasis is established most reliably by open liver biopsy?, 74 Although fungal elements can be identified histopathologically, Candidu spp. can be isolated from tissue culture in only about 50% of cases. Most cases have been caused by C . albicans, but C . tropicalis, C. glabrata, C . krusei, and other Candida spp. are responsible for a few cases." 4, 66, 74 There is evidence that
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the routine use of fluconazole resulted in the increased isolation of the nonulbicans Candida spp. as causes of both candidemiaS9and CDC.76Satisfactory results have been obtained in selected patients by laparoscopic liver biopsy.* 5, 74 Cundida spp. infrequently are isolated from cultures of blood from patients with CDC.9.32 74 Early diagnosis of CDC before the lesions are large enough to be detected by imaging techniques is desirable. Considerable effort has been invested in developing nonculture methods for diagnosing disseminated candidiasis. Promising methods include detection of serum Candida enolase, serum D-arabhitol, and serum c-reactive protein by detection of Cundida mannan by radioimmunoassay; and detection of polymerase chain reaction (PCR)using Candidu speciesspecific probes?* =, = Unfortunately, none of these approaches has proven to be entirely satisfactory. More work is needed in this important area for early and specific diagnosis of the syndrome. TREATMENT
The optimal management of CDC is not yet well established. The most appropriate therapeutic regimens and the end points of treatment are not adequately defined; therefore, a relapse of the infection could occur owing to either premature discontinuation of antifungal therapy or inadequate antifungal therapy in patients with chemotherapy-inducedneutropenia. Because CDC is an uncommon disease, comparative controlled studies are difficult to conduct. Historically, the usual therapy for CDC has been the antifungal agent amphotericin B deoxycholate, yet, in almost 50% of cases, administration for periods up to 6 months and up to a total dose of 6 g is still not enough to stop the infection from progressing.&42The frequent failure of this therapy may be due to the pharmacokinetic properties of amphotericin B. It has been demonstrated that Candida infection can persist in the livers of patients despite the presence of concentrations of amphotericin B that exceed by a hundredfold the minimal inhibitory concentration (MIC) for Cundidu.17 In addition, prolonged treatment with amphotericin B of a chronic infection such as CDC frequently causes considerable toxicity, especially renal.& a Some investigators have advocated using a combination of amphotericin B and 5-fluorocytosine on the basis of an experimental model of hepatosplenic candidiasis in rabbits with prolonged neutropenia." Whether this combination offers sigruficant advantages, however, is not clear." 75 The 1990s saw the introduction of promising agents such as the triazoles and the liposomal formulations of amphotericin B." The liposomal formulations of amphotericin B and fluconazole have a more favorable therapeutic index and 78 A ll of the commercially available parenmore favorable pharmacokinetic~.~~~ teral liposomal formulations of amphotericin B (Amphotericin B Lipid Complex, Liposomal Amphotericin B, Amphotericin B Colloidal Dispersion) permit the administration of the drug at much higher dosesm They also are targeted naturally to the liver and spleen (to different degrees), which promotes their selective interactions with the Cundida membrane?7,78 No extensive experience with the liposomal formulation of amphotericin B, however, has been published.30,s,= A limited series using a liposomal formulation of amphotericin B suggests a response rate of about 85% to 90%." Fluconazole, an azole antifungal, is tolerated well, readily absorbed from the gastrointestinal tract, and distributed widely in body tissues including the liver, spleen, and kidneysz9Fluconazole has a response rate of about 80% and
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is effective even among patients who failed to respond to previous amphotericin B treatment?,21, Some investigators have suggested that the high response to fluconazole is due in part to the previously administered amphotericin B. This conclusion is incorrect, however, because the patients who were given fluconazole after amphotericin B were given the fluconazole because they showed no evidence of response or had progression of disease while receiving amphotericin B therapy.” As noted earlier, the high hepatic concentrations of amphotericin B do not result in the clinical activity of this drug.17It is believed that fluconazole should be the drug of choice for CDC because it is at least as effective as amphotericin B, is less toxic (especially important because of the need for prolonged therapy), can be given orally, and is less expensive than lipid formulations of amphotericin B.= Fluconazole should be administered at a dose of 600 to 800 mg/day, starting on the intravenous route and switching to the oral route, once the patient stabilizes (typically in about 1 to 2 weeks). Usually it takes 2 to 3 weeks to see a measurable response. Fluconazole plus 5-fluorocytosine at lower-than-conventional doses (8 to 10 mg/kg/day) may be superior, but no experience with this combination has been reported. Finally, surgery might be useful in selected cases. Case reports and small series suggest a beneficial role of splenectomy or percutaneous drainage in conjunction with antifungal therapy in immunosuppressed patients with Candida splenic abscesses.34,35, CDC can be a debilitating and persisting chronic infection. It has the potential to interfere with the administration of subsequent antileukemic therapy. During periods of intensification of chemotherapy, the risk of early relapse of CDC and its conversion to acute disseminated candidiasis exists, especially when the infection has shown signs of progression before the onset of chemotherapy. On the other hand, as Walsh et a1 showed, adequately treated CDC seldom progresses to ADC or breakthrough candidemia, especially when antifungal therapy continues though the n e ~ t r o p e n i aWalsh . ~ ~ et a1 recommend that stable infection (defined as no further development of new lesions, no expansion in size of existing lesions, and no further clinical deterioration) be the initial goal of management of CDC before continuation of chern~therapy.~~ Therefore, the duration of therapy should be highly individualized and typically should last for about 6 months. Some patients have been cured with only 1 to 2 months of therapy. Evidence of a response to therapy includes improvement in clinical signs and symptoms, along with decreasing number and size of hepatic and splenic lesions. Residual lesions can remain, even after successful therapy, due to scarring or calcification. Such radiologic findings in a patient who also has no signs and symptoms of the infection and has been in hematologic remission should be reasonable end points for cessation of antifungal therapy. Prognostic factors associated with unfavorable outcome are the development of leukemic relapse during therapy2 recurrent neutropenia, delayed antifungal therapy, and lack of adequate secondary prophylaxis during neutropenia.
PROPHYLAXIS AND FUTURE THERAPEUTIC APPROACHES TO CDC
Although less common now, CDC still occurs despite prophylaxis or preemptive therapy with azoles. Leukemia relapse and Candida colonization of the gastrointestinal tract are risk factors.18 This is not surprising, because we and
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others have found that azoles have no decolonizing effect in at least one mouse model of persistent gastrointestinal colonization by C . albicuns.60, Future therapeutic approaches to CDC should focus on the availability of more effective and safer antifungals that preferably are given orally and once daily, for both therapy and prophylaxis. The deficiencies in the antifungal spectrum of fluconazole limit its use against fluconazole-resistant Candida infections, whose incidence has increased during the last decade.%In light of the preclinical data, the newer generation of triazoles (e.g., voriconazole, SCH 56592, and D0870) and other novel classes of antifungals (e.g., the lipopeptides) show considerable promise in addressing those shortcomings while avoiding the wellknown toxicities of polyenes.28Therefore, the use of these agents alone or in combination with the current antifungal agents for the treatment of CDC should be explored. On the other hand, in the only prospective study of the prevention of CDC reported so fx, Karthaus reported that intensive low-dose intravenous amphotericin (1 mg/kg every other day) was a highly effective and welltolerated prophylactic approach.39The optimal secondary prophylaxis for preventing recurrence in patients with CDC during subsequent chemotherapy is still unclear." It is also likely that cytokine modulation can enhance the therapeutic response in Rfractory cases of CDC.27,* 61 Interferon gamma showed a convincing effect in clearing hepatosplenic lesions in two patients with leukemia and biopsy-proven hepatosplenic candidiasis, whose disease still persisted after 6 weeks of treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) and liposomal amphotericin B (AmBisome).61 @
CDC IN SPECIAL GROUPS Pediatric Patients
CDC has been described in pediatric leukemia patients.16The clinical manifestations and the diagnostic yield of CT in these patients appear to be similar to those in adults." 16, 26 Walsh et a1 studied the pharmacokinetics, tolerability, and clinical efficacy of amphotericin B lipid complex (ABLC) given at a dose of 2.5 mg/kg for 6 weeks in six children with CDC. ABLC levels reached a steady state in the liver within 1 week of therapy, and the drug was well tolerated and efficacious in all patients.86 Bone Marrow Transplant Recipients
The diagnosis of hepatic involvement by Candida could be challenging in bone marrow recipients, who often have other causes of elevation of liver function tests, such as veno-occlusive disease and liver graft-versus-host disease.@Rossetti et a1 reported a disappointingly low sensitivity of the routine imaging studies, even during the last week of life in BMT recipients with autopsy-proven hepatic candidiasis." Fortunately, the syndrome appears to have decreased dramatically in frequency since the introduction of fluconazole as routine prophylaxis in these patients76(see Table 2). Small studies of and pediatric BMT recipient^*^ have provided reassurances that CDC complicating chemotherapy for the treatment of leukemia is not an absolute contraindication to subsequent BMT, provided that the infection is well controlled before the
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transplant and that antifungal therapy (amphotericin B) is continued at least throughout the preengraftment period. SUMMARY
Much progress has been made over the last decade in diagnosing and treating CDC, a chronic and debilitating infection that interferes with the delivery of intensive cytotoxic chemotherapy in patients with leukemia. The use of fluconazole prophylaxis in these patients has decreased the incidence of CDC dramatically. The greatest future challenges are gaining a better understanding of its pathophysiology, and the continued development of effective diagnostic and therapeutic strategies to treat this unusual manifestation of systemic candidiasis.
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87. Walsh TJ,Whitcomb PO, Revankar SG, et al: Successful treatment of hepatosplenic candidiasis through repeated cycles of chemotherapy and neutropenia. Cancer 762357, 1995 88. Woolley I, Curtis D, Szer J, et ak High dose cytosine arabinoside is a major risk factor for the development of hepatosplenic candidiasis in patients with leukemia. Leuk Lymphoma 27:469,1997 Address reprint requests to D. P. Kontoyiannis, MD The University of Texas M. D. Anderson Cancer Center Department of Internal Medicine Speaalties Section of Infectious Diseases 1515 Holcombe Blvd., Box 47 Houston, TX 77030