Version May 2024
INTRODUCTION — Chronic disseminated candidiasis, also referred to as hepatosplenic candidiasis, is a form of infection due to Candida spp involving the liver and spleen; it typically occurs in patients with hematologic malignancy, following prolonged neutropenia [1-3].
Clinical issues related to chronic disseminated candidiasis will be reviewed here. An overview of Candida infections as well as the clinical manifestations, diagnosis, and treatment of candidemia are presented separately. (See "Overview of Candida infections" and "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults" and "Management of candidemia and invasive candidiasis in adults".)
EPIDEMIOLOGY — Chronic disseminated candidiasis usually occurs in patients with hematologic malignancy who have recently recovered from an episode of neutropenia [4,5]. Rare cases have been reported in patients with lymphoma, aplastic anemia, and sarcoma [4-6]. A small number of cases have been described among non-neutropenic patients [7].
Given that use of antifungal agents for prophylaxis and empiric treatment has become widespread, chronic disseminated candidiasis is relatively rare [5,8]. In one autopsy study including 329 hematopoietic cell transplant recipients, the rates of Candida infections and hepatosplenic candidiasis were lower among patients who received fluconazole prophylaxis than those who did not (8 versus 27 percent and 3 versus 16 percent, respectively) [8].
Risk factors — Risk factors for chronic disseminated candidiasis include [5]:
●Acute leukemia
●Prolonged neutropenia (<500 neutrophils/microL for ≥10 days), particularly in the absence of antifungal prophylaxis
●Administration of broad-spectrum antibiotics
●Mucosal barrier disruption
●Presence of an indwelling intravascular catheter
●Administration of total parenteral nutrition
PATHOGENESIS — The pathogenesis of chronic disseminated candidiasis is not well understood.
In the context of prolonged neutropenia and a breach in mucosal integrity, the condition is thought to develop as a result of invasion of Candida species from the gastrointestinal tract into the bloodstream. However, candidemia during the period of neutropenia is not often documented. (See 'Laboratory findings' below.)
The portal system may receive the largest inoculum, leading to significant liver involvement [5,9]. Less often, involvement of the lungs, kidneys, and other organs also occurs [2].
Factors supporting the role of the host immune response in pathogenesis include (1) histopathologic findings of granulomatous (rather than suppurative) inflammation and (2) development of symptoms and radiographic findings following neutrophil recovery (eg, as a form of immune reconstitution) [2,10].
MICROBIOLOGY — Most cases of chronic disseminated candidiasis (in which an organism has been identified) have been attributable to Candida albicans. Other species, such as Candida tropicalis, Candida parapsilosis, Candida glabrata, and Candida krusei, have been reported occasionally [4,7,11-13]. (See "Candidemia in adults: Epidemiology, microbiology, and pathogenesis".)
Blood cultures at the time of presentation are typically negative and antecedent candidemia (eg, at the time of neutropenia) is not often observed. (See 'Laboratory findings' below.)
CLINICAL MANIFESTATIONS
Signs and symptoms — Patients with chronic disseminated candidiasis usually present within two weeks of neutrophil recovery; rarely, the presentation may be delayed up to a few months following neutrophil recovery. Very few cases present while neutropenic. In one series including 23 patients with acute leukemia and chronic disseminated candidiasis, clinical manifestations became apparent after neutrophil recovery in 85 percent of cases [14].
The most common clinical feature of chronic disseminated candidiasis is fever that fails to respond to broad-spectrum antibacterial therapy. Additional symptoms may include right upper quadrant tenderness, hepatomegaly, splenomegaly, nausea, vomiting, and anorexia [4,12,15,16].
Laboratory findings — Laboratory testing typically demonstrates an elevated serum alkaline phosphatase concentration [5]. In one study that included 28 patients with chronic disseminated candidiasis, three- to fivefold elevation of alkaline phosphatase was observed in 86 percent of cases [15]. However, this parameter should not be used to guide treatment response, as it usually lags behind clinical and radiographic improvement [14].
Less common laboratory abnormalities include mildly elevated aspartate aminotransferase, alanine aminotransferase, and bilirubin, as well as leukocytosis [4,5].
The utility of serum beta-D-glucan measurement for diagnosis of chronic disseminated candidiasis is uncertain; no large studies have been performed to evaluate sensitivity and specificity. Several studies suggest potential utility of beta-D-glucan for predicting chronic disseminated candidiasis; however, these have used assay formats not available in the United States [17,18].
Blood cultures at the time of presentation are typically negative and antecedent candidemia (eg, at the time of neutropenia) is not usually seen. In one series of 28 patients with chronic disseminated candidiasis, antecedent candidemia was documented in 32 percent of cases [15].
DIAGNOSIS
Clinical approach
●Whom to evaluate − Chronic disseminated candidiasis should be suspected in patients with recent neutropenia (usually within the preceding two weeks) who present with fever unresponsive to broad-spectrum antibiotic therapy; additional signs and symptoms may include right upper quadrant tenderness, hepatomegaly, splenomegaly, nausea, vomiting, and/or anorexia.
●Diagnostic evaluation − Patients with suspected chronic disseminated candidiasis should undergo diagnostic evaluation including laboratory testing (complete blood count, liver function tests, beta-D-glucan testing) and radiographic imaging (beginning with computed tomography [CT]). Blood cultures are also warranted; while often negative in patients with chronic disseminated candidiasis, they are important for evaluation of alternative diagnostic considerations.
●Establishing a diagnosis
•Presumptive diagnosis − In most patients, a presumptive diagnosis of chronic disseminated candidiasis may be made based on clinical history, elevated liver function tests (particularly alkaline phosphatase concentration), and radiographic imaging demonstrating hypodense nodular lesions in the liver and/or spleen.
•Definitive diagnosis via biopsy − A definitive diagnosis may be established by liver nodule biopsy in some cases; however, in practice, biopsy is done infrequently because the clinical picture and CT scan findings generally are adequate to make a diagnosis. In addition, biopsy is often not feasible since thrombocytopenia is common in patients at risk for chronic disseminated candidiasis.
Biopsy may demonstrate granulomas (picture 1) [4]. Other findings may include necrosis with minimal inflammatory reaction (generally observed in the setting of neutropenia), or microabscesses with severe inflammatory reaction (typically observed after neutrophil recovery) [2].
Yeasts and hyphal forms may be observed with silver methenamine staining [2]. Cultures of hepatic tissue obtained at biopsy are usually negative, particularly if antifungal therapy has been administered; hence, a negative tissue culture does not rule out the diagnosis.
Radiographic imaging
●Timing − Imaging may be performed when investigating hepatosplenomegaly and abnormally elevated liver enzymes, or specifically to address suspected disseminated candidiasis. Radiographic imaging is more sensitive following neutrophil recovery than during neutropenia. In one series including five patients, serial CT scanning demonstrated disappearance of hepatic and/or splenic lesions during neutropenia with reappearance after neutrophil recovery [10].
●Choice of modality – Ultrasound is often the initial imaging modality and it may show normal appearing organs, diffusely enlarged organs, or organs containing multiple small low attenuation lesions widely scattered throughout the parenchyma. The sensitivity of ultrasonography is lower than CT or magnetic resonance imaging (MRI) [2].
CT is less costly than MRI; its sensitivity for detection of chronic disseminated candidiasis is 57 to 90 percent [5,19,20]. If CT does not demonstrate characteristic findings, MRI should be pursued, given higher sensitivity and specificity (100 and 96 percent, respectively) [3].
●Imaging findings – Diffuse hepatic and splenic involvement may manifest as an entirely normal imaging appearance, enlarged liver and/or spleen, or multifocal small lesions diffusely distributed throughout the liver and/spleen. There is are no imaging findings specific to disseminated candidiasis; many diffuse infectious conditions may have overlapping imaging appearances.
Imaging findings consist of multiple hypodense nodular lesions (representing microabscesses) in the liver and/or spleen; sometimes the kidneys are also involved (image 1) [3,4,20]. If the examination is performed with contrast, a central enhancement with a peripheral double ring (‘target lesion’) may be seen [2].
DIFFERENTIAL DIAGNOSIS
●Tuberculosis – Disseminated (miliary) tuberculosis can involve the liver and other organs. The diagnosis is suggested by the appearance on imaging and may be established by identifying the organism obtained from a biopsy sample in culture. (See "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis".)
●Liver abscess − Liver abscesses develop in the setting of biliary infection via direct spread or in the setting of diverticulitis or other cause of peritonitis (with spread of organisms to the liver via the portal circulation). They may also result from hematogenous seeding in the setting of systemic infection. Abscesses may be single or several may occur simultaneously. Their appearance varies depending on the duration; more mature abscesses are more likely to contain fluid components. The diagnosis is established by aspiration and culture of the abscess material. (See "Pyogenic liver abscess".)
●Relapsed hematologic malignancy – Fever in patients with history of hematologic malignancy should prompt consideration of disease relapse. The diagnosis is established by bone marrow biopsy.
●Sarcoidosis – Sarcoidosis is a systemic granulomatous disease of unknown etiology characterized by the formation of non-necrotizing granulomas; hepatic involvement occurs in 5 to 20 percent of cases. Asymptomatic hepatic lesions may be first identified on the liver images of thoracic CT. On contrast-enhanced abdominal CT, the typical findings are hepatomegaly and numerous hypodense nodular lesions ranging in size from 1 mm to 3 cm. (See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis".)
●Cirrhosis – Cirrhosis represents a late stage of hepatic fibrosis characterized by distortion of the hepatic architecture and the presence multiple regenerative nodules on radiographic imaging. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)
TREATMENT
Clinical approach — Management of chronic disseminated candidiasis consists of antifungal therapy [21]. For patients with persistent fevers despite appropriate antifungal therapy (likely a reflection of immune reconstitution, given the typical clinical presentation following neutrophil recovery), adjuvant glucocorticoids may be administered. The duration of treatment should be tailored to individual circumstances.
Antifungal therapy — The optimal approach to treatment of chronic disseminated candidiasis is uncertain. We are in agreement with the 2016 Infectious Diseases Society of America guidelines for the management of candidiasis, which includes the following approach (table 1) [1]:
●Initial treatment – Initial treatment consists of one of the following regimens for at least two weeks:
•An echinocandin (dosing as follows, assuming normal hepatic function):
-Caspofungin – 70 mg loading dose, then 50 mg intravenously (IV) once daily
-Anidulafungin – 200 mg loading dose, then 100 mg IV once daily
-Micafungin – 100 mg IV once daily
OR
•A lipid formulation of amphotericin B (3 to 5 mg/kg IV daily)
●Step-down therapy – Once the patient has demonstrated improvement, step-down therapy with oral fluconazole (400 mg [6 mg/kg] orally once daily) should be administered. Fever and other symptoms may be prolonged, even in the setting of effective antimicrobial therapy; in addition, radiographic findings may worsen over time due to persistent inflammation. (See 'Follow-up management' below.)
For patients with infection due to a fluconazole-resistant isolate (such as patients who had antecedent candidemia with C. glabrata or C. krusei), we give step-down therapy with voriconazole or posaconazole. However, there is minimal experience with these agents for treatment of chronic disseminated candidiasis; they should be used only if the organism is known to be susceptible.
The duration of treatment should be tailored to individual circumstances, as discussed below. (See 'Follow-up management' below.)
●Supporting evidence – The above approach to antifungal therapy is supported by small open-label studies and case reports [1,2,21].
Amphotericin B deoxycholate has been variably successful for treatment of chronic disseminated candidiasis [14,22]. In one retrospective study including 23 patients with acute leukemia and hepatosplenic candidiasis treated with amphotericin B (mean dose 4 g; median duration 112 days), the response rate was 82 percent [14]. Lipid formulations are less toxic and likely more effective than amphotericin B deoxycholate, perhaps due to better tissue concentrations [5,23,24], but some patients do not respond to either formulation [25].
Echinocandins have been used successfully for treatment of chronic disseminated candidiasis in small case series and they are useful for treatment of infection due to fluconazole-resistant isolates [25-29]. However, treatment failures with echinocandins have been reported [30].
Fluconazole has been used successfully for treatment of hepatosplenic candidiasis in small case series [12,16]. In one retrospective study including 20 patients with chronic disseminated candidiasis treated with fluconazole (dose 100 to 400 mg; median duration 30 weeks), the response rate was 88 percent [12].
Voriconazole or posaconazole have been used successfully in small numbers of patients [31,32].
Follow-up management — Clinical manifestations generally improve within two to eight weeks after starting antifungal therapy. However, fever may persist for weeks despite appropriate antifungal treatment; this may reflect immune reconstitution, given the typical clinical presentation following neutrophil recovery [33]. In such cases, alternative causes of infection should be ruled out. (See 'Pathogenesis' above and "Immune reconstitution inflammatory syndrome".)
●Persistent fever: role of adjuvant glucocorticoids – In patients with persistent fever despite appropriate antifungal therapy, we administer adjuvant glucocorticoid therapy (prednisone 0.5 to 1 mg/kg orally daily) for a few weeks as a tapering dose, in conjunction with antifungal therapy [1].
This approach is supported by retrospective studies and case reports [2,21,33,34]. In one retrospective study including 10 patients with chronic disseminated candidiasis and persistent symptoms despite appropriate antifungal therapy who were treated with prednisone (≥0.5 mg/kg per day for at least three weeks), fever and abdominal pain resolved shortly after starting prednisone (median four to five days) [33]. However, the time to radiographic resolution (mean 106 days) was similar to historical controls.
●Treatment duration guided by imaging – Follow-up computed tomography imaging should be obtained every two to three months [1]. Antifungal therapy should be continued until there is persistent resolution or calcification of the lesions on imaging, which usually takes approximately six months (table 1) [12].
Alkaline phosphatase should not be used alone to guide treatment response; it usually lags behind clinical and radiographic improvement [14].
Subsequent immunosuppression — Management of chronic disseminated candidiasis should not delay treatment of underlying malignancy; chronic disseminated candidiasis has been treated successfully through chemotherapy-induced neutropenia and hematopoietic cell transplantation without progression or breakthrough fungemia [14,22,35].
Following completion of treatment for chronic disseminated candidiasis, we continue fluconazole (or restart if previously stopped) during subsequent periods of immunosuppression (such as chemotherapy or hematopoietic stem cell transplantation) to prevent relapse (table 1) [1,12,16,22,29,32]. This approach is supported by one series including 16 patients with chronic disseminated candidiasis treated with antifungal therapy and ongoing antineoplastic therapy; 12 patients had complete response to antifungal therapy, 2 had partial response, and 2 had progression of chronic disseminated candidiasis requiring further antifungal therapy [22].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Candidiasis".)
SUMMARY AND RECOMMENDATIONS
●Definition − Chronic disseminated candidiasis (also known as hepatosplenic candidiasis) is a form of infection due to Candida spp involving the liver and spleen; it typically occurs in patients with hematologic malignancy, following prolonged neutropenia. Given widespread use of antifungal agents in such patients, the condition has become relatively rare. (See 'Introduction' above.)
●Pathogenesis − The pathogenesis is not well understood. The condition is thought to develop as a result of Candida spp invasion from the gastrointestinal tract into the bloodstream, in the context of prolonged neutropenia. It may represent a form of immune reconstitution syndrome, given development of symptoms and radiographic findings following neutrophil recovery. (See 'Pathogenesis' above.)
●Clinical manifestations − Chronic disseminated candidiasis should be suspected in patients who present with fever unresponsive to broad-spectrum antibiotic therapy, usually within two weeks of neutrophil recovery. Additional signs and symptoms may include right upper quadrant tenderness, hepatomegaly, splenomegaly, nausea, vomiting, and/or anorexia. (See 'Signs and symptoms' above and 'Clinical approach' above.)
●Diagnosis – The diagnostic evaluation should include laboratory testing (complete blood count, liver function tests, beta-D-glucan, blood cultures) and radiographic imaging (beginning with computed tomography).
In most patients, a presumptive diagnosis of chronic disseminated candidiasis may be made based on clinical history, elevated liver function tests (particularly alkaline phosphatase concentration), and radiographic imaging demonstrating hypodense nodular lesions in the liver and/or spleen. A definitive diagnosis may be established by liver nodule biopsy in some cases; however, in practice, biopsy is done infrequently because the clinical picture and radiographic findings are generally are adequate to make a diagnosis. (See 'Diagnosis' above.)
●Treatment
•Antifungal regimen − Management of chronic disseminated candidiasis consists of antifungal therapy. We suggest initial treatment with either a lipid formulation of amphotericin B or an echinocandin (Grade 2C). Both of these agents have more robust evidence of efficacy (while still limited) than is available for azoles.
Once the patient has demonstrated clinical improvement, we transition to step-down therapy with oral fluconazole. (See 'Antifungal therapy' above.)
•Management of persistent fever − For patients with persistent fevers despite appropriate antifungal therapy, we suggest administration of adjuvant glucocorticoids (Grade 2C). (See 'Follow-up management' above.)
•Duration − Antifungal therapy should be continued until there is resolution or calcification of the lesions on radiographic imaging, which usually takes approximately six months. (See 'Follow-up management' above.)
●Subsequent immunosuppression − Management of chronic disseminated candidiasis should not delay treatment of underlying malignancy.
Following completion of treatment for chronic disseminated candidiasis, we suggest continuing fluconazole (or restarting if previously stopped) during subsequent periods of immunosuppression (such as chemotherapy or hematopoietic stem cell transplantation) to prevent relapse (Grade 2C). (See 'Subsequent immunosuppression' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kieren Marr, MD, who contributed to an earlier version of this topic review.
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