Skip Navigation

Adjuvant Corticosteroid Therapy for Chronic Disseminated Candidiasis

  1. Faézeh Legrand1,6,
  2. Marc Lecuit2,3,
  3. Bertrand Dupont2,
  4. Erianna Bellaton1,
  5. Michel Huerre4,
  6. Pierre-Simon Rohrlich1,7, and
  7. Olivier Lortholary2,5
  1. 1Université Paris-7, Service d'Hématologie-Pédiatrique, Hôpital Robert Debré, CNRS Unité de Recherche Associée 3012, Institut Pasteur, Paris
  2. 2Université Paris Descartes, Hôpital Necker-Enfants Malades, Service des Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur, CNRS Unité de Recherche Associée 3012, Institut Pasteur, Paris
  3. 3Groupe Microorganismes et Barrières de l'Hôte, équipe Avenir Inserm U604, CNRS Unité de Recherche Associée 3012, Institut Pasteur, Paris
  4. 4Unité d'Histotechnologie et Pathologie, CNRS Unité de Recherche Associée 3012, Institut Pasteur, Paris
  5. 5Centre National de Référence Mycologie et Antifongiques, Unité de Mycologie Moléculaire, CNRS Unité de Recherche Associée 3012, Institut Pasteur, Paris
  6. 6Université de Franche-Comté, Service d'Hématologie Clinique, Hôpital Jean Minjoz, Hôpital Saint Jacques, Besançon, France
  7. 7Université de Franche-Comté, Service d'Hémato-Onco-Pédiatrie, Hôpital Saint Jacques, Besançon, France
  1. Reprints or correspondence: Dr. Olivier Lortholary (olivier.lortholary{at}nck.aphp.fr).
 
Next Section

Abstract

Background. Chronic disseminated candidiasis (CDC) is typically observed during neutrophil recovery in patients with acute leukemia and requires protracted antifungal therapy.

Objective. Our objective was to document the efficacy and tolerance of corticosteroid therapy (CST) in patients with symptomatic CDC, including those who experienced fever and abdominal pain despite ongoing antifungal therapy.

Methods. We performed a retrospective, multicenter study involving 10 pediatric and adult patients who experienced ongoing symptomatic CDC despite receipt of appropriate antifungal therapy for whom adjuvant oral CST was initiated.

Results. All cases of CDC were proven or probable, as determined on the basis of the European Organization for Research and Treatment of Cancer-Mycosis Study Group definition criteria, and occurred in patients with leukemia. CDC-attributable clinical symptoms resolved with CST, which was started a mean of 33.8 days after antifungal therapy had been initiated. Fever and abdominal pain disappeared a median of 4–5 days, and serum fibrinogen and C-reactive protein levels returned to normal values within 14–30 days. The median duration of hospitalization after CST initiation was 8.8 days. Hepatosplenic microabscesses decreased or disappeared within a mean period of 107 days (range, 30–210 days). No relapses of CDC were observed during a median duration of follow-up of 6.5 years (range, 4–9 years).

Conclusions. In children and adults who experience persistently symptomatic CDC despite ongoing receipt of antifungal therapy, CST involving a prednisone equivalent at a dosage of ⩾0.5 mg/kg per day for at least 3 weeks is associated with a prompt resolution of symptoms and of inflammatory response. These findings support the pathophysiological hypothesis that CDC belongs to the spectrum of fungus-related immune reconstitution inflammatory syndrome.

Chronic disseminated candidiasis (CDC), also called “hepatosplenic candidiasis,” is a severe invasive fungal infection principally observed during neutrophil recovery in almost 5% of patients with acute leukemia treated with intensive chemotherapy [1]. The pathophysiology of CDC is not fully understood, but its clinical, radiological, and biological features have been well characterized [2]. It is assumed that initial colonization of the gastrointestinal tract with Candida species, fol-lowed by liver invasion through portal venous circulation, is the most probable scenario for the onset of this disease [3, 4].

The efficacy of treatment with various systemic antifungals has been reported for CDC. Nevertheless, several months of antifungal therapy are usually required, thus delaying completion of antileukemia treatment. Thus, CDC negatively impacts the survival of these patients [1, 5–10].

CDC often becomes clinically apparent in the course of neutrophil recovery, typically with concomitant negative results of blood and tissue fungal cultures and focal granulomatous reaction noted by examination of liver biopsy tissue specimens [4]. Thus, CDC appears to share several features with immune reconstitution inflammatory syndrome (IRIS) associated with invasive fungal infections (IFIs), as has been described in patients who have HIV infection or who have undergone solid organ transplantation, in whom corticosteroid therapy has been shown to be beneficial [11, 12].

We hypothesized that corticosteroid therapy could also accelerate the recovery from CDC-associated clinical symptoms (abdominal pain and fever) and biological parameters (inflammatory response and elevated liver enzyme levels) that persist despite ongoing antifungal therapy. We report the results of a multicenter, retrospective study conducted in university hospitals in Paris, France, that included all children and adult patients for whom we prescribed CST for severe CDC.

Previous SectionNext Section

Methods

Patients. A multicenter, retrospective study involving 5 University hospitals of the Paris area (Robert Debré, Kremlin-Bicêtre, Necker-Enfants Malades, Hôtel Dieu, and Percy hospitals) was coordinated by the Centre d'Infectiologie Necker-Pasteur to review medical files for 6 adults and 4 children with leukemia who had CDC that was treated with adjuvant CST after administration of appropriate antifungal therapy during 1991–2004. For all cases, CDC occurred after intensive antineoplastic chemotherapy.

Diagnostic criteria of CDC. Patients were classified according to the 2002 European Organization for Research and Treatment of Cancer-Mycosis Study Group criteria for IFI [13]. Cases were considered to be “proven” if histopathologic or cytopathologic examination of needle aspiration or liver biopsy samples revealed yeast cells or if liver biopsy specimens had positive culture results and the liver and/or spleen exhibited clinical/biological or radiologic symptoms consistent with infection. Cases were classified as “probable” in all patients with hematologic malignancies for whom small, peripheral, “target-like” images in the liver and/or spleen were observed by CT or ultrasound and who had elevated serum alkaline phosphatase levels (and/or elevated γ-glutamyl transferase levels in children, because serum alkaline phosphatase level correlates with bone growth and is not a reliable marker for cholestasis), without any evidence of an alternative diagnosis.

Antineoplastic and antimicrobial therapies. Antineo-plastic chemotherapy was administered as described in table 1. All neutropenic patients received conventional broad-spectrum antibacterial therapy in accordance with the guidelines of the Infectious Diseases Society of America [16], as well as empirical amphotericin B therapy (except for patient 1), 1 mg/kg per day, at 5–15 days after the initiation of antibacterial therapy in cases involving prolonged persistent fever. None of the patients received systemic antifungal therapy as a prophylactic regimen before the occurrence of neutropenia. Treatment with granulocyte colony-stimulating factor, which was started between days 5 and 10 of neutropenia, was prescribed for 4 patients.

Corticosteroid therapy. Daily oral CST was introduced at a dose of 0.5–0.8 mg/kg for adult patients and 1 mg/kg for children (except for 2 patients who received 0.5 mg/kg and 2 mg/kg) after confirmation of CDC diagnosis and always in association with systemic antifungal therapy (table 2). CST was initiated in association with daily fluconazole at 6–9 mg/kg in 3 children (weight, <35 kg), 200 mg in 1 child (weight, 45 kg) and 2 adults, 400 mg in 1 adult and 1 child (weight, 45 kg), with liposomal amphotericin B in 1 patient and amphotericin B lipid complex in 1 patient (3 days per week). Three of our patients experienced relapse shortly after CDC diagnosis, received a long duration of steroid therapy, and finally died of leukemia.

A chemistry panel, including liver function tests and determination of the alkaline phosphatase level, γ-glutamyl transferase level, blood urea nitrogen level, creatinine level, and electrolyte level, was obtained at least 3 times per week from all patients during their hospital stay. Complete blood cell counts were obtained daily during hospitalization.

The following criteria were used as end points for evaluating the efficacy of antifungal and corticosteroid therapies: complete resolution of clinical symptoms attributable to CDC, disappearance of CDC-associated visceral images on abdominal CT and/or ultrasound, and normalization of serum levels of alkaline phosphatase and of inflammatory markers.

Centralized review of histopathologic analysis of liver biopsy specimens. A single pathologist reviewed all liver biopsy specimens. Formalin-fixed embedded biopsy specimens were sectioned and stained with hematoxylin and eosin, Giemsa, and Periodic acid schiff stains. Immunohistochemistry was performed using a streptavidin peroxidase method and amino-ethyl carbazole as a chromogen. Monoclonal antibodies to CD3 and UCHL-1 were used to label T lymphocytes (Dako) and a polyclonal anti-Candida albicans antibody (Biogenesis; Argene).

Previous SectionNext Section

Results

The main characteristics of the patients are summarized in table 1. All patients had an implanted vascular device and experienced mucositis and acute diarrhea during chemotherapy.

Patient Characteristics at CDC Diagnosis

Clinical and radiological findings. The clinical and radiological signs of CDC are summarized in table 1. In the 3 patients with acute myeloblastic leukemia, there was an interval of 4–18 days without symptoms of CDC after neutrophil recovery. Two of these patients were discharged from the hospital during this period and were readmitted for persistent fever. In patients with acute lymphoblastic leukemia, the clinical symptoms of CDC appeared before or immediately after neutrophil recovery. Two patients received steroids before the CDC diagnosis (for respiratory distress syndrome in one patient and for consolidation chemotherapy by COPADM [i.e., vincristine, methotrexate, cyclophosphanamide, doxorubicin, and prednisone] in the other); in these 2 patients, clinical signs reappeared after discontinuation or tapering of CST, and clinical symptoms of CDC appeared 5 days thereafter, with a concomitant rapid increase in the neutrophil count.

Biological findings. Biological abnormalities included elevated C-reactive protein and/or fibrinogen serum levels in all patients, elevated alkaline phosphatase serum levels in 3 patients, elevated γ-glutamyl transferase serum level in 5 patients, and cholestasis in a total of 8 patients. The median duration of neutropenia was 17.8 days (range, 5–30 days), and the median neutrophil count at the time of CDC diagnosis was 19,372 cells/mL (range, 6400–36,000 cells/mL). The mean time between neutrophil recovery and diagnosis of CDC was 5.9 days (range, 1–18 days) (table 1).

Microbiological findings. Results of microbiological investigations included blood cultures positive for C. albicans in 1 patient. Eight patients had positive stool fungal cultures (C. albicans in 7 patients [70%], with Geotrichum candidum coinfection in 1 patient). One patient had a urine culture positive for C. albicans, and 1 patient had a urine culture positive for Sacccharomyces species (table 1). The results of liver biopsy cultures were negative for all patients who underwent biopsy (9 of 10 patients), except for 1 who did not receive antifungal treatment before undergoing liver biopsy (table 1).

Liver biopsy specimen analysis. Laparoscopy or coelioscopy was performed in 3 patients and revealed multiple whitish nodules in the liver and/or spleen, with peritoneal inflammatory reaction. Ten transcutaneous liver biopsies were performed in 6 patients; 3 patients underwent 1 biopsy, 2 underwent 2 biopsies (one before and the other after the appearance of liver micronodules), and 1 patient underwent 3 biopsies (the first was on day 60, when liver micronodules appeared; the second was 1 month later, after receipt of fluconazole treatment; and the last was 3 months after receipt of CST and fluconazole treatment). At diagnosis, yeasts were observed on direct examination of a cytological smear of the liver biopsy specimen for 3 patients.

Histologic examination revealed yeasts with pseudomycelia in 2 patients; this was associated with necrotic areas that contained numerous polymorphonuclear cells surrounded by lymphocytes, a few plasma cells, and fibroblasts embedded within areas of fibrosis in 4 patients (data not shown). Granuloma were observed in 2 patients, with clusters of epithelioid macrophages, which were sometimes vacuolated and were always CD68 positive (data not shown). Images suggestive of yeasts and pseudohyphae debris labelled by the anti-Candida antibody could be detected in these necrotic areas (figure 1A). T lymphocytes were observed, predominantly at the periphery of granulomatous lesions (figure 1B). Overall, the diagnosis of CDC was proven for 6 patients and probable for the 4 other patients.

Figure 1
View larger version:
Figure 1

A, Immunolabeled yeasts and pseudohyphae debris of Candida albicans surrounded by polymorphonuclear cells in the necrotic areas (hematoxylin counter-staining; original magnification, ×200). B, CD3-positive lymphocytes surrounding granuloma areas (hematoxylin counter-staining; original magnification, ×100).

Patient Characteristics when CST Was Started

Antifungal therapy for CDC prior to CST initiation included amphotericin deoxycholate, liposomal amphotericin B, and fluconazole (table 2). After a median duration of 33.8 days (range, 6–60 days) of treatment with amphotericin B alone (except for patient 10, who was treated with multiple antifungals during 120 days), fever persisted in 9 patients in association with other clinical symptoms suggesting CDC evolution. Hepatosplenic and/or kidney and lung micronodules persisted, despite the receipt of antifungal therapy, with biological signs of persisting inflammation (table 1).

Table 1
View larger version:
Table 1

Demographic and clinical characteristics of 10 patients with chronic disseminated candidiasis (CDC) before commencement of corticosteroid therapy.

CST Administration and Outcome

CST administration. The median interval between CDC diagnosis and CST initiation was 40 days (range, 1–120 days). Fever disappeared after a mean period of 1.2 days (range, 1–3 days) after onset of CST, except in 1 patient for whom disappearance of fever occurred within 30 days after onset. All patients left the hospital within a mean of 8.8 days (range, 1–30 days) after initiation of CST. Serum fibrinogen and/or C-reactive protein levels decreased 1 week after commencement of CST and returned to normal values within a median period of 14.4 days (range, 2–30 days). The findings of radiologic investigations returned to normal or to with residual microcalcification after a mean period of 107 days (range, 30–210 days) after initiation of CST (table 2).

Table 2
View larger version:
Table 2

Antifungal treatment and patient outcome after commencement of corticosteroid treatment (CST).

Full-dose CST was maintained for a mean duration of 21 days (range, 10–60 days), after which the CST dose was tapered progressively on the basis of clinical and biological parameters. The mean duration of CST, always given in association with antifungal therapy, was 124.9 days (range, 49–240 days). In 3 patients, CST was maintained for a long period (180–240 days) because of a relapse of leukemia, without any adverse event.

Antifungal therapies administered after commencement of CST include liposomal amphotericin B, which was given for 1 month to 2 patients. All patients received fluconazole, with a median duration of treatment of 109 days (range, 49–240 days) (table 2).

Outcome. Of the 10 patients, 5 (3 adults and 2 children) underwent bone marrow transplantation 90 days to 4 years after CDC diagnosis. Neither reactivation of CDC nor emerging systemic fungal infection was observed in any of the patients. During the conditioning regimen, 4 children switched their treatment from fluconazole to deoxycholate amphotericin B (1 mg/kg per infusion) for 30 days after bone marrow transplantation 3 times per week. Six patients died of relapse of leukemia without evidence of evolving infection, and 4 patients were alive 4–9 years after the onset of CDC. In our study, the median survival rate was 40.8% at 110 months (data not shown), whereas, in a historical study, the rate was 26% at 96 months [1]. In these 2 studies, there was no mortality directly attributable to CDC.

Previous SectionNext Section

Discussion

We show—to our knowledge, for the first time—that adjuvant CST, in addition to antifungal therapy, is beneficial for CDC-related clinical symptoms and inflammatory response in adults and children. Indeed, CDC-related clinical symptoms disappeared as early as 1 day after initiation of CST in almost all patients, and inflammatory markers decreased within 1 week, reaching normal values in a median of 2 weeks. In addition, our patients were able to leave the hospital after 1 week. In contrast, in historical studies, the time to resolution of fever has exceeded 4 weeks (range, 9–196 days) [4, 6, 17]; nausea and vomiting has taken 6–8 weeks to resolve [18], and increased levels of liver enzymes persisted for a mean of 4.4 months (range, 1 week to 12 months) [19]. Of note, in our study, CDC-related radiological abnormalities disappeared within a mean of 106 days (range, 30–210 days)—a result not significantly different from that of historical series (mean, 100 days; range, 28–390 days) [18], thereby suggesting that adjuvant CST does not contribute to the disappearance of radiological lesions.

Several months of antifungal treatment are typically recommended for eradication of CDC [5–8, 20]. The use of amphotericin B (or its lipid formulations), fluconazole, and flucytosine may be considered, with amphotericin B typically considered to be the therapeutic cornerstone [5, 20]. More recently, voriconazole and caspofungin have also been used, with encouraging results and better tolerance than polyenes [7, 21, 22]. However, in patients with CDC who are treated with antifungals alone, clinical symptoms often persist during a very prolonged period, and a median cumulative dose of up to 2 g has been advocated for amphotericin B [5, 6].

It should also be emphasized that the clinical improvement observed in all of our patients allowed us to minimize the interval between diagnosis of CDC and initiation of chemotherapy or allogeneic stem cell transplantation. The safety of resuming antineoplastic chemotherapy in association with antifungal therapy has already been advocated by Walsh et al. [9] and Masood et al. [20]. One might argue that corticosteroid therapy prescribed early in the course of CDC (i.e., close to the time of neutrophil recovery) might be associated with an increased risk of subsequent infection—particularly infections of fungal origin. However, no reactivation of candidiasis was observed in our patients, and no other new opportunistic infections were diagnosed. The efficacy and safety of steroid therapy observed here emphasizes that they may be considered as adjuvant therapy in association with antifungal treatment in cases of severe inflammatory-related symptoms during CDC.

It is well known that CDC becomes clinically overt on recovery from neutropenia in the context of negative liver fungal culture results, in accordance with the major role of neutrophils in the host defense against pseudohyphae, the invasive form of Candida species [23–25]. Of note, the classic histologic image of CDC includes large infiltrates of neutrophils surrounding a few Candida pseudohyphae and blastoconidia, in association with lymphocytes and macrophages in the liver, as noted here and elsewhere [2].

Studies of mice have shown that the development of a protective Th1 response against invasive candidiasis requires the coordination of a series of cytokines (namely, IFN-γ, TGF-β, IL-6, TNF-α, and IL-12) and the relative absence of cytokines (e.g., IL-4 and IL-10) that inhibit Th1 response [23, 26–29]. IL-10 has been shown to suppress phagocytosis of neutrophils against C. albicans blastoconidia and to impair neutrophil-induced hyphal damage [29]. Increased serum concentrations of IL-10, but not of IL-4, have been reported in patients with CDC, compared with control subjects; this may, in fact, be the consequence of an exacerbated Th1 response rather than a causal factor in CDC [26].

Of note, in addition to classic risk factors for CDC (e.g., younger age, prolonged neutropenia, and antibiotic prophylaxis [30]), a genetic basis has been advocated for the occurrence of CDC. Indeed, in one study, a common haplotype of the IL-4 promoter was overrepresented in patients with CDC [31]. However, a study by the same group challenged this result by showing that common polymorphisms in 6 critical genes of innate immunity did not contribute to an increased risk of CDC [32]. Knowing that steroids inhibit Th1 responses [33, 34] and IL-10 synthesis [26, 35], we propose that CST may modulate an inappropriate immune response associated with the onset of CDC by modulating T cell activation and mononuclear phagocyte function.

Overall, the occurrence of CDC during neutrophil recovery, the liver histopathologic findings in patients with CDC, and the beneficial effect of steroids towards its inflammatory symptoms strongly suggest that CDC belongs to the IFI-induced IRIS. IFI-induced IRIS was initially described in the context of profoundly immunosuppressed patients with the AIDS, often with initial severe or disseminated fungal infections, such as Pneumocystis jiroveci associated pneumonia, disseminated histoplasmosis, or Cryptococcus neoformans infection [36–40]. IRIS typically occurs after the commencement of HAART, when the HIV load markedly decreases, with or without dramatic recovery of the CD4 cell count. IRIS has also been recently reported during pulmonary aspergillosis in patients with cancer who are recovering from neutropenia [41]. Of note, reascension of the CD4+ T lymphocyte count is also known to occur after intensive antineoplastic chemotherapy [42] and might also be involved in the pathogenesis of CDC, as suggested by the presence of T lymphocytes in inflammatory areas, as noted in our patients' liver biopsy samples. A similar complication was recently reported in solid organ transplant recipients whose immunosuppressive therapy, which contained Th1-inhibiting drugs, was markedly reduced after the occurrence of severe C. neoformans infection and who, in some cases, experienced additional complications associated with graft loss [43]. Interestingly, in the context of IRIS occurring in patients who have AIDS or who have undergone solid organ transplantation, the addition of steroids to appropriate antimicrobial therapy may also be effective and safe to control this paradoxical reaction [38, 44], as evidenced in our study of CDC.

Previous SectionNext Section

Acknowledgments

We thank Dr. Emmanuel Roilides for his helpful advice.

Potential conflicts of interest. All authors: no conflicts.

  • Received July 5, 2007.
  • Accepted October 31, 2007.
Previous Section
 

References

  1. ↵
    1. Anttila VJ,
    2. Elonen E,
    3. Nordling S,
    4. Sivonen A,
    5. Ruutu T,
    6. Ruutu P
    . Hepatosplenic candidiasis in patients with acute leukemia: incidence and prognostic implications. Clin Infect Dis 1997;24:375-80.
    Abstract/FREE Full Text
  2. ↵
    1. von Eiff M,
    2. Essink M,
    3. Roos N,
    4. et al
    . Hepatosplenic candidiasis in acute leukemias. Haematol Blood Transfus 1990;33:555-7.
    Medline
  3. ↵
    1. Anaissie EJ,
    2. Rex JH,
    3. Uzun O,
    4. Vartivarian S
    . Predictors of adverse outcome in cancer patients with candidemia. Am J Med 1998;104:238-45.
    CrossRefMedlineWeb of Science
  4. ↵
    1. Thaler M,
    2. Pastakia B,
    3. Shawker TH,
    4. O'Leary T,
    5. Pizzo PA
    . Hepatic candidiasis in cancer patients: the evolving picture of the syndrome. Ann Intern Med 1988;108:88-100.
    Abstract/FREE Full Text
  5. ↵
    1. Sallah S,
    2. Semelka RC,
    3. Sallah W,
    4. Vainright JR,
    5. Philips DL
    . Amphotericin B lipid complex for the treatment of patients with acute leukemia and hepatosplenic candidiasis. Leuk Res 1999;23:995-9.
    CrossRefMedlineWeb of Science
  6. ↵
    1. Sallah S,
    2. Semelka RC,
    3. Wehbie R,
    4. Sallah W,
    5. Nguyen NP,
    6. Vos P
    . Hepatosplenic candidiasis in patients with acute leukaemia. Br J Haematol 1999;106:697-701.
    CrossRefMedlineWeb of Science
  7. ↵
    1. Antachopoulos C,
    2. Walsh TJ
    . New agents for invasive mycoses in children. Curr Opin Pediatr 2005;17:78-87.
    CrossRefMedlineWeb of Science
  8. ↵
    1. Haron E,
    2. Feld R,
    3. Tuffnell P,
    4. Patterson B,
    5. Hasselback R,
    6. Matlow A
    . Hepatic candidiasis: an increasing problem in immunocompromised patients. Am J Med 1987;83:17-26.
    MedlineWeb of Science
  9. ↵
    1. Walsh TJ,
    2. Whitcomb PO,
    3. Revankar SG,
    4. Pizzo PA
    . Successful treatment of hepatosplenic candidiasis through repeated cycles of chemotherapy and neutropenia. Cancer 1995;76:2357-62.
    CrossRefMedlineWeb of Science
  10. ↵
    1. Bjerke JW,
    2. Meyers JD,
    3. Bowden RA
    . Hepatosplenic candidiasis—a contraindication to marrow transplantation? Blood 1994;84:2811-4.
    Abstract/FREE Full Text
  11. ↵
    1. French MA,
    2. Price P,
    3. Stone SF
    . Immune restoration disease after antiretroviral therapy. AIDS 2004;18:1615-27.
    CrossRefMedlineWeb of Science
  12. ↵
    1. Singh N,
    2. Lortholary O,
    3. Alexander BD,
    4. et al
    . An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients. Clin Infect Dis 2005;40:1756-61.
    Abstract/FREE Full Text
  13. ↵
    1. Ascioglu S,
    2. Rex JH,
    3. de Pauw B,
    4. et al
    . Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 2002;34:7-14.
    Abstract/FREE Full Text
    1. Lenz G,
    2. Dreyling M,
    3. Hoster E,
    4. et al
    . Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 2005;23:1984-92.
    Abstract/FREE Full Text
    1. Atra A,
    2. Gerrard M,
    3. Hobson R,
    4. Imeson JD,
    5. Ashley S,
    6. Pinkerton CR
    . Improved cure rate in children with B-cell acute lymphoblastic leukaemia (B-ALL) and stage IV B-cell non-Hodgkin's lymphoma (B-NHL)--results of the UKCCSG 9003 protocol. Br J Cancer 1998;77:2281-5.
    MedlineWeb of Science
  16. ↵
    1. Hughes WT,
    2. Armstrong D,
    3. Bodey GP,
    4. et al
    . 2002 Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730-51.
    FREE Full Text
  17. ↵
    1. Blade J,
    2. Lopez-Guillermo A,
    3. Rozman C,
    4. et al
    . Chronic systemic candidiasis in acute leukemia. Ann Hematol 1992;64:240-4.
    CrossRefMedlineWeb of Science
  18. ↵
    1. Kauffman CA,
    2. Bradley SF,
    3. Ross SC,
    4. Weber DR
    . Hepatosplenic candidiasis: successful treatment with fluconazole. Am J Med 1991;91:137-41.
    CrossRefMedlineWeb of Science
  19. ↵
    1. von Eiff M,
    2. Fahrenkamp A,
    3. Roos N,
    4. Fegeler W,
    5. van de Loo J
    . Hepatosplenic candidosis—a late manifestation of Candida septicemia. Mycoses 1990;33:283-90.
    MedlineWeb of Science
  20. ↵
    1. Masood A,
    2. Sallah S
    . Chronic disseminated candidiasis in patients with acute leukemia: emphasis on diagnostic definition and treatment. Leuk Res 2005;29:493-501.
    CrossRefMedlineWeb of Science
  21. ↵
    1. Mora-Duarte J,
    2. Betts R,
    3. Rotstein C,
    4. et al
    . Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002;347:2020-9.
    CrossRefMedlineWeb of Science
  22. ↵
    1. Sora F,
    2. Chiusolo P,
    3. Piccirillo N,
    4. et al
    . Successful treatment with caspofungin of hepatosplenic candidiasis resistant to liposomal amphotericin B. Clin Infect Dis 2002;35:1135-6.
    FREE Full Text
  23. ↵
    1. Netea MG,
    2. van Tits LJ,
    3. Curfs JH,
    4. et al
    . Increased susceptibility of TNF-alpha lymphotoxin-alpha double knockout mice to systemic candidiasis through impaired recruitment of neutrophils and phagocytosis of Candida albicans. J Immunol 1999;163:1498-505.
    Abstract/FREE Full Text
    1. Van't Wout JW,
    2. Van der Meer JW,
    3. Barza M,
    4. Dinarello CA
    . Protection of neutropenic mice from lethal Candida albicans infection by recombinant interleukin 1. Eur J Immunol 1988;18:1143-6.
    MedlineWeb of Science
  25. ↵
    1. Kullberg BJ,
    2. Netea MG,
    3. Vonk AG,
    4. van der Meer JW
    . Modulation of neutrophil function in host defense against disseminated Candida albicans infection in mice. FEMS Immunol Med Microbiol 1999;26:299-307.
    CrossRefMedlineWeb of Science
  26. ↵
    1. Roilides E,
    2. Sein T,
    3. Schaufele R,
    4. Chanock SJ,
    5. Walsh TJ
    . Increased serum concentrations of interleukin-10 in patients with hepatosplenic candidiasis. J Infect Dis 1998;178:589-92.
    Abstract/FREE Full Text
    1. Romani L
    . Immunity to fungal infections. Nat Rev Immunol 2004;4:1-23.
    CrossRefMedline
    1. Roilides E,
    2. Pizzo PA
    . Modulation of host defenses by cytokines: evolving adjuncts in prevention and treatment of serious infections in immunocompromised hosts. Clin Infect Dis 1992;15:508-24.
    Abstract/FREE Full Text
  29. ↵
    1. Roilides E,
    2. Katsifa H,
    3. Tsaparidou S,
    4. Stergiopoulou T,
    5. Panteliadis C,
    6. Walsh TJ
    . Interleukin 10 suppresses phagocytic and antihyphal activities of human neutrophils. Cytokine 2000;12:379-87.
    CrossRefMedlineWeb of Science
  30. ↵
    1. Sallah S,
    2. Wan JY,
    3. Nguyen NP,
    4. Vos P,
    5. Sigounas G
    . Analysis of factors related to the occurrence of chronic disseminated candidiasis in patients with acute leukemia in a non-bone marrow transplant setting: a follow-up study. Cancer 2001;92:1349-53.
    CrossRefMedlineWeb of Science
  31. ↵
    1. Choi EH,
    2. Foster CB,
    3. Taylor JG,
    4. et al
    . Association between chronic disseminated candidiasis in adult acute leukemia and common IL4 promoter haplotypes. J Infect Dis 2003;187:1153-6.
    Abstract/FREE Full Text
  32. ↵
    1. Choi EH,
    2. Taylor JG,
    3. Foster CB,
    4. et al
    . Common polymorphisms in critical genes of innate immunity do not contribute to the risk for chronic disseminated candidiasis in adult leukemia patients. Med Mycol 2005;43:349-53.
    CrossRefMedlineWeb of Science
  33. ↵
    1. Miyaura H,
    2. Iwata M
    . Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids. J Immunol 2002;168:1087-94.
    Abstract/FREE Full Text
  34. ↵
    1. Zhang TY,
    2. Daynes RA
    . Glucocorticoid conditioning of myeloid progenitors enhances TLR4 signaling via negative regulation of the phosphatidylinositol 3-kinase-Akt pathway. J Immunol 2007;178:2517-26.
    Abstract/FREE Full Text
  35. ↵
    1. Kasama T,
    2. Strieter RM,
    3. Lukacs NW,
    4. Burdick MD,
    5. Kunkel SL
    . Regulation of neutrophil-derived chemokine expression by IL-10. J Immunol 1994;152:3559-69.
    Abstract
  36. ↵
    1. Cheng VC,
    2. Yuen KY,
    3. Chan WM,
    4. Wong SS,
    5. Ma ES,
    6. Chan RM
    . Immunorestitution disease involving the innate and adaptive response. Clin Infect Dis 2000;30:882-92.
    Abstract/FREE Full Text
    1. Wu AK,
    2. Cheng VC,
    3. Tang BS,
    4. et al
    . The unmasking of Pneumocystis jiroveci pneumonia during reversal of immunosuppression: case reports and literature review. BMC Infect Dis 2004;4:57.
    CrossRefMedline
  38. ↵
    1. Lortholary O,
    2. Fontanet A,
    3. Memain N,
    4. Martin A,
    5. Sitbon K,
    6. Dromer F
    . Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France. AIDS 2005;19:1043-9.
    MedlineWeb of Science
    1. Shelburne SA 3rd,
    2. Hamill RJ,
    3. Rodriguez-Barradas MC,
    4. et al
    . Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine 2002;81:213-27.
    CrossRefMedline
  40. ↵
    1. Breton G,
    2. Adle-Biassette H,
    3. Therby A,
    4. et al
    . Immune reconstitution inflammatory syndrome in HIV-infected patients with disseminated histoplasmosis. AIDS 2006;20:119-21.
    MedlineWeb of Science
  41. ↵
    1. Miceli MH,
    2. Maertens J,
    3. Buve K,
    4. et al
    . Immune reconstitution inflammatory syndrome in cancer patients with pulmonary aspergillosis recovering from neutropenia: proof of principle, description, and clinical and research implications. Cancer 2007;110:112-20.
    CrossRefMedlineWeb of Science
  42. ↵
    1. Mackall CL,
    2. Fleisher TA,
    3. Brown MR,
    4. et al
    . Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 1995;332:143-9.
    CrossRefMedlineWeb of Science
  43. ↵
    1. Singh N,
    2. Lortholary O,
    3. Alexander BD,
    4. et al
    . Allograft loss in renal transplant recipients with Cryptococcus neoformans-associated immune reconstitution syndrome. Transplantation 2005;80:1131-3.
    CrossRefMedlineWeb of Science
  44. ↵
    1. Lanternier F,
    2. Chandesris MO,
    3. Poirée S,
    4. et al
    . Cellulitis revealing a cryptococcosis-related immune reconstitution inflammatory syndrome in a renal allograft recipient. Am J Transplant 2007;7:2826-8.
    CrossRefMedlineWeb of Science
| Table of Contents

This Article

  1. Clin Infect Dis. (2008) 46 (5): 696-702. doi: 10.1086/527390
  1. AbstractFree
  2. » Full Text (HTML)Free
  3. Full Text (PDF)Free

Classifications

Share

  1. Email this article

Navigate This Article

Current Issue

  1. March 1, 2012 54 (5)
  1. Clinical Infectious Diseases
  1. Alert me to new issues

Most