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New approaches to invasive fungal infections in acute leukemia and hematopoietic stem cell transplant patients
Best Practice & Research Clinical Haematology Vol. 20, No. 1, pp. 99e107, 2007 doi:10.1016/j.beha.2006.11.008 available online at http://www.sciencedirect.com
12 New approaches to invasive fungal infections in acute leukemia and hematopoietic stem cell transplant patients John R. Wingard *
MD
Director Blood and Marrow Transplant Program, Division of Hematology/Oncology, University of Florida Shands Cancer Center, 1376 Mowry Road, Room 145, Gainesville, FL 32610-3633, USA
Recognition and treatment of invasive fungal infections in acute leukemia and hematopoietic stem cell transplant patients are important clinical challenges. New diagnostic tools, such as fungal serologic assays and high-resolution CT scans, offer the hope for earlier initiation of antifungal therapy and improved treatment results. New antifungal agents offer choices that in some cases are less toxic than older drugs and in other cases are more efficacious. Combining the new diagnostic tools with new drugs, novel strategies are being evaluated to change our approaches to these deadly infections. Key words: Aspergillus; Candida; galactomannan assay; glucan assay; hematopoietic stem cell transplant; invasive fungal infection; targeted therapy.
INTRODUCTION With improved strategies to control bacterial infections during the myelosuppression that results from acute leukemia therapy and after hematopoietic stem cell transplantation (HSCT), invasive fungal infections (IFIs) have assumed an increasing focus for clinicians. Today, IFIs are the chief life-threatening infectious complications of leukemia and transplant therapies. Candida and Aspergillus are the chief invasive fungal pathogens.1 New diagnostics and new antifungal agents have begun to reshape the landscape of antifungal therapies and offer the opportunity for new management paradigms. These offer the prospect for substantially reducing fungal morbidity and mortality. * Tel.: þ1 352 273 8010; Fax: þ1 352 273 8109. E-mail address: [email protected]. 1521-6926/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.
100 J. R. Wingard
IS EMPIRICAL ANTIFUNGAL THERAPY HERE TO STAY OR IS IT TIME TO TARGET THERAPY? The transition from fungal colonization, a harmless condition of no clinical consequence, to full-blown deep-seated IFI with tissue damage and the potential for threat to life can be viewed as a continuum (Figure 1). In between these two extremes, as fungal burden in the patient increases and as incipient tissue invasion occurs, are opportunities to make an early diagnosis. One diagnostic opportunity is the initial onset of clinical manifestations. As noted many years ago, such manifestations typically antedate definitive proof of IFI by several days. For invasive Candida infection, such clinical manifestations might include fever, a common manifestation, and other less frequent manifestations of sepsis, such as erythematous maculonodular cutaneous nodules, filling defects in the liver or spleen on CT scan, or endophthalmitis lesions on ophthalmoscopy (for non-neutropenic patients). For invasive Aspergillus infections, early clinical manifestations include signs and symptoms of pneumonia, such as cough, sputum production, hemoptysis, pleuritic pain, or pleural friction rub, or signs and symptoms of sinusitis, such as nasal discharge, nasal bleeding, nasal eschar, pain, or orbital swelling. Early start of therapy for both invasive Candida and Aspergillus has been shown to be associated with better rates of successful control.2,3 Treatment must be begun before the diagnosis is definitively made in most cases to optimize the prospects for cure. Using the clinical sign of persistent fever despite antibiotics during neutropenia as a trigger to initiate antifungal therapy has been known as empirical antifungal therapy. This has been justified by the serious complications (including death) that result from IFIs, the difficulty in accurate diagnosis, and the recognition that early initiation of therapy improves the prospect for survival. Empirical antifungal therapy was evaluated
Colonization (No disease)
Marker
Symptoms
Full-blown disease
Disease Progression Therapy Prophylaxis Empirical Targeted Pre-emptive Asymptomatic + colonization or positive novel diagnostic test
Figure 1. Opportunities for early diagnosis. This figure shows the continuum of fungal disease progression, from fungal colonization, a harmless condition of no clinical consequence, to full-blown deep-seated IFI with tissue damage and the potential for threat to life. Along this spectrum, there are opportunities for early diagnosis and treatment, including prophylaxis, preemptive, and empirical therapy.
New approaches to invasive fungal infections 101
more than two decades ago4,5 and found to be associated with less morbidity and fungal mortality. A variety of antifungal agents have been tested and found to be effective options.6 This widely practiced strategy has a number of shortcomings.7 Limitations include the lack of specificity of fever as a reliable guide of who is in need of antifungal therapy, the overuse of antifungal therapy exposing many patients to needless, costly, and potentially toxic treatment, and the inadequate course of treatment given to those truly in need (since a diagnosis is not firm and stopping at the time of neutrophil recovery may not be long enough to ensure miicrobial eradication). Over the years there has been a growing interest in establishing more definitive diagnostics. The use of high resolution CT scans of the chest to detect lesions suggestive of Aspergillus or other mould infections, such as halo signs, macronodules, and cavitary lesions, has been enormously valuable.8,9 Most patients with pulmonary Aspergillosis have one or more nodular lesions with or without a halo on chest CT very early in the course of infection. Over time, the infiltrates tend to become less well defined, but eventually cavitation occurs and the air-crescent sign forms. Sinus CT scans may show fluid or more ominously boney erosion; the latter is strongly suggestive of infections by Aspergillus or Zygomycetes. The presence of any of these radiological findings should give the clinician a high level of suspicion of Aspergillus and is a justifiable reason to initiate antifungal therapy. Since other mould pathogens (and occasionally bacteria, such as Nocardia) can give rise to similar radiographic features, and there may be more than one pathogen, it is very important to vigorously pursue a specific diagnosis. Bronchoscopic biopsy, bronchoalveolar lavage, or an invasive biopsy are important to evaluate pulmonary infiltrates. Sinus endoscopic exam with aspiration and biopsy is valuable to evaluate sinusitis. One or 2 days of presumptive antifungal treatment will not materially affect the diagnostic yield of these tests. If the diagnostic testing is negative, one should reconsider whether the correct treatment path is being followed and consider additional, more invasive testing. However, even with aggressive testing a positive culture may not always be obtained. Thus, one may be justified to continue antifungal therapy based on presumption even in the absence of confirmation. New noninvasive diagnostic tools offer the possibility to better target those in need of fungal therapy and to permit an earlier start of therapy, even before radiographic changes are apparent. Fungal biomarkers, indicative of fungal invasion, fungal growth, or tissue damage may be present in incipient IFI, even before the appearance of clinical signs and symptoms. Serologic or PCR probes can detect such fungal antigens during the incipient phase of infection. Evaluation of such tests has been the subject of inquiry over the past decade and several assays have now been licensed and others are in development. The galactomannan and glucan assays have both been FDA approved in the US. Published reports indicate sensitivity and specificity of at least 80% in various studies.10e15 Both are serum assays that detect infection early during tissue invasion. The glucan test detects a broad array of fungal pathogens including Candida, Aspergillus, Trichosporon, and Fusarium. The galactomannan picks up just Aspergillus and Penicillium (a rare pathogen in the US). Neither test detects Zygomycetes. Several polymerase chain reaction (PCR) assays are also in development but none are commercially available. Although both serologic tests have highly desirable attributes and have the promise to be clinically useful, it is important to note that these assays were licensed with only a small body of clinical data to support their utility and much is still needed to fully understand their promise and limitations. The most clinical experience has been with the galactomannan assay. Several shortcomings have been noted: False
102 J. R. Wingard
positives may be seen in patients receiving pipercillin-tazobactam, invasive infections may occur at lower thresholds of positivity in patients receiving mould-active agents, the presence of Aspergillus antibodies in certain patients may affect performance of the test, and sensitivity may be suboptimal in solid organ transplant patients. Moreover, more experience is needed in children and several recent studies suggest the sensitivity is lower than that reported in early studies. Several studies have attempted to integrate these various diagnostic tools into a strategy of targeted therapy (sometimes known as preemptive therapy). In one study16, acute leukemia and HSCT patients were given fluconazole prophylaxis to eliminate the risk for most Candida infections. Thus, the chief fungal pathogen of concern in the study patients was Aspergillus. Each patient underwent routine serial testing with screening galactomannan assays and CT scans and bronchoscopy when pulmonary infection was suspected. Only patients with a positive diagnostic test (not just fever) received mould-active antifungal therapy (liposomal amphotericin B). In this study, only one of 22 IFIs (zygomycosis) was missed, but it would have also been missed by an empirical antifungal therapy approach. Importantly, a number of IFIs were detected even while the patient was afebrile. This approach allowed earlier start of antifungal therapy in many infected patients than the more traditional approach. An added advantage is that many patients with persistent unexplained fever with negative diagnostic tests were spared of needless antifungal therapy. In a second study17, allogeneic HSCT patients were also given fluconazole prophylaxis and randomized to empirical antifungal therapy prompted by persistent fever for 5 days or to intensive screening with serial testing with a blood PCR assay that detected all pertinent fungal pathogens. Antifungal therapy was initiated if the PCR test was positive and there were signs of infection. In a preliminary analysis, there was no reduction in antifungal use or reduction in the rate of IFIs in the intensive screening arm. However, the day 30 mortality was reduced and there was a trend for fewer fatal IFIs in the intensive screening arm, presumably because of earlier start of therapy. These studies suggest enormous promise for such targeted approaches to antifungal therapy in patients suspected to have IFIs. Both studies should be regarded as preliminary. Clearly, greater study of such approaches is needed. Several new PCR assays are being tested and the prospects are excellent that in the upcoming years such tools may revolutionize our approach to the febrile neutropenic patient. WHEN IS AN OUNCE OF PREVENTION BETTER? For patients at a very high risk for IFIs, prophylaxis may be an appropriate consideration. Invasive Candida infection rates have been variously reported to range from 8%e30% in acute leukemia and HSCT patients. Fluconazole prophylaxis has been shown to significantly reduce the rate of invasive Candida infections during chemotherapyinduced neutropenia after HSCT and in some groups of acute leukemia patients.18,19 In one meta-analysis, definite benefits were seen in patients in which the risk was 15% or higher19, a rate of infection generally seen in HSCT patients receiving myeloablative conditioning regimens and in many acute myelogenous leukemia induction regimens. With routine fluconazole prophylaxis, the risk of Candida infections has dramatically fallen, and today the major risk in leukemia and HSCT patients receiving fluconazole prophylaxis is from Aspergillus and other mould infections. The rate of invasive Aspergillus infections in allogeneic HSCT patients has been reported to range
New approaches to invasive fungal infections 103
from 10%e15%20,21; the risk with acute myelogenous leukemia therapy has not been well documented in contemporary treatment settings. Table 1 highlights recent antimould prophylaxis trials in leukemia and HSCT patients. Two randomized trials have evaluated itraconazole prophylaxis after allogeneic HSCT and found fewer IFIs as compared to fluconazole, but no improvement in fungal-free survival.22,23 Further, concerns of tolerance and toxicity were raised by these studies. Two randomized trials evaluating posaconazole, a recently licensed mould-active azole, have shown a reduction in IFIs as compared with fluconazole, with a decrease in Aspergillus infections.24,25 A trial evaluating voriconazole prophylaxis after allogeneic HSCT has completed enrollment but analysis has not yet been performed.26 Other agents besides the azoles have also been tested in prophylaxis trials. Micafungin, caspofungin, and an alternate day schedule of low doses of liposomal amphotericin B have also shown promise as prophylaxis.27e30 Although Aspergillus is the cause of most invasive mould infections, a minority of infections are caused by Zygomycetes or other pathogens. An increase in zygomycosis has been noted over the past decade or longer in several single center reports.20,31
Table 1. Recent antimould prophylaxis trials in leukemia and HSCT patients. Study author
Agents compared
Winston22
Itraconazole vs Fluconazole
Allogeneic HSCT
9% vs 25%
Marr23
Itraconazole vs Fluconazole
Allogeneic HSCT
12% vs 16%
Cornely24
Posaconazole vs fluconazole or itraconazole Posaconazole vs fluconazole
Acute myelogenous leukemia
2% vs 8%
Allogeneic HSCT with acute or chronic GVHD
van Burik27
Micafungin vs fluconazole
HSCT before engraftment
5% vs 9% at anytime; 7% vs 14% during study period 1% vs 2%
Mattiuzzi28
Itraconazole vs caspofungin Low dose liposomal amphotericin B vs no prophylaxis
Hematologic malignancies Neutropenic hematologic malignancies
6% vs 6%
Liposomal amphotericin B vs itraconazole þ fluconazole
Hematologic malignancies
4% vs 4%
Ullmann25
Penack29
Mattiuzzi30
Patients
Rates of IFI
5% vs 20%
Comments Imbalance in risk factors in two arms; no improvement in fungal-free survival Trial stopped prematurely due to excess toxicity in Itraconazole arm
Short interval did not encompass the major risk period for Aspergillus
Fewer pneumonias of unknown etiology; well tolerated without differences in renal or hepatic tests
104 J. R. Wingard
Although the apparent increase began long before the introduction of voriconazole, several reports of single center experience suggest that the increasing practice of voriconazole prophylaxis may also be a contributing factor.32e37 This would not be surprising since voriconazole does not have activity against this pathogen. Prospective studies are needed since there may be multiple potential contributors to these observations.38 IF ONE DRUG IS GOOD, CERTAINLY TWO ARE BETTER! Combinations of drugs that have different mechanisms of action are commonplace in antineoplastic treatment regimens, but have only been used in isolated situations as antifungal therapy. Controlled trials of combination therapy for invasive aspergillosis are listed in Table 2. Combination antifungal therapy has only been found to be useful in randomized trials for Cryptococcus and Candida infections.39,40 Although in vitro evidence suggested a combination of an azole with a polyene against Aspergillus was antagonistic41, there is an abundance of in vitro and in vivo animal data suggesting additive (even synergistic) effects against Aspergillus with a combination of an agent targeting ergosterol in the fungal cell membrane (polyenes and certain azoles) with an agent targeting beta glucan in the fungal cell wall (echinocandins).42e47 Several case series have examined this issue as salvage therapy for patients not responding to first-line therapy.48e51 Combination antifungal therapy offers the promise to eradicate fungal pathogens more efficiently and quickly, reducing tissue damage and improving treatment outcomes. However, there are potential downsides including the potential for greater toxicity and higher cost. Much of the clinical evidence to date is uncontrolled, from small case series where documentation of infection in many cases did not use currently accepted documentation criteria for proven or probable IFI, and some treatment assignment strategies were subject to considerable potential bias. One small pilot randomized trial compared high-dose liposomal amphotericin B to standard-dose liposomal amphotericin B plus caspofungin for first-line therapy of invasive Aspergillosis; trends toward improved response and survival rates were noted in a preliminary report.52 However, the numbers in the sample were too small to be definitive.
Table 2. Controlled trials of combination therapy for invasive aspergillosis. Study
Patients
Design
Type of therapy
Singh48
Solid organ transplant
Case control
First-line therapy
Caillot52
Immunocompromised patients
Randomized
First-line therapy
Marr51
Allogeneic HSCT
Case control
Second-line therapy
Comparators Voriconazole plus caspofungin vs voriconazole Liposomal amphotericin B plus caspofungin vs liposomal amphotericin B Voriconazole plus caspofungin vs voriconazole
Favorable responses Trend to improved 90 day survival Trends to improved responses and survival at 12 weeks but sample size too small Greater survival at 90 days with combination
New approaches to invasive fungal infections 105
Another case-controlled study of salvage voriconazole plus caspofungin versus voriconazole alone suggested a survival advantage at 90 days.51 However, the numbers were small, the patients in the two arms were not concurrent, and changes in practice over time may have introduced considerable bias; moreover, there was not an enduring survival advantage with longer follow-up. Two large randomized trials comparing voriconazole plus an echinocandin are in the planning stages. CONCLUSIONS Today, new diagnostics and new antifungal drugs provide the clinician with a much greater opportunity to recognize IFIs early, to more accurately distinguish the febrile patient with IFI, and to employ treatments that may be more active against the target pathogen with less toxicity. New strategies combining diagnostics and new drugs may ultimately lead to improved treatment outcomes and alter our approach to IFIs. REFERENCES *1. Pfaller MA, Pappas PG & Wingard JR. Invasive fungal pathogens: current epidemiological trends. Clinical Infectious Diseases 2006; 43: S3eS14. 2. Morrell M, Fraser VJ & Kollef MH. Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrobial Agents and Chemotherapy 2005; 49: 3640e3645. 3. Greene RE, Schlamm HT, Oestmann JW et al. Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clinical Infectious Diseases [in press]. 4. Pizzo PA, Robichaud KJ, Gill FA & Witebsky FG. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. The American Journal of Medicine 1982; 72: 101e111. 5. EORTC International Antimicrobial Therapy Cooperative Project Group. Empiric antifungal therapy in febrile granulocytopenic patients. The American Journal of Medicine 1989; 86: 668e672. 6. Wingard JR. Empirical antifungal therapy in treating febrile neutropenic patients. Clinical Infectious Diseases 2004; 39(supplement 1): S38eS43. *7. De Pauw BE. Between over- and undertreatment of invasive fungal disease. Clinical Infectious Diseases 2005; 41: 1251e1253. *8. Caillot D, Casasnovas O, Bernard A et al. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. Journal of Clinical Oncology 1997; 15: 139e147. *9. Greene R. The radiological spectrum of pulmonary aspergillosis. Medical Mycology 2005; 43(supplement 1): S147eS154. *10. Alexander BD & Pfeiffer RM. Contemporary tools for diagnosis and managment of invasive mycoses. Clinical Infectious Diseases 2006; 43: S15eS27. *11. Marr KA, Balajee SA, McLaughlin L et al. Detection of galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive aspergillosis: variables that affect performance. The Journal of Infectious Diseases 2004; 190: 641e649. *12. Hope WW, Walsh TJ & Denning DW. Laboratory diagnosis of invasive aspergillosis. The Lancet Infectious Diseases 2005; 5: 609e622. 13. Odabasi Z, Mattiuzzi G, Estey E et al. Beta-D-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clinical Infectious Diseases 2004; 39: 199e205. 14. Ostrosky-Zeichner L, Alexander BD, Kett DH et al. Multicenter clinical evaluation of the (1e>3) beta-D-glucan assay as an aid to diagnosis of fungal infections in humans. Clinical Infectious Diseases 2005; 41: 654e659.
106 J. R. Wingard *15. Mennink-Kersten MA, Donnelly JP & Verweij PE. Detection of circulating galactomannan for the diagnosis and management of invasive aspergillosis. The Lancet Infectious Diseases 2004; 4: 349e357. *16. Maertens J, Theunissen K, Verhoef G et al. Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clinical Infectious Diseases 2005; 41: 1242e1250. 17. Hebart H, Klingspor L, Klingebiel T et al. PCR-based liposomal amphotericin B treatment following allogeneic stem cell transplantation is a safe treatment strategy: Preliminary results of a prospective study. Blood 2004; 104: 59a (abstract). *18. Bow EJ, Laverdiere M, Lussier N et al. Antifungal prophylaxis for severely neutropenic chemotherapy recipients: a meta analysis of randomized-controlled clinical trials. Cancer 2002; 94: 3230e3246. 19. Kanda Y, Yamamoto R, Chizuka A et al. Prophylactic action of oral fluconazole against fungal infection in neutropenic patients. A meta-analysis of 16 randomized, controlled trials. Cancer 2000; 89: 1611e1625. 20. Marr KA, Carter RA, Crippa F et al. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clinical Infectious Diseases 2002; 34: 909e917. 21. Grow WB, Moreb JS, Roque D et al. Late onset of invasive aspergillus infection in bone marrow transplant patients at a university hospital. Bone Marrow Transplantation 2002; 29: 15e19. 22. Winston DJ, Maziarz RT, Chandrasekar PH et al. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial. Annals of Internal Medicine 2003; 138: 705e713. 23. Marr KA, Crippa F, Leisenring W et al. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood 2004; 103: 1527e1533. 24. Cornely O, Maertens J, Winston D et al. Posaconazole vs standard azole (FLU/ITRA) therapy for prophylaxis of invasive fungal infections (IFIs) among high-risk neutropenic patients: results of a randomized, multicenter trial. Blood 2005; 106: 524a (abstract). 25. Ullmann AJ, Lipton JH, Vesole DH et al. A multicenter trial of oral posaconazole vs fluconazole for the prophylaxis of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplantation with graft-vs-host disease. Interscience Conference on Antimicrobial Agents and Chemotherapy 2005 (abstract M-716). 26. Wingard JR. Design issues in a prospective randomized double-blinded trial of prophylaxis with fluconazole versus voriconazole after allogeneic hematopoietic cell transplantation. Clinical Infectious Diseases 2004; 39(supplement 4): S176eS180. 27. van Burik JA, Ratanatharathorn V, Stepan DE et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clinical Infectious Diseases 2004; 39: 1407e1416. 28. Mattiuzzi GN, Alvarado G, Giles FJ et al. Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies. Antimicrobial Agents and Chemotherapy 2006; 50: 143e147. 29. Penack O, Reinwald M, Schmidt-Hieber M et al. Low dose liposomal amphotericin B (L-AmB) as prophylaxis of invasive fungal infections (IFI) in patients (pts) with prolonged neutropenia (N): results from a phase-III trial. Interscience Conference on Antimicrobial Agents and Chemotherapy 2005 (abstract M-975). 30. Mattiuzzi GN, Estey E, Raad I et al. Liposomal amphotericin B versus the combination of fluconazole and itraconazole as prophylaxis for invasive fungal infections during induction chemotherapy for patients with acute myelogenous leukemia and myelodysplastic syndrome. Cancer 2003; 97: 450e456. 31. Kontoyiannis DP, Lionakis MS, Lewis RE et al. Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases. The Journal of Infectious Diseases 2005; 191: 1350e1360. 32. Mattner F, Weissbrodt H & Strueber M. Two case reports: fatal Absidia corymbifera pulmonary tract infection in the first postoperative phase of a lung transplant patient receiving voriconazole prophylaxis, and transient bronchial Absidia corymbifera colonization in a lung transplant patient. Scandinavian Journal of Infectious Diseases 2004; 36: 312e314. 33. Imhof A, Balajee SA, Fredricks DN et al. Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole. Clinical Infectious Diseases 2004; 39: 743e746. 34. Marty FM, Cosimi LA & Baden LR. Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants. The New England Journal of Medicine 2004; 350: 950e952.
New approaches to invasive fungal infections 107 35. Siwek GT, Dodgson KJ, de Magalhaes-Silverman M et al. Invasive zygomycosis in hematopoietic stem cell transplant recipients receiving voriconazole prophylaxis. Clinical Infectious Diseases 2004; 39: 584e587. 36. Kobayashi K, Kami M, Murashige N et al. Breakthrough zygomycosis during voriconazole treatment for invasive aspergillosis. Haematologica 2004; 89: ECR42. 37. Vigouroux S, Morin O, Moreau P et al. Zygomycosis after prolonged use of voriconazole in immunocompromised patients with hematologic disease: attention required. Clinical Infectious Diseases 2005; 40: e35ee37. 38. Wingard JR. Zygomycosis: epidemiology and treamtnet options. Johns Hopkins Advanced Studies in Medicine 2006; 6: S526eS530. 39. Bennett JE, Dismukes WE, Duma RJ et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptoccal meningitis. The New England Journal of Medicine 1979; 301: 126e131. 40. Rex JH, Bennett JE, Sugar AM et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. The New England Journal of Medicine 1994; 331: 1325e1330. 41. Schaffner A & Frick PG. The effect of ketoconazole on amphotericin B in a model of disseminated aspergillosis. The Journal of Infectious Diseases 1985; 151: 902e910. 42. Steinbach WJ. Combination antifungal therapy for invasive aspergillosis: utilizing new targeting strategies. Current Drug Targets Infectious Disorders 2005; 5: 203e210. 43. Wheat LJ. Combination therapy for aspergillosis: is it needed, and which combination? The Journal of Infectious Diseases 2003; 187: 1831e1833. 44. Johnson MD, MacDougall C, Ostrosky-Zeichner L et al. Combination antifungal therapy. Antimicrobial Agents and Chemotherapy 2004; 48: 693e715. 45. Kontoyiannis DP & Lewis RE. Toward more effective antifungal therapy: the prospects of combination therapy. British Journal of Haematology 2004; 126: 165e175. 46. Mukherjee PK, Sheehan DJ, Hitchcock CA & Ghannoum MA. Combination treatment of invasive fungal infections. Clinical Microbiology Reviews 2005; 18: 163e194. 47. Cuenca-Estrella M. Combinations of antifungal agents in therapyewhat value are they? The Journal of Antimicrobial Chemotherapy 2004; 54: 854e869. 48. Singh N, Limaye AP, Forrest G et al. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Transplantation 2006; 81: 320e326. 49. Aliff TB, Maslak PG, Jurcic JG et al. Refractory Aspergillus pneumonia in patients with acute leukemia: successful therapy with combination caspofungin and liposomal amphotericin. Cancer 2003; 97: 1025e1032. 50. Kontoyiannis DP, Hachem R, Lewis RE et al. Efficacy and toxicity of caspofungin in combination with liposomal amphotericin B as primary or salvage treatment of invasive aspergillosis in patients with hematologic malignancies. Cancer 2003; 98: 292e299. 51. Marr KA, Boeckh M, Carter RA et al. Combination antifungal therapy for invasive aspergillosis. Clinical Infectious Diseases 2004; 39: 797e802. 52. Caillot D, Thiebault A, Herbrecht R et al. Liposomal amphotericin B in combination with caspofungin versus liposomal amphotericin B high dose regimen for the treatment of invasive aspergillosis in immunocompromised patients: randomized pilot study (Combistrat trial). Focus on Fungal Infections 2006; 16: 174 (abstract P-004).
12 New approaches to invasive fungal infections in acute leukemia and hematopoietic stem cell transplant patients John R. Wingard *
MD
Director Blood and Marrow Transplant Program, Division of Hematology/Oncology, University of Florida Shands Cancer Center, 1376 Mowry Road, Room 145, Gainesville, FL 32610-3633, USA
Recognition and treatment of invasive fungal infections in acute leukemia and hematopoietic stem cell transplant patients are important clinical challenges. New diagnostic tools, such as fungal serologic assays and high-resolution CT scans, offer the hope for earlier initiation of antifungal therapy and improved treatment results. New antifungal agents offer choices that in some cases are less toxic than older drugs and in other cases are more efficacious. Combining the new diagnostic tools with new drugs, novel strategies are being evaluated to change our approaches to these deadly infections. Key words: Aspergillus; Candida; galactomannan assay; glucan assay; hematopoietic stem cell transplant; invasive fungal infection; targeted therapy.
INTRODUCTION With improved strategies to control bacterial infections during the myelosuppression that results from acute leukemia therapy and after hematopoietic stem cell transplantation (HSCT), invasive fungal infections (IFIs) have assumed an increasing focus for clinicians. Today, IFIs are the chief life-threatening infectious complications of leukemia and transplant therapies. Candida and Aspergillus are the chief invasive fungal pathogens.1 New diagnostics and new antifungal agents have begun to reshape the landscape of antifungal therapies and offer the opportunity for new management paradigms. These offer the prospect for substantially reducing fungal morbidity and mortality. * Tel.: þ1 352 273 8010; Fax: þ1 352 273 8109. E-mail address: [email protected]. 1521-6926/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.
100 J. R. Wingard
IS EMPIRICAL ANTIFUNGAL THERAPY HERE TO STAY OR IS IT TIME TO TARGET THERAPY? The transition from fungal colonization, a harmless condition of no clinical consequence, to full-blown deep-seated IFI with tissue damage and the potential for threat to life can be viewed as a continuum (Figure 1). In between these two extremes, as fungal burden in the patient increases and as incipient tissue invasion occurs, are opportunities to make an early diagnosis. One diagnostic opportunity is the initial onset of clinical manifestations. As noted many years ago, such manifestations typically antedate definitive proof of IFI by several days. For invasive Candida infection, such clinical manifestations might include fever, a common manifestation, and other less frequent manifestations of sepsis, such as erythematous maculonodular cutaneous nodules, filling defects in the liver or spleen on CT scan, or endophthalmitis lesions on ophthalmoscopy (for non-neutropenic patients). For invasive Aspergillus infections, early clinical manifestations include signs and symptoms of pneumonia, such as cough, sputum production, hemoptysis, pleuritic pain, or pleural friction rub, or signs and symptoms of sinusitis, such as nasal discharge, nasal bleeding, nasal eschar, pain, or orbital swelling. Early start of therapy for both invasive Candida and Aspergillus has been shown to be associated with better rates of successful control.2,3 Treatment must be begun before the diagnosis is definitively made in most cases to optimize the prospects for cure. Using the clinical sign of persistent fever despite antibiotics during neutropenia as a trigger to initiate antifungal therapy has been known as empirical antifungal therapy. This has been justified by the serious complications (including death) that result from IFIs, the difficulty in accurate diagnosis, and the recognition that early initiation of therapy improves the prospect for survival. Empirical antifungal therapy was evaluated
Colonization (No disease)
Marker
Symptoms
Full-blown disease
Disease Progression Therapy Prophylaxis Empirical Targeted Pre-emptive Asymptomatic + colonization or positive novel diagnostic test
Figure 1. Opportunities for early diagnosis. This figure shows the continuum of fungal disease progression, from fungal colonization, a harmless condition of no clinical consequence, to full-blown deep-seated IFI with tissue damage and the potential for threat to life. Along this spectrum, there are opportunities for early diagnosis and treatment, including prophylaxis, preemptive, and empirical therapy.
New approaches to invasive fungal infections 101
more than two decades ago4,5 and found to be associated with less morbidity and fungal mortality. A variety of antifungal agents have been tested and found to be effective options.6 This widely practiced strategy has a number of shortcomings.7 Limitations include the lack of specificity of fever as a reliable guide of who is in need of antifungal therapy, the overuse of antifungal therapy exposing many patients to needless, costly, and potentially toxic treatment, and the inadequate course of treatment given to those truly in need (since a diagnosis is not firm and stopping at the time of neutrophil recovery may not be long enough to ensure miicrobial eradication). Over the years there has been a growing interest in establishing more definitive diagnostics. The use of high resolution CT scans of the chest to detect lesions suggestive of Aspergillus or other mould infections, such as halo signs, macronodules, and cavitary lesions, has been enormously valuable.8,9 Most patients with pulmonary Aspergillosis have one or more nodular lesions with or without a halo on chest CT very early in the course of infection. Over time, the infiltrates tend to become less well defined, but eventually cavitation occurs and the air-crescent sign forms. Sinus CT scans may show fluid or more ominously boney erosion; the latter is strongly suggestive of infections by Aspergillus or Zygomycetes. The presence of any of these radiological findings should give the clinician a high level of suspicion of Aspergillus and is a justifiable reason to initiate antifungal therapy. Since other mould pathogens (and occasionally bacteria, such as Nocardia) can give rise to similar radiographic features, and there may be more than one pathogen, it is very important to vigorously pursue a specific diagnosis. Bronchoscopic biopsy, bronchoalveolar lavage, or an invasive biopsy are important to evaluate pulmonary infiltrates. Sinus endoscopic exam with aspiration and biopsy is valuable to evaluate sinusitis. One or 2 days of presumptive antifungal treatment will not materially affect the diagnostic yield of these tests. If the diagnostic testing is negative, one should reconsider whether the correct treatment path is being followed and consider additional, more invasive testing. However, even with aggressive testing a positive culture may not always be obtained. Thus, one may be justified to continue antifungal therapy based on presumption even in the absence of confirmation. New noninvasive diagnostic tools offer the possibility to better target those in need of fungal therapy and to permit an earlier start of therapy, even before radiographic changes are apparent. Fungal biomarkers, indicative of fungal invasion, fungal growth, or tissue damage may be present in incipient IFI, even before the appearance of clinical signs and symptoms. Serologic or PCR probes can detect such fungal antigens during the incipient phase of infection. Evaluation of such tests has been the subject of inquiry over the past decade and several assays have now been licensed and others are in development. The galactomannan and glucan assays have both been FDA approved in the US. Published reports indicate sensitivity and specificity of at least 80% in various studies.10e15 Both are serum assays that detect infection early during tissue invasion. The glucan test detects a broad array of fungal pathogens including Candida, Aspergillus, Trichosporon, and Fusarium. The galactomannan picks up just Aspergillus and Penicillium (a rare pathogen in the US). Neither test detects Zygomycetes. Several polymerase chain reaction (PCR) assays are also in development but none are commercially available. Although both serologic tests have highly desirable attributes and have the promise to be clinically useful, it is important to note that these assays were licensed with only a small body of clinical data to support their utility and much is still needed to fully understand their promise and limitations. The most clinical experience has been with the galactomannan assay. Several shortcomings have been noted: False
102 J. R. Wingard
positives may be seen in patients receiving pipercillin-tazobactam, invasive infections may occur at lower thresholds of positivity in patients receiving mould-active agents, the presence of Aspergillus antibodies in certain patients may affect performance of the test, and sensitivity may be suboptimal in solid organ transplant patients. Moreover, more experience is needed in children and several recent studies suggest the sensitivity is lower than that reported in early studies. Several studies have attempted to integrate these various diagnostic tools into a strategy of targeted therapy (sometimes known as preemptive therapy). In one study16, acute leukemia and HSCT patients were given fluconazole prophylaxis to eliminate the risk for most Candida infections. Thus, the chief fungal pathogen of concern in the study patients was Aspergillus. Each patient underwent routine serial testing with screening galactomannan assays and CT scans and bronchoscopy when pulmonary infection was suspected. Only patients with a positive diagnostic test (not just fever) received mould-active antifungal therapy (liposomal amphotericin B). In this study, only one of 22 IFIs (zygomycosis) was missed, but it would have also been missed by an empirical antifungal therapy approach. Importantly, a number of IFIs were detected even while the patient was afebrile. This approach allowed earlier start of antifungal therapy in many infected patients than the more traditional approach. An added advantage is that many patients with persistent unexplained fever with negative diagnostic tests were spared of needless antifungal therapy. In a second study17, allogeneic HSCT patients were also given fluconazole prophylaxis and randomized to empirical antifungal therapy prompted by persistent fever for 5 days or to intensive screening with serial testing with a blood PCR assay that detected all pertinent fungal pathogens. Antifungal therapy was initiated if the PCR test was positive and there were signs of infection. In a preliminary analysis, there was no reduction in antifungal use or reduction in the rate of IFIs in the intensive screening arm. However, the day 30 mortality was reduced and there was a trend for fewer fatal IFIs in the intensive screening arm, presumably because of earlier start of therapy. These studies suggest enormous promise for such targeted approaches to antifungal therapy in patients suspected to have IFIs. Both studies should be regarded as preliminary. Clearly, greater study of such approaches is needed. Several new PCR assays are being tested and the prospects are excellent that in the upcoming years such tools may revolutionize our approach to the febrile neutropenic patient. WHEN IS AN OUNCE OF PREVENTION BETTER? For patients at a very high risk for IFIs, prophylaxis may be an appropriate consideration. Invasive Candida infection rates have been variously reported to range from 8%e30% in acute leukemia and HSCT patients. Fluconazole prophylaxis has been shown to significantly reduce the rate of invasive Candida infections during chemotherapyinduced neutropenia after HSCT and in some groups of acute leukemia patients.18,19 In one meta-analysis, definite benefits were seen in patients in which the risk was 15% or higher19, a rate of infection generally seen in HSCT patients receiving myeloablative conditioning regimens and in many acute myelogenous leukemia induction regimens. With routine fluconazole prophylaxis, the risk of Candida infections has dramatically fallen, and today the major risk in leukemia and HSCT patients receiving fluconazole prophylaxis is from Aspergillus and other mould infections. The rate of invasive Aspergillus infections in allogeneic HSCT patients has been reported to range
New approaches to invasive fungal infections 103
from 10%e15%20,21; the risk with acute myelogenous leukemia therapy has not been well documented in contemporary treatment settings. Table 1 highlights recent antimould prophylaxis trials in leukemia and HSCT patients. Two randomized trials have evaluated itraconazole prophylaxis after allogeneic HSCT and found fewer IFIs as compared to fluconazole, but no improvement in fungal-free survival.22,23 Further, concerns of tolerance and toxicity were raised by these studies. Two randomized trials evaluating posaconazole, a recently licensed mould-active azole, have shown a reduction in IFIs as compared with fluconazole, with a decrease in Aspergillus infections.24,25 A trial evaluating voriconazole prophylaxis after allogeneic HSCT has completed enrollment but analysis has not yet been performed.26 Other agents besides the azoles have also been tested in prophylaxis trials. Micafungin, caspofungin, and an alternate day schedule of low doses of liposomal amphotericin B have also shown promise as prophylaxis.27e30 Although Aspergillus is the cause of most invasive mould infections, a minority of infections are caused by Zygomycetes or other pathogens. An increase in zygomycosis has been noted over the past decade or longer in several single center reports.20,31
Table 1. Recent antimould prophylaxis trials in leukemia and HSCT patients. Study author
Agents compared
Winston22
Itraconazole vs Fluconazole
Allogeneic HSCT
9% vs 25%
Marr23
Itraconazole vs Fluconazole
Allogeneic HSCT
12% vs 16%
Cornely24
Posaconazole vs fluconazole or itraconazole Posaconazole vs fluconazole
Acute myelogenous leukemia
2% vs 8%
Allogeneic HSCT with acute or chronic GVHD
van Burik27
Micafungin vs fluconazole
HSCT before engraftment
5% vs 9% at anytime; 7% vs 14% during study period 1% vs 2%
Mattiuzzi28
Itraconazole vs caspofungin Low dose liposomal amphotericin B vs no prophylaxis
Hematologic malignancies Neutropenic hematologic malignancies
6% vs 6%
Liposomal amphotericin B vs itraconazole þ fluconazole
Hematologic malignancies
4% vs 4%
Ullmann25
Penack29
Mattiuzzi30
Patients
Rates of IFI
5% vs 20%
Comments Imbalance in risk factors in two arms; no improvement in fungal-free survival Trial stopped prematurely due to excess toxicity in Itraconazole arm
Short interval did not encompass the major risk period for Aspergillus
Fewer pneumonias of unknown etiology; well tolerated without differences in renal or hepatic tests
104 J. R. Wingard
Although the apparent increase began long before the introduction of voriconazole, several reports of single center experience suggest that the increasing practice of voriconazole prophylaxis may also be a contributing factor.32e37 This would not be surprising since voriconazole does not have activity against this pathogen. Prospective studies are needed since there may be multiple potential contributors to these observations.38 IF ONE DRUG IS GOOD, CERTAINLY TWO ARE BETTER! Combinations of drugs that have different mechanisms of action are commonplace in antineoplastic treatment regimens, but have only been used in isolated situations as antifungal therapy. Controlled trials of combination therapy for invasive aspergillosis are listed in Table 2. Combination antifungal therapy has only been found to be useful in randomized trials for Cryptococcus and Candida infections.39,40 Although in vitro evidence suggested a combination of an azole with a polyene against Aspergillus was antagonistic41, there is an abundance of in vitro and in vivo animal data suggesting additive (even synergistic) effects against Aspergillus with a combination of an agent targeting ergosterol in the fungal cell membrane (polyenes and certain azoles) with an agent targeting beta glucan in the fungal cell wall (echinocandins).42e47 Several case series have examined this issue as salvage therapy for patients not responding to first-line therapy.48e51 Combination antifungal therapy offers the promise to eradicate fungal pathogens more efficiently and quickly, reducing tissue damage and improving treatment outcomes. However, there are potential downsides including the potential for greater toxicity and higher cost. Much of the clinical evidence to date is uncontrolled, from small case series where documentation of infection in many cases did not use currently accepted documentation criteria for proven or probable IFI, and some treatment assignment strategies were subject to considerable potential bias. One small pilot randomized trial compared high-dose liposomal amphotericin B to standard-dose liposomal amphotericin B plus caspofungin for first-line therapy of invasive Aspergillosis; trends toward improved response and survival rates were noted in a preliminary report.52 However, the numbers in the sample were too small to be definitive.
Table 2. Controlled trials of combination therapy for invasive aspergillosis. Study
Patients
Design
Type of therapy
Singh48
Solid organ transplant
Case control
First-line therapy
Caillot52
Immunocompromised patients
Randomized
First-line therapy
Marr51
Allogeneic HSCT
Case control
Second-line therapy
Comparators Voriconazole plus caspofungin vs voriconazole Liposomal amphotericin B plus caspofungin vs liposomal amphotericin B Voriconazole plus caspofungin vs voriconazole
Favorable responses Trend to improved 90 day survival Trends to improved responses and survival at 12 weeks but sample size too small Greater survival at 90 days with combination
New approaches to invasive fungal infections 105
Another case-controlled study of salvage voriconazole plus caspofungin versus voriconazole alone suggested a survival advantage at 90 days.51 However, the numbers were small, the patients in the two arms were not concurrent, and changes in practice over time may have introduced considerable bias; moreover, there was not an enduring survival advantage with longer follow-up. Two large randomized trials comparing voriconazole plus an echinocandin are in the planning stages. CONCLUSIONS Today, new diagnostics and new antifungal drugs provide the clinician with a much greater opportunity to recognize IFIs early, to more accurately distinguish the febrile patient with IFI, and to employ treatments that may be more active against the target pathogen with less toxicity. New strategies combining diagnostics and new drugs may ultimately lead to improved treatment outcomes and alter our approach to IFIs. REFERENCES *1. Pfaller MA, Pappas PG & Wingard JR. Invasive fungal pathogens: current epidemiological trends. Clinical Infectious Diseases 2006; 43: S3eS14. 2. Morrell M, Fraser VJ & Kollef MH. Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrobial Agents and Chemotherapy 2005; 49: 3640e3645. 3. Greene RE, Schlamm HT, Oestmann JW et al. Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clinical Infectious Diseases [in press]. 4. Pizzo PA, Robichaud KJ, Gill FA & Witebsky FG. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. The American Journal of Medicine 1982; 72: 101e111. 5. EORTC International Antimicrobial Therapy Cooperative Project Group. Empiric antifungal therapy in febrile granulocytopenic patients. The American Journal of Medicine 1989; 86: 668e672. 6. Wingard JR. Empirical antifungal therapy in treating febrile neutropenic patients. Clinical Infectious Diseases 2004; 39(supplement 1): S38eS43. *7. De Pauw BE. Between over- and undertreatment of invasive fungal disease. Clinical Infectious Diseases 2005; 41: 1251e1253. *8. Caillot D, Casasnovas O, Bernard A et al. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. Journal of Clinical Oncology 1997; 15: 139e147. *9. Greene R. The radiological spectrum of pulmonary aspergillosis. Medical Mycology 2005; 43(supplement 1): S147eS154. *10. Alexander BD & Pfeiffer RM. Contemporary tools for diagnosis and managment of invasive mycoses. Clinical Infectious Diseases 2006; 43: S15eS27. *11. Marr KA, Balajee SA, McLaughlin L et al. Detection of galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive aspergillosis: variables that affect performance. The Journal of Infectious Diseases 2004; 190: 641e649. *12. Hope WW, Walsh TJ & Denning DW. Laboratory diagnosis of invasive aspergillosis. The Lancet Infectious Diseases 2005; 5: 609e622. 13. Odabasi Z, Mattiuzzi G, Estey E et al. Beta-D-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clinical Infectious Diseases 2004; 39: 199e205. 14. Ostrosky-Zeichner L, Alexander BD, Kett DH et al. Multicenter clinical evaluation of the (1e>3) beta-D-glucan assay as an aid to diagnosis of fungal infections in humans. Clinical Infectious Diseases 2005; 41: 654e659.
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