Immune reconstitution Aspergillus infections in allogeneic stem cell transplant recipients: have we made any progress?

Transcription

1 (2002) 30, Nature Publishing Group All rights reserved /02 $ Immune reconstitution Aspergillus infections in allogeneic stem cell transplant recipients: have we made any progress? E Jantunen 1, V-J Anttila 2 and T Ruutu 2 1 Department of Medicine, Kuopio University Hospital, Kuopio, Finland; and 2 Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland Summary: Invasive aspergillosis (IA) is common in allogeneic SCT recipients, with an incidence of 4 10%. The majority of these infections are diagnosed several months after SCT and they are frequently associated with GVHD. The diagnosis is difficult and often delayed. Established IA is notoriously difficult to treat with a death rate of 80 90%. This review summarises recent data on this problem to assess whether there has been any progress. Effective prophylactic measures are still lacking. Severe immunosuppression is the main obstacle to the success of therapy. Recent and ongoing developments in diagnostic measures and new antifungal agents may improve treatment results to some extent, but Aspergillus infections still remain a formidable problem in allogeneic transplantation. Further studies in this field will focus on the role of various cytokines and combinations of antifungal agents. (2002) 30, doi: /sj.bmt Keywords: invasive aspergillosis; allogeneic stem cell transplantation; epidemiology; prevention; diagnosis; therapy Infections are common in allogeneic SCT recipients. Along with improved diagnosis and management of bacterial and viral infections, fungal infections have gained an even more important role. Recent reports have suggested that the majority of fungal infections in allogeneic SCT recipients are caused by Aspergillus species. 1,2 The incidence of invasive aspergillosis (IA) seems to be increasing. 3,4 This paper summarises some recent data on IA in allogeneic SCT recipients. Epidemiology and risk factors The incidence of IA has ranged from 4% to more than 10% after allogeneic bone marrow transplantation. 2,3,5-9 Most Correspondence: E Jantunen, Department of Medicine, Kuopio University Hospital, POB 1777, Kuopio, Finland Received 14 February 2002; accepted 11 July 2002 cases are diagnosed relatively late after SCT. The median time to diagnosis is 3 4 months from SCT. 6,10 A study by Wald and co-workers 3 suggests a bimodal distribution of cases. A smaller proportion was observed early ( 40 days) after the transplant, while the majority of the cases were late infections with different risk factors, notably GVHD. Aspergillus fumigatus has been the most common causative organism, but invasive infections caused by Aspergillus flavus, Aspergillus niger and Aspergillus terreus have also been recorded. Several risk factors for IA have been identified. 3,11 These factors may be useful in identifying optimal patients for various prophylactic strategies. Neutropenia is a classical risk factor for IA, but acute GVHD and extensive chronic GVHD might be even more important. Other risk factors include previous IA, 12 CMV disease, 4 HLA mismatch, unrelated donor, T cell depletion of the graft, and care in a room without efficient air filtration. 3 Also, patients who fail to engraft are at high risk of IA. 5 Advances in diagnosis Symptoms and signs of IA are frequently non-specific, often leading to considerable delays in diagnosis. Fever is a common symptom, although a significant proportion of the patients are afebrile 10 probably due to the use of concomitant glucocorticoid. Respiratory symptoms and neurological symptoms and signs may also be seen in a high proportion of patients. The lungs are the most common organ affected by aspergillosis ( 90%), but disseminated infection is also commonly seen in allogeneic SCT recipients. 10,13 Bronchoalveolar lavage has a diagnostic sensitivity of 30 50% in transplant recipients. 10,14 Radiological findings on computed tomography are often suggestive of invasive pulmonary aspergillosis (IPA) and may allow earlier diagnosis. 15 In some cases, radiologically guided fine needle lung biopsy may yield the diagnosis. 16 However, new and promising methods are likely to change diagnostic strategies in the near future. Galactomannan, a constituent of the fungal cell wall, can be measured in urine or serum. Recently, a sensitive ELISA assay for determination of serum galactomannan has been developed Serial measurements may allow earlier

2 926 diagnosis of IA, with high sensitivity and specificity. 21 It has been suggested that two consecutive positive tests are indicative of IA in high-risk patients and an indication for radiological studies (eg high-resolution computed tomography of the chest). Prospective studies are ongoing, with serial measurements of serum galactomannan as a guide to start pre-emptive antifungal therapy in transplant recipients. Fungal DNA can be studied from either bronchoalveolar fluid 22,23 or serum by polymerase chain reaction (PCR). These methods are very sensitive, but false positive findings based on contamination have also been observed. In addition, these methods have to be developed separately in every center, which may limit their application to the bestresourced transplant units. Studies using serial determinations of Aspergillus DNA with PCR in serum specimens to start antifungal therapy have been initiated. At the present time, computed tomography of the chest in high-risk patients is the method of choice to identify more or less typical radiological appearances of pulmonary aspergillosis. Both galactomannan and PCR-based methods are, at present, investigational and more prospective data are needed concerning their contribution to the earlier diagnosis of IA in allogeneic SCT recipients. Therapeutic measures Antifungal therapy Amphotericin B deoxycholate (AmB) (1 1.5 mg/kg/day) has been the standard treatment of IA for decades. This drug, however, has severe side-effects which preclude its prolonged use in many allogeneic SCT recipients. The toxicity of AmB has led to the development of lipid formulations including liposomal AmB (LAMB), AmB in lipid complex (ABLC), and AmB in colloidal dispersion (ABCD). Several reports have been published on the feasibility and efficacy of LAMB, ABLC and ABCD. 35,36 in transplant recipients. In general, these preparations are less nephrotoxic than AmB, but current evidence suggests that their efficacy is comparable to that of AmB. A recent randomised study suggests that LAMB has fewer infusion-related side-effects than ABLC. 37 An optimal dose of various lipid formulations of AmB is not yet known. In most studies, doses ranging from 1 to 5 mg/kg/day have been used, but higher doses are also under evaluation. Itraconazole ( mg/day) is active against Aspergillus sp. 38 In allogeneic SCT recipients, oral capsules are, however, problematic. Intestinal absorption is variable and, hence, drug level monitoring is recommended. Itraconazole also has clinically important drug interactions. Recently, oral cyclodextrin solution 39 as well as intravenous formulation 40 have expanded the potential use of this drug in allogeneic transplant recipients. The main therapeutic use of itraconazole may be the long-term management of IA in patients initially successfully treated with AmB preparations. 11 Several new antifungal drugs are under clinical evaluation and some of them may soon come into routine use. Voriconazole, an azole drug, has good penetration into the central nervous system, and some responses have also been described in patients with central nervous system aspergillosis. Voriconazole improved the outcome of aspergillosis when compared to AmB or other licenced therapy. 41 A recent study showed good responses in 60% of patients with pulmonary or tracheobronchial IA. 42 Other azole drugs such as ravuconazole and posaconazole are under clinical evaluation. Echinocandins are a new class of antifungal agents with potential broad-spectrum activity. Their action is based on the inhibition of glucan synthesis in the fungal cell wall. 43 Caspofungin has already been licenced for use in patients with invasive aspergillosis who have failed or are intolerant to earlier therapy based on a study showing activity in this patient group. 44 Other echinocandins under investigation include micafungin and anindulafungin. All these new antifungal drugs hold some promise, but their contribution to the current therapies is as yet unsettled. Other therapies Since immunosuppression is the major risk factor for IA, amelioration of immunosuppression is the key factor in the success of therapy. Reduction in steroid dose should be considered in all patients with IA, but discontinuation of cyclosporine may cause serious problems with GVHD. Although not formally proven, granulocyte colony-stimulating factors are logical adjuncts to the therapy of neutropenic patients with IA. Granulocyte macrophage colony-stimulating factor (GM-CSF) may also be useful in patients with IA, but no randomised studies are available at present. GM-CSF has the additional advantage of stimulating monocytes and macrophages, which might have some importance in these patients. Interferon gamma improves neutrophil function and has shown activity in patients with chronic granulomatous disease, 45 but has not been systematically evaluated in transplant recipients with aspergillosis. Surgery has been suggested in transplant recipients with IA. If the patient has a single lesion in the lung, resection should be considered. 46,47 A recent retrospective analysis suggested that patients who had had a lung resection had a better outcome than did patients who did not undergo surgery. 48 If the patient has invasive sinusitis caused by Aspergillus sp., surgery should also be considered. 49 Surgery is not optional in a significant proportion of transplant recipients due to co-morbid conditions; in these patients, new antifungals with GM-CSF might be a viable alternative. Treatment outcome Until now, the treatment of invasive aspergillosis in allogeneic SCT recipients has largely failed, with mortality rates of 90% or more. 11,50 In a French series, however, six out of 27 patients (22%) were cured. 51 In our study of 20 consecutive patients with IA only two patients (10%) were cured, but an objective treatment response was observed in 37% of the patients. 52 Acute GVHD and steroid dose were predictors of outcome in one study. 51 Spread of infection into the central

3 nervous system is common in allogeneic SCT recipients 6,10 and is associated with a very poor outcome. 53 Treatment response is often difficult to define, although radiological studies are helpful. Serial measurements of either serum galactomannan or fungal PCR might be useful adjuncts to the assessment of treatment response in these patients. Prophylactic measures Since the prognosis of established IA is poor, effective prophylaxis is of paramount importance. Unfortunately, very limited data are currently available on this topic. This is partly due to the fact that allogeneic SCT recipients have been either excluded from prophylactic studies 54 or have formed only a minority of the study population. 55 Moreover, several studies have used historical cohorts for comparison, making the results less meaningful. The relative infrequency of IA even in the allogeneic setting has often led to statistically underpowered studies. Since fungal spores are common in the environment and the route of acquisition is via the respiratory tract, a rational way of decreasing the risk of invasive infection is the use of high-efficiency particulate air filtration with or without laminar air flow. There are some data suggesting that the risk of early infections can be reduced, 3,56 although the issue has never been studied prospectively in a randomised fashion. However, these measures are not suited to longterm use, and the risk of IA may last for 6 months from SCT or even longer in patients with chronic GVHD. In a previous observational study in BMT recipients using prophylactic AmB inhalations, a low incidence of IA was reported. 57 A large randomised trial was subsequently started. 54 In this study, there were some problems with tolerance of AmB, and no efficacy of the regimen used was noted. However, allogeneic SCT recipients were excluded from the study. Thus, the issue of the efficacy of this approach in the allogeneic setting remained unsettled. Itraconazole either in oral solution or intravenous formulation might be a prophylactic approach at least in highrisk patients. A recent randomised comparison between itraconazole and fluconazole showed a lower risk for invasive fungal infections in allogeneic recipients receiving itraconazole, but the incidence of IA was low in both arms. 40 Similarly, no convincing data exist on the efficacy of AmB on the prophylaxis of IA in this setting. 58 One prospective placebo-controlled study of liposomal AmB has been published, with inconclusive results. 59 Since most cases of IA in the allogeneic setting are associated with GVHD, more accurate tissue-typing methods may be useful in reducing the risk of IA. Furthermore, more effective prophylactic regimens against GVHD might reduce the risk of invasive fungal infections. 60 Secondary prophylaxis of IA in allogeneic SCT recipients with a previous history of definite or probable IA is also an important issue. A retrospective analysis suggested that patients receiving oral or intravenous antifungals had less relapses that those patients who did not. 12 The optimal secondary prophylaxis is not known, but a combination of surgery and antifungal therapy might represent the best option. Future perspectives Although our therapeutic measures have been broadened, and significant advances have been made in identifying high-risk patients and diagnosing invasive infection at an earlier stage, invasive aspergillosis still remains an important issue in allogeneic transplantation. Several changes in patient characteristics as well as in transplant procedures, including higher recipient age and the continuously increasing use of unrelated 61 or mismatched donors, 62 may even increase the risk of IA. Reduced intensity-conditioning 63 has recently gained some popularity, but risk of invasive fungal infection may be as high as with conventional myeloablative conditioning. 64 Pre-emptive strategies based on the evaluation of either fungal PCR or galactomannan antigen are under investigation. The results of these trials may be of importance for future management of transplant recipients. Also, more effective treatment modalities are needed. Besides new antifungal drugs, combinations of antifungal drugs with different modes of action may also be of use. Dendritic cellmediated stimulation of lymphocytes, 65 cytokines or, in selected cases, surgery may also prove to be useful adjuncts to the treatment measures against invasive aspergillosis. References 1 de Bock R. Epidemiology of invasive fungal infection in bone marrow transplantation. Bone Marrow Transplant 1994; 14 (Suppl. 5): S1 S2. 2 Jantunen E, Ruutu P, Niskanen L et al. Incidence and risk factors of invasive fungal infections in allogeneic BMT recipients. Bone Marrow Transplant 1997; 19: Wald A, Leisenring W, Burik J-A, Bowden RA. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 1997; 175: Marr KA, Carter RA, Crippa F et al. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002; 34: McWhinney PHM, Kibbler CC, Hamon MD et al. Progress in the diagnosis and management of aspergillosis in bone marrow transplantation: 13 years experience. Clin Infect Dis 1993; 17: Saugier-Veber P, Devergie A, Sulahian A et al. Epidemiology and diagnosis of invasive pulmonary aspergillosis in bone marrow transplant recipients: results of a 5-year retrospective study. Bone Marrow Transplant 1993; 12: Morrison VA, Haake RJ, Weisdorf DJ. Non-Candida fungal infections after bone marrow transplantation: risk factors and outcome. Am J Med 1994; 96: Hovi L, Saarinen-Pihkala UM, Vettenranta K, Saxen H. Invasive fungal infections in pediatric bone marrow transplant recipients: single center experience of 10 years. Bone Marrow Transplant 2000; 26: Baddley JW, Stroud TP, Salzman D, Pappas PG. Invasive mold infections in allogeneic bone marrow transplant recipients. Clin Infect Dis 2001; 32: Jantunen E, Piilonen A, Volin L et al. Diagnostic aspects of invasive Aspergillus infections in allogeneic BMT recipients. Bone Marrow Transplant 2000; 25: Paterson DL, Singh N. Invasive aspergillosis in transplant recipients. Medicine 1999; 78:

4 Offner F, Cordonnier C, Ljungman P et al. Impact of previous aspergillosis on the outcome of bone marrow transplantation. Clin Infect Dis 1998; 26: Denning DW. Invasive aspergillosis. Clin Infect Dis 1998; 26: Reichenberger F, Habicht J, Matt P et al. Diagnostic yield of bronchoscopy in histologically proven pulmonary aspergillosis. Bone Marrow Transplant 1999; 24: Caillot D, Casanovas PO, Bernard A et al. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin Oncol 1997; 15: Jantunen E, Piilonen A, Volin L et al. Radiologically guided fine needle lung biopsies in the evaluation of focal pulmonary lesions in allogeneic stem cell transplant recipients. Bone Marrow Transplant 2002; 29: Bretagne S, Costa J-M, Bart-Delabasse A et al. Comparison of serum galactomannan antigen detection and competitive polymerase chain reaction for diagnosing invasive aspergillosis. Clin Infect Dis 1998; 26: Machetti M, Feasi M, Mordini N et al. Comparison of an enzyme immunoassay and a latex agglutination system for diagnosis of invasive aspergillosis in bone marrow transplant recipients. Bone Marrow Transplant 1998; 21: Maertens J, Verhaegen J, Demuynck D et al. Autopsy-controlled prospective evaluation of serial screening for circulating galactomannan by a sandwich enzyme-linked immunosorbent assay for hematological patients at risk for invasive aspergillosis. J Clin Microbiol 1999; 37: Sulahian A, Boutboul F, Ribaud P et al. Value of antigen detection using an enzyme immunoassay in the diagnosis and prediction of invasive aspergillosis in two adult and one pediatric hematology units during a 4-year prospective study. Cancer 2001; 91: Maertens J, Verhaegen J, Lagrou K et al. Screening for circulating galactomannan as a non-invasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: a prospective validation. Blood 2001; 97: Bretagne S, Costa JM, Marmoral KM et al. Detection of Aspergillus species DNA in bronchoalveolar lavage samples by competitive PCR. J Clin Microbiol 1995; 33: Einsele H, Quabeck K, Muller K-D. Prediction of invasive pulmonary aspergillosis from colonization of lower respiratory tract before marrow transplantation. Lancet 1998; 352: Einsele H, Hebart H, Roller G et al. Detection and identification of fungal pathogens in blood by using molecular probes. J Clin Microbiol 1997; 35: van Burik J-A, Myerson D, Schreckhise RW, Bowden RA. Panfungal PCR assay for detection of fungal infection in human blood specimen. J Clin Microbiol 1998; 36: Hebart H, Loffler J, Meisner C et al. Early detection of Aspergillus infection after allogeneic stem cell transplantation by polymerase chain reaction screening. J Infect Dis 2000; 181: Williamson ECM, Leeming JP, Palmer HM et al. Diagnosis of invasive aspergillosis in bone marrow transplant recipients by polymerase chain reaction. Br J Haematol 2000; 108: Ellis M, Spence D, de Pauw B et al. An EORTC international multicenter trial (EORTC number 19923) comparing two doses of liposomal amphotericin B for treatment of invasive aspergillosis. Clin Infect Dis 1998; 27: Leenders ACAP, Daenen S, Jansen RLH et al. Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropeniaassociated invasive fungal infections. Br J Haematol 1998; 103: Walsh TJ, Finberg RW, Arndt C et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. New Engl J Med 1999; 340: Herbrecht R, Auvrignon A, Andres E et al.efficacy of amphotericin B lipid complex in the treatment of invasive fungal infections in immunosuppressed paediatric patients. Eur J Clin Microbiol Infect Dis 2001; 20: Mehta J, Kelsey S, Chu P et al. Amphotericin B lipid complex (ABLC) for the treatment of confirmed or presumed fungal infections in immunocompromised patients with hematologic malignancies. Bone Marrow Transplant 1997; 20: Wingard JR. Efficacy of amphotericin B lipid complex injection (ABLC) in bone marrow transplant recipients with lifethreatening systemic mycoses. Bone Marrow Transplant 1997; 19: Walsh TJ, Hiemenz JW, Seibel NL et al. Amphotericin B lipid complex for invasive fungal infections: analysis on safety and efficacy in 556 cases. Clin Infect Dis 1998; 26: White MH, Anaissie EJ, Kusne S et al. Amphotericin B colloidal dispersion vs. amphotericin B as therapy for invasive aspergillosis. Clin Infect Dis 1997; 24: Noskin G, Pietrelli L, Gurwith M, Bowden R. Treatment of invasive fungal infections with amphotericin B colloidal dispersion in bone marrow transplant recipients. Bone Marrow Transplant 1999; 23: Wingard JR, White M, Anaissie E et al. A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. Clin Infect Dis 2000; 31: Denning DW, Lee JY, Hostetler JS et al. NIAID Mycoses Study Group multicenter trial of oral itraconazole therapy of invasive pulmonary aspergillosis. Am J Med 1994; 97: Foot ABM, Veys PA, Gibson BES. Itraconazole oral solution as antifungal prophylaxis in children undergoing stem cell transplantation or intensive chemotherapy for haematological disorders. Bone Marrow Transplant 1999; 24: Winston DJ, Maziarz RT, Chandrasekar PH et al. Long-term antifungal prophylaxis in allogeneic bone marrow transplant patients: a multicenter, randomized trial of intravenous/oral itraconazole versus intravenous/oral fluconazole. Blood 2001; 98: 479a (abstr.). 41 Herbrecht R, Denning DW, Patterson TF et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. New Engl J Med 2002; 347: Denning DW, Ribaud P, Milpied N et al. Efficacy and safety of voriconazole in the treatment of invasive aspergillosis. Clin Infect Dis 2002; 34: Keating GM, Jarvis B. Caspofungin. Drugs 2001; 61: Maertens J, Raad I, Sable CA et al. Multicenter, noncomparative study to evaluate safety and efficacy of caspofungin (CAS) in adults with invasive aspergillosis (IA) refractory or intolerant to amphotericin B (AMB), AMB lipid formulations (lipid AMB), or azoles. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, p 370, poster 1103, Toronto Rex JH, Bennett JE, Gallin JI et al. In vivo interferon-gamma therapy augments the in vitro ability of chronic granulomatous disease neutrophils to damage Aspergillus hyphae. J Infect Dis 1991; 163: Reichenberger F, Habicht J, Kaim A et al. Lung resection for

5 invasive pulmonary aspergillosis in neutropenic patients with hematologic diseases. Am J Respir Crit Care Med 1998; 158: Salerno CT, Ouyang DW, Pederson TS et al. Surgical therapy for pulmonary aspergillosis in immunocompromised patients. Ann Thorac Surg 1998; 65: Yeghen T, Kibbler CC, Prentice HG et al. Management of invasive aspergillosis in hematology patients: a review of 87 consecutive cases at a single institution. Clin Infect Dis 2000; 31: Kennedy CA, Adams GL, Neglia JP, Giebink GS. Impact of surgical treatment on paranasal fungal infections in bone marrow transplant patients. Otolaryngol Head Neck Surg 1997; 116: Denning DW. Therapeutic outcome of invasive aspergillosis. Clin Infect Dis 1996; 23: Ribaud P, Chastang C, Latge J-P et al. Survival and prognostic factors of invasive aspergillosis after allogeneic bone marrow transplantation. Clin Infect Dis 1999; 28: Jantunen E, Ruutu P, Piilonen A et al. Treatment and outcome of invasive Aspergillus infections in allogeneic BMT recipients. Bone Marrow Transplant 2000; 26: Hagensee ME, Bauwens JE, Kjos B, Bowden RA. Brain abscess following marrow transplantation: experience at the Fred Hutchinson Cancer Research Center, Clin Infect Dis 1994; 19: Schwartz S, Behre G, Heinemann V et al. Aerosolized amphotericin B inhalations as prophylaxis of invasive Aspergillus infections during prolonged neutropenia: results of a prospective randomized multicenter trial. Blood 1999; 93: Morgenstern GR, Prentice AG, Prentice HG et al. A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematological malignancies. Br J Haematol 1999; 105: Sherertz RJ, Belani A, Krames BS et al. Impact of air filtration on nosocomial Aspergillus infections. Unique risk of bone marrow transplant recipients. Am J Med 1987; 83: Hertenstein B, Kern WV, Schmeiser T et al. Low incidence of invasive fungal infections after bone marrow transplantation in patients receiving amphotericin B inhalations during neutropenia. Ann Hematol 1994; 68: Wingard JR. Fungal infections after bone marrow transplant. Biol Blood Marrow Transplant 1999; 5: Tollemar J, Ringden O, Andersson S et al. Randomized double-blind study of liposomal amphotericin B (AmBisome) prophylaxis of invasive fungal infections in bone marrow transplant recipients. Bone Marrow Transplant 1993; 12: Ruutu T, Volin L, Parkkali T et al. Cyclosporine, methotrexate, and methylprednisolone compared with cyclosporine and methotrexate for the prevention of graft-versus-host disease in bone marrow transplantation from HLA-identical sibling donor: a prospective randomized study. Blood 2000; 96: Heslop H. Haemopoietic stem cell transplantation from unrelated donors. Br J Haematol 1999; 105: Aversa F, Tabilio A, Velardi A et al. Treatment of high-risk acute leukemia with T-cell depleted stem cells from related donors with one fully mismatched HLA haplotype. New Engl JMed1998; 339: Carella AM, Champlin R, Slavin S et al. Mini-allografts: ongoing trials in humans. Bone Marrow Transplant 2000; 25: Junghans C, Marr KA, Carter RA et al. Incidence of bacterial and fungal infections after nonmyeloablative compared to myeloablative allogeneic hematopoietic stem cell transplantation (HSCT). Blood 2001; 98: 479a (Abstr.). 65 Grazziutti M, Przepiorka D, Rex JH et al. Dendritic cellmediated stimulation of the in vitro lymphocyte response to Aspergillus. Bone Marrow Transplant 2001; 27: