International Multicenter Experience in the Treatment Outcome of Invasive Aspergillosis in Immunocompromised Cancer Patients
Department of Infectious Diseases, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
2 Division of Infectious Diseases, American University of Beirut Medical Center, Beirut, Lebanon.
3 Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
4 Division of Infectious Diseases, St. Luke's International Hospital, Tokyo, Japan.
5 Hospital das Clinicas da Faculdade de Medicina de Sao Paulo, Sao Paulo, Brazil.
Received: September 19, 2018
Accepted: November 8, 2018
Mediterr J Hematol Infect Dis 2019, 11(1): e2019003 DOI 10.4084/MJHID.2019.003
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Invasive aspergillosis (IA) is a life-threatening infection in
immunocompromised patients. In this study, we compared the efficacy of
voriconazole containing regimen vs non-voriconazole containing regimen
in patients with IA.
The study was approved by the Institutional Review Board of all participating centers under a waiver of informed consent due to the retrospective nature of the study.
Definitions. Proven and probable IA were defined according to the European Organization for Research and Treatment of Cancer and Mycoses Study Group criteria. In brief, proven IA was documented by Histopathologic or cytopathologic examination showing hyphae from needle aspiration or biopsy specimen with evidence of associated tissue damage; or positive culture result for a sample obtained by sterile procedure from a normally sterile and clinically or radiologically abnormal site consistent with infection. Probable IA was characterized by the presence of radiologic and microbiologic features supporting an IA diagnosis (the presence of nodules or cavities or a halo or air-crescent sign computerized tomography and documentation of Aspergillus spp. infection by direct microscopy or culture or Galactomannan (GM) positive from serum or Bronchoalveolar lavage (BAL)[11,12] in a patient with an absolute neutrophil count of <500 cells/mm3, who had undergone prolonged steroid therapy, or who had used cytotoxic agents. Aspergillosis-attributable mortality was defined as:
Aspergillosis was considered to have contributed to the death of a patient if the patient died with clinical, radiographic or microbiological evidence of aspergillosis and had not had a favorable response to the anti-mold therapy, regardless of the presence of other causes contributing to the death.
Primary antifungal therapy was defined as the first antifungal regimen (single agent or combination) that was administered for at least 7 consecutive days. Salvage therapy was defined as any other regimen administered after primary antifungal therapy.
Successful Response to Primary Therapy: was defined as improvement (partial or complete) resolution of the clinical signs and symptoms assessed by the treating physician and or radiological findings after receiving at least 7 days of same antifungal therapy.
Statistical analysis. Categorical variables were compared using the chi-square or Fisher’s exact test, as appropriate. Continuous variables were compared using Wilcoxon rank-sum test. Logistic regression method was used to identify the independent predictors of response to primary therapy and mortality within 6 months of IA diagnosis, respectively. All tests were two-sided with a significance level of 0.05. The statistical analyses were performed using SAS version 9.3 (SAS Institute Inc., Cary, NC).
|Table 1. Characteristics of patients with different primary therapies.|
|Table 2. Comparing the intervention and outcomes of patients receiving voriconazole vs mon-voriconazole regimen.|
Most baseline characteristics were comparable between the two groups including age, gender, underlying disease, steroid treatment prior to infection and neutropenia at infection onset (Tables 1 and 2). However, patients treated with voriconazole-containing regimens were more likely to have had a HSCT in the year preceding aspergillosis infection (34% vs 10%, p=0.04). All patients who received Computed Tomography (CT) scans (chest or sinus) in both groups had positive findings. Similarly, among patients with galactomannan tests, e.g. serum GM index was > 0.5 in all patients while BAL GM index was > 1. Overall, 11% of patents in the Vori-group and 10% in the non- Vori group had definite aspergillosis while all others were diagnosed as probable cases (p >.99). The infection type was also similar between the Vori- and non-Vori groups respectively: 86% vs 81% for invasive pulmonary infections, 9% vs 10% for disseminated infections and 6% vs 10% for sinus infections.
The majority of patients in this study (63%) received antifungal prophylaxis prior to the diagnosis of IA including prophylactic fluconazole (45%) and mold-active azoles (16%) (Table 2). Regarding primary therapy, in the non-Vori group, 17 patients (81%) were treated with amphotericin B alone, 2 (10%) treated with amphotericin B in combination with echinocandin, and 2 (10%) treated with echinocandin alone. In the Vori group, 26 patients (74%) were treated with voriconazole alone, 8 (23%) treated with voriconazole in combination with amphotericin B, and 1 (3%) treated with voriconazole in combination with amphotericin B and echinocandin. Data on resistance against the antifungal regimens in primary therapy was unknown.
Patients in the Vori-group had a significantly longer duration of primary therapy compared to those in the non-Vori group (median: 45 vs 19 days, p=0.01). However, there was no significant difference in the duration of the overall therapy (primary and salvage) for their infections (median: 58 vs 80 days, p=0.87). Overall patients in Vori-group had better outcomes. They had higher rates of response to primary therapy compared to those in non-Vori group (85% vs 38%, p=0.003) (Table 2), had lower mortality rates within 6 months of diagnosis of IA (31% vs 70%, p=0.006) and lower aspergillosis-attributable mortality rate during the same time period (9% vs 44%, p=0.01). On the other hand, 5% of the patients in non-Vori group and 17% in Vori-group had adverse events related to their primary therapy (p=0.24). Lastly, we performed multivariate analysis to identify the independent predictors of response to primary therapy and all-cause mortality, respectively. Data showed that patients receiving mechanical ventilatory support were less likely to respond to primary therapy (odds ratio (OR)=0.11, p=0.024) and patients receiving a primary therapy containing voriconazole were more likely to have a successful response (OR=18.1, p=0.002) (Table 3A). Regarding mortality, we found that patients with leukemia (OR=4.9, p=0.038) or those receiving mechanical ventilation support (OR=5.3, p=0.026) were more likely to die within 6 months after IA diagnosis while those receiving primary therapy with voriconazole were less likely to die within this time period (OR=0.14, p=0.011) (Table 3B).
|Table 3. Predictors of outcomes by multivariate logistic regression analysis.|
These findings are also in accordance with the international guidelines that recommend Voriconazole as primary treatment for invasive aspergillosis.[13-15]
Our study showed higher response rate to primary therapy for IA in patients on initial therapy with voriconazole. In addition voriconazole was an independent predictor of successful response, by multivariate analysis (OR=18.1, p=0.002). Similar findings were reported by Herbrecht et al, 2002, in a randomized, unblinded trial, where successful treatment outcomes at 12 weeks were observed in 52.8% of the patients receiving voriconazole (144 patients) compared to 31.6 % of those receiving amphotericin B (133 patients) . Furthermore, in the setting where the antifungal were giving empirically, and despite that, voriconazole group had favorable outcome compared to the non-vori group. It is to note that 90% of the patients in the non vori group were treated with Amphotericin B based regimen.
In a randomized, multicenter trial Walsh et al compared voriconazole, versus liposomal amphotericin B as empirical antifungal therapy in a total of 837 patients. Voriconazole was shown to be reasonable alternative to amphotericin B in patients with neutropenia and persistent fever, which is in accordance with our results. Furthermore, in a study by Ramos et al from MD Anderson Cancer Center showed that the anti- mold active azole agents such as voriconazole in their uses as primary or salvage therapy were associated with improves overall clinical outcome as well as overall mortality.
Invasive aspergillosis is a common cause of infection-related mortality in hematologic and hematopoietic cell transplant (HCT) recipients. The overall mortality, one year after diagnosis, ranges from 70% to 93%.[7,17,18] In our study, the treatment of IA with an antifungal regimen containing voriconazole was associated with significantly lower overall mortality rate and aspergillosis-attributable mortality rate within 6 months of IA diagnosis despite the relatively small number of patients included in this current study. Similar results were reported by Upton et al, in a retrospective clinical chart review of 405 cases of proven and probable IA diagnosed in HCT recipients. Their study showed that treatment with voriconazole was independently associated with reduce risk of IA- related death. Moreover, another study by Nivoix et al showed that voriconazole was associated with increase probability of survival compared with all other therapy.
- Nicolle MC, Benet T, Thiebaut A, Bienvenu AL,
Voirin N, Duclos A, Sobh M, Cannas G, Thomas X, Nicolini FE, De
Monbrison F, Piens MA, Picot S, Michallet M, Vanhems P. Invasive
aspergillosis in patients with hematologic malignancies: incidence and
description of 127 cases enrolled in a single institution prospective
survey from 2004 to 2009. Haematologica. 2011;96:1685-91. https://doi.org/10.3324/haematol.2011.044636 PMid:21791468 PMCid:PMC3208687
L, Caira M, Picardi M, Candoni A, Melillo L, Fianchi L, Offidani M,
Nosari A. Invasive Aspergillosis in patients with acute leukemia:
update on morbidity and mortality--SEIFEM-C Report. Clin Infect Dis.
2007;44:1524-5. https://doi.org/10.1086/517849 PMid:17479958
DP, Marr KA, Park BJ, Alexander BD, Anaissie EJ, Walsh TJ, Ito J, Andes
DR, Baddley JW, Brown JM, Brumble LM, Freifeld AG, Hadley S, Herwaldt
LA, Kauffman CA, Knapp K, Lyon GM, Morrison VA, Papanicolaou G,
Patterson TF, Perl TM, Schuster MG, Walker R, Wannemuehler KA, Wingard
JR, Chiller TM, Pappas PG. Prospective surveillance for invasive fungal
infections in hematopoietic stem cell transplant recipients, 2001-2006:
overview of the Transplant-Associated Infection Surveillance Network
(TRANSNET) Database. Clin Infect Dis. 2010;50:1091-100. https://doi.org/10.1086/651263 PMid:20218877
R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, Kern
WV, Marr KA, Ribaud P, Lortholary O, Sylvester R, Rubin RH, Wingard JR,
Stark P, Durand C, Caillot D, Thiel E, Chandrasekar PH, Hodges MR,
Schlamm HT, Troke PF, de Pauw B, Invasive Fungal Infections Group of
the European Organisation for R, Treatment of C, the Global Aspergillus
Study G. Voriconazole versus amphotericin B for primary therapy of
invasive aspergillosis. N Engl J Med. 2002;347:408-15. https://doi.org/10.1056/NEJMoa020191 PMid:12167683
A, Kirby KA, Carpenter P, Boeckh M, Marr KA. Invasive aspergillosis
following hematopoietic cell transplantation: outcomes and prognostic
factors associated with mortality. Clin Infect Dis. 2007;44:531-40. https://doi.org/10.1086/510592 PMid:17243056
ER, Jiang Y, Hachem R, Kassis C, Kontoyiannis DP, Raad I. Outcome
analysis of invasive aspergillosis in hematologic malignancy and
hematopoietic stem cell transplant patients: the role of novel antimold
azoles. Oncologist. 2011;16:1049-60. https://doi.org/10.1634/theoncologist.2010-0290 PMid:21659609 PMCid:PMC3228136
Y, Velten M, Letscher-Bru V, Moghaddam A, Natarajan-Ame S, Fohrer C,
Lioure B, Bilger K, Lutun P, Marcellin L, Launoy A, Freys G, Bergerat
JP, Herbrecht R. Factors associated with overall and attributable
mortality in invasive aspergillosis. Clin Infect Dis. 2008;47:1176-84. https://doi.org/10.1086/592255 PMid:18808352
G, Porcher R, Bergeron A, Robin M, Peffault de Latour R, Ferry C, Rocha
V, Petropoulou A, Xhaard A, Lacroix C, Sulahian A, Socie G, Ribaud P.
Persistent poor long-term prognosis of allogeneic hematopoietic stem
cell transplant recipients surviving invasive aspergillosis.
Haematologica. 2012;97:1357-63. https://doi.org/10.3324/haematol.2011.058255 PMid:22371177 PMCid:PMC3436236
TF, Thompson GR, 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R,
Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, Segal BH, Steinbach
WJ, Stevens DA, Walsh TJ, Wingard JR, Young JA, Bennett JE. Practice
Guidelines for the Diagnosis and Management of Aspergillosis: 2016
Update by the Infectious Diseases Society of America. Clin Infect Dis.
2016;63:e1-e60. https://doi.org/10.1093/cid/ciw326 PMid:27365388 PMCid:PMC4967602
Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T,
Pappas PG, Maertens J, Lortholary O, Kauffman CA, Denning DW, Patterson
TF, Maschmeyer G, Bille J, Dismukes WE, Herbrecht R, Hope WW, Kibbler
CC, Kullberg BJ, Marr KA, Munoz P, Odds FC, Perfect JR, Restrepo A,
Ruhnke M, Segal BH, Sobel JD, Sorrell TC, Viscoli C, Wingard JR,
Zaoutis T, Bennett JE, European Organization for R, Treatment of
Cancer/Invasive Fungal Infections Cooperative G, National Institute of
A, Infectious Diseases Mycoses Study Group Consensus G. Revised
definitions of invasive fungal disease from the European Organization
for Research and Treatment of Cancer/Invasive Fungal Infections
Cooperative Group and the National Institute of Allergy and Infectious
Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect
Dis. 2008;46:1813-21. https://doi.org/10.1086/588660 PMid:18462102 PMCid:PMC2671227
J, Theunissen K, Vermeulen E, Schoemans H, De Vlieger G, Lammertijn L,
Meersseman P, Meersseman W, Lagrou K, Maertens J. Detection of
galactomannan in bronchoalveolar lavage fluid samples of patients at
risk for invasive pulmonary aspergillosis: analytical and clinical
validity. J Clin Microbiol. 2012;50:1258-63. https://doi.org/10.1128/JCM.06423-11 PMid:22301025 PMCid:PMC3318563
RF, Sanchez-Ortega I, Cuesta I, Arnan M, Patino B, Fernandez de Sevilla
A, Gudiol C, Ayats J, Cuenca-Estrella M. Serum galactomannan-based
early detection of invasive aspergillosis in hematology patients
receiving effective antimold prophylaxis. Clin Infect Dis.
2014;59:1696-702. https://doi.org/10.1093/cid/ciu673 PMid:25165088
O, Gangneux JP, Sitbon K, Lebeau B, de Monbrison F, Le Strat Y,
Coignard B, Dromer F, Bretagne S, French Mycosis Study G.
Epidemiological trends in invasive aspergillosis in France: the SAIF
network (2005-2007). Clin Microbiol Infect. 2011;17:1882-9. https://doi.org/10.1111/j.1469-0691.2011.03548.x PMid:21668573
TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA,
Morrison VA, Segal BH, Steinbach WJ, Stevens DA, van Burik JA, Wingard
JR, Patterson TF, Infectious Diseases Society of A. Treatment of
aspergillosis: clinical practice guidelines of the Infectious Diseases
Society of America. Clin Infect Dis. 2008;46:327-60. https://doi.org/10.1086/525258 PMid:18177225
J, Marchetti O, Herbrecht R, Cornely OA, Fluckiger U, Frere P, Gachot
B, Heinz WJ, Lass-Florl C, Ribaud P, Thiebaut A, Cordonnier C, Third
European Conference on Infections in L. European guidelines for
antifungal management in leukemia and hematopoietic stem cell
transplant recipients: summary of the ECIL 3--2009 update. Bone Marrow
Transplant. 2011;46:709-18. https://doi.org/10.1038/bmt.2010.175 PMid:20661235
TJ, Pappas P, Winston DJ, Lazarus HM, Petersen F, Raffalli J, Yanovich
S, Stiff P, Greenberg R, Donowitz G, Schuster M, Reboli A, Wingard J,
Arndt C, Reinhardt J, Hadley S, Finberg R, Laverdiere M, Perfect J,
Garber G, Fioritoni G, Anaissie E, Lee J, National Institute of A,
Infectious Diseases Mycoses Study G. Voriconazole compared with
liposomal amphotericin B for empirical antifungal therapy in patients
with neutropenia and persistent fever. N Engl J Med. 2002;346:225-34. https://doi.org/10.1056/NEJM200201243460403 PMid:11807146
P, Chastang C, Latge JP, Baffroy-Lafitte L, Parquet N, Devergie A,
Esperou H, Selimi F, Rocha V, Esperou H, Selimi F, Rocha V, Derouin F,
Socie G, Gluckman E. Survival and prognostic factors of invasive
aspergillosis after allogeneic bone marrow transplantation. Clin Infect
Dis. 1999;28:322-30. https://doi.org/10.1086/515116 PMid:10064251
C, Ribaud P, Herbrecht R, Milpied N, Valteau-Couanet D, Morgan C, Wade
A, Societe Francaise de Greffe de Moelle et de Therapie C. Prognostic
factors for death due to invasive aspergillosis after hematopoietic
stem cell transplantation: a 1-year retrospective study of consecutive
patients at French transplantation centers. Clin Infect Dis.
2006;42:955-63. https://doi.org/10.1086/500934 PMid:16511759