International Multicenter Experience in the Treatment Outcome of Invasive Aspergillosis in Immunocompromised Cancer Patients
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. |
Abstract Background:
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. |
Introduction
Methods
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.[10] 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).
Results
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. |
Discussion
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.[16] 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.[6]
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.[5] Moreover, another study by Nivoix et al showed that voriconazole was associated with increase probability of survival compared with all other therapy.
Conclusions
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