Prior Invasive Aspergillosis Research Articles

False-positive Aspergillus galactomannan immunoassays associated with intravenous human immunoglobulin administration

ObjectivesEvidence of false-positive galactomannan enzyme immunoassay (GM-EIA) results associated with intravenous immunoglobulin (IVIG) administration is scarce. Here, we aimed to determine the false-positive rate of GM-EIA after IVIG administration and to identify the related factors. MethodsStandard GM-EIA was performed using diluted and pure human IVIG samples with and without heat treatment. We also included adult patients who had at least one GM-EIA result within 1 week of IVIG administration for analysis. Those who had prior invasive aspergillosis within 1 year before IVIG therapy were excluded. The clinical characteristics and galactomannan index (GMI) kinetics between patients with false-positive and true-positive GMI were compared. ResultsAll diluted and pure IVIG samples tested positive for GM. Heat treatment resulted in the considerable elevation of GMI. Of 48 patients with positive GM-EIA results within 1 week of IVIG administration, 22 (45.8%) were considered to have false-positive antigenaemia (false-positive group, FPG). After the completion of IVIG administration, a decline in GMI was observed in all FPG patients but in only 18 out of 26 patients (69.2%) with true-positive results (true-positive group, TPG). By 7, 14, and 18 days of IVIG administration, GMI reverted to negative values in 7/15 (46.7%), 18/20 (90%) and 22/22 (100%) FPG patients, respectively, and 6/24 (25%), 14/24 (58.3%), and 16/26 (61.5%) of TPG patients, respectively. The TPG was more likely to have two or more consecutively positive GMIs after IVIG administration than the FPG (adjusted odds ratio, 9.01; 95% confidence interval, 1.99–40.9). ConclusionsIVIG treatment may produce false-positive GM-EIA results. A positive GMI among patients receiving human IVIG should be interpreted with caution.

Antifungal prophylaxis with fluconazole in allogeneic stem cell transplantation recipients who had prior invasive aspergillosis with subsequent complete resolution by computed tomography

Background: Consensus has yet to be reached regarding secondary prophylaxis in allogeneic hematopoietic stem cell transplantation (HSCT) with a complete resolution of invasive aspergillosis (IA) confirmed by chest computed tomography (CT).Methods: We retrospectively evaluated the feasibility of antifungal prophylaxis with fluconazole in allogeneic HSCT recipients who had previously developed IA which showed complete resolution as confirmed by chest CT before HSCT. Consecutive adult patients who underwent allogeneic HSCT at our institution and who had received fluconazole as systemic antifungal prophylaxis from June 2007 to January 2015 were included. We compared the clinical outcomes between patients with a past history of IA who showed a complete resolution of chest CT abnormalities (n = 13) and those without a previous history of IA (n = 137).Results: The cumulative incidence of proven or probable IA was 8.8% in the group without a past history of IA and 0.0% in the group with a past history of IA (p = .268). The cumulative incidence of proven or probable invasive fungal disease (IFD) within 100 days after allogeneic HSCT was 10.9% in the group without a past history of IA and 15.4% in the group with a past history of IA (p = .647). Fluconazole was switched to anti-mould agents in two-thirds of the patients in each group by day 100 after HSCT.Conclusions: Fluconazole was confirmed to be an acceptable prophylactic agent early after allogeneic HSCT in appropriately selected patients.

Changes of serum aspergillus galactomannan during hematopoietic stem cell transplantation in children with prior invasive aspergillosis.

BackgroundInvasive aspergillosis (IA) has recently increased and has a high mortality rate in immunocompromised patients. IA before hematopoietic stem cell transplantation (HSCT) is not uncommon, but how to cope with it is very tough. The serum aspergillus galactomannan antigen (GM) is a helpful marker for diagnosis of IA, and a serial follow-up of GM levels is important to evaluate the response of treatment. However, data on the changes of GM during HSCT are very limited.Case presentationPatient 1 was a 2-year-old female with severe aplastic anemia. A typical lung lesion in the computed tomography of the chest with elevated GM levels was noted, and probable IA was diagnosed. After a combination treatment of voriconazole and caspofungin, the GM levels decreased. Although of significant improvement, the pulmonary lesion in the chest X-ray did not disappear before HSCT. The GM levels increased when she received the conditioning regimen during HSCT. The GM levels remained high during the use of steroids for the graft-versus-host disease and declined gradually after tapering off steroids and cyclosporine. Patient 2 was a 12-year-old female with severe aplastic anemia. Voriconazole was administered after the diagnosis of a probable IA. The pulmonary lesions in the chest X-ray disappeared before HSCT. The GM levels flared up during the administration of conditioning regimen and declined after neutrophil engraftment. At present, the two patients were cured of the disease without requiring surgical resection of their pulmonary IA.ConclusionTo our knowledge, this is the first report about the changes of GM during HSCT in patients with prior IA. With appropriate antifungal therapy and restoration of patient’s immunity, IA can be cured without surgical resection. Further studies are warranted.

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Prior Invasive Aspergillosis

Background: Introducing a new antifungals and diagnostic procedures has improved prognosis of the invasive aspergillosis (IA) in hematological patients. The number of patients with IA who are candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT) has increased. The influence of IA on survival and on allo-HSCT related complications has not been investigated in a prospective study.Aim: to estimate impact of prior proven and probable IA on outcome of allo-HSCT compared to patients without IA.Methods: In prospective observational single center study 362 allo-HSCT recipients (336 - first and 26 - second allo-HSCT) were included from Jan 2012 to Dec 2014. The median age was 34 y, males - 54%. Most of pts had high-risk acute leukemia (70%). Allo-HSCT with MUD were performed in 57%, MRD - 24%, haplo - 11%, MMUD - 8%, predominantly with RIC (80%). All patients with lesions in CT scan before allo-HSCT have undergone bronchoscopy with BAL microscopy, culture and GM test. EORTC/MSG 2008 criteria were used for the diagnosis of proven and probable IA as well as to evaluate response to therapy. "Active" invasive IA - IA diagnosed just before allo-HSCT. All patients were observed with the median 2 years follow up. We analyze status of pts before HSCT, donor types, source of HSCT, CMV status, conditioning regimens and type of immunosuppression, relapse or progression of IA, relapse of underlying disease, duration of antifungal therapy and prophylaxis, acute and chronic GvHD. The cumulative incidences were determined with cumulative incidence method. Differences between the two cohorts were verified with Gray test. Overall survival after allo-HSCT was estimated with Kaplan-Meier method and cohorts were compared by log-rank test.Results: Incidence of IA before allo-HSCT was 20% (n=72/362). According to EORTC/MSG 2008 criteria 92% of pts had probable IA and 8% - proven IA. The main sites of IA were lungs - 95%, central nervous system - 3%, and colon - 3%, other sites were observed in a combination with lungs involvement: sinuses - 5%, spleen - 3%, and liver - 3%. The median time from IA to allo-HSCT was 3 months (3 days - 30 months). Antifungal therapy before allo-HSCT was used in 69% pts (voriconazole - 95%, other - 5%) with the median duration of therapy - 2 months. Complete response to antifungal therapy was registered in 19 (26%) patients, partial response or stabilization - 31 (43%), and "active IA" - 22 (31%). After allo-HSCT all patients received antifungal therapy with voriconazole (first line - 31%, continuation of treatment - 43%, and secondary prophylaxis - 26%). Median length of treatment was 166 days (37 - 394) with the median duration to effect 99 days (31 - 217). No toxicity of the antifungal treatment was registered. Cumulative incidence of relapse or progression of IA at 2 year after allo-HSCT was 14% (n=10). "Active" underlying disease before D+100 post transplant was the only risk factor for the relapse or progression of IA after allo-HSCT (6% vs 33%, p=0,007). 100-days OS after allo-HSCT was 77%, 2-year OS after allo-HSCT was 62%. There was no significant difference in OS in patients with or without IA prior to allo-HSCT (57% vs 65%, p=0,3). Duration of antifungal therapy before HSCT (<90 days vs ≥90 days), status of IA at the moment of HSCT ("active" IA vs PR vs CR), relapse/progression of IA after HSCT was not affected on 2-year OS after allo-HSCT in patients with prior IA.Conclusions: Incidence of proven and probable invasive aspergillosis before allo-HSCT was 20%. Cumulative incidence of relapse or progression of the invasive aspergillosis after allo-HSCT was 14% and "active" underlying disease before D+100 post transplant was the only risk factor. Invasive aspergillosis prior to allo-HSCT did not impair the outcome of the procedure with effective diagnosis and prophylaxis being used. DisclosuresNo relevant conflicts of interest to declare.

Influence of pre-existing invasive aspergillosis on allo-HSCT outcome: a retrospective EBMT analysis by the Infectious Diseases and Acute Leukemia Working Parties.

Historically, invasive aspergillosis (IA) has been a major barrier for allogeneic hematopoietic stem cell transplantation (allo-HSCT). The influence of invasive IA on long-term survival and on transplant-related complications has not been investigated in a larger patient cohort under current conditions. Our aim was to analyze the long-term outcome of patients undergoing allo-HSCT with a history of prior IA. We used European Society for Blood and Marrow Transplantation database data of first allo-HSCTs performed between 2005 and 2010 in patients with acute leukemia. One thousand one hundred and fifty patients with data on IA before allo-HSCT were included in the analysis. The median follow-up time was 52.1 months. We found no significant impact of IA on major transplant outcome variables such as overall survival, relapse-free survival, non-relapse mortality, cumulative incidence of acute GvHD grade II-IV, chronic GvHD, pulmonary complications and leukemia relapse. However, we found a trend toward lower overall survival (P=0.078, hazard ratio (HR) (95% confidence interval (CI)): 1.16 (0.98, 1.36)) and higher non-relapse mortality (P=0.150, HR (95% CI): 1.19 (0.94, 1.50)) in allo-HSCT recipients with pre-existing IA. Our data suggest that a history of IA should not generally be a contraindication when considering the performance of allo-HSCT in patients with acute leukemia.

Influence of Preexisting Invasive Aspergillosis on Allo-HSCT Outcome: A Retrospective EBMT Analysis from the Infectious Diseases and Acute Leukemia Working Parties

▪Introduction: Invasive aspergillosis (IA) frequently occurs during treatment for acute leukemia. Historically IA has been a major barrier for allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the recent decade there has been significant improvement of anti-fungal management including novel anti-fungal agents and diagnostics. The influence of invasive IA on long term survival and on transplant related complications has not been investigated in a larger patient cohort under current conditions.Specific Aim: The aim of this retrospective study was to analyze the long term outcome of patients undergoing allo-HSCT with history of prior proven, probable and possible IA as compared to patients without history of IA.Methodology: Patient-, disease-, and transplant-related variables were collected according to the data entries in the EBMT database. Inclusion criteria were as follows: first allo-HSCT performed between 2005 and 2010 in patients with acute leukemia; availability of data on IA prior to allo-HSCT. The median time of death after allo-HSCT was estimated using the Kaplan-Meier method and cohorts were compared by the log-rank test. The following variables entered the multivariate model as possible confounders: age (as continuous variable), gender (M vs. F), underlying disease (ALL vs. AML), status at SCT (1st CR vs. ≥2 CR vs. Prim Refr/noCR), time from diagnosis to SCT (as continuous variable), donor type (sibling vs. matched UD vs. mismatched UD vs. Haplo), source of SCT (BM vs. PB vs. CB), donor age, d/r gender match, d/r CMV status, conditioning regimens (MAC vs. RIC, TBI yes/no), type of immunosuppression (in vivo T depletion y/n, in vitro T-depletion y/n). The cumulative incidences were computed using the cumulative incidence method. Differences between the two cohorts were verified with the Gray test.Results: 1150 patients fulfilled the entry criteria and were included in the analysis (patient characteristics, table 1). The median follow up time was 52.1 months (95% CI 49.0, 56.6). The impact of prior IA on overall survival in allo-HSCT recipients with acute leukemia was not statistically significant (figure 1). We detected no significant differences in the cumulative incidence of acute GVHD grade II-IV [29.1% IA vs. 32.0% no IA, p=0.27, hazard ratio (HR) (95% CI) 0.89 (0.71, 1.10)]; chronic GVHD [43.9% IA vs. 49.3% no IA, p=0.26, HR (95% CI) 0.89 (0.73, 1.09)]; relapse [33.7% IA vs. 33.0% no IA, p=0.35, HR (95% CI) 1.11 (0.9, 1.36)] and pulmonary complications [8.3% IA vs. 6.9% no IA, p=0.4, odds ratio (95% CI) 1.21 (0.77, 1.90)]Conclusion: Prior IA had no significant impact on transplant-related complications and overall survival in this large data set of patients with acute leukemia undergoing allo-HSCT. We speculate that an overall better management of IA may have contributed to this result. Considering that we did not assess the impact of the type of IA (proven/probable vs. possible) and the status of IA before allo-HSCT, these data deserve to be confirmed by a prospective study. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Impact of prior invasive aspergillosis on outcome in patients receiving reduced-intensity conditioning allogeneic hematopoietic stem cell transplant

Invasive aspergillosis (IA) is a major cause of morbidity in patients with hematological malignancies, and a major impediment to the success of allogeneic stem cell transplant (allo-SCT). The aim of this single-center retrospective study was to determine the impact of pre-transplant IA on the outcome of allo-SCT after reduced-intensity conditioning (RIC). Twenty-eight cases of proven or probable IA were diagnosed prior to RIC allo-SCT at the Paoli-Calmettes Institute Cancer Center between January 2000 and January 2008. These cases were identified among 360 patients undergoing allo-SCT. IA was defined according to EORTC criteria. Patients had predominantly (82%) acute myeloid leukemia, were diagnosed with IA at a median of 8 months (range, 1–16) pre-transplant, and received antifungal therapy for a median of 5 months (range, 1–13). IA therapy included: voriconazole (71%); single-agent itraconazole (14%); and a combination of agents (14%). Secondary prophylaxis against aspergillosis was maintained during conditioning and post-transplant in 89% of patients. After transplant, only three patients (11%) had reactivation of their IA and one patient developed disseminated fusariosis. The latter four patients experienced severe acute GVHD treated with high-dose corticosteroids. None of these patients died of IA. Eighteen patients (64%) are still alive, with a median follow-up of 23.5 months (range, 12.6–48.5). Overall survival at 2 years was 59% (95% CI, 43–83%). These data suggest that patients with adequately controlled IA can tolerate RIC allo-SCT without significant post-transplant complications.

Strategy for Managing Patients with Prior Invasive Aspergillosis through Allogeneic Transplant.

Background: A history of invasive aspergillus infection (IA) often leads to exclusion of patients from future allogeneic hematopoietic stem cell transplant (AHSCT). With the advent of newer, more potent antifungal drugs, IA is better controlled and patients are more likely to be considered for AHSCT. We evaluated the clinical course and outcome of this patient population and propose a strategy to manage these complex cases.Methods: A retrospective chart review was performed on adult patients that received AHSCT from November 2000 through October 2005 to identify cases with preceding IA. Demographic data, underlying disease, probability of IA as assessed by Mycoses Study Group (MSG) criteria, primary therapy of IA, secondary prophylaxis, adverse effects of antifungal agents, graft-versus-host disease (GVHD) status, steroid use, survival and relapse of IA were collected.Results: IA prior to AHSCT was identified in 4.13% (9 of 218) patients (8 proven, 1 probable by MSG criteria) who underwent AHSCT in the 5 years reviewed. Pulmonary IA was documented in 6 and 1 each had sinusitis, otitis externa and localized skin infecion. Underlying diseases were AML (5), and 1 each of MDS, CLL, pre B-ALL, and mantle cell lymphoma. Three underwent surgical resection (lung nodule, ear and sinus disease) and all received primary therapy with a variety of antifungal agents, either sequentially or in combination (4 Amphotericin B lipid complex, 4 Itraconazole [I], 6 Voriconazole [V], 4 Caspofungin [C]). Median duration of primary IA therapy was 150 days (range: 42 – 393). Median duration from diagnosis of IA to AHSCT was 180 days (range: 42 – 870). In all cases IA had completely resolved before AHSCT. Secondary prophylaxis consisted of: V + C for the duration of neutropenia post AHSCT, followed by V in 5 cases. The remainder received single agent V in 2 cases, single agent I in 1 case or multiple agents in 1 case of A. terreus. Secondary prophylaxis was continued indefinitely or until death in all cases. GVHD requiring steroids developed in 7 patients with only 1 IA reactivation and death in a patient with A. terreus at 72 days. Two other non IA deaths occurred; 1 due to multiorgan failure 2 weeks post AHSCT, and 1 due to pulmonary embolism and enteric bleed at 547 days. Median survival was 547 days and median followup of survivors was 625 days (range: 280 – 960) post AHSCT. Probability of survival, post AHSCT, at 100 days was 78% (95%CI: 36% – 94%) and at 2 years was 58% (95%CI: 16% – 85%).Conclusions: The availability of newer, more active antifungal agents has improved the outcome of patients with IA. In our study, a majority of patients with IA prior to AHSCT (8 of 9) did not relapse with a strategy of treating the infection to complete remission before transplant, and utilizing aggressive secondary prophylaxis with a voriconazole-based regimen in most cases (7 of 9). One relapse and subsequent death occurred in a patient with A. terreus, a species typically resistant to Amphotericin B. As also suggested by a recent large study, V appears to be a useful agent for secondary prophylaxis during and after AHSCT, as it covers all species of aspergillus. Combination therapy may be useful during neutropenia in this high risk group. Our data suggests that patients with a history of prior IA can safely undergo AHSCT with a low risk of recurrence of IA. Ideal duration of secondary prophylaxis is unknown. Larger studies are needed to assess the utility of this approach.

Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: a retrospective survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation

AbstractIn this retrospective study, we analyzed the outcomes of 129 patients who underwent an allogeneic hematopoietic stem cell transplantation (allo-HSCT) and had a history of probable or proven invasive aspergillosis (IA), of whom 57 (44%) received a reduced-intensity conditioning (RIC). Overall, 27 patients with IA progressed after the allo-HSCT (cumulative incidence [CumInc] at 2 years, 22%). The variables that increased the 2-year CumInc of IA progression were (1) longer duration of neutropenia after transplantation; (2) advanced status of the underlying disease; and (3) less than 6 weeks from start of systemic anti-Aspergillus therapy and the allo-HSCT. In addition, (4) conventional myeloablative conditioning increased the risk of progression early after transplantation (before day 30) only, while 3 variables increased the risk beyond day 30 were (5) cytomegalovirus disease; (6) bone marrow or cord blood as source of stem cells; and (7) grades II to IV acute graft-versus-host disease (GVHD). A risk model for progression was generated, defined as low (0-1 risk factors, 6% incidence), intermediate (2-3 risk factors, 27% incidence), or high risk (≥ 3 risk factors, 72% incidence [P < .001]). These findings may help in the interpretation and design of future studies on secondary prophylaxis of IA after an allo-HSCT.

Invasive aspergillosis before allogeneic hematopoietic stem cell transplantation: 10-year experience at a single transplant center.

Hematopoietic stem cell transplantation (HCT) in patients with prior or active invasive aspergillosis (IA) is a frequent consideration. We reviewed outcomes of 2319 patients who underwent transplantation between 1992 and 2001 in our institution, among whom 45 patients (1.9%) had a known history of IA before HCT. Posttransplantation IA occurred in 13 of these 45 patients with a pretransplantation history (29%). Nine infections were considered recurrent by anatomic site and timing. Compared with all other patients who received allogeneic HCT during the same period, patients with histories of IA had lower overall survival (56% versus 77%; P =.0001) and higher transplant-related mortality (TRM; 38% versus 21%; P =.0001) 100 days after HCT, associated mainly with IA and other pulmonary complications. Among patients with prior IA, posttransplantation IA occurred more frequently in patients who received <1 month of antifungal therapy before HCT (4/6 versus 6/39; P =.001). The probability of posttransplantation IA and overall survival among patients who received >1 month of antifungal therapy and had resolution of radiographic abnormalities were not different from those of patients without prior IA. Patients with prior IA who received conditioning with total body irradiation (TBI) had higher TRM compared with those who received nonmyeloablative and non-total body irradiation-based regimens (16/31 versus 2/14; P =.024). Thus, the duration of antifungal therapy before transplantation, the resolution of radiographic abnormalities, and conditioning regimens are important variables to consider for minimizing the risk for IA recurrence and TRM after allogeneic HCT.