Antifungal Therapy For Invasive Aspergillosis Research Articles

Quandaries of deciding when to change first-line therapy in invasive pulmonary aspergillosis.

We read the excellent viewpoint by Slavin et al. (J Antimicrob Chemother 2022; 77: 16-23) that draws upon the experience of an advisory board of notable experts to comprehensively address many of the clinical factors that drive the need for changes in antifungal therapy for invasive aspergillosis (IA). As noted by the authors, there remains a paucity of quality data to support many of the decisions faced by clinicians managing patients with IA. However, we would like to highlight several other important issues, not fully addressed in that viewpoint, that play an important role in deciding when to change antifungal therapy for IA.

Combination of invasive aspergillosis and mucormycosis in children: a case report and the results of a multicenter study

Objective. To study risk factors, etiology, clinical signs and treatment outcomes of invasive aspergillosis (IA) and mucormycosis combination (IAM) in children. Materials and Methods. A retrospective review of Saint-Petersburg register (1998–2021) of patients with IA was done and children with IAM were included. EORTC/MSGERG 2019 criteria were used for diagnosing and treatment results evaluation of invasive mycosis. We presented a clinical case of IAM in a child with acute lymphoblastic leukemia relapse. Results. A total of 12 children with IAM were included. They accounted 8% of all pediatric patients with invasive aspergillosis (n = 152). IAM was diagnosed in children with hematological malignancies and solid tumors from 4 to 16 years (median age – 11.5 years), mostly in girls (83%). Main risk factors of IAM were prolonged lymphopenia (75%, median 22 days) and neutropenia (67%, median 30 days) due to chemotherapy, systemic corticosteroids and/or immunosuppressive therapy, as well as HSCT. The predominant etiological agents of IA were Aspergillus niger (33%), A. nidulans (33%) and A. fumigatus (17%), of mucormycosis – Lichtheimia corymbifera (50%) and Rhizomucor spp. (50%). Based on EORTC/MSGERG 2019 criteria, «proven» mucormycosis was diagnosed in 83% of patients, «probable» – in 17%. «Probable» IA was found in 100% of patients. The most common clinical sites of IAM were the lungs (75%) and paranasal sinuses (43%), multifocal involvement was revealed in 33% of patients. Mucormycosis developed during antifungal therapy of IA in 83% of patients. Antifungal therapy of mucormycosis received 75% of patients (amphotericin B lipid complex – 89%, posaconazole – 78%, caspofungin – 33%), combined antifungal therapy – 33%, surgery – 50%; combination of surgical and antifungal treatment was used in 42% of patients. The overall 12-week survival was 77.8%. The use of combined surgical and antifungal treatment significantly improved the survival of children with IAM (p = 0.023). Conclusions. Mucormycosis was diagnosed in 8% of children with IA. IAM developed mostly in patients with hematological malignancies (83%), prolonged lymphopenia (75%) and neutropenia (67%) against the background of chemotherapy, systemic corticosteroids and/or immunosuppressive therapy, as well as HSCT. In 83% of patients mucormycosis was diagnosed during antifungal therapy for IA. The development of IAM increased overall 12-week mortality (50%). The combination of antifungal therapy with surgical treatment significantly improved prognosis of IAM (p = 0.023).

Correction: Combination Antifungal Therapy for Invasive Aspergillosis

Correction: Combination Antifungal Therapy for Invasive Aspergillosis

Treating invasive aspergillosis in patients with hematologic malignancy: diagnostic-driven approach versus empiric therapies

BackgroundEarly antifungal therapy for invasive aspergillosis (IA) has been associated with improved outcome. Traditionally, of empiric antifungal therapy has been used for clinically suspected IA. We compared outcomes of patients with hematologic malignancy and IA who were treated with voriconazole using the diagnostic driven DDA (DDA-Vori) that includes galactomannan testing vs. empiric therapy with a non-voriconazole-containing regimen (EMP-non-Vori) or empiric therapy with voriconazole (EMP-Vori).MethodsWe retrospectively reviewed the medical records of 342 hematologic malignancy patients diagnosed with proven, or probable IA between July 1993 and February 2016 at our medical center who received at least 7 days of DDA-Vori, EMP-Vori, or EMP-non-Vori. Outcome assessment included response to therapy (clinical and radiographic), all-cause mortality, and IA-attributable mortality.ResultsBy multivariate analysis, factors predictive of a favorable response included localized/sinus IA vs. disseminated/pulmonary IA (p < 0.0001), not receiving white blood cell transfusion (p < 0.01), and DDA-Vori vs. EMP-non-Vori (p < 0.0001). In contrast, predictors of mortality within 6 weeks of initiating IA therapy included disseminated/pulmonary infection vs. localized/sinus IA (p < 0.01), not undergoing stem cell transplantation within 1 year before IA (p = 0.01), and EMP-non-Vori vs. DDA-Vori (p < 0.001).ConclusionsDDA-Vori was associated with better outcome (response and survival) compared with EMP-non-Vori and with equivalent outcome to EMP-Vori in hematologic malignancy patients. These outcomes associated with the implementation of DDA could lead to a reduction in the unnecessary costs and adverse events associated with the widespread use of empiric therapy.

How We Approach Combination Antifungal Therapy for Invasive Aspergillosis and Mucormycosis in Transplant Recipients.

Invasive aspergillosis and mucormycosis are life-threatening infections in solid organ and hematopoietic cell transplant recipients. Despite medical advancements in the care of these patients and the availability of new mold-active drugs, the outcomes remain suboptimal. Therefore, there has been increased interest in the use of combination antifungal therapy, in hopes that leveraging the possible in vitro synergy of these agents will improve the prognosis of invasive mold disease. However, there has been a large disconnect between the results of experimental and clinical investigations, as clinical studies have not unequivocally demonstrated the superiority of combination therapy over monotherapy. This is particularly true for mucormycosis, where the rarity of the condition has made it nearly impossible to prospectively study novel therapeutic strategies. We review the current standard of antifungal therapy and the preclinical and clinical data addressing the merit of combination therapy, and we provide guidance to optimize the management of these mycoses.

Combination Antifungal Therapy for Invasive Aspergillosis Among Patients with Hematopoietic Cell Transplantation and Positive Galactomannan

Combination Antifungal Therapy for Invasive Aspergillosis Among Patients with Hematopoietic Cell Transplantation and Positive Galactomannan

Combination Antifungal Therapy for Invasive Aspergillosis Revisited.

Invasive aspergillosis (IA) causes significant morbidity and mortality among immunocompromised hosts. Combination therapy with mold-active triazoles and echinocandins has been used with the hope of improving outcomes over monotherapy, especially in the setting of refractory disease. Herein, I update our prior systematic review and meta-analysis on combination therapy for salvage IA in the context of the recently published randomized clinical trial of combination therapy for primary IA. Clinicians should consider combination antifungals for IA in refractory disease despite immune reconstitution when there are concerns for resistance or pharmacokinetic variability.

Ibrutinib—a new standard treatment for relapsed mantle cell lymphoma?

728 www.thelancet.com Vol 387 February 20, 2016 In The Lancet, Martin Dreyling and colleagues present the results of a large, international, randomised phase 3 trial comparing the only two drugs approved for previously treated mantle cell lymphoma in Europe: temsirolimus and ibrutinib. Among 280 patients, those randomly assigned to daily oral ibrutinib 560 mg (n=139) showed a signifi cant improvement in progression-free survival, the trial’s primary endpoint, compared with patients (n=141) assigned to daily intravenous temsirolimus 175 mg (14·6 months vs 6·2 months; hazard ratio 0·43 [95% CI 0·32–0·58]). Ibrutinib was also better tolerated than temsirolimus, with fewer study discontinuations because of adverse events. Therefore, the results from this trial clearly establish ibrutinib as a new standard for treatment of relapsed mantle cell lymphoma. Representing only 5% of all non-Hodgkin lymphomas, mantle cell lymphoma is not the most epidemiologically relevant disease. Its natural history and poor prognosis, however, have garnered substantial attention. After an initial chemotherapy-induced remission of varying duration, patients with mantle cell lymphoma generally undergo a series of subsequent therapies, with successes measured in months as the disease and treatment-related side-eff ects slowly take their toll. A constant unmet need, mantle cell lymphoma has been a model for the accelerated development of novel targeted drugs. The US Food and Drug Administration (FDA) approved bortezomib and lenalidomide for patients with mantle cell lymphoma who had received previous treatments, on the basis of results from phase 2 trials that showed an overall response rate of about 30% and equally high occurrences of study discontinuation because of adverse events. The development of temsirolimus was less straightforward. Results from two clinical trials showed that temsirolimus possessed substantial activity against mantle cell lymphoma (with overall response rates of about 40%), but also a therapeutic index that favoured lower doses. An international phase 3 trial compared two doses of temsirolimus against investigator’s choice of treatment (a variety of single chemotherapy drugs), and showed that 22% of patients receiving higher-dose temsirolimus (175 mg per week for 3 weeks followed by 75 mg per week thereafter) achieved an objective response, with a median progression-free survival of 4·8 months, compared with investigator’s choice (2% and 1·9 months, respectively). 22% of patients receiving the higher dose of temsirolimus discontinued treatment because of an adverse event, compared with 11% of patients receiving the investigator’s choice who discontinued for the same reason. These results were suffi cient for approval of temsirolimus for the treatment of mantle cell lymphoma by the European Medicines Agency (EMA) in 2008, but not by the FDA. In 2009, the fi rst-in-class, oral, small molecule inhibitor of Bruton’s tyrosine kinase, ibrutinib, entered clinical development. On the basis of promising results in seven of nine patients with mantle cell lymphoma treated in a phase 1 trial, a non-pivotal, phase 2 trial (PCYC-1104) was designed with the intention of better Ibrutinib—a new standard treatment for relapsed mantle cell lymphoma? 4 Marr KA, Schlamm HT, Herbrecht R, et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med 2015; 162: 81–89. 5 Miceli MH, Kauff man CA. Isavuconazole: a new broad-spectrum triazole antifungal agent. Clin Infect Dis 2015; 61: 1558–65. 6 Teusink A, Vinks AA, Zhang K, et al. Genotype-directed dosing leads to optimized voriconazole levels in pediatric patients receiving hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2015; published oline Nov 23. DOI:10.1016/j.bbmt.2015.11.011. 7 Lutsar I, Hodges MR, Tomaszewski K, Troke PF, Wood ND. Safety of voriconazole and dose individualization. Clin Infect Dis 2003; 36: 1087–88. 8 Ashbee HR, Barnes RA, Johnson EM, Richardson MD, Gorton R, Hope WW. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother 2014; 69: 1162–76. 9 Ananda-Rajah MR, Cheng A, Morrissey CO, et al. Attributable hospital cost and antifungal treatment of invasive fungal diseases in high-risk hematology patients: an economic modeling approach. Antimicrob Agents Chemother 2011; 55: 1953–60. 10 Munoz P, Valerio M, Vena A, Bouza E. Antifungal stewardship in daily practice and health economic implications. Mycoses 2015; 58 (suppl 2): 14–25. 11 Ananda-Rajah MR, Slavin MA, Thursky KT. The case for antifungal stewardship. Curr Opin Infect Dis 2012; 25: 107–15. 12 Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347: 408–15.

Combination antifungal therapy for invasive aspergillosis: a randomized trial.

Invasive aspergillosis (IA) is associated with poor outcomes in patients with hematologic malignancies (HMs) and hematopoietic cell transplantation (HCT). Small studies suggest a role for combination antifungal therapy. To assess the safety and efficacy of voriconazole and anidulafungin compared with voriconazole monotherapy for treatment of IA. Randomized, double-blind, placebo-controlled multicenter trial. (ClinicalTrials.gov: NCT00531479). 93 international sites. 454 patients with HM or HCT and suspected or documented IA were randomly assigned to treatment with voriconazole and anidulafungin or placebo. Primary analysis was done in the modified intention-to-treat population of 277 patients in whom IA was confirmed. The primary outcome was 6-week mortality; secondary outcomes included 12-week mortality, mortality in major subgroups, and safety measures. Mortality rates at 6 weeks were 19.3% (26 of 135) for combination therapy and 27.5% (39 of 142) for monotherapy (difference, -8.2 percentage points [95% CI, -19.0 to 1.5]; P = 0.087). Secondary mortality outcomes favored combination therapy. Multivariable regression analysis suggested that maximum galactomannan value, Karnofsky score, and baseline platelet count had prognostic significance. Most patients (218 of 277 [78.7%]) had IA diagnosis established by radiographic findings and maximum galactomannan positivity. In a post hoc analysis of this dominant subgroup, 6-week mortality was lower in combination therapy than monotherapy (15.7% [17 of 108] vs. 27.3% [30 of 110]; difference, -11.5 percentage points [CI, -22.7 to -0.4]; P= 0.037). Safety measures, including hepatotoxicity, were not different. Mortality at 6 weeks was higher than expected, and the difference in mortality was lower than expected, which reduced power to detect a treatment effect. Enrollment was restricted to patients with HM or HCT, which limited generalizability. Compared with voriconazole monotherapy, combination therapy with anidulafungin led to higher survival in subgroups of patients with IA. Limitations in power preclude definitive conclusions about superiority. Pfizer.

How to manage aspergillosis in non-neutropenic intensive care unit patients.

Invasive aspergillosis has been mainly reported among immunocompromised patients during prolonged periods of neutropenia. Recently, however, non-neutropenic patients in the ICU population have shown an increasing risk profile for aspergillosis. Associations with chronic obstructive pulmonary disease and corticosteroid therapy have been frequently documented in this cohort. Difficulties in achieving a timely diagnosis of aspergillosis in non-neutropenic patients is related to the non-specificity of symptoms and to lower yields with microbiological tests compared to neutropenic patients. Since high mortality rates are typical of invasive aspergillosis in critically ill patients, a high level of suspicion and prompt initiation of adequate antifungal treatment are mandatory. Epidemiology, risk factors, diagnostic algorithms, and different approaches in antifungal therapy for invasive aspergillosis in non-neutropenic patients are reviewed.

Usefulness of the Serum Galactomannan Assay for Early Response Assessment and Treatment Stratifications of Invasive Aspergillosis

The galactomannan (GM) Enzyme Immunoassay (EIA) is an upcoming tool not only for diagnosis but also monitoring of invasive Aspergillosis (IA). Various studies were performed over the last years to apply such a promising instrument correctly. New findings show the potential of this test to segregate affected patients into treatment responders and non-responders at a time point as early as 7–14 days after initiation of antifungal therapy. Current data suggest that serial GM testing in patients receiving antifungal therapy for IA is essential as GMI kinetics may offer the clinician a substantial support in decision making concerning early therapeutic stratifications. The correct interpretation of GM EIA results with respect to the individual context of the patient is, however, absolutely necessary. The following review shall give an overview about the GM-EIA as a tool for IA monitoring and therapy stratification.

Pulmonary aspergillosis: clinical presentation, diagnostic tests, management and complications

When functioning properly, the immune system recognizes inhaled fungi and controls their growth, while avoiding injurious inflammation and allergy. 'Aspergillosis' represents a spectrum of clinical diseases resulting from impaired or excessive immune responses. Invasive aspergillosis is principally disease of severely immunocompromised patients, whereas allergic forms of aspergillosis result from an excessive inflammatory response to hyphae colonizing the sinopulmonary tract. We will review insights gained in host defense against Aspergillus species and the immunopathogenesis of Aspergillus-related diseases as well as important advances made in fungal diagnostics and antifungal therapy. Important advances have been made in diagnosis of invasive aspergillosis and in antifungal agents. Voriconazole was superior to amphotericin B deoxycholate as primary therapy for invasive aspergillosis. There is significant interest in combination antifungal therapy for invasive aspergillosis. Fungal genomics offers a powerful opportunity to gain knowledge about fungal virulence factors that can be targets for drug development. In addition, new insights have been gained regarding host defense against Aspergillus species that may be exploited therapeutically. We have gained substantial knowledge regarding how the immune system recognizes inhaled fungi and calibrates the inflammatory response. There has also been substantial progress in tools to diagnose aspergillosis and in antifungal therapeutics. Future progress will likely involve the development of more refined diagnostic tools, new classes of antifungal agents, and greater knowledge of pathogen and host factors that predispose to aspergillosis.

Current Strategies in Antifungal Therapy for Invasive Aspergillosis in Immunocompromised Patients Following Hematopoietic Stem Cell Transplantation

Current Strategies in Antifungal Therapy for Invasive Aspergillosis in Immunocompromised Patients Following Hematopoietic Stem Cell Transplantation

Invasive Aspergillosis in Solid Organ Transplant Recipients

This chapter discusses the current status and evolving trends in the epidemiology, risk factors, diagnostic laboratory assays, and the approach to antifungal prophylaxis and treatment of invasive aspergillosis in Solid Organ Transplant (SOT) recipients. Most invasive fungal infections in these high-risk patients occur within the first month posttransplant; the median time to onset of invasive aspergillosis after renal replacement therapy and retransplantation was 13 and 28 days, respectively, in one study. Other factors associated with invasive aspergillosis in liver transplant recipients include transplantation for fulminate hepatic failure, cytomegalovirus (CMV) infection, and prolonged intensive care unit stay. A retrospective survey documented invasive pulmonary aspergillosis in 7.5% (19/251) of lung transplant recipients, of whom 47% (9/19) had disseminated aspergillosis. In a survey of antifungal prophylactic strategies in lung transplant units in the United States, aerosolized amphotericin B was the most frequently employed antifungal prophylactic agent. In order of preference, the prophylactic agents used in lung transplant centers in this study were inhaled amphotericin B (61%), itraconazole (46%), parenteral amphotericin formulations (25%), and fluconazole (21%); many centers used more than one agent. Preemptive therapy, where antifungal prophylaxis is directed towards lung transplant recipients colonized with Aspergillus spp. immediately before or within 6 to 9 months after transplantation, is another approach to the prevention of invasive aspergillosis in lung transplant recipients.

Combination antifungal therapy for invasive aspergillosis: can it replace high-risk surgery at the skull base?

Combination antifungal therapy for invasive aspergillosis: can it replace high-risk surgery at the skull base?

Combination antifungal therapy for invasive aspergillosis: can it replace high-risk surgery at the skull base?

Objective The increasing volume of literature on Aspergillus sinus infection is confusing because different authors stress different aspects of the disease. It is generally accepted that standard therapy consists of surgical debridement and medication with systemic amphotericin B. Patients who fail the standard therapy or those who cannot tolerate amphotericin B pose a dilemma. This study attempted to address the issues concerning combination therapy in invasive aspergillosis. Materials and methods We conducted a prospective randomized study on 6 apparently immunocompetent patients with invasive aspergillosis complicated by orbital and intracranial spread. All the patients were treated with a combination of amphotericin B (2.5 g) and itraconazole (6 months). They were monitored clinically and radiologically before, during, and after their combined antifungal therapy management. Results Among the 6 immunocompetent patients, orbital involvement was seen in 5, skull base erosion with intracranial extension was seen in 2, and infratemporal fossa extension was seen in 2. After completion of treatment with 1.5 g of amphotericin, the paranasal sinus part of the lesion disappeared. However, there was residual lesion in the intracranial part that completely disappeared only after treatment with 2.5 g of amphotericin and 6 months of itraconazole therapy. Conclusions Invasive aspergillosis has been increasingly reported among immunocompetent patients. No single surgical or medical maneuver, including orbital exenteration, guarantees cure. The combination of amphotericin B and itraconazole for skull base aspergillosis represents a real step forward in the treatment of invasive aspergillosis.

Is combination antifungal therapy for invasive aspergillosis a necessity in hematopoietic stem-cell transplant recipients?

The use of combination antifungal therapy in hematopoietic stem-cell transplantation patients is controversial and limited by a paucity of controlled data. The recent literature is reviewed and the relative arguments for and against combination antifungal therapy are outlined with summative recommendations to assist practitioners in decision-making. There is an abundance of in-vitro and murine in-vivo combination antifungal literature, whereas clinical data are less abundant and controlled. Of the published case series there is a suggested benefit to combination therapy over monotherapy, although there are limitations to the available literature. Other issues in the combination debate that are addressed include the following: improved response rates and a survival advantage have been demonstrated in recent monotherapy studies; response rates in most published combination therapy studies do not suggest large gains over monotherapy; the lack of sustained survival advantage to combination therapy studies; and finally the consideration of host defenses in treatment responses. Based on available data, combination therapy is not warranted at the initial diagnosis of invasive aspergillosis. Randomized, controlled trials with rigorous study design are needed.

Combination Antifungal Therapy in Organ Transplant Recipients

We thank Dr. Bal for his interest in our report and for his comments. Somewhat lower overall mortality rates in lung transplant recipients with invasive aspergillosis in the literature are attributable largely to cases with tracheobronchitis or bronchial anastomotic infections, a locally invasive form of aspergillosis (1). Mortality in the lung transplant recipients with invasive pulmonary aspergillosis is similar to that in other types of organ transplant recipients (1). In our study, 11/13 lung transplant recipients in the combination therapy group had invasive pulmonary aspergillosis, and only two had anastomotic infections (biopsy proven). A beneficial effect of combination therapy in the overall study population could not be attributed to a marginally higher number (P=0.21) of lung transplant recipients in this group (2). Indeed, most of the benefit of combination therapy appeared to be in non-lung transplant recipients. As shown in Table 3 (2), combination therapy was less beneficial in lung transplant recipients and was most beneficial in renal transplant recipients. Lung transplantation when added to the multivariate model in Table 2 (2) showed no correlation with mortality (hazard ratio 1.25; 95% CI: 0.53–2.97, P=0.60). The control group in the study by Herbrecht and colleagues received amphotericin B deoxycholate, and not a lipid formulation of amphotericin B (3). Indeed, there has been much speculation if the results of this study would have been different had a lipid formulation of amphotericin B been used instead of amphotericin B deoxycholate (4). At the time that our study was conceived and planned, lipid formulations of amphotericin B were the standard antifungal therapy for invasive aspergillosis in organ transplant recipients. With regards to mechanical ventilation, combination therapy appeared to be of greater benefit than lipid amphotericin B in ventilated patients. Mortality rate at 90 days was 46% (6/13) in mechanically ventilated patients in the combination therapy group and 74% (17/23) in those in the lipid amphotericin B group (hazard ratio 0.48; 95% CI: 0.20–1.15, P=0.10). Multivariate analysis showed that combination therapy was associated with improved survival in mechanically ventilated patients, but not in nonventilated patients (Table 1). Finally, we concur with the author and have explicitly noted in our paper the need for further studies in this important area.TABLE 1: Effect of combination therapy on 90-day mortality stratified by mechanical ventilationNina Singh Marilyn M. Wagener VA Medical Center and University of Pittsburgh Pittsburgh, PA

Combination antifungal therapy for invasive aspergillosis - Is it indicated?

The optimal therapy for invasive aspergillosis (IA) is unknown, and there is little agreement on the exact antifungal management of IA. The previously stagnant landscape of antifungal choices for IA is rapidly changing with newer antifungals and newer targets. While amphotericin B had historically been the preferred therapy, recent studies support voriconazole as primary therapy or caspofungin as salvage therapy. However, in vitro studies, animal models, and limited clinical reports suggest that combination antifungal therapy might offer improved outcome. While treatment of malignancy or HIV has advanced after years of clinical trials investigating optimal combinations, therapy for IA is comparatively decades behind. Until very recently, combination antifungal therapy for IA was of little consequence since there were a limited number of possible permutations available. There have been a great deal of new data published exploring the possibilities of combination therapy, but clinicians need to be aware of the potential advantages and disadvantages of combination antifungal therapy for IA as well as the difficulties in interpreting the available data.

Combination Antifungal Therapy for Invasive Aspergillosis: Utilizing New Targeting Strategies

The optimal therapy for invasive aspergillosis (IA) is unknown, and there is little agreement on the exact antifungal management of IA. The previously stagnant landscape of antifungal choices for IA is rapidly changing with newer antifungals and newer targets. While amphotericin B has historically been the preferred therapy, recent studies support voriconazole as primary therapy or caspofungin as salvage therapy. However, even these newer therapies have only elevated clinical response rates to approximately 50%. Recent in vitro studies, animal models, and limited clinical reports suggest that combination antifungal therapy utilizing novel targeting strategies might offer improved outcome. Until very recently, combination antifungal therapy for IA was of little consequence since there were a limited number of possible permutations available. There has been a great deal of new data published exploring the possibilities of combination therapy, but clinicians need to be aware of the potential advantages and disadvantages of combination antifungal therapy for IA.