Causes of Death in a Contemporary Cohort of Patients with Invasive Aspergillosis

March Causes of Death in a Contemporary Cohort of Patients with Invasive Aspergillosis Data Availability Statement: All relevant data are within the paper. 0 1 Carolina Garcia-Vidal 0 1 Maddalena Peghin 0 1 Carlos Cervera 0 1 Carlota Gudiol 0 1 Isabel Ruiz-Camps 0 1 Asuncin Moreno 0 1 Cristina Royo-Cebrecos 0 1 Eva Rosell 0 1 Jordi Puig de la Bellacasa 0 1 Josefina Ayats 0 1 Jordi Carratal 0 1 0 1 Department of Infectious Diseases, Hospital Universitari de Bellvitge, IDIBELL (Institut d Investigacio Biomedica de Bellvitge), Universitat de Barcelona , Barcelona, Spain, 2 REIPI (Spanish Network for Research in Infectious Diseases), Barcelona , Spain , 3 Hospital Universitari de la Vall d'Hebron , Barcelona , Spain , 4 Hospital Clinic i Provincial de Barcelona , Barcelona , Spain 1 Academic Editor: David N Fredricks, Fred Hutchinson Cancer Center , UNITED STATES Information regarding the processes leading to death in patients with invasive aspergillosis (IA) is lacking. We sought to determine the causes of death in these patients, the role that IA played in the cause, and the timing of death. The factors associated with IA-related mortality are also analyzed. We conducted a multicenter study (2008-2011) of cases of proven and probable IA. The causes of death and whether mortality was judged to be IA-related or IAunrelated were determined by consensus using a six-member review panel. A multivariate analysis was performed to determine risk factors for IA-related death. Of 152 patients with IA, 92 (60.5%) died. Mortality was judged to be IA-related in 62 cases and IA-unrelated in 30. The most common cause of IA-related death was respiratory failure (50/62 patients), caused primarily by Aspergillus infection, although also by concomitant infections or severe comorbidities. Progression of underlying disease and bacteremic shock were the most frequent causes of IA-unrelated death. IA-related mortality accounted for 98% and 87% of deaths within the first 14 and 21 days, respectively. Liver disease (HR 4.54; 95% CI, 1.6912.23) was independently associated with IA-related mortality, whereas voriconazole treatment was associated with reduced risk of death (HR 0.43; 95% CI, 0.20-0.93). In conclusion, better management of lung injury after IA diagnosis is the main challenge for physicians to improve IA outcomes. There are significant differences in causes and timing between IA-related and IA-unrelated mortality and these should be considered in future research to assess the quality of IA care. - Funding: This study was supported by research grants from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III [FIS 10/01318], ESCMID Research grant 2013, and Ministerio de Ciencia e Innovacin, Instituto de Salud Carlos III co-financed by the European Development Regional Fund A way to achieve Europe ERDF, Spanish Network for the Research in Infectious Diseases [REIPI RD06/0008]. Dr Garcia-Vidal is the recipient of a Juan de la Cierva research grant from the Instituto de Salud Carlos III, Introduction Invasive aspergillosis (IA) is a leading cause of infection-related death in immunocompromised patients [14]. Recent data suggest that the outcomes of this infection appear to be improving compared with observations in the 1990s, this being due to advances in diagnosis and the introduction of new antifungal agents [58]. Competing Interests: The authors have declared that no competing interests exist. However, knowledge regarding the cause of death in patients with IA remains scarce for a number of reasons. First, patients with IA are complex hosts with severe underlying diseases, aggressive treatments, coexisting infections, and/or treatment complications. Second, studies focusing specifically on the processes leading to death in these patients are lacking. Third, a multidisciplinary approach involving a large number of physicians is common in the management of these patients, and the final cause of death reported on the death certificate may depend on the experience of the signing physician. And fourth, there is no clear consensus about how to define the cause of a patients death or the role that IA may have played in this event. This knowledge gap limits our understanding of optimal treatment strategies. It is not clear, therefore, whether IA-related mortality is caused by factors that could be modifiable through medical intervention. Previous studies of IA prognosis have focused mainly on overall mortality, and they have assessed risk factors for all-cause mortality [7]. Moreover, definitions of IA-related mortality are vague [5, 6, 8]. A further aspect requiring elucidation is whether causes of death and factors associated with mortality within the first few days differ from those associated with mortality occurring later. The present study sought 1) to identify the immediate causes of death in a contemporary cohort of hospitalized patients with IA, 2) to determine the role that IA played in the cause of death, and 3) to analyze the timing of death and risk factors associated with IA-related mortality in this cohort of patients. Materials and Methods Setting, patients, and study design We conducted a retrospective multicenter study of all adults diagnosed with IA between 1 January 2008 and 31 December 2011 at three tertiary teaching hospitals in Barcelona, Spain. Patients who developed IA were identified by review of clinical records, of microbiology and pathology records, and of the diagnostic codes recorded on hospital discharge. The following information was carefully collected from medical records: demographic characteristics, underlying disease, use of immunosuppressive treatment, neutropenia, clinical features, diagnostic tools, infecting Aspergillus species, antifungal and adjunctive treatment, and outcomes. Informed consent was waived by the Clinical Research Ethics Committee because no intervention was involved and no patient identifying information was included. The study was approved by the Ethical Committee of the Hospital Universitari de Bellvitge. We included only patients with proven and probable IA according to the definitions published by the European Organization for Research and Treatment of Cancer/National Institute of Allergy and Infectious Diseases Mycosis Study Group (EORTC/MSG) [9]. Neutropenia was defined as an absolute neutrophil count of <500/mm3. Disseminated IA was defined as evidence of infection in at least two noncontiguous sites or isolated CNS infection. The day of IA diagnosis was the day on which the first positive test was performed. For patients whose diagnosis was obtained from postmortem examination, the day of death was considered to be the day of diagnosis. Assessment of mortality and the cause of death Mortality was assessed at 90 days from day of diagnosis (overall mortality). Cause of death and the role of IA in causing death were reviewed by members of clinical review panel. This panel was composed by 6 investigators. (...truncated)