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Byline: Adrian Plunkett (1), Rachel S. Agbeko (1), KaWah Li (2), Steve E. Humphries (2), Nigel J. Klein (3), Mark J. Peters (1) Keywords: Angiotensin-converting enzyme; Acute respiratory distress syndrome; Child; Genetic polymorphism Abstract: Objective The D allele of the I/D polymorphism in the angiotensin-converting enzyme (ACE) gene has been associated with an increased risk of ARDS in critically ill adults and severity of bronchopulmonary dysplasia in pre-term infants. We hypothesised that the presence of the hypoxia-associated ACE D allele would increase susceptibility to acute hypoxic respiratory failure (AHRF) in a cohort of critically ill children. Design and setting Single-centre prospective observational cohort study. Patients Children under 16 years of age requiring admission to a tertiary general PICU. Measurements and results A total of 216 Caucasian patients were enrolled. Thirty (13.9%) children developed AHRF and 13 were diagnosed with ARDS (6.0%). There was no significant difference in ACE D allele frequency between patient groups with or without AHRF (0.53 vs. 0.54). Conclusions Variation in ACE activity does not influence the development of paediatric AHRF. This may reflect a different pathogenesis from adult ARDS. Author Affiliation: (1) Paediatric Intensive Care Unit, Great Ormond Street Hospital for Children NHS Trust, London, UK (2) Department of Medicine, Centre for Cardiovascular Genetics, University College London, London, UK (3) Infectious Diseases and Microbiology Unit, Institute of Child Health, London, UK Article History: Registration Date: 26/08/2008 Received Date: 20/05/2008 Accepted Date: 20/08/2008 Online Date: 12/09/2008

Byline: Jesus Villar (1,2,3), Carlos Flores (2,4,5), Lina Perez-Mendez (2,6), Nicole Maca-Meyer (4), Elena Espinosa (7), Jesus Blanco (2,8), Ruben Sanguesa (7), Arturo Muriel (8), Paula Tejera (4), Mercedes Muros (2,9), Arthur S. Slutsky (3,10) Keywords: Association study; Genetic susceptibility; Genetic variation; Human sepsis Abstract: Objective The insertion/deletion (I/D) of a 289 base pair Alu repeat sequence polymorphism in the angiotensin-converting enzyme gene (ACE) has been shown to predict susceptibility and outcome in the acute respiratory distress syndrome (ARDS). We hypothesized that the I/D polymorphism also confers susceptibility to sepsis and is a predisposing factor for morbidity and mortality of patients with severe sepsis. Design and setting Case-control study including 212 consecutive patients fulfilling criteria for severe sepsis admitted to a Spanish network of postsurgical and critical care units, and 364 population-based controls. Susceptibility to severe sepsis was evaluated as primary outcome mortality in severe sepsis, susceptibility to sepsis-induced ARDS, and mortality in sepsis-induced ARDS were examined as secondary outcomes. An additive model of inheritance in which patients were classified into three genotype groups (II, ID, and DD) was used for association testing. Measurements and results Genotype and allele frequencies of I/D were distributed similarly in all septic, ARDS, and non-ARDS patients and in population-based controls. ACE I/D polymorphism was not associated with severe sepsis susceptibility or mortality. The ACE I/D polymorphism was associated neither with sepsis-induced ARDS susceptibility (pa-=a-0.895) or mortality (pa-=a-0.950). These results remained nonsignificant when adjusted for other covariates using multiple logistic regression analysis or Kaplan--Meier estimates of 28-day survival. Conclusions Our data do not support an association of the ACE gene I/D polymorphism with susceptibility or mortality in severe sepsis or with sepsis-induced ARDS in Spanish patients. Author Affiliation: (1) Multidisciplinary Organ Dysfunction Evaluation Research Network (MODERN), Research Unit, Hospital Universitario Dr. Negrin, Barranco de la Ballena, s/n - 4th floor, south wing, 35010, Las Palmas de Gran Canaria, Canary Islands, Spain (2) Instituto de Salud Carlos III, CIBER de Enfermedades Respiratorias, Madrid, Spain (3) Keenan Research Center, St. Michael's Hospital, Toronto, Ontario, Canada (4) Division of Human Genetics, Research Unit, Hospital Universitario NS de Candelaria, Tenerife, Spain (5) Department of Medicine, Division of Pulmonary and Critical Care, University of Chicago, Chicago, Ill, USA (6) Division of Clinical and Genetic Epidemiology, Research Unit, Hospital Universitario NS de Candelaria, Tenerife, Spain (7) Department of Anesthesia, Hospital Universitario NS de Candelaria, Tenerife, Spain (8) Intensive Care Unit, Hospital Universitario Rio Hortega, Valladolid, Spain (9) Department of Clinical Biochemistry, Hospital Universitario NS de Candelaria, Tenerife, Spain (10) Department of Medicine, Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada Article History: Registration Date: 06/11/2007 Received Date: 28/05/2007 Accepted Date: 17/09/2007 Online Date: 05/12/2007 Article note: This research was supported by grants from FUNCIS (53/04) and the Ministerio de Educacion y Ciencia, Spain (SAF2004-06833). J.V. is the principal investigator in both grants. The authors named above wrote this article on behalf of the GRECIA and GEN-SEP groups. The members of the GRECIA and GEN-SEP groups are listed under Acknowledgements at the end of the article. J. Villar, C. Flores, and L. Perez-Mendez contributed equally to this work. Electronic supplementary material The online version of this article (doi: 10.1007/s00134-007-0937-z) contains supplementary material, which is available to authorized users.

Byline: Jesus Villar (1,3), Carlos Flores (2,3) Keywords: Genetic association studies; Severe sepsis Author Affiliation: (1) Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrin, Barranco de la Ballena, s/n, 35010, Las Palmas de Gran Canaria, Canary Islands, Spain (2) Research Unit, Hospital Universitario NS de Candelaria, Tenerife, Spain (3) CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain Article History: Registration Date: 30/04/2008 Accepted Date: 26/04/2008 Online Date: 30/05/2008 Article note: This reply refers to the comment available at doi: 10.1007/s00134-008-1143-3.