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Sepsis endotypes and phenotypes : biomarkers and clinical phenotypes upon ICU admission : a systematic review
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Resumo(s)
A sépsis, definida como uma resposta desregulada por parte do hospedeiro face a uma infeção, é uma das principais causas de morbimortalidade a nível mundial. Apesar de grandes avanços na compreensão dos mecanismos fisiopatológicos que lhe estão subjacentes, a sua natureza complexa atrasa o desenvolvimento de tratamentos personalizados, pelo que a modulação dirigida de vias alvo ainda não é uma prática clínica corrente. Os biomarcadores são ferramentas importantes nesta área, pois permitem identificar subgrupos de doentes em maior risco de desfechos desfavoráveis. Definir estes subgrupos através de características clínicas, bioquímicas, celulares, moleculares, genómicas ou transcriptómicas pode ajudar a selecionar doentes que beneficiem de intervenções dirigidas. Esta revisão sistemática tem como objetivo reunir informação relativa a fenótipos na sépsis potencialmente reconhecíveis nas primeiras 24 horas após admissão na Unidade de Cuidados Intensivos (UCI). Neste sentido, procedemos a uma pesquisa sistemática da PubMed/MEDLINE, tendo obtido 855 artigos, 39 dos quais foram incluídos na nossa revisão. Vários foram os biomarcadores investigados, o que apenas reiterou o desafio que é esta busca por um modelo preditivo consensual que sirva de base para o desenho de ensaios clínicos robustos que avaliem a segurança, eficácia e tolerabilidade de terapêuticas instituídas de acordo com biomarcadores. Sublinhamos sobretudo biomarcadores já conhecidos. Apesar de grande parte apresentar um valor preditivo modesto, salientamos o papel da adrenomedulina (ADM). O estudo AdrenOSS-1 concluiu que níveis séricos elevados de ADM se associavam a piores desfechos a curto-prazo. Esta constatação permitiu desenhar o estudo AdrenOSS- 2, que investigou o impacto terapêutico da administração de Adrecizumab em doentes com choque séptico e níveis elevados de ADM à admissão na UCI. Este tipo de ensaios clínicos são o futuro e só serão possíveis se reunirmos esforços no sentido de desenvolver, calibrar e validar modelos preditivos que incluam biomarcadores que reflitam vias potencialmente passíveis de modulação terapêutica.
Sepsis, defined as a dysregulated host response against infection, is a leading cause of mortality and morbidity worldwide. Despite a growing understanding of its pathobiology, the intricate nature of sepsis slows progress in designing tailored treatments, and thus targeted modulation of key pathways is still far from standard practice. Biomarkers have emerged as important tools in this field since they provide an objective framework for the identification of subgroups of septic patients at higher risk of unfavorable outcomes. Recognizing these subgroups according to unique clinical, biochemical, cellular, molecular, genomic, and transcriptomic profiles may help select patients who could benefit from tailored interventions. This systematic review aimed to compile current information about sepsis phenotypes potentially recognizable within 24 hours of admission in the Intensive Care Unit (ICU). A systematic search of the literature was conducted on PubMed/MEDLINE, yielding 855 results, of which 39 were finally included. Overall, a milieu of biomarkers was investigated, thereby reaffirming the challenges faced in the quest for consensual predictive models that can serve as a framework for designing robust clinical trials aiming to investigate the safety, efficacy, and tolerability of biomarker-guided therapies. We highlight previously described noteworthy biomarkers. Despite the fact that most studied biomarkers displayed frail predictive value, adrenomedullin (ADM) stood out. The AdrenOSS-1 study established that initial high circulating levels of ADM related to unfavorable short-term outcomes. This observation served as the backbone for the design of the AdrenOSS-2 study, which ventured to investigate the therapeutic impact of Adrecizumab in septic shock patients with high bio-ADM levels upon ICU admission. The road ahead calls for more of these biomarker-guided clinical trials. This can only be made possible if future efforts focus on deriving, calibrating, and validating predictive models that include biomarkers that serve as surrogates for pathways known to be potentially amenable to targeted modulation.
Sepsis, defined as a dysregulated host response against infection, is a leading cause of mortality and morbidity worldwide. Despite a growing understanding of its pathobiology, the intricate nature of sepsis slows progress in designing tailored treatments, and thus targeted modulation of key pathways is still far from standard practice. Biomarkers have emerged as important tools in this field since they provide an objective framework for the identification of subgroups of septic patients at higher risk of unfavorable outcomes. Recognizing these subgroups according to unique clinical, biochemical, cellular, molecular, genomic, and transcriptomic profiles may help select patients who could benefit from tailored interventions. This systematic review aimed to compile current information about sepsis phenotypes potentially recognizable within 24 hours of admission in the Intensive Care Unit (ICU). A systematic search of the literature was conducted on PubMed/MEDLINE, yielding 855 results, of which 39 were finally included. Overall, a milieu of biomarkers was investigated, thereby reaffirming the challenges faced in the quest for consensual predictive models that can serve as a framework for designing robust clinical trials aiming to investigate the safety, efficacy, and tolerability of biomarker-guided therapies. We highlight previously described noteworthy biomarkers. Despite the fact that most studied biomarkers displayed frail predictive value, adrenomedullin (ADM) stood out. The AdrenOSS-1 study established that initial high circulating levels of ADM related to unfavorable short-term outcomes. This observation served as the backbone for the design of the AdrenOSS-2 study, which ventured to investigate the therapeutic impact of Adrecizumab in septic shock patients with high bio-ADM levels upon ICU admission. The road ahead calls for more of these biomarker-guided clinical trials. This can only be made possible if future efforts focus on deriving, calibrating, and validating predictive models that include biomarkers that serve as surrogates for pathways known to be potentially amenable to targeted modulation.
Descrição
Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2023
Palavras-chave
Sepsis Biomarcadores Fenótipos Endotipos Prognóstico