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Publication
Potencial Diagnóstico e Prognóstico de KL-6 e MMP-7 nas Doenças do Interstício Pulmonar com Fibrose Progressiva: Revisão Sistemática
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Abstract(s)
Introdução: As doenças do interstício pulmonar (DIP) constituem um grupo heterogéneo
de patologias que frequentemente resultam num processo irreversível de fibrose pulmonar.
Ainda que a fibrose pulmonar idiopática (FPI) seja reconhecida como o paradigma da
doença intersticial pulmonar fibrosante progressiva, uma proporção significativa de
doentes com outras formas de DIP (pneumonite de hipersensibilidade, DIP associada a
doenças do tecido conjuntivo, sarcoidose, entre outras) evolui com um fenótipo progressivo,
caracterizado por crescente deterioração imagiológica e funcional, redução da qualidade de
vida e aumento da mortalidade, apesar de tratamento otimizado. A investigação de vias
comuns envolvidas na fibrose pulmonar progressiva e a identificação de biomarcadores são
determinantes na otimização do diagnóstico, tratamento, monitorização da atividade da
doença e prognóstico.
Objetivo: Explorar os mecanismos envolvidos no processo de fibrose pulmonar, bem como
rever o estado da arte no que diz respeito ao conhecimento de potenciais biomarcadores,
nomeadamente a krebs von den Lungen-6 (KL-6) e a metaloproteinase da matriz-7 (MMP7), no diagnóstico precoce e prognóstico de DIP com padrão fibrosante progressivo, visando
formas de monitorização e tratamento dirigido.
Métodos: Foi realizada uma revisão sistemática da literatura, com base nas diretrizes do
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
Realizou-se uma pesquisa bibliográfica nas bases de dados PubMed, Cochrane e b-on,
considerando o algoritmo e os critérios de elegibilidade previamente definidos, assim como
o intervalo temporal entre 1 de janeiro de 2014 e 14 de dezembro de 2024, sendo esta a data
da última pesquisa; foram integrados estudos originais, observacionais longitudinais, de
coorte, randomizados, casos-controlo e transversais, concordantes com o tema.
Resultados: Procedeu-se à análise dos 25 artigos selecionados para a tabela dos
resultados, abrangendo estudos retrospetivos, prospetivos, randomizados e transversais. A
maioria investigou a FPI, comparando-a com indivíduos saudáveis ou outras DIP. Alguns
estudos analisaram a progressão da FPI ao longo do tempo, enquanto outros exploraram
diversas DIP associadas a doenças autoimunes e condições pulmonares específicas. Os
participantes tinham entre 50 e 70 anos, com diferenças de género e histórico de tabagismo
conforme a patologia estudada. A maior parte dos estudos realizou-se na Ásia, enquanto
alguns ocorreram na Europa e América do Norte. A KL-6 foi o biomarcador mais estudado,
enquanto a MMP-7 teve menor representatividade. Os estudos utilizaram diferentes critérios para definir a progressão da doença e adotaram critérios de exclusão variados para
evitar fatores de confusão.
Conclusão: A KL-6 demonstrou, na generalidade dos estudos, elevada capacidade para
diferenciar doentes de indivíduos saudáveis, prever a progressão da doença e indicar pior
função pulmonar e menor sobrevida. A MMP-7 também apresentou relevância, mas a
escassez de estudos limitou a robustez das conclusões sobre o seu papel prognóstico. A
heterogeneidade metodológica e a predominância de estudos em populações asiáticas
dificultaram a generalização dos resultados. Assim, são necessários mais estudos
multicêntricos padronizados para otimizar a aplicabilidade clínica destes biomarcadores.
Introduction: Interstitial lung diseases (ILD) represent a heterogeneous group of pathologies that often result in an irreversible process of pulmonary fibrosis. Although Idiopathic Pulmonary Fibrosis (IPF) is recognized as the paradigm of progressive fibrosing interstitial lung disease, a significant proportion of patients with other forms of ILD (hypersensitivity pneumonitis, ILD associated with connective tissue diseases, sarcoidosis, among others) develop a progressive phenotype characterized by worsening imaging and functional parameters, reduced quality of life, and increased mortality, despite optimized treatment. Research into common pathways involved in progressive pulmonary fibrosis and the identification of biomarkers is crucial for optimizing diagnosis, treatment, disease activity monitoring, and prognosis. Objective: Explore the mechanisms involved in the process of pulmonary fibrosis, as well as review the state of the art regarding the knowledge of potential biomarkers, namely krebs von den Lungen-6 (KL-6) and matrix metalloproteinase-7 (MMP-7), in the early diagnosis and prognosis of interstitial lung diseases with a progressive fibrosing pattern, aiming at methods for monitoring and targeted treatment. Methods: A systematic literature review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A bibliographic search was performed in the PubMed, Cochrane, and b-on databases, considering the predefined algorithm and eligibility criteria, as well as the time frame between 1 January 2014 and 14 December 2024, the date of the last search; original studies, including longitudinal observational, cohort, randomised, case-control, and cross-sectional studies relevant to the topic, were included. Results: The analysis of the 25 articles selected for the results table was carried out, encompassing retrospective, prospective, randomised, and cross-sectional studies. Most studies investigated IPF, comparing it with healthy individuals or other ILDs. Some studies analysed the progression of IPF over time, while others explored various ILD associated with autoimmune diseases and specific pulmonary conditions. Participants were aged between 50 and 70 years, with differences in gender and smoking history depending on the pathology studied. Most studies were conducted in Asia, while some took place in Europe and North America. KL-6 was the most studied biomarker, whereas MMP-7 was less represented. The studies used different criteria to define disease progression and adopted various exclusion criteria to avoid confounding factors. Conclusion: KL-6 demonstrated, in most studies, a high capacity to differentiate patients from healthy individuals, predict disease progression, and indicate poorer lung function and reduced survival. MMP-7 also showed relevance, but the limited number of studies restricted the robustness of conclusions regarding its prognostic role. Methodological heterogeneity and the predominance of studies in Asian populations make it difficult to generalise the results. Therefore, more standardised multicentric studies are needed to optimise the clinical applicability of these biomarkers.
Introduction: Interstitial lung diseases (ILD) represent a heterogeneous group of pathologies that often result in an irreversible process of pulmonary fibrosis. Although Idiopathic Pulmonary Fibrosis (IPF) is recognized as the paradigm of progressive fibrosing interstitial lung disease, a significant proportion of patients with other forms of ILD (hypersensitivity pneumonitis, ILD associated with connective tissue diseases, sarcoidosis, among others) develop a progressive phenotype characterized by worsening imaging and functional parameters, reduced quality of life, and increased mortality, despite optimized treatment. Research into common pathways involved in progressive pulmonary fibrosis and the identification of biomarkers is crucial for optimizing diagnosis, treatment, disease activity monitoring, and prognosis. Objective: Explore the mechanisms involved in the process of pulmonary fibrosis, as well as review the state of the art regarding the knowledge of potential biomarkers, namely krebs von den Lungen-6 (KL-6) and matrix metalloproteinase-7 (MMP-7), in the early diagnosis and prognosis of interstitial lung diseases with a progressive fibrosing pattern, aiming at methods for monitoring and targeted treatment. Methods: A systematic literature review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A bibliographic search was performed in the PubMed, Cochrane, and b-on databases, considering the predefined algorithm and eligibility criteria, as well as the time frame between 1 January 2014 and 14 December 2024, the date of the last search; original studies, including longitudinal observational, cohort, randomised, case-control, and cross-sectional studies relevant to the topic, were included. Results: The analysis of the 25 articles selected for the results table was carried out, encompassing retrospective, prospective, randomised, and cross-sectional studies. Most studies investigated IPF, comparing it with healthy individuals or other ILDs. Some studies analysed the progression of IPF over time, while others explored various ILD associated with autoimmune diseases and specific pulmonary conditions. Participants were aged between 50 and 70 years, with differences in gender and smoking history depending on the pathology studied. Most studies were conducted in Asia, while some took place in Europe and North America. KL-6 was the most studied biomarker, whereas MMP-7 was less represented. The studies used different criteria to define disease progression and adopted various exclusion criteria to avoid confounding factors. Conclusion: KL-6 demonstrated, in most studies, a high capacity to differentiate patients from healthy individuals, predict disease progression, and indicate poorer lung function and reduced survival. MMP-7 also showed relevance, but the limited number of studies restricted the robustness of conclusions regarding its prognostic role. Methodological heterogeneity and the predominance of studies in Asian populations make it difficult to generalise the results. Therefore, more standardised multicentric studies are needed to optimise the clinical applicability of these biomarkers.
Description
Keywords
Diagnóstico Precoce Doenças do Interstício Pulmonar Fibrose Pulmonar Progressiva Kl-6 Mmp-7 Monitorização Prognóstico