Intubated patients developing tracheobronchitis or pneumonia have distinctive complement system gene expression signatures in the pre-infection period: A pilot study

Abstract

Introduction: It remains unknown why some intubated patients remain infection-free while others develop tracheobronchitis (VAT) or pneumonia (VAP).Objective: To identify and compare VAP/VAT gene expression ''signatures'' using genome-wide oligonucleotide microarrays. Material and methods: A prospective translational study of gene expression profiles of VAP and VAT groups was carried out, establishing comparisons in both pre-infection and infection phases. Pathway and functional analyses were performed with Ingenuity Pathway Analysis (IPA). Data analysis and hierarchical clustering of the genes involved in the signalling pathways expressed differentially in the two groups were performed with GeneSpring GX 11.0. Results: Eight patients developing respiratory infections (3 VAP and 5 VAT) after 4 days of mechanical ventilation were assessed. Comparison of gene expression profiles in the preinfection period revealed 5595 genes expressed differentially between VAP and VAT (p < 0.01, fold change >2). Comparative IPA analysis identified a significant depression of the complement system signalling pathway in the VAP group, affecting the classical pathway along with the final common pathway (p < 0.05). In addition, the cAMP and calcium signalling pathways were also significantly depressed in the VAP group during the pre-infection phase also. Conclusion: Intubated patients complicated with pneumonia developed immune impairment in the pre-infection period, manifesting as a relatively lower expression of genes involved in the complement system that differed from patients developing tracheobronchitis. These findings suggest that a significant proportion of VAP episodes cannot be prevented, but might be treatable through pre-emptive therapy. PALABRAS CLAVE traqueobronquitis (TAV) o neumonía (NAV).Objetivo: Identificar y comparar los patrones de la expresión genética de la NAV/TAV usando micromatrices multigénicas oligonucleotídicas. Material y métodos: Se realizó un estudio aplicado prospectivo de los patrones de la expresión genética de los grupos con NAV y TAV, estableciendo comparaciones tanto en la fase previa a la infección como en la fase infecciosa. Se realizaron análisis de vías y funcionales con Ingenuity Pathway (IPA). Los análisis de datos y el agrupamiento jerárquico de los genes implicados en las vías de señalización expresados de forma diferenciada en ambos grupos se realizaron con GeneSpring GX 11.0. Resultados: Se evaluaron ocho pacientes que presentaron infecciones respiratorias (3 NAV y 5 TAV) después de 4 días con la ventilación mecánica. La comparación de los perfiles de la expresión genética durante el período previo a la infección reveló 5.595 genes expresados de forma diferenciada entre la NAV y la TAV (p < 0,01, cambio múltiplo > 2). Los análisis comparativos de los IPA identificaron una depresión importante de la vía de señalización del sistema del complemento en el grupo con NAV, que afectó a la vía clásica además de a la vía común final (p < 0,05). Por otra parte, el monofosfato cíclico de...

Looking Beyond Respiratory Cultures: Microbiome-Cytokine Signatures of Bacterial Pneumonia and Tracheobronchitis in Lung Transplant Recipients

“…Observational studies of ventilator‐associated pneumonia (VAP) and ventilator‐associated tracheobronchitis (VAT) have revealed subsets of patients who progress directly from asymptomatic airway colonization to either type of infection as well as those with tracheobronchitis who progress to pneumonia . Pilot studies of VAP and VAT patients have found distinctive complement system gene expression signatures in the preinfection period, suggesting that these diseases have distinct pathways of pathogenesis . The unique signatures of pneumonia and tracheobronchitis in our study lend support to a similar model of divergent pathogenesis among lung transplant recipients who are not mechanically ventilated (Figure ).…”

23rd International Symposium on Infections in the Critically Ill Patient

“…Immune factors are likely to play a role in determining whether a patient with VAT goes on to develop VAP. In a study of mechanically ventilated patients with VAP, patients showed a relative depression of genes involved in calcium signaling pathways, the complement system and cyclic adenosine monophosphate (Martin-Loeches I, 2012). Patients with VAP exhibit increased inflammation and worse outcomes than those with VAT, and this may be related to an immunosuppressed state (Martin-Loeches I, 2015).…”

Contrary to popular belief, ventilator-associated lower respiratory tract infections are less common in immunocompromised patients

“…It might be that specific immunological mechanisms of importance are not affected in all immunocompromised patients [1]. One of the few studies on this topic suggests that complement activation is an important mechanism in the containment of VAT and this part of the innate response is little influenced by most of the studied immunosuppressed states [20]. However, there is a strong need for more evidence on the immunological and biochemical mechanisms that determine the progression towards pneumonia.…”