Three biologically distinct pulmonary inflammatory endotypes have been identified and validated among mechanically ventilated patients with suspected severe pneumonia, which could lead to the development of personalised therapies for this patient group, according to a recent study. <\/p>\n
Pneumonia is the leading infectious cause of death worldwide and a major cause of intensive care unit (ICU) admission, as well as the most common trigger for acute respiratory distress syndrome (ARDS)<\/a>. However, its underlying biology remains unclear and responses to immunomodulatory treatments have varied. <\/p>\n A phenotype groups patients according to shared clinical or biological characteristics, while an endotype is defined by a distinct underlying biological mechanism. Patients with similar clinical features, such as comparable severity of respiratory failure, may therefore have different endotypes reflecting different inflammatory processes. <\/p>\n Previous attempts to identify pathophysiological phenotypes have largely focused on peripheral blood<\/a>, despite inflammatory responses being compartmentalised within the lungs. <\/p>\n Commenting on the unmet need in this area, Dr Andrew Conway Morris, associate professor of anaesthesia at the University of Cambridge and honorary consultant in intensive care medicine at Cambridge University Hospitals NHS Foundation Trust, said: \u2018Even though we\u2019re able to treat the initial infection, many patients with severe pneumonia still struggle to come off the ventilator and can develop lung failure. Therapies to tackle inflammation in the lungs have had mixed results in clinical trials \u2013 some suggest they are beneficial, others that they\u2019re harmful. <\/p>\n \u2018The current approach of classifying patients by their clinical syndromes \u2013 sepsis, ARDS and so on \u2013 without looking at the underlying biology risks missing what\u2019s key. Instead of asking \u201cDoes this patient have pneumonia?\u201d, we should be asking \u201cWhat\u2019s the inflammatory pattern in this patient\u2019s lungs?\u201d.\u2019 <\/p>\n Lung endotypes in severe pneumonia<\/p>\n As such, a new study, published in the journal Nature Communications<\/a>, for which Dr Conway Morris is corresponding author, aimed to characterise pulmonary immune responses and identify biologically distinct pulmonary endotypes that could inform personalised treatment. <\/p>\n The discovery cohort comprised 95 mechanically ventilated adults with clinically suspected pneumonia recruited from a mixed medical-surgical ICU, of whom 80 had sufficient sequenceable RNA from bronchoalveolar lavage (BAL) cells, alongside blood samples. <\/p>\n Some 43% (n=34) had pneumonia confirmed following expert consensus review, while 40% were immunosuppressed and in-hospital mortality was 33%, which the authors said was typical of pneumonia requiring ICU admission and mechanical ventilation. <\/p>\n Analysis of BAL gene expression identified three pulmonary endotypes, termed Pneumotypes (Pn) 1, 2 and 3. Despite comparable severity of respiratory failure and similar proportions of patients with ARDS, the three Pneumotypes had distinct biological mechanisms and clinical outcomes. <\/p>\n Pn1, the most common endotype, comprised 39 patients and was characterised by low alveolar cytokine concentrations, expansion of tolerogenic or alternatively activated macrophages and epithelial damage. <\/p>\n Pn3, identified in 22 patients with suspected severe pneumonia, showed marked inflammatory activation, immature neutrophil infiltration, interleukin (IL)-6-related signalling and impaired alveolar fluid clearance and surfactant function. <\/p>\n The authors suggested this endotype might benefit from targeted immunomodulation alongside pathogen control, with selective IL-6 blockade identified as one potential approach requiring further investigation. Importantly, they cautioned that the same intervention could potentially be harmful in Pn1 and offer minimal benefit in Pn2. <\/p>\n Pn2, comprising 19 patients, demonstrated a more balanced immune response alongside epithelial and endothelial repair signatures and was associated with the fastest resolution of respiratory failure. Patients with Pn2 had significantly faster extubation than those with Pn3, while the endotype also showed the lowest antimicrobial use following lavage. <\/p>\n Guiding personalised treatments<\/p>\n Among 48 inflammatory proteins measured, 35 differed significantly between Pneumotypes in BAL, whereas plasma inflammatory proteins were largely comparable. Peripheral blood gene-expression patterns also did not reliably distinguish the three pulmonary endotypes. <\/p>\n This led the researchers to caution against using blood phenotypes alone to guide therapy decisions for severe pneumonia. <\/p>\n Findings were triangulated against three external pulmonary datasets, although differences in sampling methods, patient populations and disease severity meant replication was incomplete. <\/p>\n Other limitations included the single-centre discovery cohort, the selection of patients fit for bronchoscopy and limited serial sampling. The authors said full replication using comparable recruitment, sampling and analytical methods was required, alongside serial studies to establish phenotype stability and trajectories during recovery. Larger cohorts may also identify additional pulmonary endotypes, they added. <\/p>\n The authors concluded that the three pulmonary-confined endotypes were driven by distinct mechanisms with different outcomes and therapeutic implications, providing potential targets for more personalised approaches to severe pneumonia and acute lung injury. <\/p>\n Indeed, study author Dr Vilas Navapurkar, consultant anaesthetist at Cambridge University Hospitals NHS Foundation Trust, said: \u2018If we know which subtype of pneumonia an individual has, we can potentially tailor their treatment more precisely, boosting the immune response in some, while calming harmful inflammation in others. <\/p>\n \u2018This has the potential to help critically ill patients, reduce deaths from pneumonia, shorten ICU stays and cut unnecessary antibiotic use<\/a>.\u2019 <\/p>\n