Stability of ARDS subphenotypes over time in two randomised controlled trials

Delucchi, Kevin; Famous, Katie R.; Ware, Lorraine B.; Parsons, Polly E.; Thompson, B. Taylor; Calfee, Carolyn S.

doi:10.1136/thoraxjnl-2017-211090

Cited by 120 publications

(99 citation statements)

References 21 publications

(26 reference statements)

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“…It is tempting to speculate that virus-associated CRS and the neutrophilic response are the main culprits in severe COVID-19-pneumonia, which occurs with a delay only when the "misguided antiviral-immune response" hits 23 . One might argue, that ARDS per se implies alveolar endothelial injury, complement-, neutrophil-activation, and NETosis and thus entails a systemic hyperin ammatory response [32][33][34] . Still, others have reported, that an increased NLR is apparent already before the onset of ARDS, and was an independent predictor for severe COVID-19 in 61 patients 31,35 .…”

Section: Discussionmentioning

confidence: 99%

Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients

Lorenz

Moog

Bachmann

et al. 2020

Preprint

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Background: Severe COVID-19 associated respiratory failure, poses the one challenge of our days. Assessment and treatment of COVID-19 associated hyperinflammation may be key to improve outcomes. It was speculated that in subgroups of patients secondary hemophagocytic lymphohistiocytosis (sHLH) or cytokine release syndrome (CRS) with features of macrophage activation syndrome might drive severe disease trajectories. If confirmed, profound immunosuppressive therapy would be a rationale treatment approach.Methods: Over a median observation period of 11 (IQR: 8; 16) days, 19 consecutive confirmed severe COVID-19-patients admitted to our intensive-care-unit were tested for presence of sHLH by two independent experts. HScores and 2004-HLH diagnostic criteria were assessed. Patients were grouped according to short-term clinical courses: discharge from ICU versus ongoing ARDS or death at time of analysis.Results: The median HScore at admission was 157 (IQR: 98;180), without the key clinical triad of HLH, i.e. progressive cytopenia, persistent fever and organomegaly. Independent expert chart review revealed the absence of sHLH in all cases. No patient reached more than 3/6 of modified HLH 2004 criteria. Nevertheless, patients presented hyperinflammation with peripheral neutrophilic signatures (neutrophil/lymphocyte-ratio>3.5). The latter best paralleled their short-term clinical courses, with declining relative neutrophil numbers prior to extubation (4.4, [IQR: 2.5;6.3]; n=8) versus those with unfavourable courses (7.6, [IQR: 5.2;31], n=9).Conclusion: Our study rules out virus induced sHLH as the leading cause of most severe-COVID-19 trajectories. Instead, an associated innate neutrophilic hyperinflammatory response or virus-associated-CRS appears dominant in patients with an unfavourable clinical course. Therapeutic implications are discussed.

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Section: Discussionmentioning

confidence: 99%

Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients

Lorenz

Moog

Bachmann

et al. 2020

Preprint

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“…Furthermore, a high PEEP strategy was associated with a significant decrease in mortality in the hyperinflammatory group suggesting a possible therapeutic implication of distinguishing phenotypes [8] . These two types persisted over time with > 94% of patients remaining within their initial phenotype by hospital day three [46] . A follow up study with 2 distinct cohorts demonstrated increased levels of markers of epithelial cell injury with decreased levels of markers of endothelial injury in direct ARDS (defined as those with pulmonary cause such as pneumonia) compared with indirect ARDS (caused by non-pulmonary etiologies such as sepsis) [47] .…”

Section: Cytokines In Ardsmentioning

confidence: 98%

Diagnosis and treatment of acute pulmonary inflammation in critically ill patients: The role of inflammatory biomarkers

Chalmers¹,

Khawaja²,

Wieruszewski³

et al. 2019

WJCCM

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Pneumonia and acute respiratory distress syndrome are common and important causes of respiratory failure in the intensive care unit with a significant impact on morbidity, mortality and health care utilization despite early antimicrobial therapy and lung protective mechanical ventilation. Both clinical entities are characterized by acute pulmonary inflammation in response to direct or indirect lung injury. Adjunct anti-inflammatory treatment with corticosteroids is increasingly used, although the evidence for benefit is limited. The treatment decisions are based on radiographic, clinical and physiological variables without regards to inflammatory state. Current evidence suggests a role of biomarkers for the assessment of severity, and distinguishing sub-phenotypes (hyperinflammatory versus hypo-inflammatory) with important prognostic and therapeutic implications. Although many inflammatory biomarkers have been studied the most common and of interest are C-reactive protein, procalcitonin, and pro-inflammatory cytokines including interleukin 6. While extensively studied as prognostic tools (prognostic enrichment), limited data are available for the role of biomarkers in determining appropriate initiation, timing and dosing of adjunct anti-inflammatory treatment (predictive enrichment)

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“…[8–10] The subgroups are clinically and biologically distinct from one another and remain stable over the first three days of enrollment. [11] The hyper-inflammatory subphenotype was associated with increased inflammatory biomarkers, a higher prevalence of shock, and worse clinical outcomes. Crucially, in the hyper-inflammatory subphenotype, we observed treatment responses to positive end-expiratory pressure (PEEP) and conservative fluid management that were significantly different from the hypo-inflammatory class.…”

Section: Introductionmentioning

confidence: 99%

Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study

et al. 2018

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Purpose: Using latent class analysis (LCA), we have consistently identified two distinct subphenotypes in four randomized controlled trial cohorts of ARDS. One subphenotype has hyper-inflammatory characteristics and is associated with worse clinical outcomes. Further, within 3 negative clinical trials, we observed differential treatment response by subphenotype to randomly assigned interventions. The main purpose of this study was to identify ARDS subphenotypes in a contemporary NHLBI Network trial of infection-associated ARDS (SAILS) using LCA and to test for differential treatment response to rosuvastatin therapy in the subphenotypes. Methods: LCA models were constructed using a combination of biomarker and clinical data at baseline in the SAILS study (n=745). LCA modeling was then repeated using an expanded set of clinical class-defining variables. Subphenotypes were tested for differential treatment response to rosuvastatin. Results: The 2-class LCA model best fit the population. 40% of the patients were classified as the “hyper-inflammatory” subphenotype. Including additional clinical variables in the LCA models did not identify new classes. Mortality at Day 60 and Day 90 was higher in the hyper-inflammatory subphenotype. No differences in outcome were observed between hyper-inflammatory patients randomized to rosuvastatin therapy versus placebo. Conclusions: Using LCA, a 2-subphenotype model best described the SAILS population. The subphenotypes have features consistent with those previously reported in 4 other cohorts. Addition of new class-defining variables in the LCA model did not yield additional subphenotypes. No treatment effect was observed with rosuvastatin. These findings further validate the presence of two subphenotypes and demonstrates their utility for patient stratification in ARDS.

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Stability of ARDS subphenotypes over time in two randomised controlled trials

Abstract: ARDS subphenotypes are largely stable over the first 3 days of enrolment in two ARDS Network trials, suggesting that subphenotype identification may be feasible in the context of clinical trials.

Cited by 120 publications

References 21 publications

Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients

Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients

Diagnosis and treatment of acute pulmonary inflammation in critically ill patients: The role of inflammatory biomarkers

Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study

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