Advertisement

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

  • Pratik Sinha
  • Kevin L. Delucchi
  • B. Taylor Thompson
  • Daniel F. McAuley
  • Michael A. Matthay
  • Carolyn S. Calfee
  • for the NHLBI ARDS Network
Original

Abstract

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 three 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 two-class LCA model best fit the population. Forty percent 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

LCA using a two-subphenotype model best described the SAILS population. The subphenotypes have features consistent with those previously reported in four 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 demonstrate their utility for patient stratification in ARDS.

Keywords

ARDS Subphenotypes Latent class analysis Statins 

Notes

Funding

HL131621, HL133390, HL140026 (CSC), 2T32GM008440-21 (PS); SAILS was supported by a grant from the National Heart, Lung, and Blood Institute, National Institutes of Health (HHSN268200 536165C-536179C), and the Investigator-Sponsored Study Program of AstraZeneca.

Supplementary material

134_2018_5378_MOESM1_ESM.jpg (31 kb)
Supplementary material 1 (JPEG 31 kb)
134_2018_5378_MOESM2_ESM.jpg (16 kb)
Supplementary material 2 (JPEG 16 kb)
134_2018_5378_MOESM3_ESM.doc (94 kb)
Supplementary material 3 (DOC 94 kb)

References

  1. 1.
    Frank AJ, Thompson BT (2010) Pharmacological treatments for acute respiratory distress syndrome. Curr Opin Crit Care 16:62–68CrossRefGoogle Scholar
  2. 2.
    Bosma KJ, Taneja R, Lewis JF (2010) Pharmacotherapy for prevention and treatment of acute respiratory distress syndrome: current and experimental approaches. Drugs 70:1255–1282CrossRefGoogle Scholar
  3. 3.
    Jacobson JR, Barnard JW, Grigoryev DN, Ma SF, Tuder RM, Garcia JG (2005) Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol 288:L1026–L1032CrossRefGoogle Scholar
  4. 4.
    Chopra V, Rogers MA, Buist M, Govindan S, Lindenauer PK, Saint S, Flanders SA (2012) Is statin use associated with reduced mortality after pneumonia? A systematic review and meta-analysis. Am J Med 125:1111–1123CrossRefGoogle Scholar
  5. 5.
    Shyamsundar M, McKeown ST, O’Kane CM, Craig TR, Brown V, Thickett DR, Matthay MA, Taggart CC, Backman JT, Elborn JS, McAuley DF (2009) Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers. Am J Respir Crit Care Med 179:1107–1114CrossRefGoogle Scholar
  6. 6.
    McAuley DF, Laffey JG, O’Kane CM, Perkins GD, Mullan B, Trinder TJ, Johnston P, Hopkins PA, Johnston AJ, McDowell C, McNally C, HARP-2 Investigators, Irish Critical Care Trials Group (2014) Simvastatin in the acute respiratory distress syndrome. N Engl J Med 371:1695–1703CrossRefGoogle Scholar
  7. 7.
    National Heart, Lung, and Blood Institute ARDS Clinical Trials Network, Truwit JD, Bernard GR, Steingrub J, Matthay MA, Liu KD, Albertson TE, Brower RG, Shanholtz C, Rock P, Douglas IS, deBoisblanc BP, Hough CL, Hite RD, Thompson BT (2014) Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med 370:2191–2200CrossRefGoogle Scholar
  8. 8.
    Calfee CS, Delucchi K, Famous KR (2017) Reply: next step to understanding subphenotypes of acute respiratory distress syndrome. Am J Respir Crit Care Med 196:796CrossRefGoogle Scholar
  9. 9.
    Famous KR, Delucchi K, Ware LB, Kangelaris KN, Liu KD, Thompson BT, Calfee CS, Network A (2017) Acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy. Am J Respir Crit Care Med 195:331–338PubMedPubMedCentralGoogle Scholar
  10. 10.
    Calfee CS, Delucchi KL, Sinha P, Matthay MA, Hackett J, Shankar-Hari M, McDowell C, Laffey JG, O’Kane CM, McAuley DF, Irish Critical Care Trials Group (2018) Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. Lancet Respir Med 6:691–698CrossRefGoogle Scholar
  11. 11.
    Delucchi K, Famous KR, Ware LB, Parsons PE, Thompson BT, Calfee CS, ARDS Network (2018) Stability of ARDS subphenotypes over time in two randomised controlled trials. Thorax 73:439–445CrossRefGoogle Scholar
  12. 12.
    Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA, NHLBI ARDS Network (2014) Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med 2:611–620CrossRefGoogle Scholar
  13. 13.
    Calfee CS, Delucchi KL, Sinha P, Matthay MA, Hackett J, Shankar-Hari M, McDowell C, Laffey JG, O’Kane CM, McAuley DF (2018) ARDS subphenotypes and differential response to simvastatin: secondary analysis of a randomized controlled trial. Lancet Respir Med 6:691–698CrossRefGoogle Scholar
  14. 14.
    Sinha P, Delucchi K, Thompson BT, McAuley DF, Matthay MA, Calfee CS (2018) Latent class analysis of acute respiratory distress syndrome (ARDS): secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) trial. Am J Respir Crit Care Med 197:A6187Google Scholar
  15. 15.
    Muthén LK, Muthén BO (2017) Mplus user’s guide (version 8). Muthen & Muthen, Los AngelesGoogle Scholar
  16. 16.
    Pierrakos C, Vincent JL (2012) The changing pattern of acute respiratory distress syndrome over time: a comparison of two periods. Eur Respir J 40:589–595CrossRefGoogle Scholar
  17. 17.
    Wurpts IC, Geiser C (2014) Is adding more indicators to a latent class analysis beneficial or detrimental? Results of a Monte-Carlo study. Front Psychol 5:920CrossRefGoogle Scholar
  18. 18.
    Maiolo G, Collino F, Vasques F, Rapetti F, Tonetti T, Romitti F, Cressoni M, Chiumello D, Moerer O, Herrmann P, Friede T, Quintel M, Gattinoni L (2018) Reclassifying acute respiratory distress syndrome. Am J Respir Crit Care Med 197:1586–1595CrossRefGoogle Scholar
  19. 19.
    Nuckton TJ, Alonso JA, Kallet RH, Daniel BM, Pittet JF, Eisner MD, Matthay MA (2002) Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med 346:1281–1286CrossRefGoogle Scholar
  20. 20.
    Warren MA, Zhao Z, Koyama T, Bastarache JA, Shaver CM, Semler MW, Rice TW, Matthay MA, Calfee CS, Ware LB (2018) Severity scoring of lung oedema on the chest radiograph is associated with clinical outcomes in ARDS. Thorax 73:840–846CrossRefGoogle Scholar
  21. 21.
    Landesberg G, Levin PD, Gilon D, Goodman S, Georgieva M, Weissman C, Jaffe AS, Sprung CL, Barak V (2015) Myocardial dysfunction in severe sepsis and septic shock: no correlation with inflammatory cytokines in real-life clinical setting. Chest 148:93–102CrossRefGoogle Scholar
  22. 22.
    Prescott HC, Calfee CS, Thompson BT, Angus DC, Liu VX (2016) Toward smarter lumping and smarter splitting: rethinking strategies for sepsis and acute respiratory distress syndrome clinical trial design. Am J Respir Crit Care Med 194:147–155CrossRefGoogle Scholar
  23. 23.
    Davenport EE, Burnham KL, Radhakrishnan J, Humburg P, Hutton P, Mills TC, Rautanen A, Gordon AC, Garrard C, Hill AV, Hinds CJ, Knight JC (2016) Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir Med 4:259–271CrossRefGoogle Scholar
  24. 24.
    Sweeney TE, Azad TD, Donato M, Haynes WA, Perumal TM, Henao R, Bermejo-Martin JF, Almansa R, Tamayo E, Howrylak JA, Choi A, Parnell GP, Tang B, Nichols M, Woods CW, Ginsburg GS, Kingsmore SF, Omberg L, Mangravite LM, Wong HR, Tsalik EL, Langley RJ, Khatri P (2018) Unsupervised analysis of transcriptomics in bacterial sepsis across multiple datasets reveals three robust clusters. Crit Care Med 46:915–925CrossRefGoogle Scholar
  25. 25.
    Scicluna BP, van Vught LA, Zwinderman AH, Wiewel MA, Davenport EE, Burnham KL, Nurnberg P, Schultz MJ, Horn J, Cremer OL, Bonten MJ, Hinds CJ, Wong HR, Knight JC, van der Poll T, MARS consortium (2017) Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. Lancet Respir Med 5:816–826CrossRefGoogle Scholar
  26. 26.
    Wong HR, Cvijanovich N, Lin R, Allen GL, Thomas NJ, Willson DF, Freishtat RJ, Anas N, Meyer K, Checchia PA, Monaco M, Odom K, Shanley TP (2009) Identification of pediatric septic shock subclasses based on genome-wide expression profiling. BMC Med 7:34CrossRefGoogle Scholar
  27. 27.
    Siempos II, Maniatis NA, Kopterides P, Magkou C, Glynos C, Roussos C, Armaganidis A (2010) Pretreatment with atorvastatin attenuates lung injury caused by high-stretch mechanical ventilation in an isolated rabbit lung model. Crit Care Med 38:1321–1328CrossRefGoogle Scholar
  28. 28.
    Craig TR, Duffy MJ, Shyamsundar M, McDowell C, O’Kane CM, Elborn JS, McAuley DF (2011) A randomized clinical trial of hydroxymethylglutaryl-coenzyme a reductase inhibition for acute lung injury (The HARP Study). Am J Respir Crit Care Med 183:620–626CrossRefGoogle Scholar
  29. 29.
    Sahebkar A, Rathouska J, Simental-Mendia LE, Nachtigal P (2016) Statin therapy and plasma cortisol concentrations: a systematic review and meta-analysis of randomized placebo-controlled trials. Pharmacol Res 103:17–25CrossRefGoogle Scholar
  30. 30.
    Sahebkar A, Serban C, Ursoniu S, Mikhailidis DP, Undas A, Lip GY, Bittner V, Ray K, Watts GF, Hovingh GK, Rysz J, Kastelein JJ, Banach M, Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group (2016) The impact of statin therapy on plasma levels of von Willebrand factor antigen. Systematic review and meta-analysis of randomised placebo-controlled trials. Thromb Haemost 115:520–532CrossRefGoogle Scholar
  31. 31.
    Bonsu KO, Reidpath DD, Kadirvelu A (2015) Effects of statin treatment on inflammation and cardiac function in heart failure: an adjusted indirect comparison meta-analysis of randomized trials. Cardiovasc Ther 33:338–346CrossRefGoogle Scholar
  32. 32.
    Smith MEB, Lee NJ, Haney E, Carson S (2009) Drug class review: HMG-CoA reductase inhibitors (statins) and fixed-dose combination products containing a statin: final report update 5. Oregon Health & Science University, PortlandGoogle Scholar
  33. 33.
    Lee CC, Lee MG, Hsu TC, Porta L, Chang SS, Yo CH, Tsai KC, Lee M (2018) A population-based cohort study on the drug-specific effect of statins on sepsis outcome. Chest 153:805–815CrossRefGoogle Scholar
  34. 34.
    Mansur A, Steinau M, Popov AF, Ghadimi M, Beissbarth T, Bauer M, Hinz J (2015) Impact of statin therapy on mortality in patients with sepsis-associated acute respiratory distress syndrome (ARDS) depends on ARDS severity: a prospective observational cohort study. BMC Med 13:128CrossRefGoogle Scholar
  35. 35.
    Lobo SM, Lobo FR, Bota DP, Lopes-Ferreira F, Soliman HM, Melot C, Vincent JL (2003) C-reactive protein levels correlate with mortality and organ failure in critically ill patients. Chest 123:2043–2049CrossRefGoogle Scholar
  36. 36.
    Castell JV, Gomez-Lechon MJ, David M, Fabra R, Trullenque R, Heinrich PC (1990) Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6. Hepatology 12:1179–1186CrossRefGoogle Scholar
  37. 37.
    Bajwa EK, Khan UA, Januzzi JL, Gong MN, Thompson BT, Christiani DC (2009) Plasma C-reactive protein levels are associated with improved outcome in ARDS. Chest 136:471–480CrossRefGoogle Scholar
  38. 38.
    Pierrakos C, Vincent JL (2010) Sepsis biomarkers: a review. Crit Care 14:R15CrossRefGoogle Scholar
  39. 39.
    Navarro SL, Kantor ED, Song X, Milne GL, Lampe JW, Kratz M, White E (2016) Factors associated with multiple biomarkers of systemic inflammation. Cancer Epidemiol Biomarkers Prev 25:521–531CrossRefGoogle Scholar
  40. 40.
    Mackenzie I, Woodhouse J (2006) C-reactive protein concentrations during bacteraemia: a comparison between patients with and without liver dysfunction. Intensive Care Med 32:1344–1351CrossRefGoogle Scholar
  41. 41.
    Bos LD, Schouten LR, van Vught LA, Wiewel MA, Ong DSY, Cremer O, Artigas A, Martin-Loeches I, Hoogendijk AJ, van der Poll T, Horn J, Juffermans N, Calfee CS, Schultz MJ, Consortium M (2017) Identification and validation of distinct biological phenotypes in patients with acute respiratory distress syndrome by cluster analysis. Thorax 72:876–883CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature and ESICM 2018

Authors and Affiliations

  • Pratik Sinha
    • 1
  • Kevin L. Delucchi
    • 2
  • B. Taylor Thompson
    • 3
  • Daniel F. McAuley
    • 4
    • 5
  • Michael A. Matthay
    • 1
    • 6
    • 7
  • Carolyn S. Calfee
    • 1
    • 6
    • 7
  • for the NHLBI ARDS Network
  1. 1.Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep MedicineUniversity of California, San FranciscoSan FranciscoUSA
  2. 2.Department of PsychiatryUniversity of California, San FranciscoSan FranciscoUSA
  3. 3.Department of Medicine, Division of Pulmonary and Critical CareMassachusetts General HospitalBostonUSA
  4. 4.Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical SciencesQueen’s University of BelfastBelfastUK
  5. 5.Regional Intensive Care UnitRoyal Victoria HospitalBelfastUK
  6. 6.Department of AnesthesiaUniversity of California, San FranciscoSan FranciscoUSA
  7. 7.Cardiovascular Research Institute, University of California, San FranciscoSan FranciscoUSA

Personalised recommendations