Sepsis pp 187-206 | Cite as

Diagnosis of Sepsis: Clinical Findings and the Role of Biomarkers

  • Daithi S. HeffernanEmail author
Part of the Respiratory Medicine book series (RM)


Sepsis accounts for approximately 50% of ICU-related deaths. Sepsis is best defined as the body’s systemic and end-organ response to an infection. The diagnosis of sepsis is particularly challenging in critically ill and immunocompromised patients. Culture-based methods of organism identification have many limitations. Advances in techniques to identify bacteria have shortened time to diagnosis of sepsis. Biomarkers, characteristics that are objective measurements of biological or pathological processes, have also emerged as promising tools for the early and accurate diagnosis of sepsis. Ultimately, reductions in sepsis-related mortality must start with a rapid and accurate diagnosis of sepsis.


Sepsis Clinical definition Diagnosis Biomarkers Organism identification 


  1. 1.
    Geroulanos S, Douka E. Historical perspective of the word "sepsis". Intensive Care Med. 2006;32(12):2077.CrossRefPubMedGoogle Scholar
  2. 2.
    Dellinger R, Levy M, Rhodes A, Annane D, Gerlach H, Opal S, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock. Crit Care Med. 2013;41(2):580–637.CrossRefPubMedGoogle Scholar
  3. 3.
    Mayr F, Yende S, Angus D. Epidemiology of severe sepsis. Virulence. 2014;5(1):4–11.CrossRefPubMedGoogle Scholar
  4. 4.
    Levy M, Fink M, Marshall J, Abraham E, Angus D, Cook D, et al. Ramsay and The international sepsis definition conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International sepsis definitions conference. Intensive Care Med. 2003;29(4):530–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Bone R, Fisher C, Clemmer T, Slotman G, Metz C, Balk P. Sepsis syndrome A valid clinical entity methylprednoslone severe sepsis study group. Crit Care Med. 1989;17(5):389–93.CrossRefPubMedGoogle Scholar
  6. 6.
    Bone R, Fisher C, Clemmer T, Slotman G, Metz C, Balk R, et al. A controlled clinical trial of high dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987;317(11):353–8.CrossRefGoogle Scholar
  7. 7.
    Bone R, Balk R, Cerra F, Dellinger R, Fein A, Knaus W, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM consensus conference committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644–55.CrossRefPubMedGoogle Scholar
  8. 8.
    Sprung C, Sakr Y, Vincent J, Gall J, Reinhart K, Ranieri V, et al. An evaluation of systemic inflammatory response syndrome signs in the Sepsis Occurrence in Acutely Ill Patients (SOAP) study. Intensive Care Med. 2006;32(3):421–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Heppner H, Cornel S, Peter W, Philipp B, Katrin S. Infections in the elderly. Crit Care Clin. 2013;29(3):757–74.CrossRefGoogle Scholar
  10. 10.
    Fox E, Heffernan D, Cioffi W, Reichner J. Neutrophils from critically ill septic patients mediate profound loss of endothelial barrier integrity. Crit Care. 2013;17(5):R226.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Czura C. Merinoff symposium 2010: sepsis – speaking with one voice. Mol Med. 2011;17:2–3.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Vincent J, Opal S, Marshall J, Tracey K. Sepsis definitions: time for change. Lancet. 2013;381:774–5.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Renaud B, Brun-Buisson C, ICU-Bacteremia Study Group. Outcomes of primary and catheter related bacteremia. A cohort and case control study in critically ill patients. Am J Respir Crit Care Med. 2001;163:1584–90.CrossRefPubMedGoogle Scholar
  14. 14.
    Levy M, Rhodes A, Phillips G, Townsend S, Schorr C, Beale R, et al. Surviving sepsis campaign: association between performance metrics and outcomes in a 7.5 year study. Crit Care Med. 2015;43(1):3–12.CrossRefPubMedGoogle Scholar
  15. 15.
    Marshall J, Dellinger R, Levy M. The surviving sepsis campaign: a history and a perspective. Surg Infect (Larchmt). 2011;11(3):275–81.CrossRefGoogle Scholar
  16. 16.
    Peres-Bota D, Melot C, Lopes Ferreira F, Vincent J. Infection probability score (IPS): a method to help assess the probability of infection in critically ill patients. Crit Care Med. 2003;31:2579–84.CrossRefPubMedGoogle Scholar
  17. 17.
    Calandra T, Cohen J. The international sepsis forum consensus conference on definitions of infection in the intensive care unit. Crit Care Med. 2005;33:1538–48.CrossRefPubMedGoogle Scholar
  18. 18.
    Phua J, Ngerng W, See K, Tay C, Kiong T, Lim H, et al. Characteristics and outcomes of culture negative versus culture positive severe sepsis. Crit Care. 2013;17(5):R202.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kumar A, Roberts D, Wood K, Light B, Parrillo J, Sharma S, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589–96.CrossRefPubMedGoogle Scholar
  20. 20.
    Mullins K, Faloona F. Specific synthesis of DNA in vitro via a polymerase catalyzed chain reaction. Methods. 1987;155:335–50.Google Scholar
  21. 21.
    Aydiner A, Lusebrink J, Schildgen V, Winterfeld I, Knuver O, Schwarz K, et al. Comparison of two commercial PCR methods for methicillin-resistant Staphylococcus aureus (MRSA) screening in a tertiary care hospital. PLoS One. 2012;7(9):e43935.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Snyder L, Loman N, Faraj L, Levi K, Weinstock G, Boswell T, et al. Epidemiological investigation of Pseudomonas aeruginosa isolates from a six-year long hospital outbreak using high-throughput whole genome screening. Euro Surveill. 2013;18(42):20611.CrossRefPubMedGoogle Scholar
  23. 23.
    Schrenzel J. Clinical relevance of new diagnostic methods for blood stream infections. Int J Antimicrob Agents. 2007;21(3):161–70.Google Scholar
  24. 24.
    Strommenger B, Schmidt C, Werner G, Roessie-Lorch B, Bachmann T, Witte W. DNA microarray for the detection of therapeutically relevant antibiotic resistance determinants in clinical isolates of Staphylococcus aureus. Mol Cell Probes. 2007;21(3):161–70.CrossRefPubMedGoogle Scholar
  25. 25.
    Otsuka J, Kondoh Y, Amemiya T, Kitamura A, Ito T, Baba S, et al. Development and validation of microarray based assay for epidemiological study of MRSA. Mol Cell Probes. 2008;22(1):1–13.CrossRefPubMedGoogle Scholar
  26. 26.
    Bhowmick T, Mirrett S, Reller L, Price C, Qi C, Weinstein M, et al. Controlled multicenter evaluation of a bacteriophage-based method for rapid detection of Staphylococcus aureus in positive blood cultures. J Clin Microbiol. 2013;51(4):1226–30.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Sullivan K, Turner N, Roundtree S, McGowan K. Rapid detection of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible Staphylococcus aureus (MSSA) using the KeyPath MRSA/MSSA blood cultre test and the BacT/ALERT system in a pediatric population. Arch Pathol Lab Med. 2013;137(8):1103–5.CrossRefPubMedGoogle Scholar
  28. 28.
    Park S, Zhang Y, Lin S, Wang T, Yang S. Advances in microfluidic PCR for point-of-care infectious disease diagnostics. Biotechnol Adv. 2011;29(6):830–9.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Lee W, Kim Y, Chung B, Demirci U, Khademhosseini A. Nano/Microfluidics for diagnosis of infectious diseases in developing countries. Adv Drug Deliv Rev. 2010;62(4–5):449–57.CrossRefPubMedGoogle Scholar
  30. 30.
    Paredes J, Alonso-Arce M, Schmidt C, Valderas D, Sedano B, Legarda J, et al. Smart central venous port for early detection of bacterial biofilm related infections. Biomed Microdevices. 2014;16(3):365–74.PubMedGoogle Scholar
  31. 31.
    Blatteis C. Age dependent changes in temperature regulation—a mini review. Gerontology. 2012;58:289–95.CrossRefPubMedGoogle Scholar
  32. 32.
    Heffernan D, Thakkar R, Monaghan S, Ravindran R, Adams C, Kozloff M, et al. Normal presenting vital signs are unreliable in geriatric blunt trauma victims. J Trauma. 2010;69(4):813–20.CrossRefPubMedGoogle Scholar
  33. 33.
    Ottinger M, Monaghan S, Gravenstein S, Cioffi W, Ayala A, Heffernan D. The geriatric cytokine response to trauma: time to consider a new threshold. Surg Infect (Larchmt). 2014;15(6):800–5.CrossRefGoogle Scholar
  34. 34.
    Boraschi D, Aguado M, Dutel C, Goronzy J, Louis J, Grubeck-Lobenstein B, et al. The gracefully aging immune system. Sci Transl Med. 2013;5(185):185ps8.CrossRefPubMedGoogle Scholar
  35. 35.
    Lee S, Chan R, Wu J, Chen H, Chang S, Lee C. Diagnostic value of procalcitonin for bacterial infection in elderly patients—a systemic review and meta-analysis. Int J Clin Pract. 2013;67(12):1350–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Gerdes J. Clinicopathologic approach to the diagnosis of neonatal sepsis. Clin Perinatol. 1991;18:361–81.PubMedGoogle Scholar
  37. 37.
    Yu Z, Liu J, Sun Q, Qui Y, Han S, Guo X. The accuracy of the procalcitonin test for the diagnosis of neonatal sepsis: a meta-analysis. Scand J Infect Dis. 2010;42(10):723–33.CrossRefPubMedGoogle Scholar
  38. 38.
    Biomarkers Definition Working Group. Biomarkers and surrogate endopoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95.CrossRefGoogle Scholar
  39. 39.
    Pierrakos C, Vincent J. Sepsis biomarkers: a review. Crit Care. 2010;14:R15.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Livaditi O, Kotanidou A, Psarra A, Dimopoulou I, Sotiropoulou C, Augustatou K, et al. Neutrophil CD64 expression and serum IL-8: sensitive markers of severity and outcome in sepsis. Cytokine. 2006;36:283–90.CrossRefPubMedGoogle Scholar
  41. 41.
    Gentile L, Cuenca A, Vanzant E, Efron P, McKinley B, Moore F, et al. Is there value in plasma cytokine measurements in patients with severe trauma and sepsis. Methods. 2013;61(1):3–9.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Hong T, Chang C, Ko W, Lin C, Liu H, Chow L, et al. Biomarkers of early sepsis may be correlated with outcome. J Transl Med. 2014;12:146.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Zhang J, She D, Feng D, Jia Y, Xie L. Dynamic changes of serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) reflect severity and can predict prognosis: a prospective study. BMC Infect Dis. 2011;11:53.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Lvovschi V, Arnaud L, Parizot C, Freund Y, Juillien G, Ghillani-Dalbin P, et al. Cytokine profiles in sepsis have limited relevance for stratifying patients in the emergency department: a prospective observational study. PLoS One. 2011;6:e28870.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Bozza F, Salluh J, Japiassu A, Soares M, Assis E, Gomes R, et al. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care. 2007;11:R49.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Andaluz-Ojeda D, Bobillo F, Iglesias V, Almansa R, Rico L, Gandia F, et al. A combined score of pro- and anti- inflammatory interleukins improves mortality prediction in severe sepsis. Cytokine. 2012;57:332–6.CrossRefPubMedGoogle Scholar
  47. 47.
    Tillett W, Francis T. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med. 1930;52:561–71.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Simon L, Gauvin F, Amre D, Saint-Louis P, Lacroix J. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis. 2004;39:206–17.CrossRefPubMedGoogle Scholar
  49. 49.
    Povoa P, Coelho L, Almeida E, Fernandes A, Mealha R, Moreira P, et al. C-Reactive protein as a marker of infection in critically ill patients. Clin Microbiol Infect. 2005;11(2):101–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Schmit X, Vincent J. The time course of blood C-reactive protein concentrations in relation to the response to initial antimicrobial therapy in patients with sepsis. Infection. 2008;36:213–9.CrossRefPubMedGoogle Scholar
  51. 51.
    O'Grady N, Barie P, Bartlett J, Bleck T, Carroll K, Kalil A, et al. Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American College of Critical Care Medicine and the Infectious Diseases Society of America. Crit Care Med. 2008;36(4):1330–49.CrossRefPubMedGoogle Scholar
  52. 52.
    Harbarth S, Holeckova K, Froidevaux C, Pittet D, Ricou B, Grau G, et al. Geneva sepsis network diagnostic value of procalcitonin, interleukin-6 and interleukin-8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med. 2001;164(3):396–402.CrossRefPubMedGoogle Scholar
  53. 53.
    Muller B, Becker K, Schachinger H, Rickenbacher P, Huber P, Zimmerli W, et al. Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med. 2000;28(4):977–83.CrossRefPubMedGoogle Scholar
  54. 54.
    Schuetz P, Muller B, Christ-Crain M, Stolz D, Tamm M, Bouadma L, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2012;9:CD007498.Google Scholar
  55. 55.
    Schuetz P, Albrich W, Christ-Crain M, Chastre J, Mueller B. Procalcitonin for guidance of antibiotic therapy. Expert Rev Anti Infect Ther. 2010;8(5):575–87.CrossRefPubMedGoogle Scholar
  56. 56.
    Wacker C, Prkno A, Brunkhorst F, Schlattmann P. Procalcitonin as a diagnostic marker for sepsis: a systematic reivew and meta-analysis. Lancet Infect Dis. 2013;13:426–35.CrossRefPubMedGoogle Scholar
  57. 57.
    Yu C, Juan L, Hsu S, Chen C, Wu C, Lee C, et al. Role of procalcitonin in the diagnosis of infective endocarditis: a meta-analysis. Am J Emerg Med. 2013;31(6):935–41.CrossRefPubMedGoogle Scholar
  58. 58.
    Tang B, Eslick G, Craig J, McLean A. Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systemic review and meta-analysis. Lancet Infect Dis. 2007;7(3):210–7.CrossRefPubMedGoogle Scholar
  59. 59.
    Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret G. Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med. 2006;34(7):1996–2003.CrossRefPubMedGoogle Scholar
  60. 60.
    Mann E, Wood G, Wade C. Use of procalcitonin for the detection of sepsis in the critically ill burn patients: a systematic review of the literature. Burns. 2011;37:549–58.CrossRefPubMedGoogle Scholar
  61. 61.
    Jensen J, Hein L, Lundgren B, Bestle M, Mohr T, Andersen M, et al. Procalcitonin guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit; a randomized trial. Crit Care Med. 39(9):2048–58.Google Scholar
  62. 62.
    Sunden-Cullberg J, Norrby-Teglund A, Rouhiainen A, Rauvala H, Herman G, Tracey K, et al. Persistent elevation of high mobility group box-1 protein (HMGB-1) in patients with severe sepsis and septic shock. Crit Care Med. 2005;33:564–73.CrossRefPubMedGoogle Scholar
  63. 63.
    Hatada T, Wada H, Nobori T, Okabayshi K, Maruyama K, Abe Y, et al. Plasma concentrations and importance of High Mobility Group Box protein in the prognosis of organ failure in patients with disseminated intravascular coagulation. Thromb Hemost. 2005;94:975–9.Google Scholar
  64. 64.
    Gibot S, Massin F, Cravoisy A, Barraud D, Nace L, Levy B, et al. High-mobility group box-1 protein plasma concentrations during septic shock. Intensive Care Med. 2007;33:1347–53.CrossRefPubMedGoogle Scholar
  65. 65.
    Narvaez-Rivera R, Rendon A, Salinas-Carmona M, Rossa-Taraco A. Soluble RAGE as a severity marker in community acquired pneumonia associated sepsis. BMC Infect Dis. 2012;12:15.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Bouchon A, Dietrich J, Colonna M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol. 2000;164:4991–5.CrossRefPubMedGoogle Scholar
  67. 67.
    Gibot S. Clinical review: role of triggering receptor expressed on myeloid cells-1 during sepsis. Crit Care. 2005;9:485–9.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Jiyong J, Tiancha H, Wei C, Huahao S. Diagnostic value of the soluble triggering receptor expressed on myeloid cells-1 in bacterial infection: a meta-analysis. Intensive Care Med. 2009;35(4):587–95.CrossRefPubMedGoogle Scholar
  69. 69.
    Jeong S, Song Y, Kim C, Kim H, Ku N, Han S, et al. Measurement of plasma sTREM-1 in patients with severe sepsis receiving early goal directed therapy and evaluation of its usefulness. Shock. 2012;37:574–8.CrossRefPubMedGoogle Scholar
  70. 70.
    Looney R. Structure and function of human and mouse Fc gamma RII. Blood Cells. 1993;19(2):353–9.PubMedGoogle Scholar
  71. 71.
    Davis B, Olsen S, Ahmad E, Bigelow N. Neutrophil CD64 is an improved indicator of infection or sepsis in emergency department patients. Arch Pathol Lab Med. 2006;130(5):654–61.PubMedGoogle Scholar
  72. 72.
    Lewis S, Treacher D, Bergmeier L, Brain S, Chambers D, Pearson J, et al. Plasma from patients with sepsis up-regulates the expression of CD49d and CD64 on blood neutrophils. Am J Respir Cell Mol Biol. 2009;40(6):724–32.CrossRefPubMedGoogle Scholar
  73. 73.
    Hsu K, Chan M, Wang J, Lin L, Wu C. Comparison of Fc-gamma receptor expression on neutrophils with procalcitonin for the diagnosis of sepsis in critically ill patients. Respirology. 2011;16(1):152–60.CrossRefPubMedGoogle Scholar
  74. 74.
    Nuutila J, Hohenthal U, Laitinen I, Kotilainen P, Rajamaki A, Nikoskelainen J, et al. Simultaneous quantitative analysis of FcGammaRI (CD64) expression on neutrophils and monocytes: a new, improved way to detect infections. J Immunol Methods. 2007;328(1–2):189–200.CrossRefPubMedGoogle Scholar
  75. 75.
    Jalava-Karvinen P, Hohenthal U, Laitinen I, Kotilainen P, Rajamaki A, Nikoskelainen J, et al. Simultaneous quantitative analysis of Fc gammaRI (CD64) and CR1 (CD35) on neutrophils in distinguishing between bacterial infections, viral infections and inflammatory diseases. Clin Immunol. 2009;133(3):314–23.CrossRefPubMedGoogle Scholar
  76. 76.
    Muller Kobold A, Zijlastra J, Koene H. Levels of soluble Fc gamma RIII correlate with disease severity in sepsis. Clin Exp Immunol. 1998;227:220.CrossRefGoogle Scholar
  77. 77.
    Christ-Crain M, Morgenthaler N, Struck J, Harbarth S, Bergmann A, Muller B. Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study. Crit Care. 2009;9:R816–24.CrossRefGoogle Scholar
  78. 78.
    Angeletti S, Battistoni F, Fioravanti M, Bernardini S, Dicuonzo G. Procalcitonin and mid-regional pro-adrenomedullin test combination in sepsis diagnosis. Clin Chem Lab Med. 2013;51(5):1059–67.CrossRefPubMedGoogle Scholar
  79. 79.
    Kofoed K, Andersen O, Kronborg G, Tvede M, Petersen J, Eugen-Olsen J, et al. Use of plasma C-reactive protein, procalcitonin, neutrophils, macrophage migration inhibitory factor, soluble urokinase-type plasminogen activator receptor, and soluble triggering receptor expressed on myeloid cells-1 in combination to diagnose infections. Crit Care. 2007;11:R38.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Haput T, Petersen J, Ellekilde G, Klausen H, Thorball C, Eugen-Olsen J, et al. Plasma suPAR levels are associated with mortality, admission time and Charlson comorbidity index in the acutely admitted medical patient: a prospective observational study. Crit Care. 2012;16:R130.CrossRefGoogle Scholar
  81. 81.
    Ricciuto D, dos Santos C, Hawkes M, Toltl L, Conroy A, Rajwans N, et al. Angiopoietin-1 and angiopoietin-2 as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsis. Crit Care Med. 2011;39:702–10.CrossRefPubMedGoogle Scholar
  82. 82.
    Bozza F, Gomes R, Japiassu A, Soares M, Castro-Faria-Neto H, Bozza P, et al. Macrophage migration inhibitory factor levels correlate with fatal outcome in sepsis. Shock. 2004;22:309–13.CrossRefPubMedGoogle Scholar
  83. 83.
    Calandra T, Echtenacher B, Roy D, Pugin J, Metz C, Hultner L, et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med. 2000;6:164–70.CrossRefPubMedGoogle Scholar
  84. 84.
    Gibot S, Bene M, Noel R, Massin F, Guy J, Cravoisy A, et al. Combination biomarkers to diagnose sepsis in the critically ill patient. Am J Respir Crit Care Med. 2012;186(1):65–71.CrossRefPubMedGoogle Scholar
  85. 85.
    Shapiro N, Trzeciak S, Hollander J, Birkhahn R, Otero R, Osborn T, et al. A prospective multicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock and death in emergency department patients with suspected sepsis. Crit Care Med. 2009;37(1):96–104.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Division of Surgical Research, Department of SurgeryRhode Island Hospital/Brown UniversityProvidenceUSA

Personalised recommendations