C-reactive protein: Difference between revisions

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Abnormal high sensitivity CRP values may assist in assessing lipid measurements in apparently healthy people due to the theory that chronic inflammation precedes [[atherosclerosis]].<ref name="pmid16818927">Lloyd-Jones DM, Liu K, Tian L, Greenland P. [http://annals.org/cgi/content/full/145/1/35 Narrative review: Assessment of C-reactive protein in risk prediction for cardiovascular disease]. Ann Intern Med. 2006 Jul 4;145(1):35-42. PMID 16818927</ref> However, a review found that the ability of the CRP to add to other methods of predicting [[coronary heart disease]] such as the [http://hp2010.nhlbihin.net/atpiii/calculator.asp Framingham risk tool] is limited<ref name="pmid16818927"/> except in one study ([[Receiver operating characteristic curve|AUC]] increased from 0.735 to 0.750)<ref name="pmid15023871">{{cite journal |author=Koenig W, Löwel H, Baumert J, Meisinger C |title=C-reactive protein modulates risk prediction based on the Framingham Score: implications for future risk assessment: results from a large cohort study in southern Germany |journal=Circulation |volume=109 |issue=11 |pages=1349–53 |year=2004 |month=March |pmid=15023871 |doi=10.1161/01.CIR.0000120707.98922.E3 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=15023871 |issn=}}</ref>. In one study, the CRP did not add to the coronary calcium score.<ref name="pmid18367736">{{cite journal |author=Detrano R, Guerci AD, Carr JJ, ''et al'' |title=Coronary calcium as a predictor of coronary events in four racial or ethnic groups |journal=N. Engl. J. Med. |volume=358 |issue=13 |pages=1336–45 |year=2008 |month=March |pmid=18367736 |doi=10.1056/NEJMoa072100 |url=http://content.nejm.org/cgi/content/full/358/13/1336 |issn=}}</ref> The Reynolds score has been validated in a large [[cohort study]].<ref>http://www.annals.org/cgi/content/full/150/2/65</ref>
Abnormal high sensitivity CRP values may assist in assessing lipid measurements in apparently healthy people due to the theory that chronic inflammation precedes [[atherosclerosis]].<ref name="pmid16818927">Lloyd-Jones DM, Liu K, Tian L, Greenland P. [http://annals.org/cgi/content/full/145/1/35 Narrative review: Assessment of C-reactive protein in risk prediction for cardiovascular disease]. Ann Intern Med. 2006 Jul 4;145(1):35-42. PMID 16818927</ref> However, a review found that the ability of the CRP to add to other methods of predicting [[coronary heart disease]] such as the [http://hp2010.nhlbihin.net/atpiii/calculator.asp Framingham risk tool] is limited<ref name="pmid16818927"/> except in one study ([[Receiver operating characteristic curve|AUC]] increased from 0.735 to 0.750)<ref name="pmid15023871">{{cite journal |author=Koenig W, Löwel H, Baumert J, Meisinger C |title=C-reactive protein modulates risk prediction based on the Framingham Score: implications for future risk assessment: results from a large cohort study in southern Germany |journal=Circulation |volume=109 |issue=11 |pages=1349–53 |year=2004 |month=March |pmid=15023871 |doi=10.1161/01.CIR.0000120707.98922.E3 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=15023871 |issn=}}</ref>. In one study, the CRP did not add to the coronary calcium score.<ref name="pmid18367736">{{cite journal |author=Detrano R, Guerci AD, Carr JJ, ''et al'' |title=Coronary calcium as a predictor of coronary events in four racial or ethnic groups |journal=N. Engl. J. Med. |volume=358 |issue=13 |pages=1336–45 |year=2008 |month=March |pmid=18367736 |doi=10.1056/NEJMoa072100 |url=http://content.nejm.org/cgi/content/full/358/13/1336 |issn=}}</ref> The Reynolds score has been validated in a large [[cohort study]].<ref>http://www.annals.org/cgi/content/full/150/2/65</ref>


Most, but not all<ref name="pmid19131384">{{cite journal |author=de Ruijter W, Westendorp RG, Assendelft WJ, ''et al'' |title=Use of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study |journal=BMJ |volume=338 |issue= |pages=a3083 |year=2009 |pmid=19131384 |pmc=2615548 |doi= |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=19131384 |issn=}}</ref>, recent studies have transformed the CPR levels prior to analysis.<ref name="pmid17182988">{{cite journal |author=Wang TJ, Gona P, Larson MG, ''et al'' |title=Multiple biomarkers for the prediction of first major cardiovascular events and death |journal=N. Engl. J. Med. |volume=355 |issue=25 |pages=2631–9 |year=2006 |month=December |pmid=17182988 |doi=10.1056/NEJMoa055373 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=17182988&promo=ONFLNS19 |issn=}}</ref> First, an analysis of Framingham data showed small improvement from using the log of the CRP ([[Receiver operating characteristic curve|AUC]] increased from 0.795 to 0.799 and 12% of patients had improved estimates - [[sensitivity and specificity|net reclassification improvement]] (NRI) = 11%).<ref>{{Cite journal | doi = 10.1161/CIRCOUTCOMES.108.831198 | volume = 1 | issue = 2 | pages = 92-97 | last = Wilson | first = Peter W.F. | coauthors = Michael Pencina, Paul Jacques, Jacob Selhub, Ralph D'Agostino, Christopher J. O'Donnell | title = C-Reactive Protein and Reclassification of Cardiovascular Risk in the Framingham Heart Study | journal = Circ Cardiovasc Qual Outcomes | accessdate = 2008-12-08 | date = 2008-11-01 | url = http://circoutcomes.ahajournals.org/cgi/content/abstract/1/2/92 }}</ref> Second, the natural logarithm transformation of the CRP is part of the Reynolds score which has been proposed as an improvement to the Framingham risk for the prediction of [[coronary heart disease]] ([[Receiver operating characteristic curve|AUC]] increased from 0.689 to 0.700 in men<ref name="pmid18997194">{{cite journal |author=Ridker PM, Paynter NP, Rifai N, Gaziano JM, Cook NR |title=C-reactive protein and parental history improve global cardiovascular risk prediction: the Reynolds Risk Score for men |journal=Circulation |volume=118 |issue=22 |pages=2243–51, 4p following 2251 |year=2008 |month=November |pmid=18997194 |doi=10.1161/CIRCULATIONAHA.108.814251 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=18997194 |issn=}}</ref> and  from 0.805 to 0.808 in women<ref name="pmid17299196">{{cite journal |author=Ridker PM, Buring JE, Rifai N, Cook NR |title=Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score |journal=JAMA |volume=297 |issue=6 |pages=611–9 |year=2007 |month=February |pmid=17299196 |doi=10.1001/jama.297.6.611 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=17299196 |issn=}}</ref>). This, the hsCRP added similarly to the predictions in the Women's Health Study.<ref name="pmid16818925">{{cite journal |author=Cook NR, Buring JE, Ridker PM |title=The effect of including C-reactive protein in cardiovascular risk prediction models for women |journal=Ann. Intern. Med. |volume=145 |issue=1 |pages=21–9 |year=2006 |month=July |pmid=16818925 |doi= |url= |issn=}}</ref>  An online calculator is at http://www.reynoldsriskscore.org/.
Most, but not all<ref name="pmid19131384">{{cite journal |author=de Ruijter W, Westendorp RG, Assendelft WJ, ''et al'' |title=Use of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study |journal=BMJ |volume=338 |issue= |pages=a3083 |year=2009 |pmid=19131384 |pmc=2615548 |doi= |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=19131384 |issn=}}</ref>, recent studies have transformed the CPR levels prior to analysis.<ref name="pmid17182988">{{cite journal |author=Wang TJ, Gona P, Larson MG, ''et al'' |title=Multiple biomarkers for the prediction of first major cardiovascular events and death |journal=N. Engl. J. Med. |volume=355 |issue=25 |pages=2631–9 |year=2006 |month=December |pmid=17182988 |doi=10.1056/NEJMoa055373 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=17182988&promo=ONFLNS19 |issn=}}</ref> First, an analysis of Framingham data showed small improvement from using the log of the CRP ([[Receiver operating characteristic curve|AUC]] increased from 0.795 to 0.799 and 12% of patients had improved estimates - [[sensitivity and specificity|net reclassification improvement]] (NRI) = 11%).<ref>{{Cite journal | doi = 10.1161/CIRCOUTCOMES.108.831198 | volume = 1 | issue = 2 | pages = 92-97 | last = Wilson | first = Peter W.F. | coauthors = Michael Pencina, Paul Jacques, Jacob Selhub, Ralph D'Agostino, Christopher J. O'Donnell | title = C-Reactive Protein and Reclassification of Cardiovascular Risk in the Framingham Heart Study | journal = Circ Cardiovasc Qual Outcomes | accessdate = 2008-12-08 | date = 2008-11-01 | url = http://circoutcomes.ahajournals.org/cgi/content/abstract/1/2/92 }}</ref> Second, the natural logarithm transformation of the CRP is part of the Reynolds score which has been proposed as an improvement to the Framingham risk for the prediction of [[coronary heart disease]] ([[Receiver operating characteristic curve|AUC]] increased from 0.689 to 0.700 in men<ref name="pmid18997194">{{cite journal |author=Ridker PM, Paynter NP, Rifai N, Gaziano JM, Cook NR |title=C-reactive protein and parental history improve global cardiovascular risk prediction: the Reynolds Risk Score for men |journal=Circulation |volume=118 |issue=22 |pages=2243–51, 4p following 2251 |year=2008 |month=November |pmid=18997194 |doi=10.1161/CIRCULATIONAHA.108.814251 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=18997194 |issn=}}</ref> and  from 0.805 to 0.808 in women<ref name="pmid17299196">{{cite journal |author=Ridker PM, Buring JE, Rifai N, Cook NR |title=Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score |journal=JAMA |volume=297 |issue=6 |pages=611–9 |year=2007 |month=February |pmid=17299196 |doi=10.1001/jama.297.6.611 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=17299196 |issn=}}</ref>). Third, the hsCRP added similarly to the predictions in the Women's Health Study.<ref name="pmid16818925">{{cite journal |author=Cook NR, Buring JE, Ridker PM |title=The effect of including C-reactive protein in cardiovascular risk prediction models for women |journal=Ann. Intern. Med. |volume=145 |issue=1 |pages=21–9 |year=2006 |month=July |pmid=16818925 |doi= |url=http://www.annals.org/cgi/content/full/145/1/21 |issn=}}</ref>  An online calculator is at http://www.reynoldsriskscore.org/.


Risk factor modification, particularly the use of [[aspirin]] and the [[hydroxymethylglutaryl-coenzyme A reductase inhibitor]]s (statins), may reduce plaque inflammation.<ref name=EM-CR{>{{citation  | journal = eMedicine  | title =Atherosclerosis | date =  Aug 10, 2006  | author = F Brian Boudi, Chowdhury H Ahsan, James L Orford, Andrew P Selwyn  | url =http://www.emedicine.com/med/topic182.htm}}</ref> [[Statin]] therapy benefited about 1 of every 170 patients with [[LDL cholesterol]] less than 130 mg per deciliter (3.4 mmol per liter), [http://hp2010.nhlbihin.net/atpiii/calculator.asp Framingham risk score] of 10%, and high-sensitivity [[C-reactive protein]] levels of 2.0 mg per liter or higher who took [[rosuvastatin]] 20 mg daily for 2 years if they are similar to the patients in the JUPITER [[randomized controlled trial]] ([[number needed to treat]] for two years is 170).<ref name="pmid18997196">{{cite journal |author=Ridker PM, Danielson E, Fonseca FA, ''et al'' |title=Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein |journal=N. Engl. J. Med. |volume= |issue= |pages= |year=2008 |month=November |pmid=18997196 |doi=10.1056/NEJMoa0807646 |url=http://content.nejm.org/cgi/content/full/NEJMoa0807646 |issn=}}</ref><ref name="pmid14609996">{{cite journal |author=Ridker PM |title=Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial |journal=Circulation |volume=108 |issue=19 |pages=2292–7 |year=2003 |month=November |pmid=14609996 |doi=10.1161/01.CIR.0000100688.17280.E6 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=14609996 |issn=}}</ref> The frequency of death from any cause fell from 2.8% to 2.2% ([[number needed to treat]] for two years is 180). However, this trial was stopped early after an interim analysis so it is likely that the results are exaggerated.
Risk factor modification, particularly the use of [[aspirin]] and the [[hydroxymethylglutaryl-coenzyme A reductase inhibitor]]s (statins), may reduce plaque inflammation.<ref name=EM-CR{>{{citation  | journal = eMedicine  | title =Atherosclerosis | date =  Aug 10, 2006  | author = F Brian Boudi, Chowdhury H Ahsan, James L Orford, Andrew P Selwyn  | url =http://www.emedicine.com/med/topic182.htm}}</ref> [[Statin]] therapy benefited about 1 of every 170 patients with [[LDL cholesterol]] less than 130 mg per deciliter (3.4 mmol per liter), [http://hp2010.nhlbihin.net/atpiii/calculator.asp Framingham risk score] of 10%, and high-sensitivity [[C-reactive protein]] levels of 2.0 mg per liter or higher who took [[rosuvastatin]] 20 mg daily for 2 years if they are similar to the patients in the JUPITER [[randomized controlled trial]] ([[number needed to treat]] for two years is 170).<ref name="pmid18997196">{{cite journal |author=Ridker PM, Danielson E, Fonseca FA, ''et al'' |title=Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein |journal=N. Engl. J. Med. |volume= |issue= |pages= |year=2008 |month=November |pmid=18997196 |doi=10.1056/NEJMoa0807646 |url=http://content.nejm.org/cgi/content/full/NEJMoa0807646 |issn=}}</ref><ref name="pmid14609996">{{cite journal |author=Ridker PM |title=Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial |journal=Circulation |volume=108 |issue=19 |pages=2292–7 |year=2003 |month=November |pmid=14609996 |doi=10.1161/01.CIR.0000100688.17280.E6 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=14609996 |issn=}}</ref> The frequency of death from any cause fell from 2.8% to 2.2% ([[number needed to treat]] for two years is 180). However, this trial was stopped early after an interim analysis so it is likely that the results are exaggerated.

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Template:TOC-right C-reactive protein (CRP) is one of the circulating blood proteins that help the host defense system begin immune defense by phagocytosis performed my macrophage. Its opsonization of target cells is much less precise than from immunoglobulin generated by B-lympocytes for T8 lymphocytes. When activated, it binds, with the antigen, to a surface receptor on macrophages and opsonize the threatening cells.

Diagnostic use

Detecting inflammation

Along with the erythrocyte sedimentation rate, when laboratory results are elevated, the clinician has warning an an acute inflammatory disorder exists.[1] CRP is a better predictor inflammatory disease than the erythrocyte sedimentation rate in a vasculitis such as giant cell arteritis, also called temporal arteritis; cranial arteritis; or Horton's disease [2] or microscopic polyangiitis[3]

Predicting risk of atherosclerosis

Altought the CRP molecule itself does not seem to directly cause cardiac disease[4], its presence may help prediction coronary heart disease.

Abnormal high sensitivity CRP values may assist in assessing lipid measurements in apparently healthy people due to the theory that chronic inflammation precedes atherosclerosis.[5] However, a review found that the ability of the CRP to add to other methods of predicting coronary heart disease such as the Framingham risk tool is limited[5] except in one study (AUC increased from 0.735 to 0.750)[6]. In one study, the CRP did not add to the coronary calcium score.[7] The Reynolds score has been validated in a large cohort study.[8]

Most, but not all[9], recent studies have transformed the CPR levels prior to analysis.[10] First, an analysis of Framingham data showed small improvement from using the log of the CRP (AUC increased from 0.795 to 0.799 and 12% of patients had improved estimates - net reclassification improvement (NRI) = 11%).[11] Second, the natural logarithm transformation of the CRP is part of the Reynolds score which has been proposed as an improvement to the Framingham risk for the prediction of coronary heart disease (AUC increased from 0.689 to 0.700 in men[12] and from 0.805 to 0.808 in women[13]). Third, the hsCRP added similarly to the predictions in the Women's Health Study.[14] An online calculator is at http://www.reynoldsriskscore.org/.

Risk factor modification, particularly the use of aspirin and the hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins), may reduce plaque inflammation.[15] Statin therapy benefited about 1 of every 170 patients with LDL cholesterol less than 130 mg per deciliter (3.4 mmol per liter), Framingham risk score of 10%, and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher who took rosuvastatin 20 mg daily for 2 years if they are similar to the patients in the JUPITER randomized controlled trial (number needed to treat for two years is 170).[16][17] The frequency of death from any cause fell from 2.8% to 2.2% (number needed to treat for two years is 180). However, this trial was stopped early after an interim analysis so it is likely that the results are exaggerated.

Lowering the C-reactive protein

Obesity and unhealthy diet may raise CRP.[18]

Medications

Both aspirin[19] and statins (lovastatin[20] and rosuvastatin[16]) can lower the C-reactive protein with a synergistic effect from combining both drugs[21]. Aspirin is especially effect in reducing coronary heart disease among people with eleveate C-reactive proteins.[22]

References

  1. ↑ Husain TM, Kim DH (Spring 2002), "C-Reactive Protein and Erythrocyte Sedimentation Rate in Orthopaedics", University of Pennsylvania Orthopedic Journal 15: 13-16
  2. ↑ Giant cell arteritis, Merck Manual for Healthcare Professionals
  3. ↑ Microscoping polyangiitis, Merck Manual for Healthcare Professionals
  4. ↑ Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG (October 2008). "Genetically elevated C-reactive protein and ischemic vascular disease". N. Engl. J. Med. 359 (18): 1897–908. DOI:10.1056/NEJMoa0707402. PMID 18971492. Research Blogging.
  5. ↑ 5.0 5.1 Lloyd-Jones DM, Liu K, Tian L, Greenland P. Narrative review: Assessment of C-reactive protein in risk prediction for cardiovascular disease. Ann Intern Med. 2006 Jul 4;145(1):35-42. PMID 16818927
  6. ↑ Koenig W, Löwel H, Baumert J, Meisinger C (March 2004). "C-reactive protein modulates risk prediction based on the Framingham Score: implications for future risk assessment: results from a large cohort study in southern Germany". Circulation 109 (11): 1349–53. DOI:10.1161/01.CIR.0000120707.98922.E3. PMID 15023871. Research Blogging.
  7. ↑ Detrano R, Guerci AD, Carr JJ, et al (March 2008). "Coronary calcium as a predictor of coronary events in four racial or ethnic groups". N. Engl. J. Med. 358 (13): 1336–45. DOI:10.1056/NEJMoa072100. PMID 18367736. Research Blogging.
  8. ↑ http://www.annals.org/cgi/content/full/150/2/65
  9. ↑ de Ruijter W, Westendorp RG, Assendelft WJ, et al (2009). "Use of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study". BMJ 338: a3083. PMID 19131384. PMC 2615548. [e]
  10. ↑ Wang TJ, Gona P, Larson MG, et al (December 2006). "Multiple biomarkers for the prediction of first major cardiovascular events and death". N. Engl. J. Med. 355 (25): 2631–9. DOI:10.1056/NEJMoa055373. PMID 17182988. Research Blogging.
  11. ↑ Wilson, Peter W.F.; Michael Pencina, Paul Jacques, Jacob Selhub, Ralph D'Agostino, Christopher J. O'Donnell (2008-11-01). "C-Reactive Protein and Reclassification of Cardiovascular Risk in the Framingham Heart Study". Circ Cardiovasc Qual Outcomes 1 (2): 92-97. DOI:10.1161/CIRCOUTCOMES.108.831198. Retrieved on 2008-12-08. Research Blogging.
  12. ↑ Ridker PM, Paynter NP, Rifai N, Gaziano JM, Cook NR (November 2008). "C-reactive protein and parental history improve global cardiovascular risk prediction: the Reynolds Risk Score for men". Circulation 118 (22): 2243–51, 4p following 2251. DOI:10.1161/CIRCULATIONAHA.108.814251. PMID 18997194. Research Blogging.
  13. ↑ Ridker PM, Buring JE, Rifai N, Cook NR (February 2007). "Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score". JAMA 297 (6): 611–9. DOI:10.1001/jama.297.6.611. PMID 17299196. Research Blogging.
  14. ↑ Cook NR, Buring JE, Ridker PM (July 2006). "The effect of including C-reactive protein in cardiovascular risk prediction models for women". Ann. Intern. Med. 145 (1): 21–9. PMID 16818925. [e]
  15. ↑ F Brian Boudi, Chowdhury H Ahsan, James L Orford, Andrew P Selwyn (Aug 10, 2006), "Atherosclerosis", eMedicine
  16. ↑ 16.0 16.1 Ridker PM, Danielson E, Fonseca FA, et al (November 2008). "Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein". N. Engl. J. Med.. DOI:10.1056/NEJMoa0807646. PMID 18997196. Research Blogging.
  17. ↑ Ridker PM (November 2003). "Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial". Circulation 108 (19): 2292–7. DOI:10.1161/01.CIR.0000100688.17280.E6. PMID 14609996. Research Blogging.
  18. ↑ Hickling S, Hung J, Knuiman M, Divitini M, Beilby J (July 2008). "Are the associations between diet and C-reactive protein independent of obesity?". Prev Med 47 (1): 71–6. DOI:10.1016/j.ypmed.2008.02.007. PMID 18329089. Research Blogging.
  19. ↑ Solheim S, Arnesen H, Eikvar L, Hurlen M, Seljeflot I (October 2003). "Influence of aspirin on inflammatory markers in patients after acute myocardial infarction". Am. J. Cardiol. 92 (7): 843–5. PMID 14516890. [e]
  20. ↑ Ridker PM, Rifai N, Clearfield M, et al (June 2001). "Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events". N. Engl. J. Med. 344 (26): 1959–65. PMID 11430324. [e]
  21. ↑ Fisher M, Cushman M, Knappertz V, Howard G (July 2008). "An assessment of the joint associations of aspirin and statin use with C-reactive protein concentration". Am. Heart J. 156 (1): 106–11. DOI:10.1016/j.ahj.2007.12.035. PMID 18585504. Research Blogging.
  22. ↑ Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH (April 1997). "Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men". N. Engl. J. Med. 336 (14): 973–9. PMID 9077376. [e]
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