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Linking Drugs to Obscure Illnesses: Lessons from Pure Red Cell Aplasia, Nephrogenic Systemic Fibrosis, and Reye’s Syndrome. A Report From the Southern Network on Adverse Reactions (SONAR)

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Abstract

Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye’s syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States’ NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common.

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References

  1. Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH. Timing of new black box warnings and withdrawals for prescription medications. JAMA. 2002;287:2215–20.

    Article  PubMed  Google Scholar 

  2. Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet. 2000;356:1000–1.

    Article  PubMed  CAS  Google Scholar 

  3. Reye RDK, Morgan G, Baral J. Encephalopathy and fatty degeneration of the viscera. A disease entity in childhood. Lancet. 1963;2:749–52.

    Article  PubMed  CAS  Google Scholar 

  4. Casadevall N, Nataf J, Viron B, et al. Pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med. 2002;346:469–75.

    Article  PubMed  CAS  Google Scholar 

  5. Marckmann P, Skov L, Rossen K, et al. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol. 2006;17:2359–62.

    Article  PubMed  Google Scholar 

  6. Starko KM, Ray GC, Dominguez LB, Stromberg WL, Woodall DF. Reye's syndrome and salicylate use. Pediatrics. 1980;66:859–64.

    PubMed  CAS  Google Scholar 

  7. Bennett CL, Luminari S, Nissenson AR, et al. Pure Red-cell aplasia and epoetin therapy. New Engl J Med. 2004;351(14):1403–1408.

    Article  PubMed  CAS  Google Scholar 

  8. Hanzlik PJ. A study of the toxicity of the salicylates based on clinical statistics. JAMA. 1913;60:957–962.

    Article  Google Scholar 

  9. Koplik H, ed. The diseases of infancy and childhood. Designed for use of students and practitioners of medicine. Philadelphia: Lea and Febiger; 1918.

    Google Scholar 

  10. Holt LE, Howland J, eds. The diseases of infancy and childhood. For the use of students and practitioners of medicine. New York: D. Appleton and Company; 1920.

    Google Scholar 

  11. Erganian JA, Forbes GB, Case DM. Salicylate intoxication in the infant and young child. J Pediatr. 1947;30:129–45.

    Article  PubMed  CAS  Google Scholar 

  12. Bain K. Death due to accidental poisoning in young children. J Pediatr. 1954;44:616–23.

    Article  PubMed  CAS  Google Scholar 

  13. Riley HD Jr, Worley L. Salicylate intoxication. Pediatrics. 1956;18:578–94.

    PubMed  Google Scholar 

  14. Segar WE, Holliday MA. Physiologic abnormalities of salicylate intoxication. N Engl J Med. 1958;259:1191–98.

    Article  PubMed  CAS  Google Scholar 

  15. Brain WR, Hunter D, Turnbull HM. Acute meningo-encephalomyelitis of childhood. Lancet. 1929;1:221–7.

    Article  Google Scholar 

  16. Partin JC, Schubert WK, Partin JS. Mitochondrial ultrastructure in Reye’s syndrome (encephlalopathy and fatty degeneration of the viscera). N Engl J Med. 1971;285:1339–43.

    Article  PubMed  CAS  Google Scholar 

  17. Mortimer EA, Lepow M. Varicella with hypoglycemia possibly due to salicylates. Am J Dis Child. 1962;103:583–90.

    PubMed  CAS  Google Scholar 

  18. Giles HM. Letter to the Editor: encephalopathy and fatty degeneration of the viscera. Lancet. 1965;1:1075.

    Article  PubMed  CAS  Google Scholar 

  19. Coburn AF. Salicylate therapy in acute rheumatic fever. Bull J Hopkins Hosp. 1943;73:435–64.

    CAS  Google Scholar 

  20. Graham JDP, Parker WA. The toxic manifestations of sodium salicylate therapy. Quart J Med. 1948;17:153–63.

    PubMed  CAS  Google Scholar 

  21. Food and Drug Administration. Over-the-counter drugs. Establishment of a monograph for OTC internal analgesic, antipyretic and antirheumtic products. Fed Regist. 1977;42:35345–621.

    Google Scholar 

  22. Follow-up on Reye Syndrome-United States. MMWR Morb Mortal Wkly Rep. 1980;29:2321–2.

    Google Scholar 

  23. Reye’s syndrome – Ohio, Michigan. MMWR Morb Mortal Wkly Rep. 1980;29:532–9.

    Google Scholar 

  24. Waldman RJ, Hall WN, McGee H, Van Amburg G. Aspirin as a risk factor in Reye's syndrome. JAMA. 1982;247:3089–94.

    Article  PubMed  CAS  Google Scholar 

  25. Halpin TJ, Holtzhauer FJ, Campbell RJ, et al. Reye's syndrome and medication use. JAMA. 1982;248:687–91.

    Article  PubMed  CAS  Google Scholar 

  26. Starko KM, Mullick FG. Hepatic and cerebral pathology findings in children with fatal salicylate intoxication: further evidence for a causal relation between salicylate and Reye’s syndrome. Lancet. 1983;1:326–29.

    Article  PubMed  CAS  Google Scholar 

  27. Pinsky PF, Hurwitz ES, Schonberger LB, Gunn WJ. Reye's syndrome and aspirin. Evidence for dose–response effect. JAMA. 1988;260:657–61.

    Article  PubMed  CAS  Google Scholar 

  28. National surveillance for Reye syndrome. 1981: update, Reye syndrome, and salicylate usage. MMWR Morb Mortal Wkly Rep. 1982;31:53–61.

    Google Scholar 

  29. Committee on Infectious Diseases. Aspirin and Reye’s syndrome. Pediatrics. 1982;69:810–12.

    Google Scholar 

  30. Centers for Disease Control (CDC). Surgeon General’s advisory on the use of salicylates and Reye syndrome. MMWR Morb Mortal Wkly Rep. 1982;31(22):289–294.

    Google Scholar 

  31. Hurwitz ES, Barrett MJ, Bregman D, et al. Public Health Service study on Reye's syndrome and medications. Report of the pilot phase. N Engl J Med. 1985;313:849–57.

    Article  PubMed  CAS  Google Scholar 

  32. Hurwitz ES, Barrett MJ, Bregman D, et al. Public Health Service study of Reye's syndrome and medications: report of the main study. JAMA. 1987;257:1905–11.

    Article  PubMed  CAS  Google Scholar 

  33. Forsyth BW, Horwitz RI, Acampora D, et al. New epidemiologic evidence confirming that bias does not explain the aspirin/Reye’s syndrome association. JAMA. 1989;261:2517–24.

    Article  PubMed  CAS  Google Scholar 

  34. Glasgow JFT. Reye’s syndrome: the case for a causal link. Drug Saf. 2006;29:1111–1121.

    Article  PubMed  Google Scholar 

  35. Arrowsmith JB, Kennedy DL, Kuritsky JN, Faich GA. National patterns of aspirin use and Reye syndrome reporting, United States, 1980–1985. Pediatrics. 1987;79:858–63.

    PubMed  CAS  Google Scholar 

  36. Belay ED, Bresee JSA, Holman RC, Khan AS, Shahriari A, Schonberger L. Reye's syndrome in the United States from 1981 through 1997. N Engl J Med. 1999;340:1377–82.

    Article  PubMed  CAS  Google Scholar 

  37. Bennett CL, Qureshi ZP, Sartor AO, Norris LB, Murday A, Xirasagar S, Thomsen HS. Gadolinium induced nephrogrenic systemic fibrosis, the rise and fall of an iatrogenic disease. Clin Kidney J. 2012;5:82–88.

    Article  PubMed  CAS  Google Scholar 

  38. Transcript of Hearings on Gadolinium-based Contrast Media Agents. Joint Cardiovascular and Renal Drugs and Drug Safety and Risk Management Advisory Committees. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM197768.pdf (Accessed 4/6/2012)

  39. Cowper SE, Bucala R, Leboit PE. Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis–setting the record straight. Semin Arthritis Rheum. 2006;35:208–10.

    Article  PubMed  Google Scholar 

  40. Marckmann P, Skov L, Rossen K, Heaf JG, Thomsen HS. Case–control study of gadodiamide-related nephrogenic systemic fibrosis. Nephrol Dial Transplant. 2007;22:3174–8.

    Article  PubMed  CAS  Google Scholar 

  41. Marckmann P. An epidemic outbreak of nephrogenic systemic fibrosis in a Danish hospital. Eur J Radiol. 2008;66:187–90.

    Article  PubMed  Google Scholar 

  42. Marckmann P, Skov L. Nephrogenic systemic fibrosis: clinical picture and treatment. Radiol Clin North Am. 2009;47:833–40.

    Article  PubMed  Google Scholar 

  43. Grobner T. Gadolinium–a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21:1104–8.

    Article  PubMed  CAS  Google Scholar 

  44. Influence of human proteins on the relaxivity of gadolinium complexes at http://www.b.dk/upload/webred/bmsandbox/uploads/2012/03/bb81a28663015b7a1d828ee723de7a26.pdf (accessed 4/6/2012)

  45. FDA: New warnings required on use of gadolinium-based contrast agents. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm225286.htm (accessed 4/6/2012).

  46. Thomsen HS. Nephrogenic systemic fibrosis: history and epidemiology. Radiol Clin North Am. 2009;47:827–31.

    Article  PubMed  Google Scholar 

  47. Lawyer Inquiry Concerning Omniscan (Advokatundersøgelse Vedrørende Omniscan). http://sum.dk/Aktuelt/Nyheder/Medicin/2010/November/∼/media/Filer%20-%20dokumenter/Omniscan-nov-2010/Omniscan-nov-2010.ashx (Accessed 4/6/2012)

  48. Stenver DI. Pharmacovigilance: what to do if you see an adverse reaction and the consequences. Eur J Radiol. 2008;66:184–6.

    Article  PubMed  Google Scholar 

  49. The Danish Medicines Agency Report on Omniscan, March 2008. 2008. http://s3.amazonaws.com/propublica/assets/omniscan/010408_FULL_Report_from_DMA.pdf (Accessed 4/6/2012)

  50. Cournoyer D, Toffelmire EB, Wells GA, et al. Anti-erythropoietin antibody-mediated pure red cell aplasia after treatment with recombinant erythropoietin products: recommendations for minimization of risk. J Am Soc Nephrol. 2004;15:2728–34.

    Article  PubMed  CAS  Google Scholar 

  51. Bennett CL, Cournoyer D, Carson KR, et al. Long-term outcome of individuals with pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant epoetin: a follow-up report from the Research on Adverse Drug Events and Reports (RADAR) Project. Blood. 2005;106:3343–7.

    Article  PubMed  CAS  Google Scholar 

  52. Macdougall IC, Rossert J, Casadevall N, et al. A peptide-based erythropoietin-receptor agonist for pure red-cell aplasia. N Engl J Med. 2009;361:1848–55.

    Article  PubMed  CAS  Google Scholar 

  53. Boven K, Stryker S, Knight J, et al. The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney Int. 2005;67:2346–53.

    Article  PubMed  Google Scholar 

  54. Perazella MA. Advanced kidney disease, gadolinium and nephrogenic systemic fibrosis: the perfect storm. Curr Opin Nephrol Hypertens. 2009;18:519–2556.

    Article  PubMed  Google Scholar 

  55. McKoy JM, Stonecash RE, Cournoyer D, Rossert J, Nissenson AR, Raisch DW, Casadevall N, Bennett CL. Epoetin-associated pure red cell aplasia: past, present, and future considerations. Transfusion. 2008;48(8):1754–62. Epub 2008 May 14.

    Article  PubMed  Google Scholar 

  56. Macdougall IC, Roger SD, de Francisco A, Goldsmith DJ, Schellekens H, Ebbers H, Jelkmann W, London G, Casadevall N, Hörl WH, Kemeny DM, Pollock C. Antibody-mediated pure red cell aplasia in chronic kidney disease patients receiving erythropoiesis-stimulating agents: new insights. Kidney Int. 2012, Feb 15. [Epub ahead of print]

  57. Seidl A, Hainzl O, Richter M, Fischer R, Böhm S, Deutel B, Hartinger M, Windisch J, Casadevall N, London GM, Macdougall I. Tungsten-Induced Denaturation and Aggregation of Epoetin Alfa During Primary Packaging as a Cause of Immunogenicity. Pharm Res. 2011 Nov 18. [Epub ahead of print]

  58. Haag-Weber M, Eckardt KU, Hörl WH, Roger SD, Vetter A, Roth K. Safety, immunogenicity and efficacy of subcutaneous biosimilar epoetin alfa (HX575) in non-dialysis patients with renal anaemia: a multi-centre, randomised, double-blind study. Clin Nephrol. 2012;77(1):8–17.

    PubMed  CAS  Google Scholar 

  59. Davis DE, Buffler P. Reduction of deaths after drug labeling for risk of Reye’s syndrome. Lancet. 1992;340:1042.

    Article  PubMed  CAS  Google Scholar 

  60. EPI News Brief. http://www.epimonitor.net/epimonday/previousissues/02-09-09.htm (accessed 5/31/2011)

  61. Wogan T. Scientific publishing. A chilling effect? Science. 2010;328:1348–9. 51.

    Article  PubMed  CAS  Google Scholar 

  62. Lichtenstein PK, Heubi JE, Daugherty CC, et al. A frequent cause of vomiting and liver dysfunction after varicella and upper respiratory tract infection. N Eng J Med. 1983;309:133–39.

    Article  CAS  Google Scholar 

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Funding

Funding was provided by grants from the National Cancer Institute (1R01CA 102713–01) (CLB) the South Carolina Center of Economic Excellence Center for Medication Safety initiative (CLB), and the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health (DRM). This paper was prepared in part by DRM as an employee of the US Government making this a “work of the US Government” and therefore the copyright is non-transferable. The opinions stated in this paper are those of the authors and do not necessarily represent views of the Department of Health and Human Services, the National Institutes of Health or the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of Interest

The authors declare that they do not have a conflict of interest.

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Author notes

  1. Donald R. Mattison MD

    Present address: Risk Sciences International, Ottawa, ON, Canada

Authors and Affiliations

  1. South Carolina College of Pharmacy, 715 Sumter Street, Suite 311, Columbia, SC, 29208, USA

    Charles L. Bennett MD, PhD, MPP, Zaina P. Qureshi PhD, MPH, P. Brandon Bookstaver PharmD, April D. Miller PharmD, LeAnn B. Norris PharmD, Alyssa Trenery, Isaac Lopez, Adam Kahn MA, Alanna Murday BS & Paul Ray DO

  2. Arnold School of Public Health of the University of South Carolina, Columbia, SC, USA

    Charles L. Bennett MD, PhD, MPP, Zaina P. Qureshi PhD, MPH & Sudha Xirasagar MBBS, PhD

  3. Hollings Cancer Center, Charleston, SC, USA

    Charles L. Bennett MD, PhD, MPP

  4. Burlingame, CA, USA

    Karen M. Starko MD

  5. Department of Diagnostic Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    Henrik S. Thomsen MD

  6. Department of Dermatology, Yale School of Medicine, New Haven, CT, USA

    Shawn Cowper MD

  7. Departments of Medicine and Urology, Tulane College of Medicine and the Tulane Cancer Center, New Orleans, LA, USA

    Oliver Sartor MD

  8. Renal Unit, King’s College Hospital, London, England, UK

    Iain C. Macdougall MD, FRCP

  9. Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy

    Stefano Luminari MD

  10. Department of Oncology, McGill University, Montreal, Canada

    Denis Cournoyer MD

  11. Department of Nephrology, Alessandro Manzoni Hospital, Lecco, Italy

    Francesco Locatelli MD

  12. Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA

    Donald R. Mattison MD

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  1. Charles L. Bennett MD, PhD, MPP
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Correspondence to Charles L. Bennett MD, PhD, MPP.

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Bennett, C.L., Starko, K.M., Thomsen, H.S. et al. Linking Drugs to Obscure Illnesses: Lessons from Pure Red Cell Aplasia, Nephrogenic Systemic Fibrosis, and Reye’s Syndrome. A Report From the Southern Network on Adverse Reactions (SONAR). J GEN INTERN MED 27, 1697–1703 (2012). https://doi.org/10.1007/s11606-012-2098-1

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