Skip to main content
SpringerLink
Log in

Role of Viral Infections in the Induction of Adverse Drug Reactions

  • Leading Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Summary

A spectrum of adverse drug reactions that are caused by the combined action of drugs and viruses has been described: ampicillin rash in acute infectious mononucleosis; Reye’s syndrome; hypersensitivity reactions to sulphonamides in patients with HIV infection; drug-induced agranulocytosis; paracetamol (acetaminophen) hepatotoxicity; aspirin (acetylsalicyclic acid)-induced asthma; Epstein-Barr virus-associated lymphoma and methotrexate; and AIDS-related Kaposi’s sarcoma and nitrite use.

Changes in pharmacokinetics have been reported for: caffeine, sulfamethoxazole and fluconazole in patients with HIV infection; theophylline, following influenza and influenza vaccination; and recently, dipyrone metabolites in carriers of the hepatitis B virus. In addition increased drug- and drug metabolite-related toxicity has been observed in virally infected cells.

Pathogenetic mechanisms for the interaction between drugs and viruses are varied, and include biological mechanisms (often immunological) and changes in drug metabolism. The combined effects of chemical and biological exposure provide a unique model for the study of disease induction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Evans ES. The clinical illness promotion factor — a third ingredient. Yale J Biol Med 1982; 55: 193–9

    PubMed  CAS  Google Scholar 

  2. Levy M. The combined effect of viruses and drugs in drug-induced diseases. Med Hypotheses 1984; 14: 293–6

    Article  PubMed  CAS  Google Scholar 

  3. Haverkos HW, Amsel Z, Drotman DP. Adverse virus-drug interactions. Rev Infect Dis 1991; 13: 697–704

    Article  PubMed  CAS  Google Scholar 

  4. Pullen H, Wright N, Murdoch JM. Hypersensitivity reactions to antibacterial drugs in infectious mononucleosis. Lancet 1967; II: 1176–8

    Article  Google Scholar 

  5. McKenzie H, Parratt D, White RG. IgM and IgG antibody levels to ampicillin in patients with infectious mononucleosis. Clin Exp Immunol 1976; 26: 214–21

    PubMed  CAS  Google Scholar 

  6. Williams RC, Kenyon AJ, Huntley CC. Immunoglobulins, viruses and speculation on their interrelationship in certain human and animal disease states. Blood 1968; 31: 522–35

    PubMed  Google Scholar 

  7. Nazareth I, Mortimer P, McKendrick GD. Ampicillin sensitivity in infectious mononucleosis-temporary or permanent?. Scand J Infect Dis 1972; 4: 229–31

    PubMed  CAS  Google Scholar 

  8. Report of a collaborative study group: a prospective study of ampicillin rash. BMJ 1973; 1: 7–9

    Google Scholar 

  9. Gregg I. Ampicillin rash and influenza [letter]. BMJ 1973; 1: 295

    Article  PubMed  CAS  Google Scholar 

  10. Reye RDK, Morgan G, Baral J. Encephalopathy and fatty degeneration of the viscera: a disease entity of childhood. Lancet 1963; II: 749–52

    Article  Google Scholar 

  11. Starko KM, Ray CG, Dominguez LB, et al. Reye’s syndrome and salicylate use. Pediatrics 1980; 66: 859–64

    PubMed  CAS  Google Scholar 

  12. Waldman RJ, Hall WN, McGee H, et al. Aspirin as a risk factor in Reye’s syndrome. JAMA 1982; 274: 3089–94

    Article  Google Scholar 

  13. Maheady DC. Reye’s syndrome: review and update. J Pediatr Health Care 1989; 3: 246–50

    Article  PubMed  CAS  Google Scholar 

  14. Hurwitz ES. The changing epidemiology of Reye’s syndrome in the United States: further evidence of a public health success. JAMA 1988; 260: 3178–80

    Article  PubMed  CAS  Google Scholar 

  15. Peters LJ, Wiener GJ, Gilliam J, et al. Reye’s Syndrome in adults, a case report and review of the literature. Arch Intern Med 1986; 146: 2401–3

    Article  PubMed  CAS  Google Scholar 

  16. Gordin FM, Simons GL, Wofsy CB, et al. Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1984; 100: 495–9

    PubMed  CAS  Google Scholar 

  17. Medina I, Mills J, Leoung G, et al. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a controlled trial of trimethoprim -sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med 1990; 323: 776–82

    Article  PubMed  CAS  Google Scholar 

  18. Jaffe HS, Abrams DI, Amman AJ, et al. Complications of cotrimoxazole of AIDS-associated Pneumocystis carinii pneumonia in homosexual men. Lancet 1983; II: 1109–11

    Article  Google Scholar 

  19. Van der Ven AJAM, Koopmans PP, Vree TB, et al. Adverse reactions to co-trimethoxazole in HIV infection. Lancet 1991; 338:431–3

    Article  PubMed  Google Scholar 

  20. Cribb AE, Spielberg SP. Sulfamethoxazole is metabolized to the hydroxylamine in humans. Clin Pharmacol Ther 1992; 51: 522–6

    Article  PubMed  CAS  Google Scholar 

  21. Carr A, Swandson C, Penny R, et al. Clinical and laboratory markers of hypersensitivity to trimethoprim/sulfamethoxazole in patients with pneumocystis carinii pneumonia and AIDS. J Infect Dis 1993; 167: 180–5

    Article  PubMed  CAS  Google Scholar 

  22. Ackerman Z, Levy M. Hypersensitivity reactions to drugs in acquired immunodeficiency syndrome. Postgrad Med J 1987; 63: 55–6

    Article  PubMed  CAS  Google Scholar 

  23. Coopman MA, Johnson RA, Platt R, et al. Cutaneous disease and drug reactions in HIV infection. N Engl J Med 1993; 328: 1670–4

    Article  PubMed  CAS  Google Scholar 

  24. Havercos HW, Pinsky PF, Drotman DP, et al. Disease manifestation among homosexual men with acquired immunodeficiency syndrome: a possible role of nitrites in Kaposi’s sarcoma. Sex Transm Dis 1985; 12: 203–8

    Article  Google Scholar 

  25. Archibald CP, Schechter MT, Le TN, et al. Evidence of a sexually transmitted cofactor for AIDS-related Kaposi’s sarcoma in a cohort of homosexual men. Epidemiology 1992; 3:203–9

    Article  PubMed  CAS  Google Scholar 

  26. Haverkos HW, Kopstein AN, Wilson H, et al. Nitrite inhalants: history, epidemiology and possible links to AIDS. Environ Health Perspect 1994; 102: 858–61

    Article  PubMed  CAS  Google Scholar 

  27. Mirvish SS, Williamson J, Babcook D, et al. Mutagenicity of iso-butyl nitrite vapor in the Ames test and some relevant chemical properties, including the reaction of iso-butyl nitrite with phosphate. Environ Mol Mutagen 1993; 21: 247–52

    Article  PubMed  CAS  Google Scholar 

  28. Macdonald MG, McGrath PP, McMartin DN. Potentiation of the toxic effects of acetaminophen in mice by concurrent infection with influenza B virus: a possible mechanism for human Reye’s syndrome. Pediatr Res 1984; 18: 181–7

    Article  PubMed  CAS  Google Scholar 

  29. Renton KW, Dickson G. The prevention of acetaminophen-induced hepatotoxicity by the interferon inducer poly (r 1. r C). Toxicol Appl Pharmacol 1984: 72: 40–5

    Article  PubMed  CAS  Google Scholar 

  30. Rosenberg DM, Meyer AA, Manning IH, et al. Acetaminophen and hepatic dysfunction in infectious mononucleosis. South Med J 1977; 70: 660–1

    Article  PubMed  CAS  Google Scholar 

  31. Ackerman Z, Flugelman MY, Wax Y, et al. Hepatitis during measles in young adults: possible role of antipyretic drugs. Hepatology 1989; 10: 203–6

    Article  PubMed  CAS  Google Scholar 

  32. Kaufman DW, Kelly JP, Levy M, et al. The drug etiology of agranulocytosis and aplastic anemia. New York: Oxford University Press, 1991

    Google Scholar 

  33. Levy M, Kelly JP, Kaufman DW, et al. Risk of agranulocytosis and aplastic anemia in relation to history of infectious mononucleosis: a report from the International Agranulocytosis and Aplastic Anemia Study. Ann Hematol 1993; 67: 187–90

    Article  PubMed  CAS  Google Scholar 

  34. Purtilo DT. Epstein-Barr virus: the spectrum of its manifestations in human beings. South Med J 1987; 80: 943–7

    Article  PubMed  CAS  Google Scholar 

  35. Szczeklik A. Aspirin-induced asthma as a viral disease. Clin Allergy 1988; 18: 15–20

    Article  PubMed  CAS  Google Scholar 

  36. Kamel OW, Van de Rijn M, Weiss LM, et al. Reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. N Engl J Med 1993; 328: 1317–21

    Article  PubMed  CAS  Google Scholar 

  37. Bass NM, Williams RL. Guide to drug dosage in hepatic disease. Clin Pharmacokinet 1988; 15: 396–420

    Article  PubMed  CAS  Google Scholar 

  38. McLean AJ, Morgan DJ. Clinical pharmacokinetics in patients with liver disease. Clin Pharmacokinet 1991; 21: 42–69

    Article  PubMed  CAS  Google Scholar 

  39. Joanne C, Paintaud G, Bresson-Hadni S, et al. Is debrisoquine hydroxylation modified during acute viral hepatitis?. Fundam Clin Pharmacol 1994; 8: 76–9

    Article  PubMed  CAS  Google Scholar 

  40. Lee BL, Wong D, Benowitz NL, et al. Altered patterns of drug metabolism in patients with acquired immunodeficiency syndrome. Clin Pharmacol Ther 1993; 53: 529–35

    Article  PubMed  CAS  Google Scholar 

  41. Dolomenie C, Grant DM, Mathelier-Fusade P, et al. N-acetylation genotype and risk of severe reactions to sulphonamides in AIDS patients. Br J Clin Pharmacol 1994; 38: 581–2

    Article  Google Scholar 

  42. Kaufman GR, Wenk M, Taeschner W, et al. N-acetyltransferase 2 polymorphism in patients infected with human immunodeficiency virus. Clin Pharmacol Ther 1996; 60: 62–7

    Article  Google Scholar 

  43. Singh G, Renton KW. Interferon-mediated depression of cytochrome P-450 dependent drug biotransformation. Mol Pharmacol 1981; 20: 681–4

    PubMed  CAS  Google Scholar 

  44. Renton KW, Knickle LC. Regulation of hepatic cytochrome P-450 during infectious diseases. Can J Physiol Pharmacol 1990; 68: 777–81

    Article  PubMed  CAS  Google Scholar 

  45. Ghezzi P, Bianchi M, Gianera L, et al. Role of reactive oxygen intermediates in the interferon-mediated depression of hepatic drug metabolism and protective effect of N-acetylcysteine in mice. Cancer Res 1985; 45: 3444–7

    PubMed  CAS  Google Scholar 

  46. Proulx M, du Souich P. Inflammation-induced decrease in hepatic cytochrome P450 in conscious rabbits is accompanied by an increase in hepatic oxidative stress. Res Commun Mol Pathol Pharmacol 1995; 87: 221–36

    PubMed  CAS  Google Scholar 

  47. Rieder MJ, Shear NH, Kanee A, et al. Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions. Clin Pharmacol Ther 1991; 49: 13–7

    Article  PubMed  CAS  Google Scholar 

  48. Carr A, Gross AS, Hoskins JM, et al. Acetylation phenotype and cutaneous hypersensitivity to trimethoprim sulphamethoxazole in HIV-infected patients. AIDS 1994; 8: 333–7

    Article  PubMed  CAS  Google Scholar 

  49. Shear NH, Spielberg SP, Grant DM, et al. Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med 1986; 105: 179–87

    PubMed  CAS  Google Scholar 

  50. Buhl R, Jaffe HA, Holroyd KJ, et al. Systemic glutathione deficiency in symptom-free HIV-sero-positive individuals. Lancet 1989; II: 1294–8

    Article  Google Scholar 

  51. Van der Ven AJAM, Vree TB, Van Ewijk-Beneken Kolmer EWJ, et al. Urinary recovery and kinetics of sulphamethoxazole and its metabolites in HIV seropositive patients and healthy volunteers after a single oral dose of sulphamethoxazole. Br J Clin Pharmacol 1995; 39: 621–5

    Article  PubMed  Google Scholar 

  52. Rieder MJ, Uetrecht J, Shear NH, et al. Diagnosis of sulfonamide hypersensitivity reactions by in vitro ‘rechallenge’ with hydroxylamine metabolites. Ann Intern Med 1989; 110: 286–9

    PubMed  CAS  Google Scholar 

  53. Carr A, Tindall B, Penny R, et al. In vitro cytotoxicity as a marker of cytotoxicity to sulphamethoxazole in patients with human immunodeficiency virus (HIV) infection. Clin Exp Immunol 1993; 94: 21–5

    Article  PubMed  CAS  Google Scholar 

  54. DeMuria D, Forrest A, Rich J, et al. Pharmacokinetics and bioavailability of fluconazole in patients with AIDS. Antimicrob Agents Chemother 1993; 37: 2187–92

    Article  PubMed  CAS  Google Scholar 

  55. Yeates RAM, Rahnke Y, Pfau SA, et al. The pharmacokinetics of fluconazole after a single intravenous dose in AIDS patients. Br J Clin Pharmacol 1994; 38: 77–9

    Article  PubMed  CAS  Google Scholar 

  56. Tett S, Moore S, Ray J. Pharmacokinetics and bioavailability of fluconazole in two groups of males with human immunodeficiency virus (HIV) infection compared with those in a group of males without HIV infection. Antimicrob Agents Chemother 1995; 39: 1835–41

    Article  PubMed  CAS  Google Scholar 

  57. Gatti G, Flaherty J, Bubp J, et al. Comparative study of bioavailability and pharmacokinetics of clindamycin in healthy volunteers and patients with AIDS. Antimicrob Agents Chemother 1993; 37: 1137–43

    Article  PubMed  CAS  Google Scholar 

  58. Levy M, Zylber-Katz E, Rosenkranz B. Clinical pharmacokinetics of dipyrone and its metabolites. Clin Pharmacokinet 1995; 28: 216–34

    Article  PubMed  CAS  Google Scholar 

  59. Levy M, Leibowitz Y, Ilan Y, et al. Dipyrone metabolites kinetics in carriers of hepatitis B virus with normal liver function tests: preliminary results [abstract]. Therapie 1995; Suppl.: 482

  60. Svensson CK, Knowlton PW. Effect of the immunomodulator tilorone on the in vivo acetylation of procainamide in the rat. Pharm Res 1989; 6: 477–80

    Article  PubMed  CAS  Google Scholar 

  61. Kramer P, McClain C. Depression of aminopyrine metabolism by influenza vaccination. N Engl J Med 1981; 305: 1262–4

    Article  PubMed  CAS  Google Scholar 

  62. Chang CK, Lauer BA, Bell TD, et al. Altered theophylline pharmacokinetics during acute respiratory viral illness. Lancet 1978; I: 1132–3

    Article  Google Scholar 

  63. Kraemer MJ, Furukawa CT, Coup J, et al. Altered theophylline clearance during an influenza B outbreak. Paediatrics 1982; 69: 476–80

    CAS  Google Scholar 

  64. Renton KW. Theophylline pharmacokinetics in respiratory viral illness. Lancet 1978; II: 160–1

    Google Scholar 

  65. Renton KW, Gray JD, Hall RI. Decreased elimination of theophylline after influenza vaccination. Can Med Assoc J 1980; 125: 288–90

    Google Scholar 

  66. Walker S, Schreiber L, Middelkamp C. Serum theophylline levels after influenza vaccination. Can Med Assoc J 1981; 125: 243–4

    PubMed  CAS  Google Scholar 

  67. Meredith CG, Christian CD, Johnson RF, et al. Effects of influenza virus vaccine on hepatic drug metabolism. Clin Pharmacol Ther 1985; 37: 396–401

    Article  PubMed  CAS  Google Scholar 

  68. Goldstein RS, Cheung OT, Seguin R, et al. Decreased elimination of theophylline after influenza vaccination. Can Med Assoc J 1982; 126:470

    PubMed  CAS  Google Scholar 

  69. San Joaquin VH, Reyes S, Marks MI. Influenza vaccination in asthmatic children on maintenance theophylline therapy. Clin Pediatr 1982; 21: 724–6

    Article  Google Scholar 

  70. Fischer RG, Booth BJ, Mitchell DQ, et al. Influence of trivalent influenza vaccine on serum theophylline levels. Can Med Assoc J 1982; 126: 1312–3

    PubMed  CAS  Google Scholar 

  71. Grabowski N, May JJ, Prett DS. No effect of split virus influenza vaccination on theophylline pharmacokinetics. Am Rev Respir Dis 1985; 131:934–8

    PubMed  CAS  Google Scholar 

  72. Kortabarria R, Duran JA, Abadin JA, et al. Influenza vaccination and plasma concentrations of theophylline in patients with asthma and COPD. Clin Drug Invest 1995; 9: 161–5

    Article  Google Scholar 

  73. Hannan SE, May JJ, Pratt DS, et al. The effect of whole virus influenza vaccination on theophylline pharmacokinetics. Am Rev Respir Dis 1988; 137: 903–6

    PubMed  CAS  Google Scholar 

  74. Kramer P, McClain CJ. Depression of aminopyrine metabolism by influenza vaccination. N Engl J Med 1981; 305: 1262–4

    Article  PubMed  CAS  Google Scholar 

  75. Kramer P, Tsuru M, Cook CE, et al. Effects of influenza vaccine on warfarin anticoagulation. Clin Pharmacol Ther 1984; 35: 416–8

    Article  PubMed  CAS  Google Scholar 

  76. Lipsky BA, Pecoraro NJ, Roben NJ, et al. The effect of the influenza vaccination (IV) on warfarin anticoagulation. Ann Intern Med 1984; 100: 835–7

    PubMed  CAS  Google Scholar 

  77. Rieder Ml, Bird IA, Dekaban GA. Kinetics of increased sensitivity to sulfonamide reactive metabolites in HIV-infected cells [abstract]. Clin Pharmacol Ther 1995; 57: 135

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Hadassah University Hospital, Ein Karem, Jerusalem, 91-120, Israel

    Micha Levy

Authors
  1. Micha Levy
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Levy, M. Role of Viral Infections in the Induction of Adverse Drug Reactions. Drug-Safety 16, 1–8 (1997). https://doi.org/10.2165/00002018-199716010-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-199716010-00001

Keywords

Search

Navigation