IBd Incidence of HSV and HPV with azathioprine Mario Cottone and Sara Renna severe infections are an established risk of immunosuppressive therapy; however, the risk of opportunistic infections in patients with IBd who receive immunosuppressive therapy has so far only been studied retrospectively. the increased incidence of herpes flares and development or worsening of viral warts in patients with IBd who receive azathioprine has now been demonstrated for the first time in a prospective study. the rate of opportunistic infections in patients with iBD is dependent on the patient’s nutritional status, degree of innate immune system activity, whether the patient has undergone surgery and their use of immunosuppressive drugs or biological therapy.1 severe infections are a welldocumented risk in patients who are treated with immunosuppressive therapy;2 however, use of immunosuppressants as maintenance therapy in patients with iBD is becoming increasingly common. in a 2004–2005 crosssectional study of 20,000 patients with iBD, conducted in France, >50% of patients with Crohn’s disease and approximately 25% of patients with ulcerative disease had received the immuno suppressant azathioprine.3 infections with varicellazoster virus and herpes simplex virus (Hsv) are common, nonfatal conditions characterized by a unilateral, painful, vesicular rash in a dermatomal distribution. Patients with iBD are hypothesized to be at increased risk of these viral infections because of diseaserelated alterations in immune function and frequent use of immunosuppressive medications. Data on infection with human papillomavirus (HPv) species in patients with iBD are scarce but seem to show an increased incidence of this infection in such patients.4 Different studies have used various metho dological approaches to evaluate the risk of these three viral infections in patients with iBD but no studies have evaluated the incidence of all three viruses. Korelitz et al.5 reported the incidence of varicellazoster infection in patients with iBD who were treated with 6mercaptopurine to be 2.2%. However, the researchers did not provide a comparison with the incidence of this infection in a control population, which limits the conclusions that can be drawn. a case–control study by toruner et al.1 sought to identify the factors associated with iBD and infection by comparing 100 consecutive patients with iBD who had opportunistic infections to patients with iBD who did not have a history of opportunistic infection. although the relative risk of infection was greatest in patients >50 years of age (compared with those ≤24 years of age) and was independent of immuno suppressant treatment, use of cortico steroids, azathioprine and infliximab was also associated with a significantly increased risk of opportunistic infection. the researchers reported a higher incidence of varicellazoster, Candida albicans and Hsv infections in patients who received immunosuppressant treatment than in those who did not receive this therapy, but did not provide values for the risk of any single infection. Gupta et al.6 carried out a similar but larger study, in which the incidence of varicellazoster infections in 7,823 patients with Crohn’s disease and 1,930 patients with ulcerative colitis was compared with its Practice points ■ The incidence of opportunistic infections, for example with varicella-zoster virus and human papillomavirus species, are increased in patients with iBD who receive immunosuppressant therapy ■ Concomitant treatment of the opportunistic infection or suspension of immunosuppressive medication are two possible therapeutic strategies ■ vaccination for human papillomavirus species is recommended for women with iBD © 2009 Macmillan Publishers Limited. All rights reserved nature reviews | gastroenterology & hepatology volume 6 | auGust 2009 | 445 news & views incidence in 79,563 individuals without iBD. Patients with Crohn’s disease or ulcerative colitis had a higher risk of varicellazoster infection than indivi duals in the control group. in a nested, case– control study, 185 patients with Crohn’s disease and varicellazoster infections and 266 patients with ulcerative colitis and varicellazoster infections were compared with 1,787 patients with iBD but without varicellazoster infection. Patients who received immuno suppressant medications had a greater risk of varicellazoster infection than those who did not receive such therapy. the unadjusted and adjusted odds ratios for receipt of a prescription for azathioprine or 6mercapto purine and varicellazoster infection were both 3.1. unfortunately, this study did not investigate the incidence of other opportunistic infections, such as Hsv. the studies described above are all retrospec tive and are, therefore, constrained by the usual limitations of this study type. retrospective analyses of safety data cannot accurately assess the true incidence of benign infections because they are transient conditions. such analyses, therefore, rely on accurate recall of information by the patient and can result in an underestimation of incidence of infection. thus, the information available from case–control studies is of limited value; no direct way exists to estimate the incidence or prevalence of disease, nor the attributable or excess risk of particular groups of patients. the study by seksik et al.7 is the first prospec tive study to investigate the incidence of opportunistic infection in patients with iBD who receive azathioprine therapy. in this study, 230 patients with iBD received either azathioprine (n = 169) or nonimmuno suppressive therapy (n = 61). the patients underwent a comprehensive skin examination and completed a questionnaire every 3–6 months, and the number of opportunistic infections, including ear, nose, and throat infections, bronchitis and oral or genital Hsv flares was recorded. the incidence of Hsv flares was significantly greater in the group of patients who received azathioprine than in patients who did not do so (1.0 ± 2.6 versus 0.2 ± 0.8 per year, P = 0.04). similarly, significantly more patients who received azathioprine treatment experienced newonset or worsening viral warts (17.2% versus 3.3% P = 0.004). these findings are in line with those from other studies that have reported an increased incidence of warts in immunosuppressed patients—an observation that was initially reported in renal transplant recipients.8 Contrary to other studies in the literature,1,5,6,9 however, seksik et al. did not show an increase in the incidence of varicellazoster or cytomegalovirus infection in patients with iBD who received immunosuppressant therapy. what are the implications of seksik et al.’s findings? a detailed history of herpes infection should be collected before immunosuppressive treatment is initiated in patients with iBD. However, no agreement exists on what to do when an Hsv or other infection is diagnosed during immunosuppressive therapy. viget et al.10 suggest that immunosuppressant therapy should be withdrawn as soon as possible after the identification of an opportunistic infection, but seksik et al. suggest azathio prine treatment should be maintained and concomitant treatment with antiHsv drugs should be initiated. no data on the risk of anogenital cancer related to persistent HPv infection exist; therefore, in the case of warts, suspension of immuno suppressive treatment is advisable. importantly, the findings from this study suggest that gynecological examination and cervical cancer screening should be planned for women with iBD before and after immuno suppressant treatment. HPv vaccination is safe, immunogenic and highly effective against infection with specific species of HPv. Predictive data also indicate that implementation of HPv vaccination within a national screening program is likely to be more costeffective than current clinical practice methods. the increasing incidence of HPv infection in young women with iBD also indicates that, in the future, emphasis may be placed on the new generation of recombinant HPv vaccines. Dipartimento di Medicina, Pneumologia e Fisiologia della Nutrizione, Università di Palermo, Palermo, Italy (M. Cottone, S. Renna). Correspondence: M. Cottone, Dipartimento di Medicina, Pneumologia e Fisiologia della Nutrizione, Università di Palermo. Ospedale V. Cervello, Via Trabucco 180, 90146 Palermo, Italy email@example.com doi:10.1038/nrgastro.2009.110 competing interests The authors declare no competing interests. 1. Toruner, M. et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology 134, 929–936 (2008). 2. Lichtenstein, G. R. et al. serious infections and mortality in association with therapies for Crohn’s disease: TReAT registry. Clin. Gastroenterol. Hepatol. 4, 621–630 (2006). 3. Beaugerie, L. et al. The use of immunomodulators and biologics in inflammatory bowel diseases (iBD): a crosssectional French nationwide cohort 2004– 2005 [Abstract]. Gastroenterology 130 (4 suppl. 2), A2 (2006). 4. Kane, s., Khatibi, B. & Reddy, D. Higher incidence of abnormal Pap smears in women with inflammatory bowel disease. Am. J. Gastroenterol. 103, 631–636 (2008). 5. Korelitz, B. i., Fuller, s. R., warman, J. i. & Goldberg, M. D. shingles during the course of treatment with 6-mercaptopurine for inflammatory bowel disease. Am. J. Gastroenterol. 94, 424–426 (1999). 6. Gupta, G., Lautenbach, e. & Lewis, J. D. incidence and risk factors for herpes zoster among patients with inflammatory bowel disease. Clin. Gastroenterol. Hepatol. 4, 1483–1490 (2006). 7. seksik, P. et al. incidence of benign upper respiratory tract infections, Hsv and HPv cutaneous infections in inflammatory bowel disease patients treated with azathioprine. Aliment. Pharmacol. Ther. 29, 1106–1113 (2009). 8. spencer, e. s. & Andersen, H. K. viral infections in renal allograft recipients treated with long-term immunosuppression. Br. Med. J. 2, 829–830 (1979). 9. warman, J. i., Korelitz, B. i., Fleisher, M. R. & Janardhanam, R. Cumulative experience with short- and long-term toxicity to 6-mercaptopurine in the treatment of Crohn’s disease and ulcerative colitis. J. Clin. Gastroenterol. 37, 220–225 (2003). 10. viget, n., vernier-Massouille, G., salmon- Ceron, D., Yazdanpanah, Y. & Colombel, J. F. Opportunistic infections in patients with inflammatory bowel disease: prevention and diagnosis. Gut 57, 549–558 (2008). Credit: CDC images © 2009 Macmillan Publishers Limited. All rights reserved
Renna, S., Cottone, M. (2009). Incidence of HSV and HPV with azathioprine. NATURE REVIEWS. GASTROENTEROLOGY & HEPATOLOGY, 6(8), 444-445.