Advertisement

European Journal of Clinical Pharmacology

, Volume 75, Issue 11, pp 1471–1480 | Cite as

m-TOR inhibitors and risk of Pneumocystis pneumonia after solid organ transplantation: a systematic review and meta-analysis

  • Maryam Ghadimi
  • Zinat Mohammadpour
  • Simin Dashti-KhavidakiEmail author
  • Alireza Milajerdi
Review

Abstract

Purpose

Although there is controversy, some evidences proposed increased risk of post-transplant Pneumocystis carinii pneumonia (PCP) in patients receiving mammalian target of rapamycin (mTOR) inhibitors. This study aimed to examine the association between m-TOR inhibitors and the risk of developing PCP in solid organ transplant (SOT) recipients.

Methods

A comprehensive search was performed to find the eligible studies that investigated the incidence of PCP in patients treated with mTOR inhibitors after SOT. Random effect model was applied for meta-analysis.

Results

Combination of 15 effect sizes showed a significant positive association between mTOR inhibitor administration and the risk of PCP (OR = 1.90, 95%CIs = 1.44, 2.75). There was no heterogeneity between studies (I2 = 3.5%). Subgroup analysis revealed increased risk of PCP after the first year of transplantation (P < 0.001).

Conclusion

In conclusion, administration of mTOR inhibitors is a potential risk factor for late-onset PCP after SOT. Targeted PCP prophylaxis based on recipients’ risk factors rather universal prophylaxis may lessen the risk.

Keywords

mTOR inhibitors Pneumocystis pneumonia Solid organ transplant Sirolimus Everolimus Meta-analysis 

Notes

Authors’ contribution

Maryam Ghadimi and Zinat Mohammadpour participated in doing literature review, data extraction from included articles, assessment of the quality of included articles, data analysis, and manuscript drafting. Simin Dashti-Khavidali provided the idea of this systematic review, participated in doing literature review, data extraction from included articles, critical evaluation of the manuscript, and finalizing the manuscript. Alireza Milajerdi participated in data analysis and manuscript drafting.

Funding

There is no funding support for this study.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

228_2019_2730_MOESM1_ESM.docx (19 kb)
ESM 1 (DOCX 18 kb)
228_2019_2730_MOESM2_ESM.docx (18 kb)
ESM 2 (DOCX 17 kb)
228_2019_2730_MOESM3_ESM.docx (18 kb)
ESM 3 (DOCX 18 kb)

References

  1. 1.
    Gordon SM, LaRosa SP, Arroliga AC, Avery RK, Longworth DL (1999) Should prophylaxis for Pneumocystis carinii pneumonia in solid organ transplant recipients ever be discontinued? Clin Infect Dis 28:240–246.  https://doi.org/10.1086/515126 CrossRefPubMedGoogle Scholar
  2. 2.
    Kramer MR, Stoehr C, Lewiston NJ, Starnes VA, Theodore J (1992) Trimethoprim-sulfamethoxazole prophylaxis for Pneumocystis carinii infections in heart-lung and lung transplantation--how effective and for how long? Transplantation 53:586–589CrossRefGoogle Scholar
  3. 3.
    Rodriguez M, Fishman JA (2004) Prevention of infection due to Pneumocystis spp. in human immunodeficiency virus-negative immunocompromised patients. Clin Microbiol Rev 17:770–782.  https://doi.org/10.1128/CMR.17.4.770-782.2004 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Green H, Paul M, Vidal L, Leibovici L (2007) Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials. Mayo Clin Proc 82:1052–1059.  https://doi.org/10.4065/82.9.1052 CrossRefGoogle Scholar
  5. 5.
    Stern A, Green H, Paul M, Vidal L, Leibovici L (2014) Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev 1:1–66.  https://doi.org/10.1002/14651858.CD005590.pub3 CrossRefGoogle Scholar
  6. 6.
    Goto N, Oka S (2011) P neumocystis jirovecii pneumonia in kidney transplantation. Transpl Infect Dis 13:551–558.  https://doi.org/10.1002/14651858.CD005590.pub3 CrossRefPubMedGoogle Scholar
  7. 7.
    Iriart X, Challan Belval T, Fillaux J, Esposito L, Lavergne RA, Cardeau-Desangles I, Roques O, del Bello A, Cointault O, Lavayssière L, Chauvin P, Menard S, Magnaval JF, Cassaing S, Rostaing L, Kamar N, Berry A (2015) Risk factors of Pneumocystis pneumonia in solid organ recipients in the era of the common use of posttransplantation prophylaxis. Am J Transplant 15:190–199.  https://doi.org/10.1111/ajt.12947 CrossRefGoogle Scholar
  8. 8.
    Martin S, Fishman J (2013) Pneumocystis pneumonia in solid organ transplantation. Am J Transplant 13:272–279.  https://doi.org/10.1111/ajt.12119 CrossRefGoogle Scholar
  9. 9.
    Radisic M, Lattes R, Chapman J et al (2005) Risk factors for Pneumocystis carinii pneumonia in kidney transplant recipients: a case–control study. Transpl Infect Dis 5:84–93.  https://doi.org/10.1111/ajt.12119 CrossRefGoogle Scholar
  10. 10.
    Faure E, Lionet A, Kipnis E, Noël C, Hazzan M (2017) Risk factors for Pneumocystis pneumonia after the first 6 months following renal transplantation. Transplant Infect Dis 19:e12735.  https://doi.org/10.1111/tid.12735 CrossRefGoogle Scholar
  11. 11.
    Eitner F, Hauser IA, Rettkowski O, Rath T, Lopau K, Pliquett RU, Fiedler R, Guba M, Hilgers RD, Floege J, Fischereder M (2011) Risk factors for Pneumocystis jiroveci pneumonia (PcP) in renal transplant recipients. Nephrol Dial Transplant 26:2013–2017.  https://doi.org/10.1093/ndt/gfq689 CrossRefPubMedGoogle Scholar
  12. 12.
    Neff RT, Jindal RM, Yoo DY, Hurst FP, Agodoa LY, Abbott KC (2009) Analysis of USRDS: incidence and risk factors for Pneumocystis jiroveci pneumonia. Transplantation 88:135–141.  https://doi.org/10.1097/TP.0b013e3181aad256 CrossRefPubMedGoogle Scholar
  13. 13.
    De Castro N, Xu F, Porcher R, Pavie J, Molina J-M, Peraldi M-N (2010) Pneumocystis jirovecii pneumonia in renal transplant recipients occurring after discontinuation of prophylaxis: a case–control study. Clin Microbiol Infect 16:1375–1377.  https://doi.org/10.1111/j.1469-0691.2009.03143.x CrossRefPubMedGoogle Scholar
  14. 14.
    Reid AB, Chen SC-A, Worth LJ (2011) Pneumocystis jirovecii pneumonia in non-HIV-infected patients: new risks and diagnostic tools. Curr Opin Infect Dis 24:534–544.  https://doi.org/10.1097/QCO.0b013e32834cac17 CrossRefPubMedGoogle Scholar
  15. 15.
    Mulpuru S, Knoll G, Weir C, Desjardins M, Johnson D, Gorn I, Fairhead T, Bissonnette J, Bruce N, Toye B, Suh K, Roth V (2016) Pneumocystis pneumonia outbreak among renal transplant recipients at a north American transplant center: risk factors and implications for infection control. Am J Infect Control 44:425–431.  https://doi.org/10.1016/j.ajic.2015.11.012 CrossRefPubMedGoogle Scholar
  16. 16.
    Dominguez J, Mahalati K, Kiberd B, McAlister VC, MacDonald AS (2000) Conversion to rapamycin immunosuppression in renal transplant recipients: report of an initial Experience1. Transplantation 70:1244–1247CrossRefGoogle Scholar
  17. 17.
    Peddi VR, Wiseman A, Chavin K, Slakey D (2013) Review of combination therapy with mTOR inhibitors and tacrolimus minimization after transplantation. Transpl Rev 27:97–107.  https://doi.org/10.1016/j.trre.2013.06.001 CrossRefGoogle Scholar
  18. 18.
    Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Me 6:e1000097.  https://doi.org/10.1371/journal.pmed.1000097 CrossRefGoogle Scholar
  19. 19.
    Schmidt CO, Kohlmann T (2008) When to use the odds ratio or the relative risk? Int J Public Health 53:165–167.  https://doi.org/10.1007/s00038-008-7068-3 CrossRefPubMedGoogle Scholar
  20. 20.
    Szumilas M (2010) Explaining odds ratios. J Can Acad Child Adolesc Psychiatry 19:227CrossRefGoogle Scholar
  21. 21.
    Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25:603–605.  https://doi.org/10.1007/s10654-010-9491-z CrossRefGoogle Scholar
  22. 22.
    Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12.  https://doi.org/10.1016/0197-2456(95)00134-4 CrossRefPubMedGoogle Scholar
  23. 23.
    Higgins JP, Green S (2011) Cochrane handbook for systematic reviews of interventions. Wiley, ChichesterGoogle Scholar
  24. 24.
    Egger M, Smith GD, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. Bmj 315:629–634.  https://doi.org/10.1136/bmj.315.7109.629 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Renoult E, Buteau C, Lamarre V, Turgeon N, Tapiero B (2005) Infectious risk in pediatric organ transplant recipients: is it increased with the new immunosuppressive agents? Pediatr Transplant 9:470–479.  https://doi.org/10.1111/j.1399-3046.2005.00325.x CrossRefPubMedGoogle Scholar
  26. 26.
    Kuypers DR (2005) Benefit-risk assessment of sirolimus in renal transplantation. Drug Saf 28:153–181.  https://doi.org/10.2165/00002018-200528020-00006 CrossRefPubMedGoogle Scholar
  27. 27.
    Augustine JJ, Bodziak KA, Hricik DE (2007) Use of sirolimus in solid organ transplantation. Drugs 67:369–391.  https://doi.org/10.2165/00003495-200767030-00004 CrossRefPubMedGoogle Scholar
  28. 28.
    Moes DJA, Guchelaar H-J, de Fijter JW (2015) Sirolimus and everolimus in kidney transplantation. Drug Discov Today 20:1243–1249.  https://doi.org/10.1016/j.drudis.2015.05.006 CrossRefPubMedGoogle Scholar
  29. 29.
    de Boer MG, Walzer P, Mori S (2018) Healthcare related transmission of Pneumocystis pneumonia: from key insights towards comprehensive prevention. Transpl Infect Dis 20:e12942.  https://doi.org/10.1111/tid.12942 CrossRefPubMedGoogle Scholar
  30. 30.
    Hosseini-Moghaddam S, Shokoohi M, Singh G et al (2019) A multicenter case-control study of the effect of acute rejection and Cytomegalovirus infection on Pneumocystis pneumonia in solid organ transplant recipients. Clin Infect Dis 68:1320–1326.  https://doi.org/10.1093/cid/ciy682 CrossRefPubMedGoogle Scholar
  31. 31.
    Werbel W, Ison M, Angarone M, Yang A, Stosor V (2018) Lymphopenia is associated with late onset Pneumocystis jirovecii pneumonia in solid organ transplantation. Transpl Infect Dis 20:e12876.  https://doi.org/10.1111/tid.12876 CrossRefPubMedGoogle Scholar
  32. 32.
    Hu YN, Lee NY, Roan JN, Hsu CH, Luo CY (2017) High dose calcineurin inhibitor free everolimus as a maintenance regimen for heart transplantation may be a risk factor for Pneumocystis pneumonia. Transpl Infect Dis 19:e12709.  https://doi.org/10.1111/tid.12709 CrossRefGoogle Scholar
  33. 33.
    Rostved AA, Sassi M, Kurtzhals JA et al (2013) Outbreak of pneumocystis pneumonia in renal and liver transplant patients caused by genotypically distinct strains of Pneumocystis jirovecii. Transplantation 15:834–842.  https://doi.org/10.1097/TP.0b013e3182a1618c CrossRefGoogle Scholar
  34. 34.
    Castro Nd XF, Porcher R, Pavie J, Molina J, Peraldi M (2010) Pneumocystis jirovecii pneumonia in renal transplant recipients occurring after discontinuation of prophylaxis: a case-control study. Clin Microbiol Infect 16:1375–1377.  https://doi.org/10.1111/j.1469-0691.2009.03143.x CrossRefGoogle Scholar
  35. 35.
    Kahan BD, Group RUS (2000) Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. Lancet 356:194–202.  https://doi.org/10.1016/S0140-6736(00)02480-6 CrossRefGoogle Scholar
  36. 36.
    Groth CG, Bäckman L, Morales J-M et al (1999) Sirolimus (rapamycin)-based therapy in human renal transplantation: Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 67:1036–1042CrossRefGoogle Scholar
  37. 37.
    Budde K, Becker T, Arns W, Sommerer C, Reinke P, Eisenberger U, Kramer S, Fischer W, Gschaidmeier H, Pietruck F (2011) Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet 377:837–847.  https://doi.org/10.1016/S0140-6736(10)62318-5 CrossRefPubMedGoogle Scholar
  38. 38.
    Neofytos D, Hirzel C, Boely E, Lecompte T, Khanna N, Mueller NJ, Boggian K, Cusini A, Manuel O, van Delden C, Swiss Transplant Cohort Study (2018) Pneumocystis jirovecii pneumonia in solid organ transplant recipients: a descriptive analysis for the Swiss transplant cohort. Transpl Infect Dis 20:e12984.  https://doi.org/10.1111/tid.12984 CrossRefGoogle Scholar
  39. 39.
    Silva HT, Felipe CR, Pestana JO (2015) Reviewing 15 years of experience with sirolimus. Transplant Res 4:6–11.  https://doi.org/10.1186/s13737-015-0028-6 CrossRefGoogle Scholar
  40. 40.
    Tedesco-Silva H, del Carmen RM, Cruz Santiago J, Mazzali M, Pacheco-Silva A, Torres R (2019) Optimizing the clinical utility of sirolimus-based immunosuppression for kidney transplantation. Clin Transpl 33:e13464.  https://doi.org/10.1111/ctr.13464 CrossRefGoogle Scholar
  41. 41.
    Baur B, Oroszlan M, Hess O, Carrel T, Mohacsi P (2011) Efficacy and safety of sirolimus and everolimus in heart transplant patients: a retrospective analysis. Transplant Proc 43:1853–1861.  https://doi.org/10.1016/j.transproceed.2011.01.174 CrossRefPubMedGoogle Scholar
  42. 42.
    Moro J, Almenar L, Martínez-Dolz L, Sánchez-Lázaro I, Agüero J, Salvador A (2008) Tolerance profile of the proliferation signal inhibitors everolimus and sirolimus in heart transplantation. Transplant Proc 40:3034–3036.  https://doi.org/10.1016/j.transproceed.2008.09.049 CrossRefPubMedGoogle Scholar
  43. 43.
    Klawitter J, Nashan B, Christians U (2015) Everolimus and sirolimus in transplantation-related but different. Expert Opin Drug Saf 14:1055–1070.  https://doi.org/10.1517/14740338.2015.1040388 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Struijk GH, Gijsen AF, Yong SL, Zwinderman AH, Geerlings SE, Lettinga KD, van Donselaar-van der Pant KAMI, ten Berge IJM, Bemelman FJ (2011) Risk of Pneumocystis jiroveci pneumonia in patients long after renal transplantation. Nephrol Dial Transplant 26:3391–3398.  https://doi.org/10.1093/ndt/gfr048 CrossRefPubMedGoogle Scholar
  45. 45.
    McKinnell JA, Cannella AP, Kunz DF et al (2012) Pneumocystis pneumonia in hospitalized patients: a detailed examination of symptoms, management, and outcomes in human immunodeficiency virus (HIV)-infected and HIV-uninfected persons. Transpl Infect Dis 14:510–518.  https://doi.org/10.1111/j.1399-3062.2012.00739.x CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    de Boer MG, Kroon FP, le Cessie S, de Fijter JW, van Dissel JT (2011) Risk factors for Pneumocystis jirovecii pneumonia in kidney transplant recipients and appraisal of strategies for selective use of chemoprophylaxis. Transpl Infect Dis 13:559–569.  https://doi.org/10.1111/j.1399-3062.2011.00645.x CrossRefPubMedGoogle Scholar
  47. 47.
    Oz HS, Hughes WT (1997) Novel anti-Pneumocystis carinii effects of the immunosuppressant mycophenolate mofetil in contrast to provocative effects of tacrolimus, sirolimus, and dexamethasone. J Infect Dis 175:901–904.  https://doi.org/10.1086/513988 CrossRefPubMedGoogle Scholar
  48. 48.
    Wang E, Partovi N, Levy R, Shapiro R, Yoshida E, Greanya E (2012) Pneumocystis pneumonia in solid organ transplant recipients: not yet an infection of the past. Transpl Infect Dis 14:519–525.  https://doi.org/10.1111/j.1399-3062.2012.00740.x CrossRefPubMedGoogle Scholar
  49. 49.
    Chapman JR, Marriott DJ, Chen SC-A, MacDonald PS (2013) Post-transplant Pneumocystis jirovecii pneumonia—a re-emerged public health problem? Kidney Int 84:240–243.  https://doi.org/10.1038/ki.2013.212 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Maryam Ghadimi
    • 1
  • Zinat Mohammadpour
    • 2
  • Simin Dashti-Khavidaki
    • 2
    • 3
    Email author
  • Alireza Milajerdi
    • 4
  1. 1.Department of Clinical Pharmacy, Faculty of PharmacyTehran University of Medical SciencesTehranIran
  2. 2.Liver Transplantation Research Center, Imam Khomeini Hospital ComplexTehran University of Medical SciencesTehranIran
  3. 3.Faculty of PharmacyTehran University of Medical SciencesTehranIran
  4. 4.Department of Community Nutrition, School of Nutritional Sciences and DieteticsTehran University of Medical SciencesTehranIran

Personalised recommendations