Switch to Everolimus for Sirolimus-Induced Pneumonitis in a Liver Transplant Recipient—Not All Proliferation Signal Inhibitors Are the Same: A Case Report P. De Simone, S. Petruccelli, A. Precisi, P. Carrai, R. Doria, F. Menichetti, and F. Filipponi ABSTRACT We report a 62-year-old female liver transplant patient who presented with sirolimus (SIR)-related pneumonitis (SIP) treated with a switch to everolimus (EVER). At 13-month follow-up, the patient is on EVER monotherapy with no recurrence of SIP. Despite common mechanisms of action, the safety profile of EVER is different from SIR, and a switch from SIR to EVER should be contemplated in cases of SIP to allow patients to benefit from the antifibrotic properties of antiproliferative immunosuppressants. E VEROLIMUS (EVER) and sirolimus (SIR) belong to a novel class of immunosuppressants—the prolifera- tion signal inhibitors–whose antiproliferative, antifibrotic properties and lack of renal and neurological toxicity make them promising alternatives to calcineurin inhibitor– based immunosuppression in select solid organ graft recipients. Despite common mechanisms of action, EVER and SIR have slightly different molecular structures and pharmaco- kinetic profiles, with possible differences in the spectrum of adverse side effects. We have reported herein a liver transplant (OLT) recipient on SIR who was switched to EVER for SIR-induced pneumonitis (SIP) with a beneficial outcome. CASE REPORT A 62-year-old female patient underwent cadaver OLT at our institution in December 2004 for UNOS-T 2 hepatocellular car- cinoma in the setting of hepatitis C virus–related cirrhosis. Due to early recurrent graft hepatitis, the patient was administered pegylated interferon and ribavirin, but the treatment was dis- continued in August 2005 upon confirmation of Ishtak’s grade 3, stage 4 cholestatic chronic hepatitis. On account of its antipro- liferative and antifibrotic profile, 1 cyclosporine monotherapy was switched to SIR monotherapy with target trough levels between 8 and 10 ng/mL. In May 2006 the patient was admitted to the hospital on an emergent basis for relentless dyspnea and fever. The routine laboratory tests showed hypochromic anemia (Hgb 9.9 g/dL; mean corpuscular volume 69.5 fL); a mild increase in transami- nases (AST 67 IU/L; ALT 35 IU/L); mild cholestasis (GGT 115 IU/L; alkaline phosphatases 207 IU/L); and hypergammaglobu- linemia (22.2 g/dL), all of which were consistent with recurrent chronic hepatitis. The SIR blood trough level was 8 ng/mL. The CD4 count was 196 cells/L with a normal CD4-to-CD8 ratio (1.12). The blood gas analysis was consistent with mild respira- tory alkalosis. The chest X-ray showed right basal fluid collec- tion associated with reticular and ground-glass infiltrates resem- bling bronchiolitis obliterans-organizing pneumonia, located in the middle and basal aspects of both lungs and consistent with interstitial pneumonitis. Viral and bacterial tests were negative. Cryoglobulinemia was absent. The patient underwent bilateral brochoalveolar lavage, which tested positive for lymphocytes, monocytes, and macrophages in the absence of viral or bacterial infection. The patient was administered meropenem (1 gr intravenously three times a day) on an empirical basis with no improvement in symptoms or radiological findings. Given the lack of evidence of any infectious disease, SIP was suspected and the patient was switched to EVER (1 mg twice a day), according to previous reports in kidney and heart transplant recipients. 2–4 EVER blood trough levels were kept between 3 and 8 ng/mL. One month after commencement of EVER, the patient dis- played resolution of the lung infiltrates and pleural fluid collec- tion. At a follow-up of 13 months after the switch to EVER, the patient is alive with no signs of recurrent pneumonitis. DISCUSSION SIP is a hypersensitivity-like interstitial pneumonitis, which may present with signs of organizing pneumonia. It is presumably related to a T-helper-cell reaction to a SIR- From the Liver Transplant Unit (P.D.S., S.P., P.C., F.F.), Laboratory (A.P.) and Infectious Diseases (R.D., F.M.), Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. Address reprint requests to Franco Filipponi, Liver Trans- plant Unit, Azienda Ospedaliero-Universitaria Pisana, Ospedale Cisanello, Via Paradisa, 2, 56124, Pisa, Italy. E-mail: f.filipponi@ med.unipi.it 0041-1345/07/$–see front matter © 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.transproceed.2007.09.040 360 Park Avenue South, New York, NY 10010-1710 3500 Transplantation Proceedings, 39, 3500 –3501 (2007)