Interstitial Lung Disease Associated with mTOR Inhibitors in Solid Organ Transplant Recipients: Results from a Large Phase III Clinical Trial Program of Everolimus and Review of the Literature
Interstitial lung disease (ILD) has been reported with the use of mammalian target of rapamycin inhibitors (mTORi). The clinical and safety databases of three Phase III trials of everolimus in de novo kidney (A2309), heart (A2310), and liver (H2304) transplant recipients (TxR) were searched using a standardized MedDRA query (SMQ) search for ILD followed by a case-by-case medical evaluation. A literature search was conducted in MEDLINE and EMBASE. Out of the 1,473 de novo TxR receiving everolimus in Phase III trials, everolimus-related ILD was confirmed in six cases (one kidney, four heart, and one liver TxR) representing an incidence of 0.4%. Everolimus was discontinued in three of the four heart TxR, resulting in ILD improvement or resolution. Outcome was fatal in the kidney TxR (in whom everolimus therapy was continued) and in the liver TxR despite everolimus discontinuation. The literature review identified 57 publications on ILD in solid organ TxR receiving everolimus or sirolimus. ILD presented months or years after mTORi initiation and symptoms were nonspecific and insidious. The event was more frequent in patients with a late switch to mTORi. In most cases, ILD was reversed after prompt mTORi discontinuation. ILD induced by mTORi is an uncommon and potentially fatal event warranting early recognition and drug discontinuation. 1. Introduction Interstitial lung disease (ILD) constitutes a heterogeneous group of noninfective lung disorders. Based on etiology, ILD is categorized into nine main groups: idiopathic interstitial pneumonia, connective tissue disease, smoking-related, vasculitis, granulomatous disease, environmental/occupational, drug-induced, inherited, and others [1]. It is the most common form of drug-induced lung toxicity. Various drug classes are known to cause ILD, including chemotherapy agents (e.g., bleomycin, cyclophosphamide, and chlorambucil), cardiovascular drugs (e.g., amiodarone, beta blockers, and statins), anti-inflammatory drugs (e.g., sulfasalazine, gold salts, and methotrexate), antimicrobial agents (e.g., nitrofurantoin and amphotericin), and biological agents (e.g., etanercept and infliximab) [2]. The clinical presentation is similar to that of infectious pneumonia, with dyspnea being the most common symptom. Typical radiological findings include bilateral reticular or reticulonodular opacities. Drug-induced ILD is mainly diagnosed by exclusion of other causes and by a thorough review of drug history, complemented by high-resolution computed tomography (CT), bronchoscopy with bronchoalveolar lavage, and bronchoscopic
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