key: cord-0791388-u1mhwo84
authors: Russell, Clark D.; Haas, Juergen
title: Cyclosporine has a potential role in the treatment of SARS
date: 2013-02-06
journal: J Infect
DOI: 10.1016/j.jinf.2013.01.004
sha: 89fb7a24a233eae11cda906a359949d00ad4d79d
doc_id: 791388
cord_uid: u1mhwo84

nan

Cyclosporine has a potential role in the treatment of SARS Dear Sir,

We welcome Jasper Chan and colleagues' review of the isolation of a novel human betacoronavirus from two patients in 2012, and share their desire for further research on this group of emerging viral pathogens. 1 The absence of an evidence-base for treating coronavirus-associated severe acute respiratory syndrome (SARS) is worrying. The authors list several agents with in vitro activity against the SARS coronavirus but do not refer to the literature describing the anti-coronavirus activity of cyclophilin inhibitors. Pfefferle and co-workers adopted a systems biology approach to identify coronavirusehost interactions by using genome-wide yeast-two hybrid screening. 2 They identified interactions between the coronavirus non-structural protein 1 (Nsp1) and several immunophilins; a group of molecules with a role in T-cell activation via the Calcineurin/NFAT pathway. In addition, Nsp1 was found to induce the expression of IL-2, thus implicating it in the cytokine dysregulation seen in SARS. High serum levels of IL-2 have previously been demonstrated to correlate with mortality (p < 0.05) and high APACHE II scores (p < 0.0001) in patients with acute respiratory distress syndrome. 3 Importantly, Pfefferle et al. found that the cyclophilin inhibitor cyclosporine A inhibited SARS coronavirus replication in cell culture, as well as inhibiting NSP1-affected IL-2 induction. de Wilde and colleagues have also reported on the in vitro anticoronavirus activity of cyclosporine A. 4 In addition, cyclosporine A has been found to suppress hepatitis C virus (HCV) replication in vitro, prompting an assessment of its role in HCV infection. 5 In a study of 120 patients with chronic HCV infection, Inoue et al. compared treatment with IFN a2b and cyclosporine A versus IFN a2b alone. 6 The two treatment groups did not differ significantly, and importantly displayed no significant difference in pre-treatment viral load nor virus genotype. They found that combination therapy was superior to monotherapy with IFN, resulting in significantly improved virological response (HCV RNA disappearance) during treatment and at follow up, and significantly improved biochemical response (ALT normalisation) at follow up. Encouragingly, there was no significant difference in the rate of adverse events during treatment between the two groups. A nonimmunosuppressive cyclosporine, DEBIO-025, has been described that retains in vitro anti-HCV activity, making it an attractive candidate for further clinical trials. 7 In summary, there is tantalising in vitro evidence for cyclosporine as an anti-coronavirus agent, as well as having a potential disease-modifying role in SARS through the inhibition of virus-mediated IL-2 induction. This latter property is interesting, considering that early corticosteroid treatment (initiated to combat pulmonary inflammation) can result in an increased level of viraemia, which may be associated with reduced survival in SARS. 8, 9 Furthermore, the in vitro anti-HCV activity of cyclosporine has translated into clinical benefit in humans and appears to be a safe therapy. Therefore, we advocate that trial of cyclosporine should be considered in the inevitable event of future cases of SARS. Aspergillus endocarditis in the era of new antifungals: Major role for antigen detection * Steinbach and colleagues recently reported in this Journal the clinical epidemiology of invasive aspergillosis using a large registry. 1 We have identified and herein describe cases of Aspergillus endocarditis (AE) which is an exceptionally rare disease. AE represents less than 25% of fungal endocarditis and is associated with mortality rates as high as 90%. 2, 3 Diagnosis is challenging and often delayed, due to non-specific clinical features and negative blood cultures in most cases, and optimal therapeutic management remains poorly understood.

To describe the clinical and microbiological characteristics and outcome of AE, we studied AE cases enrolled in the French nationwide prospective MYCENDO study, 4 and all subsequent cases declared to the French National Reference Centre for Invasive Mycoses and Antifungals (Institut Pasteur, Paris). Diagnosis of definite AE was considered in accordance with previously published modified Duke criteria. 5 When feasible, serum samples were sequentially collected for detection of Aspergillus galactomannan (Platelia Aspergillus Enzyme Immuno-Assay, Biorad, Marne-la-Coquette, France) and (1,3)-b-D-Glucan (Fungitell assay, Associates of Cape Cod, Falmouth, Mass.), blood samples and surgical cardiac material were screened for fungal DNA. Fungal DNA screening from serum and surgical cardiac material was performed as previously described. 4, 6 Eight cases observed between January 2005 and May 2011 were analyzed ( Table 1) . Two of them have previously been published in part. 7, 8 Seven patients met the modified Duke criteria for definite AE. The last case (case n 2) was also considered as AE since combining a known Aspergillus colonization of the respiratory tract, valvular vegetation, positive GM and Polymerase Chain reaction (PCR) for Aspergillus fumigatus in blood, absence of other microorganism identified in blood and a favorable outcome with antifungal therapy. Six patients (Table 1) were immunocompromised: four underwent solid organ transplantation (SOT), one had prolonged neutropenia and one received prolonged corticosteroid therapy. Five of these 6 immunocompromised patients had been recently operated (median 2.7 months, range 11 dayse9 months before the diagnosis of AE). For the two latter patients, the only risk factor for AE was a recent cardiac surgery: aortic valve replacement for aortic stenosis (case n 3) and repair of congenital heart disease (case n 7). All patients had left-sided AE and 3 had concomitant right-sided AE. Vegetations were described as large (median size, 20 mm; range, 3e28) and an annular abscess was detected in 5/8 cases. In 5 cases, at least one embolus was part of the clinical presentation.

Blood cultures were negative in 7/8 cases. Of note, three patients were receiving fluconazole when the blood cultures were performed. Cultures of cardiac surgical samples were positive in 6/6 tested cases. Detection of (1, 3)-b-D-Glucan (BG) was positive in 4/4 tested cases at diagnosis, with values >500 pg/ml in all cases; under treatment, values remained >500 pg/ml in 3/3 tested patients (median follow-up 60 days, range 40e61) despite favorable evolution in 1/3 patients. Aspergillus galactomannan (GM) was detected in 6/6 tested patients and preceded positive cultures in 4 cases. None of these patients presented described risks factors of false positive GM in the serum. 9 During follow-up, GM became negative only in 2 patients who survived (cases n 2 and 7). PCR detected A. fumigatus DNA on cardiac surgical samples of 2/2 patients, and on serum of 2/2 patients, including 1 with negative blood cultures.

Six patients underwent cardiac surgery as part of the initial management (Table 1) . Surgery was rejected in patients n 2 and 4 because of a high risk of procedurerelated mortality. All patients received voriconazole, either

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