Treatment of SARS with human interferons
Authors: J Cinatl, P Chandra, H Rabenau, HW Doerr
Journal: The Lancet (2003)

Authors' reply Sir—Guido Antonelli and colleagues are right to point out that different interferon preparations, including those we used, can have different specific activities (IU/mg protein). In clinical practice this difference can be important in pharmacokinetic and pharmacodynamic terms, since interferons with high specific activity can be used at low protein concentrations relative to interferons with low specific activity. However, our data based on the use of IU/mL suggest that even in the case of application of same protein concentrations interferon beta (specific activity 3·2×107 IU/mg) would be better than interferon alfa (2–2·4×108 IU/mg) in terms of antiviral activity. To directly address this point we tested different preparations of interferon alfa and interferon beta in Vero cells infected with SARS-CoV. The results (not presented in our research letter) showed higher antiviral potency for interferon beta than for interferon alfa independent of specific activity—ie, interferon beta-1a has a specific activity (2×108 IU/mg) similar to interferon alfa-2b, but its antiviral activity was about 40 times higher. The differences in antiviral activity of both type 1 interferons could result from their ability to differentially influence expression of cellular genes important for antiviral activity. For example, when the human fibrosarcoma cell line HT1080 is treated with 1000 IU/mL of type 1 interferons, more than 20 genes, including double-stranded RNA-activated protein kinase, are induced by interferon beta but not by interferon alfa.1Der SD Zhou A Williams BR Silverman RH Identification of genes differentially regulated by interferon α, β or γ using oligonucleotide arrays.Proc natl acad Sci USA. 1998; 95: 15623-15628Crossref PubMed Scopus (1578) Google Scholar Antonelli and colleagues also argue that selectivity index as a parameter for therapeutic efficacy cannot be ascertained without knowing cytotoxic concentrations (CC50) of the interferon used. 10 000 IU/mL was the maximum concentration we tested, since higher concentrations of interferons are probably not achievable in the infected cells of patients. CC50 value higher than 10 000 simply means that antiviral effects in our culture system are not due to non-specific toxic effects. Our initial experiments were undertaken with a range of concentrations that are commonly used in in-vitro investigations. In additional experiments done by us, interferon concentrations up to 106 IU/mL were used without increased toxicity of interferon beta versus interferon alfa in confluent layers of Vero cells. In conclusion, these results do not lend support to the notion that increased antiviral activity of interferon beta is associated with increased toxicity and thus decreasing of therapeutic index relative to interferon alfa as suggested by Antonelli and colleagues. Treatment of patients who have SARS with interferon alfa and restricted use of steroids did not improve clinical symptoms and signs.2Zhao Z Zhang F Xu M et al.Description and clinical treatment of an early outbreak of severe acute respiratory syndrome (SARS) in Guangzhou, PR China.J Med Microbiol. 2003; 52: 715-720Crossref PubMed Scopus (348) Google Scholar This finding could be explained at least partly by our observations, indicating an inability of interferon alfa to inhibit SARS-CoV replication when added to cultured cells after virus infection. Therefore, the selective antiviral activity of interferon beta justifies its clinical testing in patients with SARS. Treatment of SARS with human interferonsWe agree with J Cinatl and colleagues (July 26, p 293)1 that effective antiviral agents are urgently needed to treat severe acute respiratory syndrome (SARS). Full-Text PDF