Clinical manifestations and inflammatory cytokine responses in patients with severe acute respiratory syndrome

Background and Purpose: Severe acute respiratory syndrome (SARS) is a highly transmissible disease with significant morbidity and mortality. Death from SARS is most often due to rapidly progressive respiratory compromise (acute respiratory distress syndrome, ARDS) and subsequent multi-organ dysfunction. However, the mechanisms evoking respiratory distress and a fulminant systemic response remain unclear. In order to elucidate the pathogenic mechanisms of SARS, we analyzed clinical manifestations and levels of serum cytokines of SARS patients. Methods: Fourteen hospitalized patients with a diagnosis of SARS-associated coronavirus infection at National Taiwan University Hospital from March to May 2003 were included. Data on clinical manifestations, parameters of laboratory tests, complications and final outcomes of patients were collected retrospectively. Serial plasma inflammatory cytokines, including interleukin (IL)-1beta (IL-1β), IL-6, IL-8 and tumor necrosis factor-alpha (TNF-α) of preserved serum were measured by enzyme immunoassay. Results: All 14 patients had fever, dry cough and dyspnea. Twelve were intubated during hospitalization. The median duration from onset of fever to the nadir level or most severe condition was 9 days for hypoxia, 7 days for lymphocytopenia, 6.5 days for thrombocytopenia, 9.5 days for maximal pulmonary infiltrates; to peak serum levels was 9 days for C-reactive protein (CRP), 10.5 days for IL-6, 13.5 days for IL-8 and 12 days for TNF-α; to defervescence was 13 days. There was no significant elevation of serum IL-1β levels in any of the 14 patients. There were no significant differences in peak levels of IL-6, IL-8 and TNF-α between patients with and without ARDS. The 8 patients who died tended to have higher peak levels of serum TNF-α compared to those who survived (14 vs 9.1 pg/mL; p = 0.06). Conclusion: Rapid elevation of inflammatory cytokines-IL-6, IL-8 and TNF-α might play a role in the development of SARS-related ARDS. The timing of elevations in inflammatory cytokines and CRP is correlated with progression of pulmonary infiltrates of SARS patients. The peak level of serum TNF-α tends to be higher in patients who die of SARS than in those who survive. Our results indicate that CRP and TNF-α might be used as prognostic markers of SARS.