Multiple organ infection and the pathogenesis of SARS

Gu, Jiang; Gong, Encong; Zhang, Bo; Zheng, Jie; Gao, Zifen; Zhong, Yanfeng; Zou, Wanzhong; Zhan, Jun; Wang, Shenglan; Xie, Zhigang; Zhuang, Hui; Wu, Bingquan; Zhong, Haohao; Shao, Hongquan; Fang, Weigang; Gao, Dongshia; Pei, Fei; Li, Xingwang; He, Zhongpin; Xu, Danzhen; Shi, Xeying; Anderson, Virginia M.; Leong, Anthony S.-Y.

In addition to confirming the previously reported pathologic changes in SARS (6, 10-12), we have demonstrated widespread dissemination of the SARS virus in the immune cells of the blood, spleen, and lymph nodes, as well as in the epithelial cells of the lungs, trachea, bronchi, distal renal tubules, mucosa, and submucosa of the intestines, and neurons of the brain. The presence and localization of the virus in these target cells were confirmed by in situ hybridization, EM, and real-time PCR. It is evident that infection by the SARS virus is not confined to the lungs, but also involves other parts of the respiratory tract and other organ systems, most importantly immune cells, particularly the T lymphocytes, monocytes, and macrophages. The finding of early and consistent decreases of T lymphocytes in 65 patients who had SARS, but not in the 35 misdiagnosed patients, further suggests that lympho- cyte damage is the hallmark of SARS. Administration of glucocorticoids contributed to a decrease in lymphocyte counts in both groups of patients; however, the difference in counts between the two groups persisted after glucocorticoid therapy. It was reported that lymphopenia is one of the earliest changes, and is a reliable prognostic predictor in SARS (13) (14) (15) (16) (17) (18) . An extensive literature search has not revealed a report of any other type of pneumonitis producing such severe lymphopenia. As the only logical explanation for the early and consistent lymphopenia that is demonstrated in patients who have SARS, we suggest that lymphocytes-particularly T lymphocytes-are infected and destroyed by the virus or by other immune cells. Our study provides evidence of infection and destruction of lymphocytes in the spleen, lymph nodes, and lymphoid tissues of the gut. In these sites lymphocytes were reduced markedly, germinal centers were depleted of lymphocytes, and in situ hybridization detected SARS viral positivity in the residual immune cells in the spleen and in circulation. This destruction of lymphocytes would cause an acute immunodeficiency that would aggravate the infection of the respiratory tract. The markedly weakened immune system at the early and mid stages of the disease is likely to be the reason for the acute nature and severity of the respiratory syndrome in SARS viral infection.