Pathology of SARS

1. Pathology of SARS Jiang Gu, MD, PhD Department of Pathology School of Basic Medical Sciences Peking (Beijing) University

2. SARS – Severe Acute Respiratory Symdrome The first epidemic of the 21st century killed 788 and infected over 8000.

3. First case traced back to November 2002 in Gongdong, China Initial symptoms: High fever, headache, discomfort 7-10 days later: Cough, diarrhea, chest x-ray Death rate: 7-14% (increase with age) Misdiagnosis (Beijing): 22-35% Pathogen identified – SARS coronavirus Genome sequenced – many variants

4. SARS pathogenesis • 42 autopsies were performed worldwide • 31 autopsies were performed in China: • 23 full autopsies and 8 partial autopsies • 14 were confirmed with real-time PCR • Our team at Peking University performed 18 thorough autopsies of which 8 were confirmed with real-time PCR (15 in 2003, 3 in 2004) • 22 blood samples from early stage SARS patients • Over 700 clinical cases

5. P3 lab for SARS autopsy

6. Techniques and analyses • Clinical features • Laboratory findings • Histopathology • Electron microscope • Histochemistry • Immunohistochemistry (LM, EM) • In situ hybridization (LM, EM) • Real time PCR, RT-PCR

7. Respiratory tract

8. In situ hybridization of SARS Double staining In situ hybridization of SARS Immunohistochemistry of cytokeratin

9. Double staining In situ hybridization for SARS virus (dark blue) Immunohistochemistry for cytokerotin (brown) In situ EM of SARS In situ LM of trachea

10. Double staining In situ hybridization for SARS virus (dark blue) Immunohistochemistry for cytokerotin (brown) In situ EM of SARS In situ LM of trachea • Respiratory tract infection affected trachea, bronchi, bronchioles and alveoli. • Epithelial cells were infected. Type II cell injury led to collapse of the lungs. • Endothelial cell injury caused permeability change, effusion, edema and consolidation. • Macrophages and infiltrating leucocytes (T cells) were infected.

11. Other organs (gut, kidney, brain) In situ Gut submucosa In situ Gut mucosa In situ - kidney In situ - brain EM - kidney

12. Cortex In situ

13. Immune damage

14. Lymphopenia

15. Immune system In situ - WBC

16. 原位杂交（SARS）免疫组化（T细胞）双重染色

17. Spleen of SARS

18. CD20（B） CD3（T） S100（dendritic） CD64（macrophage） Normal spleen SARS spleen

19. CD20（B） CD3（T） S100（dendritic） CD64（macrophage） Normal spleen SARS spleen

20. SARS – decrease in apoptosis and increase in necrosis Lymph node in 15 day SARS

21. SARS Target Cells • Respiratory epithelial cells • Lung type I and type II cells • Immune cells (T lymphocytes, monocytes) • Intestinal mucosal cells • Renal distal tubule epithelial cells • Endothelial cells • Neurons in the brain

22. Summary of Findings • Respiratory tract infection affected trachea, bronchi, bronchioles. Epithelial cell infection and injury. Type II cell injury caused collapse of the alveoli. Endothelial cell injury caused permeability change, effusion, edema and consolidation. • Immune cell infection, injury and decrease, lymphoid organ damage, atrophy, acute immune deficiency, macrophage activation and proliferation. • Multiple organ infection and injury（lung, blood, spleen, kidney, gut, brain, etc.) • The new pathogenesis theory can explain all clinical symptoms and laboratory findings.

23. Pathogenesis

24. Pathogenesis

25. Pathogenesis

26. Pathogenesis

27. Pathogenesis

28. Immune damage is at the core

29. Proposed mechanism

30. Indications • Immune injury, not over reaction • Multi organ damage and complications • Mode of transmission • Animal model for vaccine

31. Questions remain unanswered • Research continues …

32. SARS autopsy team at Peking (Beijing) University

33. Thank You

34. SARS spleen and heart at 15 days