ORGAN TROPISM OF HUMAN CORONAVIUSES: WHAT DO WE REALLY KNOW.

Most of the knowledge we aquired about the target organ(s) of human coronavirus originates from the clinical,radiological and,most importantly, autoptic studies (1-5) on patients who died during the SARS- and MERS- epidemics. Most of the actual informations about SARS-CoV-2(COVID 19) infection in hospitalized persons relys on clinical „surrogate“ findings and on CT-scans of the chest for both,those who were released from the hospital and those who unfortunately died of the disease (6-9). Infact no complete autoptic studies (with one single exception,10 ) have been performed in the more than 4.200 patients who died because of COVID 19.

By putting together the main clinical, radiological and histological data from the SARS-CoV 1 and MERS-epidemic we have a quite clear picture of the sequence of events occurring after the virus reaches first the bronchial and then the alveolar epithelium.

There is the invasion of the resident macrophages and of the epithelial cells by the virus and the recruitment of inflammatory

cells (granulocytes and macrophages) follows the release of pro-inflammatory cytokines and chemokines synthesized by the infected resident macrophages and epithelial cells(11,12) with some similarities to what happens in acute viral hepatitis( 13). The inflammatory  cells also cause release of fluid into the alveoli from   the capillaries which can be  damaged and trhombosised with reduction of functional tissue. The size of the area could be dependent on the viral load reaching the respiratory tract.

The degree of the functional reduction can be proportional to the size of the pulmonary area involved in the process and could be predicted by analysing the CT-scan.

Immunohistological, and electronmicroscopy studies have given indications for the presence and multiplication of virus particles in the inflamed areas of the lung. Similar findings have not been detected in other organs even if viral RNA has been detected in liver samples and in stool-samples in patients showing

mild elevation of serum transaminase levels at a later time after beginning of the disease, of the consequent hospitalisation (14) and transfer into ICU. No hepatic functional reduction  has been described in these patients. None of the retrospective clinical publications contained data indicating reduction of hepatic function,e.g. hyperbilirubinemia, or massive increase of transaminase serum level in patients dying from COVID 19.

Intriguing however is the low albumin serum level found not only in the ICU-care patients in two of the publications (6,8  ).Albumin serum level is an indicator for the synthetic capacity of the liver which is on the one hand dependent of sufficient nutritional delivery of proteins and or amino acids to the liver, and on the other hand, on the availability of enough healthy hepatocytes .This can happen in cases of acute hepatitis, when about a third of the hepatocytes dies and serum transminase levels and bilirubin are massively elevated.

No similar data have been found in COVID 19 patients (15).

The same is true for the kidney. No indication has been given for

viral replication in the kidney (2,3). A few autoptic data seem to support the assumption that  the kidney might be suffering from massive intravasal fluid reduction (2,16) which can cause tubular necrosis (2 ).This may be due to the intention to reduce cardiac work load in patients with hypoxia due to reduction of functional lung tissue and not by cardiac insufficiency. The complexity of the handling of such patients with additional comorbidities asks for doctors who can deal not only with respiratory insufficiency but also with the protection of other vital organs while the lung needs help to win the fight against the viral infection.

 

REFERENCES

1 Nicholls JM, Poon LLM,Lee KC,et al.:Lung pathology of fatal severe    acute respiratory syndrome.Lanct 2003;361:1773-1778

2 Chong PY,Chui P, Ling AE,et al.:Analysis of Death During the severe acute respiratory Syndrome (SARS) Epidemic in Singapore.Arch Pathol Lab Med 2004;128: 195-204

3 Gu J, Gong E,Zhang B,et al.:Multiple organ infection and the pathogenesis of SARS.J Exp Med 2005;202:415-424

4 Nicholls JM,Butany J Poon LM et al. Time course and cellular localisation of SARS-CoV nucleoprotein and RNA in Lungs from fatal cases of SARS.PloS Medicine 2006; 3(2):e27

5 Liu J,Zheng X, Tong Q,et al.: Overlapping and discete aspects oft he pathology and pathogenesis oft he emerging human pathogenic coronaviruses SARS-CoV,MERS-CoV, and 2019-nCoV.J Med Virol 2020 February 13:1-4

 

 

 

6 Huang Ch,Wang Y,Li X et al.:Clinical features of patients infected with 2019 novel coronavirus in Wuhan,China.Lancet 2020;395 February 15

7 Shi H, Han X, Cao Y,et al.:Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan,China: a desciptive study.Lancet Infect Dis 2020;February 24

8 Zhou F, Du R, Fan G,et al.: Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan,China: aretrospective cohort study.Lancet 2020;March 9

9 Wang t, Du Z,Zhu F, et al.:Comorbidities and multi-organ injuries in the treatment of COVID-19.Lancet 2020;March 9

10 Zhe X, Wang Y, Zhang J,et al.: Pathological findings of COVID-19 associated with acute respiratory distress syndrome.Lancet Resp Med 2020,February 17.

11 Chien JY,HSUEH PR,Cheng WC et al.:Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome.Respirology 2006;11:715-722

12 Zhou J,Chu H,Li c et al.:Active replication of Middle east respiratory Syndrome Coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages:implications for pathogenesis.J Infec Dis 2014:209:1331-1342

13 Wietzke P, Schott P, Mihm S,et al.:Clearance of HCV RNA in a chronic hepatitis C virus-infected patient during acute hepatitis B virus superinfection.Liver 1999;19:348-353

14 Chau TN,Lee KC,Yao H, et al.:SARS-Associated Viral Hepatitis caused by a novel coronavirus:report of three cases.Hepatology 2004; 39:302-310.

15Zhang C, Shi L Wang FS.:Liver injury in COVID-19:management and challenges.Lancet Gastroenterol Hepatol 2020 March 4.

16 Ng DL, Al Hosani F, Keating K et al.:Clinicopathological,Immunohistochemical,and ultrastructural findings of a fatal case middle East Respiratory Syndrome coronavirus Infection in the United Arab Emirates,April 2014.Am J Pathol.2016;186:652-658.

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