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Covid-19: a puzzle with many missing pieces

BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m627 (Published 19 February 2020) Cite this as: BMJ 2020;368:m627

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Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2)

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SARS-COV-2 lung infection could be acquired upon exposure to the virus through the gastrointestinal tract, one important missing piece

Dear Editor

Because COVID-19 primarily manifests as a respiratory infection, airway exposure is intuitively assumed to be the infection route. However, we postulate SARS-COV-2 lung infection could be acquired upon exposure to the virus through the gastrointestinal tract, subsequently, the virus could be further transported to the lungs leading to a respiratory infection.

Several studies included a systematic review of imaging findings in 919 patients, showed that most of the lesions started from the periphery, particularly the subpleural region mainly in the lower lobe (1). The periphery and the lower lobe are the most frequently affected even in asymptomatic cases (2).

In an erect individual, the lung apex is relatively overventilated (ratio of ventilation to perfusion, 3:1), and the base is relatively overperfused (ratio, 0.6:1) (3). Furthermore, lymphatic particle clearance is relatively decreased in the apices because the lymphatic flow is driven by perfusion as well as respiratory excursion, both of which are relatively decreased in the upper lung zones (4). Prolonged transit time can increase the interaction between pathogenic factors and the peripheral lung. This suggests different viral distribution or spreading rather than direct inhalation. If SARS-COV-2 spread to the lung through inhalation we would expect upper lobe predominance.

The peripheral and lower lung predominance observed in SARS-COV-2 lung infections may be driven by the relative basilar overperfusion and the prolonged peripheral transit time (3). Hematogenous and/or lymphatic SARS-CoV-2 lung distribution or spreading could follow the viral infection of the gastrointestinal tract.

Many patients with COVID-19 present initially with digestive symptoms, such as diarrhea, anorexia, and vomiting. Early gastrointestinal symptoms could be explained by the gastrointestinal tract be the primary site of invasion by SARS-CoV-2. Several recent studies have documented the presence of SARS-CoV-2 ribonucleic acid (RNA) and/or SARS-CoV-2 virus in the stool of infected individuals. Furthermore, patients with COVID-19 had persistently positive rectal swabs even after their nasopharyngeal tests were negative (5). Extended duration of viral shedding in feces for nearly 5 weeks after the patients' respiratory samples tested negative for SARS-CoV-2 RNA, suggests high intestinal viral load distribution during Covid-19 (6).

The interaction between the SARS viruses and ACE2 has been proposed as a potential factor in their infectivity. ACE2 is in large measure present in humans in the epithelia of lung and small intestine, which might provide possible routes of entry for the SARS-CoV-2. ACE2 protein is abundantly expressed in the brush border of enterocytes of all parts of the small intestine, including the duodenum, jejunum, and ileum. The fact that enterocytes of the small intestine are in contact with the external environment and the surface expression of ACE2 protein in these cells is remarkable (7).

The pathological features of COVID-19 greatly resemble those seen in SARS-CoV and MERS (8). Using in situ hybridization, SARS-CoV has been found on the surface of small intestinal enterocytes. Active viral replication in the enterocytes of the small intestine has been reported (9). The abundant expression of ACE2 on endothelia and smooth muscle cells in virtually all organs suggests that the SARS-CoV, once present in the circulation, can spread easily hematogenously (7). Via the abundant lymphatic vessels and venules in the lamina propria of the small intestine, the virus could be transported to the right heart via the thoracic duct and superior vena cava, and disseminate mainly to the lower lung. The lung tissues of intragastrically inoculated mice with MERS-CoV exhibited minimal lung pathology at the early phase. Prominent interstitial pneumonia with thickened alveolar septa and mononuclear cell filtration occurred as the enteric infection developed; meanwhile, NP-positive cells emerged in the pulmonary parenchyma (10).
If the gastrointestinal system reveals playing a relevant role in the pathogenesis of SARS-CoV-2 infection, research should focus on boosting intestinal innate immunity as an effective strategy for overcoming insufficient antiviral immunity in the gut (11).

In conclusion, we highlight the possibility of the gastrointestinal system as a potential first route of SARS-CoV-2 invasion and transmission.

1) Salehi S, Abedi A, Balakrishnan S, Gholamrezanezhad A. Coronavirus Disease 2019 (COVID-19): A Systematic Review of Imaging Findings in 919 Patients. AJR Am J Roentgenol. 2020 Mar 14:1-7. DOI: 10.2214/AJR.20.23034.
2) 2) Inui S, Fujikawa A, Jitsu M, Kunishima N, Watanabe S, Suzuki Y, Umeda S, Uwabe Y. Chest CT Findings in Cases from the Cruise Ship “Diamond Princess” with Coronavirus Disease 2019 (COVID-19). Published Online: Mar 17 2020. https://doi.org/10.1148/ryct.2020200110.
3) Nemec SF1, Bankier AA, Eisenberg RL. Lower lobe-predominant diseases of the lung. AJR Am J Roentgenol. 2013 Apr;200(4):712-28. DOI: 10.2214/AJR.12.9253.
4) Stefan F, Nemec A, Bankier A, Eisenberg RL. Upper Lobe–Predominant Diseases of the Lung. American Journal of Roentgenology. 2013;200: W222-W237. 10.2214/AJR.12.8961
5) Wenling W, Yanli X, Ruqin G, alRoujian L, Kai H, Guizhen W, Wenjie T. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA. Published online March 11, 2020. DOI:10.1001/jama.2020.3786.
6) Yongjian W, Cheng G, Lantian T, Zhongsi H, Jianhui Z, et al. Prolonged presence of SARS-CoV-2 viral RNA in fecal samples. 2020. Vol.5;5:434-435. DOI:https://doi.org/10.1016/S2468-1253(20)30083-2
7) Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004 Jun;203(2):631-7.
8) Zhe Xu*, Lei Shi*, Yijin Wang*, Jiyuan Zhang, Lei Huang, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. Published Online. February 17, 2020. https://doi.org/10.1016/S2213-2600(20)30076-X
9) To KF, Tong JH, Chan PK, Au FW, Chim SS, Chan KC, Cheung JL, Liu EY, Tse GM, Lo AW, Lo YM, Ng HK. Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases. J Pathol. 2004 Feb;202(2):157-63.
10) Zhou J, Li C, Zhao G, Chu H, Wang D, Yan HH, et al. Human intestinal tract serves as an alternative infection route for Middle East respiratory syndrome coronavirus. Sci Adv. 2017 Nov 15;3(11):eaao4966. DOI: 10.1126/sciadv.aao4966. eCollection 2017 Nov.
11) Neil JA, Cadwell A. The Intestinal Virome and Immunity. The Intestinal Virome and Immunity Jessica A. J Immunol. 2018; 201:1615-1624; DOI: 10.4049/jimmunol.18006312018

Competing interests: No competing interests

16 April 2020
Giovanni Ghirga
Chief of Pediatrics and Neonatology Unit
Paola Ghirga MD; Patrizio Ghirga ChD; Claudia Orchi MD
San Paolo General Hospital Civitavecchia (Rome), Italy