key: cord-0989117-sof70xa1 authors: Wang, Chenxing; Wu, Heming; Ding, Xu; Ji, Huan; Jiao, Pengfei; Song, Haiyang; Li, Sheng; Du, Hongming title: Does infection of 2019 novel coronavirus cause acute and/or chronic sialadenitis? date: 2020-07-31 journal: Medical Hypotheses DOI: 10.1016/j.mehy.2020.109789 sha: 30af452b9938459299c34ecb57d583fe005c4d2a doc_id: 989117 cord_uid: sof70xa1 Abstract 2019 novel coronavirus (2019-nCoV) is widespread in China and other countries. The target of 2019-nCoV and severe acute respiratory syndrome coronavirus (SARS-CoV) is angiotensin-converting enzyme 2 (ACE2) positive cells. ACE2 is present in the salivary gland duct epithelium, and thus it could be the target of 2019-nCoV and SARS-CoV. SARS-CoV-related animal model experiments show that it can infect the epithelial cells on the salivary gland duct in Chinese rhesus macaques by targeting ACE2. Clinical studies confirmed that 2019-nCoV and SARS-CoV could be detected in saliva of human patients. We hypothesize that the infection of 2019-nCoV and SARS-CoV will lead to inflammatory pathological lesions in patients’ target organs, and possibly inflammatory lesions in salivary glands. 2019-nCoV may cause acute sialoadenitis in the acute phase of infection. After the acute phase, chronic sialoadenitis may be caused by fibrosis repairment. Although there was no direct evidence to prove this, the available indirect evidence indicates a high probability of our hypothesis. According to serological and genomic characteristics, coronaviruses are classified into four types, α, β, γ, and δ [1] . Current research shows that most coronaviruses infect animals, and only a few infect humans. The seven coronaviruses that are currently known to infect humans belong to types α and β. Both HCoV-229E and HCoV-NL63 belong to type α. HCoV-OC43, CoV-HKU1, Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and 2019 novel coronavirus (2019-nCoV), belong to type β. CoV-HKU1, SARS-CoV, MERS-CoV, and 2019-nCoV can cause human pneumonia [2] . At the end of 2019, 2019-nCoV pneumonia first occurred in Wuhan, China, and spread rapidly outward, leading to a mass epidemic, which has become a significant global public health incident [3, 4] . Because of strong virulence, 2019-nCoV can cause severe acute respiratory infections (SARIs) [5, 6] . With the accumulation of clinical cases and the progress of research, except for SARIs, 2019-CoV may also cause diarrhea, liver damage, and impaired organ function, e.g., in the kidneys and testes [7] [8] [9] [10] . The above content shows some clinical characteristics of coronavirus disease 2019 (COVID-19) caused by 2019-nCoV infection, but the clinical features still need to be further studied. Current research results show that the spike protein receptorbinding domain (RBD) of 2019-nCoV can bind to ACE2 receptor on the host cells, thereby completing the adsorption [11] . This adsorption mechanism is the same as that of SARS-CoV [12, 13] . 2019-nCoV can cause damage in respiratory and other organs and could be related to the distribution of ACE2 in human organs [5] [6] [7] [8] [9] [10] . Therefore, cells with ACE2 receptor distribution may become host cells for 2019-nCoV and further cause inflammatory reactions in related organs. Based on available publicity datasets in GTExportal (https:// gtexportal.org), mRNA and ACE2 protein are detected in salivary glands [8] . Liu et al. reported ACE2 receptors in the epithelium of salivary gland ducts in Chinese rhesus macaques by immunohistochemistry [14] . Therefore, salivary glands are very likely to become targets of 2019-nCoV. Since the discovery of SARS-CoV in 2002, many studies have proved that the RBD sequence of spike protein, which is located on the envelope of SARS-CoV, can specifically bind to the host receptor ACE2 https://doi.org/10.1016/j.mehy.2020.109789 Received 2 March 2020; Received in revised form 23 March 2020; Accepted 23 April 2020 and then be adsorbed into host cells [12, 13] . The connection between RBD and ACE2 also participates in the fusion of the virus and host cells and then stimulates the organism to produce neutralizing antibodies and to mediate cellular immune response [15, 16] . Xiao et al. found that the above process does not require the participation of other proteins, and ACE2 becomes a key target for SARS-CoV fusion with host cells [17] . Scholars have found that the RBD sequences of the spike proteins of SARS-CoV and 2019-nCoV are highly similar [5] [6] [7] [8] [9] [10] . This result suggests that the invasion mechanism of 2019-nCoV and SARS-CoV may be highly similar. ACE2 is an important member of the renin-angiotensin system. It is widely distributed in the vasculature and participates in the regulation of blood pressure [18] . According to data in the GTEx dataset (https:// gtexportal.org), except for the vasculature, ACE2 protein can also be found in other organs, such as the small intestine, testes, adipose tissue, thyroid gland, kidneys, heart muscle, colon, and ovaries ( Fig. 1 ). According to the above results, the ACE2 protein can be detected in salivary glands, and the mean expression level is 1.8 pTPM (proteincoding transcripts per million), which ranks 10th in total organs, even higher than that in the lung (Fig. 1 ). Liu et al. reported that ACE2 receptors are located on epithelial cells of salivary ducts; the epithelial cells are early targets of SARS-CoV infection [14] . The above evidence indicates that salivary glands could be the invasive target of 2019-nCoV. Since ACE2 receptors are expressed in salivary glands, they could become a target for 2019-nCoV infection. In theory, 2019-nCoV will fuse into the epithelial cells on the salivary gland duct, replicate in them, and be released into saliva at a specific time. Therefore, 2019-nCoV should be detectable in saliva. Related studies have shown that nucleic acid of 2019-nCoV could be detected in saliva samples from 91.7% (11/12) of patients by polymerase chain reaction; the live virus is confirmed by viral culture, which is isolated from saliva [19] . A study related to SARS-CoV has also shown that SARS-CoV can be detected in saliva obtained from the early phase of infected patients [20] . Peiris et al. proposed the clinical progression of SARS-CoV with a triphasic pattern [21] . In the first phase, viral replication and cytolysis cause fever, myalgia, and symptoms in other systems [21] , and lymphocytes are attacked by SARS-CoV, causing the decrease of lymphocyte counts in peripheral blood [22] . These aspects are similar to the clinical character of CONVID-19 [9] . The second phase is tissue damage associated with excessive immunoreaction. A large number of mononuclear macrophages were observed in pathological lesions of SARS-CoV target organs, and some of them activated; they play the role of phagocytosis and antigen presentation in immunoreaction [23] . In the second phase, in the immunopathological progression, secreted inflammatory cytokines, such as IL-8, IL-6, IL-16, and TNF-α, promote the inflammatory response to induce relatively severe tissue damage [23] . Based on the above evidence and the similarity between SARS-CoV and 2019-nCoV, we speculate that 2019-nCoV replicates in salivary gland cells, which are then lysed in the first phase of infection. The salivary glands and ducts may be further damaged by the immunopathological process. Based on the above evidence, we infer that 2019-nCoV may cause acute sialadenitis according to the following process. 2019-nCoV binds to ACE2 receptors on the epithelium of salivary glands, fuses with them, replicates, and lyses cells to induce obvious symptoms and signs, such as discomfort, swelling, and pain in major salivary glands (parotid and submandibular glands). The virus can be detected in saliva [19] . After acinar cells are lysed by the cytolytic effect of 2019-nCoV, salivary amylase is released into the peripheral blood. Therefore, we infer that amylase increases in peripheral blood in the early phase of infection. As the immunopathological progression proceeds, secreted inflammatory cytokines promote the inflammatory response that damages salivary gland tissue. With decreasing immunoreaction, inflammatory damage will be repaired by granulation and fibrogenesis. Based on the conventional repair mechanism of acute inflammatory damage [24] [25] [26] , we speculate that the inflammatory destruction of salivary glands will be repaired by fibroblast proliferation and fibrous connective tissue formation. The hyposecretion of salivary glands would be caused by fibrous repair of acinar cell damage. Stenosis and dilatation in the ducts of salivary glands may be caused by hyperplastic fibrous scars. Hyposecretion reduces salivary flow, which is bound to affect the flushing function of saliva for the ductal system, thereby increasing the probability of retrograde infection through ductal orifices [27] . Second, hyposecretion increases the possibility of deposition of inorganic salts on the ductal wall, causing sialolithiasis [28] . Ductal stenosis that may be caused by hyperplasia of fibrous connective tissue around ducts can also reduce the salivary flow, increasing the incidence of the above diseases [29] . Moreover, ductal dilatation also reduces salivary flow, which promotes the formation of mucous plugs that block the excretion of saliva to further aggravate obstruction [30] . The repairing changes mentioned above may be caused by inflammation, which are causes of chronic obstructive sialadenitis. Therefore, chronic obstructive sialadenitis may be caused by 2019-nCoV infection. Discussion 2019-nCoV erupted in Wuhan, China, in December 2019, causing widespread epidemics due to large-scale population movements during holidays [2] . At present, the number of confirmed cases in China has exceeded 70,000, and the scale of this infection exceeded that of SARS-CoV in 2003 (https://www.who.int/docs/default-source/coronaviruse/ situation-reports/20200225-sitrep-36-covid-19.pdf?sfvrsn=2791b4e0_ 2). At present, the clinical management of COVID-19 is mainly applied by relevant specialists in infectious diseases, respiratory diseases, and intensive care. Research on the clinical characteristics of patients has been published in various professional journals, but the focus is mainly on the related damage of the respiratory, digestive, and urinary systems [9, 10] . Of course, due to the outbreak of COVID-19 and the isolation of patients, medical professionals in other related professions are still unable to participate in the comprehensive evaluation of patients, so some clinical characteristics of COVID-19 may be missed. Therefore, specialists involved in clinical management are advised to pay attention to some subtle changes in many other organs of COVID-19 cases and to accumulate evidence with which to understand the characteristics of COVID-19 further. SARS-CoV-related animal model experiments show that the first point of invasion is the salivary ducts [14] . Patient-based clinical studies also that show that SARS-CoV can be detected early in saliva [19] . Therefore, possible early symptoms of COVID-19 may include discomfort, swelling, pain, or secretory dysfunction of the salivary glands. We speculate that with the further development of infection, amylase may enter peripheral blood after acinar cell destruction. Therefore, clinicians should pay more attention to the above symptoms and signs. For acute sialadenitis occurring in the parotid and submandibular glands, ultrasound and amylase examination in peripheral blood could be used in diagnosis. The result of amylase examination in peripheral blood must be discriminated from that of acute pancreatitis. For acute sialadenitis that may occur in the sublingual gland, it is necessary to consider the difficulty of ventilation caused by swelling of the mouthfloor. If acute sialadenitis occurs in major salivary glands, the amount of saliva secretion may decrease significantly, causing xerostomia, which could be relieved by the use of artificial saliva. Patients infected with SARS-CoV or 2019-nCoV may suffer from acute and chronic sialadenitis. Clinicians should pay more attention to the status of salivary glands during follow-up after cure, especially if the patient's health is complicated by chronic obstructive sialadenitis and salivary secretion dysfunction. For possible chronic obstructive sialadenitis, ultrasound, sialography, magnetic resonance, or salivary gland endoscopy can be used to understand the shape of the salivary gland and its catheter and to determine whether the stenosis of ducts has occurred. For possible hyposecretion, the measurement of saliva flow or radionuclide imaging could be used to determine the secretion function of salivary glands. Based on available evidence, we hypothesize that 2019-nCoV may cause acute sialadenitis and related symptoms, such as discomfort, pain, swelling, and secretory dysfunction in salivary glands; after the acute phase, the structure of salivary glands may be abnormal due to 2019-nCoV infection, which may cause chronic sialadenitis. Although not proven by direct evidence, clinicians should pay sufficient attention to such symptoms. 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We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.