Consequences of COVID-19 for the Pancreas



Authors: Urszula Abramczyk,1,*Maciej Nowaczyński,2Adam Słomczyński,2Piotr Wojnicz,2Piotr Zatyka,2 and Aleksandra Kuzan1 Int J Mol Sci. 2022 Jan; 23(2): 864.Published online 2022 Jan 13. doi: 10.3390/ijms23020864

Abstract

Although coronavirus disease 2019 (COVID-19)-related major health consequences involve the lungs, a growing body of evidence indicates that COVID-19 is not inert to the pancreas either. This review presents a summary of the molecular mechanisms involved in the development of pancreatic dysfunction during the course of COVID-19, the comparison of the effects of non-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pancreatic function, and a summary of how drugs used in COVID-19 treatment may affect this organ. It appears that diabetes is not only a condition that predisposes a patient to suffer from more severe COVID-19, but it may also develop as a consequence of infection with this virus. Some SARS-CoV-2 inpatients experience acute pancreatitis due to direct infection of the tissue with the virus or due to systemic multiple organ dysfunction syndrome (MODS) accompanied by elevated levels of amylase and lipase. There are also reports that reveal a relationship between the development and treatment of pancreatic cancer and SARS-CoV-2 infection. It has been postulated that evaluation of pancreatic function should be increased in post-COVID-19 patients, both adults and children.

1. Effects of Severe Acute Respiratory Syndrome-Related Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome-Related Coronavirus (MERS-CoV) on the Pancreas

Coronaviruses are enveloped, single- and positive-stranded RNA viruses that infect birds and mammals. In humans, coronaviruses cause respiratory tract infection, usually the common cold, but they can also cause severe respiratory illness including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), caused by severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), respectively [1]. Coronaviruses tend to cause epidemics and even pandemics. The first coronavirus pandemic was the SARS outbreak in 2002–2003 [2]. With the experience gained during the SARS pandemic, it was possible to more quickly identify subsequent outbreaks of the MERS epidemic in 2012 [3]. The pathomechanism of both viruses is very similar—they even both use transmembrane protease serine 2 (TMPRSS2), except SARS-CoV uses angiotensin-converting enzyme 2 (ACE2) as its receptor, whereas MERS uses dipeptidyl peptidase-4 (DPP4) [4,5]. Moreover, there is a difference in terms of the severity and frequency of symptoms, which was observed in MERS patients as more frequent hospitalization in the intensive care unit (ICU) compared to SARS patients [2] (Table 1). Diabetes was one of the significant and independent predictors for developing severe SARS-CoV and MERS-CoV [6,7,8]. In MERS, no viral antigen was detected in any tissue other than pneumocytes [7], despite multiple organ dysfunction syndrome in critically ill patients. In SARS-CoV, the presence of the virus was detected not only in respiratory epithelial cells, but also in small intestinal and colonic epithelial cells, in which it also revealed replication features [9]. It is known that the ACE2 receptor is also present in tissues such as the heart, kidney, and pancreas [8,9]. According to some authors, the presence of the receptor is sufficient for tissue entry and pathogenic activity, although other researchers do not support this thesis [9,10]. Yang et al. were some of the first researchers who hypothesized that SARS coronavirus enters islets using ACE2 as its receptor and damages islets causing acute diabetes [8]. Yang’s study revealed that SARS-CoV had a much higher affinity for pancreatic islet cells than for pancreatic exocrine cells, which was consistent with the hyperglycemia observed in some patients and rarely reported acute pancreatitis (AP) [8]. Furthermore, insulin-dependent diabetes mellitus (IDDM) and high fasting blood glucose values were observed in some inpatients [8]. A 3-year follow-up revealed that both abnormalities were transient, which may be indicative of only temporary damage to the pancreatic islets [8]. However, another reason (different from that given by Young et al.) for high fasting blood glucose value in patients may result from increased stress hormones release. Cortisol, catecholamines, growth hormone, and glucagon, which are released during infection, fever, and trauma, can lead to hyperglycemia to the same degree as SARS-CoV can [11]. No information was found in the literature about a direct impact of the MERS virus on the pancreas or on glycemia during or after infection. This may be due to an insufficiently detailed analysis of the available data during previous studies that oscillated primarily, for laboratory tests, between complete blood count (CBC), lactate dehydrogenase (LDH), urea, and creatinine analysis. A summary of SARS-CoV, MERS, and SARS-CoV-2 is shown in Table 1.Table 1. The summary of characteristics of SARS and MERS coronaviruses. Dipeptidyl peptidase-4 (DPP4), transmembrane protease serine 2 (TMPRSS2), hospitalization in the intensive care unit (ICU), and cathepsin L (CTSL).

Table

In 2019, a new coronavirus named SARS-CoV-2 was identified, causing COVID-19. This virus has many characteristics that are analogous to SARS-CoV, for example, ACE2 is also used as its receptor [12]. Patients with diabetes are among those with the most severe forms of COVID-19 and related mortality; insights from recent experience can guide future management [17], particularly for the consequences on the pancreas. As the COVID-19 pandemic has been ongoing for nearly two years, this study aims to collect data concerning the impact of SARS-CoV-2 on the pancreas and analyze them to estimate the future health consequences of COVID-19 in populations.

2. Pancreatic Damage during Diabetes Mellitus and COVID-19

Pancreas tissue damage may cause to the lack of control over normal blood glucose levels in the body. Type 1 diabetes (T1D) is caused by insulin deficiency due to βcell dysfunction of immunologic or idiopathic cause. In contrast, β pancreatic cells in type 2 diabetes (T2D) become depleted over time due to compensatory insulin secretion caused by insulin resistance. There is also type 3 diabetes (T3D), which is described as diabetes associated with the development of Alzheimer’s disease [18]. It should not be confused with type 3c (pancreatogenic) diabetes, which relates to the exocrine and digestive functions of the pancreas. The issue concerning the impairing effect of hyperglycemia (glucotoxicity) on the secretory function of the islets of Langerhans has also been increasingly raised. In addition to endocrine dysfunction, some diabetic patients may also develop moderate exocrine pancreatic insufficiency (EPI), in which pancreatic enzyme secretion is impaired. EPI can be observed in almost all patients with type 3c (pancreatogenic) diabetes (secondary to pancreatic pathology), whereas the prevalence of this dysfunction in patients with T1D or T2D is 40% and 27%, respectively [19].With the ongoing SARS-CoV-2 pandemic, patients with reduced normal pancreatic function are at high risk for COVID-19 requiring hospitalization. In particular, elevated blood glucose levels in patient with and without diabetes makes them at high risk of mortality [20]. Hyperglycemia impairs the immune response (e.g., by reducing the activity of macrophages and polymorphonuclear leukocytes), which in addition influences the excessive cytokine response, and thus has a strong proinflammatory effect.The receptors for ACE2, which are also present in the pancreas, are a target of SARS-CoV-2 in the body, which may result in acute failure of both the islets of Langerhans and exocrine cells [15]. Infection-induced, transient β cell dysfunction may cause an uncontrolled hyperglycemic state, especially in patients whose pancreas is already affected by diabetes mellitus. Persistent hyperglycemia usually predisposes to severe COVID-19 and to viral infection complicated by secondary infections. The aforementioned risk can be found in T1D, T2D, and gestational diabetes mellitus (GDM). In T2D patients, the much more frequent coexistence of other risk factors such as atherosclerosis, hypertension, and obesity should be taken into consideration, which usually implies a worse prognosis for the course of COVID-19 [21,22]. In GDM, SARS-CoV-2 infection not only increases the risk of more severe course of the disease in a patient, but may also result in diabetic fetopathy or, in more advanced pregnancies, increase the risk of future pathologies involving glucose metabolism (such as T2D) in a child [23].

3. Pancreatic Damage in Patients without Pre-Existing Diabetes Infected with SARS-CoV-2

It has been postulated that, either by direct invasion of pancreatic cells by the virus or by indirect mechanisms described below, SARS-CoV-2 has a destructive effect on the pancreas and can lead to insulin deficiency and development of T1D [24].If the hypothesis that SARS-CoV-2 infection causes hyperglycemia is true, increased statistics of new T1D cases should be observed. Indeed, there are publications that describe such a phenomenon. For instance, Unsworth et al. and Kamrath et al. describe an increase in new-onset T1D in children during the COVID-19 pandemic [16,25]. Although pancreatic β cell damage induced transient hyperglycemia in SARS-CoV, it is still unclear whether β cell damage is transient or permanent in SARS-CoV-2 [22]. This information appears to be of great importance because COVID-19 in children is frequently considered “harmless”. Therefore, it is reasonable to sensitize parents to the fact that the consequences of COVID-19 may be potentially dangerous for their children.Below you will find the proposed molecular mechanisms that may participate in pancreatic damage that causes carbohydrate metabolism disorders.

4. Etiology Associated with ACE2, TMPRSS2, and Na+/H+ Exchanger

As previously mentioned, SARS-CoV infection of host cells is facilitated by ACE2, but also by the transmembrane protease serine 2 (TMPRSS2) and other host cell proteases such as cathepsin L (CTSL) [13].ACE2 is an enzyme that is expressed to varying degrees in most cells of the human body [14,26,27]. This enzyme catalyzes the conversion of angiotensin II to angiotensin 1–7, taking part in the maintenance of body homeostasis by influencing the regulation of blood pressure and water–electrolyte balance through the renin–angiotensin–aldosterone (RAA) system [28]. Moreover, ACE2/angiotensin (1–7) stimulates insulin secretion, reduces insulin resistance, and increases pancreatic βcell survival [27,28].In addition to the key role it plays in maintaining body homeostasis, ACE2 is now also the best-studied target for SARS-CoV-2 S glycoprotein, enabling infection of host cells [27,29]. ACE2 in the pancreas is expressed mainly within the pericytes of pancreatic microvessels and to a lesser extent on the surface of the islets of Langerhans, including pancreatic β cells [30]. SARS-CoV-2 shows 10–20 times more activity against ACE2 than SARS-CoV, which significantly increases the infectivity of SARS-CoV-2 [31,32]. Furthermore, studies indicate that SARS-CoV may also downregulate ACE2 expression in cells. This causes an imbalance between ACE and ACE2, consequently leading to blood pressure disorders and systemic inflammation [27,33,34]. Due to the 79% genetic similarity between SARS-CoV and SARS-CoV-2 [35], it is speculated that ACE2 expression may also be downregulated during SARS-CoV-2 infection, causing i.a. MODS observed in COVID-19 [27].During cell infection by SARS-CoV-2, in addition to the role played by ACE2, it is also appropriate to consider the significant pathogenic role of TMPRSS2 that is necessary for the preparation of S glycoprotein by its cleavage, thereby enabling fusion of the virus with the host cell [36,37]. The S1 and S2 domains can be distinguished in the SARS-CoV-2 S glycoprotein. The S1 domain is involved in binding to the ACE2 receptor and then TMPRSS2 intersects with the S protein, including at the boundary of the S1 and S2 domains and within the S2 domain, which enables the virus–cell fusion [38,39]. According to studies, TMPRSS2 expression is significantly increased in obese patients, which may contribute to the poorer prognosis that is observed during COVID-19 in this patient group [40]. Moreover, obese patients are frequently already burdened with problems such as insulin resistance at baseline, while the presence of ACE2 and TMPRSS2 within the pancreas as a binding site for SARS-CoV-2 may exacerbate insulin resistance causing problems in terms of diabetes management in COVID-19 patients.There are also other mechanisms by which COVID-19 may affect the development of hyperglycemia. It is reported that the virus may also affect the glucose regulation through the Na+/H+ exchanger and lactate pathways. The mechanism is that angiotensin II, which accumulates during infection, contributes to insulin resistance and—by activating the Na+/H+ exchanger in the pancreas—it leads to hypoxia and extracellular acidification, which, through the accumulation of calcium and sodium ions in the cells and the production of reactive oxygen species, damages pancreatic tissue [41]. Simultaneously, the concentration of lactate increases, which in COVID-19 infection is intensively released, among other things, from adipose tissue, and then monocarboxylate transporters transport lactate and H+ ion inward in the cell, which increases Na+/H+ exchanger activation, further disrupting pancreatic homeostasis [41].

5. The Etiology Associated with a Systemic Proinflammatory Environment, Immune System Aggression, and Production of Novel Autoantigens

A broad spectrum of proinflammatory cytokines, such as IL-2, IL-6, IL-7, IL-8, interferon-γ, and Tumor Necrosis Factor α (TNF-α), is released during, in particular severe, COVID-19 infection [42,43,44]. Based on current studies, it is reasonable to suspect that these cytokines are released in response to the binding of the virus to ACE2 receptors that are also located in the pancreas [9,42]. The cause of pancreatic damage during COVID-19 is the cytokine storm that plays a key role in this case, because in both acute pancreatitis (AP) and severe COVID-19, elevated levels of the aforementioned interleukins are associated with the severity of these both disease entities. Particular attention should be paid to IL-6, because it is suspected to play a key role in the pathogenesis of AP as well as acute respiratory distress syndrome (ARDS) that is the most common and most severe clinical manifestation of COVID-19. In COVID-19-induced ARDS, IL-6 levels are correlated with disease-related mortality [45,46,47]. At the same time, high IL-6 levels correlate with an increased risk of developing severe pancreatitis [48,49].The production of neutralizing antibodies is also an important response of the body in the course of COVID-19 [50,51,52]. It has been observed that early seroconversion and very high antibody titers occur in patients with severe SARS-CoV-2 infection [53,54]. The available literature details a mechanism called antibody-dependent enhancement (ADE), which is associated with a pathological response of the immune system [53]. ADE exploits the existence of FcRS receptors located on various cells of the immune system, for example, macrophages and B lymphocytes [53]. This relationship may lead to a likely bypass of the classical viral infection pathway by ACE2, and virus–antibody complexes may stimulate macrophages to overproduce cytokines including significant IL-6 [53,55].Molecular mimicry may be also one of potential causes of pancreatic cell damage [56]. There are similarities in the protein structure of the virus and β-pancreatic cells, which may induce cross-reactivity and lead to autoimmunity [56]. Furthermore, viral infection may also lead to increased cytokine secretion by surrounding dendritic cells and activation of naive T cells in genetically predisposed individuals [56].

6. Pancreatitis in COVID-19

Although the impact of the discussed coronavirus-induced disease on exocrine function is not fully understood, available literature is not able to unambiguously determine whether the tissue damage leading to AP occurs as a result of direct SARS-CoV-2 infection [57] or as a result of systemic MODS with increased levels of amylase and lipase [42]. Liu et al.’s study involving 121 COVID-19 patients with a mean age of 57 years and a variable course of infection proved above-normal levels of amylase and lipase in 1–2% of patients with moderate COVID-19 infection and in 17% of patients with severe COVID-19 infection. This may support the hypothesis that SARS-CoV-2-induced disease has a destructive effect not only on the endocrine portion of this gland, but also on the exocrine one [15].However, elevated levels of pancreatic enzymes in question do not have to mean the destruction of pancreatic cells—after all, such a situation may occur during kidney failure or diarrhea in the course of COVID-19. Furthermore, there remains the question of the effect of drugs administered during SARS-CoV-2 infection on changes in pancreatic function [42], discussed further in this article.According to the International Association of Pancreatology (IAP) and the American Pancreatic Association (APA), the diagnosis of AP is based on meeting two out of three of the following criteria: clinical (epigastric pain), laboratory (serum amylase or lipase > 3 × upper limit of normal), and/or imaging criteria (computed tomography, magnetic resonance imaging, ultrasound) [58]. Pancreatic lipase is considered as a potential marker of SARS-CoV-2 severity with concomitant AP. In Hemant Goyal et al.’s study, as many as 11.7% out of 756 COVID-19 patients had hyperlipidemia and they were three times more likely to have severe COVID-19 [59]. Those with higher lipase levels—17% out of 83 patients—required hospitalization [60]. However, it is difficult to distinguish whether these patients required hospitalization for severe systemic COVID-19 infection or for pancreatitis in the course of COVID-19 infection.AP in the course of COVID-19 was analyzed in different age groups; however, some studies only involve children [61]. Compared to pancreatic islet cells, cells of the exocrine pancreatic ducts are more abundant in ACE2 and TMPRSS2 that are necessary for the virus to penetrate the cell [62]. Infection of these cells may be one of the causes of AP [63]. Infections, both bacterial and viral, are one of the causes of AP. The definitive mechanism of how viral infections affect pancreatic cells is not known; however, a study by Maria K Smatti et al. found that there is infection of pancreatic islet cells and replication of the virus within them, ultimately resulting in autoimmune reactions that eventually affect both diabetes and AP in a negative way [64]. For non-SARS-CoV-2 patients, the etiology of AP is known and confirmed in most cases, although 69% of those undergoing infection do not have definite etiology of AP while meeting the AP-Atlanta criteria for diagnosis [65].Hegyi et al. show the mechanism of MODS formation during COVID-19 infection and AP [66]. This is lipotoxicity, involving an interstitial increase in pancreatic lipase levels, which leads to the breakdown of triacylglycerols contained in adipose tissue cells and the release of unsaturated fatty acids. These in turn exert a toxic effect on mitochondria causing the release of cytokines, which results in a cytokine storm.There is also a hypothesis, which claims that AP can develop because of blood circulatory centralization resulting from uncontrolled cytokine storm created by SARS-CoV-2 infection [67]. There exist reports that say that pancreatic ischemia may be the cause of different degrees of acute pancreatitis [68,69]. This statement can be supported by the reports that state that pancreatic blood reperfusion inhibits the development of AP and accelerate pancreas recovery [70].Another mechanism of developing AP during COVID-19 may be a coagulation cascade activation caused by active inflammatory process due to SARS-CoV-2 infection [71]. The ongoing inflammatory process causes not only hemostasis imbalance for blood clotting, but it also leads to intensification of coagulation by removing epithelial cell protein C receptor (EPCR) from epithelial by the means of inflammatory mediators and thrombin [71]. This means that both processes intensify each other. Simultaneously, it was proved that COVID-19 predisposes patients to venous thromboembolism resulting from excessive inflammation, platelet activation, and endothelial dysfunction [72]. It is also important to notice that AP is inherently connected with a coagulation cascade activation, increased fibrinolysis and, hence, higher level of D-dimers [73]. Acute pancreatitis severity may depend on hemostasis imbalance; local coagulation results in mild AP whereas, in more severe AP cases, the imbalance may lead to development of disseminated intravascular coagulation (DIC) [74]. These observations have been supported by the results of experimental studies showing that the inhibition of coagulation reduces the development of AP [75,76,77] and exhibits therapeutic effect in this disease [78,79]. Additionally it is worth noticing that infection-related hyperglycemia has powerful inflammation-promoting effects on the organism (especially when organism is under stress), thus increasing the number of inflammatory mediators [74]. Unfortunately, it is impossible to decide which process is dominant in causing AP in COVID-19 patients: local inflammation caused by SARS-CoV-2 or systemic hemostasis imbalance.Clinical reports on low molecular weight heparin (LMWH) treatment in AP seem to emphasize a more significant role of hemostasis imbalance in causing AP [74,80,81]. Heparin is extremely significant in the treatment of COVID19 patients due to its properties, mainly its similarity to heparan sulphate, which appears in a respiratory tract, its interactions with SARS-CoV-2 S protein, leading to viral adhesion inhibiting to the cell membrane [82], and its anti-inflammatory effects. Thanks to these properties, heparin may not only show its therapeutic effect as the anticoagulant, but also its protective role in acute pancreatitis or respiratory inflammations [83,84,85].

7. Drugs Used against SARS-CoV-2 Infection (Glucocorticoids, Lopinavir, Ritonavir, Remedesivir, Interferon-β1 (IFN-β1), and Azithromycin) Induce Pancreatic β Cell Damage

Statistical analyses revealed a significantly higher incidence of AP with the concomitant systemic use of glucocorticosteroids (GCS) [86]. In one study analyzing the development of drug-induced AP, dexamethasone, was classified as type IB—there was one case report in which administration of this drug-induced AP occurred; however, other causes of pancreatitis such as alcohol consumption could not be excluded [87]. Other GCS such as hydrocortisone, prednisone, and prednisolone were used in patients with mild to moderate AP; however, they cannot be classified into any group because they are frequently used together with other drugs that cause AP [86,87]. However, it has been determined that GCS independently increase the risk of AP, and patients with residual AP risk factors during GCS treatment should be more monitored for the development of AP [23]. Javier A. Cienfuegos et al. additionally observed that one of mechanisms of AP formation in COVID-19 patients may be GCS administered at the time of admission to the ICU with severe respiratory failure [88]. Because GCS were used in severe COVID-19 cases, it is difficult to say what true reason for AP was—either a severe course of COVID-19 or GCS application or both.GCS are used in the treatment of many diseases due to their immunosuppressive and anti-inflammatory nature. They induce diabetes in previously healthy patients as well as significantly exacerbate diabetes in diabetic patients [89,90]. Diabetes develops in these patients likely due to pancreatic β cell dysfunction, decreased insulin secretion, and increased insulin resistance in other tissues, which may depend on the timing and the dose of GCS used [89,91]. Long-acting or intermediate-acting insulin alone or combined with short-acting insulin should be used during the treatment [90]. At the same time, no advantage was found over the use of oral hypoglycemics [92]. Certainly, patients after long-term GCS therapy will need further observation for diabetes.Lopinavir/ritonavir was classified in the previously mentioned study as a type IV drug—medications reported with little information [87]. Both drugs are included in the group of antiretrovirals that act as protease inhibitors, and they are primarily used for HIV infection. Although Lopinavir is an active drug, it is not used alone. There have been reports about the occurrence of AP during the use of protease inhibitors in question, which is also described in the Summary of Product Characteristics (SmPC) of products approved by Committee for Medicinal Products for Human Use (CHMP). It has been proved that the use of lopinavir/ritonavir causes hyperglycemia [93,94].Remdesivir is an adenosine analogue with antiviral activity. There are single reports about the occurrence of pancreatitis as a result of the use of the aforementioned medication [95,96]. At the same time, it should be noted that other nucleoside-derivative drugs may cause pancreatitis [97].The current state of knowledge does not clearly indicate the therapeutic benefit of interferon-β in the treatment of COVID-19 patients [98,99]. To date, only single cases suggesting induction of pancreatitis by interferon-β have been reported. Based on this, Badalov et al. classified interferon into type III [87].There are few reports about the development of AP due to the use of azithromycin [100]. In the previously mentioned study by Badalov et al., two macrolide antibiotics were classified as type II and III. Unfortunately, there are no direct data concerning azithromycin. Interestingly, there were cases of patients with concomitant symptoms of AP and viral pneumonia caused by SARS-CoV-2 who were treated with azithromycin, which resulted in complete resolution of symptoms for both conditions [96,101]. Based on available data, the risk of azithromycin-induced AP is low.There is no clear evidence that azithromycin affects blood glucose levels in humans. However, it is known for its prokinetic effects, which may be helpful in patients who suffer from diabetic gastroparesis [102]). The incidence of hypo- and hyperglycemic episodes was not proved to be significant for azithromycin [103]; however, the risk of dysglycemia is emphasized [94]. In the SmPC, where azithromycin is the main ingredient, it is not possible to establish a causal relationship between the occurrence of pancreatitis and taking medications (Zithromax) based on the available data. In contrast, glycemic disturbances were not indicated as side effects (Zithromax) [104].Hydroxychloroquine has been extensively promoted for COVID-19 due to its anti-inflammatory and antiviral action; yet, the use of this agent in diabetes deserves particular attention for its documented hypoglycemic action, and its benefit on COVID-19 is controversial, although there is large usage [105].Table 2 shows a comparison of the side effects of medications in question.Table 2. Side effects of medications used in SARS-CoV-2 infection in the area of pancreatic effects and hyperglycemia.

Table

8. COVID-19, Pancreas, and Glycation

In T2D diabetics, oxidative stress leading to pancreatic damage may be stimulated by, among other things, the intense glycation that accompanies hyperglycemia [24]. Glycation is a non-enzymatic process involving reducing sugar and amino groups of proteins, which contributes to the formation of advanced glycation end products (AGEs). These products have significantly altered biochemical properties relative to the substrates, including proteins that have altered conformation, increased rigidity, resistance to proteolysis, etc. [106,107].Part of the pathomechanism involved in facilitating coronavirus infection in diabetics may be due to glycation of ACE2 and SARS-CoV-2 spike protein [108,109].An interesting hypothesis is that COVID-19 has a worse prognosis in patients with intense glycation, and thus high tissue AGE content. Glycated hemoglobin (HbA1c) is a commonly used diagnostic tool that estimates intensity of glycation. The parameter is not only a marker of long-term persistent hyperglycemia, but an active participant in immune processes, as HbA1c levels are associated with NK cell activity [110].Zhang et al.’s retrospective cohort study concerning COVID-19 patients revealed that glycated hemoglobin correlates negatively with saturation (SaO2) and positively with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fibrinogen (Fbg). It was concluded that determination of HbA1c levels may be helpful in assessing inflammation, hypercoagulability, and prognosis of COVID-19 patients [111].According to the meta-analysis by Chen et al. (2020), Hba1c levels were slightly higher in patients with severe COVID-19 compared to patients with mild COVID-19; however, this correlation was not statistically significant. However, it is of great importance to note that only two studies analyzing HbA1c in COVID-19 patients were included in this analysis because only these studies were available in May 2020 [112].Glycation plays its physiological effects not only directly by changing the properties of various proteins, but also indirectly through various receptors. RAGE is the most common receptor for AGEs. Binding of RAGE to its ligands activates a proinflammatory response primarily by mitogen-activated protein kinase (MAPK) and nuclear factor κβ (NFκβ) pathways. This interaction was proved to be significant in the pathogenesis of cancer, diabetes mellitus, and other inflammatory disorders [113]. RAGE was found to be expressed in the pancreas, and S100P-derived RAGE antagonistic peptide (RAP) reduces pancreatic tumor growth and metastasis [113]. The implications of this fact may also apply to the etiology and treatment of COVID-19. It has been postulated that targeting RAGE by various antagonists of this receptor may inhibit damage to various organs including the pancreas [114].

9. COVID-19 vs. Pancreatic Cancer

Immunosuppression as a treatment effect, elevated cytokine levels, altered expression of receptors for SARS-CoV-2, and a prothrombotic state in patients with various types of cancer may exacerbate the effects of COVID-19 [115].Focusing on pancreatic cancer, it can be observed that the pathomechanism of both diseases—COVID-19 and tumorigenesis in the pancreas—overlap in several molecular mechanisms. As mentioned above, SARS-CoV-2 infection of host cells is facilitated by ACE-2, TMPRSS2, and CTSL. Cathepsin L is upregulated in a wide variety of cancers, including pancreatic adenocarcinoma [13]. TMPRSS2 upregulation in pancreatic cancers is moderate, whereas ACE-2 is overexpressed in some cancers, including pancreatic carcinomas [115]. Interestingly, ACE2 upregulation seems to be associated with favorable survival in pancreatic cancer [116], and it is known that SARS-CoV-2 reduces ACE2 expression [22]. Furthermore, the above-mentioned RAGE may also participate in both pancreatic cancer development and SARS-CoV-2 infection. RAGE facilitates neutrophil extracellular trap (NET) formation in pancreatic cancer [117]. In conclusion, pancreatic cancer predisposes to an increased risk of COVID-19 and its more severe course, and coronavirus infection may contribute to pancreatic cancer.It also seems important how the COVID-19 epidemic has affected the treatment of patients with pancreatic cancer of SARS-CoV-2-independent etiology. According to the study by Pergolini et al., care of patients with pancreatic cancer can be disrupted or delayed, particularly in the context of treatment selection, postoperative course, and outpatient care [118].A separate issue is how patients after pancreatoduodenectomy respond to SARS-CoV-2 infection. A case series reported by Bacalbasa reveal that patients who develop SARS-CoV-2 infection postoperatively require re-admission in the ICU and a longer hospital stay; however, these infections are not fatal [119]. Although the analysis was performed on single cases, it is concluded that these results are an argument to perform elective oncological surgeries [119].There are also reports that chemotherapy in pancreatic cancer patients who become ill between treatment series can be successfully completed after a complete cure of the infection [120]. Guidelines for, e.g., prioritization and treatment regimens regarding pancreatic cancer treatment in the era of the pandemic, are developed and described, for example, by Catanese et al. or Jones et al. [121,122].

10. Conclusions

Evidence shows that SARS-CoV-2 infection contributes to damage within the pancreas. The mechanisms that are involved in this include but are not limited to direct cytopathic effect of SARS-CoV-2 replication and systemic and local inflammatory response [123]. At the current state of knowledge, it is certain that the virus attacks the endocrine portion of the pancreas as well as, to a much lesser extent, the exocrine portion. It has been shown that a bidirectional relationship between COVID-19 and diabetes exists; indeed, diabetes is associated with COVID-19 severity and mortality but, at the same time, patients with COVID-19 have shown new onset of diabetes [124]. SARS-CoV-2 virus infection not only directly affects glycemic levels, but also exacerbates already existing hyperglycemia through its negative impact on the functional competence of the islets of Langerhans. It cannot be excluded that the real cause of exocrine dysfunction of this gland is the negative effect of the drugs used for treatment of the infection. As the pandemic progresses, special attention should be given to the evaluation of chronic and acute pancreatic diseases, including pancreatic cancer, so that faster diagnosis enables faster implementation of treatment.

Author Contributions

Conceptualization, A.K.; investigation, U.A., M.N., A.S., P.W., P.Z. and A.K.; resources, U.A., M.N., A.S., P.W., P.Z. and A.K.; writing—original draft preparation, U.A., M.N., A.S., P.W., P.Z. and A.K.; visualization, U.A.; supervision, A.K. All authors have read and agreed to the published version of the manuscript.

References

  1. Zhang, S.F.; Tuo, J.L.; Huang, X.B.; Zhu, X.; Zhang, D.M.; Zhou, K.; Yuan, L.; Luo, H.J.; Zheng, B.J.; Yuen, K.Y.; et al. Epidemiology characteristics of human coronaviruses in patients with respiratory infection symptoms and phylogenetic analysis of HCoV-OC43 during 2010–2015 in Guangzhou. PLoS ONE 201813, e0191789. [Google Scholar] [CrossRef]
  2. De Wit, E.; Van Doremalen, N.; Falzarano, D.; Munster, V.J. SARS and MERS: Recent insights into emerging coronaviruses. Nat. Rev. Microbiol. 201614, 523–534. [Google Scholar] [CrossRef]
  3. Zaki, A.M.; van Boheemen, S.; Bestebroer, T.M.; Osterhaus, A.D.M.E.; Fouchier, R.A.M. Isolation of a Novel Coronavirus from a Man with Pneumonia in Saudi Arabia. N. Engl. J. Med. 2012367, 1814–1820. [Google Scholar] [CrossRef] [PubMed]
  4. Song, Z.; Xu, Y.; Bao, L.; Zhang, L.; Yu, P.; Qu, Y.; Zhu, H.; Zhao, W.; Han, Y.; Qin, C. From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses 201911, 59. [Google Scholar] [CrossRef]
  5. Shirato, K.; Kawase, M.; Matsuyama, S. Middle East Respiratory Syndrome Coronavirus Infection Mediated by the Transmembrane Serine Protease TMPRSS2. J. Virol. 201387, 12552. [Google Scholar] [CrossRef]
  6. Azhar, E.I.; Hui, D.S.C.; Memish, Z.A.; Drosten, C.; Zumla, A. The Middle East Respiratory Syndrome (MERS). Infect. Dis. Clin. N. Am. 202033, 891–905. [Google Scholar] [CrossRef]
  7. Arabi, Y.M.; Balkhy, H.H.; Hayden, F.G.; Bouchama, A.; Luke, T.; Baillie, J.K.; Al-Omari, A.; Hajeer, A.H.; Senga, M.; Denison, M.R.; et al. Middle East Respiratory Syndrome. N. Engl. J. Med. 2017376, 584–594. [Google Scholar] [CrossRef]
  8. Yang, J.K.; Lin, S.S.; Ji, X.J.; Guo, L.M. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol. 201047, 193–199. [Google Scholar] [CrossRef] [PubMed]
  9. Leung, W.K.; To, K.; Chan, P.K.; Chan, H.L.; Wu, A.K.; Lee, N.; Yuen, K.Y.; Sung, J.J. Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection. Gastroenterology 2003125, 1011–1017. [Google Scholar] [CrossRef]
  10. Shi, X.; Gong, E.; Gao, D.; Zhang, B.; Zheng, J.; Gao, Z.; Zhong, Y.; Zou, W.; Wu, B.; Fang, W.; et al. Severe acute respiratory syndrome associated coronavirus is detected in intestinal tissues of fatal cases. Am. J. Gastroenterol. 2005100, 169–176. [Google Scholar] [CrossRef]
  11. Buczkowska, E.O. Alterations of blood glucose homeostasis during septic or injury stress-hyperglycemia. Wiad Lek. 200255, 731–744. [Google Scholar] [PubMed]
  12. Zippi, M.; Hong, W.; Traversa, G.; Maccioni, F.; De Biase, D.; Gallo, C.; Fiorino, S. Involvement of the exocrine pancreas during COVID-19 infection and possible pathogenetic hypothesis: A concise review. Infez. Med. 202028, 507–515. [Google Scholar]
  13. Katopodis, P.; Anikin, V.; Randeva, H.S.; Spandidos, D.A.; Chatha, K.; Kyrou, I.; Karteris, E. Pan-cancer analysis of transmembrane protease serine 2 and cathepsin L that mediate cellular SARS‑CoV‑2 infection leading to COVID-19. Int. J. Oncol. 202057, 533–539. [Google Scholar] [CrossRef] [PubMed]
  14. Zou, X.; Chen, K.; Zou, J.; Han, P.; Hao, J.; Han, Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front. Med. 202014, 185–192. [Google Scholar] [CrossRef] [PubMed]
  15. Liu, F.; Long, X.; Zhang, B.; Zhang, W.; Chen, X.; Zhang, Z. ACE2 Expression in Pancreas May Cause Pancreatic Damage after SARS-CoV-2 Infection. Clin. Gastroenterol. Hepatol. 202018, 2128–2130. [Google Scholar] [CrossRef]
  16. Unsworth, R.; Wallace, S.; Oliver, N.S.; Yeung, S.; Kshirsagar, A.; Naidu, H.; Kwong, R.M.W.; Kumar, P.; Logan, K.M. New-Onset Type 1 Diabetes in Children During COVID-19: Multicenter Regional Findings in the U.K. Diabetes Care 202043, e170–e171. [Google Scholar] [CrossRef] [PubMed]
  17. Stoian, A.P.; Banerjee, Y.; Rizvi, A.A.; Rizzo, M. Diabetes and the COVID-19 Pandemic: How Insights from Recent Experience Might Guide Future Management. Metab. Syndr. Relat. Disord. 202018, 173–175. [Google Scholar] [CrossRef]
  18. Nguyen, T.T.; Ta, Q.T.H.; Nguyen, T.K.O.; Nguyen, T.T.D.; Giau, V. Van Type 3 Diabetes and Its Role Implications in Alzheimer’s Disease. Int. J. Mol. Sci. 202021, 3165. [Google Scholar] [CrossRef]
  19. Pezzilli, R.; Andriulli, A.; Bassi, C.; Balzano, G.; Cantore, M.; Fave, G.D.; Falconi, M.; Group, L.F. the E.P.I. collaborative (EPIc) Exocrine pancreatic insufficiency in adults: A shared position statement of the Italian association for the study of the pancreas. World J. Gastroenterol. 201319, 7930–7946. [Google Scholar] [CrossRef]
  20. Abramczyk, U.; Kuzan, A. What Every Diabetologist Should Know about SARS-CoV-2: State of Knowledge at the Beginning of 2021. J. Clin. Med. 202110, 1022. [Google Scholar] [CrossRef]
  21. Apicella, M.; Campopiano, M.C.; Mantuano, M.; Mazoni, L.; Coppelli, A.; Del Prato, S. COVID-19 in people with diabetes: Understanding the reasons for worse outcomes. Lancet Diabetes Endocrinol. 20209, 782–792. [Google Scholar] [CrossRef]
  22. Boddu, S.K.; Aurangabadkar, G.; Kuchay, M.S. New onset diabetes, type 1 diabetes and COVID-19. Diabetes Metab. Syndr. 202014, 2211–2217. [Google Scholar] [CrossRef] [PubMed]
  23. Sadr-Azodi, O.; Mattsson, F.; Bexlius, T.S.; Lindblad, M.; Lagergren, J.; Ljung, R. Association of oral glucocorticoid use with an increased risk of acute pancreatitis: A population-based nested case-control study. JAMA Intern. Med. 2013173, 444–449. [Google Scholar] [CrossRef]
  24. Hayden, M.R. An Immediate and Long-Term Complication of COVID-19 May Be Type 2 Diabetes Mellitus: The Central Role of β-Cell Dysfunction, Apoptosis and Exploration of Possible Mechanisms. Cells 20209, 2475. [Google Scholar] [CrossRef]
  25. Kamrath, C.; Mönkemöller, K.; Biester, T.; Rohrer, T.R.; Warncke, K.; Hammersen, J.; Holl, R.W. Ketoacidosis in Children and Adolescents with Newly Diagnosed Type 1 Diabetes During the COVID-19 Pandemic in Germany. JAMA 2020324, 801–804. [Google Scholar] [CrossRef] [PubMed]
  26. Hamming, I.; Timens, W.; Bulthuis, M.; Lely, A.; Navis, G.; Goor, H. van Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J. Pathol. 2004203, 631–637. [Google Scholar] [CrossRef]
  27. Ni, W.; Yang, X.; Yang, D.; Bao, J.; Li, R.; Xiao, Y.; Hou, C.; Wang, H.; Liu, J.; Yang, D.; et al. Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Crit. Care 202024, 422. [Google Scholar] [CrossRef] [PubMed]
  28. Santos, R.A.S.; Sampaio, W.O.; Alzamora, A.C.; Motta-Santos, D.; Alenina, N.; Bader, M.; Campagnole-Santos, M.J. The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7). Physiol. Rev. 201898, 505–553. [Google Scholar] [CrossRef]
  29. Li, W.; Moore, M.J.; Vasilieva, N.; Sui, J.; Wong, S.K.; Berne, M.A.; Somasundaran, M.; Sullivan, J.L.; Luzuriaga, K.; Greenough, T.C.; et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003426, 450–454. [Google Scholar] [CrossRef] [PubMed]
  30. Fignani, D.; Licata, G.; Brusco, N.; Nigi, L.; Grieco, G.E.; Marselli, L.; Overbergh, L.; Gysemans, C.; Colli, M.L.; Marchetti, P.; et al. SARS-CoV-2 Receptor Angiotensin I-Converting Enzyme Type 2 (ACE2) Is Expressed in Human Pancreatic β-Cells and in the Human Pancreas Microvasculature. Front. Endocrinol. 202011, 596898. [Google Scholar] [CrossRef] [PubMed]
  31. Wrapp, D.; Wang, N.; Corbett, K.S.; Goldsmith, J.A.; Hsieh, C.-L.; Abiona, O.; Graham, B.S.; McLellan, J.S. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020367, 1260–1263. [Google Scholar] [CrossRef]
  32. Glowacka, I.; Bertram, S.; Herzog, P.; Pfefferle, S.; Steffen, I.; Muench, M.O.; Simmons, G.; Hofmann, H.; Kuri, T.; Weber, F.; et al. Differential Downregulation of ACE2 by the Spike Proteins of Severe Acute Respiratory Syndrome Coronavirus and Human Coronavirus NL63. J. Virol. 201084, 1198–1205. [Google Scholar] [CrossRef] [PubMed]
  33. Haga, S.; Yamamoto, N.; Nakai-Murakami, C.; Osawa, Y.; Tokunaga, K.; Sata, T.; Yamamoto, N.; Sasazuki, T.; Ishizaka, Y. Modulation of TNF-α-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-α production and facilitates viral entry. Proc. Natl. Acad. Sci. USA 2008105, 7809–7814. [Google Scholar] [CrossRef] [PubMed]
  34. Oudit, G.Y.; Kassiri, Z.; Jiang, C.; Liu, P.P.; Poutanen, S.M.; Penninger, J.M.; Butany, J. SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur. J. Clin. Investig. 200939, 618–625. [Google Scholar] [CrossRef] [PubMed]
  35. Muniangi-Muhitu, H.; Akalestou, E.; Salem, V.; Misra, S.; Oliver, N.S.; Rutter, G.A. COVID-19 and Diabetes: A Complex Bidirectional Relationship. Front. Endocrinol. 202011, 758. [Google Scholar] [CrossRef]
  36. Baughn, L.B.; Sharma, N.; Elhaik, E.; Sekulic, A.; Bryce, A.H.; Fonseca, R. Targeting TMPRSS2 in SARS-CoV-2 Infection. Mayo Clin. Proc. 202095, 1989–1999. [Google Scholar] [CrossRef] [PubMed]
  37. Matsuyama, S.; Nao, N.; Shirato, K.; Kawase, M.; Saito, S.; Takayama, I.; Nagata, N.; Sekizuka, T.; Katoh, H.; Kato, F.; et al. Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells. Proc. Natl. Acad. Sci. USA 2020117, 7001–7003. [Google Scholar] [CrossRef]
  38. Thunders, M.; Delahunt, B. Gene of the month: TMPRSS2 (transmembrane serine protease 2). J. Clin. Pathol. 202073, 773–776. [Google Scholar] [CrossRef]
  39. Shen, L.W.; Mao, H.J.; Wu, Y.L.; Tanaka, Y.; Zhang, W. TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections. Biochimie 2017142, 1–10. [Google Scholar] [CrossRef]
  40. Taneera, J.; El-Huneidi, W.; Hamad, M.; Mohammed, A.K.; Elaraby, E.; Hachim, M.Y. Expression Profile of SARS-CoV-2 Host Receptors in Human Pancreatic Islets Revealed Upregulation of ACE2 in Diabetic Donors. Biology 20209, 215. [Google Scholar] [CrossRef]
  41. Cure, E.; Cure, M.C. COVID-19 may affect the endocrine pancreas by activating Na+/H+ exchanger 2 and increasing lactate levels. J. Endocrinol. Investig. 202043, 1167–1168. [Google Scholar] [CrossRef]
  42. Zippi, M.; Fiorino, S.; Occhigrossi, G.; Hong, W. Hypertransaminasemia in the course of infection with SARS-CoV-2: Incidence and pathogenetic hypothesis. World J. Clin. Cases 20208, 1385–1390. [Google Scholar] [CrossRef]
  43. Tisoncik, J.R.; Korth, M.J.; Simmons, C.P.; Farrar, J.; Martin, T.T.; Katze, M.G. Into the eye of the cytokine storm. Microbiol. Mol. Biol. Rev. 201276, 16–32. [Google Scholar] [CrossRef]
  44. Mehta, P.; McAuley, D.F.; Brown, M.; Sanchez, E.; Tattersall, R.S.; Manson, J.J. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020395, 1033–1034. [Google Scholar] [CrossRef]
  45. Zhou, F.; Yu, T.; Du, R.; Fan, G.; Liu, Y.; Liu, Z.; Xiang, J.; Wang, Y.; Song, B.; Gu, X.; et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020395, 1054–1062. [Google Scholar] [CrossRef]
  46. Hojyo, S.; Uchida, M.; Tanaka, K.; Hasebe, R.; Tanaka, Y.; Murakami, M.; Hirano, T. How COVID-19 induces cytokine storm with high mortality. Inflamm. Regen. 202040, 37. [Google Scholar] [CrossRef]
  47. Liu, B.; Li, M.; Zhou, Z.; Guan, X.; Xiang, Y. Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J. Autoimmun. 2020111, 102452. [Google Scholar] [CrossRef] [PubMed]
  48. Rao, S.A.; Kunte, A.R. Interleukin-6: An Early Predictive Marker for Severity of Acute Pancreatitis. Indian J. Crit. Care Med. 201721, 424–428. [Google Scholar] [CrossRef] [PubMed]
  49. Sathyanarayan, G.; Garg, P.K.; Prasad, H.; Tandon, R.K. Elevated level of interleukin-6 predicts organ failure and severe disease in patients with acute pancreatitis. J. Gastroenterol. Hepatol. 200722, 550–554. [Google Scholar] [CrossRef]
  50. Cao, Y.; Liu, X.; Xiong, L.; Cai, K. Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2: A systematic review and meta-analysis. J. Med. Virol. 202092, 1449–1459. [Google Scholar] [CrossRef]
  51. Assis, R.R.; de Jain, A.; Nakajima, R.; Jasinskas, A.; Felgner, J.; Obiero, J.M.; Norris, P.J.; Stone, M.; Simmons, G.; Bagri, A.; et al. Analysis of SARS-CoV-2 antibodies in COVID-19 convalescent blood using a coronavirus antigen microarray. Nat. Commun. 202112, 6. [Google Scholar] [CrossRef]
  52. Zhao, J.; Yuan, Q.; Wang, H.; Liu, W.; Liao, X.; Su, Y.; Wang, X.; Yuan, J.; Li, T.; Li, J.; et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin. Infect. Dis. 202071, 2027–2034. [Google Scholar] [CrossRef]
  53. Iwasaki, A.; Yang, Y. The potential danger of suboptimal antibody responses in COVID-19. Nat. Rev. Immunol. 202020, 339–341. [Google Scholar] [CrossRef]
  54. Lee, N.; Chan, P.K.S.; Ip, M.; Wong, E.; Ho, J.; Ho, C.; Cockram, C.S.; Hui, D.S. Anti-SARS-CoV IgG response in relation to disease severity of severe acute respiratory syndrome. J. Clin. Virol. 200635, 179–184. [Google Scholar] [CrossRef]
  55. Yasui, F.; Kai, C.; Kitabatake, M.; Inoue, S.; Yoneda, M.; Yokochi, S.; Kase, R.; Sekiguchi, S.; Morita, K.; Hishima, T.; et al. Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV. J. Immunol. 2008181, 6337–6348. [Google Scholar] [CrossRef]
  56. Caruso, P.; Longo, M.; Esposito, K.; Maiorino, M.I. Type 1 diabetes triggered by COVID19 pandemic: A potential outbreak? Diabetes Res. Clin. Pract. 2020164, 108219. [Google Scholar] [CrossRef]
  57. de-Madaria, E.; Capurso, G. COVID-19 and acute pancreatitis: Examining the causality. Nat. Rev. Gastroenterol. Hepatol. 202118, 3–4. [Google Scholar] [CrossRef] [PubMed]
  58. Group, W.; Apa, I.A.P.; Pancreatitis, A. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology 201313, e1–e15. [Google Scholar] [CrossRef]
  59. Goyal, H.; Sachdeva, S.; Perisetti, A.; Mann, R.; Inamdar, S.; Tharian, B. Hyperlipasemia and Potential Pancreatic Injury Patterns in COVID-19: A Marker of Severity or Innocent Bystander? Gastroenterology 2021160, 946–948. [Google Scholar] [CrossRef] [PubMed]
  60. Barlass, U.; Wiliams, B.; Dhana, K.; Adnan, D.; Khan, S.R.; Mahdavinia, M.; Bishehsari, F. Marked elevation of lipase in COVID-19 Disease: A cohort study. Clin. Transl. Gastroenterol. 202011, e00215. [Google Scholar] [CrossRef] [PubMed]
  61. Suchman, K.; Raphael, K.L.; Liu, Y.; Wee, D.; Trindade, A.J. Acute pancreatitis in children hospitalized with COVID-19. Pancreatology 202121, 31–33. [Google Scholar] [CrossRef]
  62. Müller, J.A.; Groß, R.; Conzelmann, C.; Krüger, J.; Merle, U.; Steinhart, J.; Weil, T.; Koepke, L.; Bozzo, C.P.; Read, C.; et al. SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nat. Metab. 20213, 149–165. [Google Scholar] [CrossRef] [PubMed]
  63. Correia de Sá, T.; Soares, C.; Rocha, M. Acute pancreatitis and COVID-19: A literature review. World J. Gastrointest. Surg. 202113, 574–584. [Google Scholar] [CrossRef] [PubMed]
  64. Smatti, M.K.; Cyprian, F.S.; Nasrallah, G.K.; Al Thani, A.A.; Almishal, R.O.; Yassine, H.M. Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms. Viruses 201911, 762. [Google Scholar] [CrossRef] [PubMed]
  65. Inamdar, S.; Benias, P.C.; Liu, Y.; Sejpal, D.V.; Satapathy, S.K.; Trindade, A.J.; Northwell COVID-19 Research Consortium. Prevalence, Risk Factors, and Outcomes of Hospitalized Patients with Coronavirus Disease 2019 Presenting as Acute Pancreatitis. Gastroenterology 2020159, 2226–2228.e2. [Google Scholar] [CrossRef] [PubMed]
  66. Hegyi, P.; Szakács, Z.; Sahin-Tóth, M. Lipotoxicity and Cytokine Storm in Severe Acute Pancreatitis and COVID-19. Gastroenterology 2020159, 824–827. [Google Scholar] [CrossRef] [PubMed]
  67. Hu, B.; Huang, S.; Lianghong, Y. Lianghong The cytokine storm and COVID-19. J. Med. Virol. 202193, 250–256. [Google Scholar] [CrossRef] [PubMed]
  68. Gullo, L.; Cavicchi, L.; Tomassetti, P.; Spagnolo, C.; Freyrie, A.; D’addato, M. Effects of Ischemia on the Human Pancreas. Gastroenterology 1996111, 1033–1038. [Google Scholar] [CrossRef]
  69. Lonardo, A.; Grisendi, A.; Bonilauri, S.; Rambaldi, M.; Selmi, I.; Tondelli, E. Ischaemic necrotizing pancreatitis after cardiac surgery. A case report and review of the literature. Ital. J. Gastroenterol. Hepatol. 199931, 872–875. [Google Scholar] [PubMed]
  70. Warzecha, Z.; Dembiński, A.; Ceranowicz, P.; Konturek, P.C.; Stachura, J.; Konturek, S.J.; Niemiec, J. Protective effect of calcitonin gene-related peptide against caerulein-induced pancreatitis in rats. J. Physiol. Pharmacol. 199748, 775–787. [Google Scholar]
  71. Esmon, C.T. Crosstalk between inflammation and thrombosis. Maturitas 200861, 122–131. [Google Scholar] [CrossRef]
  72. Wang, D.; Hu, B.; Hu, C.; Zhu, F.; Liu, X.; Zhang, J.; Wang, B.; Xiang, H.; Cheng, Z.; Xiong, Y.; et al. Clinical Characteristics of 138 Hospitalized Patients with 2019 NovelCoronavirus–Infected Pneumonia in Wuhan, China. JAMA 2020323, 1061–1069. [Google Scholar] [CrossRef] [PubMed]
  73. Lasson, Å.; Ohlsson, K. Consumptive coagulopathy, fibrinolysis and protease-antiprotease interactions during acute human pancreatitis. Thromb. Res. 198641, 167–183. [Google Scholar] [CrossRef]
  74. Du, J.D.; Zheng, X.; Huang, Z.Q.; Cai, S.W.; Tan, J.W.; Li, Z.L.; Yao, Y.M.; Jiao, H.B.; Yin, H.N.; Zhu, Z.M. Effects of intensive insulin therapy combined with low molecular weight heparin anticoagulant therapy on severe pancreatitis. Exp. Ther. Med. 20148, 141–146. [Google Scholar] [CrossRef] [PubMed]
  75. Maduzia, D.; Ceranowicz, P.; Cieszkowski, J.; Gałazka, K.; Kusnierz-Cabala, B.; Warzecha, Z. Pretreatment with Warfarin Attenuates the Development of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats. Molecules 202025, 2493. [Google Scholar] [CrossRef]
  76. Warzecha, Z.; Sendur, P.; Ceranowicz, P.; Dembinski, M.; Cieszkowski, J.; Kusnierz-Cabala, B.; Tomaszewska, R.; Dembinski, A. Pretreatment with low doses of acenocoumarol inhibits the development of acute ischemia/reperfusion-induced pancreatitis. J. Physiol. Pharmacol. 201566, 731–740. [Google Scholar] [PubMed]
  77. Warzecha, Z.; Sendur, P.; Ceranowicz, P.; Dembiński, M.; Cieszkowski, J.; Kuśnierz-Cabala, B.; Olszanecki, R.; Tomaszewska, R.; Ambroży, T.; Dembiński, A. Protective Effect of Pretreatment with Acenocoumarol in Cerulein-Induced Acute Pancreatitis. Int. J. Mol. Sci. 20167, 1709. [Google Scholar] [CrossRef] [PubMed]
  78. Maduzia, D.; Ceranowicz, P.; Cieszkowski, J.; Chmura, A.; Galazka, K.; Kusnierz-Cabala, B.; Warzecha, Z. Administration of warfarin accelerates the recovery in ischemia/reperfusion-induced acute pancreatitis. J. Physiol. Pharmacol. 202071, 417–427. [Google Scholar] [CrossRef]
  79. Ceranowicz, P.; Dembinski, A.; Warzecha, Z.; Dembinski, M.; Cieszkowski, J.; Rembiasz, K.; Konturek, S.J.; Kusnierz-Cabala, B.; Tomaszewska, R.; Pawlik, W.W. Protective and therapeutic effect of heparin in acute pancreatitis. J. Physiol. Pharmacol. 200859, 103–125. [Google Scholar]
  80. Xin-Sheng, L.; Fu, Q.; Jie-Qin, L.; Qin-Qiao, F.; Ri-Guang, Z.; Yu-Hang, A.; Kai-Cheng, Z.; Yi-Xiong, L. Low Molecular Weight Heparin in the Treatment of Severe Acute Pancreatitis: A Multiple Centre Prospective Clinical Study. Asian J. Surg. 200932, 89–94. [Google Scholar] [CrossRef]
  81. Tozlu, M.; Kayar, Y.; Ince, A.T.; Baysal, B.; Şenturk, H. Low molecular weight heparin treatment of acute moderate and severe pancreatitis: A randomized, controlled, open-label study. Turk. J. Gastroenterol. 201930, 81–87. [Google Scholar] [CrossRef]
  82. Agarwal, R.N.; Aggarwal, H.; Verma, A.; Tripathi, M.K. A case report of a patient on therapeutic warfarin who died of COVID19 infection with a sudden rise in d-dimer. Biomedicines 20219, 1382. [Google Scholar] [CrossRef]
  83. Di Micco, P.; Imbalzano, E.; Russo, V.; Attena, E.; Mandaliti, V.; Orlando, L.; Lombardi, M.; Micco, G.; Di Camporese, G.; Annunziata, S.; et al. Heparin and SARS-CoV-2: Multiple Pathophysiological Links. Viruses 202113, 2486. [Google Scholar] [CrossRef] [PubMed]
  84. Bukowczan, J.; Warzecha, Z.; Ceranowicz, P.; Kusnierz-Cabala, B.; Tomaszewska, R.; Dembinski, A. Therapeutic effect of ghrelin in the course of ischemia/reperfusion-induced acute pancreatitis. Curr. Pharm. Des. 201521, 2284–2290. [Google Scholar] [CrossRef]
  85. Warzecha, Z.; Dembiñski, A.; Ceranowicz, P.; Konturek, S.J.; Tomaszewska, R.; Stachura, J.; Konturek, P.C. IGF-1 stimulates production of interleukin-10 and inhibits development of caerulein-induced pancreatitis. J. Physiol. Pharmacol. 200354, 575–590. [Google Scholar] [PubMed]
  86. Nango, D.; Hirose, Y.; Goto, M.; Echizen, H. Analysis of the Association of Administration of various glucocorticoids with development of acute pancreatitis using US Food and Drug Administration adverse event reporting system (FAERS). J. Pharm. Healthc. Sci. 20195, 5. [Google Scholar] [CrossRef]
  87. Badalov, N.; Baradarian, R.; Iswara, K.; Li, J.; Steinberg, W.; Tenner, S. Drug-Induced Acute Pancreatitis: An Evidence-Based Review. Clin. Gastroenterol. Hepatol. 20075, 648–661. [Google Scholar] [CrossRef]
  88. Cienfuegos, J.A.; Almeida, A.; Aliseda, D. Pancreatic injury and acute pancreatitis in COVID-19 patients. Rev. Esp. Enferm. Dig. 2021113, 389. [Google Scholar] [CrossRef] [PubMed]
  89. Hwang, J.L.; Weiss, R.E. Steroid-induced diabetes: A clinical and molecular approach to understanding and treatment. Diabetes Metab. Res. Rev. 201430, 96–102. [Google Scholar] [CrossRef]
  90. Radhakutty, A.; Burt, M.G. Management of endocrine disease: Critical review of the evidence underlying management of glucocorticoid-induced hyperglycaemia. Eur. J. Endocrinol. 2018179, R207–R218. [Google Scholar] [CrossRef]
  91. Van Raalte, D.H.; Nofrate, V.; Bunck, M.C.; Van Iersel, T.; Schaap, J.E.; Nässander, U.K.; Heine, R.J.; Mari, A.; Dokter, W.H.A.; Diamant, M. Acute and 2-week exposure to prednisolone impair different aspects of β-cell function in healthy men. Eur. J. Endocrinol. 2010162, 729–735. [Google Scholar] [CrossRef] [PubMed]
  92. Klarskov, C.K.; Holm Schultz, H.; Wilbek Fabricius, T.; Persson, F.; Pedersen-Bjergaard, U.; Lommer Kristensen, P. Oral treatment of glucocorticoid-induced diabetes mellitus: A systematic review. Int. J. Clin. Pract. 202074, e13529. [Google Scholar] [CrossRef]
  93. Kaletra 200 mg/50 mg Film-Coated Tablets—Summary of Product Characteristics (SmPC)—(emc). Available online: https://www.medicines.org.uk/emc/product/221/smpc (accessed on 10 January 2022).
  94. Rimesh Pal, S.K.B. COVID-19 and diabetes mellitus: An unholy interaction of two pandemics. Diabetes Metab. Syndr. Clin. Res. Rev. 202014, 513–517. [Google Scholar] [CrossRef]
  95. Khadka, S.; Williams, K.; Solanki, S. Remdesivir-Associated Pancreatitis. Am. J. Ther. 2021. [Google Scholar] [CrossRef]
  96. Ehsan, P.; Haseeb, M.; Khan, Z.; Rehan, A.; Singh, R. Coronavirus Disease 2019 Pneumonia and Acute Pancreatitis in a Young Girl. Cureus 202113, e15374. [Google Scholar] [CrossRef]
  97. Jorgensen, S.C.J.; Kebriaei, R.; Dresser, L.D. Remdesivir: Review of Pharmacology, Pre-Clinical Data, and Emerging Clinical Experience for COVID-19. Pharmacotherapy 202040, 659–671. [Google Scholar] [CrossRef]
  98. Pan, H.; Peto, R.; Henao-Restrepo, A.; Preziosi, M.; Sathiyamoorthy, V.; Abdool Karim, Q.; Alejandria, M.; Hernández García, C.; Kieny, M.; Malekzadeh, R.; et al. Repurposed Antiviral Drugs for COVID19—Interim WHO Solidarity. N. Engl. J. Med. 2021384, 497–511. [Google Scholar] [CrossRef] [PubMed]
  99. Rahmani, H.; Davoudi-Monfared, E.; Nourian, A.; Khalili, H.; Hajizadeh, N.; Jalalabadi, N.Z.; Fazeli, M.R.; Ghazaeian, M.; Yekaninejad, M.S. Interferon β-1b in treatment of severe COVID-19: A randomized clinical trial. Int. Immunopharmacol. 202088, 106903. [Google Scholar] [CrossRef] [PubMed]
  100. Gonzalo-Voltas, A.; Fernández-Pérez-Torres, C.U.; Baena-Díez, J.M. Acute pancreatitis in a patient with COVID-19 infection. Med. Clin. 2020155, 183–184. [Google Scholar] [CrossRef] [PubMed]
  101. Díaz Lobato, S.; Carratalá Perales, J.M.; Alonso Íñigo, J.M. Can we use noninvasive respiratory therapies in COVID-19 pandemic? Med. Clin. 2020155, 183. [Google Scholar] [CrossRef] [PubMed]
  102. Sutera, L.; Dominguez, L.J.; Belvedere, M.; Putignano, E.; Vernuccio, L.; Ferlisi, A.; Fazio, G.; Costanza, G.; Barbagallo, M. Azithromycin in an older woman with diabetic gastroparesis. Am. J. Ther. 200815, 85–88. [Google Scholar] [CrossRef]
  103. Aspinall, S.L.; Good, C.B.; Jiang, R.; McCarren, M.; Dong, D.; Cunningham, F.E. Severe dysglycemia with the fluoroquinolones: A class effect? Clin. Infect. Dis. 200949, 402–408. [Google Scholar] [CrossRef] [PubMed]
  104. Zithromax Powder for Oral Suspension—Summary of Product Characteristics (SmPC)—(emc). Available online: https://www.medicines.org.uk/emc/product/3006/smpc#gref (accessed on 10 January 2022).
  105. Stoian, A.P.; Catrinoiu, D.; Rizzo, M.; Ceriello, A. Hydroxychloroquine, COVID-19 and diabetes. Why it is a different story. Diabetes Metab. Res. Rev. 202137, e3379. [Google Scholar] [CrossRef] [PubMed]
  106. Kuzan, A. Toxicity of advanced glycation end products (Review). Biomed. Rep. 202114, 46. [Google Scholar] [CrossRef] [PubMed]
  107. Kuzan, A.; Chwiłkowska, A.; Maksymowicz, K.; Bronowicka-Szydełko, A.; Stach, K.; Pezowicz, C.; Gamian, A. Advanced glycation end products as a source of artifacts in immunoenzymatic methods. Glycoconj. J. 201835, 95–103. [Google Scholar] [CrossRef]
  108. Liao, Y.-H.; Zheng, J.-Q.; Zheng, C.-M.; Lu, K.-C.; Chao, Y.-C. Novel Molecular Evidence Related to COVID-19 in Patients with Diabetes Mellitus. J. Clin. Med. 20209, 3962. [Google Scholar] [CrossRef]
  109. Sartore, G.; Ragazzi, E.; Faccin, L.; Lapolla, A. A role of glycation and methylation for SARS-CoV-2 infection in diabetes? Med. Hypotheses 2020144, 110247. [Google Scholar] [CrossRef]
  110. Kim, J.H.; Park, K.; Lee, S.B.; Kang, S.; Park, J.S.; Ahn, C.W.; Nam, J.S. Relationship between natural killer cell activity and glucose control in patients with type 2 diabetes and prediabetes. J. Diabetes Investig. 201910, 1223–1228. [Google Scholar] [CrossRef]
  111. Zhang, W.; Li, C.; Xu, Y.; He, B.; Hu, M.; Cao, G.; Li, L.; Wu, S.; Wang, X.; Zhang, C.; et al. Hyperglycemia and Correlated High Levels of Inflammation Have a Positive Relationship with the Severity of Coronavirus Disease 2019. Mediat. Inflamm. 20212021, 8812304. [Google Scholar] [CrossRef]
  112. Chen, J.; Wu, C.; Wang, X.; Yu, J.; Sun, Z. The Impact of COVID-19 on Blood Glucose: A Systematic Review and Meta-Analysis. Front. Endocrinol. 202011, 574541. [Google Scholar] [CrossRef]
  113. Arumugam, T.; Ramachandran, V.; Gomez, S.B.; Schmidt, A.M.; Logsdon, C.D. S100P-Derived RAGE Antagonistic Peptide Reduces Tumor Growth and Metastasis. Clin. Cancer Res. 201218, 4356–4364. [Google Scholar] [CrossRef]
  114. Chiappalupi, S.; Salvadori, L.; Vukasinovic, A.; Donato, R.; Sorci, G.; Riuzzi, F. Targeting RAGE to prevent SARS-CoV-2-mediated multiple organ failure: Hypotheses and perspectives. Life Sci. 2021272, 119251. [Google Scholar] [CrossRef]
  115. van Dam, P.A.; Huizing, M.; Mestach, G.; Dierckxsens, S.; Tjalma, W.; Trinh, X.B.; Papadimitriou, K.; Altintas, S.; Vermorken, J.; Vulsteke, C.; et al. SARS-CoV-2 and cancer: Are they really partners in crime? Cancer Treat. Rev. 202089, 102068. [Google Scholar] [CrossRef] [PubMed]
  116. Zhang, Z.; Li, L.; Li, M.; Wang, X. The SARS-CoV-2 host cell receptor ACE2 correlates positively with immunotherapy response and is a potential protective factor for cancer progression. Comput. Struct. Biotechnol. J. 202018, 2438–2444. [Google Scholar] [CrossRef] [PubMed]
  117. Boone, B.A.; Orlichenko, L.; Schapiro, N.E.; Loughran, P.; Gianfrate, G.C.; Ellis, J.T.; Singhi, A.D.; Kang, R.; Tang, D.; Lotze, M.T.; et al. The Receptor for Advanced Glycation End Products (RAGE) Enhances Autophagy and Neutrophil Extracellular Traps in Pancreatic Cancer. Cancer Gene Therapy 201522, 326–334. [Google Scholar] [CrossRef]
  118. Pergolini, I.; Demir, I.E.; Stöss, C.; Emmanuel, K.; Rosenberg, R.; Friess, H.; Novotny, A. Effects of COVID-19 Pandemic on the Treatment of Pancreatic Cancer: A Perspective from Central Europe. Dig. Surg. 202138, 158–165. [Google Scholar] [CrossRef] [PubMed]
  119. Bacalbasa, N.; Diaconu, C.; Savu, C.; Savu, C.; Stiru, O.; Balescu, I. The impact of COVID-19 infection on the postoperative outcomes in pancreatic cancer patients. In Vivo 202135, 1307–1311. [Google Scholar] [CrossRef]
  120. Nagai, K.; Kitamura, K.; Hirai, Y.; Nutahara, D.; Nakamura, H.; Taira, J.; Matsue, Y.; Abe, M.; Kikuchi, M.; Itoi, T. Successful and Safe Reinstitution of Chemotherapy for Pancreatic Cancer after COVID-19. Intern. Med. 202160, 231–234. [Google Scholar] [CrossRef] [PubMed]
  121. Catanese, S.; Pentheroudakis, G.; Douillard, J.Y.; Lordick, F. ESMO Management and treatment adapted recommendations in the COVID-19 era: Pancreatic Cancer. ESMO Open 20205, e000804. [Google Scholar] [CrossRef]
  122. Jones, C.M.; Radhakrishna, G.; Aitken, K.; Bridgewater, J.; Corrie, P.; Eatock, M.; Goody, R.; Ghaneh, P.; Good, J.; Grose, D.; et al. Considerations for the treatment of pancreatic cancer during the COVID-19 pandemic: The UK consensus position. Br. J. Cancer 2020123, 709–713. [Google Scholar] [CrossRef]
  123. Ugwueze, C.V.; Ezeokpo, B.C.; Nnolim, B.I.; Agim, E.A.; Anikpo, N.C.; Onyekachi, K.E. COVID-19 and Diabetes Mellitus: The Link and Clinical Implications. Dubai Diabetes Endocrinol. J. 202026, 69–77. [Google Scholar] [CrossRef]
  124. Al Mahmeed, W.; Al-Rasadi, K.; Banerjee, Y.; Ceriello, A.; Cosentino, F.; Galia, M.; Goh, S.-Y.; Kempler, P.; Lessan, N.; Papanas, N.; et al. Promoting a Syndemic Approach for Cardiometabolic Disease Management During COVID-19: The CAPISCO International Expert Panel. Front. Cardiovasc. Med. 20218, 787761. [Google Scholar] [CrossRef] [PubMed]
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