key: cord-0702591-yv4d8ka8
authors: Alyammahi, Shatha K.; Abdin, Shifaa M.; Alhamad, Dima W.; Elgendy, Sara M.; Altell, Amani T.; Omar, Hany A.
title: The dynamic association between COVID-19 and chronic disorders: An updated insight into prevalence mechanism and therapeutic modalities
date: 2020-11-29
journal: Infect Genet Evol
DOI: 10.1016/j.meegid.2020.104647
sha: c66392c861520e1ecea4f47feee0a70875d0c65a
doc_id: 702591
cord_uid: yv4d8ka8

The devastating pandemic of coronavirus disease 2019 (COVID-19) has caused thousands of deaths and left millions of restless patients suffering from its complications. Increasing data indicate that the disease presents in a severe form in patients with pre-existing chronic conditions like cardiovascular diseases, diabetes, respiratory system diseases, and renal diseases. This indicates that these patients seem to be more susceptible to COVID-19 and have higher mortality rates compared to patients with no comorbid conditions. Several factors can explain the heightened susceptibility to and fatal presentation of COVID-19 in these patients, for example, the enhanced expression of the angiotensin-converting enzyme-2 receptor (ACE2) in specific organs, cytokine storm, and drug interactions contribute to the increased morbidity and mortality. Adding to the findings that individuals with pre-existing conditions may be more susceptible to COVID-19, it has also been shown that COVID-19 can induce chronic diseases in previously healthy patients. Therefore, understanding the interlinked relationship between COVID-19 and chronic diseases helps in optimizing the management of susceptible patients. This review comprehensively described the molecular mechanisms that contribute to worse COVID-19 prognosis in patients with pre-existing comorbidities such as diabetes, cardiovascular diseases, respiratory diseases, gastrointestinal and renal diseases, blood disorders, autoimmune diseases and finally, obesity. It also focused on how COVID-19 could, in some cases, lead to chronic conditions as a result of long-term multi-organ damage. Lastly, this work carefully discusses the tailored management plans for each specific patient population, aiming to achieve the best therapeutic outcome with minimum complications.

In December 2019, a breakout of pneumonia of unknown aetiology was identified in Wuhan City, in China (1) . Patients most notably presented with clinical symptoms of fever, cough, fatigue, dyspnea, and bilateral lung infiltrates on imaging (2) . Soon later, the causative agent was (23) . Indeed, a study found that rheumatoid arthritis (RA) patients are at more than 2-fold increased risk of serious COVID-19 than the general population (24) . Furthermore, in French a time-series analysis has been done to repoet the incidence of COVID-19 associated Kawasaki disease (KD), results showed that incidence of KD related to SARS-CoV-2 was increasing as 80% of diagnosed KD in short period of time was due to COVID-19 infection (35) .

The prevalence of obesity is also reported in many studies, for example, among 340 patients with severe COVID-19, 85 (25%) of them suffered from obesity (BMI ≥ 30 kg/m 2 ) (36), which is classified as a potential risk factor for increased COVID-19 severity (37, 38) . Blood disorders and haemoglobin abnormalities have also been associated with an increased risk of illness from COVID-19. For example, a meta-analysis entailed that the haemoglobin value was found to be significantly lower in COVID-19 patients with severe conditions than in those with milder forms, yielding a weighted mean difference (WMD) of −7.1 g/L and 95% confidence interval (CI), ranging from 8.3 to −5.9 g/L (39).

Genetic variability of ACE2 between individuals may affect viral fusion with the host cell, which alters the susceptibility to and severity of COVID-19 between different individuals (40) .

Interestingly, Benetti et al reported ACE2 variants that might alter the protein"s stability (40) .

The most common variants identified were p.(Asn720Asp), p.(Lys26Arg), and p.(Gly211Arg) (40) . Those three substitution variants are represented in the European and the Italian populations, but very rare in the Asian population (40) . More importantly, when ACE2 wholeexome sequencing was compared between controls and COVID-19 Italian patients, statistically significant higher ACE2 allelic variability was identified in the control group (40) . Therefore, the differential morbidity and mortality between patients could also be linked to the genetic variability of ACE2.

COVID-19 outbreak, diabetes has been identified as a risk factor for a more severe COVID- 19. In fact, it is one of the most frequently reported comorbidities in ICU admitted and deceased COVID-19 patients (26, 27, 30) . In a study consisting of 52 ICU admitted COVID-19 patients, 32 (61·5%) patients had died at 28 days; diabetes (22%) and cerebrovascular diseases (22%)

were the most common comorbidities in those patients (31) . In another study, including 44,672 COVID-19 patients, COVID-19 CFR was 7.3% in patients with diabetes compared with 2.3% in those without diabetes (30). Although the reason behind the poor prognosis of COVID-19 in diabetic patients is unclear (43) , several factors may contribute to the severe presentation. First, poorly controlled diabetes impairs the immune response to viral infections (44) . In particular, defective T-cell action impairs natural defence mechanisms, which reduces the capability of viral clearance (45) . Second, patients with diabetes have an elevated plasminogen level (46) . This particular protein cleaves the spike protein of SARS-CoV-2, which enhances the cellular entry of the virus; this, in turn, increases the virulence and infectivity of the virus (46) . Furthermore, COVID-19 patients with diabetes presented with a higher level of inflammatory biomarkers such as D-dimer, IL-6, and C-reactive protein in compared to those without diabetes, indicating that diabetes might raise the risk for worse COVID-19 outcomes (47) . Third, SARS-CoV-2 gains entry inside the cell through ACE2 (48) . Many diabetic patients receive ACE inhibitors for their renal protective effects. This class of medication increases the expression level of ACE2, which could aid viral entry into the host cells (48) . Additionally, when microarray-based transcriptome profiling data retrieved for several diseases including type II diabetes were analysed, SARS-CoV-2 related genes including the transmembrane protease serine (TMPRSS) and FURIN which are crucial for viral fusion and entry were found to be upregulated in type II diabetes (49) . Lastly, diabetic patients with other comorbidities like hypertension, coronary artery disease, and chronic kidney disease have even worse disease

The presence of ACE2 receptors in metabolic organs and tissues such as pancreatic beta cells and adipose tissues (14, 19) provides a possible damaging effect of SARS-CoV-2 in these organs through altering the metabolism of glucose, which may worsen preexisting diabetes or lead to new onset of the disease (19) . Indeed, it was found that SARS-CoV induces damage in the islets of the pancreas leading to acute diabetes (50) . A report demonstrated that 20 out of 39 previously healthy patients infected with SARS-CoV became diabetic during hospitalization (50) . After three years follow up, only two of these patients had diabetes (50) . Fortunately, it seemed that the damage induced by SARS-CoV to the pancreatic islets was transient (50) . On the other hand, COVID-19 extended the length of hospital stay in patients with diabetes; it induced ketoacidosis and diabetic ketoacidosis (DKA) in healthy and diabetic patients, respectively (51) (Fig.2) . There is a possible mechanism through which COVID-19 induced DKA. It is largely attributed to the interaction with the renin-angiotensin-aldosterone system (RAAS) (52) . Upon binding of SARS-CoV-2 with ACE2 receptors, viral entry via endocytosis occurs, and ACE2 gets downregulated, resulting in an unopposed accumulation of angiotensin II (Ang II) (53) . The elevated Ang II binds to Ang II type 1 receptor (AT1R) and impairs the glucose-stimulated insulin secretion (GSIS), thus inhibiting insulin biosynthesis (54, 55) . A study in China reported nine COVID-19 patients with pancreatic injury and abnormalities in amylase or lipase levels (56) , moreover, six of them were found to have abnormal blood glucose levels. The cytopathic effect mediated by local replication of the virus might be a possible reason for the pancreatic injury. Another explanation could be the invasive immune response induced by COVID-19 infection leading to pneumonia and respiratory failure, which contributes to multi-organ damage (56) . Nevertheless, there is limited data available concerning pancreatic manifestation in COVID-19 patients. Hence, further examination is warranted to assess the consequences of COVID-19 infection on diabetic patients (56).

There are special considerations that should be taken regarding the treatment modality of diabetic patients infected with COVID-19. Firstly, more emphasis should be placed on optimizing glycemic control in order to reduce the risk of severe outcomes (57) . A majority of patients with type 2 diabetes (T2D) have other metabolic syndromes like hypertension and dyslipidemia. Thus it is of great importance to choose the suitable antihypertensive and lipid-J o u r n a l P r e -p r o o f Journal Pre-proof lowering agents in these patients (57) . There are special concerns in relation to glucose-lowering agents when used in diabetic COVID-19 patients. Considering the risk of lactic acidosis or euglycaemic ketoacidosis associated with metformin and sodium-glucose-co-transporter 2 (SGLT-2) inhibitors respectively, these medications should preferably be suspended in patients with severe manifestations of COVID-19 to reduce the risk of acute metabolic decompensation (57, 58) . Otherwise, careful monitoring of renal function is needed during the illness due to the high risk of chronic kidney disease or acute kidney injury (57) . On the other hand, dipeptidyl peptidase-4 (DPP-4) inhibitors such as alogliptin, linagliptin, and saxagliptin are usually welltolerated and can be continued. In general, if the discontinuation of those drugs is inevitably needed, the alternative treatment of choice is insulin (57) . Care should be taken to maintain fluid balance to avoid the risk of fluid accumulation that can aggravate pulmonary oedema in the severely inflamed lungs (57) . An important point needs to be addressed regarding potassium balance in COVID-9 patients. A high prevalence of hypokalemia was found in COVID-19 patients that is associated with disease severity (59) . This is possibly linked to disordered reninangiotensin system (RAS) activity, as when SARS-CoV-2 binds to ACE2 and down-regulates its expression, this is accompanied by increasing aldosterone which in turn enhances the excretion of potassium (59) . Insulin is a known stimulus for hypokalemia. Thus, careful assessment of potassium levels in those patients before the initiation of insulin is required (59).

Although the majority of COVID-19 cases are mild, the disease can be presented in a more severe form in patients with pre-existing cardiovascular diseases (60) . These patients were shown to be more susceptible to COVID-19 and have a five to ten-fold increased risk of mortality (61) . A nationwide study in China revealed that COVID-19 fatality rates were 10.5% in patients suffering from cardiovascular diseases, compared to only 0.9% in patients with no comorbid conditions (62) . It has been shown that individuals suffering from heart failure express significantly higher levels of ACE2 at both mRNA and protein levels (13) . Therefore, this could partially explain the severe presentation of COVID-19 in this specific patient population (13) . A large retrospective observational study showed that hypertensive patients are at a remarkably higher risk of mortality due to COVID-19 regardless of whether they are taking antihypertensive J o u r n a l P r e -p r o o f Journal Pre-proof medication or not (63) . In fact, those who were not treated for hypertension had even higher mortality rates compared to those who were treated (63) . This might exclude antihypertensive medication as a possible cause for the poor prognosis. Instead, it suggests that pathologic and metabolic features of hypertension predispose patients to a more severe form of COVID-19.

ACE2 genetic variants are expected to alter patients" susceptibility to COVID-19 (64) . They might also influence the RAS system, which in turn regulates cardiovascular function (63) . One of the ACE2 unique variants is p.Arg514Gly, and because this variant is located in the angiotensinogen-ACE2 interaction surface, it can influence the function of RAS (63) . Since the dysfunction in RAS is associated with cardiovascular complications, the characteristic location of p.Arg514Gly could hint why COVID-19 leads to more severe cardiovascular complications in certain groups of people.

Some COVID-19 patients present to the hospital with symptoms of cardiac arrest, elevated troponin levels, and echocardiogram abnormalities (18) . Cardiac injury is one of the severe complications of COVID-19, and several mechanisms have been proposed to explain how SARS-CoV-2 leads to such complications. First, direct infection of cardiomyocytes by the virus could contribute to the pathophysiology of cardiovascular complications. After infecting the lung, SARS-CoV-2 could invade pulmonary artery vascular cells, then it recruits immune cells and initiates an inflammatory response (18) . Subsequently, through the pulmonary artery, the virus can gain access to the bloodstream (18) . Since the heart is the first target of the pulmonary circulation, and it expresses high levels of ACE2, this pathway enables SARS-CoV-2 to attack and injure the heart (18) . The inflammatory responses and cytokine storm also play a major role in many cardiovascular complications. Many COVID-19 patients display high levels of interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP1), IL-1B, interferon gammainduced protein 10 (IP10), and interferon-gamma (IFNγ)(1). These inflammatory cytokines can activate T-helper-1 (Th1) cells (1) . Cardiotropism and migration of Th1 cells occur through the Proinflammatory cytokines such as IL-6 might displace a desmosomal protein known as plakoglobin from the membrane of cardiomyocytes (65) . When this protein is lacking, the adhesion between cells becomes inadequate, leading to damage in the cell membrane, cardiac cell death, and replacement of cardiomyocytes by fibrofatty material (65) . Other mechanisms by which COVID-19 induce arrhythmia include direct injury to cardiomyocytes, which disturbs the plasma membrane and electrical conduction of the heart muscle (65) . In addition, infecting the pericardium results in oedema, fluid overload, and electrolyte imbalances (65) .

Patients with coronary artery disease could be at considerable risk for myocardial infarction due to COVID-19. These patients have a built-up plaque in their coronary vessels, which becomes unstable due to the heightened inflammation (18) . The result is plaque disruption and thrombus formation, ultimately leading to myocardial infarction (18) . Myocarditis is another major complication of COVID-19. This condition is an inflammatory disease of the myocardium that is not associated with an ischemic cause (65) . Instead, the pathophysiology involves a combination of T-lymphocyte mediated toxicity, cytokine storm, and direct cell injury (65).

patients ACE inhibitors and ARBs are first-line agents in heart failure, hypertension, and post-myocardial infarction (66) . However, their administration to COVID-19 patients has been controversial (66) .

Especially that patients with cardiovascular comorbidities are frequently prescribed these medications, and have been associated with higher mortality rates due to COVID-19 (66) .

Indeed, ACE inhibitors can increase the expression level of ACE2 (67)that they increase patients" susceptibility of developing severe COVID-19 (67) . Nevertheless, there is no consensus on whether these agents alter the susceptibility and severity of SARS-CoV-2 infection (53) .

Several clinical studies did not observe an association between their use and increased risk of COVID-19 or its mortality (66, 68, 69) . As a result, health care professionals warned against discontinuing such drugs because it could exacerbate cardiovascular conditions and increase the mortality (70) . On the other hand, despite the function of ACE2 in viral entry and infection, it acts as a counter regulatory enzyme in the RAS and degrades Ang II into the cardioprotective Ang (1-7) (53). However, when SARS-CoV-2 enters the host cell, it downregulates ACE2 and leads to accumulation of Ang II which could lead to left ventricular remodeling (53) . In fact, J o u r n a l P r e -p r o o f Journal Pre-proof administration of recombinant ACE2 could normalize the levels of Ang II, and protect against myocardial injury in COVID-19 (53) . Hence, there is an ongoing randomized clinical trial to evaluate recombinant ACE2 in COVID-19 (NCT04287686). Besides, losartan, an angiotensin receptor blocker, is also being investigated in clinical trials for treating COVID-19 (NCT04312009, NCT04311177) (53) .

The destructive cytokine storm associated with COVID-19 compels the use of immunemodulating agents in the management of this disease. Tocilizumab is a monoclonal antibody that blocks IL-6 receptors, and therefore it might be beneficial in reducing myocardial inflammation (65) . Several clinical trials are currently ongoing to test its efficacy in COVID-19; NCT04361552, NCT04445272, NCT04435717, NCT04403685. In patients with arrhythmia, IV amiodarone is the drug of choice (71) . However, since COVID-19 patients are often prescribed hydroxychloroquine or azithromycin, the benefit of administering amiodarone should be weighed against the risk since the combination of these drugs might cause QT prolongation (71) .

In cases of myocarditis, IV immunoglobulins were shown to be of value in the management protocol (72) . However, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is not encouraged by both the American Heart Association (AHA) and the European Society of Cardiology (ESC). NSAIDs are known to cause renal impairment and sodium retention, which possibly leads to exacerbated acute ventricular dysfunction (65).

Asthma is an inflammatory chronic respiratory disease that has been associated with the susceptibility and severity of viral respiratory infections. Moreover, the association of viral infections like rhinoviruses with asthma exacerbation has been established by several studies (73) (74) (75) . The susceptibility of asthmatics to respiratory viral infections and virus-induced asthma exacerbations could be attributed to the elevated type 2 immune responses present in many asthmatic patients (76) . Type 2 immunity is mediated by T-helper 2 (Th2) cells that secrete the interleukins IL-4, IL-5, and IL-13. These interleukins contribute to immunoglobin E (IgE) production and accumulation, eosinophil activation, and mucus production (77) . Previous studies have linked this type of immune response to weakened anti-viral responses and diminished J o u r n a l P r e -p r o o f Journal Pre-proof production of the antiviral interferons, explaining the vulnerability of asthmatic patients to several respiratory viruses (78) .

Based on this knowledge, it was initially anticipated that asthmatic patients would be highly susceptible to COVID-19. Till now, there has been a discrepancy in data reporting the prevalence of asthma in reported cases of COVID-19. Both China and Italy witnessed a surprisingly low incidence of COVID-19 in asthmatic patients (78, 79) . These findings are consistent with data published from 12 other studies that also showed asthma to be underreported in COVID-19

patients (80) . The USA reported a prevalence of asthma in COVID-19 patients higher than the regional asthma prevalence in a study reporting the characteristics of 5700 COVID-19 patients in New York City (11) . Yet, asthma was still not one of the most common comorbidities in this study (11) . There is also some controversy regarding the effect of asthma on COVID-19 severity.

Few reports linked asthma to COVID-19 severity; however, in most of the studies, asthma was not identified as a risk factor for severe illness (81). Moreover, cases of COVID-19 patients with severe asthma were reported to have a good outcome despite expectations of severe infection and poor prognosis in this subset of patients (82) .

There are several lines of evidence that could explain why asthmatic patients generally do not seem to be highly vulnerable to COVID-19. The expression levels of the ACE2 and TMPRSS2 encoding genes were reported to be similar in both asthmatic patients and healthy controls (83) . This could justify why asthmatic patients are not at a higher risk of infection with SARS-CoV-2.

Interestingly, some reported that the vulnerability of asthmatic patients to COVID-19 depends on the asthma phenotype. Jackson et al. recognized a significant reduction in ACE2 expression in patients with allergic asthma but found no association between non-allergic asthma and ACE2 reduction (84) .

Moreover, another study found non-allergic asthma to be linked to COVID-19 severity but reported no such findings with allergic asthma (85) . The apparent protective role of allergic asthma in COVID-19 could be explained by the type 2 immune responses associated with this type of asthma. Studies elucidated the role of type 2 associated cytokines like IL-4 and IL-13 in inhibiting the release of proinflammatory cytokines like IL-6 and TNF alpha (77) . Elevation in these proinflammatory cytokines was found to be associated with the cytokine storm syndrome and poor outcomes in COVID-19 patients (86) . Hence their inhibition could improve the clinical J o u r n a l P r e -p r o o f Journal Pre-proof outcomes of patients. Another point to be considered is the reduction in eosinophil levels detected in COVID-19 patients (77) . As type 2 asthma is associated with eosinophilia, this could have positive effects on the patients by compensating the low eosinophil levels during the infection.

COPD is another chronic respiratory disease that could be exacerbated predominantly by viral and bacterial infections (87) . Factors associated with COPD, such as old age, compromised innate antiviral response, exacerbated inflammatory responses, and impaired mucociliary function all contribute to patient"s predisposition to viral respiratory infections and virus-induced exacerbations (88) . The main culprit associated with inducing these dysregulated mechanisms in COPD patients is cigarette smoking, the main risk factor for COPD in the industrialized world (87) . Taking these facts into consideration, it would be logical to assume that COPD and cigarette smoking would be attributable to a high number of morbidity and mortality cases of COVID-19, instead, there seems to be a more complex relationship involved.

With regard to COPD, the current literature surprisingly reveals a low prevalence of COPD patients in COVID-19 studies. The prevalence rates of COPD in China, New York, and Italy"s studies were low (75, 89, 90) . Contrarily, it was observed that COPD was associated with a higher risk of death and COVID-19 associated complications (91). In a meta-analysis, including 1558 patients, individuals with COPD were 5.9 times more prone to COVID-19 exacerbations than patients without COPD (27) . Intriguing data regarding cigarette smoking has also been reported. The prevalence data revealed an unanticipated low percentage of smokers in COVID-Overall, these data show lower than expected prevalence rates of COPD and smoking among COVID-19 patients; however, a higher risk of COVID-19 severity is associated with COPD.

Surprisingly, there was not enough evidence to associate COVID-19 severity and mortality with smoking. The risk of severity of COVID-19 infection with COPD could be explained by the elevated inflammatory responses associated with COPD, which could exacerbate the COVID-19 associated cytokine storm (88) . In addition, an elevation in ACE2 was found in COPD patients and smokers, which could further explain the high virulence of SARS-CoV-2 in this group of patients (93) . Till now, there is no explanation for the low prevalence of infection in these groups, and the conflicting data regarding smoking and disease severity. It has been proposed that nicotine could provide protective effects against COVID-19 complications through its antiinflammatory properties. Nicotine can activate the a7-nicotinic acetylcholine receptors (a7nAChR) that are expressed on macrophages. Through the activation of this receptor, the activity of nuclear factor kappa B (NF-κB) is suppressed, hence suppressing the release of proinflammatory cytokines associated with the cytokine storm (94) . Another probable explanation would be that during these circumstances, some data regarding the patients" diagnosis and smoking history could have gone missing or been unreported. Interesting findings by Cai et al. hint at the existence of gene-smoking interactions. After analysing several transcriptomic datasets of normal lung tissue, Asian current smokers were predicted to have a higher ACE2 gene expression compared to Caucasian current smokers, implying that ethnicity could have a role in smokers susceptibility to COVID-19 (95) . All in all, more studies should be done before making conclusions on the actual effect of COPD and smoking on COVID-19.

The lung is obviously the organ that is most affected by SARS-CoV-2 infection, making respiratory failure the leading cause of death of COVID-19 patients (96) . There are several mechanisms implicated in causing acute respiratory complications in COVID-19 patients. The first one involves the entry of SARS-CoV-2 into ACE2-expressing pneumocytes in the epithelial lining of the alveoli, which can cause direct pulmonary injury, evident as diffuse alveolar damage in the lungs of COVID-19 patients (97) . Another main trigger of acute lung damage is the cytokine storm, caused by the sustained release of proinflammatory cytokines, which in turn precipitates an overly aggressive immune response storm (98) . This is initiated when RNA J o u r n a l P r e -p r o o f Journal Pre-proof fragments of SARS-CoV-2 are recognized by the toll-like receptors (TLR) of innate immune cells (99) . This action not only prompts an antiviral immune response through the release of type I interferon, but also activates the expression of the NF-κB, which plays a significant role in the production of many proinflammatory cytokines including IL-6, IL-1, and TNF alpha (99) . The rapid and excessive release of these cytokines causes severe inflammation, which leads to detrimental effects on body organs, especially the lungs causing pulmonary complications like ARDS. Clinical findings associated with ARDS such as pulmonary edema with desquamation of pneumocytes as well as hyaline membrane formation have been observed in lung autopsies of deceased COVID-19 patients (100).

Pulmonary thrombosis is another cause of lung damage in COVID-19 patients. Several processes have been speculated to be involved in causing this pathological feature. Firstly, SARS-CoV-2 can invade ACE2 expressing endothelial cells of the capillaries surrounding the alveolar walls (101) . Endothelial damage, in turn, could activate the coagulation cascades and cause platelet activation (102). The cytokine storm also plays a role in activating thrombotic pathways through the overproduction of the proinflammatory cytokine IL-6, which plays a role in platelet proliferation and activation ( Fig.4) (103) . Lastly, the RAS system could also be involved in causing thrombotic abnormalities. The binding of SARS-CoV-2 to ACE2 receptors eventually causes downregulation in ACE2 expression. Because Ang II binds to ACE2 to be metabolized when there is a downregulation in this receptor, an accumulation of angiotensin II occurs (53) .

Elevated levels of angiotensin II have been found to promote thrombus formation (104) .

In addition to inducing acute lung injury, it has been speculated that SARS-CoV-2 infections could even cause long term pulmonary impairment in COVID-19 survivors, based on previous clinical data from SARS and MERS patients (105) . One of the long-term consequences of ARDS is pulmonary fibrosis, associated with an accumulation of fibroblasts and excessive deposition of extracellular matrix components such as collagen in the lung tissues (106) . Pulmonary fibrosis is a progressive disease, so patients with this condition would suffer from a persistent decline in lung function, eventually turning to respiratory failure (105) . Currently, there is limited data on whether pulmonary fibrosis occurs in COVID-19 survivors; however, evidence of declining pulmonary function in discharged COVID-19 patients has been reported (60) . It is therefore essential to determine the real impact of fibrosis on the surviving population to know whether to J o u r n a l P r e -p r o o f Journal Pre-proof consider antifibrotic therapy as a prophylactic measure against the possible long-term repercussions of COVID-19.

One of the classes of drugs that have raised the most concern during this pandemic is corticosteroids. Clinical evidence showed that the use of systemic corticosteroids in previous SARS-CoV and MERS-CoV infections did not show added benefits and was even associated with worse outcomes due to their immunosuppressive effects (107) . Moreover, the WHO advised against the use of systemic corticosteroids in such patients unless indicated for exacerbations of asthma or COPD (108) . As a result, physicians were initially apprehensive about the routine use of inhaled corticosteroids (ICS), which are the cornerstone of asthma and COPD treatment, during the COVID-19 pandemic. Nevertheless, the current evidence does not reveal any link between the use of ICS and COVID-19 susceptibility and severity. Contrarily, the maintenance of routine therapy during this pandemic could maintain lung function and prevent future respiratory exacerbations, including ones that could be precipitated by viral infections (109) . More interestingly, Peters et al.

reported an association between the use of ICS and a decrease in the expression level of both ACE2 and TMPRSS2. They analysed gene expression data in induced sputum samples from 330 participants of the SARP-3 (Severe Asthma Research Program-3) program, a well-characterized cohort of asthma subjects and healthy controls designed to study the molecular phneotypes of asthma. Their findings revealed a dose-dependent association between ICS and reduced ACE2 and TMPRSS2 mRNA expression, which could hint at a protective role for these medications against SARS-CoV-2 entry (83) . In a randomized controlled trial to determine whether ICS administration altered the gene expression of key SARS-CoV-2 related genes in COPD patients, wholetranscriptome RNA sequencing was performed on bronchial brush samples of COPD patients treated with ICS. ICS cause the downregulation of both the ACE2 gene and the host cell protease gene ADAM17 (110) . The leukotriene modifier montelukast is another anti-asthmatic medication whose use is encouraged in asthmatic patients, due to their anti-inflammatory properties. They can reduce levels of the proinflammatory cytokines TNF alpha and IL-6, and hence could prevent the development of the COVID-19 associated cytokine storm (111) . As for biologic medications used in severe asthma to target eosinophil production, there is no clear data regarding whether its use puts patients at risk of COVID-19 progression. However, eosinophil levels should be monitored J o u r n a l P r e -p r o o f (112) . In general, both the Global Initiative for Asthma (GINA) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend that patients should be maintained on their regular therapy and that no medication should be discontinued (113, 114) . In patients infected with COVID-19 who have asthma or COPD exacerbations, the usual course of management, including the administration of a short course of oral corticosteroids should be followed but only under the supervision of a physician (115) . Lastly, an important point to consider in clinics is the risk of viral transmission via nebulized treatment. It has been recommended that patients with COVID-19 associated asthma or COPD exacerbation should not be administered bronchodilators or corticosteroids through nebulization, to avoid the risk of infecting other patients and healthcare providers (115) . In these cases, metered-dose inhalers are preferred, however if not possible then patients using the nebuliser in their homes or in a clinical setting should take their medication in an isolated room and take the necessary precautions (115).

Renal disease is considered as one of the players that significantly impact COVID-19 patients" prognosis, and attribute to the disease severity. In fact, reports show that more than 40% of COVID-19 positive cases commonly have abnormal proteinuria (116) , with acute kidney injury (AKI) being reported in 20-40% of the critically ill patients in the ICU (11) . In addition, a prospective cohort study was carried out on 701 COVID-19 positive patients admitted to a tertiary hospital in Wuhan, with the goal to assess the association between deteriorated kidney function and death rates among patients (116) . In this study, 43.9% of the patients presented with proteinuria, and 26.7% displayed haematuria. Moreover, during the hospitalization, 5.1% showed AKI. In this subgroup of patients with renal abnormalities, Kaplen Mayer's analysis revealed that they have a significantly higher risk for in-hospital death (116) . On the other hand, another report analyzed the possible contributing factors to AKI development in 161 ICU patients (117) . The results showed that AKI incidence was 28%, and 35% of the patients who were diagnosed with AKI had a previous history of chronic kidney disease stage 3-5. In comparison, 28% of patients with CKD stage 3-5 didn"t further develop AKI (117) . Therefore, further investigation to determine clear criteria and risk factors for developing AKI in COVID-19 patients is of crucial need. It is worth mentioning that the impact of the renal injury on COVID-19 prognosis might be underestimated, as the creatinine level prior to admission that would reflect the status of the J o u r n a l P r e -p r o o f Journal Pre-proof kidney function is not readily available (118) . Hence, due to the established relation between kidney function and COVID-19, early detection of renal abnormalities in COVID-19 patients is of essence to allow rapid proper intervention and provide better management for the mortality rates.

Based on the ascending evidence that shows the association between COVID-19 and renal injury, multiple studies were conducted to exploit the possible link. For instance, the immunohistochemistry of kidney tissues from six patients revealed the existence of SARS-CoV-2 nucleocapsid protein in the kidney tubule, which can be linked with direct tubular injury (119).

In addition, the viral RNA was detected in the urine of patients (120) . On a molecular level, SARS-CoV-2 receptor ACE2 is seen to be highly abundant in the kidneys. In fact, the comparative analysis by Xu et al. found that the expression of ACE2 receptor in the kidneys is similar to that of the lungs (120). Moreover, renal cells such as podocytes and proximal convoluted tubules were found to be particularly rich with ACE2 and TMPRSS genes, the main targets for SARS-CoV-2 (121) . Besides the role of ACE2 receptors in providing viral entry to the kidney tissues, another factor plays a pivotal role in COVID-19 induced kidney injury. The cytokine storm that gets activated upon the viral infection is reported to have a direct role in causing renal tissue damage and acute tubular necrosis (ATN) (119, 122) . In fact, the autopsies of six kidney tissues revealed that the ATN is associated with macrophages infiltration, along with the marked presence of T-lymphocytes and natural killers in the kidney tissues (119) . Thus, the immune hyperactivation initiated by SARS-CoV-2 infection is evidently contributing to renal damage. Organ cross-talk also explains the kidney involvement after SARS-CoV-2 infection.

The lung-kidney axes seem to play an interesting role, where a retrospective study showed that in 357 patients who did not have a history of any renal abnormality prior to ARDS development, 68% of them displayed AKI (123).

Renal damage associated with SARS-CoV-2 infection does not seem to be influenced by genetic 

To date, there is no tailored protocol to optimize the management of COVID-19 patients with underlying kidney disease. However, this issue requires urgent attention as the proper and early intervention would impart an effect on reducing COVID-19 patients' mortality rates (125) . It is advised with COVID-19 positive patients to follow the supportive care guidelines for their renal health. For instance, the use of nephrotoxic agents should be off-limits, and constant monitoring of the patient"s creatinine and urine output is highly advised for critically ill patients, as it will help in reducing the risk of developing AKI (126) . Of note, there is an urgent need to have consistent renal damage biomarkers that can be used for early prediction of AKI in COVID-19

patients. This matter should be properly investigated in clinical settings (127) . Adjusting the fluid volume is a crucial factor to be assessed. COVID-19 patients tend to be hypovolemic on admission. Therefore, this needs to be carefully corrected early to prevent AKI (128) . The initiation of Renal Replacement Therapy (RRT) has been proven to be efficient in critically ill COVID-19 patients with hemodynamic instability (129) . However, the safety and the correct integration of such treatment modality in COVID-19 patients needs to be further confirmed in clinical trials. Lastly, it is also advised to incorporate the use of cytokine blockers to counteract the sustained release of harmful proinflammatory cytokines (130).

Emerging studies indicate that gastrointestinal (GI) symptoms may precede respiratory symptoms in some COVID-19 patients (12, 131) . This could worsen disease outcomes since patients suffering from diarrhoea, abdominal pain, and loss of appetite do not usually suspect having COVID-19 and tend to delay their hospital checkup, thereby delaying the diagnosis (132) . Indeed, it was shown that patients with COVID-19 and GI involvement had more complications, such as ARDS (132) , liver injury (132), and even higher mortality rates (133) . In addition, abdominal pain was approximately four-fold associated with an increased risk of severe COVID-19 (134) . Nevertheless, there are some discrepancies in the literature, where the higher J o u r n a l P r e -p r o o f Journal Pre-proof mortality in patients with GI symptoms is not always supported. It has been demonstrated that the length of hospital stay and mortality did not significantly differ between COVID-19 patients with and without GI involvement (132) . On the other hand, the outcome of COVID-19 in patients with pre-existing inflammatory bowel disease (IBD) can fall into two categories. First, the presentation of COVID-19 might be severe in this population because of their inflamed gut and immunosuppressive medications (135) . The other possibility is that COVID-19 would be milder in patients with IBD. The latter theory can be explained by the fact that ACE2 is present in two distinct functional forms in the human body (136) . The first one is the membrane-bound ACE2 that is used by SARS-CoV-2 for cellular entry, while the second form is the soluble ACE2 that lacks a membrane anchor and circulates in the blood. It has been shown that soluble ACE2 is upregulated in patients with IBD and can competitively bind the virus, reducing its cellular entry (136) .

Several mechanisms have been proposed for the GI complications associated with COVID-19.

First, ACE2 is highly expressed in the GI tract, and the viral nucleocapsid was identified in duodenal, gastric, and rectal glandular epithelial cells, suggesting direct injury to the GI tract by the virus (21) . ACE2 has a recognized role in regulating intestinal inflammation and bowel movement. Therefore the binding of SARS-CoV-2 to this protein can disturb the absorptive functions of ACE2 expressing enterocytes, which results in malabsorption, distorted intestinal secretion, and stimulated enteric nervous system, all of which lead to diarrhoea (137) . Second, SARS-CoV-2 might disturb the intestinal flora, which results in digestive symptoms (133) .

Interestingly, disturbed intestinal flora can affect respiratory function, and the respiratory tract flora also affects the gastrointestinal tract (138) . The connection between the two systems is referred to as the "gut-lung axis", and it could be involved in the clinical manifestations of COVID-19 (138) . Third, the exaggerated inflammation in COVID-19 patients can also contribute to adverse effects on the GI system (133) . And finally, the fourth mechanism is that long-term hypoxemia brought about by respiratory failure can cause GI mucosal cell injury and necrosis, leading to ulceration and bleeding (21).

The management of GI complications in COVID-19 is usually symptomatic. Antidiarrheal agents such as loperamide can be administered to the patients. In addition, antispasmodics might help in the case of abdominal pain (21) . Proper rehydration is critical to maintaining electrolyte balance. Otherwise, the clinical stability of the patients would deteriorate (139) . Monitoring potassium levels is also an important practice in patients with GI symptoms because abnormal levels might lead to cardiovascular complications, especially that some medications used in COVID-19 can increase the risk of QT prolongation in the case of electrolyte imbalances (140).

Another useful management strategy is the administration of probiotics to replenish the gut microbiota (141) , which could enhance the overall function of the GI tract.

Liver impairment seems to be a frequent feature among COVID-19 patients (142) . In fact, multiple reports present evidence of elevated liver enzymes as one of the frequently altered parameters in patients with severe cases, which therefore proposes questions on the clinical significance of such hepatic abnormalities as risk factors and markers for COVID-19 prognosis.

COVID-19 patients tend to show an elevation in many of the crucial liver enzymes (139, 142) , such as alanine aminotransferase (ALT) where the incidence of its elevation range between 2.5-50.0% (143) . Similarly, aspartate aminotransferase (AST) levels are frequently increased in COVID-19 cases with an incidence ranging between 2.5-61.1% (144) . Studies demonstrate that this noticeable rise in liver enzyme levels was found to be associated with COVID-19 severity.

For example, in a cohort study with 1099 patients assembled from 552 hospitals, the elevation of AST enzyme was more dominant in severe patients as compared to the non-severe cases. 

Several studies were conducted with the purpose of revealing how SAR-CoV-2 can induce hepatic damage. Autopsy of COVID-19 deceased patients showed the abundant presence of the viral protein in liver cells (10) . This can be explained by the fact that the liver is rich in ACE2 receptors, especially on the surface of hepatic endothelial cells (15) . Hence, besides the lungs, the liver seems to be an additional target for SARS-CoV-2. Noticeably, ACE2 expression is more prominent in the bile duct compared to liver cells, with an expression level similar to that of the alveolar type-2 cells of the lungs (22) . This suggests that liver injury is mostly due to the COVID-19 damaging the bile duct rather than the hepatocytes (22) . It is worth mentioning that the respiratory failure in COVID-19 patients can be one of the players in liver injury, as the induced anoxia can subsequently affect liver function by the emerging hypoxic hepatitis (145) .

The cytokine storm and the severe inflammatory state triggered by COVID-19 also participate in liver damage, where reports showed that the level of elevated cytokines was significantly higher in patients with liver abnormalities compared to those without hepatic deficits (Fig.5) (139, 146) .

While studying the mechanistic process through which COVID-19 causes liver damage, other factors come to the forefront that should be carefully considered. For instance, infected patients tend to be treated with many of the hepatotoxic agents that by themselves can initiate the noted liver damage such as many of the antibiotics, antivirals, and steroids (147) . Also, the patient history with liver diseases or infections is also a major factor that can contribute to the deteriorated liver function, taking into account that the hepatitis virus replication is noted to be enhanced in COVID-19 patients (148) . To date, there is no clear elucidation on the COVID-19 molecular mechanism in damaging the liver function, which warrants the need for further elaboration.

On the light of the building evidence that shows that SARS-CoV-2 is causing hepatic dysfunction, it is of the essence to pay special attention and implement preventive considerations to protect the patients from impairments in their liver functions (149) . For instance, it is crucial to constantly monitor liver biochemistry for all COVID-19 patients. In addition, it is recommended to screen COVID-19 patients for hepatitis B or hepatitis C infection and inspect for any existing hepatic disease (145) . Moreover, since there is no clear margin on whether the reported injuries are caused directly by the COVID-19 virus or it is induced by the hepatotoxic J o u r n a l P r e -p r o o f used agents(100), it is very crucial to investigate the safety of the implemented treatment protocols on the liver, especially that this currently overlooked. Also, it is recommended that in patients with liver disease, early initiation of antiviral therapy is needed (149) . Lastly, it is always beneficial to promote the inclusion of liver protecting agents that can as well attenuate the inflammatory process such as ammonium glycyrrhizinate to increase the recovery rate and enhance patients outcomes (150).

Since the outbreak of the pandemic, concerns have been raised about the risk of COVID-19 and its associated complications in patients with systemic autoimmune diseases (23) . In general, patients with autoimmune diseases like rheumatoid arthritis (RA) are more vulnerable to serious infections (24) , this is attributed to several reasons, for example, these patients have disturbed innate and adaptive immune responses, and they continuously use potent immunomodulatory drugs (24) . This puts those patients at more than a 2-fold increased risk of serious infections than the general population (24) . A comparative cohort study elucidated the risks of COVID-19 in RA patients (151) , intensive care admission and mechanical ventilation were more often in those with the rheumatic disease than those without (151) . Another autoimmune disease, in particular psoriasis, a retrospective multicenter observational study in Italy including 5,206 chronic psoriasis patients, data showed that there was no significant number of hospitalizations or deaths from COVID-19 (152) . Due to the limited data, it remains unknown how COVID-19 impacts psoriasis patients. On the other hand, the link of viral infection and exacerbation of psoriasis has been documented in a previous study which aimed to investigate the cases of acute psoriasis flares following respiratory tract infection, rhinovirus and coronavirus are the most frequently detected causative pathogens (153) . The acute flares may be explained by the activation of Tolllike receptor 3 (TLR3) that triggers several inflammatory cytokines such as IL-36 which has been shown to be pathogenic in psoriasis subtypes like generalized pustular psoriasis and plaque psoriasis vulgaris (153) . A systemic review and systematic review and meta-analysis included 6 studies (154), investigated the relationship between severe or dead COVID-19 cases and autoimmune diseases. Results revealed that patients with autoimmune diseases were marginally correlated with increased risk of COVID-19 severity and mortality, but the statistical difference J o u r n a l P r e -p r o o f Journal Pre-proof was not significant (154) . However, we can not ignore the risk of COVID-19 in these diseases due to the limited sample size (154) .

The emerging clinical data indeed support that COVID-19 can trigger autoimmune diseases and/or auto-inflammatory mechanisms (155, 156) . A study in Germany aimed to investigate the possible role of autoimmunity in SARS-CoV-2-associated respiratory failure (157) , based on serological, radiological, and histomorphological findings; researchers suggest that infection with SARS-CoV-2 could cause or simulate a form of organ-specific autoimmunity in predisposed patients (157) . Furthermore, in China a retrospective study included 21 severe and critically ill COVID-19 patients, laboratory findings showed that the prevalence of autoimmune disease-related autoantibodies such as anti-52 kDa SSA/Ro antibody, anti-60 kDa SSA/Ro antibody, and antinuclear antibody were 20%, 25%, and 50%, respectively (158) . These important findings raised the question of whether COVID-19 is able to induce an autoimmune disease associated with long-lasting symptoms and delayed complications.

Indeed, a pattern of pro-inflammatory cytokines induced in COVID-19 share similarities with those in RA (159) , musculoskeletal symptoms including arthralgia and more frequently myalgia were reported in patients with COVID-19 (159) . Although there is no report in the current pandemic indicates that patients develop autoimmune inflammatory arthritis such as RA (159) .

However, in a study aimed to examine the effects of respiratory viral infections on the development of RA, results revealed that infections with parainfluenza, coronavirus, and metapneumovirus are associated with increased cases of RA (160) .

Other autoimmune complications following COVID-19 infection, an incidence of idiopathic thrombocytopenic purpura have been reported in one patient, four days following COVID-19 infection (161) . Furthermore symptoms of Guillain-Barré syndrome including severe deficits and axonal involvement along with neuromuscular failure that reported in five patients after infection with COVID-19 (162) . Autoimmune haemolytic anaemia was also recorded following COVID-19 that was observed in seven cases (163) . On the other hand, in children, COVID-19 is reported to cause a serious of autoinflammatory complications affecting children up to 17 years old, named as a paediatric inflammatory multisystemic syndrome (PIMS), which includes wide-J o u r n a l P r e -p r o o f ranging manifestations such as Kawasaki-like disease, toxic shock syndrome, myocarditis and macrophage activation syndrome (25) .

Although the exact mechanism behind an appearance of autoimmune and autoinflammatory diseases has not yet been firmly established (25) . Scientist postulated that COVID-19 itself could act as a direct trigger of these conditions by molecular mimicry (25) , also the hyperinflammatory state and dysregulated immune response following COVID-19 may also trigger and promote other environmental factors in predisposed individuals to cause the observed pathologies (25) . Genetic predisposition also plays a crucial role in children to develop a COVID-19 associated Kawasaki disease (25) . Indeed, a study identified various Kawasaki disease susceptibility genes (164) 

The usage of immunosuppressant agents in counteracting the consequences of COVID-19 associated hyperinflammatory state have been discussed extensively in many reports (165) . On the other hand, the continuous use of potent immunomodulatory drugs putting patients with autoimmune diseases at increased risk of severe COVID-19 infection (24) . Thus careful assessment should be made in case of COVID-19 autoimmune patients who are already taking these medications. There are also several questions that need to be answered, whether to continue or discontinue these medications, and whether the immunomodulatory therapies, including biologic drugs, will benefit in suppressing the cytokine storm.

In the setting of rheumatic diseases, according to the American College of Rheumatology Guideline (166) , for patients with presumptive COVID-19, it is recommended to temporarily stop all immunosuppressant drugs, non-IL-6 biologics, and JAK inhibitors, waiting for negative results or symptoms free observation (166) , while chloroquine, hydroxychloroquine, NSAIDs and sulfasalazine may be continued (166) . On the other hand, patients with documented COVID-19, regardless of COVID-19 severity, sulfasalazine, methotrexate, leflunomide, J o u r n a l P r e -p r o o f Journal Pre-proof immunosuppressants, JAK inhibitors, and non-IL-6 biologics should be withheld (166) . The main concern is these agents particularly sulfasalazine cause a panel of adverse effects similar to signs of COVID-19, such as gastrointestinal upset, diarrhoea, cytopenias and uncommonly pneumonitis, and withholding this treatment unlikely resulting in rheumatic disease flares (166) .

On the other hand, the spectrum of autoimmune and autoinflammatory diseases that are triggered by COVID-19 should be carefully monitored and early diagnosis is essential for effective recovery and preventing end-organ damage. Several reports showed that these patients were most responsive to intravenous immunoglobulin (IVIG) treatment (164) . However, in the case of COVID-19 associated Kawasaki disease, patients were less sensitive to IVIG therapy compared to classic Kawasaki disease, thus addition of steroids was helpful (164) . regarding children with COVID-19 associated PIMS, clinical data showed that administration of anakinra, an IL-1 receptor antagonist showed promising results (25) . Previous reports showed that patients with PIMS have an elevated level of IL-6 similar to severe COVID-19 adults" patients (167, 168) , and clinical data showed that administration of IL-6 targeted immunotherapies showed promising results in critically ill COVID-19 adults patients (25) .

Hence, consideration of IL-6 receptors such as tocilizumab and sarilumab blocker may be feasible in patients with COVID-19 associated PIMS (25).

Another factor that was recognized to play an underlying role in compromising the recovery of COVID-19 patients is obesity. The link between obesity and viral respiratory infections, such as influenza A (H1N1), has already been recognized in the past (169, 170) . As such, obesity was identified as an independent risk factor for patient hospitalizations during flu season and the development of pulmonary complications such as ARDS (169) . Taking into account the vast spread of the COVID-19 pandemic as well as the fact that more than a third of the world"s population range from being overweight to obese (171) , any association between weight gain and retrospective cohort study on 124 patients and observed that patients with a BMI > 35 were 7 times more at risk of requiring invasive mechanical ventilation during their ICU stay than patients with a BMI < 25 (173) . Though the younger population is generally considered to be at a lower risk for COVID-19 associated complications, it was found that obesity could pose a threat to patients less than 60 years old and make them liable to poor clinical outcomes. This was described by Lighter et al. when they demonstrated that patients aged < 60 years with a high BMI were more likely to be admitted to acute and critical care than patients in the same age group with a lower BMI (174) . This was also backed up by another study that reported the high likelihood of obesity in young COVID-19 patients admitted to the ICU (175) .

Furthermore, the genetic predisposition to obesity could increase the risk of developing severe COVID-19 (176) . Utilizing genome-wide genotyping data from the Genetic Investigation of Anthropometric Traits (GIANT) consortium and United Kingdom Biobank, the polygenic risk scores for three obesity measures (BMI, BMI-adjusted waist-to-hip ratio, and BMI-adjusted waist circumference) were calculated (176) . The results demonstrated that individuals with a high polygenic risk score for BMI had a significantly higher risk of hospitalization due to severe COVID-19 (176) . Although no statistically significant association was found between the polygenic risk score of the other two obesity measures, they had a positive correlation with COVID-19 severity (176) . Intriguingly, this links the genetic predisposition to obesity with a higher risk of developing severe COVID-19.

There are several possible explanations for the relationship between obesity and COVID-19.

Along with obesity being linked to other comorbidities, which could increase the risk of COVID-19 susceptibility and severity, there are other factors that make obesity an independent risk factor for poor outcomes. Firstly, there could be a direct link between the pathogenicity of SARS-CoV-2 and excessive adipose tissue in obese patients, as adipose tissue was found to express ACE2 at significantly higher levels than lungs (177) . Large amounts of adipose tissue in obese patients mean higher levels of ACE2, and as ACE2 is the main point of entry for SARS-CoV-2, this could facilitate viral entry into the host cells and their propagation (178) . Obesity could also have a role in aggravating the cytokine storm. Obesity is characterized by a state of chronic inflammation, caused by an imbalance in the release of adipokines from adipose tissue. The proinflammatory adipokine leptin is upregulated in obesity, causing overexpression of J o u r n a l P r e -p r o o f Journal Pre-proof proinflammatory cytokines such as IL-6 and TNF alpha (179) . Elevation in these cytokines was found to be associated with poor outcomes in COVID-19 patients (86) . Chronic inflammation in obesity also plays a role in inducing endothelial dysfunction (180) . Endothelial damage is one of the mechanisms of SARS-CoV-2 pathogenicity, as the virus could invade endothelial cells through ACE2 receptors expressed on their surface (180) . Endothelial damage is linked to further aggravation of the cytokine storm, as well as platelet hyperactivation, leading to a coagulative state in patients (181) . This suggests that obesity-related endothelial dysfunction could further add to the harm caused by SARS-CoV-2-induced endothelial damage, and increase the risk of developing COVID-19-associated complications like ARDS and thrombotic events.

These accounts point to the importance of dealing with obese patients as a high-risk group in COVID-19 regardless of age. It is also crucial to take into account that in these exceptional times, a vast number of the population is under quarantine and isolation. As these circumstances make individuals more prone to stress eating and lack of physical activity, it is critical to raise more awareness of the dangers of obesity in the current situation.

As COVID-19 remains a threat on the health of those infected, research indicates that the consideration of patients with blood disorders is uniquely essential due to the impact infectious complications may have on their haematology (182) . Due to their immunodeficiency, these patients carry an excess risk for viral infections like SARS-CoV-2 and have a poorer prognosis (183) . In fact, records of hospitalized patients during two previous influenza periods (2003) (2004) (2005) in the United States indicated that the rate of children hospitalized was 56 times higher in those with sickle cell disease (SCD) than those without SCD and twice as high than those with cystic fibrosis (184) . Additionally, it has been shown that several factors linked to the infection could also initiate COVID-19 associated blood disorders (185) . Leukaemia is another disease that was correlated to a higher susceptibility of SARS-CoV-2 infection. In a study analysing array-based gene expression data for 30 diseases including leukaemia, an upregulation in ACE2 and the proteases TMPRSS and FURIN were observed in six leukaemia subtypes (49) . A recent multicenter, international cohort study conducted by Mato et al. (186) , data on the overall survival of 198 COVID-19 cases with chronic lymphocytic leukaemia (CLL) was provided.

Although the primary goal of this study (186) is the estimation of overall survival for patients diagnosed with COVID-19, investigators found that 90% of patients required hospital admission, of which 92% required supplemental oxygen, 38% received intensive care unit care. 27% required intravenous vasopressor support, and 11% required hemodialysis. Investigators also noticed that these rates were very similar in both the subgroup consisting of patients who had previously received CLL directed therapy and the other of which patients had not previously received CLL directed therapy. Further, 66 deaths were documented, with no differences in overall survival between both subgroups (186) . On the other hand, an earlier epidemiological study performed by Guan et al. (187) provided data on 1,099 COVID-19 cases throughout China and compared disease severity through clinical differences between patients. In contrast to the study conducted by Mato et al. (186) , only 5.0% of patients during this study received intensive care unit care, of which 2.3% underwent invasive mechanical ventilation, and 1.4% died. The data presented in this study (187) shows that patients screened for severe COVID-19 infection and those with higher rates of ICU admission, mechanical ventilation, and deaths are those presented with lymphocytopenia (83.2%), thrombocytopenia (36.2%), and leukopenia (33.7%).

In a subsequent series of studies (1, 10, 12, 188) also conducted in China, the association between lymphocytopenia and the need for intensive care unit care was emphasized.

Additionally, a recent computational proteomic analysis (177) explained how some SARS-CoV-2 proteins have the ability of binding to porphyrins as three other viral proteins synchronously coordinate to attack the heme on the haemoglobin specific 1-beta chain, leading to the dissociation of iron to form porphyrin (177) . Deoxyhemoglobin is at a greater risk of viral attacks than oxidized haemoglobin (177); hence, a decline, whether gradual or drastic, in haemoglobinan oxygen and carbon dioxide carrierconcentration may result in respiratory distress symptoms and worse prognosis of COVID-19. It is worth noting that while computational studies often only represent points of concern, data from a meta-analysis illustrate patients presenting severe COVID-19 infection often demonstrate a decline in haemoglobin values compared to those with milder COVID-19 infection (39). Even with the limited clinical evidence, it is noticeable that patients with pre-existing blood disorders are amongst those most vulnerable to SARS-CoV-2 infection, and that those at risk of developing blood abnormalities may have a poorer prognosis of the COVID-19 disease. Hence, initial detection and close monitoring of haemoglobin levels in infected patients should be contemplated (189) .

In an attempt to identify host genetic factors that contribute to the severity of COVID-19, a genome-wide association study consisting of a total of 1610 patients and 2205 controls was conducted in Europe (190) . COVID-19 patients were recruited to the study only if they had a severe presentation of the disease, represented by hospitalization with respiratory failure (190) .

The results of this study revealed that individuals with blood group A are more prone to the severe presentation of COVID-19 compared to individuals with other blood groups (190) . In the meantime, blood group O offered a protective effect against the infection (190) . Therefore, the ABO blood-group system could explain the variable clinical presentation between patients suffering from COVID-19.

Studies on the characteristics of the blood mechanism through which SARS-CoV-2 infection can directly induce existing blood disorders are limited. However, several studies have been conducted to show the impacts of COVID-19 associated blood abnormalities (39, 191, 192) .

Understanding these impacts could be beneficial as it provides critical information to clinicians whilst taking approaches regarding therapy, prognosis, and disease course. Considering the high binding affinity of SARS-CoV-2 to tissues expressing ACE2 receptors, it is also predicted that the activation and damage of endothelial cells could occur, also possibly resulting in a disturbance of the natural antithrombotic state (193) . It has also been indicated that SARS-CoV-2 induced oxidative stress can aggravate DNA methylation defect likely leading to further ACE2 demethylation, thus enhancing the presence of the virus in the blood (194) . The cytokine storm and inflammation associated with COVID-19 could further result in the activation of coagulation (Fig.4) . This is additionally triggered by the elevated levels of IL-6, D-dimer, increased C-reactive protein, erythrocyte sedimentation rate, and elevated fibrinogen that coexist with SARS-CoV-2 infection (195) . In the time of the infection spreading throughout the bloodstream, a significant decrease in peripheral blood lymphocytes occurs, including both T and B lymphocytes, which ultimately leads to inflammatory factors (183) . Also, it is found that patients showing a more serious response to SARS-CoV-2 infection could have an even higher elevation of D-dimer along with prolonged prothrombin time (PT) and gradual decrease of fibrinogen (FBG) and platelet, especially as the disease progresses (183) . At this stage, inflammatory factors in peripheral blood continue to rise and patients hypercoagulable state may appear abnormal, potentially leading to disseminated intravascular coagulopathy (196) . To this J o u r n a l P r e -p r o o f day, the cause of elevation of D-dimer levels in COVID-19 patients is uncertain as it has been associated with many different conditions, yet infection-associated inflammation remains to be the most probable cause (197) . Research shows that elevated D-dimer levels as the disease progress, could be linked to increased mortality as patients with a pronounced inflammatory response to infection and extreme coagulation abnormalities could develop disseminated intravascular coagulation (DIC) (198) . DIC, characterized by the simultaneous occurrence of widespread vascular clot deposition, eventually leads to multiple organ failure and, in some cases, mortality (199) . While knowing that D-dimer, sepsis physiology and microvascular thrombosis in COVID-19 patients are all associated with mortality (198) , there does not exist enough research to support the use of anticoagulation curative doses for these findings; which calls for further research to help improve COVID-19 patient care.

With the continuing spread of COVID-19, individuals with haemoglobin disorders remain of the most vulnerable populations. To date, inadequate research is available to verify the link between these disorders and COVID-19; however, the haematology community continues to effectively minimize the risk of patients facing new emerging threats (189) . Sickle cell patients, for example, are often treated with hydroxycarbamide (hydroxyurea), a cytotoxic agent, having possible immune-compromising effects. Hence, SARS-CoV-2 infection may prompt serious complications in patients with SCD requiring an elevated need for intensive and cautious medical care (184) . Hence, it has been advised that low doses of hydroxyurea are used to prevent primary and secondary stroke in children with SCD receiving regular blood transfusion therapy (200) . The ability of hydroxyurea treatment to decrease acute vaso-occlusive pain (VOS) and acute chest syndrome (ACS) events where regular blood transfusion is absent makes it especially important for hydroxyurea to be present in areas with severe blood shortages (200) Thalassemia patients, unlike SCD patients, are not at a high risk of lung infections; however, their chronic condition may be associated with several comorbidities, including heart disease and diabetes, which make them more vulnerable to the virus (194) . Although a recent cohort study analyzed that thalassemic patients did not recognize increased COVID-19 severity, physicians, health-care professionals, and caregivers are advised to handle thalassemic COVID-19 with extra caution and to not disregard their possibility of developing severe forms of COVID-19 through other complications (202) . Furthermore, many comorbidities in thalassemia are related to iron overload where patients receive iron chelation treatment -it has been advised that iron chelation treatment should be interrupted for moderate to severe COVID-19 patients with ongoing communication between the treating physicians and the haematologist (203) . On the other hand, for COVID-19 patients with hematologic malignancies such as chronic lymphocytic leukaemia, the AHS recommends assessment of risk vs. benefits of any treatment. Moreover, given the higher risk of thromboembolic events (TE) with COVID-19, it is suggested that TE symptoms are closely monitored. For patients with COVID-19 associated coagulopathy (CAC) / DIC; platelet count, prothrombin time (PT), activated partial thromboplastin time, D-dimer, and fibrinogen are recommended to be monitored. In fact, an abnormal elevation or drop of these levels; specifically, D-dimer levels, has been linked to progressive severity of COVID-19 infection and mortality (198) . This requires more aggressive critical care and the consideration of experimental therapies for COVID-19 infection. While knowing that these factors may result in a higher mortality rate, current data still does not support the use of therapeutic doses of anticoagulation (198) . Adding on to the discovery that D-dimer could be used to track the severity of infection and mortality, researchers have also found that lymphopenia is an effective and reliable indicator of the severity of the disease, inflammation, and hospitalization in COVID-19 patients (189) .

As research involving the interaction between haemoglobin and SARS-CoV-2 continues to grow, preventative measures and early identification of potentially fatal complications is necessary. For example, initial detection and close monitoring of haemoglobin values in infected patients could be an effective intervention in improving patient outcomes and possibly reducing the overall J o u r n a l P r e -p r o o f Journal Pre-proof mortality rate (39). Subsequently, it is also important that clinicians consider designing tailored treatment approaches for haematology patients with severe disease and/or comorbidities as they might require more intensive care and appropriate therapeutic care.

The rapid outbreak of the COVID-19 pandemic has caused a soaring number of morbidity and mortality cases worldwide. With no cure or vaccine still in hand, it continues to affect a significant portion of the population. Because the disease is relatively new, many aspects of the virus have not been extensively studied yet. From the cases that have been reported; however, it was observed that patients with underlying comorbidities were, in many cases, more liable to contracting the virus and suffering from poorer outcomes. The recently reported data links chronic illnesses like diabetes, cardiovascular disease, and obesity to a higher susceptibility of COVID-19 (26) . Interestingly, different regions reported conflicting results regarding the prevalence of chronic respiratory diseases like asthma and COPD in COVID-19 patients. In addition, patients with underlying diseases such as diabetes, hypertension, heart failure, COPD, CLL, and obesity were at a higher risk of hospitalization and developing severe cases of COVID-19 (31, 60, 75, 91, 173, 186) . Till now, it is not clear how asthma, GI diseases such as IBD, and chronic kidney disease contribute to the outcomes of COVID-19 patients, as there is a discrepancy in the data reported (81, 117, 132) . Although some studies attributed these diseases to COVID-19 severity, there were also other studies that have reported cases of mild disease in these groups of people. Hence, this review reveals that there is still a gap in knowledge that needs to be filled regarding the real association between underlying comorbidities and COVID-19 patients.

Understanding how certain comorbidities affect the outcome of COVID-19 patients is crucial, as it will aid healthcare providers in stratifying the high-risk groups and designing a tailored management plan for them accordingly. Given the limited healthcare resources in these difficult times, it is also essential to know which groups of patients to prioritize when it comes to providing intensive care. current evidence suggests no serious risk associated with their use. Contrarily, these medications are currently under investigation for their potential beneficial effects (53, 83) . It is also important to consider the clinical state of the patient when adjusting the treatment regimen. In severe cases for COVID-19, for example, where the risk of acidosis is high, glucose-lowering agents like metformin and SGLT-2 inhibitors should be withheld (57, 58) . Drug-drug interactions between chronic medications and COVID-19 treatments are another important point to consider, as medications like azithromycin could have severe consequences in patients under anti-arrhythmic medications.

Lastly, we also discussed how SARS-CoV-2 could induce multi-organ damage in COVID-19 patients, and even possibly cause long term consequences to the survivors of the disease. In addition to pulmonary injury, clinicians also reported pathological features associated with coagulopathy, pancreatic injury, cardiac arrest and arrhythmias, AKI, hepatic damage, and GI complications in COVID-19 patients. Furthermore, COVID-19 has been associated with autoimmune and/or autoinflammatory diseases, particularly in children. Whether these damages on the patients" organs are transient or lasting is still questionable, so follow-up studies after patients" recovery are needed to assess the long-standing effects of the disease. Though not conclusive, many of the evidence point to the abundance of ACE-2 receptors in these organs and the cytokine storm as the main instigators of all the damaging effects of SARS-CoV-2. Hence, we believe that by inhibiting viral entry via ACE-2 receptors by the administration of agents such as soluble ACE-2, or through targeting the cytokine storm by using agents like IL-6 and IL-1 inhibitors or corticosteroids, multi-organ damage and COVID-19 associated complications could be prevented. Through results from ongoing clinical trials, a better insight shall be provided about the value of these agents in ameliorating COVID-19 severity. 

Ref.

J o u r n a l P r e -p r o o f Abbreviations: ACE-2, Angiotensin-converting enzyme 2; IL-6, Interleukin 6; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; AKI, acute kidney injury; ARDS, Acute respiratory distress syndrome. (195, 198) J o u r n a l P r e -p r o o f

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The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2

ACE2 Expression in Pancreas May Cause Pancreatic Damage After SARS-CoV-2 Infection. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Tackling the cytokine storm in COVID-19, challenges and hopes

The COVID-19 Cytokine Storm; What We Know So Far

Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)

New-Onset Diabetes in Covid-19

Review article: gastrointestinal features in COVID-19 and the possibility of faecal transmission

Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection

Are my patients with rheumatic diseases at higher risk of COVID-19? Annals of the Rheumatic Diseases

The risk of infections associated with rheumatoid arthritis, with its comorbidity and treatment

Autoimmune and inflammatory diseases following COVID-19

Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 -United States

Does comorbidity increase the risk of patients with COVID-19: evidence from meta-analysis

Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series

Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

COVID-19 infection: the China and Italy perspectives

OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients

Emergence of Kawasaki disease related to SARS-CoV-2 infection in an epicentre of the French COVID-19 epidemic: a time-series analysis

Prevalence of obesity among adult inpatients with COVID-19 in France

Potential pathophysiology of COVID-19 in patients with obesity

Obesity Is a Risk Factor for Severe COVID-19 Infection: Multiple Potential Mechanisms

ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population

Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS. Diabetic medicine : a journal of the British Diabetic Association

Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection

Diabetes and COVID-19: evidence, current status and unanswered research questions

Risk of Infection in Type 1 and Type 2 Diabetes Compared With the General Population: A Matched Cohort Study

T-cell activation and cardiovascular risk in adults with type 2 diabetes mellitus: A systematic review and meta-analysis

Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility

Diabetes is a risk factor for the progression and prognosis of COVID-19

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

A Meta-analysis of Comorbidities in COVID-19: Which Diseases increase the Susceptibility of SARS-CoV-2 Infection? Preprints

Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes

COVID-19 infection may cause ketosis and ketoacidosis

Diabetic ketoacidosis precipitated by Covid-19 in a patient with newly diagnosed diabetes mellitus

Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19

Angiotensin II induces cholesterol accumulation and impairs insulin secretion by regulating ABCA1 in beta cells

Evidence for a local angiotensin-generating system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II in isolated pancreatic islets

Pancreatic Injury Patterns in Patients With Coronavirus Disease 19 Pneumonia

Practical recommendations for the management of diabetes in patients with COVID-19

SGLT2 Inhibitor-Associated Euglycemic Diabetic Ketoacidosis: A South Australian Clinical Case Series and Australian Spontaneous Adverse Event Notifications

Assessment of Hypokalemia and Clinical Characteristics in Patients With Coronavirus Disease

The relationship of COVID-19 severity with cardiovascular disease and its traditional risk factors: A systematic review and metaanalysis. medRxiv

The Science Underlying COVID-19: Implications for the Cardiovascular System

Epidemiology Working Group for Ncip Epidemic Response CCfDC, Prevention

Association of hypertension and antihypertensive treatment with COVID-19 mortality: a retrospective observational study

New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis

Recognizing COVID-19-related myocarditis: The possible pathophysiology and proposed guideline for diagnosis and management

Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19

Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic?

Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19

Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19

Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic

Covid-19 and cardiovascular disease

Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin

The September epidemic of asthma exacerbations in children: a search for etiology

Regional, age and respiratory-secretion-specific prevalence of respiratory viruses associated with asthma exacerbation: a literature review

Clinical Characteristics of Covid-19 in New York City

The Role of Type 2 Inflammation in the Pathogenesis of Asthma Exacerbations

COVID-19 and Asthma: Reflection During the Pandemic

Is asthma protective against COVID-19?

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan

novel coronavirus (2019-nCoV) outbreak: A new challenge

COVID-19, severe asthma, and biologics

COVID-19-related Genes in Sputum Cells in Asthma. Relationship to Demographic Features and Corticosteroids

Association of respiratory allergy, asthma, and expression of the SARS-CoV-2 receptor ACE2

Association of asthma and its genetic predisposition with the risk of severe COVID-19

Dysregulation of Immune Response in Patients With Coronavirus

The influence of cigarette smoking on viral infections: translating bench science to impact COPD pathogenesis and acute exacerbations of COPD clinically

Chronic obstructive pulmonary disease is associated with severe coronavirus disease 2019 (COVID-19)

Prevalence of Underlying Diseases in Hospitalized Patients with COVID-19: a Systematic Review and Meta-Analysis

Baseline Characteristics and Outcomes of 1591

Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease

ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19

Cytokine Release Syndrome (CRS) and Nicotine in COVID-19 Patients: Trying to Calm the Storm

Bulk and single-cell transcriptomics identify tobacco-use disparity in lung gene expression of ACE2, the receptor of 2019-nCov

Understanding pathways to death in patients with COVID-19

Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

Cytokine storm and sepsis disease pathogenesis

The Pyrin Inflammasome in Health and Disease

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Endothelial cell infection and endotheliitis in COVID-19

Roles of IL-6-gp130 Signaling in Vascular Inflammation

Angiotensin II enhances thrombosis development in renovascular hypertensive rats

Pulmonary fibrosis secondary to COVID-19: a call to arms?

COVID-19: The Potential Treatment of Pulmonary Fibrosis Associated with SARS-CoV-2 Infection

Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury

WHO. Clinical management of COVID-19 interim guidance 2020

Addressing therapeutic questions to help Canadian health care professionals optimize COPD management for their patients during the COVID-19 pandemic

Inhaled corticosteroids downregulate SARS-CoV-2-related gene expression in COPD: results from a RCT

As a potential treatment of COVID-19: Montelukast

COVID-19, asthma, and biological therapies: What we need to know

RECOMMENDATIONS FOR INHALED ASTHMA CONTROLLER MEDICATIONS 2020

Use of corticosteroids in asthma and COPD patients with or without COVID-19

Kidney disease is associated with in-hospital death of patients with COVID-19

Acute kidney injury associated with coronavirus disease 2019 in Urban New Orleans

Renal Involvement and Early Prognosis in Patients with COVID-19 Pneumonia

Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection

COVID-19 Pandemic Causing Acute Kidney Injury and Impact on Patients With Chronic Kidney Disease and Renal Transplantation

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Kidney involvement in COVID-19 and rationale for extracorporeal therapies

Genetic Roadmap for Kidney Involvement of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection

Management of acute kidney injury in patients with COVID-19

Kidney disease: improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury

Acute kidney injury

Treatment for severe acute respiratory distress syndrome from COVID-19

Extracorporeal organ support (ECOS) in critical illness and acute kidney injury: from native to artificial organ crosstalk

Chimeric antigen receptor T-cell therapyassessment and management of toxicities

Digestive Symptoms in COVID-19 Patients With Mild Disease Severity: Clinical Presentation, Stool Viral RNA Testing, and Outcomes

Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis

Clinical Characteristics of COVID-19 Patients With Digestive Symptoms in Hubei, China: A Descriptive, Cross-Sectional, Multicenter Study

Gastrointestinal symptoms associated with severity of coronavirus disease 2019 (COVID-19): a pooled analysis

Risk of Severe COVID-19 in Patients with Inflammatory Bowel Disease in United States. A Multicenter Research Network Study

Are patients with inflammatory bowel disease at increased risk for Covid-19 infection?

The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes

Emerging pathogenic links between microbiota and the gut-lung axis

Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms

Chloroquine-induced QTc prolongation in COVID-19 patients

Diarrhea During COVID-19 Infection: Pathogenesis, Epidemiology, Prevention, and Management. Clinical gastroenterology and hepatology : the official clinical practice journal of the

Review article: COVID-19 and liver disease-what we know on 1st

Clinical characteristics of non-ICU hospitalized patients with coronavirus disease 2019 and liver injury: A retrospective study

Non-alcoholic fatty liver diseases in patients with COVID-19: A retrospective study

COVID-19 and liver disease

Clinical characteristics and mechanism of liver injury in patients with severe acute respiratory syndrome

Clinical characteristics and mechanism of liver damage in patients with severe acute respiratory syndrome

Coronavirus disease 2019 and prevalence of chronic liver disease: A meta-analysis

Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper

CSH guidelines for the diagnosis and treatment of druginduced liver injury

Clinical characteristics and outcomes of patients with coronavirus disease 2019 (COVID-19) and rheumatic disease: a comparative cohort study from a US "hot spot

The impact of the COVID-19 pandemic on patients with chronic plaque psoriasis being treated with biological therapy: the Northern Italy experience

Respiratory virus infection triggers acute psoriasis flares across different clinical subtypes and genetic backgrounds

The association between severe or dead COVID-19 and autoimmune diseases: A systematic review and meta-analysis

Covid-19 and autoimmunity

Could Sars-coronavirus-2 trigger autoimmune and/or autoinflammatory mechanisms in genetically predisposed subjects?

COVID-19-induced acute respiratory failure: an exacerbation of organ-specific autoimmunity?

Clinical and Autoimmune Characteristics of Severe and Critical Cases of COVID-19

COVID-19 revisiting inflammatory pathways of arthritis

Respiratory viral infections and the risk of rheumatoid arthritis

Immune Thrombocytopenic Purpura in a Patient with Covid-19. The New England journal of medicine

Guillain-Barré Syndrome Associated with SARS-CoV-2. The New England journal of medicine

Autoimmune haemolytic anaemia associated

Predisposing factors, pathogenesis and therapeutic intervention of Kawasaki disease

Immunosuppression for hyperinflammation in COVID-19: a double-edged sword?

American College of Rheumatology Guidance for the Management of Rheumatic Disease in Adult Patients During the COVID-19 Pandemic: Version 1

An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study

Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic

Obesity and the risk and outcome of infection

Obesity and susceptibility to severe outcomes following respiratory viral infection

The Epidemiology of Obesity: A Big Picture

Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV]. Zhonghua xin xue guan bing za zhi

High Prevalence of Obesity in Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Requiring Invasive Mechanical Ventilation. Obesity (Silver Spring)

Obesity in Patients Younger Than 60 Years Is a Risk Factor for COVID-19 Hospital Admission

Obesity could shift severe COVID-19 disease to younger ages

Association of obesity and its genetic predisposition with the risk of severe COVID-19: Analysis of populationbased cohort data

Two Things about COVID-19 Might Need Attention. Preprints.org

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Obesity, adipokines and COVID-19

Obesity and Outcomes in COVID-19: When an Epidemic and Pandemic Collide

The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection

Care of haematology patients in a COVID-19 epidemic

COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus

Burden of influenza-related hospitalizations among children with sickle cell disease

Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study

Outcomes of COVID-19 in patients with CLL: a multicenter international experience

Clinical Characteristics of Coronavirus Disease 2019 in China

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease

Management of Hemoglobin Disorders During the COVID-19

Genomewide Association Study of Severe Covid-19 with Respiratory Failure

Hematologic parameters in patients with COVID-19 infection

The clinical impact of COVID-19 epidemic in the hematologic setting

Assessment of some variables affecting the blanching activity of betamethasone 17-valerate cream

Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)?

Clinical observation and management of COVID-19 patients

Differential diagnoses for sepsis-induced disseminated intravascular coagulation: communication from the SSC of the ISTH

Causes of elevated D-dimer in patients admitted to a large urban emergency department

COVID-19 and its implications for thrombosis and anticoagulation

How I treat disseminated intravascular coagulation

Initiating adjunct low-dose hydroxyurea therapy for stroke prevention in children with SCA during the COVID-19 pandemic

COVID-19 and Sickle Cell Disease: Frequently Asked Questions 2020

SARS-CoV-2 infection in beta thalassemia: Preliminary data from the Italian experience

COVID-19 and Thalassemia: Frequently Asked Questions 2020