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SARS-CoV-2\n\n6.1 SARS-CoV-2 – heart disease\nACE2 plays a vital role in the cardiovascular system and is mainly involved in the functioning of the heart and development of hypertension and type II diabetes. Since ACE2 is the main target for the SARS-CoV-2 to enter inside the host cell and the ACE2 is also highly expressed in the heart apart from the lungs, indicating a chance of developing cardiac issues during SARS-CoV-2 infection. The anti-hypertensive therapy that has been prescribed for the patients is the usage of ACEi and ARBs should be carefully considered. The COVID-19 patients with comorbidities hypertension, taking the drug of ACEi or blocker of angiotensin receptor, need to switch off to other anti-hypertensive medications found to be controversial and require further studies this co-morbid conditions. The severity of the viral infection is higher in patients with comorbidities than those infected only by the virus without any predisposed health issue [85].\nThe interaction of the SARS-CoV-2 with ACE2 triggers a signal, which might be the reason to develop heart injury through the immune response triggered by T-helper cells creating a cytokine response. The SARS-CoV-2 has a structural similarity with that of SARS-CoV. SARS-CoV caused severe cardiovascular damage during its pandemic period. Therefore, it is essential to investigate SARS-CoV-2 treatment options and ensure a cardio-protective effect. The age and the predisposition of the acute coronary syndrome are the two critical factors which need to be considered in patients affected with COVID-19 [85].\nSince the ACE2 is highly expressed in pericytes, the patients infected with SARS-CoV-2 and predisposed with cardiac failure are more susceptible to develop severe cardiac problems [86]. The usage of mineralocorticoids receptor blocker can attenuates oxidative stress, reduces the level of ACE with the augmented production of the angiotensin 1–7 and attenuates the angiotensin II generation and increases the activity of ACE2 The antagonist of angiotensin II type 1 receptor, have modulates the profilin-1 expression and ACE2 [87]. The selective of the angiotensin II activity or synthesis mediated the augmented level of ACE2 expression and its activity in cardiac. Still, the combination of the lisinopril and losartan increases the activity of ACE2 but not ACE2 mRNA. The inhibition of ACE results in reduced formation of angiotensin II and metabolism of angiotensin 1–7, the angiotensin II type 1 receptor antagonist increases the metabolism of angiotensin II via ACE2 [88]. SARS-CoV 2 enters into the cell via the ACE2 receptor; this causes the decreased level of the ACE2 due to the binding of the spike protein to the ACE2 and no changes in ACE. This process causes the virus's entry, replicates it, and causes tissue injury via decreasing anti-atrophy, anti0-fibrosis, anti-inflammation, anti-oxidant, and vasodilation. On the other hand, the angiotensin II type 1 receptor causes pro-atrophy, pro-fibrosis, pro-inflammation, pro-oxidant, severe myocardial remodeling, vasoconstriction and vascular permeability which leads to tissue injury [89] (represented in Table 1).\nTherefore, the use of ACEi, ARBs, and mineralocorticoids has shown to have an impact on the cardiac patients affected by COVID-19, but the exact mechanism behind it is not clear. Aliskiren, a direct inhibitor of renin, resulted in reduced expression of ACE2 besides reducing the blood pressure that has been elucidated in diabetic nephropathy animal models [90]. Therefore, renin blockers, especially aliskiren, need to be further investigated as a treatment option for COVID-19 patients with comorbidities [91].\n\n6.2 SARS-CoV-2 – gastrointestinal risk\nThe ACE2 is also highly expressed in the small intestine and large intestine of the gastrointestinal tract. The S protein present on the envelope of the SARS-CoV-2 ensures higher binding affinity, thereby mediating the entry of the virus into the host cell. The presence of SARS-CoV-2 in the gastrointestinal tract was confirmed by nucleocapsid staining of the virus. The virus was found to be visualized in the cytoplasm of epithelia of duodenum and rectum [92] (represented in Table 1). Apart from the pulmonary infection, the COVID-19 affected patients also exhibited vomiting, abdominal pain, and diarrhea, which was first reported in a 35 years old man from the United States. He was presented with nausea and diarrhea on 2nd day of the infection and was hospitalized. Stools examination revealed the presence of SARS-CoV-2 RNA, which was confirmed by using reverse transcriptase-polymerase chain reaction (RT-PCR) on day 7 of infection [93]. Out of 171 COVID-19 affected children, 6.4% of them have shown vomiting, and 8.8% of them and 3 out of ten affected children have shown diarrhea as symptoms [94]. Also, previously there were two COVID-19 young cases reported with vomiting and diarrhea.\nIn China, from 552 hospitals, 1099 cases were reported, of which 3.8% and 5% were diagnosed with diarrhea and vomiting as symptoms [95]. According to another report, out of 140 COVID-19 patients from Wuhan, 39.6% exhibited gastrointestinal symptoms apart from 5% exhibiting vomiting, 12.9% exhibiting diarrhea, and 17.3% exhibiting nausea [96]. It was reported that 17 patients had shown a negative result when tested using pulmonary samples, but when tested using rectal swabs have shown to have a positive result [96].\nSimilarly, 8 out of 10 children affected by SARS-CoV-2 had shown dual results, negative results when tested by nasopharyngeal samples, and positive results when tested using a rectal swab [97]. The percentage of patients exhibiting nausea, vomiting, and diarrhea as symptoms vary between the cohort groups, whereas, in the case of certain groups, these symptoms contributed very few percent. In contrast, in the case of the other groups, a high percentage of these gastrointestinal symptoms have been recorded.\n\n6.3 SARS-CoV-2- kidney risk\nIt is suspected that whether the patients with predisposed kidney issues or COVID-19 induced acute kidney injury is fatal to the affected patients. In an article posted on March 19 by HospiMedica International staff writers, it was mentioned that patients affected by COVID-19 developed proteinuria estimated by the elevated levels of albumin in urine were diagnosed in the initial stages of infection. The majority of the affected members, i.e., 34% out of 59 patients, developed proteinuria where the elevated albumin levels serve as a biomarker for kidney damage, and 63% of the patients exhibited proteinuria and hematuria characterized by the presence of blood in the urine. In another study conducted on 710 patients hospitalized due to COVID-19. The impairment in the functioning of the kidney was observed in 27% of the 59 patients and 66% of the corona infected patients. In a later study conducted on COVID-19 affected patients from 710 hospitals, 26.7% exhibited only hematuria, and 44% exhibited proteinuria and hematuria. The impaired kidney function was found in 15% of the study population [98].\nAccording to an article published by Wang L and his colleagues reported that out of 116 COVID-19 positive cases from Renmin Hospital of Wuhan University, out of whom 111 didn't have any kidney issues in their history and the remaining five patients had chronic kidney disease (CDK). Also, out of the 111 patients, only 10.8% of the patients exhibited a slight increase in creatine or blood urea nitrogen levels, and 7.2% of the patients had shown a minute raise in the albuminuria levels. None of the patients out of 111 didn't exhibit any acute kidney injury (AKI) after the COVID-19 infection. The remaining five patients who were already undergoing continuous renal replacement therapy (CRRT) also didn't show any fatal effects after COVID-19 infection confirmed by diagnosing the renal indicators [99]. Out of 701 patients, 2% of the patients were found to have CKD, and the average lymphocytic number was found to be reduced than the normal. High sensitivity C-reactive protein levels were significantly increased. In patients reported with high levels of serum, creatine indicated high levels of serum lactose dehydrogenase. Among hospitalized patients, patients with high levels of serum creatine were mostly old and male sex. Also, they exhibited lower platelet and lymphocytic count and elevated leukocytic count. The patients with elevated procalcitonin also exhibited elevated levels of aspartate aminotransferase and lactate dehydrogenase. Acute kidney injury was significantly higher in those patients with high serum creatine levels. AKI eventually results in mortality [100] (represented in Table 1). Therefore, advanced identification of kidney diseases in patients affected by COVID-19 may help the clinicians to reduce the mortality rate due to comorbidities such as chronic kidney disease, acute kidney injury, proteinuria, and hematuria.\n\n6.4 SARS-CoV-2 – diabetes mellitus\nPatients with diabetes mellitus exhibit high levels of ACE2, and treatment with the inhibitors of ACE and ARBs augments the expression of ACE2. Diabetes condition may lead to the suspicion that the excessive expression of ACE2 aids the entry of SARS-CoV-2 into the host cells resulting in COVID-19. Since diabetes mellitus and hypertension conditions are treated, ACE2 increasing drugs are having a severe risk of COVID-19 [10].\nSimultaneously, the elevated expression of ACE2 ensures the entry of the SARS-CoV-2, attaching to the ACE2 enzyme with the help of S protein present on its envelope's surface. There forth, it became controversial whether COVID-19 affected patients who are predisposed with diabetes mellitus should be resumed with their treatment with ACEi and ARBs or not. Also, if the medication is abruptly ceased, there are chances that the patient may die due to hypertension instead of COVID-19. For this reason, it has been suggested that there is no need to stop the medication of a diabetic patient even though if he is affected by COVID-19 because there is no scientific evidence available conducted on human subjects regarding whether to use ACEi and ARBs [10].\n\n6.5 SARS-CoV-2-liver injury\nThe SARS-CoV-2 infection has shown to increase the levels of ALT, AST, and bilirubin levels, indicating injury to the hepatic tissue [9,95,101,102]. Apart from these liver serum enzymes indicating hepatic damage, the levels of albumin were significantly decreased, indicating the severity of the infection [101]. The elated levels of gamma-glutamyl transferase (GGT) were observed only in patients with severe cases. In contrast, thealkaline phosphatize (AKP) levels remained unchanged irrespective of the severity of the infection [37] (represented in Table 1).\nSARS-CoV and SARS-CoV-2 share the similarity in making an entry into the host cell through the ACE2 receptor. In addition to the type 2 cells in the lungs, both the bile duct cells and hepatocytes also express ACE2, which might be the reason that liver injury occurs during SARS-CoV-2 infection [103]. The bile duct epithelial cells are involved in immune responses and the regeneration of the hepatocytes [104]. Besides possessing a high number of ACE2 on its surface, bile duct cells are more prone to the SARS-CoV-2 infection resulting in liver injury, which indicates that the hepatocytes are not directly involved in the hepatic injury [37]. The histopathological manifestations of SARS-CoV-2 infected patients revealed mild lobular and portal activity and restrained microvascular steatosis [105]. The degree of liver damage is directly proportional to the severity of the SARS-CoV-2 infection. Still, the reason for the liver injury remains elusive. A recent study reported that the use of anti-viral medication lopinavir might result in hepatic damage [102]. Therefore, whether the liver injury is due to the virus entry or due to the drugs used as anti-viral medication needs to be elucidated.\n\n6.6 SARS-CoV-2-lung injury\nIt was possible to study the lung pathology of COVID-19 patients diagnosed with COVID-19 retrospectively after undergoing lung lobectomy surgery for adenocarcinoma. Also, the patients didn't present pneumonia at the time of surgery, indicating the initial stages of COVID-19. A female patient who was 80 years old was hospitalized due to an irregularly shaped solid nodule in the right middle lobe. On a postoperative day 1, a CT scan was performed, which indicated a few clinical manifestations. Later, the patient was presented with increased leucocytes, decreased lymphocytic count, chest tightness, wheezing, dry cough, and difficulty in breathing. Later findings confirmed that SARS-CoV-2 infected her from a patient in the same room who was already affected. Another patient who was 73 years old and had a medical history of hypertension from 20 years who underwent surgery for adenocarcinoma was discharged on the 6th-day post-operation. On postoperative day 9, the patient exhibited chest tightness, muscle pain, dry cough, and decreased lymphocytic count. His CT-scan findings revealed for viral pneumonia, and he was also tested positive for the 20,189-nC0V test. He was admitted to the infectious disease ward. After, 20 days he was discharged as he recovered. Histopathological findings showed focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, edema, multinucleated giant cells, protruding hyaline membranes, and proteinaceous exudates [106] (represented in Table 1).\nThe patients, who are recovered from COVID-19, have a possibility of chronic lung damage. Out of 70 COVID-19 pneumonia patients, 66 patients have lung damage in a different manner, which was determined by CT. This damage is in a diverse range; in the alveoli, there is a hardened tissue with the dense clumps which block the vessels in the tiny air sacs, which absorb the oxygen and cause tissue lesions. This tissue lesion acts as a sign of the long-term lung disease. Similar reports have been found in both the SARS CoV and MERS. The patients admitted with lung pneumonia shows damage in both the lungs. The CT scan of the COVID-19 patients indicates that there is a tissue lesion found over the alveoli and which can develop into the scars. There are \u003e2.9 million people have COVID-19 disease worldwide, according to April 27. 80% of the patients are having a high risk of problems, such as from breathing to respiratory failure [107].\n\n6.7 SARS-CoV-2-CNS risk\nMathew reported that it might be due to the obstructions in the nervous system, which may restrict the entry of air into the lungs [108]. The virus enters the medullary neurons during the latency phase. A possible mechanism explained was that the SARS-CoV-2 might enter the olfactory lobe of the brain through nasal chambers upon inhalation and may lead to inflammation and demyelination. Later, it spreads to the whole brain due to its ability to cross the blood-brain barrier. Some neurological symptoms exhibited by the COVID-19 infection patients include nausea, vomiting, and headache (represented in Table 1). Since the SARS-CoV-2 possess the ability to cross the blood-brain barrier, it is important to design the drugs in such a way that they can cross the blood-brain barrier and scavenges the brain from viral infection. Also, it is essential to note that the respiratory illness accompanies neurological invasion by the virus, therapeutic care must be taken to prevent the viral entry into the central nervous system (CNS) [7].\n\n6.8 SARS-CoV-2 – immunopathology\nSARS-CoV-2 infection mediates immune response, both innate and adaptive. The enhanced level of the innate response and decreased level of adaptive causes tissue damage. Upon viral infection, there is an immune response. T cells, especially the cluster of differentiation 4 (CD4+) and a group of differentiation 8 (CD8+), have an anti-viral role. CD8+ T cells are highly cytotoxic, and they killed infected cells. This T cell induces the pro-inflammatory cytokines through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling. This process further activates the cytokines and chemokines [7]. Similar to SARS-CoV, MERS, SARS-CoV-2 infection in the immune effector cells are also having the enhanced level of the cytokines such as IFN-γ, IFN-α, IL-6, IL-1β, IL-18, IL-12, TGFβ, IL-33 and TNF-α and chemokines such as CCL2, CCL5, CCL3, CXCL10, CXCL9, and CXCL8. Similar to this, severe MERS-CoV infected patient's serum shows an increased level of the cytokines and chemokines. This cytokine storm further causes multiple organ failures to further leads to the death of the SARS-CoV-2 patient [109].\nOn the other hand, the T-cells are having four types of it, such as Th1, Th2, Th17 (inflammatory), and anti-inflammatory Tregs. These Th2 cells generate IL-4 cells. The compound which can block the Th1 (Boost immune system) tends to augments the level of the Th2 (anti-inflammatory response). IL-4 triggers the Th2 cells and obstructs the Th1 response. This Th2 helps to repair form tissue dysfunction and another type of malfunction. It is found to be good that the increased level of the Th1 and Th17 plays an important role in hyperactive immune response and during autoimmune conditions. It is showed that there is an induction of the Th1/Th17 and the production of antibodies upon COVID-19 condition [110]. Contradict to this; the patient has a high level of Th2 in need of intensive care [111]. During the MERS condition, there is a reduced level of both the Th1 and Th2, which further enhances the inflammatory cytokines and causes more infection and death [112]. SARS patients who died with an older age have higher cytokines of Th2, such as IL-4, IL-10, and IL-5 [113]. This incidence supports the increased Th2 level of COVID-19 patients who needs intensive care. The mechanism behind this is based on the molecular weight of the protein of SARS-CoV2; the activity of the immune system is changed. The recent research by the F. Javier Martín Oncina in 2020 showed that based on the antigen molecular weight, the host's immune response is varied. The proteins of the SARS-CoV2 are spike protein with 140 kDa, Envelope protein with 10 kDa, Membrane protein with 25 kDa, and nucleocapsid protein with 50 kDa. The protein with more than \u003e70 kDa, such as spike protein, cannot be arrested by the B-cell, thereby it activates the inflammatory response through the Th1 response with the macrophages. This process occurs in the subcapsular sinus and through dendritic cells phagocytosis. The other proteins with \u003c70 kDa are found in the protein of SARS-CoV2, which activates the receptor of B-cell and stimulates Th2 immune response. The unremittingviral particle overload, which is unrestricted by the viral cell lysing, will be terminated by the Th1 (pro-inflammatory response). Further, it increases the protein level with a weight of \u003c70 kDa stimulates the B cells in large amounts. This induction of the B-cells leads to the condition called as Activated Induced Cell Death (AICD), which speediness the apoptosis and release of pro-inflammatory cytokines cause lymphopenia, thereby it produces IL-10, augments the shift of Th2 form Th1 response which causes further suppression of immune system, COVID-19 sepsis [114]. Correlative to that that COVID-19 patients with the high level of Th2 immune response need intensive care [111], which shows that they might be having apoptosis, lymphopenia, and suppression of immune system further causes COVID-19 sepsis [114]. Though the cell death is via Th2 immune response but the level of IL-4 is not elucidated yet. The role of IL-4 and its mechanism behind COVID-19 remain elusive (Represented in Fig. 2 ).\nFig. 2 SARS-CoV-2 enters into the host cell via binding with the cellular receptor ACE-2. It undergoes the fusion with the joining of the plasma membrane and the virus. Then it undergoes the process of the proteolytic cleavage; further, it will undergo replication and lead to the formation of the proteins. This process activates the signaling pathway, such as the NF-kB pathway, via TRIF. The interaction between the cells and the virus activates many cytokine storms. On the other hand, once the virus enters into the cell, the antigen present in that would undergo the antigen presentation cells (APC); further, this stimulates the humoral and cellular immunity. COVID-19 infects the macrophage cells, which presents to the T cell, further, which leads to the activation, differentiation of T-cells, along with the production of cytokines. This shows the negative action on the activation of CD8 T cells. Thus the mediator produced by the CD8+ T cells clears the infection of SARS-CoV. Upon COVID-19 infection, there is a reduced CD4+ and CD8+ cell level, further increasing the cytokine level in the cells, which triggers the inflammation. This mediates the production of the cytokine storm via secreting chemokine and cytokines such as IL-1β, IL-6, TNF-α, IL-8, IL-21, CCL2, CCL3, CCL5, CXCL10, TNF-β, and MCP-1 and triggers the tissue injury. On the other hand, based on the weight of the protein of SARS-CoV2, there is an activation of Th1/Th17 (boosts immune system) when the spike protein is \u003e70 kDa. In case of the Th2 (anti-inflammatory) is activated by the majority of the protein with \u003c70 kDa, then the activation of the B-cell receptor, which causes activation-induced cell death such as apoptosis and lymphopenia which is by releasing IL-10, shifting of Th1 to Th2 immune response, suppression of the immune system and further leads to the COVID-19 sepsis. The role of IL-4 has not been elucidated yet. It remains unanswerable upon COVID-19 condition with the mechanism of Th2 and Th1/Th17.\nThe wet lung is also known as acute respiratory distress syndrome (ARDS). The patient with COVID-19 has lung edema, and it needs more attention clinically. Lung edema is found to be a symptom of acute lung injury, which development to hypoxemia condition and which leads to acute respiratory distress syndrome (ARDS). The patients who are found with ARDS have more mortality. Though there is no proper treatment or vaccine treatment, ventilation with the therapy of oxygen and ventilation mechanically is mandatory. Sometimes, the treatment with the glucocorticoids (systemic or locally) would help attenuate lung edema and pulmonary inflammation [115]. But there is a need for more research to correlate the cytokine storm with wet lung pneumonia in COVID-19 patients.\n\n6.9 SARS-CoV-2 – ocular risk\nThe ACE2 receptors are also widely distributed in the superficial parts such as conjunctiva and cornea inferior parts such as iris, ciliary body, aqueous humor, trabecular meshwork, retina, and non-pigmented ciliary epithelium of the ocular globe which is mentioned out to be the intraocular renin-angiotensin system. Therefore, the distribution of ACE2 and TMPRSS2 protein must be taken into consideration to study the passage of infection through the ocular route [116]. Also, there is a chance for the virus to enter into the nasal cavity, which causes respiratory illness and the digestive system through the lacrimal canaliculi aided by the effectiveness of the tear film [117,118]. Out of 38 COVID-19 positive patients, 12 exhibited clinical manifestations, which include chemosis, epiphora, increased secretions, conjunctivitis, and conjunctival hyperemia. Researchers reported that patients exhibiting ocular symptoms would have elevated neutrophilic and lymphocytic counts, elated procalcitonin, lactate dehydrogenase, and C-reactive protein levels than those without ocular manifestations. The patients with ocular manifestations exhibited severe illness [119].\nEven though there is no such evidence, the presence of ACE2 and TMPRSS2 protein in the corneal limbal stem cells suggests that the SARS-CoV-2 may enter the bloodstream and travel to the other parts including the brain [120]. Even though there is no viral load in the conjunctiva of the SARS-CoV-2 infected patients without conjunctivitis, the risk of transmission of the virus through tears is low [121]. The exact mechanism behind the ocular risk and SARS-CoV-2 need to be elucidated further.\n\n6.10 SARS-CoV-2 – cancer risk\nCancer patients are highly vulnerable to SARS-CoV-2 infection. 18 out of 1590 COVID-19 positive cases exhibited cancer history. 5 out of 18 patients suffered from lung cancer, 4 out of 18 patients had no past information on medication and had undergone surgery or chemotherapy in the previous month, and the remaining 12 were cancer survivors. The COVID-19 was highly severe in cancer patients than non-cancer COVID-19 affected patients. Also, COVID-19 patients with cancer exhibited a severe chain of symptoms than those without a history of cancer. Also, patients with lung cancer did not exhibit severe symptoms when compared to those with other types of cancers [122].\nIn a retrospective study conducted among 1276 patients, 28 patients who have cancer were selected for the study. The mean age group people belonged to the elderly category, and 60.7% of them were males. Lung cancer was the most frequent type, followed by oesophageal and breast cancers among cancer affected patients. 10 out of 28 patients were presented with IV stage cancer. 28.6% of the patients developed COVID-19 while receiving antitumor therapy, whereas 71.4% of them developed due to the presence of infection in their vicinity. Besides, 39.2% of the patients exhibited chronic co-morbid conditions apart from cancer. 28.6% of patients died, and the remaining patients developed serious consequences even after receiving anti-viral and corticosteroids. The most common complication developed by the patients includes septic shock, acute myocardial infarction, and ARDS [123]. Therefore, more focus should be laid on the research for medication and treatment options for COVID-19 affected cancer patients. More studies are required to determine the exact mechanism behind cancer and SARS-CoV-2.\n\n6.11 SARS-CoV-2 – tuberculosis\nA study was conducted in February 2020, Shenyang, China, which involved 36 COVID-19 positive patients and was classified based on the severity of the symptoms as mild and critical. The results of these patients were compared with that of the patients affected by pneumonia caused by Mycobacterium tuberculosis from Shenyang chest hospital. The study was conducted to determine which one caused severe pneumonia, either the viral or the bacterial strain. Then the severity of tuberculosis was compared between the mild and severe COVID-19 cases and confirmed that tuberculosis due to mycobacterial strain affected patients are more susceptible to COVID-19 and enhance the severity of COVID-19 [124]. Patients with HIV undergoing treatment with antiretroviral medicines exhibit weak immune systems and are more susceptible to viral infections. Also, until now, only one HIV case had been reported with COVID-19 infection from china. The patient recovered from the infection the same as that of those without HIV. There is no evidence on whether HIV patients are more susceptible to COVID-19 infection [125].\nThe COVID-19 associated TB is found in 94th day of the nonexistence of public health interventions and 138th day in the occurrence of interventions. This occurs at the peak of an outbreak where the implementation of the intervention, out of it 11,066, is with the presence of interventions. 27,968 COVID-19 cases found in the absence of interventions, out of it 14,823, are with no interventions. This scenario shows that there is a need to take preventive measures of TB associated with COVID-19 patients. They need a prior diagnosis and proper management [126]. The main reasons for mortality are age, sex, and other co-morbid factors such as diabetes, cardiovascular diseases, and renal diseases are the main reasons for mortality.\n\n6.12 SARS-CoV-2 – Venous thromboembolism\nPeople affected with pneumonia are more prone to venous thromboembolism. Out of 1026 COVID-19 patients, 40% of them exhibited high risk, and 11% of them at high risk of developing venous thromboembolism without any prophylaxis. Prophylactic measures can prevent venous thromboembolism. Only 7 out of 140 patients at high risk for venous thromboembolism had recorded about the anticoagulation treatment. And 44 out of 407 exhibited a higher risk for bleeding. In these patients, the mechanical compressions such as intermittent pneumatic compression and elastic compression stockings are instructed, and the duration and dosage of anticoagulants should be adjusted. Also, the COVID-19 patients, along with other co-morbid conditions such as cardiovascular manifestations, respiratory failure, renal and hepatic problems, can affect the bleeding status and venous thromboembolism. Therefore, further investigations are required to reduce the risk due to venous thromboembolism and bleeding in the case of COVID-19 patients [127].\n\n6.13 SARS-CoV-2- reproductive risk\nViral infections during the first 20 weeks of gestation have shown to be more severe. The infections, such as SARS and MERS, which occurred due to coronaviruses, had reported an increased risk for pregnancy-related mortality and morbidity. Such cases among COVID-19 affected patients are not yet reported. Nine women who are in their third semester and infected with COVID-19 were reported to have outcomes as that of non-pregnant COVID-19 affected adults. In another study, out of 33 newborn infants, three infants were shown to be tested positive for COVID-19 who got the disease transferred from their mother through intrauterine vertical transmission mode [128].\n\n6.14 SARS-CoV-2 – mental illness\nAccording to a report, out of a group of 50 COVID-19 cases from a psychiatric hospital in Wuhan, China has uplifted the worry about the role of mental disorder in coronavirus transmission. The conditions include incomplete or no awareness of the risk, inability to have personal protection, and cognitive impairment. The treatment has become more challenging for people with COVID-19 infection and health disorders as co-morbid conditions [129].\n\n6.15 SARS-CoV-2 – aging and cardiovascular risk\nIt has been reported that the expression of ACE2 reduces with the increasing age. Since young patients possess high levels of ACE2, they are more prone to COVID-19 infection. Whereas, in old age people other than reduced ACE2 levels, other co-morbid conditions such as cardiovascular problems, diabetes, and hypertension might be present. The medication prescribed for these patients helps in elevating the ACE2 levels, which might enhance the viral entry. Though the treatment reduces the co-morbid severities, the viral infection is enhanced in those patients. Therefore, it is conclusive that young patients, even though they are more susceptible to the COVID-19 infection, they are less severely affected and exhibit elevated angiotensin II signaling. Whereas, the older patients who exhibit low levels of ACE2 and higher angiotensin II signaling leads to hypertension. The usage of ACEi and ARBs help in promoting the vasodilatory effects by elevating the ACE2 levels, thereby becoming susceptible to COVID-19 infection and are severely affected [130]."}

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SARS-CoV-2\n\n6.1 SARS-CoV-2 – heart disease\nACE2 plays a vital role in the cardiovascular system and is mainly involved in the functioning of the heart and development of hypertension and type II diabetes. Since ACE2 is the main target for the SARS-CoV-2 to enter inside the host cell and the ACE2 is also highly expressed in the heart apart from the lungs, indicating a chance of developing cardiac issues during SARS-CoV-2 infection. The anti-hypertensive therapy that has been prescribed for the patients is the usage of ACEi and ARBs should be carefully considered. The COVID-19 patients with comorbidities hypertension, taking the drug of ACEi or blocker of angiotensin receptor, need to switch off to other anti-hypertensive medications found to be controversial and require further studies this co-morbid conditions. The severity of the viral infection is higher in patients with comorbidities than those infected only by the virus without any predisposed health issue [85].\nThe interaction of the SARS-CoV-2 with ACE2 triggers a signal, which might be the reason to develop heart injury through the immune response triggered by T-helper cells creating a cytokine response. The SARS-CoV-2 has a structural similarity with that of SARS-CoV. SARS-CoV caused severe cardiovascular damage during its pandemic period. Therefore, it is essential to investigate SARS-CoV-2 treatment options and ensure a cardio-protective effect. The age and the predisposition of the acute coronary syndrome are the two critical factors which need to be considered in patients affected with COVID-19 [85].\nSince the ACE2 is highly expressed in pericytes, the patients infected with SARS-CoV-2 and predisposed with cardiac failure are more susceptible to develop severe cardiac problems [86]. The usage of mineralocorticoids receptor blocker can attenuates oxidative stress, reduces the level of ACE with the augmented production of the angiotensin 1–7 and attenuates the angiotensin II generation and increases the activity of ACE2 The antagonist of angiotensin II type 1 receptor, have modulates the profilin-1 expression and ACE2 [87]. The selective of the angiotensin II activity or synthesis mediated the augmented level of ACE2 expression and its activity in cardiac. Still, the combination of the lisinopril and losartan increases the activity of ACE2 but not ACE2 mRNA. The inhibition of ACE results in reduced formation of angiotensin II and metabolism of angiotensin 1–7, the angiotensin II type 1 receptor antagonist increases the metabolism of angiotensin II via ACE2 [88]. SARS-CoV 2 enters into the cell via the ACE2 receptor; this causes the decreased level of the ACE2 due to the binding of the spike protein to the ACE2 and no changes in ACE. This process causes the virus's entry, replicates it, and causes tissue injury via decreasing anti-atrophy, anti0-fibrosis, anti-inflammation, anti-oxidant, and vasodilation. On the other hand, the angiotensin II type 1 receptor causes pro-atrophy, pro-fibrosis, pro-inflammation, pro-oxidant, severe myocardial remodeling, vasoconstriction and vascular permeability which leads to tissue injury [89] (represented in Table 1).\nTherefore, the use of ACEi, ARBs, and mineralocorticoids has shown to have an impact on the cardiac patients affected by COVID-19, but the exact mechanism behind it is not clear. Aliskiren, a direct inhibitor of renin, resulted in reduced expression of ACE2 besides reducing the blood pressure that has been elucidated in diabetic nephropathy animal models [90]. Therefore, renin blockers, especially aliskiren, need to be further investigated as a treatment option for COVID-19 patients with comorbidities [91].\n\n6.2 SARS-CoV-2 – gastrointestinal risk\nThe ACE2 is also highly expressed in the small intestine and large intestine of the gastrointestinal tract. The S protein present on the envelope of the SARS-CoV-2 ensures higher binding affinity, thereby mediating the entry of the virus into the host cell. The presence of SARS-CoV-2 in the gastrointestinal tract was confirmed by nucleocapsid staining of the virus. The virus was found to be visualized in the cytoplasm of epithelia of duodenum and rectum [92] (represented in Table 1). Apart from the pulmonary infection, the COVID-19 affected patients also exhibited vomiting, abdominal pain, and diarrhea, which was first reported in a 35 years old man from the United States. He was presented with nausea and diarrhea on 2nd day of the infection and was hospitalized. Stools examination revealed the presence of SARS-CoV-2 RNA, which was confirmed by using reverse transcriptase-polymerase chain reaction (RT-PCR) on day 7 of infection [93]. Out of 171 COVID-19 affected children, 6.4% of them have shown vomiting, and 8.8% of them and 3 out of ten affected children have shown diarrhea as symptoms [94]. Also, previously there were two COVID-19 young cases reported with vomiting and diarrhea.\nIn China, from 552 hospitals, 1099 cases were reported, of which 3.8% and 5% were diagnosed with diarrhea and vomiting as symptoms [95]. According to another report, out of 140 COVID-19 patients from Wuhan, 39.6% exhibited gastrointestinal symptoms apart from 5% exhibiting vomiting, 12.9% exhibiting diarrhea, and 17.3% exhibiting nausea [96]. It was reported that 17 patients had shown a negative result when tested using pulmonary samples, but when tested using rectal swabs have shown to have a positive result [96].\nSimilarly, 8 out of 10 children affected by SARS-CoV-2 had shown dual results, negative results when tested by nasopharyngeal samples, and positive results when tested using a rectal swab [97]. The percentage of patients exhibiting nausea, vomiting, and diarrhea as symptoms vary between the cohort groups, whereas, in the case of certain groups, these symptoms contributed very few percent. In contrast, in the case of the other groups, a high percentage of these gastrointestinal symptoms have been recorded.\n\n6.3 SARS-CoV-2- kidney risk\nIt is suspected that whether the patients with predisposed kidney issues or COVID-19 induced acute kidney injury is fatal to the affected patients. In an article posted on March 19 by HospiMedica International staff writers, it was mentioned that patients affected by COVID-19 developed proteinuria estimated by the elevated levels of albumin in urine were diagnosed in the initial stages of infection. The majority of the affected members, i.e., 34% out of 59 patients, developed proteinuria where the elevated albumin levels serve as a biomarker for kidney damage, and 63% of the patients exhibited proteinuria and hematuria characterized by the presence of blood in the urine. In another study conducted on 710 patients hospitalized due to COVID-19. The impairment in the functioning of the kidney was observed in 27% of the 59 patients and 66% of the corona infected patients. In a later study conducted on COVID-19 affected patients from 710 hospitals, 26.7% exhibited only hematuria, and 44% exhibited proteinuria and hematuria. The impaired kidney function was found in 15% of the study population [98].\nAccording to an article published by Wang L and his colleagues reported that out of 116 COVID-19 positive cases from Renmin Hospital of Wuhan University, out of whom 111 didn't have any kidney issues in their history and the remaining five patients had chronic kidney disease (CDK). Also, out of the 111 patients, only 10.8% of the patients exhibited a slight increase in creatine or blood urea nitrogen levels, and 7.2% of the patients had shown a minute raise in the albuminuria levels. None of the patients out of 111 didn't exhibit any acute kidney injury (AKI) after the COVID-19 infection. The remaining five patients who were already undergoing continuous renal replacement therapy (CRRT) also didn't show any fatal effects after COVID-19 infection confirmed by diagnosing the renal indicators [99]. Out of 701 patients, 2% of the patients were found to have CKD, and the average lymphocytic number was found to be reduced than the normal. High sensitivity C-reactive protein levels were significantly increased. In patients reported with high levels of serum, creatine indicated high levels of serum lactose dehydrogenase. Among hospitalized patients, patients with high levels of serum creatine were mostly old and male sex. Also, they exhibited lower platelet and lymphocytic count and elevated leukocytic count. The patients with elevated procalcitonin also exhibited elevated levels of aspartate aminotransferase and lactate dehydrogenase. Acute kidney injury was significantly higher in those patients with high serum creatine levels. AKI eventually results in mortality [100] (represented in Table 1). Therefore, advanced identification of kidney diseases in patients affected by COVID-19 may help the clinicians to reduce the mortality rate due to comorbidities such as chronic kidney disease, acute kidney injury, proteinuria, and hematuria.\n\n6.4 SARS-CoV-2 – diabetes mellitus\nPatients with diabetes mellitus exhibit high levels of ACE2, and treatment with the inhibitors of ACE and ARBs augments the expression of ACE2. Diabetes condition may lead to the suspicion that the excessive expression of ACE2 aids the entry of SARS-CoV-2 into the host cells resulting in COVID-19. Since diabetes mellitus and hypertension conditions are treated, ACE2 increasing drugs are having a severe risk of COVID-19 [10].\nSimultaneously, the elevated expression of ACE2 ensures the entry of the SARS-CoV-2, attaching to the ACE2 enzyme with the help of S protein present on its envelope's surface. There forth, it became controversial whether COVID-19 affected patients who are predisposed with diabetes mellitus should be resumed with their treatment with ACEi and ARBs or not. Also, if the medication is abruptly ceased, there are chances that the patient may die due to hypertension instead of COVID-19. For this reason, it has been suggested that there is no need to stop the medication of a diabetic patient even though if he is affected by COVID-19 because there is no scientific evidence available conducted on human subjects regarding whether to use ACEi and ARBs [10].\n\n6.5 SARS-CoV-2-liver injury\nThe SARS-CoV-2 infection has shown to increase the levels of ALT, AST, and bilirubin levels, indicating injury to the hepatic tissue [9,95,101,102]. Apart from these liver serum enzymes indicating hepatic damage, the levels of albumin were significantly decreased, indicating the severity of the infection [101]. The elated levels of gamma-glutamyl transferase (GGT) were observed only in patients with severe cases. In contrast, thealkaline phosphatize (AKP) levels remained unchanged irrespective of the severity of the infection [37] (represented in Table 1).\nSARS-CoV and SARS-CoV-2 share the similarity in making an entry into the host cell through the ACE2 receptor. In addition to the type 2 cells in the lungs, both the bile duct cells and hepatocytes also express ACE2, which might be the reason that liver injury occurs during SARS-CoV-2 infection [103]. The bile duct epithelial cells are involved in immune responses and the regeneration of the hepatocytes [104]. Besides possessing a high number of ACE2 on its surface, bile duct cells are more prone to the SARS-CoV-2 infection resulting in liver injury, which indicates that the hepatocytes are not directly involved in the hepatic injury [37]. The histopathological manifestations of SARS-CoV-2 infected patients revealed mild lobular and portal activity and restrained microvascular steatosis [105]. The degree of liver damage is directly proportional to the severity of the SARS-CoV-2 infection. Still, the reason for the liver injury remains elusive. A recent study reported that the use of anti-viral medication lopinavir might result in hepatic damage [102]. Therefore, whether the liver injury is due to the virus entry or due to the drugs used as anti-viral medication needs to be elucidated.\n\n6.6 SARS-CoV-2-lung injury\nIt was possible to study the lung pathology of COVID-19 patients diagnosed with COVID-19 retrospectively after undergoing lung lobectomy surgery for adenocarcinoma. Also, the patients didn't present pneumonia at the time of surgery, indicating the initial stages of COVID-19. A female patient who was 80 years old was hospitalized due to an irregularly shaped solid nodule in the right middle lobe. On a postoperative day 1, a CT scan was performed, which indicated a few clinical manifestations. Later, the patient was presented with increased leucocytes, decreased lymphocytic count, chest tightness, wheezing, dry cough, and difficulty in breathing. Later findings confirmed that SARS-CoV-2 infected her from a patient in the same room who was already affected. Another patient who was 73 years old and had a medical history of hypertension from 20 years who underwent surgery for adenocarcinoma was discharged on the 6th-day post-operation. On postoperative day 9, the patient exhibited chest tightness, muscle pain, dry cough, and decreased lymphocytic count. His CT-scan findings revealed for viral pneumonia, and he was also tested positive for the 20,189-nC0V test. He was admitted to the infectious disease ward. After, 20 days he was discharged as he recovered. Histopathological findings showed focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, edema, multinucleated giant cells, protruding hyaline membranes, and proteinaceous exudates [106] (represented in Table 1).\nThe patients, who are recovered from COVID-19, have a possibility of chronic lung damage. Out of 70 COVID-19 pneumonia patients, 66 patients have lung damage in a different manner, which was determined by CT. This damage is in a diverse range; in the alveoli, there is a hardened tissue with the dense clumps which block the vessels in the tiny air sacs, which absorb the oxygen and cause tissue lesions. This tissue lesion acts as a sign of the long-term lung disease. Similar reports have been found in both the SARS CoV and MERS. The patients admitted with lung pneumonia shows damage in both the lungs. The CT scan of the COVID-19 patients indicates that there is a tissue lesion found over the alveoli and which can develop into the scars. There are \u003e2.9 million people have COVID-19 disease worldwide, according to April 27. 80% of the patients are having a high risk of problems, such as from breathing to respiratory failure [107].\n\n6.7 SARS-CoV-2-CNS risk\nMathew reported that it might be due to the obstructions in the nervous system, which may restrict the entry of air into the lungs [108]. The virus enters the medullary neurons during the latency phase. A possible mechanism explained was that the SARS-CoV-2 might enter the olfactory lobe of the brain through nasal chambers upon inhalation and may lead to inflammation and demyelination. Later, it spreads to the whole brain due to its ability to cross the blood-brain barrier. Some neurological symptoms exhibited by the COVID-19 infection patients include nausea, vomiting, and headache (represented in Table 1). Since the SARS-CoV-2 possess the ability to cross the blood-brain barrier, it is important to design the drugs in such a way that they can cross the blood-brain barrier and scavenges the brain from viral infection. Also, it is essential to note that the respiratory illness accompanies neurological invasion by the virus, therapeutic care must be taken to prevent the viral entry into the central nervous system (CNS) [7].\n\n6.8 SARS-CoV-2 – immunopathology\nSARS-CoV-2 infection mediates immune response, both innate and adaptive. The enhanced level of the innate response and decreased level of adaptive causes tissue damage. Upon viral infection, there is an immune response. T cells, especially the cluster of differentiation 4 (CD4+) and a group of differentiation 8 (CD8+), have an anti-viral role. CD8+ T cells are highly cytotoxic, and they killed infected cells. This T cell induces the pro-inflammatory cytokines through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling. This process further activates the cytokines and chemokines [7]. Similar to SARS-CoV, MERS, SARS-CoV-2 infection in the immune effector cells are also having the enhanced level of the cytokines such as IFN-γ, IFN-α, IL-6, IL-1β, IL-18, IL-12, TGFβ, IL-33 and TNF-α and chemokines such as CCL2, CCL5, CCL3, CXCL10, CXCL9, and CXCL8. Similar to this, severe MERS-CoV infected patient's serum shows an increased level of the cytokines and chemokines. This cytokine storm further causes multiple organ failures to further leads to the death of the SARS-CoV-2 patient [109].\nOn the other hand, the T-cells are having four types of it, such as Th1, Th2, Th17 (inflammatory), and anti-inflammatory Tregs. These Th2 cells generate IL-4 cells. The compound which can block the Th1 (Boost immune system) tends to augments the level of the Th2 (anti-inflammatory response). IL-4 triggers the Th2 cells and obstructs the Th1 response. This Th2 helps to repair form tissue dysfunction and another type of malfunction. It is found to be good that the increased level of the Th1 and Th17 plays an important role in hyperactive immune response and during autoimmune conditions. It is showed that there is an induction of the Th1/Th17 and the production of antibodies upon COVID-19 condition [110]. Contradict to this; the patient has a high level of Th2 in need of intensive care [111]. During the MERS condition, there is a reduced level of both the Th1 and Th2, which further enhances the inflammatory cytokines and causes more infection and death [112]. SARS patients who died with an older age have higher cytokines of Th2, such as IL-4, IL-10, and IL-5 [113]. This incidence supports the increased Th2 level of COVID-19 patients who needs intensive care. The mechanism behind this is based on the molecular weight of the protein of SARS-CoV2; the activity of the immune system is changed. The recent research by the F. Javier Martín Oncina in 2020 showed that based on the antigen molecular weight, the host's immune response is varied. The proteins of the SARS-CoV2 are spike protein with 140 kDa, Envelope protein with 10 kDa, Membrane protein with 25 kDa, and nucleocapsid protein with 50 kDa. The protein with more than \u003e70 kDa, such as spike protein, cannot be arrested by the B-cell, thereby it activates the inflammatory response through the Th1 response with the macrophages. This process occurs in the subcapsular sinus and through dendritic cells phagocytosis. The other proteins with \u003c70 kDa are found in the protein of SARS-CoV2, which activates the receptor of B-cell and stimulates Th2 immune response. The unremittingviral particle overload, which is unrestricted by the viral cell lysing, will be terminated by the Th1 (pro-inflammatory response). Further, it increases the protein level with a weight of \u003c70 kDa stimulates the B cells in large amounts. This induction of the B-cells leads to the condition called as Activated Induced Cell Death (AICD), which speediness the apoptosis and release of pro-inflammatory cytokines cause lymphopenia, thereby it produces IL-10, augments the shift of Th2 form Th1 response which causes further suppression of immune system, COVID-19 sepsis [114]. Correlative to that that COVID-19 patients with the high level of Th2 immune response need intensive care [111], which shows that they might be having apoptosis, lymphopenia, and suppression of immune system further causes COVID-19 sepsis [114]. Though the cell death is via Th2 immune response but the level of IL-4 is not elucidated yet. The role of IL-4 and its mechanism behind COVID-19 remain elusive (Represented in Fig. 2 ).\nFig. 2 SARS-CoV-2 enters into the host cell via binding with the cellular receptor ACE-2. It undergoes the fusion with the joining of the plasma membrane and the virus. Then it undergoes the process of the proteolytic cleavage; further, it will undergo replication and lead to the formation of the proteins. This process activates the signaling pathway, such as the NF-kB pathway, via TRIF. The interaction between the cells and the virus activates many cytokine storms. On the other hand, once the virus enters into the cell, the antigen present in that would undergo the antigen presentation cells (APC); further, this stimulates the humoral and cellular immunity. COVID-19 infects the macrophage cells, which presents to the T cell, further, which leads to the activation, differentiation of T-cells, along with the production of cytokines. This shows the negative action on the activation of CD8 T cells. Thus the mediator produced by the CD8+ T cells clears the infection of SARS-CoV. Upon COVID-19 infection, there is a reduced CD4+ and CD8+ cell level, further increasing the cytokine level in the cells, which triggers the inflammation. This mediates the production of the cytokine storm via secreting chemokine and cytokines such as IL-1β, IL-6, TNF-α, IL-8, IL-21, CCL2, CCL3, CCL5, CXCL10, TNF-β, and MCP-1 and triggers the tissue injury. On the other hand, based on the weight of the protein of SARS-CoV2, there is an activation of Th1/Th17 (boosts immune system) when the spike protein is \u003e70 kDa. In case of the Th2 (anti-inflammatory) is activated by the majority of the protein with \u003c70 kDa, then the activation of the B-cell receptor, which causes activation-induced cell death such as apoptosis and lymphopenia which is by releasing IL-10, shifting of Th1 to Th2 immune response, suppression of the immune system and further leads to the COVID-19 sepsis. The role of IL-4 has not been elucidated yet. It remains unanswerable upon COVID-19 condition with the mechanism of Th2 and Th1/Th17.\nThe wet lung is also known as acute respiratory distress syndrome (ARDS). The patient with COVID-19 has lung edema, and it needs more attention clinically. Lung edema is found to be a symptom of acute lung injury, which development to hypoxemia condition and which leads to acute respiratory distress syndrome (ARDS). The patients who are found with ARDS have more mortality. Though there is no proper treatment or vaccine treatment, ventilation with the therapy of oxygen and ventilation mechanically is mandatory. Sometimes, the treatment with the glucocorticoids (systemic or locally) would help attenuate lung edema and pulmonary inflammation [115]. But there is a need for more research to correlate the cytokine storm with wet lung pneumonia in COVID-19 patients.\n\n6.9 SARS-CoV-2 – ocular risk\nThe ACE2 receptors are also widely distributed in the superficial parts such as conjunctiva and cornea inferior parts such as iris, ciliary body, aqueous humor, trabecular meshwork, retina, and non-pigmented ciliary epithelium of the ocular globe which is mentioned out to be the intraocular renin-angiotensin system. Therefore, the distribution of ACE2 and TMPRSS2 protein must be taken into consideration to study the passage of infection through the ocular route [116]. Also, there is a chance for the virus to enter into the nasal cavity, which causes respiratory illness and the digestive system through the lacrimal canaliculi aided by the effectiveness of the tear film [117,118]. Out of 38 COVID-19 positive patients, 12 exhibited clinical manifestations, which include chemosis, epiphora, increased secretions, conjunctivitis, and conjunctival hyperemia. Researchers reported that patients exhibiting ocular symptoms would have elevated neutrophilic and lymphocytic counts, elated procalcitonin, lactate dehydrogenase, and C-reactive protein levels than those without ocular manifestations. The patients with ocular manifestations exhibited severe illness [119].\nEven though there is no such evidence, the presence of ACE2 and TMPRSS2 protein in the corneal limbal stem cells suggests that the SARS-CoV-2 may enter the bloodstream and travel to the other parts including the brain [120]. Even though there is no viral load in the conjunctiva of the SARS-CoV-2 infected patients without conjunctivitis, the risk of transmission of the virus through tears is low [121]. The exact mechanism behind the ocular risk and SARS-CoV-2 need to be elucidated further.\n\n6.10 SARS-CoV-2 – cancer risk\nCancer patients are highly vulnerable to SARS-CoV-2 infection. 18 out of 1590 COVID-19 positive cases exhibited cancer history. 5 out of 18 patients suffered from lung cancer, 4 out of 18 patients had no past information on medication and had undergone surgery or chemotherapy in the previous month, and the remaining 12 were cancer survivors. The COVID-19 was highly severe in cancer patients than non-cancer COVID-19 affected patients. Also, COVID-19 patients with cancer exhibited a severe chain of symptoms than those without a history of cancer. Also, patients with lung cancer did not exhibit severe symptoms when compared to those with other types of cancers [122].\nIn a retrospective study conducted among 1276 patients, 28 patients who have cancer were selected for the study. The mean age group people belonged to the elderly category, and 60.7% of them were males. Lung cancer was the most frequent type, followed by oesophageal and breast cancers among cancer affected patients. 10 out of 28 patients were presented with IV stage cancer. 28.6% of the patients developed COVID-19 while receiving antitumor therapy, whereas 71.4% of them developed due to the presence of infection in their vicinity. Besides, 39.2% of the patients exhibited chronic co-morbid conditions apart from cancer. 28.6% of patients died, and the remaining patients developed serious consequences even after receiving anti-viral and corticosteroids. The most common complication developed by the patients includes septic shock, acute myocardial infarction, and ARDS [123]. Therefore, more focus should be laid on the research for medication and treatment options for COVID-19 affected cancer patients. More studies are required to determine the exact mechanism behind cancer and SARS-CoV-2.\n\n6.11 SARS-CoV-2 – tuberculosis\nA study was conducted in February 2020, Shenyang, China, which involved 36 COVID-19 positive patients and was classified based on the severity of the symptoms as mild and critical. The results of these patients were compared with that of the patients affected by pneumonia caused by Mycobacterium tuberculosis from Shenyang chest hospital. The study was conducted to determine which one caused severe pneumonia, either the viral or the bacterial strain. Then the severity of tuberculosis was compared between the mild and severe COVID-19 cases and confirmed that tuberculosis due to mycobacterial strain affected patients are more susceptible to COVID-19 and enhance the severity of COVID-19 [124]. Patients with HIV undergoing treatment with antiretroviral medicines exhibit weak immune systems and are more susceptible to viral infections. Also, until now, only one HIV case had been reported with COVID-19 infection from china. The patient recovered from the infection the same as that of those without HIV. There is no evidence on whether HIV patients are more susceptible to COVID-19 infection [125].\nThe COVID-19 associated TB is found in 94th day of the nonexistence of public health interventions and 138th day in the occurrence of interventions. This occurs at the peak of an outbreak where the implementation of the intervention, out of it 11,066, is with the presence of interventions. 27,968 COVID-19 cases found in the absence of interventions, out of it 14,823, are with no interventions. This scenario shows that there is a need to take preventive measures of TB associated with COVID-19 patients. They need a prior diagnosis and proper management [126]. The main reasons for mortality are age, sex, and other co-morbid factors such as diabetes, cardiovascular diseases, and renal diseases are the main reasons for mortality.\n\n6.12 SARS-CoV-2 – Venous thromboembolism\nPeople affected with pneumonia are more prone to venous thromboembolism. Out of 1026 COVID-19 patients, 40% of them exhibited high risk, and 11% of them at high risk of developing venous thromboembolism without any prophylaxis. Prophylactic measures can prevent venous thromboembolism. Only 7 out of 140 patients at high risk for venous thromboembolism had recorded about the anticoagulation treatment. And 44 out of 407 exhibited a higher risk for bleeding. In these patients, the mechanical compressions such as intermittent pneumatic compression and elastic compression stockings are instructed, and the duration and dosage of anticoagulants should be adjusted. Also, the COVID-19 patients, along with other co-morbid conditions such as cardiovascular manifestations, respiratory failure, renal and hepatic problems, can affect the bleeding status and venous thromboembolism. Therefore, further investigations are required to reduce the risk due to venous thromboembolism and bleeding in the case of COVID-19 patients [127].\n\n6.13 SARS-CoV-2- reproductive risk\nViral infections during the first 20 weeks of gestation have shown to be more severe. The infections, such as SARS and MERS, which occurred due to coronaviruses, had reported an increased risk for pregnancy-related mortality and morbidity. Such cases among COVID-19 affected patients are not yet reported. Nine women who are in their third semester and infected with COVID-19 were reported to have outcomes as that of non-pregnant COVID-19 affected adults. In another study, out of 33 newborn infants, three infants were shown to be tested positive for COVID-19 who got the disease transferred from their mother through intrauterine vertical transmission mode [128].\n\n6.14 SARS-CoV-2 – mental illness\nAccording to a report, out of a group of 50 COVID-19 cases from a psychiatric hospital in Wuhan, China has uplifted the worry about the role of mental disorder in coronavirus transmission. The conditions include incomplete or no awareness of the risk, inability to have personal protection, and cognitive impairment. The treatment has become more challenging for people with COVID-19 infection and health disorders as co-morbid conditions [129].\n\n6.15 SARS-CoV-2 – aging and cardiovascular risk\nIt has been reported that the expression of ACE2 reduces with the increasing age. Since young patients possess high levels of ACE2, they are more prone to COVID-19 infection. Whereas, in old age people other than reduced ACE2 levels, other co-morbid conditions such as cardiovascular problems, diabetes, and hypertension might be present. The medication prescribed for these patients helps in elevating the ACE2 levels, which might enhance the viral entry. Though the treatment reduces the co-morbid severities, the viral infection is enhanced in those patients. Therefore, it is conclusive that young patients, even though they are more susceptible to the COVID-19 infection, they are less severely affected and exhibit elevated angiotensin II signaling. Whereas, the older patients who exhibit low levels of ACE2 and higher angiotensin II signaling leads to hypertension. The usage of ACEi and ARBs help in promoting the vasodilatory effects by elevating the ACE2 levels, thereby becoming susceptible to COVID-19 infection and are severely affected [130]."}

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SARS-CoV-2\n\n6.1 SARS-CoV-2 – heart disease\nACE2 plays a vital role in the cardiovascular system and is mainly involved in the functioning of the heart and development of hypertension and type II diabetes. Since ACE2 is the main target for the SARS-CoV-2 to enter inside the host cell and the ACE2 is also highly expressed in the heart apart from the lungs, indicating a chance of developing cardiac issues during SARS-CoV-2 infection. The anti-hypertensive therapy that has been prescribed for the patients is the usage of ACEi and ARBs should be carefully considered. The COVID-19 patients with comorbidities hypertension, taking the drug of ACEi or blocker of angiotensin receptor, need to switch off to other anti-hypertensive medications found to be controversial and require further studies this co-morbid conditions. The severity of the viral infection is higher in patients with comorbidities than those infected only by the virus without any predisposed health issue [85].\nThe interaction of the SARS-CoV-2 with ACE2 triggers a signal, which might be the reason to develop heart injury through the immune response triggered by T-helper cells creating a cytokine response. The SARS-CoV-2 has a structural similarity with that of SARS-CoV. SARS-CoV caused severe cardiovascular damage during its pandemic period. Therefore, it is essential to investigate SARS-CoV-2 treatment options and ensure a cardio-protective effect. The age and the predisposition of the acute coronary syndrome are the two critical factors which need to be considered in patients affected with COVID-19 [85].\nSince the ACE2 is highly expressed in pericytes, the patients infected with SARS-CoV-2 and predisposed with cardiac failure are more susceptible to develop severe cardiac problems [86]. The usage of mineralocorticoids receptor blocker can attenuates oxidative stress, reduces the level of ACE with the augmented production of the angiotensin 1–7 and attenuates the angiotensin II generation and increases the activity of ACE2 The antagonist of angiotensin II type 1 receptor, have modulates the profilin-1 expression and ACE2 [87]. The selective of the angiotensin II activity or synthesis mediated the augmented level of ACE2 expression and its activity in cardiac. Still, the combination of the lisinopril and losartan increases the activity of ACE2 but not ACE2 mRNA. The inhibition of ACE results in reduced formation of angiotensin II and metabolism of angiotensin 1–7, the angiotensin II type 1 receptor antagonist increases the metabolism of angiotensin II via ACE2 [88]. SARS-CoV 2 enters into the cell via the ACE2 receptor; this causes the decreased level of the ACE2 due to the binding of the spike protein to the ACE2 and no changes in ACE. This process causes the virus's entry, replicates it, and causes tissue injury via decreasing anti-atrophy, anti0-fibrosis, anti-inflammation, anti-oxidant, and vasodilation. On the other hand, the angiotensin II type 1 receptor causes pro-atrophy, pro-fibrosis, pro-inflammation, pro-oxidant, severe myocardial remodeling, vasoconstriction and vascular permeability which leads to tissue injury [89] (represented in Table 1).\nTherefore, the use of ACEi, ARBs, and mineralocorticoids has shown to have an impact on the cardiac patients affected by COVID-19, but the exact mechanism behind it is not clear. Aliskiren, a direct inhibitor of renin, resulted in reduced expression of ACE2 besides reducing the blood pressure that has been elucidated in diabetic nephropathy animal models [90]. Therefore, renin blockers, especially aliskiren, need to be further investigated as a treatment option for COVID-19 patients with comorbidities [91].\n\n6.2 SARS-CoV-2 – gastrointestinal risk\nThe ACE2 is also highly expressed in the small intestine and large intestine of the gastrointestinal tract. The S protein present on the envelope of the SARS-CoV-2 ensures higher binding affinity, thereby mediating the entry of the virus into the host cell. The presence of SARS-CoV-2 in the gastrointestinal tract was confirmed by nucleocapsid staining of the virus. The virus was found to be visualized in the cytoplasm of epithelia of duodenum and rectum [92] (represented in Table 1). Apart from the pulmonary infection, the COVID-19 affected patients also exhibited vomiting, abdominal pain, and diarrhea, which was first reported in a 35 years old man from the United States. He was presented with nausea and diarrhea on 2nd day of the infection and was hospitalized. Stools examination revealed the presence of SARS-CoV-2 RNA, which was confirmed by using reverse transcriptase-polymerase chain reaction (RT-PCR) on day 7 of infection [93]. Out of 171 COVID-19 affected children, 6.4% of them have shown vomiting, and 8.8% of them and 3 out of ten affected children have shown diarrhea as symptoms [94]. Also, previously there were two COVID-19 young cases reported with vomiting and diarrhea.\nIn China, from 552 hospitals, 1099 cases were reported, of which 3.8% and 5% were diagnosed with diarrhea and vomiting as symptoms [95]. According to another report, out of 140 COVID-19 patients from Wuhan, 39.6% exhibited gastrointestinal symptoms apart from 5% exhibiting vomiting, 12.9% exhibiting diarrhea, and 17.3% exhibiting nausea [96]. It was reported that 17 patients had shown a negative result when tested using pulmonary samples, but when tested using rectal swabs have shown to have a positive result [96].\nSimilarly, 8 out of 10 children affected by SARS-CoV-2 had shown dual results, negative results when tested by nasopharyngeal samples, and positive results when tested using a rectal swab [97]. The percentage of patients exhibiting nausea, vomiting, and diarrhea as symptoms vary between the cohort groups, whereas, in the case of certain groups, these symptoms contributed very few percent. In contrast, in the case of the other groups, a high percentage of these gastrointestinal symptoms have been recorded.\n\n6.3 SARS-CoV-2- kidney risk\nIt is suspected that whether the patients with predisposed kidney issues or COVID-19 induced acute kidney injury is fatal to the affected patients. In an article posted on March 19 by HospiMedica International staff writers, it was mentioned that patients affected by COVID-19 developed proteinuria estimated by the elevated levels of albumin in urine were diagnosed in the initial stages of infection. The majority of the affected members, i.e., 34% out of 59 patients, developed proteinuria where the elevated albumin levels serve as a biomarker for kidney damage, and 63% of the patients exhibited proteinuria and hematuria characterized by the presence of blood in the urine. In another study conducted on 710 patients hospitalized due to COVID-19. The impairment in the functioning of the kidney was observed in 27% of the 59 patients and 66% of the corona infected patients. In a later study conducted on COVID-19 affected patients from 710 hospitals, 26.7% exhibited only hematuria, and 44% exhibited proteinuria and hematuria. The impaired kidney function was found in 15% of the study population [98].\nAccording to an article published by Wang L and his colleagues reported that out of 116 COVID-19 positive cases from Renmin Hospital of Wuhan University, out of whom 111 didn't have any kidney issues in their history and the remaining five patients had chronic kidney disease (CDK). Also, out of the 111 patients, only 10.8% of the patients exhibited a slight increase in creatine or blood urea nitrogen levels, and 7.2% of the patients had shown a minute raise in the albuminuria levels. None of the patients out of 111 didn't exhibit any acute kidney injury (AKI) after the COVID-19 infection. The remaining five patients who were already undergoing continuous renal replacement therapy (CRRT) also didn't show any fatal effects after COVID-19 infection confirmed by diagnosing the renal indicators [99]. Out of 701 patients, 2% of the patients were found to have CKD, and the average lymphocytic number was found to be reduced than the normal. High sensitivity C-reactive protein levels were significantly increased. In patients reported with high levels of serum, creatine indicated high levels of serum lactose dehydrogenase. Among hospitalized patients, patients with high levels of serum creatine were mostly old and male sex. Also, they exhibited lower platelet and lymphocytic count and elevated leukocytic count. The patients with elevated procalcitonin also exhibited elevated levels of aspartate aminotransferase and lactate dehydrogenase. Acute kidney injury was significantly higher in those patients with high serum creatine levels. AKI eventually results in mortality [100] (represented in Table 1). Therefore, advanced identification of kidney diseases in patients affected by COVID-19 may help the clinicians to reduce the mortality rate due to comorbidities such as chronic kidney disease, acute kidney injury, proteinuria, and hematuria.\n\n6.4 SARS-CoV-2 – diabetes mellitus\nPatients with diabetes mellitus exhibit high levels of ACE2, and treatment with the inhibitors of ACE and ARBs augments the expression of ACE2. Diabetes condition may lead to the suspicion that the excessive expression of ACE2 aids the entry of SARS-CoV-2 into the host cells resulting in COVID-19. Since diabetes mellitus and hypertension conditions are treated, ACE2 increasing drugs are having a severe risk of COVID-19 [10].\nSimultaneously, the elevated expression of ACE2 ensures the entry of the SARS-CoV-2, attaching to the ACE2 enzyme with the help of S protein present on its envelope's surface. There forth, it became controversial whether COVID-19 affected patients who are predisposed with diabetes mellitus should be resumed with their treatment with ACEi and ARBs or not. Also, if the medication is abruptly ceased, there are chances that the patient may die due to hypertension instead of COVID-19. For this reason, it has been suggested that there is no need to stop the medication of a diabetic patient even though if he is affected by COVID-19 because there is no scientific evidence available conducted on human subjects regarding whether to use ACEi and ARBs [10].\n\n6.5 SARS-CoV-2-liver injury\nThe SARS-CoV-2 infection has shown to increase the levels of ALT, AST, and bilirubin levels, indicating injury to the hepatic tissue [9,95,101,102]. Apart from these liver serum enzymes indicating hepatic damage, the levels of albumin were significantly decreased, indicating the severity of the infection [101]. The elated levels of gamma-glutamyl transferase (GGT) were observed only in patients with severe cases. In contrast, thealkaline phosphatize (AKP) levels remained unchanged irrespective of the severity of the infection [37] (represented in Table 1).\nSARS-CoV and SARS-CoV-2 share the similarity in making an entry into the host cell through the ACE2 receptor. In addition to the type 2 cells in the lungs, both the bile duct cells and hepatocytes also express ACE2, which might be the reason that liver injury occurs during SARS-CoV-2 infection [103]. The bile duct epithelial cells are involved in immune responses and the regeneration of the hepatocytes [104]. Besides possessing a high number of ACE2 on its surface, bile duct cells are more prone to the SARS-CoV-2 infection resulting in liver injury, which indicates that the hepatocytes are not directly involved in the hepatic injury [37]. The histopathological manifestations of SARS-CoV-2 infected patients revealed mild lobular and portal activity and restrained microvascular steatosis [105]. The degree of liver damage is directly proportional to the severity of the SARS-CoV-2 infection. Still, the reason for the liver injury remains elusive. A recent study reported that the use of anti-viral medication lopinavir might result in hepatic damage [102]. Therefore, whether the liver injury is due to the virus entry or due to the drugs used as anti-viral medication needs to be elucidated.\n\n6.6 SARS-CoV-2-lung injury\nIt was possible to study the lung pathology of COVID-19 patients diagnosed with COVID-19 retrospectively after undergoing lung lobectomy surgery for adenocarcinoma. Also, the patients didn't present pneumonia at the time of surgery, indicating the initial stages of COVID-19. A female patient who was 80 years old was hospitalized due to an irregularly shaped solid nodule in the right middle lobe. On a postoperative day 1, a CT scan was performed, which indicated a few clinical manifestations. Later, the patient was presented with increased leucocytes, decreased lymphocytic count, chest tightness, wheezing, dry cough, and difficulty in breathing. Later findings confirmed that SARS-CoV-2 infected her from a patient in the same room who was already affected. Another patient who was 73 years old and had a medical history of hypertension from 20 years who underwent surgery for adenocarcinoma was discharged on the 6th-day post-operation. On postoperative day 9, the patient exhibited chest tightness, muscle pain, dry cough, and decreased lymphocytic count. His CT-scan findings revealed for viral pneumonia, and he was also tested positive for the 20,189-nC0V test. He was admitted to the infectious disease ward. After, 20 days he was discharged as he recovered. Histopathological findings showed focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, edema, multinucleated giant cells, protruding hyaline membranes, and proteinaceous exudates [106] (represented in Table 1).\nThe patients, who are recovered from COVID-19, have a possibility of chronic lung damage. Out of 70 COVID-19 pneumonia patients, 66 patients have lung damage in a different manner, which was determined by CT. This damage is in a diverse range; in the alveoli, there is a hardened tissue with the dense clumps which block the vessels in the tiny air sacs, which absorb the oxygen and cause tissue lesions. This tissue lesion acts as a sign of the long-term lung disease. Similar reports have been found in both the SARS CoV and MERS. The patients admitted with lung pneumonia shows damage in both the lungs. The CT scan of the COVID-19 patients indicates that there is a tissue lesion found over the alveoli and which can develop into the scars. There are \u003e2.9 million people have COVID-19 disease worldwide, according to April 27. 80% of the patients are having a high risk of problems, such as from breathing to respiratory failure [107].\n\n6.7 SARS-CoV-2-CNS risk\nMathew reported that it might be due to the obstructions in the nervous system, which may restrict the entry of air into the lungs [108]. The virus enters the medullary neurons during the latency phase. A possible mechanism explained was that the SARS-CoV-2 might enter the olfactory lobe of the brain through nasal chambers upon inhalation and may lead to inflammation and demyelination. Later, it spreads to the whole brain due to its ability to cross the blood-brain barrier. Some neurological symptoms exhibited by the COVID-19 infection patients include nausea, vomiting, and headache (represented in Table 1). Since the SARS-CoV-2 possess the ability to cross the blood-brain barrier, it is important to design the drugs in such a way that they can cross the blood-brain barrier and scavenges the brain from viral infection. Also, it is essential to note that the respiratory illness accompanies neurological invasion by the virus, therapeutic care must be taken to prevent the viral entry into the central nervous system (CNS) [7].\n\n6.8 SARS-CoV-2 – immunopathology\nSARS-CoV-2 infection mediates immune response, both innate and adaptive. The enhanced level of the innate response and decreased level of adaptive causes tissue damage. Upon viral infection, there is an immune response. T cells, especially the cluster of differentiation 4 (CD4+) and a group of differentiation 8 (CD8+), have an anti-viral role. CD8+ T cells are highly cytotoxic, and they killed infected cells. This T cell induces the pro-inflammatory cytokines through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling. This process further activates the cytokines and chemokines [7]. Similar to SARS-CoV, MERS, SARS-CoV-2 infection in the immune effector cells are also having the enhanced level of the cytokines such as IFN-γ, IFN-α, IL-6, IL-1β, IL-18, IL-12, TGFβ, IL-33 and TNF-α and chemokines such as CCL2, CCL5, CCL3, CXCL10, CXCL9, and CXCL8. Similar to this, severe MERS-CoV infected patient's serum shows an increased level of the cytokines and chemokines. This cytokine storm further causes multiple organ failures to further leads to the death of the SARS-CoV-2 patient [109].\nOn the other hand, the T-cells are having four types of it, such as Th1, Th2, Th17 (inflammatory), and anti-inflammatory Tregs. These Th2 cells generate IL-4 cells. The compound which can block the Th1 (Boost immune system) tends to augments the level of the Th2 (anti-inflammatory response). IL-4 triggers the Th2 cells and obstructs the Th1 response. This Th2 helps to repair form tissue dysfunction and another type of malfunction. It is found to be good that the increased level of the Th1 and Th17 plays an important role in hyperactive immune response and during autoimmune conditions. It is showed that there is an induction of the Th1/Th17 and the production of antibodies upon COVID-19 condition [110]. Contradict to this; the patient has a high level of Th2 in need of intensive care [111]. During the MERS condition, there is a reduced level of both the Th1 and Th2, which further enhances the inflammatory cytokines and causes more infection and death [112]. SARS patients who died with an older age have higher cytokines of Th2, such as IL-4, IL-10, and IL-5 [113]. This incidence supports the increased Th2 level of COVID-19 patients who needs intensive care. The mechanism behind this is based on the molecular weight of the protein of SARS-CoV2; the activity of the immune system is changed. The recent research by the F. Javier Martín Oncina in 2020 showed that based on the antigen molecular weight, the host's immune response is varied. The proteins of the SARS-CoV2 are spike protein with 140 kDa, Envelope protein with 10 kDa, Membrane protein with 25 kDa, and nucleocapsid protein with 50 kDa. The protein with more than \u003e70 kDa, such as spike protein, cannot be arrested by the B-cell, thereby it activates the inflammatory response through the Th1 response with the macrophages. This process occurs in the subcapsular sinus and through dendritic cells phagocytosis. The other proteins with \u003c70 kDa are found in the protein of SARS-CoV2, which activates the receptor of B-cell and stimulates Th2 immune response. The unremittingviral particle overload, which is unrestricted by the viral cell lysing, will be terminated by the Th1 (pro-inflammatory response). Further, it increases the protein level with a weight of \u003c70 kDa stimulates the B cells in large amounts. This induction of the B-cells leads to the condition called as Activated Induced Cell Death (AICD), which speediness the apoptosis and release of pro-inflammatory cytokines cause lymphopenia, thereby it produces IL-10, augments the shift of Th2 form Th1 response which causes further suppression of immune system, COVID-19 sepsis [114]. Correlative to that that COVID-19 patients with the high level of Th2 immune response need intensive care [111], which shows that they might be having apoptosis, lymphopenia, and suppression of immune system further causes COVID-19 sepsis [114]. Though the cell death is via Th2 immune response but the level of IL-4 is not elucidated yet. The role of IL-4 and its mechanism behind COVID-19 remain elusive (Represented in Fig. 2 ).\nFig. 2 SARS-CoV-2 enters into the host cell via binding with the cellular receptor ACE-2. It undergoes the fusion with the joining of the plasma membrane and the virus. Then it undergoes the process of the proteolytic cleavage; further, it will undergo replication and lead to the formation of the proteins. This process activates the signaling pathway, such as the NF-kB pathway, via TRIF. The interaction between the cells and the virus activates many cytokine storms. On the other hand, once the virus enters into the cell, the antigen present in that would undergo the antigen presentation cells (APC); further, this stimulates the humoral and cellular immunity. COVID-19 infects the macrophage cells, which presents to the T cell, further, which leads to the activation, differentiation of T-cells, along with the production of cytokines. This shows the negative action on the activation of CD8 T cells. Thus the mediator produced by the CD8+ T cells clears the infection of SARS-CoV. Upon COVID-19 infection, there is a reduced CD4+ and CD8+ cell level, further increasing the cytokine level in the cells, which triggers the inflammation. This mediates the production of the cytokine storm via secreting chemokine and cytokines such as IL-1β, IL-6, TNF-α, IL-8, IL-21, CCL2, CCL3, CCL5, CXCL10, TNF-β, and MCP-1 and triggers the tissue injury. On the other hand, based on the weight of the protein of SARS-CoV2, there is an activation of Th1/Th17 (boosts immune system) when the spike protein is \u003e70 kDa. In case of the Th2 (anti-inflammatory) is activated by the majority of the protein with \u003c70 kDa, then the activation of the B-cell receptor, which causes activation-induced cell death such as apoptosis and lymphopenia which is by releasing IL-10, shifting of Th1 to Th2 immune response, suppression of the immune system and further leads to the COVID-19 sepsis. The role of IL-4 has not been elucidated yet. It remains unanswerable upon COVID-19 condition with the mechanism of Th2 and Th1/Th17.\nThe wet lung is also known as acute respiratory distress syndrome (ARDS). The patient with COVID-19 has lung edema, and it needs more attention clinically. Lung edema is found to be a symptom of acute lung injury, which development to hypoxemia condition and which leads to acute respiratory distress syndrome (ARDS). The patients who are found with ARDS have more mortality. Though there is no proper treatment or vaccine treatment, ventilation with the therapy of oxygen and ventilation mechanically is mandatory. Sometimes, the treatment with the glucocorticoids (systemic or locally) would help attenuate lung edema and pulmonary inflammation [115]. But there is a need for more research to correlate the cytokine storm with wet lung pneumonia in COVID-19 patients.\n\n6.9 SARS-CoV-2 – ocular risk\nThe ACE2 receptors are also widely distributed in the superficial parts such as conjunctiva and cornea inferior parts such as iris, ciliary body, aqueous humor, trabecular meshwork, retina, and non-pigmented ciliary epithelium of the ocular globe which is mentioned out to be the intraocular renin-angiotensin system. Therefore, the distribution of ACE2 and TMPRSS2 protein must be taken into consideration to study the passage of infection through the ocular route [116]. Also, there is a chance for the virus to enter into the nasal cavity, which causes respiratory illness and the digestive system through the lacrimal canaliculi aided by the effectiveness of the tear film [117,118]. Out of 38 COVID-19 positive patients, 12 exhibited clinical manifestations, which include chemosis, epiphora, increased secretions, conjunctivitis, and conjunctival hyperemia. Researchers reported that patients exhibiting ocular symptoms would have elevated neutrophilic and lymphocytic counts, elated procalcitonin, lactate dehydrogenase, and C-reactive protein levels than those without ocular manifestations. The patients with ocular manifestations exhibited severe illness [119].\nEven though there is no such evidence, the presence of ACE2 and TMPRSS2 protein in the corneal limbal stem cells suggests that the SARS-CoV-2 may enter the bloodstream and travel to the other parts including the brain [120]. Even though there is no viral load in the conjunctiva of the SARS-CoV-2 infected patients without conjunctivitis, the risk of transmission of the virus through tears is low [121]. The exact mechanism behind the ocular risk and SARS-CoV-2 need to be elucidated further.\n\n6.10 SARS-CoV-2 – cancer risk\nCancer patients are highly vulnerable to SARS-CoV-2 infection. 18 out of 1590 COVID-19 positive cases exhibited cancer history. 5 out of 18 patients suffered from lung cancer, 4 out of 18 patients had no past information on medication and had undergone surgery or chemotherapy in the previous month, and the remaining 12 were cancer survivors. The COVID-19 was highly severe in cancer patients than non-cancer COVID-19 affected patients. Also, COVID-19 patients with cancer exhibited a severe chain of symptoms than those without a history of cancer. Also, patients with lung cancer did not exhibit severe symptoms when compared to those with other types of cancers [122].\nIn a retrospective study conducted among 1276 patients, 28 patients who have cancer were selected for the study. The mean age group people belonged to the elderly category, and 60.7% of them were males. Lung cancer was the most frequent type, followed by oesophageal and breast cancers among cancer affected patients. 10 out of 28 patients were presented with IV stage cancer. 28.6% of the patients developed COVID-19 while receiving antitumor therapy, whereas 71.4% of them developed due to the presence of infection in their vicinity. Besides, 39.2% of the patients exhibited chronic co-morbid conditions apart from cancer. 28.6% of patients died, and the remaining patients developed serious consequences even after receiving anti-viral and corticosteroids. The most common complication developed by the patients includes septic shock, acute myocardial infarction, and ARDS [123]. Therefore, more focus should be laid on the research for medication and treatment options for COVID-19 affected cancer patients. More studies are required to determine the exact mechanism behind cancer and SARS-CoV-2.\n\n6.11 SARS-CoV-2 – tuberculosis\nA study was conducted in February 2020, Shenyang, China, which involved 36 COVID-19 positive patients and was classified based on the severity of the symptoms as mild and critical. The results of these patients were compared with that of the patients affected by pneumonia caused by Mycobacterium tuberculosis from Shenyang chest hospital. The study was conducted to determine which one caused severe pneumonia, either the viral or the bacterial strain. Then the severity of tuberculosis was compared between the mild and severe COVID-19 cases and confirmed that tuberculosis due to mycobacterial strain affected patients are more susceptible to COVID-19 and enhance the severity of COVID-19 [124]. Patients with HIV undergoing treatment with antiretroviral medicines exhibit weak immune systems and are more susceptible to viral infections. Also, until now, only one HIV case had been reported with COVID-19 infection from china. The patient recovered from the infection the same as that of those without HIV. There is no evidence on whether HIV patients are more susceptible to COVID-19 infection [125].\nThe COVID-19 associated TB is found in 94th day of the nonexistence of public health interventions and 138th day in the occurrence of interventions. This occurs at the peak of an outbreak where the implementation of the intervention, out of it 11,066, is with the presence of interventions. 27,968 COVID-19 cases found in the absence of interventions, out of it 14,823, are with no interventions. This scenario shows that there is a need to take preventive measures of TB associated with COVID-19 patients. They need a prior diagnosis and proper management [126]. The main reasons for mortality are age, sex, and other co-morbid factors such as diabetes, cardiovascular diseases, and renal diseases are the main reasons for mortality.\n\n6.12 SARS-CoV-2 – Venous thromboembolism\nPeople affected with pneumonia are more prone to venous thromboembolism. Out of 1026 COVID-19 patients, 40% of them exhibited high risk, and 11% of them at high risk of developing venous thromboembolism without any prophylaxis. Prophylactic measures can prevent venous thromboembolism. Only 7 out of 140 patients at high risk for venous thromboembolism had recorded about the anticoagulation treatment. And 44 out of 407 exhibited a higher risk for bleeding. In these patients, the mechanical compressions such as intermittent pneumatic compression and elastic compression stockings are instructed, and the duration and dosage of anticoagulants should be adjusted. Also, the COVID-19 patients, along with other co-morbid conditions such as cardiovascular manifestations, respiratory failure, renal and hepatic problems, can affect the bleeding status and venous thromboembolism. Therefore, further investigations are required to reduce the risk due to venous thromboembolism and bleeding in the case of COVID-19 patients [127].\n\n6.13 SARS-CoV-2- reproductive risk\nViral infections during the first 20 weeks of gestation have shown to be more severe. The infections, such as SARS and MERS, which occurred due to coronaviruses, had reported an increased risk for pregnancy-related mortality and morbidity. Such cases among COVID-19 affected patients are not yet reported. Nine women who are in their third semester and infected with COVID-19 were reported to have outcomes as that of non-pregnant COVID-19 affected adults. In another study, out of 33 newborn infants, three infants were shown to be tested positive for COVID-19 who got the disease transferred from their mother through intrauterine vertical transmission mode [128].\n\n6.14 SARS-CoV-2 – mental illness\nAccording to a report, out of a group of 50 COVID-19 cases from a psychiatric hospital in Wuhan, China has uplifted the worry about the role of mental disorder in coronavirus transmission. The conditions include incomplete or no awareness of the risk, inability to have personal protection, and cognitive impairment. The treatment has become more challenging for people with COVID-19 infection and health disorders as co-morbid conditions [129].\n\n6.15 SARS-CoV-2 – aging and cardiovascular risk\nIt has been reported that the expression of ACE2 reduces with the increasing age. Since young patients possess high levels of ACE2, they are more prone to COVID-19 infection. Whereas, in old age people other than reduced ACE2 levels, other co-morbid conditions such as cardiovascular problems, diabetes, and hypertension might be present. The medication prescribed for these patients helps in elevating the ACE2 levels, which might enhance the viral entry. Though the treatment reduces the co-morbid severities, the viral infection is enhanced in those patients. Therefore, it is conclusive that young patients, even though they are more susceptible to the COVID-19 infection, they are less severely affected and exhibit elevated angiotensin II signaling. Whereas, the older patients who exhibit low levels of ACE2 and higher angiotensin II signaling leads to hypertension. The usage of ACEi and ARBs help in promoting the vasodilatory effects by elevating the ACE2 levels, thereby becoming susceptible to COVID-19 infection and are severely affected [130]."}

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SARS-CoV-2\n\n6.1 SARS-CoV-2 – heart disease\nACE2 plays a vital role in the cardiovascular system and is mainly involved in the functioning of the heart and development of hypertension and type II diabetes. Since ACE2 is the main target for the SARS-CoV-2 to enter inside the host cell and the ACE2 is also highly expressed in the heart apart from the lungs, indicating a chance of developing cardiac issues during SARS-CoV-2 infection. The anti-hypertensive therapy that has been prescribed for the patients is the usage of ACEi and ARBs should be carefully considered. The COVID-19 patients with comorbidities hypertension, taking the drug of ACEi or blocker of angiotensin receptor, need to switch off to other anti-hypertensive medications found to be controversial and require further studies this co-morbid conditions. The severity of the viral infection is higher in patients with comorbidities than those infected only by the virus without any predisposed health issue [85].\nThe interaction of the SARS-CoV-2 with ACE2 triggers a signal, which might be the reason to develop heart injury through the immune response triggered by T-helper cells creating a cytokine response. The SARS-CoV-2 has a structural similarity with that of SARS-CoV. SARS-CoV caused severe cardiovascular damage during its pandemic period. Therefore, it is essential to investigate SARS-CoV-2 treatment options and ensure a cardio-protective effect. The age and the predisposition of the acute coronary syndrome are the two critical factors which need to be considered in patients affected with COVID-19 [85].\nSince the ACE2 is highly expressed in pericytes, the patients infected with SARS-CoV-2 and predisposed with cardiac failure are more susceptible to develop severe cardiac problems [86]. The usage of mineralocorticoids receptor blocker can attenuates oxidative stress, reduces the level of ACE with the augmented production of the angiotensin 1–7 and attenuates the angiotensin II generation and increases the activity of ACE2 The antagonist of angiotensin II type 1 receptor, have modulates the profilin-1 expression and ACE2 [87]. The selective of the angiotensin II activity or synthesis mediated the augmented level of ACE2 expression and its activity in cardiac. Still, the combination of the lisinopril and losartan increases the activity of ACE2 but not ACE2 mRNA. The inhibition of ACE results in reduced formation of angiotensin II and metabolism of angiotensin 1–7, the angiotensin II type 1 receptor antagonist increases the metabolism of angiotensin II via ACE2 [88]. SARS-CoV 2 enters into the cell via the ACE2 receptor; this causes the decreased level of the ACE2 due to the binding of the spike protein to the ACE2 and no changes in ACE. This process causes the virus's entry, replicates it, and causes tissue injury via decreasing anti-atrophy, anti0-fibrosis, anti-inflammation, anti-oxidant, and vasodilation. On the other hand, the angiotensin II type 1 receptor causes pro-atrophy, pro-fibrosis, pro-inflammation, pro-oxidant, severe myocardial remodeling, vasoconstriction and vascular permeability which leads to tissue injury [89] (represented in Table 1).\nTherefore, the use of ACEi, ARBs, and mineralocorticoids has shown to have an impact on the cardiac patients affected by COVID-19, but the exact mechanism behind it is not clear. Aliskiren, a direct inhibitor of renin, resulted in reduced expression of ACE2 besides reducing the blood pressure that has been elucidated in diabetic nephropathy animal models [90]. Therefore, renin blockers, especially aliskiren, need to be further investigated as a treatment option for COVID-19 patients with comorbidities [91].\n\n6.2 SARS-CoV-2 – gastrointestinal risk\nThe ACE2 is also highly expressed in the small intestine and large intestine of the gastrointestinal tract. The S protein present on the envelope of the SARS-CoV-2 ensures higher binding affinity, thereby mediating the entry of the virus into the host cell. The presence of SARS-CoV-2 in the gastrointestinal tract was confirmed by nucleocapsid staining of the virus. The virus was found to be visualized in the cytoplasm of epithelia of duodenum and rectum [92] (represented in Table 1). Apart from the pulmonary infection, the COVID-19 affected patients also exhibited vomiting, abdominal pain, and diarrhea, which was first reported in a 35 years old man from the United States. He was presented with nausea and diarrhea on 2nd day of the infection and was hospitalized. Stools examination revealed the presence of SARS-CoV-2 RNA, which was confirmed by using reverse transcriptase-polymerase chain reaction (RT-PCR) on day 7 of infection [93]. Out of 171 COVID-19 affected children, 6.4% of them have shown vomiting, and 8.8% of them and 3 out of ten affected children have shown diarrhea as symptoms [94]. Also, previously there were two COVID-19 young cases reported with vomiting and diarrhea.\nIn China, from 552 hospitals, 1099 cases were reported, of which 3.8% and 5% were diagnosed with diarrhea and vomiting as symptoms [95]. According to another report, out of 140 COVID-19 patients from Wuhan, 39.6% exhibited gastrointestinal symptoms apart from 5% exhibiting vomiting, 12.9% exhibiting diarrhea, and 17.3% exhibiting nausea [96]. It was reported that 17 patients had shown a negative result when tested using pulmonary samples, but when tested using rectal swabs have shown to have a positive result [96].\nSimilarly, 8 out of 10 children affected by SARS-CoV-2 had shown dual results, negative results when tested by nasopharyngeal samples, and positive results when tested using a rectal swab [97]. The percentage of patients exhibiting nausea, vomiting, and diarrhea as symptoms vary between the cohort groups, whereas, in the case of certain groups, these symptoms contributed very few percent. In contrast, in the case of the other groups, a high percentage of these gastrointestinal symptoms have been recorded.\n\n6.3 SARS-CoV-2- kidney risk\nIt is suspected that whether the patients with predisposed kidney issues or COVID-19 induced acute kidney injury is fatal to the affected patients. In an article posted on March 19 by HospiMedica International staff writers, it was mentioned that patients affected by COVID-19 developed proteinuria estimated by the elevated levels of albumin in urine were diagnosed in the initial stages of infection. The majority of the affected members, i.e., 34% out of 59 patients, developed proteinuria where the elevated albumin levels serve as a biomarker for kidney damage, and 63% of the patients exhibited proteinuria and hematuria characterized by the presence of blood in the urine. In another study conducted on 710 patients hospitalized due to COVID-19. The impairment in the functioning of the kidney was observed in 27% of the 59 patients and 66% of the corona infected patients. In a later study conducted on COVID-19 affected patients from 710 hospitals, 26.7% exhibited only hematuria, and 44% exhibited proteinuria and hematuria. The impaired kidney function was found in 15% of the study population [98].\nAccording to an article published by Wang L and his colleagues reported that out of 116 COVID-19 positive cases from Renmin Hospital of Wuhan University, out of whom 111 didn't have any kidney issues in their history and the remaining five patients had chronic kidney disease (CDK). Also, out of the 111 patients, only 10.8% of the patients exhibited a slight increase in creatine or blood urea nitrogen levels, and 7.2% of the patients had shown a minute raise in the albuminuria levels. None of the patients out of 111 didn't exhibit any acute kidney injury (AKI) after the COVID-19 infection. The remaining five patients who were already undergoing continuous renal replacement therapy (CRRT) also didn't show any fatal effects after COVID-19 infection confirmed by diagnosing the renal indicators [99]. Out of 701 patients, 2% of the patients were found to have CKD, and the average lymphocytic number was found to be reduced than the normal. High sensitivity C-reactive protein levels were significantly increased. In patients reported with high levels of serum, creatine indicated high levels of serum lactose dehydrogenase. Among hospitalized patients, patients with high levels of serum creatine were mostly old and male sex. Also, they exhibited lower platelet and lymphocytic count and elevated leukocytic count. The patients with elevated procalcitonin also exhibited elevated levels of aspartate aminotransferase and lactate dehydrogenase. Acute kidney injury was significantly higher in those patients with high serum creatine levels. AKI eventually results in mortality [100] (represented in Table 1). Therefore, advanced identification of kidney diseases in patients affected by COVID-19 may help the clinicians to reduce the mortality rate due to comorbidities such as chronic kidney disease, acute kidney injury, proteinuria, and hematuria.\n\n6.4 SARS-CoV-2 – diabetes mellitus\nPatients with diabetes mellitus exhibit high levels of ACE2, and treatment with the inhibitors of ACE and ARBs augments the expression of ACE2. Diabetes condition may lead to the suspicion that the excessive expression of ACE2 aids the entry of SARS-CoV-2 into the host cells resulting in COVID-19. Since diabetes mellitus and hypertension conditions are treated, ACE2 increasing drugs are having a severe risk of COVID-19 [10].\nSimultaneously, the elevated expression of ACE2 ensures the entry of the SARS-CoV-2, attaching to the ACE2 enzyme with the help of S protein present on its envelope's surface. There forth, it became controversial whether COVID-19 affected patients who are predisposed with diabetes mellitus should be resumed with their treatment with ACEi and ARBs or not. Also, if the medication is abruptly ceased, there are chances that the patient may die due to hypertension instead of COVID-19. For this reason, it has been suggested that there is no need to stop the medication of a diabetic patient even though if he is affected by COVID-19 because there is no scientific evidence available conducted on human subjects regarding whether to use ACEi and ARBs [10].\n\n6.5 SARS-CoV-2-liver injury\nThe SARS-CoV-2 infection has shown to increase the levels of ALT, AST, and bilirubin levels, indicating injury to the hepatic tissue [9,95,101,102]. Apart from these liver serum enzymes indicating hepatic damage, the levels of albumin were significantly decreased, indicating the severity of the infection [101]. The elated levels of gamma-glutamyl transferase (GGT) were observed only in patients with severe cases. In contrast, thealkaline phosphatize (AKP) levels remained unchanged irrespective of the severity of the infection [37] (represented in Table 1).\nSARS-CoV and SARS-CoV-2 share the similarity in making an entry into the host cell through the ACE2 receptor. In addition to the type 2 cells in the lungs, both the bile duct cells and hepatocytes also express ACE2, which might be the reason that liver injury occurs during SARS-CoV-2 infection [103]. The bile duct epithelial cells are involved in immune responses and the regeneration of the hepatocytes [104]. Besides possessing a high number of ACE2 on its surface, bile duct cells are more prone to the SARS-CoV-2 infection resulting in liver injury, which indicates that the hepatocytes are not directly involved in the hepatic injury [37]. The histopathological manifestations of SARS-CoV-2 infected patients revealed mild lobular and portal activity and restrained microvascular steatosis [105]. The degree of liver damage is directly proportional to the severity of the SARS-CoV-2 infection. Still, the reason for the liver injury remains elusive. A recent study reported that the use of anti-viral medication lopinavir might result in hepatic damage [102]. Therefore, whether the liver injury is due to the virus entry or due to the drugs used as anti-viral medication needs to be elucidated.\n\n6.6 SARS-CoV-2-lung injury\nIt was possible to study the lung pathology of COVID-19 patients diagnosed with COVID-19 retrospectively after undergoing lung lobectomy surgery for adenocarcinoma. Also, the patients didn't present pneumonia at the time of surgery, indicating the initial stages of COVID-19. A female patient who was 80 years old was hospitalized due to an irregularly shaped solid nodule in the right middle lobe. On a postoperative day 1, a CT scan was performed, which indicated a few clinical manifestations. Later, the patient was presented with increased leucocytes, decreased lymphocytic count, chest tightness, wheezing, dry cough, and difficulty in breathing. Later findings confirmed that SARS-CoV-2 infected her from a patient in the same room who was already affected. Another patient who was 73 years old and had a medical history of hypertension from 20 years who underwent surgery for adenocarcinoma was discharged on the 6th-day post-operation. On postoperative day 9, the patient exhibited chest tightness, muscle pain, dry cough, and decreased lymphocytic count. His CT-scan findings revealed for viral pneumonia, and he was also tested positive for the 20,189-nC0V test. He was admitted to the infectious disease ward. After, 20 days he was discharged as he recovered. Histopathological findings showed focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, edema, multinucleated giant cells, protruding hyaline membranes, and proteinaceous exudates [106] (represented in Table 1).\nThe patients, who are recovered from COVID-19, have a possibility of chronic lung damage. Out of 70 COVID-19 pneumonia patients, 66 patients have lung damage in a different manner, which was determined by CT. This damage is in a diverse range; in the alveoli, there is a hardened tissue with the dense clumps which block the vessels in the tiny air sacs, which absorb the oxygen and cause tissue lesions. This tissue lesion acts as a sign of the long-term lung disease. Similar reports have been found in both the SARS CoV and MERS. The patients admitted with lung pneumonia shows damage in both the lungs. The CT scan of the COVID-19 patients indicates that there is a tissue lesion found over the alveoli and which can develop into the scars. There are \u003e2.9 million people have COVID-19 disease worldwide, according to April 27. 80% of the patients are having a high risk of problems, such as from breathing to respiratory failure [107].\n\n6.7 SARS-CoV-2-CNS risk\nMathew reported that it might be due to the obstructions in the nervous system, which may restrict the entry of air into the lungs [108]. The virus enters the medullary neurons during the latency phase. A possible mechanism explained was that the SARS-CoV-2 might enter the olfactory lobe of the brain through nasal chambers upon inhalation and may lead to inflammation and demyelination. Later, it spreads to the whole brain due to its ability to cross the blood-brain barrier. Some neurological symptoms exhibited by the COVID-19 infection patients include nausea, vomiting, and headache (represented in Table 1). Since the SARS-CoV-2 possess the ability to cross the blood-brain barrier, it is important to design the drugs in such a way that they can cross the blood-brain barrier and scavenges the brain from viral infection. Also, it is essential to note that the respiratory illness accompanies neurological invasion by the virus, therapeutic care must be taken to prevent the viral entry into the central nervous system (CNS) [7].\n\n6.8 SARS-CoV-2 – immunopathology\nSARS-CoV-2 infection mediates immune response, both innate and adaptive. The enhanced level of the innate response and decreased level of adaptive causes tissue damage. Upon viral infection, there is an immune response. T cells, especially the cluster of differentiation 4 (CD4+) and a group of differentiation 8 (CD8+), have an anti-viral role. CD8+ T cells are highly cytotoxic, and they killed infected cells. This T cell induces the pro-inflammatory cytokines through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling. This process further activates the cytokines and chemokines [7]. Similar to SARS-CoV, MERS, SARS-CoV-2 infection in the immune effector cells are also having the enhanced level of the cytokines such as IFN-γ, IFN-α, IL-6, IL-1β, IL-18, IL-12, TGFβ, IL-33 and TNF-α and chemokines such as CCL2, CCL5, CCL3, CXCL10, CXCL9, and CXCL8. Similar to this, severe MERS-CoV infected patient's serum shows an increased level of the cytokines and chemokines. This cytokine storm further causes multiple organ failures to further leads to the death of the SARS-CoV-2 patient [109].\nOn the other hand, the T-cells are having four types of it, such as Th1, Th2, Th17 (inflammatory), and anti-inflammatory Tregs. These Th2 cells generate IL-4 cells. The compound which can block the Th1 (Boost immune system) tends to augments the level of the Th2 (anti-inflammatory response). IL-4 triggers the Th2 cells and obstructs the Th1 response. This Th2 helps to repair form tissue dysfunction and another type of malfunction. It is found to be good that the increased level of the Th1 and Th17 plays an important role in hyperactive immune response and during autoimmune conditions. It is showed that there is an induction of the Th1/Th17 and the production of antibodies upon COVID-19 condition [110]. Contradict to this; the patient has a high level of Th2 in need of intensive care [111]. During the MERS condition, there is a reduced level of both the Th1 and Th2, which further enhances the inflammatory cytokines and causes more infection and death [112]. SARS patients who died with an older age have higher cytokines of Th2, such as IL-4, IL-10, and IL-5 [113]. This incidence supports the increased Th2 level of COVID-19 patients who needs intensive care. The mechanism behind this is based on the molecular weight of the protein of SARS-CoV2; the activity of the immune system is changed. The recent research by the F. Javier Martín Oncina in 2020 showed that based on the antigen molecular weight, the host's immune response is varied. The proteins of the SARS-CoV2 are spike protein with 140 kDa, Envelope protein with 10 kDa, Membrane protein with 25 kDa, and nucleocapsid protein with 50 kDa. The protein with more than \u003e70 kDa, such as spike protein, cannot be arrested by the B-cell, thereby it activates the inflammatory response through the Th1 response with the macrophages. This process occurs in the subcapsular sinus and through dendritic cells phagocytosis. The other proteins with \u003c70 kDa are found in the protein of SARS-CoV2, which activates the receptor of B-cell and stimulates Th2 immune response. The unremittingviral particle overload, which is unrestricted by the viral cell lysing, will be terminated by the Th1 (pro-inflammatory response). Further, it increases the protein level with a weight of \u003c70 kDa stimulates the B cells in large amounts. This induction of the B-cells leads to the condition called as Activated Induced Cell Death (AICD), which speediness the apoptosis and release of pro-inflammatory cytokines cause lymphopenia, thereby it produces IL-10, augments the shift of Th2 form Th1 response which causes further suppression of immune system, COVID-19 sepsis [114]. Correlative to that that COVID-19 patients with the high level of Th2 immune response need intensive care [111], which shows that they might be having apoptosis, lymphopenia, and suppression of immune system further causes COVID-19 sepsis [114]. Though the cell death is via Th2 immune response but the level of IL-4 is not elucidated yet. The role of IL-4 and its mechanism behind COVID-19 remain elusive (Represented in Fig. 2 ).\nFig. 2 SARS-CoV-2 enters into the host cell via binding with the cellular receptor ACE-2. It undergoes the fusion with the joining of the plasma membrane and the virus. Then it undergoes the process of the proteolytic cleavage; further, it will undergo replication and lead to the formation of the proteins. This process activates the signaling pathway, such as the NF-kB pathway, via TRIF. The interaction between the cells and the virus activates many cytokine storms. On the other hand, once the virus enters into the cell, the antigen present in that would undergo the antigen presentation cells (APC); further, this stimulates the humoral and cellular immunity. COVID-19 infects the macrophage cells, which presents to the T cell, further, which leads to the activation, differentiation of T-cells, along with the production of cytokines. This shows the negative action on the activation of CD8 T cells. Thus the mediator produced by the CD8+ T cells clears the infection of SARS-CoV. Upon COVID-19 infection, there is a reduced CD4+ and CD8+ cell level, further increasing the cytokine level in the cells, which triggers the inflammation. This mediates the production of the cytokine storm via secreting chemokine and cytokines such as IL-1β, IL-6, TNF-α, IL-8, IL-21, CCL2, CCL3, CCL5, CXCL10, TNF-β, and MCP-1 and triggers the tissue injury. On the other hand, based on the weight of the protein of SARS-CoV2, there is an activation of Th1/Th17 (boosts immune system) when the spike protein is \u003e70 kDa. In case of the Th2 (anti-inflammatory) is activated by the majority of the protein with \u003c70 kDa, then the activation of the B-cell receptor, which causes activation-induced cell death such as apoptosis and lymphopenia which is by releasing IL-10, shifting of Th1 to Th2 immune response, suppression of the immune system and further leads to the COVID-19 sepsis. The role of IL-4 has not been elucidated yet. It remains unanswerable upon COVID-19 condition with the mechanism of Th2 and Th1/Th17.\nThe wet lung is also known as acute respiratory distress syndrome (ARDS). The patient with COVID-19 has lung edema, and it needs more attention clinically. Lung edema is found to be a symptom of acute lung injury, which development to hypoxemia condition and which leads to acute respiratory distress syndrome (ARDS). The patients who are found with ARDS have more mortality. Though there is no proper treatment or vaccine treatment, ventilation with the therapy of oxygen and ventilation mechanically is mandatory. Sometimes, the treatment with the glucocorticoids (systemic or locally) would help attenuate lung edema and pulmonary inflammation [115]. But there is a need for more research to correlate the cytokine storm with wet lung pneumonia in COVID-19 patients.\n\n6.9 SARS-CoV-2 – ocular risk\nThe ACE2 receptors are also widely distributed in the superficial parts such as conjunctiva and cornea inferior parts such as iris, ciliary body, aqueous humor, trabecular meshwork, retina, and non-pigmented ciliary epithelium of the ocular globe which is mentioned out to be the intraocular renin-angiotensin system. Therefore, the distribution of ACE2 and TMPRSS2 protein must be taken into consideration to study the passage of infection through the ocular route [116]. Also, there is a chance for the virus to enter into the nasal cavity, which causes respiratory illness and the digestive system through the lacrimal canaliculi aided by the effectiveness of the tear film [117,118]. Out of 38 COVID-19 positive patients, 12 exhibited clinical manifestations, which include chemosis, epiphora, increased secretions, conjunctivitis, and conjunctival hyperemia. Researchers reported that patients exhibiting ocular symptoms would have elevated neutrophilic and lymphocytic counts, elated procalcitonin, lactate dehydrogenase, and C-reactive protein levels than those without ocular manifestations. The patients with ocular manifestations exhibited severe illness [119].\nEven though there is no such evidence, the presence of ACE2 and TMPRSS2 protein in the corneal limbal stem cells suggests that the SARS-CoV-2 may enter the bloodstream and travel to the other parts including the brain [120]. Even though there is no viral load in the conjunctiva of the SARS-CoV-2 infected patients without conjunctivitis, the risk of transmission of the virus through tears is low [121]. The exact mechanism behind the ocular risk and SARS-CoV-2 need to be elucidated further.\n\n6.10 SARS-CoV-2 – cancer risk\nCancer patients are highly vulnerable to SARS-CoV-2 infection. 18 out of 1590 COVID-19 positive cases exhibited cancer history. 5 out of 18 patients suffered from lung cancer, 4 out of 18 patients had no past information on medication and had undergone surgery or chemotherapy in the previous month, and the remaining 12 were cancer survivors. The COVID-19 was highly severe in cancer patients than non-cancer COVID-19 affected patients. Also, COVID-19 patients with cancer exhibited a severe chain of symptoms than those without a history of cancer. Also, patients with lung cancer did not exhibit severe symptoms when compared to those with other types of cancers [122].\nIn a retrospective study conducted among 1276 patients, 28 patients who have cancer were selected for the study. The mean age group people belonged to the elderly category, and 60.7% of them were males. Lung cancer was the most frequent type, followed by oesophageal and breast cancers among cancer affected patients. 10 out of 28 patients were presented with IV stage cancer. 28.6% of the patients developed COVID-19 while receiving antitumor therapy, whereas 71.4% of them developed due to the presence of infection in their vicinity. Besides, 39.2% of the patients exhibited chronic co-morbid conditions apart from cancer. 28.6% of patients died, and the remaining patients developed serious consequences even after receiving anti-viral and corticosteroids. The most common complication developed by the patients includes septic shock, acute myocardial infarction, and ARDS [123]. Therefore, more focus should be laid on the research for medication and treatment options for COVID-19 affected cancer patients. More studies are required to determine the exact mechanism behind cancer and SARS-CoV-2.\n\n6.11 SARS-CoV-2 – tuberculosis\nA study was conducted in February 2020, Shenyang, China, which involved 36 COVID-19 positive patients and was classified based on the severity of the symptoms as mild and critical. The results of these patients were compared with that of the patients affected by pneumonia caused by Mycobacterium tuberculosis from Shenyang chest hospital. The study was conducted to determine which one caused severe pneumonia, either the viral or the bacterial strain. Then the severity of tuberculosis was compared between the mild and severe COVID-19 cases and confirmed that tuberculosis due to mycobacterial strain affected patients are more susceptible to COVID-19 and enhance the severity of COVID-19 [124]. Patients with HIV undergoing treatment with antiretroviral medicines exhibit weak immune systems and are more susceptible to viral infections. Also, until now, only one HIV case had been reported with COVID-19 infection from china. The patient recovered from the infection the same as that of those without HIV. There is no evidence on whether HIV patients are more susceptible to COVID-19 infection [125].\nThe COVID-19 associated TB is found in 94th day of the nonexistence of public health interventions and 138th day in the occurrence of interventions. This occurs at the peak of an outbreak where the implementation of the intervention, out of it 11,066, is with the presence of interventions. 27,968 COVID-19 cases found in the absence of interventions, out of it 14,823, are with no interventions. This scenario shows that there is a need to take preventive measures of TB associated with COVID-19 patients. They need a prior diagnosis and proper management [126]. The main reasons for mortality are age, sex, and other co-morbid factors such as diabetes, cardiovascular diseases, and renal diseases are the main reasons for mortality.\n\n6.12 SARS-CoV-2 – Venous thromboembolism\nPeople affected with pneumonia are more prone to venous thromboembolism. Out of 1026 COVID-19 patients, 40% of them exhibited high risk, and 11% of them at high risk of developing venous thromboembolism without any prophylaxis. Prophylactic measures can prevent venous thromboembolism. Only 7 out of 140 patients at high risk for venous thromboembolism had recorded about the anticoagulation treatment. And 44 out of 407 exhibited a higher risk for bleeding. In these patients, the mechanical compressions such as intermittent pneumatic compression and elastic compression stockings are instructed, and the duration and dosage of anticoagulants should be adjusted. Also, the COVID-19 patients, along with other co-morbid conditions such as cardiovascular manifestations, respiratory failure, renal and hepatic problems, can affect the bleeding status and venous thromboembolism. Therefore, further investigations are required to reduce the risk due to venous thromboembolism and bleeding in the case of COVID-19 patients [127].\n\n6.13 SARS-CoV-2- reproductive risk\nViral infections during the first 20 weeks of gestation have shown to be more severe. The infections, such as SARS and MERS, which occurred due to coronaviruses, had reported an increased risk for pregnancy-related mortality and morbidity. Such cases among COVID-19 affected patients are not yet reported. Nine women who are in their third semester and infected with COVID-19 were reported to have outcomes as that of non-pregnant COVID-19 affected adults. In another study, out of 33 newborn infants, three infants were shown to be tested positive for COVID-19 who got the disease transferred from their mother through intrauterine vertical transmission mode [128].\n\n6.14 SARS-CoV-2 – mental illness\nAccording to a report, out of a group of 50 COVID-19 cases from a psychiatric hospital in Wuhan, China has uplifted the worry about the role of mental disorder in coronavirus transmission. The conditions include incomplete or no awareness of the risk, inability to have personal protection, and cognitive impairment. The treatment has become more challenging for people with COVID-19 infection and health disorders as co-morbid conditions [129].\n\n6.15 SARS-CoV-2 – aging and cardiovascular risk\nIt has been reported that the expression of ACE2 reduces with the increasing age. Since young patients possess high levels of ACE2, they are more prone to COVID-19 infection. Whereas, in old age people other than reduced ACE2 levels, other co-morbid conditions such as cardiovascular problems, diabetes, and hypertension might be present. The medication prescribed for these patients helps in elevating the ACE2 levels, which might enhance the viral entry. Though the treatment reduces the co-morbid severities, the viral infection is enhanced in those patients. Therefore, it is conclusive that young patients, even though they are more susceptible to the COVID-19 infection, they are less severely affected and exhibit elevated angiotensin II signaling. Whereas, the older patients who exhibit low levels of ACE2 and higher angiotensin II signaling leads to hypertension. The usage of ACEi and ARBs help in promoting the vasodilatory effects by elevating the ACE2 levels, thereby becoming susceptible to COVID-19 infection and are severely affected [130]."}

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SARS-CoV-2\n\n6.1 SARS-CoV-2 – heart disease\nACE2 plays a vital role in the cardiovascular system and is mainly involved in the functioning of the heart and development of hypertension and type II diabetes. Since ACE2 is the main target for the SARS-CoV-2 to enter inside the host cell and the ACE2 is also highly expressed in the heart apart from the lungs, indicating a chance of developing cardiac issues during SARS-CoV-2 infection. The anti-hypertensive therapy that has been prescribed for the patients is the usage of ACEi and ARBs should be carefully considered. The COVID-19 patients with comorbidities hypertension, taking the drug of ACEi or blocker of angiotensin receptor, need to switch off to other anti-hypertensive medications found to be controversial and require further studies this co-morbid conditions. The severity of the viral infection is higher in patients with comorbidities than those infected only by the virus without any predisposed health issue [85].\nThe interaction of the SARS-CoV-2 with ACE2 triggers a signal, which might be the reason to develop heart injury through the immune response triggered by T-helper cells creating a cytokine response. The SARS-CoV-2 has a structural similarity with that of SARS-CoV. SARS-CoV caused severe cardiovascular damage during its pandemic period. Therefore, it is essential to investigate SARS-CoV-2 treatment options and ensure a cardio-protective effect. The age and the predisposition of the acute coronary syndrome are the two critical factors which need to be considered in patients affected with COVID-19 [85].\nSince the ACE2 is highly expressed in pericytes, the patients infected with SARS-CoV-2 and predisposed with cardiac failure are more susceptible to develop severe cardiac problems [86]. The usage of mineralocorticoids receptor blocker can attenuates oxidative stress, reduces the level of ACE with the augmented production of the angiotensin 1–7 and attenuates the angiotensin II generation and increases the activity of ACE2 The antagonist of angiotensin II type 1 receptor, have modulates the profilin-1 expression and ACE2 [87]. The selective of the angiotensin II activity or synthesis mediated the augmented level of ACE2 expression and its activity in cardiac. Still, the combination of the lisinopril and losartan increases the activity of ACE2 but not ACE2 mRNA. The inhibition of ACE results in reduced formation of angiotensin II and metabolism of angiotensin 1–7, the angiotensin II type 1 receptor antagonist increases the metabolism of angiotensin II via ACE2 [88]. SARS-CoV 2 enters into the cell via the ACE2 receptor; this causes the decreased level of the ACE2 due to the binding of the spike protein to the ACE2 and no changes in ACE. This process causes the virus's entry, replicates it, and causes tissue injury via decreasing anti-atrophy, anti0-fibrosis, anti-inflammation, anti-oxidant, and vasodilation. On the other hand, the angiotensin II type 1 receptor causes pro-atrophy, pro-fibrosis, pro-inflammation, pro-oxidant, severe myocardial remodeling, vasoconstriction and vascular permeability which leads to tissue injury [89] (represented in Table 1).\nTherefore, the use of ACEi, ARBs, and mineralocorticoids has shown to have an impact on the cardiac patients affected by COVID-19, but the exact mechanism behind it is not clear. Aliskiren, a direct inhibitor of renin, resulted in reduced expression of ACE2 besides reducing the blood pressure that has been elucidated in diabetic nephropathy animal models [90]. Therefore, renin blockers, especially aliskiren, need to be further investigated as a treatment option for COVID-19 patients with comorbidities [91].\n\n6.2 SARS-CoV-2 – gastrointestinal risk\nThe ACE2 is also highly expressed in the small intestine and large intestine of the gastrointestinal tract. The S protein present on the envelope of the SARS-CoV-2 ensures higher binding affinity, thereby mediating the entry of the virus into the host cell. The presence of SARS-CoV-2 in the gastrointestinal tract was confirmed by nucleocapsid staining of the virus. The virus was found to be visualized in the cytoplasm of epithelia of duodenum and rectum [92] (represented in Table 1). Apart from the pulmonary infection, the COVID-19 affected patients also exhibited vomiting, abdominal pain, and diarrhea, which was first reported in a 35 years old man from the United States. He was presented with nausea and diarrhea on 2nd day of the infection and was hospitalized. Stools examination revealed the presence of SARS-CoV-2 RNA, which was confirmed by using reverse transcriptase-polymerase chain reaction (RT-PCR) on day 7 of infection [93]. Out of 171 COVID-19 affected children, 6.4% of them have shown vomiting, and 8.8% of them and 3 out of ten affected children have shown diarrhea as symptoms [94]. Also, previously there were two COVID-19 young cases reported with vomiting and diarrhea.\nIn China, from 552 hospitals, 1099 cases were reported, of which 3.8% and 5% were diagnosed with diarrhea and vomiting as symptoms [95]. According to another report, out of 140 COVID-19 patients from Wuhan, 39.6% exhibited gastrointestinal symptoms apart from 5% exhibiting vomiting, 12.9% exhibiting diarrhea, and 17.3% exhibiting nausea [96]. It was reported that 17 patients had shown a negative result when tested using pulmonary samples, but when tested using rectal swabs have shown to have a positive result [96].\nSimilarly, 8 out of 10 children affected by SARS-CoV-2 had shown dual results, negative results when tested by nasopharyngeal samples, and positive results when tested using a rectal swab [97]. The percentage of patients exhibiting nausea, vomiting, and diarrhea as symptoms vary between the cohort groups, whereas, in the case of certain groups, these symptoms contributed very few percent. In contrast, in the case of the other groups, a high percentage of these gastrointestinal symptoms have been recorded.\n\n6.3 SARS-CoV-2- kidney risk\nIt is suspected that whether the patients with predisposed kidney issues or COVID-19 induced acute kidney injury is fatal to the affected patients. In an article posted on March 19 by HospiMedica International staff writers, it was mentioned that patients affected by COVID-19 developed proteinuria estimated by the elevated levels of albumin in urine were diagnosed in the initial stages of infection. The majority of the affected members, i.e., 34% out of 59 patients, developed proteinuria where the elevated albumin levels serve as a biomarker for kidney damage, and 63% of the patients exhibited proteinuria and hematuria characterized by the presence of blood in the urine. In another study conducted on 710 patients hospitalized due to COVID-19. The impairment in the functioning of the kidney was observed in 27% of the 59 patients and 66% of the corona infected patients. In a later study conducted on COVID-19 affected patients from 710 hospitals, 26.7% exhibited only hematuria, and 44% exhibited proteinuria and hematuria. The impaired kidney function was found in 15% of the study population [98].\nAccording to an article published by Wang L and his colleagues reported that out of 116 COVID-19 positive cases from Renmin Hospital of Wuhan University, out of whom 111 didn't have any kidney issues in their history and the remaining five patients had chronic kidney disease (CDK). Also, out of the 111 patients, only 10.8% of the patients exhibited a slight increase in creatine or blood urea nitrogen levels, and 7.2% of the patients had shown a minute raise in the albuminuria levels. None of the patients out of 111 didn't exhibit any acute kidney injury (AKI) after the COVID-19 infection. The remaining five patients who were already undergoing continuous renal replacement therapy (CRRT) also didn't show any fatal effects after COVID-19 infection confirmed by diagnosing the renal indicators [99]. Out of 701 patients, 2% of the patients were found to have CKD, and the average lymphocytic number was found to be reduced than the normal. High sensitivity C-reactive protein levels were significantly increased. In patients reported with high levels of serum, creatine indicated high levels of serum lactose dehydrogenase. Among hospitalized patients, patients with high levels of serum creatine were mostly old and male sex. Also, they exhibited lower platelet and lymphocytic count and elevated leukocytic count. The patients with elevated procalcitonin also exhibited elevated levels of aspartate aminotransferase and lactate dehydrogenase. Acute kidney injury was significantly higher in those patients with high serum creatine levels. AKI eventually results in mortality [100] (represented in Table 1). Therefore, advanced identification of kidney diseases in patients affected by COVID-19 may help the clinicians to reduce the mortality rate due to comorbidities such as chronic kidney disease, acute kidney injury, proteinuria, and hematuria.\n\n6.4 SARS-CoV-2 – diabetes mellitus\nPatients with diabetes mellitus exhibit high levels of ACE2, and treatment with the inhibitors of ACE and ARBs augments the expression of ACE2. Diabetes condition may lead to the suspicion that the excessive expression of ACE2 aids the entry of SARS-CoV-2 into the host cells resulting in COVID-19. Since diabetes mellitus and hypertension conditions are treated, ACE2 increasing drugs are having a severe risk of COVID-19 [10].\nSimultaneously, the elevated expression of ACE2 ensures the entry of the SARS-CoV-2, attaching to the ACE2 enzyme with the help of S protein present on its envelope's surface. There forth, it became controversial whether COVID-19 affected patients who are predisposed with diabetes mellitus should be resumed with their treatment with ACEi and ARBs or not. Also, if the medication is abruptly ceased, there are chances that the patient may die due to hypertension instead of COVID-19. For this reason, it has been suggested that there is no need to stop the medication of a diabetic patient even though if he is affected by COVID-19 because there is no scientific evidence available conducted on human subjects regarding whether to use ACEi and ARBs [10].\n\n6.5 SARS-CoV-2-liver injury\nThe SARS-CoV-2 infection has shown to increase the levels of ALT, AST, and bilirubin levels, indicating injury to the hepatic tissue [9,95,101,102]. Apart from these liver serum enzymes indicating hepatic damage, the levels of albumin were significantly decreased, indicating the severity of the infection [101]. The elated levels of gamma-glutamyl transferase (GGT) were observed only in patients with severe cases. In contrast, thealkaline phosphatize (AKP) levels remained unchanged irrespective of the severity of the infection [37] (represented in Table 1).\nSARS-CoV and SARS-CoV-2 share the similarity in making an entry into the host cell through the ACE2 receptor. In addition to the type 2 cells in the lungs, both the bile duct cells and hepatocytes also express ACE2, which might be the reason that liver injury occurs during SARS-CoV-2 infection [103]. The bile duct epithelial cells are involved in immune responses and the regeneration of the hepatocytes [104]. Besides possessing a high number of ACE2 on its surface, bile duct cells are more prone to the SARS-CoV-2 infection resulting in liver injury, which indicates that the hepatocytes are not directly involved in the hepatic injury [37]. The histopathological manifestations of SARS-CoV-2 infected patients revealed mild lobular and portal activity and restrained microvascular steatosis [105]. The degree of liver damage is directly proportional to the severity of the SARS-CoV-2 infection. Still, the reason for the liver injury remains elusive. A recent study reported that the use of anti-viral medication lopinavir might result in hepatic damage [102]. Therefore, whether the liver injury is due to the virus entry or due to the drugs used as anti-viral medication needs to be elucidated.\n\n6.6 SARS-CoV-2-lung injury\nIt was possible to study the lung pathology of COVID-19 patients diagnosed with COVID-19 retrospectively after undergoing lung lobectomy surgery for adenocarcinoma. Also, the patients didn't present pneumonia at the time of surgery, indicating the initial stages of COVID-19. A female patient who was 80 years old was hospitalized due to an irregularly shaped solid nodule in the right middle lobe. On a postoperative day 1, a CT scan was performed, which indicated a few clinical manifestations. Later, the patient was presented with increased leucocytes, decreased lymphocytic count, chest tightness, wheezing, dry cough, and difficulty in breathing. Later findings confirmed that SARS-CoV-2 infected her from a patient in the same room who was already affected. Another patient who was 73 years old and had a medical history of hypertension from 20 years who underwent surgery for adenocarcinoma was discharged on the 6th-day post-operation. On postoperative day 9, the patient exhibited chest tightness, muscle pain, dry cough, and decreased lymphocytic count. His CT-scan findings revealed for viral pneumonia, and he was also tested positive for the 20,189-nC0V test. He was admitted to the infectious disease ward. After, 20 days he was discharged as he recovered. Histopathological findings showed focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, edema, multinucleated giant cells, protruding hyaline membranes, and proteinaceous exudates [106] (represented in Table 1).\nThe patients, who are recovered from COVID-19, have a possibility of chronic lung damage. Out of 70 COVID-19 pneumonia patients, 66 patients have lung damage in a different manner, which was determined by CT. This damage is in a diverse range; in the alveoli, there is a hardened tissue with the dense clumps which block the vessels in the tiny air sacs, which absorb the oxygen and cause tissue lesions. This tissue lesion acts as a sign of the long-term lung disease. Similar reports have been found in both the SARS CoV and MERS. The patients admitted with lung pneumonia shows damage in both the lungs. The CT scan of the COVID-19 patients indicates that there is a tissue lesion found over the alveoli and which can develop into the scars. There are \u003e2.9 million people have COVID-19 disease worldwide, according to April 27. 80% of the patients are having a high risk of problems, such as from breathing to respiratory failure [107].\n\n6.7 SARS-CoV-2-CNS risk\nMathew reported that it might be due to the obstructions in the nervous system, which may restrict the entry of air into the lungs [108]. The virus enters the medullary neurons during the latency phase. A possible mechanism explained was that the SARS-CoV-2 might enter the olfactory lobe of the brain through nasal chambers upon inhalation and may lead to inflammation and demyelination. Later, it spreads to the whole brain due to its ability to cross the blood-brain barrier. Some neurological symptoms exhibited by the COVID-19 infection patients include nausea, vomiting, and headache (represented in Table 1). Since the SARS-CoV-2 possess the ability to cross the blood-brain barrier, it is important to design the drugs in such a way that they can cross the blood-brain barrier and scavenges the brain from viral infection. Also, it is essential to note that the respiratory illness accompanies neurological invasion by the virus, therapeutic care must be taken to prevent the viral entry into the central nervous system (CNS) [7].\n\n6.8 SARS-CoV-2 – immunopathology\nSARS-CoV-2 infection mediates immune response, both innate and adaptive. The enhanced level of the innate response and decreased level of adaptive causes tissue damage. Upon viral infection, there is an immune response. T cells, especially the cluster of differentiation 4 (CD4+) and a group of differentiation 8 (CD8+), have an anti-viral role. CD8+ T cells are highly cytotoxic, and they killed infected cells. This T cell induces the pro-inflammatory cytokines through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling. This process further activates the cytokines and chemokines [7]. Similar to SARS-CoV, MERS, SARS-CoV-2 infection in the immune effector cells are also having the enhanced level of the cytokines such as IFN-γ, IFN-α, IL-6, IL-1β, IL-18, IL-12, TGFβ, IL-33 and TNF-α and chemokines such as CCL2, CCL5, CCL3, CXCL10, CXCL9, and CXCL8. Similar to this, severe MERS-CoV infected patient's serum shows an increased level of the cytokines and chemokines. This cytokine storm further causes multiple organ failures to further leads to the death of the SARS-CoV-2 patient [109].\nOn the other hand, the T-cells are having four types of it, such as Th1, Th2, Th17 (inflammatory), and anti-inflammatory Tregs. These Th2 cells generate IL-4 cells. The compound which can block the Th1 (Boost immune system) tends to augments the level of the Th2 (anti-inflammatory response). IL-4 triggers the Th2 cells and obstructs the Th1 response. This Th2 helps to repair form tissue dysfunction and another type of malfunction. It is found to be good that the increased level of the Th1 and Th17 plays an important role in hyperactive immune response and during autoimmune conditions. It is showed that there is an induction of the Th1/Th17 and the production of antibodies upon COVID-19 condition [110]. Contradict to this; the patient has a high level of Th2 in need of intensive care [111]. During the MERS condition, there is a reduced level of both the Th1 and Th2, which further enhances the inflammatory cytokines and causes more infection and death [112]. SARS patients who died with an older age have higher cytokines of Th2, such as IL-4, IL-10, and IL-5 [113]. This incidence supports the increased Th2 level of COVID-19 patients who needs intensive care. The mechanism behind this is based on the molecular weight of the protein of SARS-CoV2; the activity of the immune system is changed. The recent research by the F. Javier Martín Oncina in 2020 showed that based on the antigen molecular weight, the host's immune response is varied. The proteins of the SARS-CoV2 are spike protein with 140 kDa, Envelope protein with 10 kDa, Membrane protein with 25 kDa, and nucleocapsid protein with 50 kDa. The protein with more than \u003e70 kDa, such as spike protein, cannot be arrested by the B-cell, thereby it activates the inflammatory response through the Th1 response with the macrophages. This process occurs in the subcapsular sinus and through dendritic cells phagocytosis. The other proteins with \u003c70 kDa are found in the protein of SARS-CoV2, which activates the receptor of B-cell and stimulates Th2 immune response. The unremittingviral particle overload, which is unrestricted by the viral cell lysing, will be terminated by the Th1 (pro-inflammatory response). Further, it increases the protein level with a weight of \u003c70 kDa stimulates the B cells in large amounts. This induction of the B-cells leads to the condition called as Activated Induced Cell Death (AICD), which speediness the apoptosis and release of pro-inflammatory cytokines cause lymphopenia, thereby it produces IL-10, augments the shift of Th2 form Th1 response which causes further suppression of immune system, COVID-19 sepsis [114]. Correlative to that that COVID-19 patients with the high level of Th2 immune response need intensive care [111], which shows that they might be having apoptosis, lymphopenia, and suppression of immune system further causes COVID-19 sepsis [114]. Though the cell death is via Th2 immune response but the level of IL-4 is not elucidated yet. The role of IL-4 and its mechanism behind COVID-19 remain elusive (Represented in Fig. 2 ).\nFig. 2 SARS-CoV-2 enters into the host cell via binding with the cellular receptor ACE-2. It undergoes the fusion with the joining of the plasma membrane and the virus. Then it undergoes the process of the proteolytic cleavage; further, it will undergo replication and lead to the formation of the proteins. This process activates the signaling pathway, such as the NF-kB pathway, via TRIF. The interaction between the cells and the virus activates many cytokine storms. On the other hand, once the virus enters into the cell, the antigen present in that would undergo the antigen presentation cells (APC); further, this stimulates the humoral and cellular immunity. COVID-19 infects the macrophage cells, which presents to the T cell, further, which leads to the activation, differentiation of T-cells, along with the production of cytokines. This shows the negative action on the activation of CD8 T cells. Thus the mediator produced by the CD8+ T cells clears the infection of SARS-CoV. Upon COVID-19 infection, there is a reduced CD4+ and CD8+ cell level, further increasing the cytokine level in the cells, which triggers the inflammation. This mediates the production of the cytokine storm via secreting chemokine and cytokines such as IL-1β, IL-6, TNF-α, IL-8, IL-21, CCL2, CCL3, CCL5, CXCL10, TNF-β, and MCP-1 and triggers the tissue injury. On the other hand, based on the weight of the protein of SARS-CoV2, there is an activation of Th1/Th17 (boosts immune system) when the spike protein is \u003e70 kDa. In case of the Th2 (anti-inflammatory) is activated by the majority of the protein with \u003c70 kDa, then the activation of the B-cell receptor, which causes activation-induced cell death such as apoptosis and lymphopenia which is by releasing IL-10, shifting of Th1 to Th2 immune response, suppression of the immune system and further leads to the COVID-19 sepsis. The role of IL-4 has not been elucidated yet. It remains unanswerable upon COVID-19 condition with the mechanism of Th2 and Th1/Th17.\nThe wet lung is also known as acute respiratory distress syndrome (ARDS). The patient with COVID-19 has lung edema, and it needs more attention clinically. Lung edema is found to be a symptom of acute lung injury, which development to hypoxemia condition and which leads to acute respiratory distress syndrome (ARDS). The patients who are found with ARDS have more mortality. Though there is no proper treatment or vaccine treatment, ventilation with the therapy of oxygen and ventilation mechanically is mandatory. Sometimes, the treatment with the glucocorticoids (systemic or locally) would help attenuate lung edema and pulmonary inflammation [115]. But there is a need for more research to correlate the cytokine storm with wet lung pneumonia in COVID-19 patients.\n\n6.9 SARS-CoV-2 – ocular risk\nThe ACE2 receptors are also widely distributed in the superficial parts such as conjunctiva and cornea inferior parts such as iris, ciliary body, aqueous humor, trabecular meshwork, retina, and non-pigmented ciliary epithelium of the ocular globe which is mentioned out to be the intraocular renin-angiotensin system. Therefore, the distribution of ACE2 and TMPRSS2 protein must be taken into consideration to study the passage of infection through the ocular route [116]. Also, there is a chance for the virus to enter into the nasal cavity, which causes respiratory illness and the digestive system through the lacrimal canaliculi aided by the effectiveness of the tear film [117,118]. Out of 38 COVID-19 positive patients, 12 exhibited clinical manifestations, which include chemosis, epiphora, increased secretions, conjunctivitis, and conjunctival hyperemia. Researchers reported that patients exhibiting ocular symptoms would have elevated neutrophilic and lymphocytic counts, elated procalcitonin, lactate dehydrogenase, and C-reactive protein levels than those without ocular manifestations. The patients with ocular manifestations exhibited severe illness [119].\nEven though there is no such evidence, the presence of ACE2 and TMPRSS2 protein in the corneal limbal stem cells suggests that the SARS-CoV-2 may enter the bloodstream and travel to the other parts including the brain [120]. Even though there is no viral load in the conjunctiva of the SARS-CoV-2 infected patients without conjunctivitis, the risk of transmission of the virus through tears is low [121]. The exact mechanism behind the ocular risk and SARS-CoV-2 need to be elucidated further.\n\n6.10 SARS-CoV-2 – cancer risk\nCancer patients are highly vulnerable to SARS-CoV-2 infection. 18 out of 1590 COVID-19 positive cases exhibited cancer history. 5 out of 18 patients suffered from lung cancer, 4 out of 18 patients had no past information on medication and had undergone surgery or chemotherapy in the previous month, and the remaining 12 were cancer survivors. The COVID-19 was highly severe in cancer patients than non-cancer COVID-19 affected patients. Also, COVID-19 patients with cancer exhibited a severe chain of symptoms than those without a history of cancer. Also, patients with lung cancer did not exhibit severe symptoms when compared to those with other types of cancers [122].\nIn a retrospective study conducted among 1276 patients, 28 patients who have cancer were selected for the study. The mean age group people belonged to the elderly category, and 60.7% of them were males. Lung cancer was the most frequent type, followed by oesophageal and breast cancers among cancer affected patients. 10 out of 28 patients were presented with IV stage cancer. 28.6% of the patients developed COVID-19 while receiving antitumor therapy, whereas 71.4% of them developed due to the presence of infection in their vicinity. Besides, 39.2% of the patients exhibited chronic co-morbid conditions apart from cancer. 28.6% of patients died, and the remaining patients developed serious consequences even after receiving anti-viral and corticosteroids. The most common complication developed by the patients includes septic shock, acute myocardial infarction, and ARDS [123]. Therefore, more focus should be laid on the research for medication and treatment options for COVID-19 affected cancer patients. More studies are required to determine the exact mechanism behind cancer and SARS-CoV-2.\n\n6.11 SARS-CoV-2 – tuberculosis\nA study was conducted in February 2020, Shenyang, China, which involved 36 COVID-19 positive patients and was classified based on the severity of the symptoms as mild and critical. The results of these patients were compared with that of the patients affected by pneumonia caused by Mycobacterium tuberculosis from Shenyang chest hospital. The study was conducted to determine which one caused severe pneumonia, either the viral or the bacterial strain. Then the severity of tuberculosis was compared between the mild and severe COVID-19 cases and confirmed that tuberculosis due to mycobacterial strain affected patients are more susceptible to COVID-19 and enhance the severity of COVID-19 [124]. Patients with HIV undergoing treatment with antiretroviral medicines exhibit weak immune systems and are more susceptible to viral infections. Also, until now, only one HIV case had been reported with COVID-19 infection from china. The patient recovered from the infection the same as that of those without HIV. There is no evidence on whether HIV patients are more susceptible to COVID-19 infection [125].\nThe COVID-19 associated TB is found in 94th day of the nonexistence of public health interventions and 138th day in the occurrence of interventions. This occurs at the peak of an outbreak where the implementation of the intervention, out of it 11,066, is with the presence of interventions. 27,968 COVID-19 cases found in the absence of interventions, out of it 14,823, are with no interventions. This scenario shows that there is a need to take preventive measures of TB associated with COVID-19 patients. They need a prior diagnosis and proper management [126]. The main reasons for mortality are age, sex, and other co-morbid factors such as diabetes, cardiovascular diseases, and renal diseases are the main reasons for mortality.\n\n6.12 SARS-CoV-2 – Venous thromboembolism\nPeople affected with pneumonia are more prone to venous thromboembolism. Out of 1026 COVID-19 patients, 40% of them exhibited high risk, and 11% of them at high risk of developing venous thromboembolism without any prophylaxis. Prophylactic measures can prevent venous thromboembolism. Only 7 out of 140 patients at high risk for venous thromboembolism had recorded about the anticoagulation treatment. And 44 out of 407 exhibited a higher risk for bleeding. In these patients, the mechanical compressions such as intermittent pneumatic compression and elastic compression stockings are instructed, and the duration and dosage of anticoagulants should be adjusted. Also, the COVID-19 patients, along with other co-morbid conditions such as cardiovascular manifestations, respiratory failure, renal and hepatic problems, can affect the bleeding status and venous thromboembolism. Therefore, further investigations are required to reduce the risk due to venous thromboembolism and bleeding in the case of COVID-19 patients [127].\n\n6.13 SARS-CoV-2- reproductive risk\nViral infections during the first 20 weeks of gestation have shown to be more severe. The infections, such as SARS and MERS, which occurred due to coronaviruses, had reported an increased risk for pregnancy-related mortality and morbidity. Such cases among COVID-19 affected patients are not yet reported. Nine women who are in their third semester and infected with COVID-19 were reported to have outcomes as that of non-pregnant COVID-19 affected adults. In another study, out of 33 newborn infants, three infants were shown to be tested positive for COVID-19 who got the disease transferred from their mother through intrauterine vertical transmission mode [128].\n\n6.14 SARS-CoV-2 – mental illness\nAccording to a report, out of a group of 50 COVID-19 cases from a psychiatric hospital in Wuhan, China has uplifted the worry about the role of mental disorder in coronavirus transmission. The conditions include incomplete or no awareness of the risk, inability to have personal protection, and cognitive impairment. The treatment has become more challenging for people with COVID-19 infection and health disorders as co-morbid conditions [129].\n\n6.15 SARS-CoV-2 – aging and cardiovascular risk\nIt has been reported that the expression of ACE2 reduces with the increasing age. Since young patients possess high levels of ACE2, they are more prone to COVID-19 infection. Whereas, in old age people other than reduced ACE2 levels, other co-morbid conditions such as cardiovascular problems, diabetes, and hypertension might be present. The medication prescribed for these patients helps in elevating the ACE2 levels, which might enhance the viral entry. Though the treatment reduces the co-morbid severities, the viral infection is enhanced in those patients. Therefore, it is conclusive that young patients, even though they are more susceptible to the COVID-19 infection, they are less severely affected and exhibit elevated angiotensin II signaling. Whereas, the older patients who exhibit low levels of ACE2 and higher angiotensin II signaling leads to hypertension. The usage of ACEi and ARBs help in promoting the vasodilatory effects by elevating the ACE2 levels, thereby becoming susceptible to COVID-19 infection and are severely affected [130]."}

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SARS-CoV-2\n\n6.1 SARS-CoV-2 – heart disease\nACE2 plays a vital role in the cardiovascular system and is mainly involved in the functioning of the heart and development of hypertension and type II diabetes. Since ACE2 is the main target for the SARS-CoV-2 to enter inside the host cell and the ACE2 is also highly expressed in the heart apart from the lungs, indicating a chance of developing cardiac issues during SARS-CoV-2 infection. The anti-hypertensive therapy that has been prescribed for the patients is the usage of ACEi and ARBs should be carefully considered. The COVID-19 patients with comorbidities hypertension, taking the drug of ACEi or blocker of angiotensin receptor, need to switch off to other anti-hypertensive medications found to be controversial and require further studies this co-morbid conditions. The severity of the viral infection is higher in patients with comorbidities than those infected only by the virus without any predisposed health issue [85].\nThe interaction of the SARS-CoV-2 with ACE2 triggers a signal, which might be the reason to develop heart injury through the immune response triggered by T-helper cells creating a cytokine response. The SARS-CoV-2 has a structural similarity with that of SARS-CoV. SARS-CoV caused severe cardiovascular damage during its pandemic period. Therefore, it is essential to investigate SARS-CoV-2 treatment options and ensure a cardio-protective effect. The age and the predisposition of the acute coronary syndrome are the two critical factors which need to be considered in patients affected with COVID-19 [85].\nSince the ACE2 is highly expressed in pericytes, the patients infected with SARS-CoV-2 and predisposed with cardiac failure are more susceptible to develop severe cardiac problems [86]. The usage of mineralocorticoids receptor blocker can attenuates oxidative stress, reduces the level of ACE with the augmented production of the angiotensin 1–7 and attenuates the angiotensin II generation and increases the activity of ACE2 The antagonist of angiotensin II type 1 receptor, have modulates the profilin-1 expression and ACE2 [87]. The selective of the angiotensin II activity or synthesis mediated the augmented level of ACE2 expression and its activity in cardiac. Still, the combination of the lisinopril and losartan increases the activity of ACE2 but not ACE2 mRNA. The inhibition of ACE results in reduced formation of angiotensin II and metabolism of angiotensin 1–7, the angiotensin II type 1 receptor antagonist increases the metabolism of angiotensin II via ACE2 [88]. SARS-CoV 2 enters into the cell via the ACE2 receptor; this causes the decreased level of the ACE2 due to the binding of the spike protein to the ACE2 and no changes in ACE. This process causes the virus's entry, replicates it, and causes tissue injury via decreasing anti-atrophy, anti0-fibrosis, anti-inflammation, anti-oxidant, and vasodilation. On the other hand, the angiotensin II type 1 receptor causes pro-atrophy, pro-fibrosis, pro-inflammation, pro-oxidant, severe myocardial remodeling, vasoconstriction and vascular permeability which leads to tissue injury [89] (represented in Table 1).\nTherefore, the use of ACEi, ARBs, and mineralocorticoids has shown to have an impact on the cardiac patients affected by COVID-19, but the exact mechanism behind it is not clear. Aliskiren, a direct inhibitor of renin, resulted in reduced expression of ACE2 besides reducing the blood pressure that has been elucidated in diabetic nephropathy animal models [90]. Therefore, renin blockers, especially aliskiren, need to be further investigated as a treatment option for COVID-19 patients with comorbidities [91].\n\n6.2 SARS-CoV-2 – gastrointestinal risk\nThe ACE2 is also highly expressed in the small intestine and large intestine of the gastrointestinal tract. The S protein present on the envelope of the SARS-CoV-2 ensures higher binding affinity, thereby mediating the entry of the virus into the host cell. The presence of SARS-CoV-2 in the gastrointestinal tract was confirmed by nucleocapsid staining of the virus. The virus was found to be visualized in the cytoplasm of epithelia of duodenum and rectum [92] (represented in Table 1). Apart from the pulmonary infection, the COVID-19 affected patients also exhibited vomiting, abdominal pain, and diarrhea, which was first reported in a 35 years old man from the United States. He was presented with nausea and diarrhea on 2nd day of the infection and was hospitalized. Stools examination revealed the presence of SARS-CoV-2 RNA, which was confirmed by using reverse transcriptase-polymerase chain reaction (RT-PCR) on day 7 of infection [93]. Out of 171 COVID-19 affected children, 6.4% of them have shown vomiting, and 8.8% of them and 3 out of ten affected children have shown diarrhea as symptoms [94]. Also, previously there were two COVID-19 young cases reported with vomiting and diarrhea.\nIn China, from 552 hospitals, 1099 cases were reported, of which 3.8% and 5% were diagnosed with diarrhea and vomiting as symptoms [95]. According to another report, out of 140 COVID-19 patients from Wuhan, 39.6% exhibited gastrointestinal symptoms apart from 5% exhibiting vomiting, 12.9% exhibiting diarrhea, and 17.3% exhibiting nausea [96]. It was reported that 17 patients had shown a negative result when tested using pulmonary samples, but when tested using rectal swabs have shown to have a positive result [96].\nSimilarly, 8 out of 10 children affected by SARS-CoV-2 had shown dual results, negative results when tested by nasopharyngeal samples, and positive results when tested using a rectal swab [97]. The percentage of patients exhibiting nausea, vomiting, and diarrhea as symptoms vary between the cohort groups, whereas, in the case of certain groups, these symptoms contributed very few percent. In contrast, in the case of the other groups, a high percentage of these gastrointestinal symptoms have been recorded.\n\n6.3 SARS-CoV-2- kidney risk\nIt is suspected that whether the patients with predisposed kidney issues or COVID-19 induced acute kidney injury is fatal to the affected patients. In an article posted on March 19 by HospiMedica International staff writers, it was mentioned that patients affected by COVID-19 developed proteinuria estimated by the elevated levels of albumin in urine were diagnosed in the initial stages of infection. The majority of the affected members, i.e., 34% out of 59 patients, developed proteinuria where the elevated albumin levels serve as a biomarker for kidney damage, and 63% of the patients exhibited proteinuria and hematuria characterized by the presence of blood in the urine. In another study conducted on 710 patients hospitalized due to COVID-19. The impairment in the functioning of the kidney was observed in 27% of the 59 patients and 66% of the corona infected patients. In a later study conducted on COVID-19 affected patients from 710 hospitals, 26.7% exhibited only hematuria, and 44% exhibited proteinuria and hematuria. The impaired kidney function was found in 15% of the study population [98].\nAccording to an article published by Wang L and his colleagues reported that out of 116 COVID-19 positive cases from Renmin Hospital of Wuhan University, out of whom 111 didn't have any kidney issues in their history and the remaining five patients had chronic kidney disease (CDK). Also, out of the 111 patients, only 10.8% of the patients exhibited a slight increase in creatine or blood urea nitrogen levels, and 7.2% of the patients had shown a minute raise in the albuminuria levels. None of the patients out of 111 didn't exhibit any acute kidney injury (AKI) after the COVID-19 infection. The remaining five patients who were already undergoing continuous renal replacement therapy (CRRT) also didn't show any fatal effects after COVID-19 infection confirmed by diagnosing the renal indicators [99]. Out of 701 patients, 2% of the patients were found to have CKD, and the average lymphocytic number was found to be reduced than the normal. High sensitivity C-reactive protein levels were significantly increased. In patients reported with high levels of serum, creatine indicated high levels of serum lactose dehydrogenase. Among hospitalized patients, patients with high levels of serum creatine were mostly old and male sex. Also, they exhibited lower platelet and lymphocytic count and elevated leukocytic count. The patients with elevated procalcitonin also exhibited elevated levels of aspartate aminotransferase and lactate dehydrogenase. Acute kidney injury was significantly higher in those patients with high serum creatine levels. AKI eventually results in mortality [100] (represented in Table 1). Therefore, advanced identification of kidney diseases in patients affected by COVID-19 may help the clinicians to reduce the mortality rate due to comorbidities such as chronic kidney disease, acute kidney injury, proteinuria, and hematuria.\n\n6.4 SARS-CoV-2 – diabetes mellitus\nPatients with diabetes mellitus exhibit high levels of ACE2, and treatment with the inhibitors of ACE and ARBs augments the expression of ACE2. Diabetes condition may lead to the suspicion that the excessive expression of ACE2 aids the entry of SARS-CoV-2 into the host cells resulting in COVID-19. Since diabetes mellitus and hypertension conditions are treated, ACE2 increasing drugs are having a severe risk of COVID-19 [10].\nSimultaneously, the elevated expression of ACE2 ensures the entry of the SARS-CoV-2, attaching to the ACE2 enzyme with the help of S protein present on its envelope's surface. There forth, it became controversial whether COVID-19 affected patients who are predisposed with diabetes mellitus should be resumed with their treatment with ACEi and ARBs or not. Also, if the medication is abruptly ceased, there are chances that the patient may die due to hypertension instead of COVID-19. For this reason, it has been suggested that there is no need to stop the medication of a diabetic patient even though if he is affected by COVID-19 because there is no scientific evidence available conducted on human subjects regarding whether to use ACEi and ARBs [10].\n\n6.5 SARS-CoV-2-liver injury\nThe SARS-CoV-2 infection has shown to increase the levels of ALT, AST, and bilirubin levels, indicating injury to the hepatic tissue [9,95,101,102]. Apart from these liver serum enzymes indicating hepatic damage, the levels of albumin were significantly decreased, indicating the severity of the infection [101]. The elated levels of gamma-glutamyl transferase (GGT) were observed only in patients with severe cases. In contrast, thealkaline phosphatize (AKP) levels remained unchanged irrespective of the severity of the infection [37] (represented in Table 1).\nSARS-CoV and SARS-CoV-2 share the similarity in making an entry into the host cell through the ACE2 receptor. In addition to the type 2 cells in the lungs, both the bile duct cells and hepatocytes also express ACE2, which might be the reason that liver injury occurs during SARS-CoV-2 infection [103]. The bile duct epithelial cells are involved in immune responses and the regeneration of the hepatocytes [104]. Besides possessing a high number of ACE2 on its surface, bile duct cells are more prone to the SARS-CoV-2 infection resulting in liver injury, which indicates that the hepatocytes are not directly involved in the hepatic injury [37]. The histopathological manifestations of SARS-CoV-2 infected patients revealed mild lobular and portal activity and restrained microvascular steatosis [105]. The degree of liver damage is directly proportional to the severity of the SARS-CoV-2 infection. Still, the reason for the liver injury remains elusive. A recent study reported that the use of anti-viral medication lopinavir might result in hepatic damage [102]. Therefore, whether the liver injury is due to the virus entry or due to the drugs used as anti-viral medication needs to be elucidated.\n\n6.6 SARS-CoV-2-lung injury\nIt was possible to study the lung pathology of COVID-19 patients diagnosed with COVID-19 retrospectively after undergoing lung lobectomy surgery for adenocarcinoma. Also, the patients didn't present pneumonia at the time of surgery, indicating the initial stages of COVID-19. A female patient who was 80 years old was hospitalized due to an irregularly shaped solid nodule in the right middle lobe. On a postoperative day 1, a CT scan was performed, which indicated a few clinical manifestations. Later, the patient was presented with increased leucocytes, decreased lymphocytic count, chest tightness, wheezing, dry cough, and difficulty in breathing. Later findings confirmed that SARS-CoV-2 infected her from a patient in the same room who was already affected. Another patient who was 73 years old and had a medical history of hypertension from 20 years who underwent surgery for adenocarcinoma was discharged on the 6th-day post-operation. On postoperative day 9, the patient exhibited chest tightness, muscle pain, dry cough, and decreased lymphocytic count. His CT-scan findings revealed for viral pneumonia, and he was also tested positive for the 20,189-nC0V test. He was admitted to the infectious disease ward. After, 20 days he was discharged as he recovered. Histopathological findings showed focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, edema, multinucleated giant cells, protruding hyaline membranes, and proteinaceous exudates [106] (represented in Table 1).\nThe patients, who are recovered from COVID-19, have a possibility of chronic lung damage. Out of 70 COVID-19 pneumonia patients, 66 patients have lung damage in a different manner, which was determined by CT. This damage is in a diverse range; in the alveoli, there is a hardened tissue with the dense clumps which block the vessels in the tiny air sacs, which absorb the oxygen and cause tissue lesions. This tissue lesion acts as a sign of the long-term lung disease. Similar reports have been found in both the SARS CoV and MERS. The patients admitted with lung pneumonia shows damage in both the lungs. The CT scan of the COVID-19 patients indicates that there is a tissue lesion found over the alveoli and which can develop into the scars. There are \u003e2.9 million people have COVID-19 disease worldwide, according to April 27. 80% of the patients are having a high risk of problems, such as from breathing to respiratory failure [107].\n\n6.7 SARS-CoV-2-CNS risk\nMathew reported that it might be due to the obstructions in the nervous system, which may restrict the entry of air into the lungs [108]. The virus enters the medullary neurons during the latency phase. A possible mechanism explained was that the SARS-CoV-2 might enter the olfactory lobe of the brain through nasal chambers upon inhalation and may lead to inflammation and demyelination. Later, it spreads to the whole brain due to its ability to cross the blood-brain barrier. Some neurological symptoms exhibited by the COVID-19 infection patients include nausea, vomiting, and headache (represented in Table 1). Since the SARS-CoV-2 possess the ability to cross the blood-brain barrier, it is important to design the drugs in such a way that they can cross the blood-brain barrier and scavenges the brain from viral infection. Also, it is essential to note that the respiratory illness accompanies neurological invasion by the virus, therapeutic care must be taken to prevent the viral entry into the central nervous system (CNS) [7].\n\n6.8 SARS-CoV-2 – immunopathology\nSARS-CoV-2 infection mediates immune response, both innate and adaptive. The enhanced level of the innate response and decreased level of adaptive causes tissue damage. Upon viral infection, there is an immune response. T cells, especially the cluster of differentiation 4 (CD4+) and a group of differentiation 8 (CD8+), have an anti-viral role. CD8+ T cells are highly cytotoxic, and they killed infected cells. This T cell induces the pro-inflammatory cytokines through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling. This process further activates the cytokines and chemokines [7]. Similar to SARS-CoV, MERS, SARS-CoV-2 infection in the immune effector cells are also having the enhanced level of the cytokines such as IFN-γ, IFN-α, IL-6, IL-1β, IL-18, IL-12, TGFβ, IL-33 and TNF-α and chemokines such as CCL2, CCL5, CCL3, CXCL10, CXCL9, and CXCL8. Similar to this, severe MERS-CoV infected patient's serum shows an increased level of the cytokines and chemokines. This cytokine storm further causes multiple organ failures to further leads to the death of the SARS-CoV-2 patient [109].\nOn the other hand, the T-cells are having four types of it, such as Th1, Th2, Th17 (inflammatory), and anti-inflammatory Tregs. These Th2 cells generate IL-4 cells. The compound which can block the Th1 (Boost immune system) tends to augments the level of the Th2 (anti-inflammatory response). IL-4 triggers the Th2 cells and obstructs the Th1 response. This Th2 helps to repair form tissue dysfunction and another type of malfunction. It is found to be good that the increased level of the Th1 and Th17 plays an important role in hyperactive immune response and during autoimmune conditions. It is showed that there is an induction of the Th1/Th17 and the production of antibodies upon COVID-19 condition [110]. Contradict to this; the patient has a high level of Th2 in need of intensive care [111]. During the MERS condition, there is a reduced level of both the Th1 and Th2, which further enhances the inflammatory cytokines and causes more infection and death [112]. SARS patients who died with an older age have higher cytokines of Th2, such as IL-4, IL-10, and IL-5 [113]. This incidence supports the increased Th2 level of COVID-19 patients who needs intensive care. The mechanism behind this is based on the molecular weight of the protein of SARS-CoV2; the activity of the immune system is changed. The recent research by the F. Javier Martín Oncina in 2020 showed that based on the antigen molecular weight, the host's immune response is varied. The proteins of the SARS-CoV2 are spike protein with 140 kDa, Envelope protein with 10 kDa, Membrane protein with 25 kDa, and nucleocapsid protein with 50 kDa. The protein with more than \u003e70 kDa, such as spike protein, cannot be arrested by the B-cell, thereby it activates the inflammatory response through the Th1 response with the macrophages. This process occurs in the subcapsular sinus and through dendritic cells phagocytosis. The other proteins with \u003c70 kDa are found in the protein of SARS-CoV2, which activates the receptor of B-cell and stimulates Th2 immune response. The unremittingviral particle overload, which is unrestricted by the viral cell lysing, will be terminated by the Th1 (pro-inflammatory response). Further, it increases the protein level with a weight of \u003c70 kDa stimulates the B cells in large amounts. This induction of the B-cells leads to the condition called as Activated Induced Cell Death (AICD), which speediness the apoptosis and release of pro-inflammatory cytokines cause lymphopenia, thereby it produces IL-10, augments the shift of Th2 form Th1 response which causes further suppression of immune system, COVID-19 sepsis [114]. Correlative to that that COVID-19 patients with the high level of Th2 immune response need intensive care [111], which shows that they might be having apoptosis, lymphopenia, and suppression of immune system further causes COVID-19 sepsis [114]. Though the cell death is via Th2 immune response but the level of IL-4 is not elucidated yet. The role of IL-4 and its mechanism behind COVID-19 remain elusive (Represented in Fig. 2 ).\nFig. 2 SARS-CoV-2 enters into the host cell via binding with the cellular receptor ACE-2. It undergoes the fusion with the joining of the plasma membrane and the virus. Then it undergoes the process of the proteolytic cleavage; further, it will undergo replication and lead to the formation of the proteins. This process activates the signaling pathway, such as the NF-kB pathway, via TRIF. The interaction between the cells and the virus activates many cytokine storms. On the other hand, once the virus enters into the cell, the antigen present in that would undergo the antigen presentation cells (APC); further, this stimulates the humoral and cellular immunity. COVID-19 infects the macrophage cells, which presents to the T cell, further, which leads to the activation, differentiation of T-cells, along with the production of cytokines. This shows the negative action on the activation of CD8 T cells. Thus the mediator produced by the CD8+ T cells clears the infection of SARS-CoV. Upon COVID-19 infection, there is a reduced CD4+ and CD8+ cell level, further increasing the cytokine level in the cells, which triggers the inflammation. This mediates the production of the cytokine storm via secreting chemokine and cytokines such as IL-1β, IL-6, TNF-α, IL-8, IL-21, CCL2, CCL3, CCL5, CXCL10, TNF-β, and MCP-1 and triggers the tissue injury. On the other hand, based on the weight of the protein of SARS-CoV2, there is an activation of Th1/Th17 (boosts immune system) when the spike protein is \u003e70 kDa. In case of the Th2 (anti-inflammatory) is activated by the majority of the protein with \u003c70 kDa, then the activation of the B-cell receptor, which causes activation-induced cell death such as apoptosis and lymphopenia which is by releasing IL-10, shifting of Th1 to Th2 immune response, suppression of the immune system and further leads to the COVID-19 sepsis. The role of IL-4 has not been elucidated yet. It remains unanswerable upon COVID-19 condition with the mechanism of Th2 and Th1/Th17.\nThe wet lung is also known as acute respiratory distress syndrome (ARDS). The patient with COVID-19 has lung edema, and it needs more attention clinically. Lung edema is found to be a symptom of acute lung injury, which development to hypoxemia condition and which leads to acute respiratory distress syndrome (ARDS). The patients who are found with ARDS have more mortality. Though there is no proper treatment or vaccine treatment, ventilation with the therapy of oxygen and ventilation mechanically is mandatory. Sometimes, the treatment with the glucocorticoids (systemic or locally) would help attenuate lung edema and pulmonary inflammation [115]. But there is a need for more research to correlate the cytokine storm with wet lung pneumonia in COVID-19 patients.\n\n6.9 SARS-CoV-2 – ocular risk\nThe ACE2 receptors are also widely distributed in the superficial parts such as conjunctiva and cornea inferior parts such as iris, ciliary body, aqueous humor, trabecular meshwork, retina, and non-pigmented ciliary epithelium of the ocular globe which is mentioned out to be the intraocular renin-angiotensin system. Therefore, the distribution of ACE2 and TMPRSS2 protein must be taken into consideration to study the passage of infection through the ocular route [116]. Also, there is a chance for the virus to enter into the nasal cavity, which causes respiratory illness and the digestive system through the lacrimal canaliculi aided by the effectiveness of the tear film [117,118]. Out of 38 COVID-19 positive patients, 12 exhibited clinical manifestations, which include chemosis, epiphora, increased secretions, conjunctivitis, and conjunctival hyperemia. Researchers reported that patients exhibiting ocular symptoms would have elevated neutrophilic and lymphocytic counts, elated procalcitonin, lactate dehydrogenase, and C-reactive protein levels than those without ocular manifestations. The patients with ocular manifestations exhibited severe illness [119].\nEven though there is no such evidence, the presence of ACE2 and TMPRSS2 protein in the corneal limbal stem cells suggests that the SARS-CoV-2 may enter the bloodstream and travel to the other parts including the brain [120]. Even though there is no viral load in the conjunctiva of the SARS-CoV-2 infected patients without conjunctivitis, the risk of transmission of the virus through tears is low [121]. The exact mechanism behind the ocular risk and SARS-CoV-2 need to be elucidated further.\n\n6.10 SARS-CoV-2 – cancer risk\nCancer patients are highly vulnerable to SARS-CoV-2 infection. 18 out of 1590 COVID-19 positive cases exhibited cancer history. 5 out of 18 patients suffered from lung cancer, 4 out of 18 patients had no past information on medication and had undergone surgery or chemotherapy in the previous month, and the remaining 12 were cancer survivors. The COVID-19 was highly severe in cancer patients than non-cancer COVID-19 affected patients. Also, COVID-19 patients with cancer exhibited a severe chain of symptoms than those without a history of cancer. Also, patients with lung cancer did not exhibit severe symptoms when compared to those with other types of cancers [122].\nIn a retrospective study conducted among 1276 patients, 28 patients who have cancer were selected for the study. The mean age group people belonged to the elderly category, and 60.7% of them were males. Lung cancer was the most frequent type, followed by oesophageal and breast cancers among cancer affected patients. 10 out of 28 patients were presented with IV stage cancer. 28.6% of the patients developed COVID-19 while receiving antitumor therapy, whereas 71.4% of them developed due to the presence of infection in their vicinity. Besides, 39.2% of the patients exhibited chronic co-morbid conditions apart from cancer. 28.6% of patients died, and the remaining patients developed serious consequences even after receiving anti-viral and corticosteroids. The most common complication developed by the patients includes septic shock, acute myocardial infarction, and ARDS [123]. Therefore, more focus should be laid on the research for medication and treatment options for COVID-19 affected cancer patients. More studies are required to determine the exact mechanism behind cancer and SARS-CoV-2.\n\n6.11 SARS-CoV-2 – tuberculosis\nA study was conducted in February 2020, Shenyang, China, which involved 36 COVID-19 positive patients and was classified based on the severity of the symptoms as mild and critical. The results of these patients were compared with that of the patients affected by pneumonia caused by Mycobacterium tuberculosis from Shenyang chest hospital. The study was conducted to determine which one caused severe pneumonia, either the viral or the bacterial strain. Then the severity of tuberculosis was compared between the mild and severe COVID-19 cases and confirmed that tuberculosis due to mycobacterial strain affected patients are more susceptible to COVID-19 and enhance the severity of COVID-19 [124]. Patients with HIV undergoing treatment with antiretroviral medicines exhibit weak immune systems and are more susceptible to viral infections. Also, until now, only one HIV case had been reported with COVID-19 infection from china. The patient recovered from the infection the same as that of those without HIV. There is no evidence on whether HIV patients are more susceptible to COVID-19 infection [125].\nThe COVID-19 associated TB is found in 94th day of the nonexistence of public health interventions and 138th day in the occurrence of interventions. This occurs at the peak of an outbreak where the implementation of the intervention, out of it 11,066, is with the presence of interventions. 27,968 COVID-19 cases found in the absence of interventions, out of it 14,823, are with no interventions. This scenario shows that there is a need to take preventive measures of TB associated with COVID-19 patients. They need a prior diagnosis and proper management [126]. The main reasons for mortality are age, sex, and other co-morbid factors such as diabetes, cardiovascular diseases, and renal diseases are the main reasons for mortality.\n\n6.12 SARS-CoV-2 – Venous thromboembolism\nPeople affected with pneumonia are more prone to venous thromboembolism. Out of 1026 COVID-19 patients, 40% of them exhibited high risk, and 11% of them at high risk of developing venous thromboembolism without any prophylaxis. Prophylactic measures can prevent venous thromboembolism. Only 7 out of 140 patients at high risk for venous thromboembolism had recorded about the anticoagulation treatment. And 44 out of 407 exhibited a higher risk for bleeding. In these patients, the mechanical compressions such as intermittent pneumatic compression and elastic compression stockings are instructed, and the duration and dosage of anticoagulants should be adjusted. Also, the COVID-19 patients, along with other co-morbid conditions such as cardiovascular manifestations, respiratory failure, renal and hepatic problems, can affect the bleeding status and venous thromboembolism. Therefore, further investigations are required to reduce the risk due to venous thromboembolism and bleeding in the case of COVID-19 patients [127].\n\n6.13 SARS-CoV-2- reproductive risk\nViral infections during the first 20 weeks of gestation have shown to be more severe. The infections, such as SARS and MERS, which occurred due to coronaviruses, had reported an increased risk for pregnancy-related mortality and morbidity. Such cases among COVID-19 affected patients are not yet reported. Nine women who are in their third semester and infected with COVID-19 were reported to have outcomes as that of non-pregnant COVID-19 affected adults. In another study, out of 33 newborn infants, three infants were shown to be tested positive for COVID-19 who got the disease transferred from their mother through intrauterine vertical transmission mode [128].\n\n6.14 SARS-CoV-2 – mental illness\nAccording to a report, out of a group of 50 COVID-19 cases from a psychiatric hospital in Wuhan, China has uplifted the worry about the role of mental disorder in coronavirus transmission. The conditions include incomplete or no awareness of the risk, inability to have personal protection, and cognitive impairment. The treatment has become more challenging for people with COVID-19 infection and health disorders as co-morbid conditions [129].\n\n6.15 SARS-CoV-2 – aging and cardiovascular risk\nIt has been reported that the expression of ACE2 reduces with the increasing age. Since young patients possess high levels of ACE2, they are more prone to COVID-19 infection. Whereas, in old age people other than reduced ACE2 levels, other co-morbid conditions such as cardiovascular problems, diabetes, and hypertension might be present. The medication prescribed for these patients helps in elevating the ACE2 levels, which might enhance the viral entry. Though the treatment reduces the co-morbid severities, the viral infection is enhanced in those patients. Therefore, it is conclusive that young patients, even though they are more susceptible to the COVID-19 infection, they are less severely affected and exhibit elevated angiotensin II signaling. Whereas, the older patients who exhibit low levels of ACE2 and higher angiotensin II signaling leads to hypertension. The usage of ACEi and ARBs help in promoting the vasodilatory effects by elevating the ACE2 levels, thereby becoming susceptible to COVID-19 infection and are severely affected [130]."}

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SARS-CoV-2\n\n6.1 SARS-CoV-2 – heart disease\nACE2 plays a vital role in the cardiovascular system and is mainly involved in the functioning of the heart and development of hypertension and type II diabetes. Since ACE2 is the main target for the SARS-CoV-2 to enter inside the host cell and the ACE2 is also highly expressed in the heart apart from the lungs, indicating a chance of developing cardiac issues during SARS-CoV-2 infection. The anti-hypertensive therapy that has been prescribed for the patients is the usage of ACEi and ARBs should be carefully considered. The COVID-19 patients with comorbidities hypertension, taking the drug of ACEi or blocker of angiotensin receptor, need to switch off to other anti-hypertensive medications found to be controversial and require further studies this co-morbid conditions. The severity of the viral infection is higher in patients with comorbidities than those infected only by the virus without any predisposed health issue [85].\nThe interaction of the SARS-CoV-2 with ACE2 triggers a signal, which might be the reason to develop heart injury through the immune response triggered by T-helper cells creating a cytokine response. The SARS-CoV-2 has a structural similarity with that of SARS-CoV. SARS-CoV caused severe cardiovascular damage during its pandemic period. Therefore, it is essential to investigate SARS-CoV-2 treatment options and ensure a cardio-protective effect. The age and the predisposition of the acute coronary syndrome are the two critical factors which need to be considered in patients affected with COVID-19 [85].\nSince the ACE2 is highly expressed in pericytes, the patients infected with SARS-CoV-2 and predisposed with cardiac failure are more susceptible to develop severe cardiac problems [86]. The usage of mineralocorticoids receptor blocker can attenuates oxidative stress, reduces the level of ACE with the augmented production of the angiotensin 1–7 and attenuates the angiotensin II generation and increases the activity of ACE2 The antagonist of angiotensin II type 1 receptor, have modulates the profilin-1 expression and ACE2 [87]. The selective of the angiotensin II activity or synthesis mediated the augmented level of ACE2 expression and its activity in cardiac. Still, the combination of the lisinopril and losartan increases the activity of ACE2 but not ACE2 mRNA. The inhibition of ACE results in reduced formation of angiotensin II and metabolism of angiotensin 1–7, the angiotensin II type 1 receptor antagonist increases the metabolism of angiotensin II via ACE2 [88]. SARS-CoV 2 enters into the cell via the ACE2 receptor; this causes the decreased level of the ACE2 due to the binding of the spike protein to the ACE2 and no changes in ACE. This process causes the virus's entry, replicates it, and causes tissue injury via decreasing anti-atrophy, anti0-fibrosis, anti-inflammation, anti-oxidant, and vasodilation. On the other hand, the angiotensin II type 1 receptor causes pro-atrophy, pro-fibrosis, pro-inflammation, pro-oxidant, severe myocardial remodeling, vasoconstriction and vascular permeability which leads to tissue injury [89] (represented in Table 1).\nTherefore, the use of ACEi, ARBs, and mineralocorticoids has shown to have an impact on the cardiac patients affected by COVID-19, but the exact mechanism behind it is not clear. Aliskiren, a direct inhibitor of renin, resulted in reduced expression of ACE2 besides reducing the blood pressure that has been elucidated in diabetic nephropathy animal models [90]. Therefore, renin blockers, especially aliskiren, need to be further investigated as a treatment option for COVID-19 patients with comorbidities [91].\n\n6.2 SARS-CoV-2 – gastrointestinal risk\nThe ACE2 is also highly expressed in the small intestine and large intestine of the gastrointestinal tract. The S protein present on the envelope of the SARS-CoV-2 ensures higher binding affinity, thereby mediating the entry of the virus into the host cell. The presence of SARS-CoV-2 in the gastrointestinal tract was confirmed by nucleocapsid staining of the virus. The virus was found to be visualized in the cytoplasm of epithelia of duodenum and rectum [92] (represented in Table 1). Apart from the pulmonary infection, the COVID-19 affected patients also exhibited vomiting, abdominal pain, and diarrhea, which was first reported in a 35 years old man from the United States. He was presented with nausea and diarrhea on 2nd day of the infection and was hospitalized. Stools examination revealed the presence of SARS-CoV-2 RNA, which was confirmed by using reverse transcriptase-polymerase chain reaction (RT-PCR) on day 7 of infection [93]. Out of 171 COVID-19 affected children, 6.4% of them have shown vomiting, and 8.8% of them and 3 out of ten affected children have shown diarrhea as symptoms [94]. Also, previously there were two COVID-19 young cases reported with vomiting and diarrhea.\nIn China, from 552 hospitals, 1099 cases were reported, of which 3.8% and 5% were diagnosed with diarrhea and vomiting as symptoms [95]. According to another report, out of 140 COVID-19 patients from Wuhan, 39.6% exhibited gastrointestinal symptoms apart from 5% exhibiting vomiting, 12.9% exhibiting diarrhea, and 17.3% exhibiting nausea [96]. It was reported that 17 patients had shown a negative result when tested using pulmonary samples, but when tested using rectal swabs have shown to have a positive result [96].\nSimilarly, 8 out of 10 children affected by SARS-CoV-2 had shown dual results, negative results when tested by nasopharyngeal samples, and positive results when tested using a rectal swab [97]. The percentage of patients exhibiting nausea, vomiting, and diarrhea as symptoms vary between the cohort groups, whereas, in the case of certain groups, these symptoms contributed very few percent. In contrast, in the case of the other groups, a high percentage of these gastrointestinal symptoms have been recorded.\n\n6.3 SARS-CoV-2- kidney risk\nIt is suspected that whether the patients with predisposed kidney issues or COVID-19 induced acute kidney injury is fatal to the affected patients. In an article posted on March 19 by HospiMedica International staff writers, it was mentioned that patients affected by COVID-19 developed proteinuria estimated by the elevated levels of albumin in urine were diagnosed in the initial stages of infection. The majority of the affected members, i.e., 34% out of 59 patients, developed proteinuria where the elevated albumin levels serve as a biomarker for kidney damage, and 63% of the patients exhibited proteinuria and hematuria characterized by the presence of blood in the urine. In another study conducted on 710 patients hospitalized due to COVID-19. The impairment in the functioning of the kidney was observed in 27% of the 59 patients and 66% of the corona infected patients. In a later study conducted on COVID-19 affected patients from 710 hospitals, 26.7% exhibited only hematuria, and 44% exhibited proteinuria and hematuria. The impaired kidney function was found in 15% of the study population [98].\nAccording to an article published by Wang L and his colleagues reported that out of 116 COVID-19 positive cases from Renmin Hospital of Wuhan University, out of whom 111 didn't have any kidney issues in their history and the remaining five patients had chronic kidney disease (CDK). Also, out of the 111 patients, only 10.8% of the patients exhibited a slight increase in creatine or blood urea nitrogen levels, and 7.2% of the patients had shown a minute raise in the albuminuria levels. None of the patients out of 111 didn't exhibit any acute kidney injury (AKI) after the COVID-19 infection. The remaining five patients who were already undergoing continuous renal replacement therapy (CRRT) also didn't show any fatal effects after COVID-19 infection confirmed by diagnosing the renal indicators [99]. Out of 701 patients, 2% of the patients were found to have CKD, and the average lymphocytic number was found to be reduced than the normal. High sensitivity C-reactive protein levels were significantly increased. In patients reported with high levels of serum, creatine indicated high levels of serum lactose dehydrogenase. Among hospitalized patients, patients with high levels of serum creatine were mostly old and male sex. Also, they exhibited lower platelet and lymphocytic count and elevated leukocytic count. The patients with elevated procalcitonin also exhibited elevated levels of aspartate aminotransferase and lactate dehydrogenase. Acute kidney injury was significantly higher in those patients with high serum creatine levels. AKI eventually results in mortality [100] (represented in Table 1). Therefore, advanced identification of kidney diseases in patients affected by COVID-19 may help the clinicians to reduce the mortality rate due to comorbidities such as chronic kidney disease, acute kidney injury, proteinuria, and hematuria.\n\n6.4 SARS-CoV-2 – diabetes mellitus\nPatients with diabetes mellitus exhibit high levels of ACE2, and treatment with the inhibitors of ACE and ARBs augments the expression of ACE2. Diabetes condition may lead to the suspicion that the excessive expression of ACE2 aids the entry of SARS-CoV-2 into the host cells resulting in COVID-19. Since diabetes mellitus and hypertension conditions are treated, ACE2 increasing drugs are having a severe risk of COVID-19 [10].\nSimultaneously, the elevated expression of ACE2 ensures the entry of the SARS-CoV-2, attaching to the ACE2 enzyme with the help of S protein present on its envelope's surface. There forth, it became controversial whether COVID-19 affected patients who are predisposed with diabetes mellitus should be resumed with their treatment with ACEi and ARBs or not. Also, if the medication is abruptly ceased, there are chances that the patient may die due to hypertension instead of COVID-19. For this reason, it has been suggested that there is no need to stop the medication of a diabetic patient even though if he is affected by COVID-19 because there is no scientific evidence available conducted on human subjects regarding whether to use ACEi and ARBs [10].\n\n6.5 SARS-CoV-2-liver injury\nThe SARS-CoV-2 infection has shown to increase the levels of ALT, AST, and bilirubin levels, indicating injury to the hepatic tissue [9,95,101,102]. Apart from these liver serum enzymes indicating hepatic damage, the levels of albumin were significantly decreased, indicating the severity of the infection [101]. The elated levels of gamma-glutamyl transferase (GGT) were observed only in patients with severe cases. In contrast, thealkaline phosphatize (AKP) levels remained unchanged irrespective of the severity of the infection [37] (represented in Table 1).\nSARS-CoV and SARS-CoV-2 share the similarity in making an entry into the host cell through the ACE2 receptor. In addition to the type 2 cells in the lungs, both the bile duct cells and hepatocytes also express ACE2, which might be the reason that liver injury occurs during SARS-CoV-2 infection [103]. The bile duct epithelial cells are involved in immune responses and the regeneration of the hepatocytes [104]. Besides possessing a high number of ACE2 on its surface, bile duct cells are more prone to the SARS-CoV-2 infection resulting in liver injury, which indicates that the hepatocytes are not directly involved in the hepatic injury [37]. The histopathological manifestations of SARS-CoV-2 infected patients revealed mild lobular and portal activity and restrained microvascular steatosis [105]. The degree of liver damage is directly proportional to the severity of the SARS-CoV-2 infection. Still, the reason for the liver injury remains elusive. A recent study reported that the use of anti-viral medication lopinavir might result in hepatic damage [102]. Therefore, whether the liver injury is due to the virus entry or due to the drugs used as anti-viral medication needs to be elucidated.\n\n6.6 SARS-CoV-2-lung injury\nIt was possible to study the lung pathology of COVID-19 patients diagnosed with COVID-19 retrospectively after undergoing lung lobectomy surgery for adenocarcinoma. Also, the patients didn't present pneumonia at the time of surgery, indicating the initial stages of COVID-19. A female patient who was 80 years old was hospitalized due to an irregularly shaped solid nodule in the right middle lobe. On a postoperative day 1, a CT scan was performed, which indicated a few clinical manifestations. Later, the patient was presented with increased leucocytes, decreased lymphocytic count, chest tightness, wheezing, dry cough, and difficulty in breathing. Later findings confirmed that SARS-CoV-2 infected her from a patient in the same room who was already affected. Another patient who was 73 years old and had a medical history of hypertension from 20 years who underwent surgery for adenocarcinoma was discharged on the 6th-day post-operation. On postoperative day 9, the patient exhibited chest tightness, muscle pain, dry cough, and decreased lymphocytic count. His CT-scan findings revealed for viral pneumonia, and he was also tested positive for the 20,189-nC0V test. He was admitted to the infectious disease ward. After, 20 days he was discharged as he recovered. Histopathological findings showed focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, edema, multinucleated giant cells, protruding hyaline membranes, and proteinaceous exudates [106] (represented in Table 1).\nThe patients, who are recovered from COVID-19, have a possibility of chronic lung damage. Out of 70 COVID-19 pneumonia patients, 66 patients have lung damage in a different manner, which was determined by CT. This damage is in a diverse range; in the alveoli, there is a hardened tissue with the dense clumps which block the vessels in the tiny air sacs, which absorb the oxygen and cause tissue lesions. This tissue lesion acts as a sign of the long-term lung disease. Similar reports have been found in both the SARS CoV and MERS. The patients admitted with lung pneumonia shows damage in both the lungs. The CT scan of the COVID-19 patients indicates that there is a tissue lesion found over the alveoli and which can develop into the scars. There are \u003e2.9 million people have COVID-19 disease worldwide, according to April 27. 80% of the patients are having a high risk of problems, such as from breathing to respiratory failure [107].\n\n6.7 SARS-CoV-2-CNS risk\nMathew reported that it might be due to the obstructions in the nervous system, which may restrict the entry of air into the lungs [108]. The virus enters the medullary neurons during the latency phase. A possible mechanism explained was that the SARS-CoV-2 might enter the olfactory lobe of the brain through nasal chambers upon inhalation and may lead to inflammation and demyelination. Later, it spreads to the whole brain due to its ability to cross the blood-brain barrier. Some neurological symptoms exhibited by the COVID-19 infection patients include nausea, vomiting, and headache (represented in Table 1). Since the SARS-CoV-2 possess the ability to cross the blood-brain barrier, it is important to design the drugs in such a way that they can cross the blood-brain barrier and scavenges the brain from viral infection. Also, it is essential to note that the respiratory illness accompanies neurological invasion by the virus, therapeutic care must be taken to prevent the viral entry into the central nervous system (CNS) [7].\n\n6.8 SARS-CoV-2 – immunopathology\nSARS-CoV-2 infection mediates immune response, both innate and adaptive. The enhanced level of the innate response and decreased level of adaptive causes tissue damage. Upon viral infection, there is an immune response. T cells, especially the cluster of differentiation 4 (CD4+) and a group of differentiation 8 (CD8+), have an anti-viral role. CD8+ T cells are highly cytotoxic, and they killed infected cells. This T cell induces the pro-inflammatory cytokines through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling. This process further activates the cytokines and chemokines [7]. Similar to SARS-CoV, MERS, SARS-CoV-2 infection in the immune effector cells are also having the enhanced level of the cytokines such as IFN-γ, IFN-α, IL-6, IL-1β, IL-18, IL-12, TGFβ, IL-33 and TNF-α and chemokines such as CCL2, CCL5, CCL3, CXCL10, CXCL9, and CXCL8. Similar to this, severe MERS-CoV infected patient's serum shows an increased level of the cytokines and chemokines. This cytokine storm further causes multiple organ failures to further leads to the death of the SARS-CoV-2 patient [109].\nOn the other hand, the T-cells are having four types of it, such as Th1, Th2, Th17 (inflammatory), and anti-inflammatory Tregs. These Th2 cells generate IL-4 cells. The compound which can block the Th1 (Boost immune system) tends to augments the level of the Th2 (anti-inflammatory response). IL-4 triggers the Th2 cells and obstructs the Th1 response. This Th2 helps to repair form tissue dysfunction and another type of malfunction. It is found to be good that the increased level of the Th1 and Th17 plays an important role in hyperactive immune response and during autoimmune conditions. It is showed that there is an induction of the Th1/Th17 and the production of antibodies upon COVID-19 condition [110]. Contradict to this; the patient has a high level of Th2 in need of intensive care [111]. During the MERS condition, there is a reduced level of both the Th1 and Th2, which further enhances the inflammatory cytokines and causes more infection and death [112]. SARS patients who died with an older age have higher cytokines of Th2, such as IL-4, IL-10, and IL-5 [113]. This incidence supports the increased Th2 level of COVID-19 patients who needs intensive care. The mechanism behind this is based on the molecular weight of the protein of SARS-CoV2; the activity of the immune system is changed. The recent research by the F. Javier Martín Oncina in 2020 showed that based on the antigen molecular weight, the host's immune response is varied. The proteins of the SARS-CoV2 are spike protein with 140 kDa, Envelope protein with 10 kDa, Membrane protein with 25 kDa, and nucleocapsid protein with 50 kDa. The protein with more than \u003e70 kDa, such as spike protein, cannot be arrested by the B-cell, thereby it activates the inflammatory response through the Th1 response with the macrophages. This process occurs in the subcapsular sinus and through dendritic cells phagocytosis. The other proteins with \u003c70 kDa are found in the protein of SARS-CoV2, which activates the receptor of B-cell and stimulates Th2 immune response. The unremittingviral particle overload, which is unrestricted by the viral cell lysing, will be terminated by the Th1 (pro-inflammatory response). Further, it increases the protein level with a weight of \u003c70 kDa stimulates the B cells in large amounts. This induction of the B-cells leads to the condition called as Activated Induced Cell Death (AICD), which speediness the apoptosis and release of pro-inflammatory cytokines cause lymphopenia, thereby it produces IL-10, augments the shift of Th2 form Th1 response which causes further suppression of immune system, COVID-19 sepsis [114]. Correlative to that that COVID-19 patients with the high level of Th2 immune response need intensive care [111], which shows that they might be having apoptosis, lymphopenia, and suppression of immune system further causes COVID-19 sepsis [114]. Though the cell death is via Th2 immune response but the level of IL-4 is not elucidated yet. The role of IL-4 and its mechanism behind COVID-19 remain elusive (Represented in Fig. 2 ).\nFig. 2 SARS-CoV-2 enters into the host cell via binding with the cellular receptor ACE-2. It undergoes the fusion with the joining of the plasma membrane and the virus. Then it undergoes the process of the proteolytic cleavage; further, it will undergo replication and lead to the formation of the proteins. This process activates the signaling pathway, such as the NF-kB pathway, via TRIF. The interaction between the cells and the virus activates many cytokine storms. On the other hand, once the virus enters into the cell, the antigen present in that would undergo the antigen presentation cells (APC); further, this stimulates the humoral and cellular immunity. COVID-19 infects the macrophage cells, which presents to the T cell, further, which leads to the activation, differentiation of T-cells, along with the production of cytokines. This shows the negative action on the activation of CD8 T cells. Thus the mediator produced by the CD8+ T cells clears the infection of SARS-CoV. Upon COVID-19 infection, there is a reduced CD4+ and CD8+ cell level, further increasing the cytokine level in the cells, which triggers the inflammation. This mediates the production of the cytokine storm via secreting chemokine and cytokines such as IL-1β, IL-6, TNF-α, IL-8, IL-21, CCL2, CCL3, CCL5, CXCL10, TNF-β, and MCP-1 and triggers the tissue injury. On the other hand, based on the weight of the protein of SARS-CoV2, there is an activation of Th1/Th17 (boosts immune system) when the spike protein is \u003e70 kDa. In case of the Th2 (anti-inflammatory) is activated by the majority of the protein with \u003c70 kDa, then the activation of the B-cell receptor, which causes activation-induced cell death such as apoptosis and lymphopenia which is by releasing IL-10, shifting of Th1 to Th2 immune response, suppression of the immune system and further leads to the COVID-19 sepsis. The role of IL-4 has not been elucidated yet. It remains unanswerable upon COVID-19 condition with the mechanism of Th2 and Th1/Th17.\nThe wet lung is also known as acute respiratory distress syndrome (ARDS). The patient with COVID-19 has lung edema, and it needs more attention clinically. Lung edema is found to be a symptom of acute lung injury, which development to hypoxemia condition and which leads to acute respiratory distress syndrome (ARDS). The patients who are found with ARDS have more mortality. Though there is no proper treatment or vaccine treatment, ventilation with the therapy of oxygen and ventilation mechanically is mandatory. Sometimes, the treatment with the glucocorticoids (systemic or locally) would help attenuate lung edema and pulmonary inflammation [115]. But there is a need for more research to correlate the cytokine storm with wet lung pneumonia in COVID-19 patients.\n\n6.9 SARS-CoV-2 – ocular risk\nThe ACE2 receptors are also widely distributed in the superficial parts such as conjunctiva and cornea inferior parts such as iris, ciliary body, aqueous humor, trabecular meshwork, retina, and non-pigmented ciliary epithelium of the ocular globe which is mentioned out to be the intraocular renin-angiotensin system. Therefore, the distribution of ACE2 and TMPRSS2 protein must be taken into consideration to study the passage of infection through the ocular route [116]. Also, there is a chance for the virus to enter into the nasal cavity, which causes respiratory illness and the digestive system through the lacrimal canaliculi aided by the effectiveness of the tear film [117,118]. Out of 38 COVID-19 positive patients, 12 exhibited clinical manifestations, which include chemosis, epiphora, increased secretions, conjunctivitis, and conjunctival hyperemia. Researchers reported that patients exhibiting ocular symptoms would have elevated neutrophilic and lymphocytic counts, elated procalcitonin, lactate dehydrogenase, and C-reactive protein levels than those without ocular manifestations. The patients with ocular manifestations exhibited severe illness [119].\nEven though there is no such evidence, the presence of ACE2 and TMPRSS2 protein in the corneal limbal stem cells suggests that the SARS-CoV-2 may enter the bloodstream and travel to the other parts including the brain [120]. Even though there is no viral load in the conjunctiva of the SARS-CoV-2 infected patients without conjunctivitis, the risk of transmission of the virus through tears is low [121]. The exact mechanism behind the ocular risk and SARS-CoV-2 need to be elucidated further.\n\n6.10 SARS-CoV-2 – cancer risk\nCancer patients are highly vulnerable to SARS-CoV-2 infection. 18 out of 1590 COVID-19 positive cases exhibited cancer history. 5 out of 18 patients suffered from lung cancer, 4 out of 18 patients had no past information on medication and had undergone surgery or chemotherapy in the previous month, and the remaining 12 were cancer survivors. The COVID-19 was highly severe in cancer patients than non-cancer COVID-19 affected patients. Also, COVID-19 patients with cancer exhibited a severe chain of symptoms than those without a history of cancer. Also, patients with lung cancer did not exhibit severe symptoms when compared to those with other types of cancers [122].\nIn a retrospective study conducted among 1276 patients, 28 patients who have cancer were selected for the study. The mean age group people belonged to the elderly category, and 60.7% of them were males. Lung cancer was the most frequent type, followed by oesophageal and breast cancers among cancer affected patients. 10 out of 28 patients were presented with IV stage cancer. 28.6% of the patients developed COVID-19 while receiving antitumor therapy, whereas 71.4% of them developed due to the presence of infection in their vicinity. Besides, 39.2% of the patients exhibited chronic co-morbid conditions apart from cancer. 28.6% of patients died, and the remaining patients developed serious consequences even after receiving anti-viral and corticosteroids. The most common complication developed by the patients includes septic shock, acute myocardial infarction, and ARDS [123]. Therefore, more focus should be laid on the research for medication and treatment options for COVID-19 affected cancer patients. More studies are required to determine the exact mechanism behind cancer and SARS-CoV-2.\n\n6.11 SARS-CoV-2 – tuberculosis\nA study was conducted in February 2020, Shenyang, China, which involved 36 COVID-19 positive patients and was classified based on the severity of the symptoms as mild and critical. The results of these patients were compared with that of the patients affected by pneumonia caused by Mycobacterium tuberculosis from Shenyang chest hospital. The study was conducted to determine which one caused severe pneumonia, either the viral or the bacterial strain. Then the severity of tuberculosis was compared between the mild and severe COVID-19 cases and confirmed that tuberculosis due to mycobacterial strain affected patients are more susceptible to COVID-19 and enhance the severity of COVID-19 [124]. Patients with HIV undergoing treatment with antiretroviral medicines exhibit weak immune systems and are more susceptible to viral infections. Also, until now, only one HIV case had been reported with COVID-19 infection from china. The patient recovered from the infection the same as that of those without HIV. There is no evidence on whether HIV patients are more susceptible to COVID-19 infection [125].\nThe COVID-19 associated TB is found in 94th day of the nonexistence of public health interventions and 138th day in the occurrence of interventions. This occurs at the peak of an outbreak where the implementation of the intervention, out of it 11,066, is with the presence of interventions. 27,968 COVID-19 cases found in the absence of interventions, out of it 14,823, are with no interventions. This scenario shows that there is a need to take preventive measures of TB associated with COVID-19 patients. They need a prior diagnosis and proper management [126]. The main reasons for mortality are age, sex, and other co-morbid factors such as diabetes, cardiovascular diseases, and renal diseases are the main reasons for mortality.\n\n6.12 SARS-CoV-2 – Venous thromboembolism\nPeople affected with pneumonia are more prone to venous thromboembolism. Out of 1026 COVID-19 patients, 40% of them exhibited high risk, and 11% of them at high risk of developing venous thromboembolism without any prophylaxis. Prophylactic measures can prevent venous thromboembolism. Only 7 out of 140 patients at high risk for venous thromboembolism had recorded about the anticoagulation treatment. And 44 out of 407 exhibited a higher risk for bleeding. In these patients, the mechanical compressions such as intermittent pneumatic compression and elastic compression stockings are instructed, and the duration and dosage of anticoagulants should be adjusted. Also, the COVID-19 patients, along with other co-morbid conditions such as cardiovascular manifestations, respiratory failure, renal and hepatic problems, can affect the bleeding status and venous thromboembolism. Therefore, further investigations are required to reduce the risk due to venous thromboembolism and bleeding in the case of COVID-19 patients [127].\n\n6.13 SARS-CoV-2- reproductive risk\nViral infections during the first 20 weeks of gestation have shown to be more severe. The infections, such as SARS and MERS, which occurred due to coronaviruses, had reported an increased risk for pregnancy-related mortality and morbidity. Such cases among COVID-19 affected patients are not yet reported. Nine women who are in their third semester and infected with COVID-19 were reported to have outcomes as that of non-pregnant COVID-19 affected adults. In another study, out of 33 newborn infants, three infants were shown to be tested positive for COVID-19 who got the disease transferred from their mother through intrauterine vertical transmission mode [128].\n\n6.14 SARS-CoV-2 – mental illness\nAccording to a report, out of a group of 50 COVID-19 cases from a psychiatric hospital in Wuhan, China has uplifted the worry about the role of mental disorder in coronavirus transmission. The conditions include incomplete or no awareness of the risk, inability to have personal protection, and cognitive impairment. The treatment has become more challenging for people with COVID-19 infection and health disorders as co-morbid conditions [129].\n\n6.15 SARS-CoV-2 – aging and cardiovascular risk\nIt has been reported that the expression of ACE2 reduces with the increasing age. Since young patients possess high levels of ACE2, they are more prone to COVID-19 infection. Whereas, in old age people other than reduced ACE2 levels, other co-morbid conditions such as cardiovascular problems, diabetes, and hypertension might be present. The medication prescribed for these patients helps in elevating the ACE2 levels, which might enhance the viral entry. Though the treatment reduces the co-morbid severities, the viral infection is enhanced in those patients. Therefore, it is conclusive that young patients, even though they are more susceptible to the COVID-19 infection, they are less severely affected and exhibit elevated angiotensin II signaling. Whereas, the older patients who exhibit low levels of ACE2 and higher angiotensin II signaling leads to hypertension. The usage of ACEi and ARBs help in promoting the vasodilatory effects by elevating the ACE2 levels, thereby becoming susceptible to COVID-19 infection and are severely affected [130]."}

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SARS-CoV-2\n\n6.1 SARS-CoV-2 – heart disease\nACE2 plays a vital role in the cardiovascular system and is mainly involved in the functioning of the heart and development of hypertension and type II diabetes. Since ACE2 is the main target for the SARS-CoV-2 to enter inside the host cell and the ACE2 is also highly expressed in the heart apart from the lungs, indicating a chance of developing cardiac issues during SARS-CoV-2 infection. The anti-hypertensive therapy that has been prescribed for the patients is the usage of ACEi and ARBs should be carefully considered. The COVID-19 patients with comorbidities hypertension, taking the drug of ACEi or blocker of angiotensin receptor, need to switch off to other anti-hypertensive medications found to be controversial and require further studies this co-morbid conditions. The severity of the viral infection is higher in patients with comorbidities than those infected only by the virus without any predisposed health issue [85].\nThe interaction of the SARS-CoV-2 with ACE2 triggers a signal, which might be the reason to develop heart injury through the immune response triggered by T-helper cells creating a cytokine response. The SARS-CoV-2 has a structural similarity with that of SARS-CoV. SARS-CoV caused severe cardiovascular damage during its pandemic period. Therefore, it is essential to investigate SARS-CoV-2 treatment options and ensure a cardio-protective effect. The age and the predisposition of the acute coronary syndrome are the two critical factors which need to be considered in patients affected with COVID-19 [85].\nSince the ACE2 is highly expressed in pericytes, the patients infected with SARS-CoV-2 and predisposed with cardiac failure are more susceptible to develop severe cardiac problems [86]. The usage of mineralocorticoids receptor blocker can attenuates oxidative stress, reduces the level of ACE with the augmented production of the angiotensin 1–7 and attenuates the angiotensin II generation and increases the activity of ACE2 The antagonist of angiotensin II type 1 receptor, have modulates the profilin-1 expression and ACE2 [87]. The selective of the angiotensin II activity or synthesis mediated the augmented level of ACE2 expression and its activity in cardiac. Still, the combination of the lisinopril and losartan increases the activity of ACE2 but not ACE2 mRNA. The inhibition of ACE results in reduced formation of angiotensin II and metabolism of angiotensin 1–7, the angiotensin II type 1 receptor antagonist increases the metabolism of angiotensin II via ACE2 [88]. SARS-CoV 2 enters into the cell via the ACE2 receptor; this causes the decreased level of the ACE2 due to the binding of the spike protein to the ACE2 and no changes in ACE. This process causes the virus's entry, replicates it, and causes tissue injury via decreasing anti-atrophy, anti0-fibrosis, anti-inflammation, anti-oxidant, and vasodilation. On the other hand, the angiotensin II type 1 receptor causes pro-atrophy, pro-fibrosis, pro-inflammation, pro-oxidant, severe myocardial remodeling, vasoconstriction and vascular permeability which leads to tissue injury [89] (represented in Table 1).\nTherefore, the use of ACEi, ARBs, and mineralocorticoids has shown to have an impact on the cardiac patients affected by COVID-19, but the exact mechanism behind it is not clear. Aliskiren, a direct inhibitor of renin, resulted in reduced expression of ACE2 besides reducing the blood pressure that has been elucidated in diabetic nephropathy animal models [90]. Therefore, renin blockers, especially aliskiren, need to be further investigated as a treatment option for COVID-19 patients with comorbidities [91].\n\n6.2 SARS-CoV-2 – gastrointestinal risk\nThe ACE2 is also highly expressed in the small intestine and large intestine of the gastrointestinal tract. The S protein present on the envelope of the SARS-CoV-2 ensures higher binding affinity, thereby mediating the entry of the virus into the host cell. The presence of SARS-CoV-2 in the gastrointestinal tract was confirmed by nucleocapsid staining of the virus. The virus was found to be visualized in the cytoplasm of epithelia of duodenum and rectum [92] (represented in Table 1). Apart from the pulmonary infection, the COVID-19 affected patients also exhibited vomiting, abdominal pain, and diarrhea, which was first reported in a 35 years old man from the United States. He was presented with nausea and diarrhea on 2nd day of the infection and was hospitalized. Stools examination revealed the presence of SARS-CoV-2 RNA, which was confirmed by using reverse transcriptase-polymerase chain reaction (RT-PCR) on day 7 of infection [93]. Out of 171 COVID-19 affected children, 6.4% of them have shown vomiting, and 8.8% of them and 3 out of ten affected children have shown diarrhea as symptoms [94]. Also, previously there were two COVID-19 young cases reported with vomiting and diarrhea.\nIn China, from 552 hospitals, 1099 cases were reported, of which 3.8% and 5% were diagnosed with diarrhea and vomiting as symptoms [95]. According to another report, out of 140 COVID-19 patients from Wuhan, 39.6% exhibited gastrointestinal symptoms apart from 5% exhibiting vomiting, 12.9% exhibiting diarrhea, and 17.3% exhibiting nausea [96]. It was reported that 17 patients had shown a negative result when tested using pulmonary samples, but when tested using rectal swabs have shown to have a positive result [96].\nSimilarly, 8 out of 10 children affected by SARS-CoV-2 had shown dual results, negative results when tested by nasopharyngeal samples, and positive results when tested using a rectal swab [97]. The percentage of patients exhibiting nausea, vomiting, and diarrhea as symptoms vary between the cohort groups, whereas, in the case of certain groups, these symptoms contributed very few percent. In contrast, in the case of the other groups, a high percentage of these gastrointestinal symptoms have been recorded.\n\n6.3 SARS-CoV-2- kidney risk\nIt is suspected that whether the patients with predisposed kidney issues or COVID-19 induced acute kidney injury is fatal to the affected patients. In an article posted on March 19 by HospiMedica International staff writers, it was mentioned that patients affected by COVID-19 developed proteinuria estimated by the elevated levels of albumin in urine were diagnosed in the initial stages of infection. The majority of the affected members, i.e., 34% out of 59 patients, developed proteinuria where the elevated albumin levels serve as a biomarker for kidney damage, and 63% of the patients exhibited proteinuria and hematuria characterized by the presence of blood in the urine. In another study conducted on 710 patients hospitalized due to COVID-19. The impairment in the functioning of the kidney was observed in 27% of the 59 patients and 66% of the corona infected patients. In a later study conducted on COVID-19 affected patients from 710 hospitals, 26.7% exhibited only hematuria, and 44% exhibited proteinuria and hematuria. The impaired kidney function was found in 15% of the study population [98].\nAccording to an article published by Wang L and his colleagues reported that out of 116 COVID-19 positive cases from Renmin Hospital of Wuhan University, out of whom 111 didn't have any kidney issues in their history and the remaining five patients had chronic kidney disease (CDK). Also, out of the 111 patients, only 10.8% of the patients exhibited a slight increase in creatine or blood urea nitrogen levels, and 7.2% of the patients had shown a minute raise in the albuminuria levels. None of the patients out of 111 didn't exhibit any acute kidney injury (AKI) after the COVID-19 infection. The remaining five patients who were already undergoing continuous renal replacement therapy (CRRT) also didn't show any fatal effects after COVID-19 infection confirmed by diagnosing the renal indicators [99]. Out of 701 patients, 2% of the patients were found to have CKD, and the average lymphocytic number was found to be reduced than the normal. High sensitivity C-reactive protein levels were significantly increased. In patients reported with high levels of serum, creatine indicated high levels of serum lactose dehydrogenase. Among hospitalized patients, patients with high levels of serum creatine were mostly old and male sex. Also, they exhibited lower platelet and lymphocytic count and elevated leukocytic count. The patients with elevated procalcitonin also exhibited elevated levels of aspartate aminotransferase and lactate dehydrogenase. Acute kidney injury was significantly higher in those patients with high serum creatine levels. AKI eventually results in mortality [100] (represented in Table 1). Therefore, advanced identification of kidney diseases in patients affected by COVID-19 may help the clinicians to reduce the mortality rate due to comorbidities such as chronic kidney disease, acute kidney injury, proteinuria, and hematuria.\n\n6.4 SARS-CoV-2 – diabetes mellitus\nPatients with diabetes mellitus exhibit high levels of ACE2, and treatment with the inhibitors of ACE and ARBs augments the expression of ACE2. Diabetes condition may lead to the suspicion that the excessive expression of ACE2 aids the entry of SARS-CoV-2 into the host cells resulting in COVID-19. Since diabetes mellitus and hypertension conditions are treated, ACE2 increasing drugs are having a severe risk of COVID-19 [10].\nSimultaneously, the elevated expression of ACE2 ensures the entry of the SARS-CoV-2, attaching to the ACE2 enzyme with the help of S protein present on its envelope's surface. There forth, it became controversial whether COVID-19 affected patients who are predisposed with diabetes mellitus should be resumed with their treatment with ACEi and ARBs or not. Also, if the medication is abruptly ceased, there are chances that the patient may die due to hypertension instead of COVID-19. For this reason, it has been suggested that there is no need to stop the medication of a diabetic patient even though if he is affected by COVID-19 because there is no scientific evidence available conducted on human subjects regarding whether to use ACEi and ARBs [10].\n\n6.5 SARS-CoV-2-liver injury\nThe SARS-CoV-2 infection has shown to increase the levels of ALT, AST, and bilirubin levels, indicating injury to the hepatic tissue [9,95,101,102]. Apart from these liver serum enzymes indicating hepatic damage, the levels of albumin were significantly decreased, indicating the severity of the infection [101]. The elated levels of gamma-glutamyl transferase (GGT) were observed only in patients with severe cases. In contrast, thealkaline phosphatize (AKP) levels remained unchanged irrespective of the severity of the infection [37] (represented in Table 1).\nSARS-CoV and SARS-CoV-2 share the similarity in making an entry into the host cell through the ACE2 receptor. In addition to the type 2 cells in the lungs, both the bile duct cells and hepatocytes also express ACE2, which might be the reason that liver injury occurs during SARS-CoV-2 infection [103]. The bile duct epithelial cells are involved in immune responses and the regeneration of the hepatocytes [104]. Besides possessing a high number of ACE2 on its surface, bile duct cells are more prone to the SARS-CoV-2 infection resulting in liver injury, which indicates that the hepatocytes are not directly involved in the hepatic injury [37]. The histopathological manifestations of SARS-CoV-2 infected patients revealed mild lobular and portal activity and restrained microvascular steatosis [105]. The degree of liver damage is directly proportional to the severity of the SARS-CoV-2 infection. Still, the reason for the liver injury remains elusive. A recent study reported that the use of anti-viral medication lopinavir might result in hepatic damage [102]. Therefore, whether the liver injury is due to the virus entry or due to the drugs used as anti-viral medication needs to be elucidated.\n\n6.6 SARS-CoV-2-lung injury\nIt was possible to study the lung pathology of COVID-19 patients diagnosed with COVID-19 retrospectively after undergoing lung lobectomy surgery for adenocarcinoma. Also, the patients didn't present pneumonia at the time of surgery, indicating the initial stages of COVID-19. A female patient who was 80 years old was hospitalized due to an irregularly shaped solid nodule in the right middle lobe. On a postoperative day 1, a CT scan was performed, which indicated a few clinical manifestations. Later, the patient was presented with increased leucocytes, decreased lymphocytic count, chest tightness, wheezing, dry cough, and difficulty in breathing. Later findings confirmed that SARS-CoV-2 infected her from a patient in the same room who was already affected. Another patient who was 73 years old and had a medical history of hypertension from 20 years who underwent surgery for adenocarcinoma was discharged on the 6th-day post-operation. On postoperative day 9, the patient exhibited chest tightness, muscle pain, dry cough, and decreased lymphocytic count. His CT-scan findings revealed for viral pneumonia, and he was also tested positive for the 20,189-nC0V test. He was admitted to the infectious disease ward. After, 20 days he was discharged as he recovered. Histopathological findings showed focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, edema, multinucleated giant cells, protruding hyaline membranes, and proteinaceous exudates [106] (represented in Table 1).\nThe patients, who are recovered from COVID-19, have a possibility of chronic lung damage. Out of 70 COVID-19 pneumonia patients, 66 patients have lung damage in a different manner, which was determined by CT. This damage is in a diverse range; in the alveoli, there is a hardened tissue with the dense clumps which block the vessels in the tiny air sacs, which absorb the oxygen and cause tissue lesions. This tissue lesion acts as a sign of the long-term lung disease. Similar reports have been found in both the SARS CoV and MERS. The patients admitted with lung pneumonia shows damage in both the lungs. The CT scan of the COVID-19 patients indicates that there is a tissue lesion found over the alveoli and which can develop into the scars. There are \u003e2.9 million people have COVID-19 disease worldwide, according to April 27. 80% of the patients are having a high risk of problems, such as from breathing to respiratory failure [107].\n\n6.7 SARS-CoV-2-CNS risk\nMathew reported that it might be due to the obstructions in the nervous system, which may restrict the entry of air into the lungs [108]. The virus enters the medullary neurons during the latency phase. A possible mechanism explained was that the SARS-CoV-2 might enter the olfactory lobe of the brain through nasal chambers upon inhalation and may lead to inflammation and demyelination. Later, it spreads to the whole brain due to its ability to cross the blood-brain barrier. Some neurological symptoms exhibited by the COVID-19 infection patients include nausea, vomiting, and headache (represented in Table 1). Since the SARS-CoV-2 possess the ability to cross the blood-brain barrier, it is important to design the drugs in such a way that they can cross the blood-brain barrier and scavenges the brain from viral infection. Also, it is essential to note that the respiratory illness accompanies neurological invasion by the virus, therapeutic care must be taken to prevent the viral entry into the central nervous system (CNS) [7].\n\n6.8 SARS-CoV-2 – immunopathology\nSARS-CoV-2 infection mediates immune response, both innate and adaptive. The enhanced level of the innate response and decreased level of adaptive causes tissue damage. Upon viral infection, there is an immune response. T cells, especially the cluster of differentiation 4 (CD4+) and a group of differentiation 8 (CD8+), have an anti-viral role. CD8+ T cells are highly cytotoxic, and they killed infected cells. This T cell induces the pro-inflammatory cytokines through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling. This process further activates the cytokines and chemokines [7]. Similar to SARS-CoV, MERS, SARS-CoV-2 infection in the immune effector cells are also having the enhanced level of the cytokines such as IFN-γ, IFN-α, IL-6, IL-1β, IL-18, IL-12, TGFβ, IL-33 and TNF-α and chemokines such as CCL2, CCL5, CCL3, CXCL10, CXCL9, and CXCL8. Similar to this, severe MERS-CoV infected patient's serum shows an increased level of the cytokines and chemokines. This cytokine storm further causes multiple organ failures to further leads to the death of the SARS-CoV-2 patient [109].\nOn the other hand, the T-cells are having four types of it, such as Th1, Th2, Th17 (inflammatory), and anti-inflammatory Tregs. These Th2 cells generate IL-4 cells. The compound which can block the Th1 (Boost immune system) tends to augments the level of the Th2 (anti-inflammatory response). IL-4 triggers the Th2 cells and obstructs the Th1 response. This Th2 helps to repair form tissue dysfunction and another type of malfunction. It is found to be good that the increased level of the Th1 and Th17 plays an important role in hyperactive immune response and during autoimmune conditions. It is showed that there is an induction of the Th1/Th17 and the production of antibodies upon COVID-19 condition [110]. Contradict to this; the patient has a high level of Th2 in need of intensive care [111]. During the MERS condition, there is a reduced level of both the Th1 and Th2, which further enhances the inflammatory cytokines and causes more infection and death [112]. SARS patients who died with an older age have higher cytokines of Th2, such as IL-4, IL-10, and IL-5 [113]. This incidence supports the increased Th2 level of COVID-19 patients who needs intensive care. The mechanism behind this is based on the molecular weight of the protein of SARS-CoV2; the activity of the immune system is changed. The recent research by the F. Javier Martín Oncina in 2020 showed that based on the antigen molecular weight, the host's immune response is varied. The proteins of the SARS-CoV2 are spike protein with 140 kDa, Envelope protein with 10 kDa, Membrane protein with 25 kDa, and nucleocapsid protein with 50 kDa. The protein with more than \u003e70 kDa, such as spike protein, cannot be arrested by the B-cell, thereby it activates the inflammatory response through the Th1 response with the macrophages. This process occurs in the subcapsular sinus and through dendritic cells phagocytosis. The other proteins with \u003c70 kDa are found in the protein of SARS-CoV2, which activates the receptor of B-cell and stimulates Th2 immune response. The unremittingviral particle overload, which is unrestricted by the viral cell lysing, will be terminated by the Th1 (pro-inflammatory response). Further, it increases the protein level with a weight of \u003c70 kDa stimulates the B cells in large amounts. This induction of the B-cells leads to the condition called as Activated Induced Cell Death (AICD), which speediness the apoptosis and release of pro-inflammatory cytokines cause lymphopenia, thereby it produces IL-10, augments the shift of Th2 form Th1 response which causes further suppression of immune system, COVID-19 sepsis [114]. Correlative to that that COVID-19 patients with the high level of Th2 immune response need intensive care [111], which shows that they might be having apoptosis, lymphopenia, and suppression of immune system further causes COVID-19 sepsis [114]. Though the cell death is via Th2 immune response but the level of IL-4 is not elucidated yet. The role of IL-4 and its mechanism behind COVID-19 remain elusive (Represented in Fig. 2 ).\nFig. 2 SARS-CoV-2 enters into the host cell via binding with the cellular receptor ACE-2. It undergoes the fusion with the joining of the plasma membrane and the virus. Then it undergoes the process of the proteolytic cleavage; further, it will undergo replication and lead to the formation of the proteins. This process activates the signaling pathway, such as the NF-kB pathway, via TRIF. The interaction between the cells and the virus activates many cytokine storms. On the other hand, once the virus enters into the cell, the antigen present in that would undergo the antigen presentation cells (APC); further, this stimulates the humoral and cellular immunity. COVID-19 infects the macrophage cells, which presents to the T cell, further, which leads to the activation, differentiation of T-cells, along with the production of cytokines. This shows the negative action on the activation of CD8 T cells. Thus the mediator produced by the CD8+ T cells clears the infection of SARS-CoV. Upon COVID-19 infection, there is a reduced CD4+ and CD8+ cell level, further increasing the cytokine level in the cells, which triggers the inflammation. This mediates the production of the cytokine storm via secreting chemokine and cytokines such as IL-1β, IL-6, TNF-α, IL-8, IL-21, CCL2, CCL3, CCL5, CXCL10, TNF-β, and MCP-1 and triggers the tissue injury. On the other hand, based on the weight of the protein of SARS-CoV2, there is an activation of Th1/Th17 (boosts immune system) when the spike protein is \u003e70 kDa. In case of the Th2 (anti-inflammatory) is activated by the majority of the protein with \u003c70 kDa, then the activation of the B-cell receptor, which causes activation-induced cell death such as apoptosis and lymphopenia which is by releasing IL-10, shifting of Th1 to Th2 immune response, suppression of the immune system and further leads to the COVID-19 sepsis. The role of IL-4 has not been elucidated yet. It remains unanswerable upon COVID-19 condition with the mechanism of Th2 and Th1/Th17.\nThe wet lung is also known as acute respiratory distress syndrome (ARDS). The patient with COVID-19 has lung edema, and it needs more attention clinically. Lung edema is found to be a symptom of acute lung injury, which development to hypoxemia condition and which leads to acute respiratory distress syndrome (ARDS). The patients who are found with ARDS have more mortality. Though there is no proper treatment or vaccine treatment, ventilation with the therapy of oxygen and ventilation mechanically is mandatory. Sometimes, the treatment with the glucocorticoids (systemic or locally) would help attenuate lung edema and pulmonary inflammation [115]. But there is a need for more research to correlate the cytokine storm with wet lung pneumonia in COVID-19 patients.\n\n6.9 SARS-CoV-2 – ocular risk\nThe ACE2 receptors are also widely distributed in the superficial parts such as conjunctiva and cornea inferior parts such as iris, ciliary body, aqueous humor, trabecular meshwork, retina, and non-pigmented ciliary epithelium of the ocular globe which is mentioned out to be the intraocular renin-angiotensin system. Therefore, the distribution of ACE2 and TMPRSS2 protein must be taken into consideration to study the passage of infection through the ocular route [116]. Also, there is a chance for the virus to enter into the nasal cavity, which causes respiratory illness and the digestive system through the lacrimal canaliculi aided by the effectiveness of the tear film [117,118]. Out of 38 COVID-19 positive patients, 12 exhibited clinical manifestations, which include chemosis, epiphora, increased secretions, conjunctivitis, and conjunctival hyperemia. Researchers reported that patients exhibiting ocular symptoms would have elevated neutrophilic and lymphocytic counts, elated procalcitonin, lactate dehydrogenase, and C-reactive protein levels than those without ocular manifestations. The patients with ocular manifestations exhibited severe illness [119].\nEven though there is no such evidence, the presence of ACE2 and TMPRSS2 protein in the corneal limbal stem cells suggests that the SARS-CoV-2 may enter the bloodstream and travel to the other parts including the brain [120]. Even though there is no viral load in the conjunctiva of the SARS-CoV-2 infected patients without conjunctivitis, the risk of transmission of the virus through tears is low [121]. The exact mechanism behind the ocular risk and SARS-CoV-2 need to be elucidated further.\n\n6.10 SARS-CoV-2 – cancer risk\nCancer patients are highly vulnerable to SARS-CoV-2 infection. 18 out of 1590 COVID-19 positive cases exhibited cancer history. 5 out of 18 patients suffered from lung cancer, 4 out of 18 patients had no past information on medication and had undergone surgery or chemotherapy in the previous month, and the remaining 12 were cancer survivors. The COVID-19 was highly severe in cancer patients than non-cancer COVID-19 affected patients. Also, COVID-19 patients with cancer exhibited a severe chain of symptoms than those without a history of cancer. Also, patients with lung cancer did not exhibit severe symptoms when compared to those with other types of cancers [122].\nIn a retrospective study conducted among 1276 patients, 28 patients who have cancer were selected for the study. The mean age group people belonged to the elderly category, and 60.7% of them were males. Lung cancer was the most frequent type, followed by oesophageal and breast cancers among cancer affected patients. 10 out of 28 patients were presented with IV stage cancer. 28.6% of the patients developed COVID-19 while receiving antitumor therapy, whereas 71.4% of them developed due to the presence of infection in their vicinity. Besides, 39.2% of the patients exhibited chronic co-morbid conditions apart from cancer. 28.6% of patients died, and the remaining patients developed serious consequences even after receiving anti-viral and corticosteroids. The most common complication developed by the patients includes septic shock, acute myocardial infarction, and ARDS [123]. Therefore, more focus should be laid on the research for medication and treatment options for COVID-19 affected cancer patients. More studies are required to determine the exact mechanism behind cancer and SARS-CoV-2.\n\n6.11 SARS-CoV-2 – tuberculosis\nA study was conducted in February 2020, Shenyang, China, which involved 36 COVID-19 positive patients and was classified based on the severity of the symptoms as mild and critical. The results of these patients were compared with that of the patients affected by pneumonia caused by Mycobacterium tuberculosis from Shenyang chest hospital. The study was conducted to determine which one caused severe pneumonia, either the viral or the bacterial strain. Then the severity of tuberculosis was compared between the mild and severe COVID-19 cases and confirmed that tuberculosis due to mycobacterial strain affected patients are more susceptible to COVID-19 and enhance the severity of COVID-19 [124]. Patients with HIV undergoing treatment with antiretroviral medicines exhibit weak immune systems and are more susceptible to viral infections. Also, until now, only one HIV case had been reported with COVID-19 infection from china. The patient recovered from the infection the same as that of those without HIV. There is no evidence on whether HIV patients are more susceptible to COVID-19 infection [125].\nThe COVID-19 associated TB is found in 94th day of the nonexistence of public health interventions and 138th day in the occurrence of interventions. This occurs at the peak of an outbreak where the implementation of the intervention, out of it 11,066, is with the presence of interventions. 27,968 COVID-19 cases found in the absence of interventions, out of it 14,823, are with no interventions. This scenario shows that there is a need to take preventive measures of TB associated with COVID-19 patients. They need a prior diagnosis and proper management [126]. The main reasons for mortality are age, sex, and other co-morbid factors such as diabetes, cardiovascular diseases, and renal diseases are the main reasons for mortality.\n\n6.12 SARS-CoV-2 – Venous thromboembolism\nPeople affected with pneumonia are more prone to venous thromboembolism. Out of 1026 COVID-19 patients, 40% of them exhibited high risk, and 11% of them at high risk of developing venous thromboembolism without any prophylaxis. Prophylactic measures can prevent venous thromboembolism. Only 7 out of 140 patients at high risk for venous thromboembolism had recorded about the anticoagulation treatment. And 44 out of 407 exhibited a higher risk for bleeding. In these patients, the mechanical compressions such as intermittent pneumatic compression and elastic compression stockings are instructed, and the duration and dosage of anticoagulants should be adjusted. Also, the COVID-19 patients, along with other co-morbid conditions such as cardiovascular manifestations, respiratory failure, renal and hepatic problems, can affect the bleeding status and venous thromboembolism. Therefore, further investigations are required to reduce the risk due to venous thromboembolism and bleeding in the case of COVID-19 patients [127].\n\n6.13 SARS-CoV-2- reproductive risk\nViral infections during the first 20 weeks of gestation have shown to be more severe. The infections, such as SARS and MERS, which occurred due to coronaviruses, had reported an increased risk for pregnancy-related mortality and morbidity. Such cases among COVID-19 affected patients are not yet reported. Nine women who are in their third semester and infected with COVID-19 were reported to have outcomes as that of non-pregnant COVID-19 affected adults. In another study, out of 33 newborn infants, three infants were shown to be tested positive for COVID-19 who got the disease transferred from their mother through intrauterine vertical transmission mode [128].\n\n6.14 SARS-CoV-2 – mental illness\nAccording to a report, out of a group of 50 COVID-19 cases from a psychiatric hospital in Wuhan, China has uplifted the worry about the role of mental disorder in coronavirus transmission. The conditions include incomplete or no awareness of the risk, inability to have personal protection, and cognitive impairment. The treatment has become more challenging for people with COVID-19 infection and health disorders as co-morbid conditions [129].\n\n6.15 SARS-CoV-2 – aging and cardiovascular risk\nIt has been reported that the expression of ACE2 reduces with the increasing age. Since young patients possess high levels of ACE2, they are more prone to COVID-19 infection. Whereas, in old age people other than reduced ACE2 levels, other co-morbid conditions such as cardiovascular problems, diabetes, and hypertension might be present. The medication prescribed for these patients helps in elevating the ACE2 levels, which might enhance the viral entry. Though the treatment reduces the co-morbid severities, the viral infection is enhanced in those patients. Therefore, it is conclusive that young patients, even though they are more susceptible to the COVID-19 infection, they are less severely affected and exhibit elevated angiotensin II signaling. Whereas, the older patients who exhibit low levels of ACE2 and higher angiotensin II signaling leads to hypertension. The usage of ACEi and ARBs help in promoting the vasodilatory effects by elevating the ACE2 levels, thereby becoming susceptible to COVID-19 infection and are severely affected [130]."}

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SARS-CoV-2\n\n6.1 SARS-CoV-2 – heart disease\nACE2 plays a vital role in the cardiovascular system and is mainly involved in the functioning of the heart and development of hypertension and type II diabetes. Since ACE2 is the main target for the SARS-CoV-2 to enter inside the host cell and the ACE2 is also highly expressed in the heart apart from the lungs, indicating a chance of developing cardiac issues during SARS-CoV-2 infection. The anti-hypertensive therapy that has been prescribed for the patients is the usage of ACEi and ARBs should be carefully considered. The COVID-19 patients with comorbidities hypertension, taking the drug of ACEi or blocker of angiotensin receptor, need to switch off to other anti-hypertensive medications found to be controversial and require further studies this co-morbid conditions. The severity of the viral infection is higher in patients with comorbidities than those infected only by the virus without any predisposed health issue [85].\nThe interaction of the SARS-CoV-2 with ACE2 triggers a signal, which might be the reason to develop heart injury through the immune response triggered by T-helper cells creating a cytokine response. The SARS-CoV-2 has a structural similarity with that of SARS-CoV. SARS-CoV caused severe cardiovascular damage during its pandemic period. Therefore, it is essential to investigate SARS-CoV-2 treatment options and ensure a cardio-protective effect. The age and the predisposition of the acute coronary syndrome are the two critical factors which need to be considered in patients affected with COVID-19 [85].\nSince the ACE2 is highly expressed in pericytes, the patients infected with SARS-CoV-2 and predisposed with cardiac failure are more susceptible to develop severe cardiac problems [86]. The usage of mineralocorticoids receptor blocker can attenuates oxidative stress, reduces the level of ACE with the augmented production of the angiotensin 1–7 and attenuates the angiotensin II generation and increases the activity of ACE2 The antagonist of angiotensin II type 1 receptor, have modulates the profilin-1 expression and ACE2 [87]. The selective of the angiotensin II activity or synthesis mediated the augmented level of ACE2 expression and its activity in cardiac. Still, the combination of the lisinopril and losartan increases the activity of ACE2 but not ACE2 mRNA. The inhibition of ACE results in reduced formation of angiotensin II and metabolism of angiotensin 1–7, the angiotensin II type 1 receptor antagonist increases the metabolism of angiotensin II via ACE2 [88]. SARS-CoV 2 enters into the cell via the ACE2 receptor; this causes the decreased level of the ACE2 due to the binding of the spike protein to the ACE2 and no changes in ACE. This process causes the virus's entry, replicates it, and causes tissue injury via decreasing anti-atrophy, anti0-fibrosis, anti-inflammation, anti-oxidant, and vasodilation. On the other hand, the angiotensin II type 1 receptor causes pro-atrophy, pro-fibrosis, pro-inflammation, pro-oxidant, severe myocardial remodeling, vasoconstriction and vascular permeability which leads to tissue injury [89] (represented in Table 1).\nTherefore, the use of ACEi, ARBs, and mineralocorticoids has shown to have an impact on the cardiac patients affected by COVID-19, but the exact mechanism behind it is not clear. Aliskiren, a direct inhibitor of renin, resulted in reduced expression of ACE2 besides reducing the blood pressure that has been elucidated in diabetic nephropathy animal models [90]. Therefore, renin blockers, especially aliskiren, need to be further investigated as a treatment option for COVID-19 patients with comorbidities [91].\n\n6.2 SARS-CoV-2 – gastrointestinal risk\nThe ACE2 is also highly expressed in the small intestine and large intestine of the gastrointestinal tract. The S protein present on the envelope of the SARS-CoV-2 ensures higher binding affinity, thereby mediating the entry of the virus into the host cell. The presence of SARS-CoV-2 in the gastrointestinal tract was confirmed by nucleocapsid staining of the virus. The virus was found to be visualized in the cytoplasm of epithelia of duodenum and rectum [92] (represented in Table 1). Apart from the pulmonary infection, the COVID-19 affected patients also exhibited vomiting, abdominal pain, and diarrhea, which was first reported in a 35 years old man from the United States. He was presented with nausea and diarrhea on 2nd day of the infection and was hospitalized. Stools examination revealed the presence of SARS-CoV-2 RNA, which was confirmed by using reverse transcriptase-polymerase chain reaction (RT-PCR) on day 7 of infection [93]. Out of 171 COVID-19 affected children, 6.4% of them have shown vomiting, and 8.8% of them and 3 out of ten affected children have shown diarrhea as symptoms [94]. Also, previously there were two COVID-19 young cases reported with vomiting and diarrhea.\nIn China, from 552 hospitals, 1099 cases were reported, of which 3.8% and 5% were diagnosed with diarrhea and vomiting as symptoms [95]. According to another report, out of 140 COVID-19 patients from Wuhan, 39.6% exhibited gastrointestinal symptoms apart from 5% exhibiting vomiting, 12.9% exhibiting diarrhea, and 17.3% exhibiting nausea [96]. It was reported that 17 patients had shown a negative result when tested using pulmonary samples, but when tested using rectal swabs have shown to have a positive result [96].\nSimilarly, 8 out of 10 children affected by SARS-CoV-2 had shown dual results, negative results when tested by nasopharyngeal samples, and positive results when tested using a rectal swab [97]. The percentage of patients exhibiting nausea, vomiting, and diarrhea as symptoms vary between the cohort groups, whereas, in the case of certain groups, these symptoms contributed very few percent. In contrast, in the case of the other groups, a high percentage of these gastrointestinal symptoms have been recorded.\n\n6.3 SARS-CoV-2- kidney risk\nIt is suspected that whether the patients with predisposed kidney issues or COVID-19 induced acute kidney injury is fatal to the affected patients. In an article posted on March 19 by HospiMedica International staff writers, it was mentioned that patients affected by COVID-19 developed proteinuria estimated by the elevated levels of albumin in urine were diagnosed in the initial stages of infection. The majority of the affected members, i.e., 34% out of 59 patients, developed proteinuria where the elevated albumin levels serve as a biomarker for kidney damage, and 63% of the patients exhibited proteinuria and hematuria characterized by the presence of blood in the urine. In another study conducted on 710 patients hospitalized due to COVID-19. The impairment in the functioning of the kidney was observed in 27% of the 59 patients and 66% of the corona infected patients. In a later study conducted on COVID-19 affected patients from 710 hospitals, 26.7% exhibited only hematuria, and 44% exhibited proteinuria and hematuria. The impaired kidney function was found in 15% of the study population [98].\nAccording to an article published by Wang L and his colleagues reported that out of 116 COVID-19 positive cases from Renmin Hospital of Wuhan University, out of whom 111 didn't have any kidney issues in their history and the remaining five patients had chronic kidney disease (CDK). Also, out of the 111 patients, only 10.8% of the patients exhibited a slight increase in creatine or blood urea nitrogen levels, and 7.2% of the patients had shown a minute raise in the albuminuria levels. None of the patients out of 111 didn't exhibit any acute kidney injury (AKI) after the COVID-19 infection. The remaining five patients who were already undergoing continuous renal replacement therapy (CRRT) also didn't show any fatal effects after COVID-19 infection confirmed by diagnosing the renal indicators [99]. Out of 701 patients, 2% of the patients were found to have CKD, and the average lymphocytic number was found to be reduced than the normal. High sensitivity C-reactive protein levels were significantly increased. In patients reported with high levels of serum, creatine indicated high levels of serum lactose dehydrogenase. Among hospitalized patients, patients with high levels of serum creatine were mostly old and male sex. Also, they exhibited lower platelet and lymphocytic count and elevated leukocytic count. The patients with elevated procalcitonin also exhibited elevated levels of aspartate aminotransferase and lactate dehydrogenase. Acute kidney injury was significantly higher in those patients with high serum creatine levels. AKI eventually results in mortality [100] (represented in Table 1). Therefore, advanced identification of kidney diseases in patients affected by COVID-19 may help the clinicians to reduce the mortality rate due to comorbidities such as chronic kidney disease, acute kidney injury, proteinuria, and hematuria.\n\n6.4 SARS-CoV-2 – diabetes mellitus\nPatients with diabetes mellitus exhibit high levels of ACE2, and treatment with the inhibitors of ACE and ARBs augments the expression of ACE2. Diabetes condition may lead to the suspicion that the excessive expression of ACE2 aids the entry of SARS-CoV-2 into the host cells resulting in COVID-19. Since diabetes mellitus and hypertension conditions are treated, ACE2 increasing drugs are having a severe risk of COVID-19 [10].\nSimultaneously, the elevated expression of ACE2 ensures the entry of the SARS-CoV-2, attaching to the ACE2 enzyme with the help of S protein present on its envelope's surface. There forth, it became controversial whether COVID-19 affected patients who are predisposed with diabetes mellitus should be resumed with their treatment with ACEi and ARBs or not. Also, if the medication is abruptly ceased, there are chances that the patient may die due to hypertension instead of COVID-19. For this reason, it has been suggested that there is no need to stop the medication of a diabetic patient even though if he is affected by COVID-19 because there is no scientific evidence available conducted on human subjects regarding whether to use ACEi and ARBs [10].\n\n6.5 SARS-CoV-2-liver injury\nThe SARS-CoV-2 infection has shown to increase the levels of ALT, AST, and bilirubin levels, indicating injury to the hepatic tissue [9,95,101,102]. Apart from these liver serum enzymes indicating hepatic damage, the levels of albumin were significantly decreased, indicating the severity of the infection [101]. The elated levels of gamma-glutamyl transferase (GGT) were observed only in patients with severe cases. In contrast, thealkaline phosphatize (AKP) levels remained unchanged irrespective of the severity of the infection [37] (represented in Table 1).\nSARS-CoV and SARS-CoV-2 share the similarity in making an entry into the host cell through the ACE2 receptor. In addition to the type 2 cells in the lungs, both the bile duct cells and hepatocytes also express ACE2, which might be the reason that liver injury occurs during SARS-CoV-2 infection [103]. The bile duct epithelial cells are involved in immune responses and the regeneration of the hepatocytes [104]. Besides possessing a high number of ACE2 on its surface, bile duct cells are more prone to the SARS-CoV-2 infection resulting in liver injury, which indicates that the hepatocytes are not directly involved in the hepatic injury [37]. The histopathological manifestations of SARS-CoV-2 infected patients revealed mild lobular and portal activity and restrained microvascular steatosis [105]. The degree of liver damage is directly proportional to the severity of the SARS-CoV-2 infection. Still, the reason for the liver injury remains elusive. A recent study reported that the use of anti-viral medication lopinavir might result in hepatic damage [102]. Therefore, whether the liver injury is due to the virus entry or due to the drugs used as anti-viral medication needs to be elucidated.\n\n6.6 SARS-CoV-2-lung injury\nIt was possible to study the lung pathology of COVID-19 patients diagnosed with COVID-19 retrospectively after undergoing lung lobectomy surgery for adenocarcinoma. Also, the patients didn't present pneumonia at the time of surgery, indicating the initial stages of COVID-19. A female patient who was 80 years old was hospitalized due to an irregularly shaped solid nodule in the right middle lobe. On a postoperative day 1, a CT scan was performed, which indicated a few clinical manifestations. Later, the patient was presented with increased leucocytes, decreased lymphocytic count, chest tightness, wheezing, dry cough, and difficulty in breathing. Later findings confirmed that SARS-CoV-2 infected her from a patient in the same room who was already affected. Another patient who was 73 years old and had a medical history of hypertension from 20 years who underwent surgery for adenocarcinoma was discharged on the 6th-day post-operation. On postoperative day 9, the patient exhibited chest tightness, muscle pain, dry cough, and decreased lymphocytic count. His CT-scan findings revealed for viral pneumonia, and he was also tested positive for the 20,189-nC0V test. He was admitted to the infectious disease ward. After, 20 days he was discharged as he recovered. Histopathological findings showed focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, edema, multinucleated giant cells, protruding hyaline membranes, and proteinaceous exudates [106] (represented in Table 1).\nThe patients, who are recovered from COVID-19, have a possibility of chronic lung damage. Out of 70 COVID-19 pneumonia patients, 66 patients have lung damage in a different manner, which was determined by CT. This damage is in a diverse range; in the alveoli, there is a hardened tissue with the dense clumps which block the vessels in the tiny air sacs, which absorb the oxygen and cause tissue lesions. This tissue lesion acts as a sign of the long-term lung disease. Similar reports have been found in both the SARS CoV and MERS. The patients admitted with lung pneumonia shows damage in both the lungs. The CT scan of the COVID-19 patients indicates that there is a tissue lesion found over the alveoli and which can develop into the scars. There are \u003e2.9 million people have COVID-19 disease worldwide, according to April 27. 80% of the patients are having a high risk of problems, such as from breathing to respiratory failure [107].\n\n6.7 SARS-CoV-2-CNS risk\nMathew reported that it might be due to the obstructions in the nervous system, which may restrict the entry of air into the lungs [108]. The virus enters the medullary neurons during the latency phase. A possible mechanism explained was that the SARS-CoV-2 might enter the olfactory lobe of the brain through nasal chambers upon inhalation and may lead to inflammation and demyelination. Later, it spreads to the whole brain due to its ability to cross the blood-brain barrier. Some neurological symptoms exhibited by the COVID-19 infection patients include nausea, vomiting, and headache (represented in Table 1). Since the SARS-CoV-2 possess the ability to cross the blood-brain barrier, it is important to design the drugs in such a way that they can cross the blood-brain barrier and scavenges the brain from viral infection. Also, it is essential to note that the respiratory illness accompanies neurological invasion by the virus, therapeutic care must be taken to prevent the viral entry into the central nervous system (CNS) [7].\n\n6.8 SARS-CoV-2 – immunopathology\nSARS-CoV-2 infection mediates immune response, both innate and adaptive. The enhanced level of the innate response and decreased level of adaptive causes tissue damage. Upon viral infection, there is an immune response. T cells, especially the cluster of differentiation 4 (CD4+) and a group of differentiation 8 (CD8+), have an anti-viral role. CD8+ T cells are highly cytotoxic, and they killed infected cells. This T cell induces the pro-inflammatory cytokines through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling. This process further activates the cytokines and chemokines [7]. Similar to SARS-CoV, MERS, SARS-CoV-2 infection in the immune effector cells are also having the enhanced level of the cytokines such as IFN-γ, IFN-α, IL-6, IL-1β, IL-18, IL-12, TGFβ, IL-33 and TNF-α and chemokines such as CCL2, CCL5, CCL3, CXCL10, CXCL9, and CXCL8. Similar to this, severe MERS-CoV infected patient's serum shows an increased level of the cytokines and chemokines. This cytokine storm further causes multiple organ failures to further leads to the death of the SARS-CoV-2 patient [109].\nOn the other hand, the T-cells are having four types of it, such as Th1, Th2, Th17 (inflammatory), and anti-inflammatory Tregs. These Th2 cells generate IL-4 cells. The compound which can block the Th1 (Boost immune system) tends to augments the level of the Th2 (anti-inflammatory response). IL-4 triggers the Th2 cells and obstructs the Th1 response. This Th2 helps to repair form tissue dysfunction and another type of malfunction. It is found to be good that the increased level of the Th1 and Th17 plays an important role in hyperactive immune response and during autoimmune conditions. It is showed that there is an induction of the Th1/Th17 and the production of antibodies upon COVID-19 condition [110]. Contradict to this; the patient has a high level of Th2 in need of intensive care [111]. During the MERS condition, there is a reduced level of both the Th1 and Th2, which further enhances the inflammatory cytokines and causes more infection and death [112]. SARS patients who died with an older age have higher cytokines of Th2, such as IL-4, IL-10, and IL-5 [113]. This incidence supports the increased Th2 level of COVID-19 patients who needs intensive care. The mechanism behind this is based on the molecular weight of the protein of SARS-CoV2; the activity of the immune system is changed. The recent research by the F. Javier Martín Oncina in 2020 showed that based on the antigen molecular weight, the host's immune response is varied. The proteins of the SARS-CoV2 are spike protein with 140 kDa, Envelope protein with 10 kDa, Membrane protein with 25 kDa, and nucleocapsid protein with 50 kDa. The protein with more than \u003e70 kDa, such as spike protein, cannot be arrested by the B-cell, thereby it activates the inflammatory response through the Th1 response with the macrophages. This process occurs in the subcapsular sinus and through dendritic cells phagocytosis. The other proteins with \u003c70 kDa are found in the protein of SARS-CoV2, which activates the receptor of B-cell and stimulates Th2 immune response. The unremittingviral particle overload, which is unrestricted by the viral cell lysing, will be terminated by the Th1 (pro-inflammatory response). Further, it increases the protein level with a weight of \u003c70 kDa stimulates the B cells in large amounts. This induction of the B-cells leads to the condition called as Activated Induced Cell Death (AICD), which speediness the apoptosis and release of pro-inflammatory cytokines cause lymphopenia, thereby it produces IL-10, augments the shift of Th2 form Th1 response which causes further suppression of immune system, COVID-19 sepsis [114]. Correlative to that that COVID-19 patients with the high level of Th2 immune response need intensive care [111], which shows that they might be having apoptosis, lymphopenia, and suppression of immune system further causes COVID-19 sepsis [114]. Though the cell death is via Th2 immune response but the level of IL-4 is not elucidated yet. The role of IL-4 and its mechanism behind COVID-19 remain elusive (Represented in Fig. 2 ).\nFig. 2 SARS-CoV-2 enters into the host cell via binding with the cellular receptor ACE-2. It undergoes the fusion with the joining of the plasma membrane and the virus. Then it undergoes the process of the proteolytic cleavage; further, it will undergo replication and lead to the formation of the proteins. This process activates the signaling pathway, such as the NF-kB pathway, via TRIF. The interaction between the cells and the virus activates many cytokine storms. On the other hand, once the virus enters into the cell, the antigen present in that would undergo the antigen presentation cells (APC); further, this stimulates the humoral and cellular immunity. COVID-19 infects the macrophage cells, which presents to the T cell, further, which leads to the activation, differentiation of T-cells, along with the production of cytokines. This shows the negative action on the activation of CD8 T cells. Thus the mediator produced by the CD8+ T cells clears the infection of SARS-CoV. Upon COVID-19 infection, there is a reduced CD4+ and CD8+ cell level, further increasing the cytokine level in the cells, which triggers the inflammation. This mediates the production of the cytokine storm via secreting chemokine and cytokines such as IL-1β, IL-6, TNF-α, IL-8, IL-21, CCL2, CCL3, CCL5, CXCL10, TNF-β, and MCP-1 and triggers the tissue injury. On the other hand, based on the weight of the protein of SARS-CoV2, there is an activation of Th1/Th17 (boosts immune system) when the spike protein is \u003e70 kDa. In case of the Th2 (anti-inflammatory) is activated by the majority of the protein with \u003c70 kDa, then the activation of the B-cell receptor, which causes activation-induced cell death such as apoptosis and lymphopenia which is by releasing IL-10, shifting of Th1 to Th2 immune response, suppression of the immune system and further leads to the COVID-19 sepsis. The role of IL-4 has not been elucidated yet. It remains unanswerable upon COVID-19 condition with the mechanism of Th2 and Th1/Th17.\nThe wet lung is also known as acute respiratory distress syndrome (ARDS). The patient with COVID-19 has lung edema, and it needs more attention clinically. Lung edema is found to be a symptom of acute lung injury, which development to hypoxemia condition and which leads to acute respiratory distress syndrome (ARDS). The patients who are found with ARDS have more mortality. Though there is no proper treatment or vaccine treatment, ventilation with the therapy of oxygen and ventilation mechanically is mandatory. Sometimes, the treatment with the glucocorticoids (systemic or locally) would help attenuate lung edema and pulmonary inflammation [115]. But there is a need for more research to correlate the cytokine storm with wet lung pneumonia in COVID-19 patients.\n\n6.9 SARS-CoV-2 – ocular risk\nThe ACE2 receptors are also widely distributed in the superficial parts such as conjunctiva and cornea inferior parts such as iris, ciliary body, aqueous humor, trabecular meshwork, retina, and non-pigmented ciliary epithelium of the ocular globe which is mentioned out to be the intraocular renin-angiotensin system. Therefore, the distribution of ACE2 and TMPRSS2 protein must be taken into consideration to study the passage of infection through the ocular route [116]. Also, there is a chance for the virus to enter into the nasal cavity, which causes respiratory illness and the digestive system through the lacrimal canaliculi aided by the effectiveness of the tear film [117,118]. Out of 38 COVID-19 positive patients, 12 exhibited clinical manifestations, which include chemosis, epiphora, increased secretions, conjunctivitis, and conjunctival hyperemia. Researchers reported that patients exhibiting ocular symptoms would have elevated neutrophilic and lymphocytic counts, elated procalcitonin, lactate dehydrogenase, and C-reactive protein levels than those without ocular manifestations. The patients with ocular manifestations exhibited severe illness [119].\nEven though there is no such evidence, the presence of ACE2 and TMPRSS2 protein in the corneal limbal stem cells suggests that the SARS-CoV-2 may enter the bloodstream and travel to the other parts including the brain [120]. Even though there is no viral load in the conjunctiva of the SARS-CoV-2 infected patients without conjunctivitis, the risk of transmission of the virus through tears is low [121]. The exact mechanism behind the ocular risk and SARS-CoV-2 need to be elucidated further.\n\n6.10 SARS-CoV-2 – cancer risk\nCancer patients are highly vulnerable to SARS-CoV-2 infection. 18 out of 1590 COVID-19 positive cases exhibited cancer history. 5 out of 18 patients suffered from lung cancer, 4 out of 18 patients had no past information on medication and had undergone surgery or chemotherapy in the previous month, and the remaining 12 were cancer survivors. The COVID-19 was highly severe in cancer patients than non-cancer COVID-19 affected patients. Also, COVID-19 patients with cancer exhibited a severe chain of symptoms than those without a history of cancer. Also, patients with lung cancer did not exhibit severe symptoms when compared to those with other types of cancers [122].\nIn a retrospective study conducted among 1276 patients, 28 patients who have cancer were selected for the study. The mean age group people belonged to the elderly category, and 60.7% of them were males. Lung cancer was the most frequent type, followed by oesophageal and breast cancers among cancer affected patients. 10 out of 28 patients were presented with IV stage cancer. 28.6% of the patients developed COVID-19 while receiving antitumor therapy, whereas 71.4% of them developed due to the presence of infection in their vicinity. Besides, 39.2% of the patients exhibited chronic co-morbid conditions apart from cancer. 28.6% of patients died, and the remaining patients developed serious consequences even after receiving anti-viral and corticosteroids. The most common complication developed by the patients includes septic shock, acute myocardial infarction, and ARDS [123]. Therefore, more focus should be laid on the research for medication and treatment options for COVID-19 affected cancer patients. More studies are required to determine the exact mechanism behind cancer and SARS-CoV-2.\n\n6.11 SARS-CoV-2 – tuberculosis\nA study was conducted in February 2020, Shenyang, China, which involved 36 COVID-19 positive patients and was classified based on the severity of the symptoms as mild and critical. The results of these patients were compared with that of the patients affected by pneumonia caused by Mycobacterium tuberculosis from Shenyang chest hospital. The study was conducted to determine which one caused severe pneumonia, either the viral or the bacterial strain. Then the severity of tuberculosis was compared between the mild and severe COVID-19 cases and confirmed that tuberculosis due to mycobacterial strain affected patients are more susceptible to COVID-19 and enhance the severity of COVID-19 [124]. Patients with HIV undergoing treatment with antiretroviral medicines exhibit weak immune systems and are more susceptible to viral infections. Also, until now, only one HIV case had been reported with COVID-19 infection from china. The patient recovered from the infection the same as that of those without HIV. There is no evidence on whether HIV patients are more susceptible to COVID-19 infection [125].\nThe COVID-19 associated TB is found in 94th day of the nonexistence of public health interventions and 138th day in the occurrence of interventions. This occurs at the peak of an outbreak where the implementation of the intervention, out of it 11,066, is with the presence of interventions. 27,968 COVID-19 cases found in the absence of interventions, out of it 14,823, are with no interventions. This scenario shows that there is a need to take preventive measures of TB associated with COVID-19 patients. They need a prior diagnosis and proper management [126]. The main reasons for mortality are age, sex, and other co-morbid factors such as diabetes, cardiovascular diseases, and renal diseases are the main reasons for mortality.\n\n6.12 SARS-CoV-2 – Venous thromboembolism\nPeople affected with pneumonia are more prone to venous thromboembolism. Out of 1026 COVID-19 patients, 40% of them exhibited high risk, and 11% of them at high risk of developing venous thromboembolism without any prophylaxis. Prophylactic measures can prevent venous thromboembolism. Only 7 out of 140 patients at high risk for venous thromboembolism had recorded about the anticoagulation treatment. And 44 out of 407 exhibited a higher risk for bleeding. In these patients, the mechanical compressions such as intermittent pneumatic compression and elastic compression stockings are instructed, and the duration and dosage of anticoagulants should be adjusted. Also, the COVID-19 patients, along with other co-morbid conditions such as cardiovascular manifestations, respiratory failure, renal and hepatic problems, can affect the bleeding status and venous thromboembolism. Therefore, further investigations are required to reduce the risk due to venous thromboembolism and bleeding in the case of COVID-19 patients [127].\n\n6.13 SARS-CoV-2- reproductive risk\nViral infections during the first 20 weeks of gestation have shown to be more severe. The infections, such as SARS and MERS, which occurred due to coronaviruses, had reported an increased risk for pregnancy-related mortality and morbidity. Such cases among COVID-19 affected patients are not yet reported. Nine women who are in their third semester and infected with COVID-19 were reported to have outcomes as that of non-pregnant COVID-19 affected adults. In another study, out of 33 newborn infants, three infants were shown to be tested positive for COVID-19 who got the disease transferred from their mother through intrauterine vertical transmission mode [128].\n\n6.14 SARS-CoV-2 – mental illness\nAccording to a report, out of a group of 50 COVID-19 cases from a psychiatric hospital in Wuhan, China has uplifted the worry about the role of mental disorder in coronavirus transmission. The conditions include incomplete or no awareness of the risk, inability to have personal protection, and cognitive impairment. The treatment has become more challenging for people with COVID-19 infection and health disorders as co-morbid conditions [129].\n\n6.15 SARS-CoV-2 – aging and cardiovascular risk\nIt has been reported that the expression of ACE2 reduces with the increasing age. Since young patients possess high levels of ACE2, they are more prone to COVID-19 infection. Whereas, in old age people other than reduced ACE2 levels, other co-morbid conditions such as cardiovascular problems, diabetes, and hypertension might be present. The medication prescribed for these patients helps in elevating the ACE2 levels, which might enhance the viral entry. Though the treatment reduces the co-morbid severities, the viral infection is enhanced in those patients. Therefore, it is conclusive that young patients, even though they are more susceptible to the COVID-19 infection, they are less severely affected and exhibit elevated angiotensin II signaling. Whereas, the older patients who exhibit low levels of ACE2 and higher angiotensin II signaling leads to hypertension. The usage of ACEi and ARBs help in promoting the vasodilatory effects by elevating the ACE2 levels, thereby becoming susceptible to COVID-19 infection and are severely affected [130]."}

{"project":"2_test","denotations":[{"id":"32450165-32231330-66451073","span":{"begin":980,"end":982},"obj":"32231330"},{"id":"32450165-32231330-66451074","span":{"begin":1588,"end":1590},"obj":"32231330"},{"id":"32450165-32227090-66451075","span":{"begin":1774,"end":1776},"obj":"32227090"},{"id":"32450165-16179584-66451076","span":{"begin":2120,"end":2122},"obj":"16179584"},{"id":"32450165-15897343-66451077","span":{"begin":2567,"end":2569},"obj":"15897343"},{"id":"32450165-30554582-66451078","span":{"begin":3531,"end":3533},"obj":"30554582"},{"id":"32450165-32004427-66451079","span":{"begin":4670,"end":4672},"obj":"32004427"},{"id":"32450165-32187458-66451080","span":{"begin":4833,"end":4835},"obj":"32187458"},{"id":"32450165-32109013-66451081","span":{"begin":5060,"end":5062},"obj":"32109013"},{"id":"32450165-32327758-66451082","span":{"begin":5638,"end":5640},"obj":"32327758"},{"id":"32450165-32247631-66451083","span":{"begin":8686,"end":8689},"obj":"32247631"},{"id":"32450165-31986264-66451084","span":{"begin":10345,"end":10346},"obj":"31986264"},{"id":"32450165-32109013-66451085","span":{"begin":10347,"end":10349},"obj":"32109013"},{"id":"32450165-32007143-66451086","span":{"begin":10350,"end":10353},"obj":"32007143"},{"id":"32450165-32007143-66451087","span":{"begin":10518,"end":10521},"obj":"32007143"},{"id":"32450165-32170806-66451088","span":{"begin":10744,"end":10746},"obj":"32170806"},{"id":"32450165-30850822-66451089","span":{"begin":11181,"end":11184},"obj":"30850822"},{"id":"32450165-32170806-66451090","span":{"begin":11416,"end":11418},"obj":"32170806"},{"id":"32450165-32114094-66451091","span":{"begin":13495,"end":13498},"obj":"32114094"},{"id":"32450165-32282863-66451092","span":{"begin":16684,"end":16687},"obj":"32282863"},{"id":"32450165-32105090-66451093","span":{"begin":17396,"end":17399},"obj":"32105090"},{"id":"32450165-32382776-66451094","span":{"begin":17485,"end":17488},"obj":"32382776"},{"id":"32450165-18832706-66451095","span":{"begin":17763,"end":17766},"obj":"18832706"},{"id":"32450165-32382776-66451096","span":{"begin":19423,"end":19426},"obj":"32382776"},{"id":"32450165-32327758-66451097","span":{"begin":23947,"end":23950},"obj":"32327758"},{"id":"32450165-32066541-66451098","span":{"begin":24921,"end":24924},"obj":"32066541"},{"id":"32450165-32199510-66451099","span":{"begin":30153,"end":30156},"obj":"32199510"}],"text":"6 SARS-CoV-2\n\n6.1 SARS-CoV-2 – heart disease\nACE2 plays a vital role in the cardiovascular system and is mainly involved in the functioning of the heart and development of hypertension and type II diabetes. Since ACE2 is the main target for the SARS-CoV-2 to enter inside the host cell and the ACE2 is also highly expressed in the heart apart from the lungs, indicating a chance of developing cardiac issues during SARS-CoV-2 infection. The anti-hypertensive therapy that has been prescribed for the patients is the usage of ACEi and ARBs should be carefully considered. The COVID-19 patients with comorbidities hypertension, taking the drug of ACEi or blocker of angiotensin receptor, need to switch off to other anti-hypertensive medications found to be controversial and require further studies this co-morbid conditions. The severity of the viral infection is higher in patients with comorbidities than those infected only by the virus without any predisposed health issue [85].\nThe interaction of the SARS-CoV-2 with ACE2 triggers a signal, which might be the reason to develop heart injury through the immune response triggered by T-helper cells creating a cytokine response. The SARS-CoV-2 has a structural similarity with that of SARS-CoV. SARS-CoV caused severe cardiovascular damage during its pandemic period. Therefore, it is essential to investigate SARS-CoV-2 treatment options and ensure a cardio-protective effect. The age and the predisposition of the acute coronary syndrome are the two critical factors which need to be considered in patients affected with COVID-19 [85].\nSince the ACE2 is highly expressed in pericytes, the patients infected with SARS-CoV-2 and predisposed with cardiac failure are more susceptible to develop severe cardiac problems [86]. The usage of mineralocorticoids receptor blocker can attenuates oxidative stress, reduces the level of ACE with the augmented production of the angiotensin 1–7 and attenuates the angiotensin II generation and increases the activity of ACE2 The antagonist of angiotensin II type 1 receptor, have modulates the profilin-1 expression and ACE2 [87]. The selective of the angiotensin II activity or synthesis mediated the augmented level of ACE2 expression and its activity in cardiac. Still, the combination of the lisinopril and losartan increases the activity of ACE2 but not ACE2 mRNA. The inhibition of ACE results in reduced formation of angiotensin II and metabolism of angiotensin 1–7, the angiotensin II type 1 receptor antagonist increases the metabolism of angiotensin II via ACE2 [88]. SARS-CoV 2 enters into the cell via the ACE2 receptor; this causes the decreased level of the ACE2 due to the binding of the spike protein to the ACE2 and no changes in ACE. This process causes the virus's entry, replicates it, and causes tissue injury via decreasing anti-atrophy, anti0-fibrosis, anti-inflammation, anti-oxidant, and vasodilation. On the other hand, the angiotensin II type 1 receptor causes pro-atrophy, pro-fibrosis, pro-inflammation, pro-oxidant, severe myocardial remodeling, vasoconstriction and vascular permeability which leads to tissue injury [89] (represented in Table 1).\nTherefore, the use of ACEi, ARBs, and mineralocorticoids has shown to have an impact on the cardiac patients affected by COVID-19, but the exact mechanism behind it is not clear. Aliskiren, a direct inhibitor of renin, resulted in reduced expression of ACE2 besides reducing the blood pressure that has been elucidated in diabetic nephropathy animal models [90]. Therefore, renin blockers, especially aliskiren, need to be further investigated as a treatment option for COVID-19 patients with comorbidities [91].\n\n6.2 SARS-CoV-2 – gastrointestinal risk\nThe ACE2 is also highly expressed in the small intestine and large intestine of the gastrointestinal tract. The S protein present on the envelope of the SARS-CoV-2 ensures higher binding affinity, thereby mediating the entry of the virus into the host cell. The presence of SARS-CoV-2 in the gastrointestinal tract was confirmed by nucleocapsid staining of the virus. The virus was found to be visualized in the cytoplasm of epithelia of duodenum and rectum [92] (represented in Table 1). Apart from the pulmonary infection, the COVID-19 affected patients also exhibited vomiting, abdominal pain, and diarrhea, which was first reported in a 35 years old man from the United States. He was presented with nausea and diarrhea on 2nd day of the infection and was hospitalized. Stools examination revealed the presence of SARS-CoV-2 RNA, which was confirmed by using reverse transcriptase-polymerase chain reaction (RT-PCR) on day 7 of infection [93]. Out of 171 COVID-19 affected children, 6.4% of them have shown vomiting, and 8.8% of them and 3 out of ten affected children have shown diarrhea as symptoms [94]. Also, previously there were two COVID-19 young cases reported with vomiting and diarrhea.\nIn China, from 552 hospitals, 1099 cases were reported, of which 3.8% and 5% were diagnosed with diarrhea and vomiting as symptoms [95]. According to another report, out of 140 COVID-19 patients from Wuhan, 39.6% exhibited gastrointestinal symptoms apart from 5% exhibiting vomiting, 12.9% exhibiting diarrhea, and 17.3% exhibiting nausea [96]. It was reported that 17 patients had shown a negative result when tested using pulmonary samples, but when tested using rectal swabs have shown to have a positive result [96].\nSimilarly, 8 out of 10 children affected by SARS-CoV-2 had shown dual results, negative results when tested by nasopharyngeal samples, and positive results when tested using a rectal swab [97]. The percentage of patients exhibiting nausea, vomiting, and diarrhea as symptoms vary between the cohort groups, whereas, in the case of certain groups, these symptoms contributed very few percent. In contrast, in the case of the other groups, a high percentage of these gastrointestinal symptoms have been recorded.\n\n6.3 SARS-CoV-2- kidney risk\nIt is suspected that whether the patients with predisposed kidney issues or COVID-19 induced acute kidney injury is fatal to the affected patients. In an article posted on March 19 by HospiMedica International staff writers, it was mentioned that patients affected by COVID-19 developed proteinuria estimated by the elevated levels of albumin in urine were diagnosed in the initial stages of infection. The majority of the affected members, i.e., 34% out of 59 patients, developed proteinuria where the elevated albumin levels serve as a biomarker for kidney damage, and 63% of the patients exhibited proteinuria and hematuria characterized by the presence of blood in the urine. In another study conducted on 710 patients hospitalized due to COVID-19. The impairment in the functioning of the kidney was observed in 27% of the 59 patients and 66% of the corona infected patients. In a later study conducted on COVID-19 affected patients from 710 hospitals, 26.7% exhibited only hematuria, and 44% exhibited proteinuria and hematuria. The impaired kidney function was found in 15% of the study population [98].\nAccording to an article published by Wang L and his colleagues reported that out of 116 COVID-19 positive cases from Renmin Hospital of Wuhan University, out of whom 111 didn't have any kidney issues in their history and the remaining five patients had chronic kidney disease (CDK). Also, out of the 111 patients, only 10.8% of the patients exhibited a slight increase in creatine or blood urea nitrogen levels, and 7.2% of the patients had shown a minute raise in the albuminuria levels. None of the patients out of 111 didn't exhibit any acute kidney injury (AKI) after the COVID-19 infection. The remaining five patients who were already undergoing continuous renal replacement therapy (CRRT) also didn't show any fatal effects after COVID-19 infection confirmed by diagnosing the renal indicators [99]. Out of 701 patients, 2% of the patients were found to have CKD, and the average lymphocytic number was found to be reduced than the normal. High sensitivity C-reactive protein levels were significantly increased. In patients reported with high levels of serum, creatine indicated high levels of serum lactose dehydrogenase. Among hospitalized patients, patients with high levels of serum creatine were mostly old and male sex. Also, they exhibited lower platelet and lymphocytic count and elevated leukocytic count. The patients with elevated procalcitonin also exhibited elevated levels of aspartate aminotransferase and lactate dehydrogenase. Acute kidney injury was significantly higher in those patients with high serum creatine levels. AKI eventually results in mortality [100] (represented in Table 1). Therefore, advanced identification of kidney diseases in patients affected by COVID-19 may help the clinicians to reduce the mortality rate due to comorbidities such as chronic kidney disease, acute kidney injury, proteinuria, and hematuria.\n\n6.4 SARS-CoV-2 – diabetes mellitus\nPatients with diabetes mellitus exhibit high levels of ACE2, and treatment with the inhibitors of ACE and ARBs augments the expression of ACE2. Diabetes condition may lead to the suspicion that the excessive expression of ACE2 aids the entry of SARS-CoV-2 into the host cells resulting in COVID-19. Since diabetes mellitus and hypertension conditions are treated, ACE2 increasing drugs are having a severe risk of COVID-19 [10].\nSimultaneously, the elevated expression of ACE2 ensures the entry of the SARS-CoV-2, attaching to the ACE2 enzyme with the help of S protein present on its envelope's surface. There forth, it became controversial whether COVID-19 affected patients who are predisposed with diabetes mellitus should be resumed with their treatment with ACEi and ARBs or not. Also, if the medication is abruptly ceased, there are chances that the patient may die due to hypertension instead of COVID-19. For this reason, it has been suggested that there is no need to stop the medication of a diabetic patient even though if he is affected by COVID-19 because there is no scientific evidence available conducted on human subjects regarding whether to use ACEi and ARBs [10].\n\n6.5 SARS-CoV-2-liver injury\nThe SARS-CoV-2 infection has shown to increase the levels of ALT, AST, and bilirubin levels, indicating injury to the hepatic tissue [9,95,101,102]. Apart from these liver serum enzymes indicating hepatic damage, the levels of albumin were significantly decreased, indicating the severity of the infection [101]. The elated levels of gamma-glutamyl transferase (GGT) were observed only in patients with severe cases. In contrast, thealkaline phosphatize (AKP) levels remained unchanged irrespective of the severity of the infection [37] (represented in Table 1).\nSARS-CoV and SARS-CoV-2 share the similarity in making an entry into the host cell through the ACE2 receptor. In addition to the type 2 cells in the lungs, both the bile duct cells and hepatocytes also express ACE2, which might be the reason that liver injury occurs during SARS-CoV-2 infection [103]. The bile duct epithelial cells are involved in immune responses and the regeneration of the hepatocytes [104]. Besides possessing a high number of ACE2 on its surface, bile duct cells are more prone to the SARS-CoV-2 infection resulting in liver injury, which indicates that the hepatocytes are not directly involved in the hepatic injury [37]. The histopathological manifestations of SARS-CoV-2 infected patients revealed mild lobular and portal activity and restrained microvascular steatosis [105]. The degree of liver damage is directly proportional to the severity of the SARS-CoV-2 infection. Still, the reason for the liver injury remains elusive. A recent study reported that the use of anti-viral medication lopinavir might result in hepatic damage [102]. Therefore, whether the liver injury is due to the virus entry or due to the drugs used as anti-viral medication needs to be elucidated.\n\n6.6 SARS-CoV-2-lung injury\nIt was possible to study the lung pathology of COVID-19 patients diagnosed with COVID-19 retrospectively after undergoing lung lobectomy surgery for adenocarcinoma. Also, the patients didn't present pneumonia at the time of surgery, indicating the initial stages of COVID-19. A female patient who was 80 years old was hospitalized due to an irregularly shaped solid nodule in the right middle lobe. On a postoperative day 1, a CT scan was performed, which indicated a few clinical manifestations. Later, the patient was presented with increased leucocytes, decreased lymphocytic count, chest tightness, wheezing, dry cough, and difficulty in breathing. Later findings confirmed that SARS-CoV-2 infected her from a patient in the same room who was already affected. Another patient who was 73 years old and had a medical history of hypertension from 20 years who underwent surgery for adenocarcinoma was discharged on the 6th-day post-operation. On postoperative day 9, the patient exhibited chest tightness, muscle pain, dry cough, and decreased lymphocytic count. His CT-scan findings revealed for viral pneumonia, and he was also tested positive for the 20,189-nC0V test. He was admitted to the infectious disease ward. After, 20 days he was discharged as he recovered. Histopathological findings showed focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, edema, multinucleated giant cells, protruding hyaline membranes, and proteinaceous exudates [106] (represented in Table 1).\nThe patients, who are recovered from COVID-19, have a possibility of chronic lung damage. Out of 70 COVID-19 pneumonia patients, 66 patients have lung damage in a different manner, which was determined by CT. This damage is in a diverse range; in the alveoli, there is a hardened tissue with the dense clumps which block the vessels in the tiny air sacs, which absorb the oxygen and cause tissue lesions. This tissue lesion acts as a sign of the long-term lung disease. Similar reports have been found in both the SARS CoV and MERS. The patients admitted with lung pneumonia shows damage in both the lungs. The CT scan of the COVID-19 patients indicates that there is a tissue lesion found over the alveoli and which can develop into the scars. There are \u003e2.9 million people have COVID-19 disease worldwide, according to April 27. 80% of the patients are having a high risk of problems, such as from breathing to respiratory failure [107].\n\n6.7 SARS-CoV-2-CNS risk\nMathew reported that it might be due to the obstructions in the nervous system, which may restrict the entry of air into the lungs [108]. The virus enters the medullary neurons during the latency phase. A possible mechanism explained was that the SARS-CoV-2 might enter the olfactory lobe of the brain through nasal chambers upon inhalation and may lead to inflammation and demyelination. Later, it spreads to the whole brain due to its ability to cross the blood-brain barrier. Some neurological symptoms exhibited by the COVID-19 infection patients include nausea, vomiting, and headache (represented in Table 1). Since the SARS-CoV-2 possess the ability to cross the blood-brain barrier, it is important to design the drugs in such a way that they can cross the blood-brain barrier and scavenges the brain from viral infection. Also, it is essential to note that the respiratory illness accompanies neurological invasion by the virus, therapeutic care must be taken to prevent the viral entry into the central nervous system (CNS) [7].\n\n6.8 SARS-CoV-2 – immunopathology\nSARS-CoV-2 infection mediates immune response, both innate and adaptive. The enhanced level of the innate response and decreased level of adaptive causes tissue damage. Upon viral infection, there is an immune response. T cells, especially the cluster of differentiation 4 (CD4+) and a group of differentiation 8 (CD8+), have an anti-viral role. CD8+ T cells are highly cytotoxic, and they killed infected cells. This T cell induces the pro-inflammatory cytokines through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling. This process further activates the cytokines and chemokines [7]. Similar to SARS-CoV, MERS, SARS-CoV-2 infection in the immune effector cells are also having the enhanced level of the cytokines such as IFN-γ, IFN-α, IL-6, IL-1β, IL-18, IL-12, TGFβ, IL-33 and TNF-α and chemokines such as CCL2, CCL5, CCL3, CXCL10, CXCL9, and CXCL8. Similar to this, severe MERS-CoV infected patient's serum shows an increased level of the cytokines and chemokines. This cytokine storm further causes multiple organ failures to further leads to the death of the SARS-CoV-2 patient [109].\nOn the other hand, the T-cells are having four types of it, such as Th1, Th2, Th17 (inflammatory), and anti-inflammatory Tregs. These Th2 cells generate IL-4 cells. The compound which can block the Th1 (Boost immune system) tends to augments the level of the Th2 (anti-inflammatory response). IL-4 triggers the Th2 cells and obstructs the Th1 response. This Th2 helps to repair form tissue dysfunction and another type of malfunction. It is found to be good that the increased level of the Th1 and Th17 plays an important role in hyperactive immune response and during autoimmune conditions. It is showed that there is an induction of the Th1/Th17 and the production of antibodies upon COVID-19 condition [110]. Contradict to this; the patient has a high level of Th2 in need of intensive care [111]. During the MERS condition, there is a reduced level of both the Th1 and Th2, which further enhances the inflammatory cytokines and causes more infection and death [112]. SARS patients who died with an older age have higher cytokines of Th2, such as IL-4, IL-10, and IL-5 [113]. This incidence supports the increased Th2 level of COVID-19 patients who needs intensive care. The mechanism behind this is based on the molecular weight of the protein of SARS-CoV2; the activity of the immune system is changed. The recent research by the F. Javier Martín Oncina in 2020 showed that based on the antigen molecular weight, the host's immune response is varied. The proteins of the SARS-CoV2 are spike protein with 140 kDa, Envelope protein with 10 kDa, Membrane protein with 25 kDa, and nucleocapsid protein with 50 kDa. The protein with more than \u003e70 kDa, such as spike protein, cannot be arrested by the B-cell, thereby it activates the inflammatory response through the Th1 response with the macrophages. This process occurs in the subcapsular sinus and through dendritic cells phagocytosis. The other proteins with \u003c70 kDa are found in the protein of SARS-CoV2, which activates the receptor of B-cell and stimulates Th2 immune response. The unremittingviral particle overload, which is unrestricted by the viral cell lysing, will be terminated by the Th1 (pro-inflammatory response). Further, it increases the protein level with a weight of \u003c70 kDa stimulates the B cells in large amounts. This induction of the B-cells leads to the condition called as Activated Induced Cell Death (AICD), which speediness the apoptosis and release of pro-inflammatory cytokines cause lymphopenia, thereby it produces IL-10, augments the shift of Th2 form Th1 response which causes further suppression of immune system, COVID-19 sepsis [114]. Correlative to that that COVID-19 patients with the high level of Th2 immune response need intensive care [111], which shows that they might be having apoptosis, lymphopenia, and suppression of immune system further causes COVID-19 sepsis [114]. Though the cell death is via Th2 immune response but the level of IL-4 is not elucidated yet. The role of IL-4 and its mechanism behind COVID-19 remain elusive (Represented in Fig. 2 ).\nFig. 2 SARS-CoV-2 enters into the host cell via binding with the cellular receptor ACE-2. It undergoes the fusion with the joining of the plasma membrane and the virus. Then it undergoes the process of the proteolytic cleavage; further, it will undergo replication and lead to the formation of the proteins. This process activates the signaling pathway, such as the NF-kB pathway, via TRIF. The interaction between the cells and the virus activates many cytokine storms. On the other hand, once the virus enters into the cell, the antigen present in that would undergo the antigen presentation cells (APC); further, this stimulates the humoral and cellular immunity. COVID-19 infects the macrophage cells, which presents to the T cell, further, which leads to the activation, differentiation of T-cells, along with the production of cytokines. This shows the negative action on the activation of CD8 T cells. Thus the mediator produced by the CD8+ T cells clears the infection of SARS-CoV. Upon COVID-19 infection, there is a reduced CD4+ and CD8+ cell level, further increasing the cytokine level in the cells, which triggers the inflammation. This mediates the production of the cytokine storm via secreting chemokine and cytokines such as IL-1β, IL-6, TNF-α, IL-8, IL-21, CCL2, CCL3, CCL5, CXCL10, TNF-β, and MCP-1 and triggers the tissue injury. On the other hand, based on the weight of the protein of SARS-CoV2, there is an activation of Th1/Th17 (boosts immune system) when the spike protein is \u003e70 kDa. In case of the Th2 (anti-inflammatory) is activated by the majority of the protein with \u003c70 kDa, then the activation of the B-cell receptor, which causes activation-induced cell death such as apoptosis and lymphopenia which is by releasing IL-10, shifting of Th1 to Th2 immune response, suppression of the immune system and further leads to the COVID-19 sepsis. The role of IL-4 has not been elucidated yet. It remains unanswerable upon COVID-19 condition with the mechanism of Th2 and Th1/Th17.\nThe wet lung is also known as acute respiratory distress syndrome (ARDS). The patient with COVID-19 has lung edema, and it needs more attention clinically. Lung edema is found to be a symptom of acute lung injury, which development to hypoxemia condition and which leads to acute respiratory distress syndrome (ARDS). The patients who are found with ARDS have more mortality. Though there is no proper treatment or vaccine treatment, ventilation with the therapy of oxygen and ventilation mechanically is mandatory. Sometimes, the treatment with the glucocorticoids (systemic or locally) would help attenuate lung edema and pulmonary inflammation [115]. But there is a need for more research to correlate the cytokine storm with wet lung pneumonia in COVID-19 patients.\n\n6.9 SARS-CoV-2 – ocular risk\nThe ACE2 receptors are also widely distributed in the superficial parts such as conjunctiva and cornea inferior parts such as iris, ciliary body, aqueous humor, trabecular meshwork, retina, and non-pigmented ciliary epithelium of the ocular globe which is mentioned out to be the intraocular renin-angiotensin system. Therefore, the distribution of ACE2 and TMPRSS2 protein must be taken into consideration to study the passage of infection through the ocular route [116]. Also, there is a chance for the virus to enter into the nasal cavity, which causes respiratory illness and the digestive system through the lacrimal canaliculi aided by the effectiveness of the tear film [117,118]. Out of 38 COVID-19 positive patients, 12 exhibited clinical manifestations, which include chemosis, epiphora, increased secretions, conjunctivitis, and conjunctival hyperemia. Researchers reported that patients exhibiting ocular symptoms would have elevated neutrophilic and lymphocytic counts, elated procalcitonin, lactate dehydrogenase, and C-reactive protein levels than those without ocular manifestations. The patients with ocular manifestations exhibited severe illness [119].\nEven though there is no such evidence, the presence of ACE2 and TMPRSS2 protein in the corneal limbal stem cells suggests that the SARS-CoV-2 may enter the bloodstream and travel to the other parts including the brain [120]. Even though there is no viral load in the conjunctiva of the SARS-CoV-2 infected patients without conjunctivitis, the risk of transmission of the virus through tears is low [121]. The exact mechanism behind the ocular risk and SARS-CoV-2 need to be elucidated further.\n\n6.10 SARS-CoV-2 – cancer risk\nCancer patients are highly vulnerable to SARS-CoV-2 infection. 18 out of 1590 COVID-19 positive cases exhibited cancer history. 5 out of 18 patients suffered from lung cancer, 4 out of 18 patients had no past information on medication and had undergone surgery or chemotherapy in the previous month, and the remaining 12 were cancer survivors. The COVID-19 was highly severe in cancer patients than non-cancer COVID-19 affected patients. Also, COVID-19 patients with cancer exhibited a severe chain of symptoms than those without a history of cancer. Also, patients with lung cancer did not exhibit severe symptoms when compared to those with other types of cancers [122].\nIn a retrospective study conducted among 1276 patients, 28 patients who have cancer were selected for the study. The mean age group people belonged to the elderly category, and 60.7% of them were males. Lung cancer was the most frequent type, followed by oesophageal and breast cancers among cancer affected patients. 10 out of 28 patients were presented with IV stage cancer. 28.6% of the patients developed COVID-19 while receiving antitumor therapy, whereas 71.4% of them developed due to the presence of infection in their vicinity. Besides, 39.2% of the patients exhibited chronic co-morbid conditions apart from cancer. 28.6% of patients died, and the remaining patients developed serious consequences even after receiving anti-viral and corticosteroids. The most common complication developed by the patients includes septic shock, acute myocardial infarction, and ARDS [123]. Therefore, more focus should be laid on the research for medication and treatment options for COVID-19 affected cancer patients. More studies are required to determine the exact mechanism behind cancer and SARS-CoV-2.\n\n6.11 SARS-CoV-2 – tuberculosis\nA study was conducted in February 2020, Shenyang, China, which involved 36 COVID-19 positive patients and was classified based on the severity of the symptoms as mild and critical. The results of these patients were compared with that of the patients affected by pneumonia caused by Mycobacterium tuberculosis from Shenyang chest hospital. The study was conducted to determine which one caused severe pneumonia, either the viral or the bacterial strain. Then the severity of tuberculosis was compared between the mild and severe COVID-19 cases and confirmed that tuberculosis due to mycobacterial strain affected patients are more susceptible to COVID-19 and enhance the severity of COVID-19 [124]. Patients with HIV undergoing treatment with antiretroviral medicines exhibit weak immune systems and are more susceptible to viral infections. Also, until now, only one HIV case had been reported with COVID-19 infection from china. The patient recovered from the infection the same as that of those without HIV. There is no evidence on whether HIV patients are more susceptible to COVID-19 infection [125].\nThe COVID-19 associated TB is found in 94th day of the nonexistence of public health interventions and 138th day in the occurrence of interventions. This occurs at the peak of an outbreak where the implementation of the intervention, out of it 11,066, is with the presence of interventions. 27,968 COVID-19 cases found in the absence of interventions, out of it 14,823, are with no interventions. This scenario shows that there is a need to take preventive measures of TB associated with COVID-19 patients. They need a prior diagnosis and proper management [126]. The main reasons for mortality are age, sex, and other co-morbid factors such as diabetes, cardiovascular diseases, and renal diseases are the main reasons for mortality.\n\n6.12 SARS-CoV-2 – Venous thromboembolism\nPeople affected with pneumonia are more prone to venous thromboembolism. Out of 1026 COVID-19 patients, 40% of them exhibited high risk, and 11% of them at high risk of developing venous thromboembolism without any prophylaxis. Prophylactic measures can prevent venous thromboembolism. Only 7 out of 140 patients at high risk for venous thromboembolism had recorded about the anticoagulation treatment. And 44 out of 407 exhibited a higher risk for bleeding. In these patients, the mechanical compressions such as intermittent pneumatic compression and elastic compression stockings are instructed, and the duration and dosage of anticoagulants should be adjusted. Also, the COVID-19 patients, along with other co-morbid conditions such as cardiovascular manifestations, respiratory failure, renal and hepatic problems, can affect the bleeding status and venous thromboembolism. Therefore, further investigations are required to reduce the risk due to venous thromboembolism and bleeding in the case of COVID-19 patients [127].\n\n6.13 SARS-CoV-2- reproductive risk\nViral infections during the first 20 weeks of gestation have shown to be more severe. The infections, such as SARS and MERS, which occurred due to coronaviruses, had reported an increased risk for pregnancy-related mortality and morbidity. Such cases among COVID-19 affected patients are not yet reported. Nine women who are in their third semester and infected with COVID-19 were reported to have outcomes as that of non-pregnant COVID-19 affected adults. In another study, out of 33 newborn infants, three infants were shown to be tested positive for COVID-19 who got the disease transferred from their mother through intrauterine vertical transmission mode [128].\n\n6.14 SARS-CoV-2 – mental illness\nAccording to a report, out of a group of 50 COVID-19 cases from a psychiatric hospital in Wuhan, China has uplifted the worry about the role of mental disorder in coronavirus transmission. The conditions include incomplete or no awareness of the risk, inability to have personal protection, and cognitive impairment. The treatment has become more challenging for people with COVID-19 infection and health disorders as co-morbid conditions [129].\n\n6.15 SARS-CoV-2 – aging and cardiovascular risk\nIt has been reported that the expression of ACE2 reduces with the increasing age. Since young patients possess high levels of ACE2, they are more prone to COVID-19 infection. Whereas, in old age people other than reduced ACE2 levels, other co-morbid conditions such as cardiovascular problems, diabetes, and hypertension might be present. The medication prescribed for these patients helps in elevating the ACE2 levels, which might enhance the viral entry. Though the treatment reduces the co-morbid severities, the viral infection is enhanced in those patients. Therefore, it is conclusive that young patients, even though they are more susceptible to the COVID-19 infection, they are less severely affected and exhibit elevated angiotensin II signaling. Whereas, the older patients who exhibit low levels of ACE2 and higher angiotensin II signaling leads to hypertension. The usage of ACEi and ARBs help in promoting the vasodilatory effects by elevating the ACE2 levels, thereby becoming susceptible to COVID-19 infection and are severely affected [130]."}