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Histopathological and molecular links of COVID-19 with novel clinical manifestations for the management of coronavirus-like complications

Coronavirus disease 2019 (COVID-19) causes transmissible viral illness of the respiratory tract prompted by the SARS-CoV-2 virus. COVID-19 is one of the worst global pandemics affecting a large population worldwide and causing catastrophic loss of life. Patients having pre-existing chronic disorders are more susceptible to contracting this viral infection. This pandemic virus is known to cause notable respiratory pathology. Besides, it can also cause extra-pulmonary manifestations. Multiple extra-pulmonary tissues express the SARS-CoV-2 entry receptor, hence causing direct viral tissue damage. This insightful review gives a brief description of the impact of coronavirus on the pulmonary system, extra-pulmonary systems, histopathology, multiorgan consequences, the possible mechanisms associated with the disease, and various potential therapeutic approaches to tackle the manifestations.


Introduction
The coronavirus of the family Coronaviridae caused corona-related diseases and devastating complications of COVID-19 which are characterized by signs and symptoms including fever, cough, fatigue, sore throat and respiratory distress (Gupta et al. 2020;Almaghaslah et al. 2020;Singhal 2020) as summarised in Table 1. This debilitating disorder upsurges the more pathological causes throughout the world as per the various scientific epidemiological reports. On March 11, 2020, the World Health Organization (WHO) pronounced SARS-CoV-2 a pandemic (Bulut and Kato 2020) which caused disease outbreak, and initial epidemiological data reported with a mortality rate of 9.56% with the involvement of 8098 patients and 774 deaths globally (Ganesh et al. 2021). In the end of 2021, the same data showed to produce a significant upsurge in the global cases, which revealed that there was 274,628,461 confirmed cases and 5,358,978 deaths. The recent reports revealed that the number of new COVID-19 cases and deaths continues to decline with over 4.1 million cases and 45,000 mortalities, with a drop rate of 9% in weekly death incidence (World Health Organization 2021a).
These pandemic cases lead to the progression of respiratory-related complications, with symptoms ranging from mild flu-like condition, acute respiratory distress syndrome (ARDS) to a life-threatening complications (Pereira, 2020). However, vital systems of our body, such as cardiovascular, gastrointestinal, hepato-biliary, renal, endocrine and neurological system, are also considered as a key pathological consideration in the COVID-19 etiopathogenesis (Mahajan et al. 2020). The pathogenesis of COVID-19 virus involves various molecular pathological outcomes which lead to the progression of metabolic and other complications of respiratory burden. The molecular and enzymatic involvement of ACE-2 (angiotensin-converting enzyme 2), IL-6 (interleukin-6), MMP (matrix metalloproteinases), peroxidase radicals, cytokines, macrophages, chemokines like CCL 2 (C-C motif chemokine ligand 2) and CXCL 10 (C-X-C motif chemokine 10) is demonstrated to have a role in the progression of coronavirus-like symptoms. The structural elucidation of coronavirus is concerned with the glycoprotein envelope, which has an affinity to bind with ACE-2 for efficient transmission of the virus into the alveolar region of the lungs, causing inflammatory and oxidative burden. Later on, it might spread in the other vital organs of the body. Similarly, in the same direction it causes endothelial damage, thrombo-inflammation, immune system dysregulation and dysfunction of ACE-2 pathways contributing towards the extra-pulmonary manifestations, leading to more worsening outcomes of the disease (Papa et al. 2020;Gupta et al. 2020). It was also illustrated by histopathological examination that coronavirus causes tissue damage with reference to hepatocyte injury, alveolar damage, mesangial cell expansion, pancreatic tissue degradation, stenosis of small intestine, edema in alveolar capillaries and brain lesions (Deshmukh et al. 2021).
The major emphasis of the current review is based upon the pathological, histopathological, molecular exploration concerned with COVID-19 virus. However, the other target of present review is also dedicated towards the clinical and therapeutic evidences for the management of COVID-19 complications. It was clinically reported that numerous interventions were proved to be beneficial including antivirals and anti-inflammatory agents, antimicrobials and antiprotozoals for the management of devastating respiratory distress induced by pandemic virus (Ruckmani et al. 2021).

History of COVID-19
Coronaviruses in humans were initially identified in 1960s and were attributed for a large number of upper respiratory tract infections in children and other age related subjects. Later on in 2003, the other novel human coronaviruses strains have been discovered, including, the SARS, NL63, representing a group of NL, the New Haven coronavirus and a newly established HKU group II coronavirus. Previously, the researchers had expressed little interest in inculcating new research gaps to study the coronavirus. However, the spotlight was highlighted in 2019 which generates a new direction for evaluating novel pathological and physiological interventions for the better understanding of SARS-CoV-2 virus. Scientists worldwide are working to produce new methods and techniques for clearing the gap and hindrance for the development of vaccines. With the continuous hard work, the Pfizer and BioNTech pharmaceutical companies were successfully able to find out the vaccine for management of COVID-19 globally (Kahn and McIntosh 2005). Within the same context, the other historical views of the coronavirus are summarized in Table 2.

Pathobiological and molecular links associated with COVID-19
The coronavirus spike protein promotes the virus entrance into the target cells via direct or indirect respiratory tract exposure through ACE2, which is engaged as an entry receptor by SARS-CoV-2 spike subunit inducing interstitial lung damage initially and parenchymal lesions later on. This protein proceeds with the priming process via transmembrane serine protease 2 (TMPRSS2) for the cell entry inside the lungs (Gupta et al. 2020). In the presence of TMPRSS2, SARS-CoV-2 enters host cells by interaction with the ACE2 entry receptor through its spike protein. The interaction between spike protein and TMPRSS2 causes downregulation of anti-inflammatory function and elevation of angiotensin II effects. Virus invades to the different cells and tissues of various vital organs leading to the progression of inflammatory changes including oedema and necrosis. These changes are associated with the release of proinflammatory cytokines which produce a situation of cytokine storm (Azer 2020). Cytokine storm can be defined as activation cascade of cytokine production due to uncontrolled host immune response with the upsurge of different causative triggers (Tong et al. 2020). The systemic inflammatory response syndrome or cytokine storm is activated by SARS-CoV-2, which thereby increases the pro-inflammatory cytokine load including, interferon γ, IL-1β (Interleukin 1 beta), IL-6 (Interleukin-6),  and chemokines, such as CCL 2 , CXCL 8 , CCL 5, CXCL 10 and CXCL 9 . Infiltrations of pro-inflammatory cells including macrophages and T helper 17 cells were reported in lung tissues of the infected patients during post-mortem investigations (Gupta et al. 2020). Tong et al. (2020) revealed that coronavirus affected patients have higher levels of white blood cells, neutrophils, procalcitonin, C-reactive protein, endothelial and epithelial cell apoptosis, vascular leakage followed by ARDS which indicate that there is generation of inflammatory and molecular pathways. These molecular and pathological triggers lead to symptomatic Olfactory/gustatory dysfunctions 64-80 Lechien et al. (2020) Anosmia/ageusia 3 Spinato et al. (2020) changes including cough, fatigue, fever, breathlessness, hypoxia, sore throat, chills and headache. Hypoxaemia, which is a leading symptom of coronavirus infection leads to accumulation of free radicals and lactic acid, alterations in intracellular pH and electrolytes imbalance finally causing cellular damage. Host immune response to coronavirus has a major involvement in disease progression, pathogenesis and clinical manifestations as depicted in Fig. 1  ). In stage 1 or the asymptomatic phase, mechanisms related to innate immunity play a role consisting of NK cells, interferon production, and some cytokines whereas during stage 2 (mild symptomatic period), adaptive immune response is essential to eradicate the virus. Lung inflammation occurs in stage 3 (severe respiratory stage) with high viral load. Immune responses should be suppressed and symptoms need to be controlled with the help of pharmacological and nonpharmacological approaches (Velikova et al. 2020).

Molecular observations associated with type 1 interferon (IFN)
Innate immunity is the first line of defence against infections caused by viruses, and it has both a preventative and a harmful response to infections. Type 1 interferons have an essential role in host defence against the virus by inducing antiviral effector molecules which are encoded by IFN-stimulated genes (McNab et al. 2015). During the  (2020) 1940 Two more animal coronaviruses, JHM that causes brain disease, murine encephalitis and mouse hepatitis virus that causes hepatitis in mice were discovered Körner et al. (2020) 1965 Researchers at the Common Cold Research Unit in Wiltshire, UK, reported cultivating a virus, B814, from a boy with a cold and the pathogen was recognised as virtually unrelated to any other known virus of the human respiratory tract Kapikian (1975) 1966 Dorothy Hamre and John Procknow described a virus, which they named 229E, isolated from a medical student with a cold. It was distinct from other known respiratory viruses Singh et al. (2020) 1967 Scientists at the National Institute of Allergy and Infectious Diseases reported using the same methods used to culture B814 to grow another new human virus with a similar morphology. They named it OC43 Monto et al. (2014) 2003 An international group of researchers reported the outbreak of severe acute respiratory syndrome (SARS), which began in late 2002 in southern China and was caused by a newly emerged human coronavirus Drosten et al. (2003) 2004  Kyriakidis et al. (2021) occurrence of viral infections, adaptive immune response is induced by type I interferon (IFN) responses, which further controls viral replication. The virus regulates antiviral IFN responses in SARS-COV and MERS infections by interfering with IFN production. Type 1 IFN response was found to be decreased in a deceased patient of MERS-CoV in comparison to the recovered patient. The phosphorylation and stimulation of IFN regulatory factor 3 (IRF3) become necessary for IFN production, which is however suppressed during SARS-CoV infection. The ORF4a, ORF4b, and ORF5 proteins of the virus block IRF3 nuclear translocation and subsequent activation of IFN β production. SARS-CoV-2, SARS-CoV and MERS-CoV have a similar genomics which likely proves that SARS-CoV-2 adopts a similar strategy in regulating type 1 IFN response. SARS-CoV-2, on the other hand, appears to be more responsive to type I IFNs, as demonstrated by sequence analysis (Alipoor et al. 2021). Choi and Shin documented that trivial levels of IFN-β, IFN-λ and ISG expression were identified in serum of coronavirus affected patients along with strong expression of the chemokines indicating that COVID patients possess impaired type 1 IFN response. This can be described by the reduction of pDC, which are type 1 IFNs producers (Choi and Shin 2021). In another study, Yoshikawa et al. (2010) revealed that induction of IFN might be delayed rather than becoming impaired as detected in infected bronchial epithelial cells. Channappanavar and Perlman carried out the studies in SARS-CoV-and MERS-CoV-infected animal models and defined the possible role of IFN as a novel therapy for COVID-19. Also, the viral replication of SARS-CoV-2 was decreased following treatment with type 1 IFN (Channappanavar and Perlman 2017). In contradiction, Choi et al. demonstrated that increased IFN generation and ISG expression are related with poor outcomes in coronavirus, and also related to atypical innate and adaptive immune responses. Increased transcriptional levels of IFNA2, IFNB1, IFNL2, and IFNL3 were observed in bronchoalveolar lavage fluid samples from COVID-19 patients. The severity of COVID-19 has been linked to high levels of IFN in serum of patients obtained 5-10 days after symptom onset. Severe patients of COVID-19 had increased IFN-α production in comparison to the patients with moderate severity (Choi and Shin 2021).

Molecular observations associated with IL-6
IL-6 is a cytokine that regulates cell proliferation and differentiation as well as the immune response. T cells, fibroblasts macrophages, endothelial cells, and monocytes secrete IL-6.
After a viral infection occurs, viral products stimulate the transcription or translation of IL-6 in fibroblasts, mesenchymal cells and endothelial cells. Increased IL-6 levels were found in SARS-CoV-2 patients, and these levels were linked 1 3 to pulmonary inflammation and significant lung damage. Decreased levels of cytokine signaling-3 suppressor, which modulates and enhances the negative feedback mechanism of IL-6, were observed in infected patients. In a critical COVID-19 group of patients, greater IL-6, IL-10 levels and C-reactive protein were more prominent in comparison to other cytokines (Vatansever and Becer 2020). Diao et al. (2020) observed that coronavirus affected people admitted in intensive care showed decreased CD8+ T cell counts, and total CD4+ and CD8+ count was inversely linked with TNF-and IL-6 levels.

Molecular observations associated with TNF-α
Tumor necrosis factor or TNF-α is the most important cytokines in the host defense system, and it plays a role in COVID-19 patients' pathogenesis. Ahmed et al. demonstrated that in COVID-19 patients, TNF-α allele A is significantly expressed when compared to controls. This suggests that people with the TNF-AA genotype are more likely to develop the condition. The TNF-AA genotype has been linked to a more severe disease pattern (Saleh et al. 2020).

Immune responses based upon antibody mediated immunity and their correlation with coronavirus infection
Lymphocyte infection plays an essential role in viral-induced pathogenicity in coronavirus disease. During the virus entrance, immunogenic peptides are released to T cells along with human leukocyte antigen (HLA). HLA polymorphism may affect SARS-CoV infection susceptibility and outcome. Some HLA alleles, such as HLA-B*4601, HLA-B*0703, and HLA-Cw*0801 and polymorphisms in the mannosebinding lectin gene, are linked to coronavirus infection susceptibility and risk. HLA-DRB1*11:01 and HLA-DQB1*02:0 alleles impose a risk for MERS-CoV infection and should be assessed in coronavirus patients. SARS-CoV-2-specific antibodies can be developed to neutralise the virus (Alipoor et al. 2021). It was documented that COVID-19 showed cross-reactivity with SARS-CoV and the serum of five patients had the ability to neutralise the coronavirus . The patients had acquired IgG or IgM seroconversion within 20 days after the onset of symptoms. Asymptomatic patients who experienced no symptoms and had negative nucleic acid results were positive for IgG and IgM tests. Hence, this highlights the need for serological testing along with RT-PCR especially in case of asymptomatic patients (Liu and Li 2020). T helper (Th) cells have an essential role in adaptive immunity during viral infection.
In SARS-CoV infection, the mild-to-moderate group had a substantial Th1 cell response and increased levels of neutralising antibodies, but the fatal group had a higher level of Th2 cytokines including IL-4, IL-5, and IL-10 and hence Th1 response becomes essential for controlling SARS-CoV-2. Controlling infection requires a balance of naive and memory T cells. The generation of cytokines by naive T cells is important for the defence against new, previously undetected infections. Memory T cells, on the other hand, stimulate antigen-specific immune responses. COVID-19 relapse may occur due to decreased memory T cells. In severe patients of coronavirus, CD8+ T cell responses were more frequent than CD4+ T cell responses. Cytotoxic granules are present in CD8+ T cell which can induce severe immune injury in patients. T cell depletion occurs as a result of T cell dysregulation during viral infections. Elevated levels of PD-1 and Tim-3, present in peripheral blood T cells of coronavirus patients are induced by T cell exhaustion due to IL-10 ( Alipoor et al. 2021).

Histopathological links associated with COVID-19 with reference to major vital organs
Early pathological findings indicate that coronavirus is broadly disseminated in the epithelial lining of the respiratory tract, digestive tract, distal convoluted tubules (DCT), sweat glands, and epithelium of the testes which is discussed in detail as follows (Vasquez-Bonilla et al. 2020;Deshmukh et al. 2021). The overall histopathological changes associated with various organ systems of the body is summarized with the help of pictorial representation (Fig. 2).

Histopathological evidences of brain tissues with references to COVID-19 progression
Neurological symptoms like headache, dizziness, seizures and altered sensorium were frequently reported in COVID-19 indicating that the virus might be neurotropic. Neurotropic respiratory viruses invade into the CNS via hematogenous and neuronal retrograde routes. Brain lesions were observed along with oedema, neuronal degeneration followed by acute hypoxic ischaemic injury (Deshmukh et al. 2021). CT scan and MRI revealed enhanced subcortical and cortical grey matter followed by appearance of fibre tracts in the brain. Dotted subarachnoid haemorrhages were present in brain as reported by Vasquez-Bonilla et al. Other findings included cyanotic and edematous meninges (Stoyanov et al. 2020;Vasquez-Bonilla et al. 2020).

Histopathological evidences of pulmonary tissues with references to COVID-19 progression
Upper respiratory tract infections often cause mild-to-moderate symptoms, whereas lower respiratory tract infections cause pneumonia-like symptoms and can lead to organ failure. Comorbidities including hypertension, chronic renal disease, obstructive sleep apnea, diabetes and obesity enhance the severity and pathological alterations might differ between the right and left lung. It was documented that coronavirus majorly affects the lungs causing alveolar damage, formation of hyaline membrane, presence of intraalveolar fibrin, macroscopic diffusely consolidated lungs, loosely organized connective tissue in alveolar septal wells, macrophage and lymphocytic infiltration (Bradley et al. 2020;Vasquez-Bonilla et al. 2020;Stoyanov et al. 2020;Bryce et al.2020). Vasquez-Bonilla et al. (2020) documented that intra-nuclear inclusions were suggestive of acute and necrotizing pneumonia, intravascular fibrin thrombi, and interstitial inflammatory infiltrate (Vasquez-Bonilla et al. 2020). It was revealed that the lungs were congestive, consisting of patches of haemorrhagic necrosis during macroscopic examination. Olfactory bulbs were found to be edematous with a pronounced oval shape (Stoyanov et al. 2020). Deshmukh et al. (2021) revealed that the microscopic features comprising alveolitis were observed along with vacuolar degradation, proliferation, atrophy and metaplasia of epithelial cells. Multinucleate giant cells, viral inclusion bodies, massive fibrinous exudate and epithelial cells in lumen were also present indicative of necrotic changes. Pneumocytes were observed to be damaged with immune cells infiltration. Further findings were indicative of intra-alveolar haemorrhages and intra-alveolar neutrophil infiltration suggestive of superimposed bacterial infection. Presence of CD3+, CD4+ T cells, CD20+ B-lymphocytes and CD68+ macrophages was suggestive of inflammatory oedema in the respiratory mucosa. In conclusion, the major findings were observed to be pneumocyte hyperplasia, hyaline membrane formation, necrosis, hemorrhage and plug formation in alveoli (Deshmukh et al. 2021). Figure 3a shows the normal histology of lung alveolar septa and bronchiolar epithelium, whereas Fig. 3b demonstrates the lung histology of a COVID-compromised patient.

Histopathological evidences of cardiac tissues and blood cells with references to COVID-19 progression
Viral infections are a major cause of myocarditis. ACE-2 receptors are present in vascular endothelial cells and can easily be targeted by the coronavirus. It was revealed that there was an inflammation of the myocardium, endocarditis, presence of viral particles, CD4+ T cells and other inflammatory infiltrates in the myocardial interstitial cells and myocardium (Bradley et al. 2020). Deshmukh et al. documented the presence of apoptotic bodies in endothelial cells, edema in alveolar capillaries and small vessels and appearance of fibrin thrombi, neutrophils and CD61+ megakaryocytes. Hence, the major histopathological findings Fig. 2 Pictorial depiction of histopathological changes of various vital organ systems including the respiratory system, renal system, gastrointestinal system, neurological system and cardiovascular system with reference to  were ruled out to be inflammation, presence of infiltrates and edema (Deshmukh et al. 2021). Figure 4a demonstrates the normal histology of heart Fig. 4b and c show the cardiac histology of COVID patients.

Histopathological evidences of hepatological tissues with references to COVID-19 progression
The coronavirus can replicate and might be present in the digestive system as well. The hepatobiliary system has also been found to contain ACE-2 receptors. Coronavirus infection can be associated with liver injury as observed by a tremendous increase in liver function impairment and elevated enzyme levels   (Li and Xiao 2020). Figure 5a is indicative of normal liver histology, whereas Fig. 5b shows the liver histology of COVIDaffected patient.

Histopathological evidences of renal tissues with references to COVID-19 progression
ACE-2 is highly expressed in COVID-19-infected people and it has been indicated by positive result of tubule immunostaining with the virus nucleoprotein antibody. Apart from the SARS-CoV-2 direct virulence, other major factors that contribute to progression towards acute kidney  (Deshmukh et al. 2021). The major findings from the above discussion were documented to be podocyte vacuolation, glomerulosclerosis, edematous epithelial cells and arteriosclerosis of arteries. Figure 6a is suggestive of

Histopathological evidences of gastrointestinal tissues with references to COVID-19 progression
Caramaschi et al. revealed that inflammation, shock and ischemia were observed in the small bowel along with endothelialitis and apoptotic bodies in small intestine (Caramaschi et al. 2021). Deshmukh et al. documented that stenosis occurred in the small intestine followed by necrosis, epithelial degeneration, shedding in gastrointestinal mucosa and gastric tissues along with the appearance of congested blood vessels presence in lamina propria and submucosa. Tissue degradation was observed in pancreas (Deshmukh et al. 2021).

Histopathological evidences of reproductive tissues with references to COVID-19 progression
The histopathological changes observed in the reproductive system included basement membrane thickness with peritubular fibrosis, vascular congestion, leucocyte infiltration, extensive germ cell destruction and increased apoptotic spermatogonic cells. Swelling, vacuolation and cytoplasmic rarefaction were observed in sertoli cells (Deshmukh et al. 2021). Figure 7a shows the normal histology of testes, Fig. 7b indicate the pathological changes in testes of patients with COVID.

Histopathological evidences of skin with references to COVID-19 progression
Caramaschi et al. demonstrated that perivascular inflammatory cells and intraluminal thrombi were found in skin vessels. Parakeratosis, acanthosis, dyskeratotic keratinocytes and necrotic keratinocytes were found in epidermis (Caramaschi et al. 2021). Figure 8a demonstrates the normal histology of skin, whereas Fig. 8b shows the histology of skin in COVID-affected patients.

Clinical evidences for the management of COVID-19
Clinical approaches with reference to pulmonary compromised subjects

Acute respiratory distress syndrome (ARDS)
The management of ARDS seems to be challenging. It is essential to monitor the respiratory drive for detection of initial phases of respiratory fatigue. Non-invasive ventilation is being used for COVID patients, in which mask is the main interface in patient's respiratory tract (Nasibova and Pashayev 2020). When a patient has mild-to-moderate dyspnea and hypoxemia and does not react to normal lowflow cannula, a high-flow nasal cannula is advised (Calligaro et al. 2020). High-flow nasal cannula has bio-aerosol dispersion system and it is recommended that the patient be placed in a negative pressure room. Apparently, when high-flow nasal cannula fails to work, NIV support and Bi-level positive airway pressure are used and they are appropriate for patients having co-morbidities including chronic obstructive pulmonary disease and heart failure. Continuous positive airway pressure is reported to be advantageous pneumonia patients affected with coronavirus as it leads to effective alveolar recruitment (Gattinoni et al. 2020). The demonstration of different phenotype of ARDS with their novel characteristics is summarised in Table 3. Severe hypoxemia can be relieved via prone positioning by reducing overinflated lungs, re-expanding previously collapsed lung areas and decreasing ventilation/ perfusion imbalance (Navas-Blanco and Dudaryk 2020). Evidently, prone positioning was known to decrease mortality of 28 and 90 days as documented in the clinical trial NCT00527813 (Guérin et al. 2013). Use of nitric oxide and prostaglandins as pulmonary vasodilators is not proven yet and is still controversial because many questions arise like if NO can be selfadministered safely to the patients at home or not, if the benefit is unique to NO and if other therapies could also increase signalling along NO axis. The studies regarding use of NO in COVID-19 patients are being conducted under clinical trials and it might have potential as a useful therapy. Another strategy is the use of extracorporeal membrane oxygenation (ECMO) for patients with severe ARDS due to reversible conditions that are not responding to the standard therapy and has also been recommended by Extracorporeal Life Support Organization (ELSO) for younger group of patients with lesser or no morbidities, healthcare providers. Besides, ELSO has given algorithm for COVID-19-associated ARDS in furnishing conservative management consisting of prone positioning, pulmonary vasodilators, high PEEP, recruitment maneuvers in affected patients who have PaO 2 /FiO 2 ratio lesser than 150 mmHg along with worsening refractory hypoxemia and PaO 2 /FiO 2 ratio greater than 150 mmHg but having poor tissue perfusion signs and hypercarbia. However, EOLIA trial shows that 60-day mortality did not improve in ECMO group patients. ELSO (Bartlett et al. 2020; Navas-Blanco and Dudaryk 2020). Tocilizumab, a potential recombinant monoclonal antibody against IL-6, has the potential for treating COVID-associated ARDS and has been widely used in patients with inflammatory diseases. However, there is a need for data from more large and randomized clinical trials to confirm its efficacy and safety (Khiali et al. 2020). In ARDS, fibrin and platelet thrombotic microclots can accumulate in the air spaces and parenchyma of lungs progressing towards respiratory failure, additionally increasing the clot activation and mobilisation, furthermore activating the coagulation system. Plasminogen activators can attenuate the severity of ARDS as it has been observed that mortality rate was reduced from 100 to 70% in ARDS patients who were administered urokinase or streptokinase. Tissue plasminogen activator (tPA) is highly efficient, decreased mortality, increased arterial pO 2 and decreased pCO 2 . tPA is a recommended treatment in the absence of ECMO for ARDS patients affected with coronavirus having PO 2 / FiO 2 ratio < 50 and pCO 2 > 60 mmHg. However, there is a  Gattinoni et al. (2013) limitation in using this therapy in patients with thrombocytopenia as tPA might cause platelet dysfunction (Lechowicz et al. 2020). Valproate is an HDAC (Histone deacetylases) inhibitor and a modulator of epigenetic changes and its inhibition results in acetylation of histones, modifies the gene expression regulating cell cycle, cell differentiation and apoptosis. It also inhibits the production of NF-κB, TNF-α, and IL-6 in lipopolysaccharide stimulated human cells, decreases nitric oxide expression along with downregulation of macrophage response and blocks NF-κB signalling. As a result, acute lung edema reduces and lung injury attenuates. Moreover, the metabolite of this drug, valproic acid Co-A, forms a stable interaction with nsp12 of coronavirus and inhibits viral replication (Bhargava et al. 2020).

Acute lung injury and pneumonia
The patients with COVID-19 pneumonia require treatment of efficacious antiviral and anti-inflammatory medications (Gallelli et al. 2020). In addition to hydroxychloroquine sulfate or tocilizumab, azithromycin use is recommended because it possesses immunomodulant effect (Gautret et al. 2020). Table 4 demonstrates the clinical status of azithromycin, alone or in combination with other drugs under clinical trials. Tocilizumab, a blocker of IL-6 signalling is used in treatment of cytokine release syndrome. Sarilumab and baricitinib, blockers of adaptor-associated protein kinase 1, are used in treating the cytokine storm. Corticosteroids exhibit anti-inflammation and immunomodulatory actions (Gallelli et al. 2020). However, the use of systemic corticosteroids is not recommended by WHO for treating viral pneumonia and ARDS as they can delay the viral clearance (World Health Organization Institutional Repository for Information Sharing 2021). Lianhuaqingwen capsule has been approved by the National Medical Products Administration of China for treating mild-to-moderate coronavirus pneumonia (Chen et al. 2021). Escin, extracted from Aesculus hippocastanum L., Aesculus wilsonii possesses anti-inflammatory, antiviral effects and has the potential in treating COVID-19 patients by reducing the degree of lung injury. At 10 μg/mL dose, it suppresses the secretion of nitric oxide, TNF-α, and IL-1β. The effect can be enhanced by combining escin and glucocorticoids because escin upregulates glucocorticoid receptor and increases antioxidant activity. The efficacy of escin is being studied under clinical trial NCT04322344 and it is under Phase 2/Phase3 of the study. However, it is being administered to COVID patients in Italy at dosage 40 mg three times daily orally or as a 20 mg IV injection (Gallelli et al. 2020).

Pulmonary fibrosis
Interstitial lung disease consists of acute and chronic lung diseases which cause progressive scarring of the lung tissues. The most common one is pulmonary fibrosis (Antoniou et al. 2020). Patients affected with COVID-19 progress from atypical pneumonia to fibrosis, which causes interstitial matrix widening, compression, pulmonary parenchyma destruction and finally respiratory failure. Transforming growth factor beta 1 (TGF-β1) is responsible for causing fibrosis and is more prevalent in older people. The pulmonary fibroblast proliferation is increased due to overexpression of fibroblast growth factor and platelet-derived growth factor. The duration of COVID disease is correlated with the degree of pulmonary fibrosis. The cytokine profile of fibrosis and COVID-19 is similar and hence drugs used in treating fibrosis can also be used in COVID-19 (Lechowicz et al. 2020). In this condition, lung function deteriorates exigently causing respiratory failure and ultimately death. The disease can be idiopathic, genetically predisposed, fibroproliferative disease and chronic inflammation play a role in it. Pulmonary fibrosis can occur as a consequence of ARDS (Vasarmidi et al. 2020). Exacerbations of pulmonary fibrosis are triggered by viral infections of the respiratory tract. The evidence of using corticosteroids is limited. Some studies have reported that there is no influence of corticosteroids in improving survival and their use increases risk of mortality and secondary infections in influenza pneumonia. However, some studies are suggestive of decreased risk of death using methylprednisolone in COVID patients. Spironolactone is also effective in treating pulmonary fibrosis by attenuating the increased aldosterone levels due to mineralocorticoid activation which further causes elevation of extracellular matrix turnover. Besides, spironolactone is also known to possess antioxidant properties. Lung tissue of patients treated with spironolactone indicate lesser number of white blood cells and macrophages in the alveoli (Lechowicz et al. 2020;Yavas et al. 2019). Many anti-fibrotic drugs having antiviral and epithelial protective effects are available which are used in acute exacerbations of idiopathic pulmonary fibrosis and also enervate profibrotic pathways involved in coronavirus infection. The FDA approved drugs used include pirfenidone (suppressor of NLRP3 inflammasome activation) and nintedanib (tyrosine kinase inhibitor), which attenuate decline of lung function (Vitiello et al. 2020;Chaudhary et al. 2020). Pirfenidone decreases the concentration of IL-6, has anti-oxidant properties whereas, nintedanib decreases concentrations of IL-1β. Both these drugs are taken orally, hence it becomes very difficult to administer them to patients on ventilator and to be effective, they should be administered within the first week of ARDS (Vasarmidi et al. 2020;George et al. 2020). The approved anti-fibrotic drugs are meant for chronic disease management and do

Pulmonary embolism (PE)
A hypercoagulable state occurs in COVID-19 patients along with elevated levels of d-dimer, fibrinogen, fibrinogen degradation products, prolonged prothrombin time and international normalized ratio (Bompard et al. 2020;Osakwe and Hart 2020). Viral infections may lead to venous thromboembolism (VTE), thereby activating systemic inflammatory response. Prophylactic treatment with heparin improved survival in the patients having sepsis-induced coagulopathy and increased d-dimer.Low molecular weight heparins at a dose 40 mg qd and subcutaneous unfractionated heparin at a dose 5000 IU tid should be started in confirmed COVID-19 cases. Pneumatic compression is suggested in immobilized patients and in the patients in whom pharmacological prophylaxis is contraindicated. Enoxaparin at a dose of 4000 IU is considered in patients with multiple risk factors for VTE and obese patients are administered with a dose 40 mg twice daily. Direct oral anticoagulants are used after the acute phase in stable patients (Sakr et al. 2020).

Other comorbid conditions and miscellaneous potential strategies for the management of pulmonary compromised situations in COVID subjects
Patients with conditions, such as lung carcinoma, autoimmune disease, pulmonary sarcoidosis, sick sinus syndrome and mild obstructive lung disease, are at a higher risk during coronavirus infection. Remdesivir is used in early stages but is restricted due to limited availability and potential toxicity (Yates et al. 2020). Patients treated with doxycycline show rapid clinical improvement. Metalloproteinases are responsible for viral entry into the cell and doxycycline is a metalloproteinase inhibitor. It is also an inhibitor of IL-6 and NF-κB (direct inhibition of DPP4 cell surface receptor) (Malek et al. 2020). OATD-01 (chitotriosidase 1) aids in the treatment of pulmonary fibrosis in COVID-19 survivors. It exhibits anti-inflammatory actions and delays fibrosis development (OncoArendi Therapeutics 2020). Ivermectin (antiparasitic drug) reduces viral load by 99.98% after treating for 48 h. However, WHO recommends its use within clinical trials because current data on its use are inconclusive (World Health Organization, Newsroom 2021b). Ciclesonide, at an effective concentration of 6.3 µM, is a blocker of SARS-CoV-2 RNA replication in vitro and is an inhibitor of its cytopathic activity (Iwabuchi et al. 2020). Tetrandrine is an alkaloid obtained from the plant Stephania tetrandra and at concentration 4.8 µmol/L affects reactive oxygen species and caspase pathways associated with treating inflammation. It has the ability to suppress virus reproduction by blocking the two-pore channel 2 (TPC2) in host cells at low micro-molar concentrations and also inhibits proliferation of T cells and not reverse fibrosis. TGF-β pathway is the main pathway or target for antifibrotic therapies including BG00011 (αvβ6 integrin), PLN-74809 and TD139 (galectins). Arg-Gly-Asp integrin-binding domain is present on spike protein of SARS-CoV-2. Hence, integrins or galectin inhibitors are beneficial in COVID-19. Combination of rapamycin (mTOR inhibitor) and oseltamivir is known to reduce viral replication. Inhibition of IL-1 prevents the development of post COVID-19 fibrosis. Anti-interleukin therapies may act as potential for treating COVID-19 (George et al. 2020). Table 5 demonstrates information on various clinical trials involving anti-interleukin therapies which could be beneficial in COVID-19.
Reduction of viral load is necessary in fibrosis. Antiviral drugs involve the use of chloroquine and hydroxychloroquine (cause disruption of coronavirus cell receptor glycosylation and modulation of immune system), teicoplanin (inhibitor of low-pH cleavage of the viral spike protein, preventing the release of genomic viral RNA with IC 50 value 1.66 μM) (Baron et al. 2020) and remdesivir, favipiravir (RNA polymerase inhibitors) and lopinavir/ritonavir (viral protease inhibitors). Combination of lopinavir/ ritonavir with interferon-1β or ribavirin might be effective against coronaviruses. Umifenovir inhibits virus binding to the cell membrane and is significant in improving clinical status of patients as compared to lopinavir/ritonavir (Nojomi et al. 2020), whereas, favipiravir inhibits virus reproduction in vitro (Ojo et al. 2020). Plasma therapy provides specific passive immunity and increased PaO 2 /FiO 2 and decreased viral load (Ray et al. 2020).

COPD (chronic obstructive pulmonary disease)
Patients with underlying COPD might have excessive risk for contracting COVID-19. However, this topic is still in debate. Epidemiological studies indicate that there is a prevalence of 1.1-38% of COPD in coronavirus affected patients. Cleveland Clinic registry investigated that out of 15,586 patients having symptoms and tested for the virus, 9.2% had COPD (Sin 2020). ACE2 expression is also increased significantly in COPD patients and escalated by smoking. During coronavirus infection, patients may have commotions in the renin-angiotensin-aldosterone system, as well as upregulation and aggravation of ACE and angiotensin II, which can lead to pulmonary hypertension and edema. Inhaled corticosteroids decreases viral entry and their use is recommended (Leung et al. 2020). Patients with COPD are advised to use already prescribed inhalers, long acting bronchodilators. In case of COVID-associated exacerbations, patients are given dexamethasone systemically if they need supplemental oxygenation and mechanical ventilation (Sin 2020).     IFNγ production. Tetrandrine has low and variable oral bioavailability which can be enhanced by making formulations of lipid nano-capsules, nanoparticles, ethosomes, and microspheres or by inhalation method (Heister and Poston 2020). Fuzheng Huayu formula and Anluohuaxian possess anti-fibrotic properties. Other treatment strategies include administrating mesenchymal stem cells and human purified amniotic fluid, having anti-inflammatory and antifibrotic properties (Lechowicz et al. 2020). Table 6 demonstrates the pharmacological therapy of coronavirus associated pulmonary fibrosis under clinical trials. Figure 9 describes the various therapeutic approaches in treating COVID-associated pulmonary fibrosis.
Clinical approaches with reference to extra-pulmonary manifestations associated with other organ systems SARS-CoV-2 is predominantly responsible for causing disorders of the respiratory tract but it can also cause extrapulmonary manifestations including thrombotic complications, dysfunction of the myocardium, arrhythmias, coronary syndrome, kidney injury, gastrointestinal disorders, hepatocellular injury, neurological disorders, ocular disorders and ketosis (Gupta et al. 2020).

Cardiovascular manifestations
SARS-COV-2 virus has major implications on cardiovascular system. Patients with cardiovascular risk factors including age above 60 years, obesity and comorbid conditions including diabetes and hypertension are at a higher mortality risk because of higher ACE 2 expression in myocytes, fibroblasts, endothelial cells, and smooth-muscle cells (Shafi et al. 2020).Cardiovascular diseases including heart failure, myocardial injury, myocarditis, arrhythmias, and acute coronary syndrome are correlated with COVID-19. Heart failure occurs as a response to infection and ARDS (Temgoua et al. 2020).Wang et al. reported that 44.4% COVID-19 patients admitted in a hospital had cardiac arrhythmias ) and were mostly affected with torsade de pointes. Risk of QT prolongation can occur due to drugs like hydroxychloroquine, renal failure and hypokalaemia. Patients are at a risk of developing venous thromboembolism due to inflammation, hypoxia, immobilization, and diffused intravascular coagulation (Temgoua et al. 2020). ACE catalyses angiotensin II to angiotensin 1-7 conversion, exerting a protective effect on the cardiovascular system. SARS-CoV-2 and ACE2 binding can decrease this catalytic effect (Dou et al. 2020). Stimulation of macrophages and leucocyte adhesion molecule expression on endothelial cells of atherosclerotic lesions makes them prone to get disrupted and causing acute coronary syndrome (Gavriatopoulou et al. 2020). Current  (Mahajan et al. 2020). In patients with ST segment elevation, percutaneous coronary intervention is recommended but fibrinolytic therapy can also be used. Obtaining baseline QTc interval is essential before administration of any drug (Gupta et al. 2020). Remdesivir 200 mg administered IV on day 1 followed by 100 mg for 9 days showed clinical improvement in the patients. Lopinavir and ritonavir show potential benefits. But the adverse effect associated with them include prolongation of QT and PR intervals and hyperlipidaemia (Nishiga et al. 2020). Other antiviral drugs consist of oseltamivir and favipiravir. But antiviral drugs might show interaction with antiplatelet agents and anticoagulants. So they should be monitored cautiously (Su et al. 2020). Chloroquine and hydroxychloroquine have antiviral and anti-inflammatory effects but they may cause QT prolongation and monitoring is essential when azithromycin is also used (Takla and Jeevaratnam 2020). Patients with cardiovascular diseases are prescribed statins. Statin shows therapeutic efficacy in hyper-inflammatory ARDS. Rosuvastatin is known to reduce pneumonia. Drug interactions between statins and protease inhibitors can occur. So, they should be cautiously used (Atri et al. 2020;Rossi et al. 2020). Amiodarone is used in treating cardiac arrhythmias and can inhibit in vitro spread of coronavirus. Colchicine reduces the release of interleukins IL-1β and IL-6. ACC/AHA recommends the use of ACE inhibitors and ARBs in patients who have been previously prescribed. But, there is still no evidence which supports their use. Mortality risk in COVID-19 patients with hypertension was reduced by administering them (Su et al. 2020;Kang et al. 2020). Camostat mesylate (inhibitor of cellular serine protease TMPRSS2) blocks SARS-CoV-2 entry, which is further dependent on ACE2 for its entry into the host cell (Madjid et al. 2020). Tranexamic acid reduces the conversion of plasminogen to plasmin and can reduce the pathogenicity and viral load. However, various adverse effects including venous and arterial thrombosis and thromboembolism are involved with its use. So, tranexamic acid must be cautiously used in patients with underlying cardiovascular diseases (Driggin et al. 2020).

Renal manifestations
The brush border present in proximal tubular cells and podocytes highly expresses ACE 2 receptors. Chronic kidney disease and transplantation are considered as risk factors for contracting the infection. Renal manifestations include acute kidney injury, proteinuria, hematuria, increased kaliuresis, decreased glomerular filtration rate (GFR), increased blood urea nitrogen (BUN) and serum creatinine levels and the presence of SARS-CoV-2 in the urine (Gavriatopoulou et al. 2020;Temgoua et al. 2020). The mechanisms responsible for acute kidney injury include dehydration, hypoxia followed by hypovolemia and ischemia, which further cause tubular necrosis, renal cell infection, cytokine storm syndrome, diabetes, hypertension, use of NSAIDs and rhabdomyolysis. Management consists of sufficient hydration and abstaining from using nephrotoxic medications and dialysis is required in second week of infection. Other options consist of haemodialysis, slow low-efficiency dialysis and continuous renal replacement therapy (Mahajan et al. 2020). Urine analysis and protein-to-creatinine ratio are evaluated at the time of patient admission. Patient can be given empiric low-dose systemic anticoagulation for renal replacement therapy. Fluid balance strategies should be applied to correct the levels of serum lactate and electrolytes. Renal replacement therapy should be considered in patients with acute kidney injury (Gupta et al. 2020).

Immuno-hematological manifestations
Clinical manifestations occurring due to virally induced hyper-inflammation consist of enlargement of spleen, atrophy and lymphoid organ atrophy. Lymphopenia occurs due direct viral cytotoxicity, followed by lymphocyte depletion due to apoptosis and inhibitory actions of lactic acid on proliferation of the lymphocytes. Spleen atrophy and lymphoid tissue destruction occur in COVID-19 (Gupta et al. 2020). Abnormalities in blood consist of anaemia, leucocytosis and neutrophilia, elevated levels of neutrophils/ lymphocytes ratio, decreased count of eosinophil, monocytes, lymphocytes (CD4/CD8) and platelets, elevated D-dimer, and decreased fibrinogen levels (Joly et al. 2020;Al-Samkari et al. 2020). Antiphospholipid antibodies are observed in case of viral infections (Marietta et al. 2020).
Hyper-inflammation causes anaemia, bacterial infections cause leucocytosis and increased neutrophils. Apoptosis induced by virus, elevated activation of lymphocytes and inhibition of lymphocyte proliferation lead to lymphopenia. Excess platelet consumption in micro-thrombosis site can cause thrombocytopenia. Inflammatory syndrome is followed by cytokine storm and changes in biochemical parameters including increased erythrocyte sedimentation rate (ESR), increased CRP, elevated levels of ferritin and procalcitonin (Temgoua et al. 2020). Coagulation activation occurs due to sepsis, cytokine storm, and multi-organ failure. Active bleeding requires transfusion. Routine risk assessment of developing VTE should be done in hospitalized COVID patients. Prophylactic treatment of anticoagulants should be considered in case of active bleeding and platelet count less than 25 × 10 9 /L (Gupta et al. 2020;Kasinathan and Sathar, 2020). Low molecular weight heparin (4000-5000 kD) is used in treatment and it has a better prognosis in COVID-19 especially in cases of elevated d-dimer (Mahajan et al. 2020;Sathler 2020; Aggarwal

Gastrointestinal manifestations
The epithelial cells present in the upper oesophagus and enterocytes in ileum and colon consist of ACE2 receptors. SARS-CoV-2 replication and high ACE2 expression causes direct cytopathic effect. Viral infections enhance the permeability of the gastrointestinal wall to pathogens (Mahajan et al. 2020). Moreover, liver function is dysregulated due to SARS-CoV-2 and ACE2 binding and it is reflected by low albumin. Liver injury may occur as a result of using lopinavir/ritonavir and hydroxychloroquine and biomarkers, such as serum transaminases and bilirubin levels, indicate the degree of injury (Temgoua et al. 2020). Gastrointestinal manifestations include nausea, vomiting, diarrhoea, abdominal pain, bleeding and anorexia. Diagnostic endoscopy should be avoided but should be reserved in patients in whom upper gastrointestinal bleeding is prominent. Regular monitoring of hepatic transaminases is necessary when giving interventions, such as remdesivir, lopinavir, and tocilizumab (Gupta et al. 2020).

Neurological manifestations
When ACE2 becomes highly expressed in the nervous system, it gives rise to symptoms, such as headache, ataxia, unconsciousness, dizziness, cerebral haemorrhage and infarction, hypogeusia, epilepsy, hyposmia, hypopsia and neuralgia (Mahajan et al. 2020). Neurological complications occur due to various mechanisms including cytokine dysregulation and up regulation of cytokines TNF-α, IL-1β, IL-6, myeloid cells, transmigration and post-infectious autoimmunity (Temgoua et al. 2020).Virus can invade via neural parenchyma and nasal epithelial cells show the highest expression for ACE2 receptors. Patients with neurological disorders including Parkinson's and Alzheimer's disease should be taken care of properly and monitored regularly. Immunomodulatory therapies should be considered in patients with multiple sclerosis. Use of tPA and anticoagulants should be evaluated as they can increase risk for intracranial bleeding and haemorrhagic conversion of stroke. Practice of telemedicine can be executed in patients with cognitive impairment. Tele neurology can be used to provide treatment to dementia patients (Kim et al. 2017). Depression and anxiety can be reduced by doing mindfulness activities and through online interaction. Physical activities done at home can help in eradicating psychological stress and hence improve the symptoms (Helmich andBloem, 2020). et al. 2020;Joly et al. 2020). Fondaparinux can reduce mortality in patients of pulmonary artery thromboembolism (Zabolotsky Dmitrii and Koryachkin Viktor 2020). Enoxaparin at a dose of 40 mg twice daily, enoxaparin 1 mg/kg daily, nadroparin 5700 IU daily and nadroparin 2850 IU twice daily are the proposed dosage regimens for prophylaxis (Orsi et al. 2020).

Septic shock
60% of COVID-19 patients experience sepsis and nearly 20% experience further complications including septic shock. The organ dysfunction in sepsis can be evaluated using Sequential Organ Failure Assessment (SOFA) score. Clinical management involves the empirical use of antimicrobials with mechanical ventilation. US FDA has approved the emergency use authorisation for remdesivir. However, there is no solid evidence for the use of other category of drugs including antivirals, interferons, tocilizumab, immunoglobulins, and plasma therapy, chloroquine phosphate and hydroxychloroquine. FDA has abrogated the use of chloroquine and hydroxychloroquine due to cardiac complications. Apparently, hydroxychloroquine is being administered in severe patients at 400-600 mg daily for 5 days (Mahajan et al. 2020).

Endocrine and metabolic manifestations
ACE2 receptors are expressed in various endocrine organs including pancreas, female ovaries, pituitary gland, thyroid and male testicles. The coronavirus infection in critical patients is followed by complications including pancreatitis, diabetes mellitus, hypogonadism and hypothyroidism (Temgoua et al. 2020).The binding of coronavirus to ACE2 receptors in the pancreas causes hyperglycemia and diabetes mellitus, followed by increased receptor expression, which enhances infection susceptibility and multiorgan failure. Glucose metabolism and blood pressure can be improved using antidiabetic medications such as glucagon-like peptide-1 agonists. Agonists of glucagon-like-peptide-1 are beneficial to enhance the metabolic activity and instigate protective ACE2 and Mas receptor pathways (Mahajan et al. 2020).Hemoglobin A1C needs to be checked in COVID-19 patients with hyperglycemia and ketoacidosis. Glucose monitoring is essential. Subcutaneous insulin should be considered in patients with mild-to-moderate diabetic ketoacidosis. Treatment of diabetic ketoacidosis should be initiated with standard protocols. Patients taking steroids should be given increased insulin (Gupta et al. 2020).

Lay summary
SARS-CoV-2-mediated manifestations have been reported in both pulmonary as well as extra-pulmonary tissues. Elderly groups of people are at higher risk because of the presence of comorbid conditions. It becomes very essential for the clinicians worldwide to understand the pathophysiological mechanisms and manifestations associated with organ systems. Various areas require attention for annotation of the mechanisms by which the coronavirus promulgates towards the extra-pulmonary tissues, viral properties which intensify the extra-pulmonary spread and effect of various pharmacological therapies. High binding affinity of the virus with the ACE2 receptors is the major mechanism for multi-systemic involvement. Mild-to-moderate cases can be resolved following precautionary measures, such as social distancing and hygiene. For severe cases, patients are admitted to ICU and are given drugs and treatment including chloroquine, hydroxychloroquine, corticosteroids, remdesivir, immunomodulatory agents, lopinavir/ritonavir, statins and prophylaxis with anticoagulants, mechanical ventilation and use of hyperbaric oxygen therapy. Many emerging therapeutic approaches, such as traditional drugs Fuzheng Huayu formula and anluohuaxian, ciclesonide, OATD-01, ivermectin and tetrandrine, have the potential in COVID-19 treatment. More large and well-designed trials are still required to evaluate the safety profile and efficacy of these emerging options. COVID-19 vaccines are available, majority of which neutralize antibodies against the spike protein and registration for the same has been started in various countries. The anti-SARS-CoV-2 vaccination may not eradicate the disease completely but will surely decrease morbidity and mortality. But the major issue is the availability of the vaccine and its unbiased distribution worldwide. In the absence of a truly effective treatment to prevent and treat COVID-19, strict adherence to social distancing and hygiene precautions must be followed for an enduring future.