Human Settlements and Ecological Footprints: As such, the ecosystems are the planet's life-support systems for the human species and all other forms of life. The ecological alterations in turn may lead to irreparable climate change, and have repercussions on human health, which are complex. The ecological alterations affect the distribution of patterns of human settlement, nutritional and health status, and disease patterns including pandemics. COVID-19 Pandemic and the Clinical Fallouts: There have been turbulent times with the novel pandemic COVID-19, engulfing, imprisoning, and debilitating the humanity all over the Globe. The unabated transmission of the virus led to immense human suffering and overwhelmed healthcare facilities. The disease has high infectivity and fatality, and the survivors have propensity to suffer with organopathies and exacerbation of other pre-existing diseases. Changing Healthcare Scenario and Options: The fallouts of COVID-19 pandemic have been striking. The pandemic has been a reality check for various provisions of available healthcare. As the existing healthcare facilities were unable to cope with the sudden surge leading to an intense pressure on the system, the pandemic has acted as a transformation catalyst and accelerated transformation in healthcare including remote and Hospitalat-Home care. Planning Healthcare for Post-Covid illness: The COVID-19 now persists as endemic in most places with the infection affecting those with a high-risk. Presently, a heightened awareness is required for diagnosing post-Covid symptoms and complications. There are needed specialized OPD services for diagnostic workup, treatment, and regular follow up, along with a dedicated indoor facility for profiling the post-Covid illness, treatment, and intensive care.

Introduction: SARS-CoV-2 life cycle: The disease which reportedly began in Chinese city Wuhan in November-December 2019 manifesting as severe respiratory illness, soon spread to various parts of the world, and was named COVID-19, and declared a pandemic by WHO. The life cycle of SARS-CoV-2 begins with membrane fusion mediated by Spike (S) protein binding to the ACE2 receptors. Following viral entry and release of genome into the host cell cytoplasm there occurs replication and transcription to generate viral structural and non-structural proteins. Finally, VLPs are produced and the mature virions are released from the host cell. Immunogenicity of the spike protein: The S protein is considered the main antigenic component among structural proteins of SARS-CoV-2 and responsible for inducing the host immune response. The neutralising antibodies (nAbs) targeting the S protein are produced and may confer a protective immunity against the viral infection. Further, the role of the S protein in infectivity also makes it an important tool for diagnostic antigen-based testing and vaccine development. The S-specific antibodies, memory B and circulating TFH cells are consistently elicited following SARS-CoV-2 infection, and COVID-19 vaccine shots in clinical trials. The emerging SARS-CoV-2 variants: The early genomic variations in SARS-CoV-2 have gone almost unnoticed having lacked an impact on disease transmission or its clinical course. Some of the recently discovered mutations, however, have impact on transmissibility, infectivity, or immune response. One such mutation is the D614G variant, which has increased in prevalence to currently become the dominant variant world-over. Another, relatively new variant, named VUI-202012/01 or B.1.1.7 has acquired 17 genomic alterations and carries the risk of enhanced infectivity. Further, its potential impact on vaccine efficacy is a worrisome issue. Conclusion: THE UNMET CHALLENGES: COVID-19 as a disease and SARS-CoV-2 as its causative organism, continue to remain an enigma. While we continue to explore the agent factors, disease transmission dynamics, pathogenesis and clinical spectrum of the disease, and therapeutic modalities, the grievous nature of the disease has led to emergency authorizations for COVID-19 vaccines in various countries. Further, the virus may continue to persist and afflict for years to come, as future course of the disease is linked to certain unknown factors like effects of seasonality on virus transmission and unpredictable nature of immune response to the disease.

The Virus Infection, The Disease and Post-DiseaseLike any other infectious disease, the prognosis of COVID-19 is influenced by infecting agent, the SARS-CoV-2 virus load and the extent of organs affliction and damage.COVID-19 having a propensity for multiorgan involvement carries an adverse prognosis during the clinical course as well as later during the post-recovery period persisting as Long Covid.The direct cytopathic effects of SARS-CoV-2 virus and the erratic and hyper-inflammatory response lead to tissue injury in various organs coupled with physiological dysfunctions and complications.In fact, the multi-system manifestations of COVID-19 are caused by a combination of specific host defence responses with associated inflammatory activity and vascular involvement with coagulopathy and a distinct propensity to develop thromboembolic complications.Simultaneously, comorbidities such as diabetes, hypertension and cardiovascular diseases influence the disease severity and mortality.

The immuno-thrombo-inflammatory disease: COVID-19 is an acute immuno-thrombogenic inflammatory viral disease manifested by dysfunctions related to multiple organs involved in its pathogenesis. Its incidence and prevalence of is related to environmental viability of the virus, various transmission factors associated with the agent and the host, possible modes of transmission, period of infectiousness, and composition and susceptibility of the population. Whereas respiratory route is dominant mode of transmission, transmission through direct contact or fomite transmission do occur.

Introduction: the perennial pandemic: There are serious challenges posed by the SARS-CoV-2 virus and COVID-19 as the disease. With the persistence of the pandemic over one and half year, it is being feared that the COVID-19 may have become the new reality associated with human existence world over and the mankind may have to live with it for years or even decades. Further, the grievous nature of the disease is evolving further with genomic changes in the virus in form of mutations and evolution of variants, with enhanced infectivity and probably virulence. Acute and chronic phases of COVID-19: Epidemiologically, it is becoming clear that apart from the advanced age and pre-existing conditions, such as diabetes, cardiovascular, pulmonary, and renal diseases, certain constituent factors render some patients more vulnerable to more severe forms of the disease. These factors influence the COVID-19 manifestations, its course, and later the convalescence period as well as the newly defined ‘Long COVID phase. The substantial continuing morbidity after resolution of the infection indicates persisting multisystem effects of ‘Long Covid’. Lung damage associated with COVID-19: COVID-19 is primarily a respiratory disease presenting with a broad spectrum of respiratory tract involvement ranging from mild upper airway affliction to progressive life-threatening viral pneumonia and respiratory failure. It affects the respiratory system in various ways across the spectrum of disease severity, depending on age, immune status, and comorbidities. The symptoms may be mild, such as cough, shortness of breath and fevers, to severe and critical disease, including respiratory failure, shock, cytokine crisis, and multi-organ failure. Implications for the post-COVID care: Depending on the severity of respiratory inflammation and damage, as well as associated comorbidities, duration of injury and genetics, the progressive fibrosis leads to constriction and compression of lung tissues and damage to pulmonary microvasculature. Consequently, the COVID-19 patients with moderate/severe symptoms are likely to have a significant degree of long-term reduction in lung function. Depending on the severity of the disease, extensive and long-lasting damage to the lungs can occur, which may persist after resolution of the infection. Managing the long COVID’s challenges: Given global scale of the pandemic, the healthcare needs for patients with sequelae of COVID-19, especially in those with lung affliction are bound to increase in the near future. The challenge can be tackled by harnessing the existing healthcare infrastructure, development of scalable healthcare models and integration across various disciplines with a combination of pharmacological and non-pharmacological modalities. Following clinical and investigational assessment, the therapeutic strategy should depend on the disease manifestations, extent of damage in lungs and other organs, and associated complications.

Vinod Nikhra* Author Affiliations Department of Medicine, Senior Chief Medical Officer and Consultant, Hindu Rao Hospital & NDMC Medical College, New Delhi, India Received: January 18, 2021 | Published: January 22, 2021 Corresponding author: Vinod Nikhra, Department of Medicine, Senior Chief Medical Officer and Consultant, Hindu Rao Hospital & NDMC Medical College, New Delhi, India DOI: 10.26717/BJSTR.2021.33.005382

Vinod Nikhra* Author Affiliations Senior Chief Medical Officer and Consultant, Department of Medicine, Hindu Rao Hospital & NDMC Medical College, India Received: August 28, 2021 | Published: October 20, 2021 Corresponding author: Vinod Nikhra, Senior Chief Medical Officer and Consultant, Department of Medicine, Hindu Rao Hospital & NDMC Medical College, New Delhi, India DOI: 10.26717/BJSTR.2021.39.006310

Introduction - the perennial pandemic: It is being increasingly realised that the COVID-19 may have become the new reality associated with human existence world over and the mankind may have to live with it for years or even decades. Further, the grievous nature of the disease is evolving further with the genomic changes in the virus in form of mutations and evolution of variants, with enhanced infectivity and probably virulence. There are serious challenges posed by the SARS-CoV-2 virus and COVID-19 as the disease. COVID-19 as acute and chronic disease: On exposure to the SARS-CoV-2 virus, not all patients develop a disease. Further, for those who develop the disease, there is a large variation in disease severity. The known factors including the constituent factors and several still unknown factors influence the disease manifestations, its course, and later the convalescent phase as well. In fact, substantial continuing morbidity after resolution of the infection indicates persisting multisystem effects of COVID-19. The ‘long COVID-19’ or ‘long haulers’: The patients who continue to suffer with persisting symptoms have been described as long haulers and the clinical condition has been called post-COVID-19 or ‘long COVID-19’. The diagnosis should be entertained if various symptoms and signs linger well beyond the period of convalescence in COVID-19. With the chronicity, there occur inflammatory changes and damage in various organs, and the extent of organ damage determines the long-term effects. Management of ‘long COVID’ syndrome: The ‘long COVID’ syndrome has multi-system involvement, variable presentation, and unpredictable course. Following clinical and investigational assessment, the patients should be managed as per clinical manifestations, extent of organ damage and associated complications. The findings from various studies indicate that preventing further organ damage in ‘long COVID’ is crucial. The long COVID’s prognostic challenges: As apparent, the ‘long COVID’ afflictions are more common than realized earlier. The symptoms can escalate in patients with co-morbid conditions. The persistent symptoms among COVID-19 survivors pose new challenges to the healthcare providers and may be suitably managed with a combination of pharmacological and non-pharmacological treatments, and holistic healthcare.

Introduction - evolution of SARS-CoV-2 variants: With the unrestrained pandemic for over last one-and-half year, SARS-CoV-2 seems to have adapted to its habitat, the human host, through mutations that facilitate its replication and transmission. The G variant incorporating D614G mutation, potently more transmissible than the ancestral virus arose during January 2020 and spread widely. Since then, various SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs) with higher infectivity or virulence or both, have evolved on the background of G variant, and spread widely. SARS-CoV-2 infection and the immunodynamics: As the virus becomes more transmissible, its lethality may drop. Apart from the humoral immunity, T-cell recognition from a previous SARS-CoV-2 infection or vaccination may modify the disease transmission correlates and its clinical manifestations. On the other hand, the immunity generated may reduce probability of re-infection as well as limit evolution of adaptive mutations, and emergence of highly infectious and immune-escape variants. There are complex issues related to the SARS-CoV-2 evolutionary dynamics and host’s immunodynamics. Trending etiopathoimmunological correlates: The evolution potential of SARS-CoV-2 is limited because of proofreading function of nsp14. The S protein mutations affect transmissibility, virulence, and vaccine efficacy. The D614G mutation in G variant with higher infectivity has turned the Chinese epidemic into a pandemic. Other SARS-CoV-2 variants, such as Alpha, Beta, Gamma, and Delta seem to have evolved as result of adaptation to selective pressures during periods of prolonged infections and subsequent transmission. Further, there is issue of convergent association of mutations. Basics of immunity and immune system failure: The nature of the immune response after natural SARS-CoV-2 infection is variable and diverse. There are pre-existing neutralizing antibodies and sensitized T cells elicited during previous infection with seasonal CoVs influencing the disease susceptibility and course. The virus has evolved adaptive mechanisms to reduce its exposure to IFN-I and there are issues related to erratic and overactive immune response. The altered neutralizing epitopes in the S protein in SARS-CoV-2 variants modify the immune landscapes and clinical manifestations. Conclusion: current scenarios and prospects: Presently, the SARS-CoV-2 infection is widespread with multiple evolving infectious variants. There is probability of its transition from epidemic to endemic phase in due course manifesting as a mild disease especially in the younger population. Conversely, the pandemic may continue with enhanced disease severity due to evolving variants, expanded infection pool, and changing immunity landscape. There is need to plan for the transition and continued circulation of the virus during the endemic phase or continuing pandemic for indefinite period.

Vinod Nikhra* Author Affiliations Department of Medicine, Hindu Rao Hospital & NDMC Medical College, Senior Chief Medical Officer and Consultant New Delhi, India Received: May 31, 2021 | Published: June 09, 2021 Corresponding author: Vinod Nikhra, Department of Medicine, Hindu Rao Hospital & NDMC Medical College, Senior Chief Medical Officer and Consultant New Delhi, India DOI: 10.26717/BJSTR.2021.36.005844

Like any other infectious disease, the prognosis of COVID-19 is influenced by infecting agent, the SARS-CoV-2 virus load and the extent of organs affliction and damage. COVID-19 having a propensity for multiorgan involvement carries an adverse prognosis during the clinical course as well as later during the post-recovery period persisting as Long Covid. The direct cytopathic effects of SARS-CoV-2 virus and the erratic and hyper-inflammatory response lead to tissue injury in various organs coupled with physiological dysfunctions and complications. In fact, the multi-system manifestations of COVID-19 are caused by a combination of specific host defence responses with associated inflammatory activity and vascular involvement with coagulopathy and a distinct propensity to develop thromboembolic complications. Simultaneously, comorbidities such as diabetes, hypertension and cardiovascular diseases influence the disease severity and mortality.

The Outbreaks and Resurgence: The disease which reportedly began in the Chinese city Wuhan in November-December 2019, soon spread to various parts of the world, and was named and declared a pandemic disease by WHO. While the European countries were recovering from the epidemic, the disease took hold in the USA, the South American countries, Arabian countries, and South Asian countries, predominantly affecting India. Presently, most of the European countries are witnessing resurgence and recurrent outbreaks of COVID-19. Spread and Evolving New Insights: Whereas there is workplace-related infection rise as people are returning to their offices, in other places the outbreaks are related to the people crowding and partying care-freely and trying to resort back to their earlier way of life. The reopening the educational facilities across the continents may make matters worse. Impact on Health and Healthcare: Most cases of COVID-19 infections go unnoticed and are followed by self-recovery. But what may appear good from the clinical perspective, appears to complicate epidemiological efforts to contain the outbreak. With the evolving information about the disease, there seem to be certain possible outcomes such as control and containment, or the persistence of the disease as global endemic accompanied with outbreaks and resurgent episodes. Gnetic Factors Linked to Disease Severity: With the COVID-19 pandemic, not all infected patients develop a severe respiratory illness. Further, there is a large variation in disease severity, which may be due to the genetic factors underlying the variable response to the virus. It is becoming clear that apart from the advanced age and pre-existing conditions, certain genetic constituent factors render some patients more vulnerable to the more severe forms of the diseases. Integration of Virus into Human Genome: A significant part of the human genome is derived from viruses especially the RNA viruses. In fact, about 8 percent of the human genome is made up of endogenous retroviruses (ERVs), which are viral gene sequences that have become a permanent part of the human lineage after they infected our ancient ancestors. With this background, an emerging novel concept holds that if COVID-19 persists for several generations, its genetic material is projected to be integrated or assimilated into human genome. The involved mechanisms are conceptualised through the transposons or transposable elements of the SARS-CoV-2.

The Global Virome: The viruses have a global distribution, phylogenetic diversity, and host specificity. They are obligate intracellular parasites with single- or double-stranded DNA or RNA genomes, and afflict bacteria, plants, animals, and human population. The infecting virus binds to receptor proteins on the host cell surface, followed by internalisation, replication, and cell lysis. Further, trans-species interactions of viruses with bacteria, small eukaryotes and host are linked with various zoonotic viral diseases and disease progression.

Biology of Aging and Longevity: The unicellular and multicellular organisms, both, age chronologically with their life span representing the average age of the organisms at death. At the cellular level, the chronological aging is mediated in part by ROS generated by mitochondria and attended by loss of mitochondrial function. Aging is, also, a major risk factor for disease-states such as atherosclerosis and cardiovascular disease, degenerative disorders including neurodegenerative diseases and disorders due to altered cellular physiology and mitosis like cancer. Identifying Pro-Aging Pathways: There is an established role of IGF-1 and Insulin signaling in the regulation of the life span. Apart from this, the Akt and Ras pathways playing an important role in IGF-1 signaling, appear to regulate aging in mammals. Ras, Akt and Serine/threonine-protein kinase (also known as serum and glucocorticoid-regulated kinase Sgk-1, encoded by the SGK1 gene) plays an essential role in cellular functions such as growth and metabolism and may accelerate aging in some tissues and organs. Proaging and Longevity Mechanisms: There are similarities between the pathways that regulate stress resistance, cellular protection and aging in lower animals like C. elegans, yeast and Drosophila as well as in mammals. Insulin and insulin-like signaling factors regulate survival and lifespan and play a significant role in longevity in various animal species, from nematodes and Drosophila to higher vertebrates. In the regulation of replicative aging, the role of Ras pathway appears to be complex and the Ras and PI3K/ Akt pathways are major intracellular mediators of the effect of IGF-1. The Ras pathway activates the RAF/MEK/ERK as well as the SEK/p38 and other pathways through IGF-1, which are associated with various cellular processes like growth, differentiation and apoptosis. Dealing with Pro-Aging Factors: Understanding biological basis of the aging process has led to insights that can potentially identify measures to slow down the aging process. The aging, thus, becomes a modifiable risk factor and there are expectant possibilities to extend the lifespan and improve health-span. Through targeted lifestyle changes and potentially effective interventions through nutraceuticals and pharmaceuticals, it is possible to reduce the age-related chronic and debilitating morbidities and improve the health-span.

The nemesis: SARS-CoV-2 pandemic: Leaving in its wake millions of infections, accompanied by an immense magnitude of morbidity and multitude of mortality, and an unfathomable economic toll, the COVID-19 pandemic has led to a global calamity. An effective and safe COVID-19 vaccine is urgently needed to prevent the disease, thwart the complications and avert deaths resulting from unrestrained transmission of the infection. The hubris: Vaccine development: While most of the platforms of vaccine candidates have focused on the spike (S) protein and its variants as the primary antigen of COVID-19 infection, various techniques involved include nucleic acid technologies (RNA and DNA), non-replicating viral vectors, peptides, recombinant proteins, live attenuated and inactivated viruses. There are novel vaccine technologies being developed using next-generation strategies for precision and flexibility for antigen manipulation relating to SARS-CoV-2 infection mechanisms. The elpis: Updates and prospects: There were nine different technology platforms under research and development to create an effective vaccine against COVID 19. Although there are no licensed vaccines against COVID-19 yet, there are various potential vaccine candidates under development and advanced clinical trials. Out of them, one having undergone phase III clinical trials, has become available in some countries for use among the high-risk groups following emergency use authorization. Other COVID-19 vaccines may soon follow the suit. Conclusion: Hopes and concerns: The hope of benefiting from the vaccine to the extent that it may be the only way to tide over and control the COVID-19 pandemic, is accompanied by the likely fear of adverse effects and opposition in public for COVID-19 vaccination, including the vaccine hesitancy. Further, there is concern among scientific circles that vaccine may have opposite of the desired effect by causing antibody-dependent disease enhancement.

There is consensus that SARS-CoV-2 originated in horseshoe bats as it shares a high sequence similarity to bat CoVs...

COVID-19 virus structural components: The 2019-nCoV, also called SARS-CoV-2, was first reported in Wuhan, China in December 2019. The disease was named Coronavirus Disease 2019 (COVID-19) and the virus responsible for it as the COVID-19 virus, respectively, by WHO. The 2019-nCoV has a round, elliptic or pleomorphic form with a diameter of 60–140 nm. It has single-stranded RNA genome containing 29891 nucleotides, a lipid shell, and spike, envelope, membrane and hemagglutinin-esterase (HE) proteins.

The global virome: The viruses have a global distribution, phylogenetic diversity and host specificity. They are obligate intracellular parasites with single- or double-stranded DNA or RNA genomes, and afflict bacteria, plants, animals and human population. The viral infection begins when surface proteins bind to receptor proteins on the host cell surface, followed by internalisation, replication and lysis. Further, trans-species interactions of viruses with bacteria, small eukaryotes and host are associated with various zoonotic viral diseases and disease progression.

The outbreaks and resurgence: The disease which reportedly began in the Chinese city Wuhan in November-December 2019, soon spread to various parts of the world, and was named and declared a pandemic disease by WHO. While the European countries were recovering from the epidemic, the disease took hold in the USA, the South American countries, Arabian countries, and South Asian countries, predominantly affecting Brazil, Peru, Iran, and India. Presently, many European countries are witnessing a resurgence and recurrent outbreaks of COVID-19. Spread and evolving new insights: Whereas there is workplace-related infection rise as people are returning to their offices, in other places the outbreaks are related to the people crowding and meeting care-freely and trying to resort back to their earlier way of life. The reopening of the educational facilities across the continents may make matters worse. Impact on health and healthcare: Most cases of COVID-19 infections go unnoticed and are followed by self-recovery. But what may appear good from the clinical perspective, appears to complicate epidemiological efforts to contain the outbreak. With the evolving information about the disease, there seem to be certain possible outcomes such as control and containment, or the persistence of the disease as global endemic accompanied with outbreaks and resurgent episodes. Gnetic factors linked to disease severity: With the COVID-19 pandemic, not all infected patients develop a severe respiratory illness. Further, there is a large variation in disease severity, which may be due to the genetic factors underlying the variable response to the virus. It is becoming clear that apart from the advanced age and pre-existing conditions, certain genetic constituent factors render some patients more vulnerable to the more severe forms of the diseases. Integration of virus into human genome: A significant part of the human genome is derived from viruses especially the RNA viruses. In fact, about 8 percent of the human genome is made up of endogenous retroviruses (ERVs), which are viral gene sequences that have become a permanent part of the human lineage after they infected our ancient ancestors. With this background, a novel concept emerging that if COVID-19 persists for several generations, its genetic material is projected to be integrated or assimilated into human genome. The involved mechanisms are conceptualized through the transposons or transposable elements of the SARS-CoV-2.