Direct, indirect, post-infection damages induced by coronavirus in the human body: an overview

Abstract

Background

Severe acute respiratory syndrome Coronavirus-2 invades the cells via ACE2 receptor and damages multiple organs of the human body. Understanding the pathological manifestation is mandatory to endure the rising post-infection sequel reported in patients with or without comorbidities.

Materials and methods

Our descriptive review emphasises the direct, indirect and post-infection damages due to COVID-19. We have performed an electronic database search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with selective inclusion and exclusion criteria.

Results

The included studies substantiated the extensive damages in the multiple organs due to direct and indirect consequences of COVID-19. After an apparent recovery, the prolonged presentation of the symptoms manifests as post-COVID that can be related with persisting viral antigens and dysregulated immune response.

Conclusion

A few of the symptoms of respiratory, cardiovascular, and neuropsychiatric systems that persist or reappear as post-COVID manifestations. Vaccination and preventive programs will effectively reduce the prevalence but, the post-COVID, a multisystem manifestation, will be a significant tribulation to the medical profession. However, the issue can be managed by implementing public health programs, rehabilitation services, and telemedicine virtual supports to raise awareness and reduce panic.

Introduction

Ever since discovering the "filterable agent" tobacco mosaic virus and the first human yellow fever virus, there were 249 (158 RNA + 91 DNA) virus species reported to infect humans [1]. They are responsible for two-thirds of newly emerging and re-emerging human pathogens and accountable for 14 million deaths worldwide [2]. About 58% of new or emerging pathogens are zoonotic that infect humans [3]. Most of these fatal zoonotic viruses belong to the single-strand ribonucleic acid (ssRNA) viruses; the list includes yellow fever virus, West Nile virus, hepatitis C, dengue, zika, rubella, mumps, chikungunya, Ebola, measles, Nipah, rabies, Lassa, influenza, severe acute respiratory syndrome (SARS), middle east respiratory syndrome (MERS), and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [4].

Coronavirus initially reported in bats evolved in few intermediate hosts before infecting humans, including wild animals such as pangolin (anteater), mink, turtle, snake, and ferret [5]. Animals share significant sequence identities with specific receptor complexes of humans that were hijacked by coronavirus's spike protein [5]. The spike protein holds critical information about the host protein and folds separately to spread faster in the ecosystem [6]. The genome of any virus undergoes several mutations to infect another species. An alarming report observed 9653 mutations at 400 mutation sites in human SARS-CoV-2 [7]. The study conveys that the viral receptor-binding domain linked with human angiotensin-converting enzyme-2 (ACE2) comprised 44 distinct mutations [7]. The report raises questions on the reinfecting ability of the virus and the protective capability of the developed vaccines and drugs designed against such mutating viral proteins.

The direct effects of SARS-CoV-2 were associated with the viral targeted cell damages, and the indirect effects were related to collateral viral damages compromising physiological functions [8, 9]. Death and multiple organ dysfunction (MOD) in Coronavirus disease-2019 (COVID-19) patients were caused by both the virus and host defence mechanism [10–12]. Autopsy reports of COVID-19 non-survivors unanimously verified the MOD. [13–19]. The information indirectly conveys that the survivors from critical situations might recover with uncertain internal organ damages manifest as post-COVID [10, 12, 20]. The host conditions such as senility, comorbidities, concurrent or previous infections, antimicrobial resistance, personal habits such as tobacco, alcohol and food choices, obesity, and medicines used for comorbidities, impact the viral pathogenesis and treatment choices during emergencies [9, 21–23]. The recovered patients with mentioned conditions burden a lifetime due to the post-COVID compromised functions of the affected organs [24, 25]. Therefore, it is prudent to recognize the post-infection sequel of the recovered COVID-19 with the evidenced viral damages, to plan and practice public health policies. This review will detail the direct and indirect impacts of the SARS-CoV-2 infection on various organs and post-COVID manifestations to understand the pathological mechanisms that required to manage the post-infection sequel.

Materials and methods

According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, records were searched in the electronic database. The following keywords, 'direct damages COVID-19' 'indirect damages COVID-19' 'collateral damages COVID-19' 'post-infection damages COVID-19' 'post-COVID' and 'long-COVID were used to search in the title and abstract fields. The inclusion criteria applied as filters in the search engine PubMed include free full text, Medline, journal articles, clinical studies, meta-analysis, systematic reviews, studies conducted in humans Species and published in English (language), and the publication date from 1st January 2020 to 30th May 2021. The final search reports collected were as of the date 17th July 2021. The results of the total number of records with the applied filters were 742, which included, Direct damages AND COVID-19 (n = 182), Indirect damages AND COVID-19 (n = 34), post-infection damages AND COVID-19 (n = 101), Collateral damages AND COVID-19 (n = 65), post-COVID (n = 347), and long-COVID (n = 13). Animals and cell-line studies, interventional studies, and studies not consistent with the inclusion criteria were excluded. After screening the titles, abstracts, and full text for inclusion criteria, and duplicate records manually about 556 records were removed. The eligible records were about 186. Direct damages AND COVID-19 (n = 86), indirect damages AND COVID-19 (n = 1), post-infection damages AND COVID-19 (n = 37), collateral damages AND COVID-19 (n = 9), post-COVID (n = 46), long-COVID (n = 7). 13 records were manually searched and added in the introduction and discussion to support the manuscript view. The final number of studies recorded in the review was 199 (Fig. 1).

Fig. 1.

PRISMA flow diagram

Results

Direct damages of the SARS-CoV-2

Direct effects were correlated with the SARS-CoV-2 induced changes in the target cells following the viral attachment and replication [26]. As an obligate intracellular parasite with no in-built metabolism, the viruses instruct the host DNA to reprogram host metabolism to work for viral replication utilising the nutrition and energy and release the viral progeny by killing the host cells [24]. The direct cytopathic effects of the virus depend on the viral load and virulence, ability to enter target cells, and severe cell machinery to manufacture, and release the viral progeny [24–27]. Coronavirus tropism of multiple organs in the body by exploiting the ACE2 protein was emphasised in some literature [28–30].

ACE2, an integral protein in the cell membranes, catalyses a group of angiotensin into active substances for specific functions in tissues of the lung, liver, kidney, heart, pancreas, muscles, adipose tissue, reproductive organs, brain, and blood vessels [28, 30, 31]. A brief explanation of the physiological role of ACE2 is explained in Fig. 2. Spike protein of the SARS-CoV-2 binds and blocks the ACE2 protein [28]. The block in the enzymatic actions of ACE2 reduces angiotensin I, the final product and accumulation of the product to be converted, the angiotensin II, causing an altered biochemical milieu that weakens the functions of tissues [28]. The actions of angiotensin II by binding with AT₁R are primarily pathological that manifests as MOD if excessively accumulated (Fig. 2) [28].

Fig. 2.

The flow chart details the role of ACE2 in RAAS system. RAAS controls blood pressure and homeostasis. Angiotensinogen secreted by the liver is converted into angiotensin I (1–10) by enzyme renin, secreted by the kidney. The angiotensin I (1–10) is converted into angiotensin II by the enzyme ACE secreted predominately by lungs. The crucial function of the ACE2 is to catalyse the conversion of angiotensin II into angiotensin I (1–7). The converted Angiotensin I (1–7) act by binding with the MasR to maintain the physiological balance by functioning with the RAAS. Angiotensin II bind with the four different types of receptors named angiotensin receptors 1 to 4 (AT1R, AT2R, AT3R and AT4R) expressed by the tissues of RS, CVS, GIT, genitourinary system, nervous system, and endocrine system. The actions of angiotensin II by binding with AT1R are primarily pathological to CVS and alter the RAAS axis. Abbreviations, RAAS-renin-angiotensin-aldosterone system, ACE-angiotensin-converting enzyme, ACE2-angiotensin-converting enzyme2, MasR-mitochondria assembly receptor, and AT1R, AT2R, AT3R and AT4R- angiotensin receptors 1 to 4

Etiopathogenesis of the direct damages was chiefly due to massive viral-induced cell death and loss of ACE2 actions in the entire body [8, 32, 33]. The loss of primary cells of the lung impedes the exchange of gases that reduced oxygen supply to the whole body [32]. The direct damages at the major organ level included pneumonia, diffuse alveolar damage (DAD), pulmonary oedema, accumulation of desquamated lung cells, reduced oxygenation manifested as hypoxia in the lung; myocarditis, tachyarrhythmias, and loss of cardioprotective functions of angiotensin compromised the functions of the heart [10, 34–37]. The kidneys' filtering ability is altered due to the epithelial cells damages in the Bowman's capsules and tubular necrosis that resulting in acute kidney injury [38–40]. Altered appetite due to loss of taste and smell sensation, colitis, microhaemorrhage, desquamation and necrosis in the lining cells of GIT coerce digestion and absorption, liver and gallbladder cells necrosis resulted in the reduction in synthesis, storage, and delivery of the proteins for defence, repair, and regeneration [22, 41–43]. The inflammation of the brain stem, damages on olfactory, gustatory, and peripheral nerves and their supporting structures, loss of control at the hypothalamus and pituitary axis that regulate the entire endocrine gland have altered the physiological homeostasis [38, 40, 42, 44–46]. Nonspecific skin rashes due to cutaneous vasculitis aggravated pre-existing dermatosis, and hair loss were reported [25, 47]. The direct and indirect SARS-CoV-2 induced damages in the human system are detailed in a flow diagram (Fig. 3).

Fig. 3.

The direct and indirect damages of COVID-19 in the human system

Direct viral involvement demonstrated in the male genital tract and gonads raises the possibility of male infertility [48]. Androgens regulate the receptor expression, such as the transmembrane serine protease 2 (TMPRSS2), a critical receptor arbitrating the entry of SARS-CoV-2 [48]. A higher number of male COVID-19 patients than women and prepubertal children were interrelated with the receptor expression influenced by the androgens [48, 49]. The demonstration of ACE2 and tissue damages in autopsy reports of testis explains the possibility of COVID-19 injuring the various organs [50]. Altered expression of ACE2 were evidenced with diabetics and hypertensive individuals, and gender polymorphism needs consideration during treatment [27, 51, 52].

Indirect damages

Indirect effects are predominantly caused by the defence mechanisms delivered against the virus that collaterally damages the naïve tissues. The indirect effects of SARS-CoV-2 include dysregulation in the cellular mechanisms, host-immune system, biochemistry, coagulation, and microvasculature resulting in loss of hemodynamic equilibria and autoimmunity [9, 10, 22, 53–58]. The reduction in the oxygen intake capacity due to the direct viral damages were aggravated by the indirect effects of cytokine storm, thrombosis, and brain stem dysfunction [45, 59–62]. Microvascular dysregulation hinders the oxygen delivery to the end organs despite the blood saturation being adequate [55, 63]. Studies reveal that acute lung injury, acute respiratory distress, and pulmonary embolism are the initial manifestation of the increased oxygen demand [12, 59, 64]. Surfactant secreted by the type II pneumocytes is vital for recoiling action of the lung to prevent alveolar collapse. The SARS-CoV-2 induced lung cell damages deplete the surfactant [65]. Asymptomatic silent hypoxia, a poor outcome in the COVID-19 patients, are correlated with brain stem inflammation [32, 61, 66].

Cardiopulmonary dysfunction, thromboembolism, and loss of cardioprotective effects of angiotensin II aggravates tachyarrhythmia and heart attack [36, 67, 68]. High viral load in the intestine and cellular damages induce dysbiosis in the microbiome of GIT and massive entry of microbes into the systemic circulation [25]. Drug-induced toxicity further burdens the liver affecting protein synthesis and delivery [41]. Kidneys' workload increases due to cardiopulmonary dysfunction, cytokine accumulation, perfusion dysfunction and microthrombosis [37, 39, 69–72]. A study correlated brainstem inflammation as a principal cause of indirect and post-infection manifestations of COVID-19 [45]. Viral encephalomyelitis, viral influence on the brainstem, hypothalamus, and pituitary axis affects the functions of entire endocrine organs [25, 48, 73]. Lymphopenia, typically reported in COVID-19 patients, was due to the destruction of virus-harbouring lymphocytes destroyed in the spleen, lymph nodes, and other lymphoid tissues that cause immunodeficiency and aids the virus to permeate the organs rapidly [74].

Cytokine storm was reported as one of the crucial causes for the worst clinical manifestations in SARS-CoV-2, like SARS-CoV-1 and MERS [75]. SARS-CoV2 patients exhibit an array of cytokines including TNFα, INFγ, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-17, G-CSF, GM-CSF, MCSF, HGF and chemokines CXCL8, MCP1, IP10, MIP1α and MIP1β [53, 76, 77]. The accumulated angiotensin II was responsible for the hyperactivation of transcription factor NF-kappa B to release massive inflammatory cytokines to stimulate cell apoptosis and fibrosis [78]. Overreactive immune system due to systemic viremia similar to viral sepsis affecting the extrapulmonary structures were proven in COVID-19 autopsy specimens [8, 27, 79, 80].

The altered biochemistry and microvascular disorders of COVID-19 manifested as abnormal coagulopathy, endothelial dysfunctions, abnormal platelet activation, fibrotic changes, and altered microRNA functions [30, 35, 41, 59, 81]. Elevated lactate dehydrogenase (LDH) and C-reactive proteins released due to liver cell damages were used to predict the severity of the COVID-19 [27, 82, 83]. The organs are under chemical insult due to the combinations of drugs used for COVID that mandates strict pharmacovigilance because there is lack of standardization in assessing the hepatotoxicity of the drugs [43]. The accumulated drugs and metabolites due to microvascular dysfunctions exaggerate liver damages [83–85]. Steroid induced acute and chronic liver failure and death was never disregarded by the medical professionals during the use of high doses for a longer duration to save life from COVID. Individuals with co-morbidities have already a burdened liver according to the duration of the diseases and drugs intake [22, 84, 85]. Comorbidities such as the hypertension, diabetics and obesity induced pathophysiological changes do augment the COVID induced damages [22, 24]. Elderly individuals having age-related physiological compromises sustain severe pathological damages due to comorbidities that explain the increased death reports in geriatric population after COVID [57]. Therefore, while treating the COVID-19 patients having comorbidities, it is prudent to calculate the chemicals delivered as drugs for the comorbidities, co-infections, and COVID-19, which further aggravate the biochemical alterations [41, 85, 86].

The abnormal chemical storm and endothelial dysfunction stimulate thrombin formation and thromboembolic manifestations [55]. Autopsy specimens of COVID-19 demonstrated both venous and arterial thrombosis, thromboembolism, and microcirculatory damages [55, 56]. SARS-CoV-2 induced hypoxia, cytokine storm, platelet activation, complement activation, stasis, and epithelial dysfunction triggering disseminated intravascular coagulation (DIC) was reported [32, 56, 60, 64, 70, 77, 79, 87]. Viral induced immune dysregulations cross-reacted with self-antigen to induce autoimmunity were reported in COVID-19 [54]. A few autoimmune disease manifestations were correlated with COVID-19 include the Guillain-Barré syndrome, Kawasaki-like manifestations, antiphospholipid syndrome, and autoimmune haemolytic anaemia [25, 88, 89]. Reports evidenced Kawasaki-like diseases in children and adolescents in the SARS CoV-2 positive individuals [63, 90]. Kawasaki-like disease is a systemic vasculitis induced by a delayed hyperimmune response correlated with unclear pathogenesis [83, 90].

Unusual microbleeding and occlusive disorders were noticed in the brain of a few critically ill patients [91, 92]. Individual reports of oral manifestation of salivary gland ectasia, ophthalmic manifestations, histiocytic hyperplasia in the lung, pneumatosis intestinalis, intestinal ischemia, bleeding, and necrotic changes in the small bowel, non-alcoholic fatty changes in the liver, retinal microhaemorrhages, and the increased risk in smokers, were witnessed in the literature [42, 85, 93–101]. Increased tubal ectopic pregnancies and fetal distress with MOD was reported in an asymptomatic SARS-CoV-2 positive pregnant woman with infected placenta [102, 103]. The impact of lethal and unexplored co-infections during SARS-CoV2, treatment modalities, and antimicrobial resistance also observed [104].

Post-infection manifestations (Post-COVID)

The term post-COVID correlated to manifestations of clinical symptoms after evidenced recovery from COVID-19. The term post-COVID in this review denotes the persistent or recurrence of clinical symptoms within six months following an apparent recovery with no positive isolation of virus [24, 25]. Sever post-Covid manifestation can be associated with persisting viral antigens and re-infection of a mutant variant [59, 105]. A few symptoms of the respiratory, cardiovascular, and neuropsychiatric systems commonly persist as post-COVID (Fig. 4) [106, 107]. Fibrosis of the lung and persistent brainstem inflammation were blamed for hypoxia, and the patients were reported with exertional dyspnea reducing exercise capacity, apart from persistent dry cough [24, 45, 108–110]. The pulmonary dysfunction, myocardial fibrosis and enduring coagulopathy manifest as palpitations, arrhythmias, cardiac arrest, and stroke [71, 111–119]. An unusual increase in cardiac complications, including acute myocardial injury, atrial fibrillation, mitral valve regurgitation and acute coronary events, were reported [67, 120–125].

Fig. 4.

The common signs and symptoms of COVID-19. The highlighted were reported as the persisting or reappearing symptoms during post-COVID manifestation

The altered hypothalamic–pituitary–adrenal axis weakens the control over the endocrine system influence the diabetic and adrenal manifestations [21, 24, 25]. The reports about genital systems have yet to strengthen the evidence of male infertility [48, 50]. The microbiota dysbiosis influencing various physiological functions were extensively narrated [126]. Human coronavirus was reported as neuroinvasive, and cytokine surge from the immune cells of local and peripheral circulation penetrating the blood–brain barrier can precipitate neurodegeneration [127–132]. The post-COVID effects on the brain were recounted more frequently among other systems because of prolonged hypoxia and the inability of the nervous system to repair [128, 133, 134]. Brain, the most metabolically active organ demands continuous oxygen supply for survival. Many reports observed continued loss of taste and smell sensation and hearing and supporting tissue functions in the resulted oropharyngeal dysphagia [129, 135–139]. The hypothesis of autonomic nervous system disturbance by the coronavirus manifesting as long-COVID was also debated [140–143].

Apart from Corona-phobia increasing psychological stress, neuropsychiatric symptoms include insomnia, depression, anxiety, obsessive–compulsive disorder, irritability, behavioural and mood changes, anhedonia, neuromuscular dysfunction, intrusive thoughts, maladaptive beliefs, suicidal risk, and psychosis, were reported [144–157]. In addition, chronic post-COVID muscular weakness, sarcopenia, and fatigue linked with the hindered flow of cerebrospinal fluid were reported [158–160]. Follow-up studies advised rehabilitation programs to support the recovered patients with a multidisciplinary approach, including psychological support [129, 144, 145, 161, 162].

Discussion

Studies revealed that COVID-19 death was due to viral damages, while the comorbidities were aggravating factors that enforced the importance of autopsies to understand the pathological mechanisms [9, 21, 24]. After the COVID-19 pandemic, individuals reporting complications of comorbidities or a new pandemic will significantly burden the physicians at a higher level [10]. The evidenced viral tropism for ACE2 protein explains the MOD that demands the importance of preventing the spread of the virus in the initial phase, which is possible only with vaccines and antiviral drugs [28]. The pathological mechanisms of post-infection damages were primarily due to prolonged dysregulated immune reactions, circulating virus antigens, re-infection with the same or mutant virus or similar infections and post-traumatic stress [10, 59, 163, 164]. The concept of prolonged hyperactive dysregulated immune responses was extensively investigated [24, 25]. The accumulated counteracting biological chemicals such as the pro-inflammatory, antiinflammatory, and cell-death related cytokines coerce the interior and exterior milieu of the host cells. Therefore, treatment modalities to control and suppress cytokine storm's ill effects need to be considered pivotal [165, 166]. Extracorporeal blood purification methods to remove the excess cytokines were suggested for critical cases with provisional approval granted by FDA [166]. Nevertheless, considering the controversial outcomes and treatment expenses compared with the benefits of dexamethasone treatment, the use of blood purification procedures was restricted only for randomised clinical trials [167].

Vaccine protection is questionable within the six weeks of vaccination because the immunity is not entirely developed. Prolonged viral shedding for 24 days and a 17% possibility of re-infection were reported in a study [168]. Infections or re-infection within this period will be worst in individuals having comorbidities. Emerging variants of mutated SARS-CoV-2 have demonstrated the ability to spread faster and manifest disease with less sensitivity to the conventional diagnostic tests and therapy together with the ability to evade the vaccine-induced immunity [www.cdc.gov]. The theory of antigenic sin explains the rapid spread during re-infection [169]. The SARS-CoV-2 antigens remaining inside the tissues need investigations adequately; however, many viruses reside dormant and re-emerge, such as the herpes virus, following a 'slow and low tactic' mechanism [59, 170]. Hypothetically the virus or viral antigen trapped in the dead and damaged tissues and immune complex might re-emerge during the repair and removal by the scavenger cells. The dormant residing ability of SARS-CoV-2 requires future research to accept yet, the left-over viral antigens, antibodies, and immune complexes were evidenced [59]. The primed immune cells initiate a chain of immune reactions by secreting the cytokines and antibodies until their removal; even though most of the immune cells' lifespan was limited, clearance of the cytokines requires stopping the priming action [171].

Silent hypoxia could be monitored with the pulse oximeters connected through mobile applications directly delivering messages to the hospital monitoring system via telemedicine. Currently operating selected COVID-centres need to be improved as rehabilitation centres for the post-COVID situations [172]. Health policies to monitor and support the recovered individuals with the help of various professionals through telemedicine and telerehabilitation are required [172]. Understanding the SARS-CoV-2 induced endocrinal disturbances will assist the physicians in recognising the manifestation to decide the clinical management at acute, convalescent, and post-infection stages.

A study reported an increase in Kawasaki-like diseases with multiple-organ failure in children diagnosed with SARS-CoV2 [173]. Health authorities should warn the healthcare workers and the infected public to prevent viral transmission to their children. Since systemic vasculitis might result in critical situations, careful observation of children is mandated during the pandemic [173]. The non-survivors of the SARS-CoV2 infected were confirmed with secondary infection and sepsis due to co-infections [79]. In addition, a sudden increase in cases of mycotic infections such as mucormycosis, an opportunistic fungal infection caused due to careless use of steroids, uncontrolled diabetics, microbial dysbiosis, and antimicrobial resistance was noticed [174].

The evidenced hypoxia, cytokine storm, microvascular dysfunctions, and related tissue necrosis need considerable time to restore physiological homeostasis [9]. While considering the whole body, sparing the brain, major organs have repeated functional cellular units and possess stem cell niches to regenerate. If the damaged cells were not renewed, tissue integrity was maintained by a non-functional fibrous tissue named scarring, which is one of the post-infection damages of viral infections, including COVID-19 [162, 175]. The lung has 480 million repeated alveoli units, the liver has 140 million cells per gram, the kidney has one million repeated units in each, and the pancreas has more than one million islets [176–178]. The loss of functional units in these organs may not be evident until a rise in physiological demand. The nerve and muscles have permanent cells with minimal potential to repair [179]. Avascular structures such as cartilages and tendons in joints deposited with antigen–antibody complexes pave a pathway for inflammation resulting in enduring damages like arthritis [180]. The nervous and muscular injuries aggravate muscle and joint pain like causalgia [181, 182]. Post-COVID manifestations related to neuromuscular disorders will increase unless an essential rehabilitation program is implemented [158, 163, 183, 184].

Stem cells have proved their efficiency in treating diseases that have no approved treatment [185]. Clinical trials reporting the success of cell transplantation or cell-derived products such as extracellular vesicles for treating infectious diseases, including COVID-19, were recounted [185]. The therapeutic ability of the stem cells was correlated with the antiinflammatory, immunomodulatory, antiapoptotic, antifibrotic, pro-proliferative, and pro-angiogenic actions. Our preclinical study on treating dengue with stem cells reported the possible antiviral ability of the stem cells [186]. Murine hepatitis virus-1 infected mice influencing the stem cell niches to reprogram the stemness to fight against the virus and secrete antiviral substances were observed in a preclinical study and recommended the possible role of stem cells in vaccine developments [187]. The tissues recovering after viral damages with MOD are expected to manifest widespread micro-necrotic environments raising the cellular stress, including the stem cell niches. Damages of stem cell niche due to microcirculation involvement and DIC resulting as fibrosis were reported with SARS and MERS [188, 189]. While stem cell treatment for infections prevails, preserving the naïve stem cells in our body is the best [175]. Nevertheless, viable stem cells population at the tissue level after viral infections were difficult to conceive unless special investigations were performed.

Also, further studies acknowledging the functional ability of the ACE2 receptors after vaccination may unravel more vital information. For this purpose, prospective studies could be done on the vaccinated individuals diagnosed with secondary infections or with the human on-chip design. The microvascular malfunctions due to obesity and lack of exercise influence the recovery. Social groups promoting the importance of balanced food, exercises, yoga, and meditation, to improve health in a holistic approach need to be encouraged [190]. Adopting harmless immunity-boosting herbal preparations, herbal therapy, aromatherapy, and sound therapy could be encouraged regardless of clinical studies [191].

Although the reduction in mortality and improved life expectancy was the success of medical fraternities, life after severe MOD might mitigate the quality of life, increase dependency, and health care consumption, causing a substantial rise in economic burden after the pandemic [162, 192]. Patients treated in ICU are prone to physical and mental problems [162]. Specific post-traumatic longitudinal research needs to be carried for these patients [151, 193]. Public health strategies must be advocated to allocate funds to manage post-COVID issues [194, 195]. The pandemic situation strongly impacted the mental health of the global population due to a drop in the economics involved in sectors including agriculture, education, research, and the medical industry that may be moderated by implementing policies minimising the burden designed for the country [196]. Fighting pandemics should include identifying the hidden dangerous outcomes and how best to overcome them [197, 198]. The learning health system (LHS) comprehensively integrating the collective hospital data, treatment protocol, vaccine efficiency, and morbidity on COVID-19 to discuss the disease's improvement with the lessons learned from pandemic situations is mandatory.

Scientists developed the COVID-19 vaccines within a year, unlike other vaccines. Similar efforts need to be directed to prevent infections at the zoonotic level. An antiviral drug or a vaccine arresting the folding ability of the viral protein can deliver a better solution [6]. Interventions targeting the viral proteins at the entry level might aid the immune responses to initiate antibodies against the invaders with minimum damage to native tissue. Also, predicting the threat before becoming pandemic by studying the virus at zoonosis level to design a vaccine for animals and humans and planning essential prophylaxis might offer better infection control [199]. Permitting and aiding crucial researches such as gene editing, stem cells, and virus manipulations with human and mammalian cell lines should be restricted to labs with a high level of control. Finally, each country must study the drug, vaccine, and post-COVID effects in their population.

Conclusion

The prevalence of COVID-19 can be reduced by vaccination and community preventive measures. However, the post-infection burden will downgrade future developments unless health policies are instituted. The message emphasised in this review is that the recovered individuals, even though considered normal, requires continuous monitoring to prevent re-hospitalisation and better living. Patient education to increase awareness will reduce the post-COVID symptoms. Future studies planned to collect data from clinical, laboratory, and epidemiological presentations of post-COVID will confirm the pathogenesis. Developing the multidisciplinary post-COVID centre to help recovered patients, especially in underdeveloped areas, needs to be considered. Stem cell therapy to boost the viable stem cell niches might improve the recovery of the infected and alleviate post-COVID issues.

Abbreviations

ACE

Angiotensin-converting enzyme

ACE2

Angiotensin-converting enzyme 2

ARB

Angiotensin receptor blockers

AT₁R, AT₂R, AT₃R and AT₄R

Angiotensin receptors 1 to 4

CVS

Cardiovascular system

COVID-19

Coronavirus disease 2019

DAD

Diffuse alveolar damage

DIC

Disseminated intravascular coagulation

DNA

Deoxyribonucleic acid

FDA

Food and Drug Administration

GIT

Gastrointestinal system

LHS

Learning health system

MasR

Mitochondria assembly receptor

MERS

Middle east respiratory syndrome

miRNA

MicroRNA

MOD

Major organ dysfunction

PRISMA

Preferred reporting items for systematic reviews and meta-analyses

RAAS

Renin-angiotensin-aldosterone system

RS

Respiratory system

SARS

Severe acute respiratory syndrome

SARS-CoV

Severe acute respiratory syndrome Coronavirus

SARS-CoV-2

Severe acute respiratory syndrome Coronavirus-2

ssRNA

Single-strand ribonucleic acid

TMPRSS2

Transmembrane serine protease 2

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declarations

Conflict of interest

The authors declare that there are no conflicts of interest regarding the publication.