Abstract
Unprecedented worldwide health catastrophe due to the COVID-19 pandemic has ended up resulting in high morbidity and mortality rates. Even though many people recover from acute infection, there is rising concern regarding post-COVID-19 conditions (PCCs), often referred to as post-acute sequelae of SARS-CoV-2 infection (PASC) or “long COVID.” The respiratory, cardiovascular, neurological, and endocrine systems are just a few of the many organ systems that can be impacted by this multifarious, complicated illness. The clinical manifestations of long COVID can vary among individuals and may include fatigue, dyspnea, chest pain, cognitive impairment, and new-onset diabetes, among others. Although the underlying processes of long COVID are not fully understood, they probably involve unregulated immune response, persistent generation of pro-inflammatory cytokines (chronic inflammation), autoimmune-like reactions, persistent viral replication, and micro-clot formation. To create successful treatments and care plans, it is essential to comprehend the immunological mechanisms causing these difficulties. The pathogenesis of long COVID should be clarified and potential biomarkers to help with diagnosis and treatment should be sought after. To reduce the burden of long COVID on people and healthcare systems around the world, the need for long-term monitoring and management of long COVID problems should be emphasized. It also underscores the significance of a multidisciplinary approach to patient care. The goal of this review is to carefully evaluate the clinical signs and symptoms of long COVID, their underlying causes, and any potential immunological implications.
Introduction
The emergence of COVID-19, caused by the novel coronavirus SARS-CoV-2, has significantly impacted human health on a global scale. Since the first reported case in December 2019, the virus has spread rapidly across the globe, infecting millions of individuals and leading to widespread morbidity and mortality [1]. Although COVID-19 primarily affects the respiratory system, emerging evidence indicates that it may also harm other organs, including the cardiovascular, neurological, gastrointestinal, dermatological, and renal systems, resulting in chronic complications in some people. These post-COVID-19 complications are known as long COVID or post-acute sequelae of SARS-CoV-2 infection (PASC) [2, 3]. Even though most COVID-19 patients recover within a few weeks, some persons experience symptoms and severity of post-COVID sequelae long after the acute infection. Although the underlying mechanisms and risk factors for long COVID are not fully understood, emerging data indicate that immunological deregulation [4] plays a significant role in the pathogenesis and prognosis of these conditions because the immune response to the virus is complex and can cause serious systemic inflammation [5]. Long COVID is a result of a complex interaction between the virus and the host immune system [6]. Understanding the underlying mechanisms of long COVID, its treatment options, and management is still a developing area with limited information available [4]. To properly comprehend COVID-19's etiology and its long-term effects on human health, research efforts must be continued while we deal with the pandemic's aftermath. In this review, we aim to provide a comprehensive overview of the current knowledge on long COVID and its immunological implications. We will also highlight the knowledge gaps and research priorities for advancing our understanding and improving the care of patients with long COVID. This review aims to contribute to the development of efficient strategies and offers a comprehensive understanding of navigating the long COVID by examining the effect of COVID-19 on various organ systems and the immune response, as well as potential interventions to reduce the burden of long COVID.
Methodology
The authors did an extensive literature search across several electronic databases, including PubMed, Scopus, and Web of Science, to find pertinent papers for this review. Medical topic headings (MeSH) and terms like “post-COVID conditions,” “COVID-19 sequelae,” “long COVID,” “COVID-19 long-term effects,” “immune response,” and “multiple organ systems” have been combined with keywords relating to post-COVID issues. Additional research has been found by searching the reference lists of pertinent journals. Duplicate papers were eliminated after the initial search. To evaluate whether the remaining publications were pertinent to this review article, the authors separately looked over their titles and abstracts. To determine if they met the inclusion and exclusion criteria for this article, the full texts of the potentially pertinent articles were chosen. Any discrepancies were resolved through discussion. The final selection was made based on the studies' quality and the inclusion and exclusion criteria.
The inclusion criteria were English-language studies published in peer-reviewed journals between January 2020 and March 2023 that examined the effects of long COVID on several organ systems and the immune response. Articles that did not address long COVID specifically, such as studies on COVID-19 prevention, diagnosis, or therapy, were excluded from consideration. Studies that were neither peer-reviewed nor published in English and exclusively addressed the acute stage of COVID-19 infection were disregarded. Overall, the review's methodology ensured a precise and methodical search for significant studies and the selection of reliable data to back up the findings. With this strategy, the review is more accurate and reliable, and the conclusions are more certain.
Long COVID/post-COVID-19 conditions
The COVID-19 symptoms range from no symptoms to severe sickness, and they can have significantly higher fatality rates [1]. The Spike or S protein of SARS-CoV-2 is essential because it interacts with ACE2 to allow entry into host cells. SARS-CoV-2 enters the body mostly through the respiratory tract, but it can also harm the neurological, circulatory, and digestive systems [3]. Some people continue to experience a variety of symptoms after their initial infection, including fatigue, post-exertion malaise, dyspnea, discomfort, and cognitive issues. The term long COVID refers to the ongoing COVID-19 health effects and is an instance of the post-acute sequelae of SARS-CoV-2 infection (PASC) [7]. The World Health Organization (WHO) states that PASC affects patients who have had a confirmed or suspected SARS-CoV-2 infection, typically 3 months after the onset of COVID-19, and lasts for at least 2 months without any other explanation for the symptoms [8]. These definitions emphasize the complexity and diversity of PASC, which can have a variety of repercussions on individuals. PASC can affect several body parts and have a wide range of symptoms which include damage to multiple organs such as the brain, heart, lungs, liver, gastrointestinal tract, muscles, and nervous system [7]. At least 65 million people worldwide currently are suffering from long COVID [9]. After conducting a thorough examination, Davis et al. discovered that long COVID is fairly common, affecting around 50–70% of hospitalized patients, 10%–30% of outpatients, and 10%–12% of vaccine recipients [9]. Long COVID is extremely burdensome, which emphasizes the need for efficient treatments to solve this problem in global health.
Risk factors for long COVID or post-COVID conditions
Having a severe acute illness, being older, not being vaccinated, or having other medical issues are all risk factors for acquiring long COVID [10]. Furthermore, it was discovered through a meta-analysis that a higher incidence of PASC was connected with severe COVID-19 disease in females [11]. It's probable that the acute COVID-19 viral load and the severity of long COVID symptoms are connected, and that rapid viral load reduction may offer protection from long COVID [12]. A cross-sectional study involving more than 50,000 patients in Germany with COVID-19 showed that lipid metabolic issues and obesity are age-independent risk factors for long COVID [13].
Reason for long COVID
Long COVID development has been linked to several pathways, including viral persistence, immune system activation caused by the SARS-CoV-2 superantigen, and autoimmunity [14]. Researchers have also hypothesized that endothelial damage, immune system dysregulation, and hypercoagulability due to thrombosis may all contribute to long-term problems [4]. Oronsky et al., took a closer look at what causes persistent long COVID syndrome and provided a helpful guide for doctors to help diagnose and treat patients who may be suffering from these symptoms [15]. Various hypotheses exist about long COVID/post-COVID Conditions. These are a) the immune system goes into overdrive after the initial virus infection, causing chronic inflammation that harms several organs; b) the presence of the virus in organs like the stomach or the reactivation of dormant infections like the Epstein-Barr virus (EBV) may be the cause of persistent inflammation; c) the COVID-19-induced autoimmunity causes the antibodies to attack the body's tissues; d) micro clots causing thrombosis and coagulopathy [7].
Prasada Kabekkodu and colleagues studied the effects of SARS-CoV infection on mitochondrial function and how the virus uses the mitochondrial route to avoid the host immune system, promoting its survival and replication [16]. Small blood clots in the microvasculature are another reason for developing long COVID [17, 18]. The formation of PASC may be facilitated by these microthrombi [19]. People with severe COVID-19 often have fewer lymphocytes (lymphopenia) which contributes to the progression of the disease [20]. It is also thought that highly activated CD16+ T cells contribute to the emergence of COVID-19 [21]. Therefore, to lessen the severity of the illness and avoid long-term problems, it may be advantageous to prevent lymphopenia, T-cell death, and improper CD16+ T-cell function [6].
Symptoms of long COVID
Numerous studies have demonstrated that COVID-19 can have long-term effects on a variety of organ systems, including cardiovascular, gastrointestinal, dermatological, renal, and hematological [22, 23, 16]. Pro-thrombotic changes, inflammatory cytokine production, and pulmonary endotheliopathy might all have a role in the complex underlying process of these chronic symptoms [24]. Children are diagnosed with COVID-19 less frequently than adults are. Some children may experience the unusual but dangerous illness multisystem inflammatory syndrome (MIS-C) in the weeks following SARS-CoV-2 infection. Fever and organ system malfunction are characteristics of MIS-C [25].
Patients with COVID-19 may experience symptoms beyond the acute phase of the illness, including fatigue, sleep difficulties, anxiety, and depression which were found to be prevalent after 6 months of acute COVID-19 infection in a cohort study [22]. The most common symptoms during follow-up (7 months) were fatigue, post-exertion malaise, and cognitive dysfunction. An international cohort study discovered that exercise, physical or mental activity, and stress caused relapses in 85.9% of the patients. Of those, 86.7% had fatigue at the time of the survey compared to 44.7% of those who had recovered. 45.2% of participants reported reduced work hours or inability to work due to illness, and cognitive impairments and memory loss were prevalent among all age groups [23]. A retrospective, multicenter cohort study has even suggested that these effects may last for up to a year following acute infection and discharge from hospitals [26]. A recent study revealed that COVID-19 survivors experienced prevalent symptoms and problems with pain or discomfort, as well as anxiety or depression, even two years after their initial infection who were hospitalized due to COVID compared to controls in a longitudinal cohort study [27]. Researchers in Spain evaluated the variations in long COVID symptoms between hospitalized and non-hospitalized patients two years after their acute infection which revealed that at least one long-COVID symptom persisted in 59.7% of hospitalized patients and 67.5% of non-hospitalized patients in a cross-sectional cohort study [28]. Another study monitored COVID-19 patients admitted to hospitals during the initial wave of the pandemic. Up to 84% of patients said they continued to experience cognitive, sensorimotor, and tiredness symptoms 24 months after acute infection in a prospective cohort study [29]. Infection with COVID-19, including long COVID, increases the risk of cardiovascular disease and death, especially in those who have suffered severe COVID-19 infection, according to a prospective cohort study in the UK for 18 months follow-up [30]. According to a meta-analysis, over half of the survivors reported at least one long-term symptom up to 12 months after the acute phase, including abnormalities in pulmonary function tests, neurological symptoms such as cognitive impairments and memory loss, and mental problems [31]. A recent meta-analysis revealed that the prevalence of long COVID among children and adolescents is 25.24% three months following acute SARS-CoV-2 infection [32].
Immune complications
The COVID-19 virus can have a potentially long-lasting influence on the immune system. By attaching to the ACE2 receptor on cells lining the upper respiratory tract, SARS-CoV-2 first infects the body. Our immune system produces mucus, antiviral metabolites, interferons, cytokines, and antibodies like IgA (if the person has a history of immunity) to stop the virus from spreading further [33]. The virus causes cytokine storm which is a severe inflammatory reaction that can damage various organs in the body, such as the heart, liver, or kidneys [5] (Fig. 1). In longitudinal analyses of severe COVID-19 patients, there is an increase in the production of various pro-inflammatory cytokines and interferons (IFNs) such as IL1β, IL6, TNF, IL12, IFNβ, IFNγ, and IL17 [34]. Bloodstream, liver, brain, and lymphoid tissues may act as viral reservoirs for up to 12 months or 15 months after infection [35, 36]. Zollner and colleagues found evidence of SARS-CoV-2 antigen in the gastrointestinal tract of patients who later developed irritable bowel disease [37]. It has been proposed that persistent viral reservoirs could contribute to immune dysregulation. This ongoing immune activation may lead to localized and systemic inflammation, which can cause various sequelae, depending on the location of the persistent antigen [38]. Adult COVID patients have increased numbers of SARS-CoV-2 specific T cells, IL17, and IL2 according to studies [39]. Probably, the continued immunological activation, inflammation, and tissue damage that are linked to long-lasting symptoms are caused by viral proteins remaining in the body according to a retrospective study of hospitalized patients [40]. After contracting SARS-CoV-2, the immune system may become overactive and produce autoantibodies, which may contribute to the onset of PASC as well as autoimmune diseases like autoimmune thrombocytopenia, Guillain-Barré syndrome, multiple sclerosis, vasculitis, and autoimmune hemolytic anemia [41]. Some children may develop Kawasaki disease, which is an autoinflammatory condition [41]. Interestingly, around 44% of patients develop antinuclear antibody (ANA) titers ≥1:160 after one year of COVID-19 onset, and were more likely to have neurocognitive symptoms found in a prospective cohort study [42].
Through the respiratory system, the SARS-CoV-2 virus enters the body and has the potential to harm multiple organ systems. SARS-CoV-2 has an impact on the immune system, triggering cytokine storm and autoimmune disease. The pulmonary system is also affected, which results in lung fibrosis, dyspnea, fatigue, chest pain, cough, and pulmonary hypertension. Long-term impacts of the virus may potentially cause hematological problems such as deep vein thrombosis and irregular coagulation (Created with Biorender.com.)
Citation: Physiology International 110, 4; 10.1556/2060.2023.00256
Sparks et al. revealed that past infections can shape an individual's baseline immune status, impacting future responses to various antigens. Even mild infections might establish lasting immunological patterns affecting subsequent reactions. This insight has implications for understanding immune dynamics after encounters like mild COVID-19 and flu vaccination, suggesting that heterologous vaccination can unveil these patterns [43].
Pulmonary complications
The aftermath of COVID-19 can leave long-lasting damage to the lungs. Patients may feel symptoms even after the acute phase because of lung vasculature damage, resulting in long-term consequences such as chronic lung fibrosis and chronic pulmonary hypertension [4, 44] (Fig. 1). According to a recent meta-analysis by Fabbri et al., about 30% of patients with SARS-CoV-2 pneumonia who were hospitalized showed evidence of fibrotic alterations that persisted up to 12 months after being released from the hospital [45]. Lung function gradually deteriorates, which is seen through the development of hypoxia and pathological alterations [46]. Among COVID-19 survivors, dyspnea is the most frequently reported respiratory symptom [47], with 22.9%–53% of patients still experiencing it about two months after the onset of symptoms [48, 49]. Recent investigations from a meta-analysis have shown that even three months after SARS-CoV-2 infection, up to 20% of people still have persistent dyspnea, fatigue, chest pain, and cough [50].
Hematologic complications
Findings showed that thromboembolic events, which can appear as pulmonary embolism, are the most frequent hematological consequence in post-COVID patients [51] (Fig. 1). In recent research, Korompoki and colleagues demonstrated the prevalence of post-acute COVID-19 hematological sequelae, including thrombosis and persistent coagulation abnormalities [52]. Long COVID patients had higher C-reactive protein, D-dimer, lactate dehydrogenase, IL6, and leukocyte levels, according to a comprehensive assessment and meta-analysis of more than 20 serum inflammatory biomarkers [53].
Cardiac complications
A study found that persons with mild COVID-19 continued to have heart inflammation which can cause long-term cardiac symptoms including rapid heartbeats and chest pain [4, 54] (Fig. 2). Cardiovascular disease risk exists even in persons who do not need hospitalization [55]. Different studies focused on the post-acute cardiovascular consequences, including myocardial damage, arrhythmias, and irregular heartbeats [56].
Myocardial damage and arrhythmias are brought on by the SARS-CoV-2 virus's impact on the cardiac system. The virus's long-term impact on the brain and neurological system may also lead to cognitive impairment and neuropsychological difficulties like anxiety, brain fog, forgetfulness, and memory loss as well as headaches, sleep disorders, tiredness, and ischemic stroke (Created with Biorender.com.)
Citation: Physiology International 110, 4; 10.1556/2060.2023.00256
Neurological complications and cognitive impairment
Numerous factors of thinking and decision-making, such as attention, problem-solving, and executive function, are affected by cognitive impairment. Loss of memory is among the most prevalent forms of cognitive impairment. A prospective multicentre study has reported that in patients with long COVID cognitive impairment is present as a common symptom [57] (Fig. 2). The “brain fog” (persistent exhaustion, confusion, forgetfulness, and difficulty concentrating), which is linked to distinctive structural alterations in the thalamus and basal ganglia revealed in a prospective observational study [58], was also observed in a large population‐based study [59]. It has been observed that COVID-19 patients may continue to experience neurological symptoms, such as fatigue, muscle weakness, sleep difficulties, myalgia, and headache, for at least 2 months following their acute infection [48]. Fatigue (37%), brain fog (32%), memory problems (28%), attention disorder (22%), myalgia (28%), anosmia (12%), dysgeusia (10%), and headaches (15%) are some of the most common neurological symptoms that have been observed in 10,530 long COVID patients at the 12-week follow-up from a meta-analysis [60]. These symptoms can persist for an extended period, such as six months after initial diagnosis [22].
Neuropsychological complications
According to recent studies conducted on post-COVID-19 patients, the majority of them reported neuropsychiatric symptoms such as sleep problems, exhaustion, muscle aches, and functional difficulties that can endure for a very long time as described in an international cohort and meta-analyses [23, 60, 61] (Fig. 2). Neurological (ischemic stroke) and psychiatric issues (anxiety disorder, psychotic disorder) have been reported in a retrospective cohort study of 236,379 patients [62].
Gastrointestinal complications
Individuals with COVID-19 disease may experience sustained functional gastrointestinal disorders (FGIDs) such as chronic bowel dysfunction, dyspeptic symptoms, and irritable bowel syndrome (IBS) for up to 6 months after the infection in a case-control study [63] (Fig. 3). Long-lasting fecal shedding of the virus even after it is no longer detected in respiratory samples suggests that the virus may still be actively replicating in the gut [64]. In a prospective cohort of patients' studies have shown that an imbalance of gut microbiota may be the reason why gastrointestinal symptoms last for up to 6 months after infection [65].
Apart from the initial stages of the infection, the SARS-CoV-2 virus can have a long-term effect on many organ systems. Irritable bowel syndrome and an imbalance in the gut microbiota are side effects of SARS-CoV-2 on the gastrointestinal system. The long-term consequences of the virus that causes Type 1 diabetes mellitus and insulin sensitivity could have a serious negative impact on the endocrine system. Due to the long-term effects of SARS-CoV-2, the damage to the skeletal muscle and synovial tissue can result in severe joint pain, exhaustion, and muscular weakening (Created with Biorender.com.)
Citation: Physiology International 110, 4; 10.1556/2060.2023.00256
Endocrine complications
Oguz and Yildiz assert that SARS-CoV-2 infection may result in the development of endocrine disorders such as hypopituitarism, diabetes mellitus (DM), and primary adrenal insufficiency [66] (Fig. 3). Some of these disorders that develop as a result of an acute infection might not go away after recovery and might even last for the rest of one's life. According to research, SARS-CoV-2 binds to the ACE2 receptors on pancreatic cells and causes an autoimmune reaction that result in type 1 DM [67]. In addition to being an established risk factor for PASC, type 2 DM has been demonstrated to raise the chance of long COVID development [68]. Researchers are concerned about a sharp increase in newly diagnosed cases of type 1 or type 2 diabetes mellitus in children under the age of 18 following SARS-CoV-2 infection [69]. While taking steroids might increase blood sugar levels, other possible causes of COVID-19-related hyperglycemia include inflammation-related insulin resistance and reduced insulin production by β cells as a direct or indirect effect of viral infection [70]. The virus may directly harm pancreatic β cells, resulting in autoimmunity or malfunction of the glucose-regulating system, or it might decrease peripheral insulin sensitivity [69]. SARS-CoV-2 viral components (RNA or proteins) and cytokine storm can cause insulin resistance, which causes the production of pro-inflammatory cytokines such as IL6 and TNFα [71].
Neuromuscular system complications
Patients who were hospitalized frequently developed long-lasting myalgia, fatigue, joint pain, and muscle weakness that continued for weeks or even months [72] (Fig. 3). Skeletal muscles and synovial tissues have ACE2 receptors, which the virus uses to enter cells, suggesting that the virus affects these tissues by invading them [73].
Dermatological complications
According to research, 3% of hospitalized patients with post-acute COVID-19 in China reported having skin rashes six months after the infection started [22]. Hair loss was reported as a more common symptom in 20% of the patients, 110 days after their hospital discharge [74] (Fig. 4).
The intensity of the SARS-CoV-2 virus infection may also affect the skin and hair, resulting in rashes on the skin and hair loss. The long-term effects of the virus that causes acute renal insufficiency and end-stage kidney disease have a serious negative influence on the renal system as well. The complex multisystem effects of the virus may continue to result in chronic fatigue, severe exhaustion, and weakness even after the acute infection has faded (Created with Biorender.com.)
Citation: Physiology International 110, 4; 10.1556/2060.2023.00256
Renal complications
Acute renal insufficiency, end-stage kidney disease, and other adverse kidney complications were more likely to develop in patients who managed to survive COVID-19 after the initial infection [75] (Fig. 4). 13% of COVID-19 survivors who initially had normal kidney function later developed renal failure and after six months, 35% of COVID-19 survivors had renal dysfunction [22].
General long-term symptoms of long COVID
Fatigue, dyspnea, and trouble concentrating are the most often reported long-term symptoms, occurring in 32%, 25%, and 22% of patients, respectively, according to an extensive meta-analysis of 257,348 people who contracted COVID-19 [76] (Fig. 4). These symptoms show that long COVID is a complicated, multisystem disorder that impacts many facets of a patient's health [76], and people with chronic fatigue often perceive it as a lifetime condition with few chances of full recovery [77]. Two years after the initial infection, the study found that 59.7% of hospitalized and 67.5% of non-hospitalized patients reported having at least one long COVID symptom [28] and 1-2 million people experienced at least one COVID-19 symptom that lasted for longer than 12 weeks [78]. According to a meta-analysis, up to 20% of individuals continue to experience persistent dyspnea, along with fatigue, chest pain, and cough, even three months after being infected with SARS-CoV-2 [50].
Burden of long COVID on public health
Long COVID is a significant global public health concern; many people are experiencing these symptoms worldwide according to an observational cohort study [79]. Long COVID can lead to a substantial burden on the healthcare system and negatively impact the quality of life of patients. Patients who experience symptoms of long COVID may need ongoing medical treatment, such as hospitalization, rehabilitation, and specialized medical services, which can increase healthcare expenditures and put a burden on available resources. To lower the likelihood of long-term effects, public health strategies ought to emphasize vaccination and preventive actions. Peter et al. performed one of the largest population-based studies, with a follow-up of six to 12 months after acute SARS-CoV-2 infection where it has been shown that long COVID can cause possible individually and societally relevant sequelae also affecting younger adults with a history of mild acute infection. Other than general fatigue and neurocognitive impairment impaired general health and reduced working capacity were also observed in them [80].
The management of long COVID
Given the complicated and varied nature of post-COVID-19 problems, multidisciplinary care is essential for optimal management. This includes seeking counseling and receiving psychological support to overcome the despair and anxiety generated by the pandemic-related melancholy, as well as employing medications and immunizations to minimize post-COVID symptoms. The multidisciplinary team may include doctors from different specialties like pulmonologists, cardiologists, neurologists, and psychiatrists. Because PASC symptoms can vary widely from patient to patient, it may be necessary to develop individualized treatment plans that consider the particular needs of each patient [7]. Long COVID can be treated with a variety of therapy, including both medication and non-medication methods.
Role of medications in the management of long COVID
Currently, medication treatments do not directly target the illness but merely help manage symptoms [81]. There is hope that effective treatments (such as paxlovid) can be found thanks to ongoing research on recently licensed COVID-19 medications [82]. The effectiveness of vaccination in lowering the likelihood of long-term symptoms has been demonstrated, and it can aid individuals with persistent symptoms by reducing the severity and negative effects of long-term COVID [10, 12, 83]. The reduction in symptoms following vaccination may be due to improved virus clearance and a decline in chronic inflammation [84]. To reduce the chance of acquiring long COVID, the COVID-19 vaccine and early treatment of the acute phase of the disease are key tools at both the individual and societal levels [85].
Vitamin C is suggested as a supplemental treatment for long COVID symptoms because it has immunomodulatory and antioxidative characteristics by enhancing the immune system [86]. Participants who took multivitamins and mineral supplements for 28 days reported significantly higher levels of quality of life, general exhaustion, and mental fatigue, according to the questionnaires employed in an observational study [87]. Melatonin may help long COVID patients who experience symptoms including fatigue, sleeplessness, sadness, and “brain fog” reduce oxidative stress [88]. Melatonin activates the transcription factor nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), which boosts glutathione expression to fight free radicals that cause oxidative stress. While encouraging, additional clinical studies are required to thoroughly assess melatonin's potential as a therapy option [88]. Magurano et al. investigated the antioxidant qualities and ability to fight COVID-19 by grapefruit seed extracts and their primary components, limonoids [89]. In long COVID, symptomatic treatment is important to manage the presenting symptoms [90]. An observational study reveals that corticosteroids may be effective in treating post-COVID inflammatory lung disease [91]. Several pharmacotherapeutic drugs, including Montelukast, Deupirfenidone, Nicotinamide riboside, Leronlimab, and Tocilizumab, are undergoing clinical trials, raising hopes for an effective long COVID treatment [92]. Given the wide variety of symptoms linked to long COVID syndrome and the patients' intricate medical histories, it is imperative to take a comprehensive and coordinated approach to provide long COVID care and treatment guidance [93].
Role of rehabilitation and psychological support in the management of long COVID
It is increasingly evident that surviving the virus is not always the end of the story as the COVID-19 epidemic continues to impact millions of individuals globally. Numerous COVID-19 survivors still deal with a range of post-acute sequelae, including lung fibrosis, and neurological, cardiovascular, and gastrointestinal issues that can significantly lower quality of life. Research indicates that several of these problems have been successfully handled via rehabilitation. Concerning pulmonary rehabilitation, this is especially true. According to Bouteleux et al., pulmonary rehabilitation programs can be quite successful in treating respiratory conditions like dyspnea [94]. By addressing the cognitive, psychological, and social aspects of recovery, rehabilitation can also help patients regain their self-assurance and sense of well-being. Psychological assistance is just as important as rehabilitation. Studies have highlighted the importance of rehabilitation and supportive care in the management of long COVID [95]. Handling long COVID issues requires careful consideration of each patient's demands. The physical and mental health of each patient must be thoroughly assessed to choose the best course of action.
Future research
Although a lot has been learned about the complications of COVID-19 infection, there is still a lot to learn about the potential connection between COVID-19 and the emergence of chronic disorders. The possible treatment measures and management of long COVID are currently under development [4, 46]. Recent studies have emphasized COVID-19's possible long-term effects, including persistent symptoms like cardiovascular disease, diabetes, chronic renal disease, cognitive impairment, shortness of breath, and exhaustion. The heterogeneity of the disease sometimes makes it difficult to understand long COVID. Patients should be more actively involved in the study design because long COVID symptoms are unique to each patient and it is unknown whether particular demographics are more susceptible to them. This could help clinical decision-making and resource allocation. Given that long-term COVID risk factors have been established, data and information from certain vulnerable population segments (such as older persons) should be gathered and studied [96].
Future research into the treatment of long COVID may find success by combining medicines that manage the symptoms with those that boost the immune system [97]. The healthcare requirements for patients with long COVID will continue to increase soon. To meet this challenge, a concerted effort to utilize current infrastructure, develop scalable healthcare models, and integrate across disciplines must be necessary [4]. Research that can pinpoint the precise mechanisms and pathways that give rise to the numerous clinical signs of long COVID is crucial. This will help us comprehend the condition better and identify suitable therapy options [7]. Researchers and doctors can collaborate to lessen COVID-19's long-term effects on world health. Long-term follow-up research, identifying risk factors, and developing efficient treatments are urgently needed due to the disease's heterogeneity. Future research should concentrate on the pandemic's most recent phases while taking into account complications including the existence of other virus strains, vaccination statuses, and reinfections [96]. This will enhance the results for those who experienced long COVID and offer important new information about the overall effects of COVID-19 on human health [98].
Concluding remarks
Global public health is still in crisis as a result of post-COVID-19. As the world continues to grapple with the aftermath of the COVID-19 pandemic, it is important to recognize the significant impact that the virus caused on human health beyond the acute phase of infection. There are a few population-based studies that provide insight into the consequences of long COVID. Whitaker et al. performed a community study of 606,434 people in England and identified a subset of participants with predominantly respiratory symptoms by clustering analysis [99]. The Understanding America Study COVID-19 Survey, conducted by Wu et al. between March 2020 and March 2021, used a sample representing the U.S. community population which surveyed around 8,000 respondents bi-weekly and the final sample includes 308 infected individuals who were interviewed one month before, around the time of, and 12 weeks after infection. It can be said that 23% of them had long COVID because they developed new symptoms during infection that lasted more than 12 weeks [100]. In a population-based longitudinal cohort research using the general population of Zurich, Switzerland, up to 18% of people who were unvaccinated before infection experienced long COVID up to two years after infection, according to Ballouz et al., with indications of an increased risk of symptoms in comparison to controls [101]. By interviewing 8,193 non-hospitalized and non-institutionalized people in December 2020, who had tested positive for COVID, the Office for National Statistics (ONS) evaluated the prevalence of long COVID in the U.K. According to the findings, 21% of respondents had symptoms that persisted for more than 5 weeks, while 10% had symptoms that persisted for more than 12 weeks [102]. Additionally, a study conducted by the same organization revealed that older persons had a higher risk of acquiring long COVID [102].
However, the research on long COVID is constrained by several issues. First off, a significant amount of long-term COVID statistics are based on hospitalized patients; as a result, these data are not typical of the infected community as a whole. Second, there is a lack of information on the trajectory of symptoms since population-level studies do not typically look at a broad variety of symptoms or the progression of their intensity. Thirdly, since there is no COVID-free control group, any extended COVID study is further constrained due to the likelihood that some symptoms could be brought on by underlying illnesses or seasonal illnesses. Last but not least, there is a recall bias because the symptoms that the long COVID patients are questioned about might easily extend back months or even years [96]. The management of long-term COVID-19 sequelae remains a significant and ongoing challenge. The task of effectively addressing the enduring consequences of COVID-19 will remain an arduous undertaking for affected individuals, their families, and healthcare services alike, as highlighted by Whitaker et al. [99]. The disease's severity and the best course of treatment depend heavily on the immune response. Long COVID risk and severity can be significantly reduced by immune-modulating drugs and immunizations that attempt to improve immune function. Additionally, given the complexity of symptom trajectories and the unique disease burden, a patient-centered multidisciplinary strategy with an emphasis on tailored treatment programs and continuing symptom monitoring should be necessary to conduct these studies going forward [96].
Consent for publication
All authors read and approved the final manuscript and concur with the submission for publication.
Author contributions
NB and PS undertook the background literature study and prepared the initial draft of the manuscript. TS supervised the study, prepared the figures, and made final corrections to the draft.
Competing interests
The authors declare that they have no conflict of interest.
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