A narrative review of SARS-CoV-2 variants and long COVID

Introduction

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). An increasing number of individuals continue to experience symptoms weeks or months after SARS-CoV-2 infection that cannot be explained by other diagnoses. Long-term COVID-19 complications and persistent sequelae are chronic, incapacitating aftereffects of SARS-CoV-2 infection. This phenomenon is also known as “long COVID” or “post-COVID syndrome”, and there are many different definitions for it (1). According to the World Health Organization (WHO), a “post-COVID condition” is defined as usually 3 months from the onset of COVID-19; symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis in individuals with a history of probable or confirmed SARS-CoV-2 infection (2).

The number of COVID-19 patients has continued to rise since the SARS-CoV-2 pandemic, leading to a corresponding increase in cases of long COVID. According to WHO data as of October 8, 2025, there have been 778,741,840 confirmed COVID-19 cases globally, with 7,102,636 deaths (2). According to conservative estimates, the incidence rate of long COVID is 10% (3), meaning that at least 77.8 million people worldwide are afflicted. This figure excludes unreported cases, suggesting the actual number may be higher. Identifying risk factors for long COVID enables risk mitigation, potentially improving patient survival rates, reducing prevalence, and aiding prognosis and recovery. Research indicates that the prevalence of long COVID increases with age (4). Additional risk factors may include female gender, multiple comorbidities, prior chronic respiratory diseases [such as chronic obstructive pulmonary disease (COPD)], severe illness requiring hospitalization (particularly those on mechanical ventilation), high viral load, reactivation of Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) reactivation, and autoantibodies against various organs and type I interferon (4-7). Smoking may also increase the likelihood of developing long COVID (8). Consequently, special attention should be given to COVID-19 patients with underlying risk factors that may prolong the duration of long COVID and complicate subsequent treatment. Researchers should remain vigilant in monitoring for potential disease progression.

It is now recognized that long COVID is a multisystem disease with a wide range of symptoms. Primary symptoms and indicators include fatigue, dyspnea, anosmia, myalgia, cough, and ageusia (3,9). According to one meta-analysis, approximately 20% of affected individuals may experience no respiratory symptoms at all, with fatigue and dyspnea being the most prevalent respiratory sequelae (10,11). Specific pulmonary sequelae, such as pulmonary fibrosis and thromboembolic disorders, require careful evaluation and may necessitate targeted research and therapy (12). Cardiovascular symptoms in patients with long COVID frequently include palpitations and chest pain. Some patients also experience arrhythmias, right ventricular dysfunction, myocarditis, myocardial infarction, and prehypertension (13,14). Research indicates a markedly elevated risk of cardiovascular disease while recovering from long COVID (15). Consequently, cardiac follow-up monitoring is essential to protect patient health. Quality of life is significantly impacted by the musculoskeletal system (13). The gradual progression of fatigue and weakness over time indicates the growing role of the musculoskeletal system in the long COVID disease process (16,17). Cutaneous manifestations are less common. One study reports that viral rash is the most common skin symptom and shows a significant correlation with the severity of COVID-19 (18). Nevertheless, such rashes are non-specific and common to many viral infections. Additionally, hair loss has been identified as another sign of long COVID (19). COVID-19 can cause acute kidney injury. Multiple studies indicate an elevated higher risk of developing chronic kidney disease (CKD), which may represent a manifestation of long COVID (20-22). Neurological symptoms are present in approximately 33% of long COVID cases. The most prevalent is fatigue, followed by headaches, polyneuropathy, neuropsychiatric problems, and cognitive impairment (6,23). Furthermore, headaches in these patients may exacerbate pre-existing primary headache disorders (24). Regarding gastrointestinal involvement, a study summarizing symptoms 12 weeks post-infection reports that diarrhea, nausea, vomiting, abdominal discomfort, and elevated liver enzymes may be prominent features of long COVID. While individuals with chronic conditions face a higher risk of developing long COVID, current evidence does not suggest that digestive system sequelae are influenced by chronic diseases (25). Notably, long COVID gastrointestinal symptoms are associated with both pre-existing and post-COVID-19 mental health disorders, although the underlying mechanisms remain unclear (26). It is important to consider mental health when addressing physical symptoms. The most common psychological symptoms are anxiety and depression, with some patients also exhibiting symptoms consistent with post-traumatic stress disorder (PTSD) (27,28).

In December 2019, a cluster of pneumonia cases of unknown origin was reported in multiple healthcare facilities, leading to the identification of a previously unidentified β-coronavirus (29). The COVID-19 pandemic was caused by this new virus, which was known as SARS-CoV-2. However, the exact origin of the virus remains uncertain (29-31). Since the emergence of the wild-type strain, SARS-CoV-2 has undergone continuous evolution, generating numerous variants. These variants exhibit significant differences in traits such as transmissibility, immune evasion, and virulence. Key scientific questions that need to be investigated and clarified, including whether these variants are required for long COVID and how they affect its development. The mutation rate of SARS-CoV-2 has been remarkably high, from the original wild-type strain to the currently circulating variants. Clinical evidence suggests that some SARS-CoV-2 variants demonstrate greater transmissibility and potential virulence compared to the wild-type strain (32). Variants of interest (VOI) and variants of concern (VOC) are the two categories into which the WHO divides variations. To date, five SARS-CoV-2 variants have been designated as VOCs: Alpha, Beta, Gamma, Delta, and Omicron (2,33).

SARS-CoV-2 is a single-stranded positive-sense RNA virus. Its genome encodes a total of 29 proteins, including 16 non-structural proteins, 4 structural proteins, and 9 accessory proteins. Together with the RNA-dependent RNA polymerase (RdRp), the four structural proteins are nucleocapsid (N), envelope (E), membrane (M), and spike (S). Among these, the S protein is particularly crucial. Its primary function is to make it easier for the viral envelope to attach to the angiotensin-converting enzyme 2 (ACE2) of the host cell by using its receptor-binding domain (RBD) and N-terminal RNA-binding domain (NTD), ultimately enabling fusion between the viral envelope and the host cell membrane (32,34). SARS-CoV-2 exhibits distinct preferences for both upper and lower respiratory tracts, specifically targeting cells with high ACE2 expression. However, ACE2 is also widely expressed in extra-respiratory tissues, including cardiomyocytes, kidney proximal convoluted tubule epithelial cells, bladder epithelial cells, and esophageal, ileal, and mesothelial cells. Consequently, SARS-CoV-2 infection can lead to multi-organ involvement. Clinically, this is reflected not only in respiratory symptoms but also in manifestations such as myalgia, diarrhea, and loss or diminished sense of smell and taste (30,34-36). This further demonstrates that long COVID is a multisystem disease.

The varied definitions of long COVID allow for greater selectivity across different research methodologies, yet they also complicate investigations into its underlying pathophysiological mechanisms. Physical and psychological symptoms may interact, potentially contributing to more severe manifestations of the condition. In addition to having an effect on our bodies, long COVID can cause life disruptions and even death. Consequently, enhanced clinical attention and comprehensive management strategies are essential to address the well-being and long-term outcomes of patients with long COVID. We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2197/rc).

Methods

This narrative review synthesizes evidence from previously published articles identified through a systematic search on PubMed. The search terms included “long COVID”, “SARS-CoV-2”, “variant”, and “treatment”. Articles published in English were comprehensively evaluated. Relevant literature on long COVID and SARS-CoV-2 variants was systematically reviewed and summarized. The search strategy is detailed in Table 1, and all included articles from January 2020 to August 2025 are cataloged in the reference list.

COVID-19 variants and long COVID

Evolution of epidemiological and clinical characteristics

Although knowledge regarding the association between SARS-CoV-2 variants and long COVID remains limited, new evidence is rapidly emerging. Several studies indicate that the frequency and characteristics of SARS-CoV-2 variants are positively correlated with COVID-19 severity. VOCs spread considerably more quickly than the wild-type strain or earlier variants, suggesting that overall numbers of severe cases and deaths might increase in connection with infection rates. Autopsy findings have shown, for instance, that individuals infected with the Alpha variant died substantially earlier than those infected with the wild-type strain during the same period (37). Mutations in SARS-CoV-2 strains primarily target the S protein, enhancing transmissibility by improving affinity for the ACE2 receptor through its RBD conformation (30,37,38). The first designated VOC, the Alpha variant (B.1.1.7 lineage), was reported in the United Kingdom (UK) in December 2020. It features 17 mutation sites, including 9 on the S protein. Compared to earlier variants, its transmissibility increased by 50–100% relative to the wild strain (39). Omicron (B.1.1.529 lineage) exhibits even more extensive genetic changes, with over 60 mutation sites, including multiple amino acid substitutions in the RBD. This variety and its sublineages have infected many people globally and are highly transmissible and capable of eluding the immune system (40,41). Further research is needed to determine whether these distinct mutational profiles across variants contribute to differing risks or presentations of long COVID (42).

While long COVID is connected to the pandemic era and the development of COVID-19 vaccines, most research indicates that certain SARS-CoV-2 variants are associated with higher viral loads. The emergence of SARS-CoV-2 and other temporal changes during the pandemic may have elevated the risk and burden for individuals with long COVID. Even among vaccinated individuals infected with the Omicron wave, the cumulative incidence of long COVID within the first year following infection has shown a declining trend throughout the pandemic (43,44). Following infection with the wild-type and Delta variants, children and adolescents show lower transmissibility compared to adults. However, transmissibility during Alpha infection remains unclear (45). Distinct mutations in the viral S protein may be associated with resistance to VOCs (6,43,44). The risk of long COVID increases with age and the number of comorbidities. Unvaccinated women appear to be at particularly heightened risk. Different SARS-CoV-2 variants may have different persistent symptoms, suggesting that the future prevalence and clinical characteristics of long COVID may evolve alongside viral progression (46). Consequently, the development of SARS-CoV-2 vaccines and COVID-19 treatment strategies should prioritize variants associated with severe long-term symptoms.

Compared to previous VOCs, infection with the Omicron variant resulted in fewer long COVID symptoms and the lowest prevalence (47). SARS-CoV-2 variations are linked to the severity and symptom presentation of long COVID, and certain lineages may have an impact on the severity and persistence of post-COVID sequelae (46). The predominant symptoms associated with different viral strains are detailed in Table 2 (47-52).

Influencing factors

Currently, it is understood that many distinct SARS-CoV-2 variants cause the same long COVID symptoms. However, the reasons for variations in symptom severity across different VOCs require further investigation and analysis. Discussions concerning the underlying pathophysiological mechanisms remain limited and underdeveloped. To more effectively address the economic and health concerns raised by the pandemic, it is imperative to investigate the ways in which SARS-CoV-2 variations influence the development of COVID-19.

Virus factors

The severity of long COVID may vary depending on the transmissibility and virulence of the infecting SARS-CoV-2 variant. The increased transmissibility associated with newer variants can lead to higher population infection rates, potentially resulting in a greater overall number of long COVID cases (53). Nevertheless, no variations in viral persistence have been found to differ from one another (54). Clinical studies indicate that the risk of developing long COVID sequelae is lower following infection with the Omicron variant compared to earlier VOCs (55). While most individuals recover from acute SARS-CoV-2 infection within a month, some with compromised immune systems may fail to fully clear the virus. The evolution of VOCs may be fueled by persistent SARS-CoV-2 replication, which speeds up the accumulation of mutations and permits the virus to remain in the respiratory system while enhancing cellular infection. SARS-CoV-2 RNA and proteins can be detected in various body tissues long after the virus is no longer present in the upper respiratory tract. However, the replicating virus has not been successfully isolated from immunocompetent individuals with long COVID (56). In addition to exhibiting diverse behavior in immune evasion, transmissibility, and clinical symptoms during infection, emerging VOCs modify the molecular properties of SARS-CoV-2 proteins. In certain lineages, long COVID symptoms may be associated with increased virus persistence in particular organs or evasion of host immune responses (46).

In the human host, the primary site of SARS-CoV-2 infection is hypothesized to be the upper respiratory tract, including nasal tissues (57). Consequently, the nasopharyngeal mucosa is considered one of the most important targets for SARS-CoV-2 infection. Outpatients who develop long COVID have been shown to exhibit higher peak nasopharyngeal viral loads within the first 21 days compared to those who fully recover, and persistent viral RNA or antigen can be detected in this region in Long COVID patients (58,59). Factors such as increased basal cell replication and the ability of SARS-CoV-2 to replicate in the face of a persistent interferon response likely contribute to this viral persistence (60). An effective early innate response in the nasal mucosa may help control viral replication and spread, thereby promoting the development of an adaptive immune response (57). Consequently, it is crucial to confirm our results with larger-scale research, which could also assist to clarify why different studies on the long-term effects of different SARS-CoV-2 infections have different results.

Immune and inflammatory responses

Different SARS-CoV-2 variants can cause innate or adaptive immune responses that differ in strength, persistence, and autoantibody formation. These differential immune profiles may contribute to the heterogeneous clinical course and duration of long COVID. SARS-CoV-2 infection has been shown to induce a persistent immune response, which can mitigate symptoms upon subsequent reinfection. Specifically, individuals with pre-existing immunity demonstrate more rapid and robust antibody responses, achieving higher antibody titers compared to those experiencing a primary infection (61). As the body’s first line of defense, the role of the innate immune system in long COVID is critical to understand (62). Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were significantly elevated in the early stages of long COVID (63). Further research is needed to determine whether these alterations in immunological markers are merely associated with, or causally linked to, the long-term risk and symptomatology of COVID-19. Direct or indirect neuronal damage—whether through viral injury to neurons or via local tissue damage—can lead to neurological impairment, which subsequently alters vascular tone, resulting in systemic hypoperfusion, orthostatic intolerance, and dysfunction of respiratory and/or gastrointestinal systems. Neuronal injury may require months to recover, reflecting the protracted convalescence observed in many individuals with long COVID. Symptoms associated with autonomic dysfunction in long COVID include postural orthostatic tachycardia syndrome (POTS), for which inflammation, tissue hypoxia, and autoimmunity are considered causal factors (59). However, our understanding of the association between long COVID and SARS-CoV-2 variants remains limited. Further investigation into its underlying etiology is essential to inform and optimize future rehabilitation strategies and therapeutic approaches.

Long COVID treatment

The management of long COVID primarily relies on symptom-based clinical guidelines and expert consensus. However, its pathogenesis is complex, and the spectrum of persistent symptoms varies among individuals infected with different SARS-CoV-2 variants. To date, there is a lack of rigorously clinically proven, variant-specific curative therapies. The cornerstone of clinical practice remains the comprehensive assessment and supportive management of patients’ multi-system symptoms.

Antiviral treatment

A meta-analysis indicates that early antiviral treatment can reduce hospitalization rates and mortality risks in patients with long COVID, and may lower the population incidence of long COVID. Antiviral medications should be recommended for the treatment of acute COVID-19 (64). Paxlovid (active ingredients: nirmatrelvir and ritonavir) and Veklury (active ingredient: remdesivir) are the two main antiviral medications that have been authorized by the European Medicines Agency (EMA) (65,66). Paxlovid is an inhibitor of the SARS-CoV-2 protease. Its active component, nirmatrelvir, selectively inhibits the viral main protease (Mpro) to prevent viral replication. Remdesivir, a nucleoside analog, has broad-spectrum effectiveness against a variety of RNA viruses and inhibits RdRp to prevent viral reproduction (67). Antiviral drugs provide stronger protection for elderly populations, males, unvaccinated individuals, and non-diabetic groups (64). Among these treatments, nirmatrelvir-ritonavir has shown particular efficacy against the Omicron variant, reducing the risk of severe and persistent COVID-19 symptoms (68). MIR2911, a bioactive microRNA derived from honeysuckle, has demonstrated antiviral activity against the original SARS-CoV-2 strain. One study indicates that MIR2911 serves as a promising therapeutic strategy to combat SARS-CoV-2 replication, showing particular efficacy against the Delta variant (69). Separately, herbal preparations (extracts) and purified compounds can exert their anti-SARS-CoV-2 effects by directly inhibiting viral replication or entry (70). Therefore, early antiviral therapy protects individuals with weakened immune systems and helps patients with prolonged COVID.

Anti-inflammatory treatment

In order to reduce SARS-CoV-2 replication and shorten patients’ duration of COVID, dexamethasone suppresses systemic inflammation and lowers pro-inflammatory cytokines, which counteract inflammatory responses. COVID-19 individuals treated with dexamethasone had a lower risk of developing long COVID symptoms (71). Additionally, dexamethasone effectively reduced the incidence of long COVID.

Monoclonal antibody (mAb)

Neutralizing antibodies that target the SARS-CoV-2 S protein can reduce the risk of COVID-19-related hospitalization, particularly in high-risk populations. mAbs are laboratory-engineered molecules derived from the B cells of SARS-CoV-2-infected hosts. By attaching to the S protein of SARS-CoV-2, mAbs can directly target the virus, neutralizing it and triggering complement activation, antibody-dependent cellular phagocytosis, and antibody-dependent cell-mediated cytotoxicity, all of which lessen the severity of COVID-19 (72,73). The mAbs amubarvimab/romlusevimab have previously been shown to reduce the risk of hospitalization or death by 79% (74). Despite being quite successful in decreasing hospitalization or death, amubarvimab/romlusevimab or amubarvimab with romlusevimab has not been shown to reduce the risk of long COVID. Therefore, additional measures are needed to prevent long COVID (64,74,75). For chronic headaches after COVID-19, especially long COVID headaches, calcitonin gene-related peptide (CGRP) mAbs may be a viable treatment option. Their application may lessen the psychological effects of chronic headaches and improve headache-related quality of life (76). The non-clinical studies revealed bebtelovimab not only effectively neutralizes broadly circulating SARS-CoV-2 and existing VOCs, such as B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta), but also maintains significant activity against the Omicron lineage, including BA.2.75, BA.4, BA.4.6, and BA.5 (77). Although mAbs can alleviate some symptoms of long COVID, additional therapeutic interventions are still required.

Vaccine

Long COVID poses a significant health risk to populations worldwide. However, vaccine hesitancy remains a challenge, partly due to fears about potential side effects. Clarifying the difference in long COVID incidence between vaccinated and unvaccinated individuals is therefore crucial. A systematic review and meta-analysis found that receiving at least one dose of SARS-CoV-2 vaccine provides protection against long COVID. Both receiving two doses of vaccine before COVID-19 infection and receiving one dose after infection reduce the risk of long COVID. Furthermore, there is no direct evidence that SARS-CoV-2 vaccines exacerbate long COVID. As a result, patients with long COVID are advised to follow the recommended SARS-CoV-2 vaccine schedule, as vaccination continues to lower the risk of long COVID over time (78-81). Following immunization, the majority of individuals with long COVID symptoms failed to observe any difference in their symptoms (80). In order to prevent long COVID, which severely reduces quality of life, vaccination is essential. Therefore, by partially preventing extended COVID, vaccination may be a method of maintaining quality of life.

Physical therapy

The majority of recent studies on physical therapy concentrate on long COVID symptoms, such as palpitations and chest pain, which are cardiovascular symptoms. Physical therapy has been established as an essential component of long COVID management, as it alleviates symptoms and improves overall physical function. Physical activity may have positive effects on long COVID patients. Exercise and manual therapy, for example, can help those who are tired or have aching muscles. Enhancing joint mobility and minimizing discomfort are the main goals of this treatment. A meta-analysis indicates that long-term physical exercise enhances quality of life for long COVID patients (82,83). It is particularly valuable for those experiencing musculoskeletal discomfort due to long COVID. Although physical therapy can enhance physical function and control mental and physical states, its full effectiveness requires consistent adherence over time. In addition to conventional physiotherapy, acupuncture has also been identified as a viable adjunctive treatment option (84). Epipharyngeal abrasive therapy (EAT), a treatment primarily performed by otolaryngologists in Japan for chronic epipharyngitis, has shown efficacy in relieving upper respiratory symptoms, including chronic cough (85). One study reported that EAT cleared residual SARS-CoV-2 RNA from the epipharynx (86). Furthermore, reducing pharyngeal inflammation through EAT has also been reported to alleviate systemic symptoms associated with Long COVID (87). One year after recovery, the majority of people have good physical and mental health, despite the vast range of long COVID symptoms. The findings demonstrate the determination of patients and stress the significance of tracking long-term health outcomes (88). These approaches form part of a multidisciplinary strategy for symptom control and disease management, enhancing quality of life for long COVID patients. There is currently no proven cure for long-term COVID, and some people recover on their own after contracting the virus.

Conclusions

The relationship between SARS-CoV-2 variants and long COVID remains an area requiring further elucidation. Different SARS-CoV-2 variants exhibit distinct characteristics in transmissibility, virulence, and the risk of causing long COVID. Additionally, they trigger distinct innate and adaptive immune responses that vary in strength and durability, which might impact how long COVID takes to start and develop. In the future, long COVID may impose substantial medical and economic burdens. To completely protect these patients’ mental and physical well-being, the immediate priority is to leverage public health systems and policies to broaden their treatment options and create individualized therapy treatments. Understanding the causes behind the start and course of the disease is so crucial. Building on this knowledge, the development of effective interventions and management protocols is essential to empower more individuals in proactively addressing long COVID.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2197/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2197/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2197/coif). The authors have no conflicts of interest to declare.

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