The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1), has resulted in over 771 million confirmed cases and more than 6.9 million deaths globally (2). It has also led to significant morbidity, adverse mental health outcomes (3–7), and substantial socioeconomic disruption (8–11). While efforts have primarily focused on the acute phase of the disease, emerging evidence of significant and concerning post-acute effects on COVID-19 survivors introduces an additional dimension to the pandemic, potentially with long-term implications. These post-acute effects are known as long COVID or by various other names such as post-COVID conditions (PCC), post-acute sequelae of COVID-19 (PASC), chronic COVID syndrome (CCS), and long-haul COVID, and they define a broad spectrum of lingering symptoms experienced by a proportion of COVID-19 survivors after clearing the acute SARS-CoV-2 infection (12). According to the United States (US) Centers for Disease Control and Prevention (CDC), post-COVID-19 conditions have various health consequences four or more weeks after SARS-CoV-2 infection. The term is loosely defined due to the diverse and heterogeneous nature of the long COVID symptoms. These may include respiratory issues like persistent breathlessness, dyspnea, tiredness, headache, fever, and multi-system complaints. Additionally, these symptoms may occur concurrently or intermittently (12, 13). Nevertheless, in certain instances, the clinical manifestations observed almost four weeks following SARS-CoV-2 infection might derive from persistent symptoms originating in the acute phase of COVID-19 (14). In light of this, the significance of defining long COVID symptoms to distinguish between patients experiencing a gradual recovery and those exhibiting symptoms that accurately align with their medical condition, has been proposed (14).

This review provides a comprehensive overview of long COVID’s clinical and biological aspects. It emphasizes the epidemiology, clinical presentation, and system-specific manifestations, focusing on the immune response and inflammation.

Following the 2003 SARS epidemic caused by SARS-CoV-1, some survivors experienced reduced functional capacity and could not return to work (15, 16). The prevalence of long COVID in the population remains uncertain, ranging from 10% to 60% for COVID-19 survivors and potentially exceeding 90% for severe cases requiring hospitalization (17–23). It is estimated that one-fifth to one-third of survivors may experience activity-limiting symptoms for weeks after the acute phase (20, 21, 24–28). Notably, post-COVID-19 persistent symptoms appear more common than other respiratory infections (19, 29). Studies in Italy found that most patients surviving COVID-19-related hospitalizations faced impaired physical functioning after discharge (19).

Furthermore, a case series of 143 COVID-19 survivors found that only 12.6% were symptom-free after an average of 60 days from disease onset (27). Additionally, 44.1% reported a declining quality of life due to fatigue and dyspnea (27) ( Figure 1 ). Long-term COVID development can be influenced by different SARS-CoV-2 variants, the number of vaccine doses received, and the time elapsed since vaccination (30). Studies indicate that Omicron cases were less likely to experience long COVID (31, 32). For instance, a study in China reported that 40.4% of patients with the Delta variants had clinical sequelae 3 to 24 months after discharge, compared to only 8.89% who had Omicron (32). Similarly, a study in the United Kingdom showed a reduction in long COVID cases from 10.8% for the Delta variant to 4.5% for the Omicron variant (31). Moreover, Omicron cases were less likely to experience long COVID regardless of their vaccination regimen (31, 32). However, early studies on this matter often had limited sample sizes and focused on specific populations, so further research is needed to reach more definitive conclusions.

The health agencies estimate that around 1 out of 5 COVID-19 survivors may develop long COVID, marking some of the most robust evidence of its prevalence thus far (22). The CDC conducted a multi-state telephone survey of symptomatic adult COVID-19 survivors in the US to assess the prevalence of disabling or activity-limiting symptoms after COVID-19. The survey found that 35% had not returned to their normal state of health after 2–3 weeks of diagnosis. It has also been reported that one in five patients aged 18–34 with no chronic medical conditions after COVID-19 did not return to their normal state of health (29). While information on the duration of long COVID is limited, reported cases have extended from weeks to over a year (18, 33). However, recent studies indicate a decline in the incidence of long COVID cases post-pandemic, and this reduction has been associated with the advancement of vaccination (34, 35) Additionally, the Wuhan variant has been associated with diverse physical symptoms and emotional and behavioral changes, indicating a substantial impact on long-term health outcomes (36). In contrast, the Omicron variant has shown fewer post-infection effects, resembling common seasonal viral illnesses. These observations suggest that the Omicron and subsequent variants may not have the same long-term health consequences as earlier SARS-CoV-2 variants (36).

Certain risk factors, including age, gender, cardiovascular disease, and diabetes, have been associated with long COVID (37–43), which are also risk factors for severe acute COVID-19 (44, 45) Although some studies suggested that long COVID incidence may correlate with COVID-19 disease severity, age, and comorbidities (38, 46–48), others did not show such a relationship (23, 49). Notably, long COVID can emerge after mild and even asymptomatic COVID-19 cases (50). Observational evidence indicates that the severity of long COVID symptoms does not necessarily correlate with COVID-19 disease severity (50). This insight is derived from a study utilizing data from the UK Biobank, an extensive health database with measurements from thousands of volunteers before and after the pandemic’s start (51). On the other hand, an association between disease severity and the intensity of lingering respiratory symptoms has also been reported (52). Available information suggests a possible link between COVID-19 severity and long COVID incidence (53), although this association may not be statistically significant in large-scale studies and thus requires further investigation.

Female gender has been identified as a risk factor for developing post-COVID-19 symptoms (54–58). Studies indicate that women (<50 years old) were more likely to report fatigue and dyspnea after acute infection compared to men of the same age (55, 56, 59). Additionally, women may be up to three times more likely to be diagnosed with long COVID, regardless of age (60). This could be attributed to biological differences in the expression of angiotensin-converting enzyme-2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) between genders (61), as well as immunological variations (62).

The role of persistent infection in long COVID remains uncertain. Various hypotheses regarding the mechanisms involved in its pathogenesis have been proposed, including circulating viral antigens or reservoirs in tissues ( Figure 1 ) (30). Clinical and epidemiological surveillance data show that individuals may have detectable viral loads yielding positive PCR results for three months or even longer after infection. Although these individuals are usually non-infectious, their persistently detectable SARS-CoV-2 genetic material may contribute to their long-term symptoms (63–65). On the other hand, emerging research has reported the detection of persistent circulating spike protein in the bloodstream of some long COVID patients, even though they have undetectable levels of viral genetic material after the acute phase of COVID-19 (66). It has been suggested that the spike protein may go across the blood-brain barrier, triggering inflammation (67). Moreover, the persistence of nucleocapsid and envelope proteins in the liver, gallbladder, lymph nodes, and intestine has been associated with endothelial cell damage, leading to cytokine release and immune response activation (68).

Although chronically SARS-CoV-2-positive patients are generally considered non-infectious, persistent viral shedding has been reported (24). This poses a concerning risk of potential new variant emergence (69, 70). Chronic infections have led to mutations that could facilitate SARS-CoV-2 evolution and the emergence of new variants (70–73). As a result, epidemiologists and infectious disease specialists have hypothesized that SARS-CoV-2 variants like Omicron may have originated through natural selection in chronically infected hosts (69). Emerging observational data suggests that vaccination against COVID-19 may help resolve chronic infections, emphasizing the potential of vaccines in preventing the emergence of new variants (72, 74). It is important to note that while the quality of the evidence is somewhat limited, it indicates a positive impact of vaccinations in mitigating the ongoing emergence of variants.

Since the widespread availability of COVID-19 vaccines in early 2021, extensive scientific scrutiny of their impact on the risk of developing long COVID and the immune profile following a post-breakthrough SARS-CoV-2 infection (15, 54, 75–89). Studies have also investigated the severity of symptoms in vaccinated individuals who develop long COVID (82–86). Initial reports have suggested that vaccination may confer protective effects against long COVID incidences (83, 85, 90). However, recent extensive cohort studies show that vaccines provide only partial protection in case of a breakthrough infection (91, 92). One of these studies, conducted using the US Department of Veteran Affairs healthcare database with substantial sample size, provides robust evidence that vaccination’s impact in reducing the incidence of long COVID is partial (82). Available data conclusively demonstrate that vaccines diminish the risk of long COVID by decreasing the likelihood of experiencing a SARS-CoV-2 infection (84, 87, 90). Other studies have shown an almost complete reduction of long COVID symptoms after vaccination, mainly for severe manifestations like fatigue (93, 94). In this context, booster doses may be considered a preventive measure against long COVID, helping to maintain a relatively low infection risk and providing protection against concerning variants (86, 95, 96).

The FDA-approved antivirals Nirmatrelvir and Molnupiravir effectively treat acute COVID-19 (97, 98). Nirmaterlvir targets the SARS-CoV-2 type 3-chymotrypsin cysteine protease enzyme (99), while Molnupiravir heightens the frequency of viral RNA mutations (98), both leading to alterations in viral replication (41, 98). Administering these antivirals during the acute phase is linked to a reduced risk of at least eight of the thirteen post-acute sequelae, including arrhythmia, pulmonary embolism, deep vein thrombosis, fatigue and malaise, liver disease, acute kidney injury, muscle pain, and neurocognitive impairment (100, 101). Their use is associated with decreased risk of long COVID in unvaccinated individuals, vaccinated individuals, and those with both a primary SARS-CoV-2 infection and reinfection (100, 101).

Immunocompromised individuals show a notably diminished humoral immune response to vaccination, underscoring the necessity of booster shots in averting COVID-19 and mitigating the onset of long COVID within this group of patients (79). In immunocompromised children, SARS-CoV-2 infection was observed to be more asymptomatic than their immunocompetent counterparts (102). Moreover, there was a lower reported frequency of long COVID among immunocompromised children relative to immunocompetent controls (102). This is crucial, especially given the limited but strong evidence suggesting that persistent infection in these individuals may contribute to the emergence of new variants, as discussed earlier (69–72). However, it is worth noting that additional protection in the case of a breakthrough infection remains a subject of scientific debate. Positively, evidence indicates that vaccination may alleviate long COVID symptoms in previously unvaccinated patients (74, 83, 93, 94, 103, 104).

Long COVID is not exclusive to adults, as it has also been observed in the pediatric population (105). For example, a retrospective cohort study found that 51% of pediatric patients from a sample of children who recovered from COVID-19 experienced persistent symptoms 1-3 months after infection. The most common manifestations in this study were fatigue, loss of taste or smell, and headaches (106). Similarly, a small case report involving Swedish children who experienced mild to moderate COVID-19 without hospitalization revealed that all five children had persistent symptoms after 6-8 months, significantly hindering their daily activities and severely impacting their ability to attend school (107).

Long COVID presents a wide range of symptoms, as mentioned before ( Figure 2 ) (12, 13, 22, 108, 109). Despite its clinical presentation, the precise pathophysiological mechanisms remain unclear. Its involvement across multiple organs suggests potential mechanisms, including direct viral tropism, cytotoxic viral proteins, and immunopathology ( Figure 2 ). Some studies propose that long COVID symptoms may result from persistent effects of the acute phase of COVID-19 and that different mechanisms may cause the different symptoms described (14, 27, 66, 67). Additionally, immune system activation can lead to an autoimmune response or prolonged, nonspecific inflammation, causing further harm to host cells ( Figure 2 ) (24, 110–115).

Reactivation of latent viral infections, including Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and human cytomegalovirus (HCMV), is a common occurrence in states of compromised immunity. Human herpesviruses like EBV and HHV-6 are prevalent globally, with over 90% of adults carrying one or more of these viruses (276, 277). Among the risk factors for viral reactivation are stress and immunosuppression, and also this reactivation has been documented in severe illness, particularly among ICU patients (278). Patients with COVID-19, whether experiencing mild or severe cases, have reported the reactivation of latent herpesviruses (279–282). However, the reactivation tends to be more severe in individuals with a critical illness and less pronounced in those with milder cases (279–282). The stress and the notable increase in cytokines and other inflammatory molecules is mainly caused by viral proteins, including ORF8, a unique accessory protein specific of SARS-CoV-2 are believed to contribute to the reactivation of these viruses (283, 284). Furthermore, this reactivation may enhance SARS-CoV-2’s entry into cells, potentially increasing viral load and symptom severity (285). While causal links have not been definitively established, it has been speculated that persistent EBV, HHV-6, and SARS-CoV-2 infections could fuel the chronic inflammation associated with long COVID (281, 286, 287). A study that compared patients with long COVID with 1 or more than 5 symptoms to those without long COVID found higher Epstein-Barr virus nuclear antigen (EBNA) IgG levels. More specifically, these patients have more neurocognitive symptoms (276). Interestingly, long COVID patients who reported preexisting autoimmune diseases like thyroiditis and have experienced fatigue showed higher levels of early antigen diffuse component (EA-D) IgG (276).

Additionally, SARS-CoV-2 has been suggested as a risk factor for various cancers (288), raising the possibility that latent herpesvirus reactivation may play a role in these oncogenic processes. This emphasizes the need to closely monitor reactivated viral infections in patients with current or past SARS-CoV-2 infections.

Moreover, the reactivation of infections has been associated with neurological complications. Long COVID shares similarities with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) due to comparable manifestations (289). ME/CFS is characterized by systemic exertion intolerance with neurological and immunological components, and viral infections can be a trigger (289, 290). In survivors of SARS-CoV-1, 27% reported ME/CFS symptoms four years after infection, a trend observed in long COVID patients (290). Opportunistic viruses like EBV, HHV-6, and HCMV have been linked to the development of ME/CFS (291). Consequently, reactivation of these viruses has been associated with long COVID symptoms (292, 293). A study found that long COVID patients had higher EBV nuclear antigen (NA) immunoglobulin G (IgG) levels compared to those without the condition (293). Also, EBV early antigen-diffuse (EA-D) IgG was correlated to long COVID manifestations, with fatigue and insomnia being the most frequently reported (292). Furthermore, the reactivation of EBV and HHV-6 was detected in long COVID patients who reported symptoms like sleep disorders, persistent cough, anosmia/ageusia, hair loss, shortness of breath, and chest pain (294).

Reactivation of latent infections related to COVID-19 extends beyond viral diseases. Notably, cases of tuberculosis (TB) reactivation following SARS-CoV-2 infection have been documented (295–299). The possible immunosuppressive effects of the disease, which remains controversial, and the treatments may contribute to infectious disease reactivation. Alarmingly, the WHO’s annual tuberculosis report indicates an increase in TB incidence since the beginning of the pandemic, exacerbating a condition that already imposes a significant global healthcare and economic burden (300).

Understanding the immune response to long COVID necessitates insight into the acute phase of the disease. The host immune reaction, encompassing innate and adaptive components, plays a crucial role in COVID-19. This involves the release of substantial quantities of pro-inflammatory cytokines and inflammatory cells such as neutrophils and macrophages (155, 301, 302) along with the generation of virus-specific CD4⁺ T cells, CD8⁺ T cells, and B cells (303–308). The impact of this immune response on the clinical manifestations of COVID-19 has been reported. Clinical research has indicated that in numerous severe cases, immunopathology —organ and tissue damage resulting from an imbalanced immune response—may be a primary factor in life-threatening injuries for patients (150, 301, 309–314). Acute exacerbated immune responses, mainly the self-sustaining inflammatory chain reaction are commonly observed in critical COVID-19 cases (301, 303, 309, 310). Additionally, markers of inflammation in the blood linked to immunopathology and multi-organ damage have been identified, including interferons, neutrophil markers, and other inflammatory cytokines (314). Immunopathology has also been demonstrated to play a substantial role in severe acute pediatric cases, with a relatively common manifestation being the severe, and at times fatal, systemic inflammatory condition known as multi-system inflammation in children (MIS-C). This syndrome involves exacerbated respiratory and cardiovascular tissue inflammation accompanied by fever (264, 265, 270–274).

Persistent immune dysregulation is suspected to play a role in specific chronic manifestations of long COVID ( Figure 2 ) (24). Evidence indicates that patients exhibiting these manifestations display altered immune mediators, both cellular and humoral, with a notable focus on modified T-cell populations (21, 104, 108). It is plausible to hypothesize that these altered populations may contribute to persistent immunopathology, potentially accounting for long-term symptoms characterized by inflammation, such as chronic fever and muscle and joint pain (20, 164, 311, 312). However, it is crucial to emphasize that the connection between acute and chronic immune regulation post-SARS-CoV-2 infection is not yet fully elucidated.

Clinical studies utilizing blood samples from COVID-19-convalescent volunteers have demonstrated that SARS-CoV-2 infection strongly induces coronavirus-specific T lymphocytes and memory B cells (315–319). Besides, evidence suggests that these lymphocytes may remain persistently elevated, potentially explaining at least some clinical manifestations of long COVID (113, 150). Additionally, it has been observed that in COVID-19-convalescent patients, there are broad alterations in the transcriptome of peripheral blood mononuclear cells (PBMCs) in those with clinical presentation compatible with long COVID (320). Significant differences in innate and adaptive immune cell populations in COVID-19 convalescent individuals compared to uninfected controls were observed (320). Furthermore, a clinical study employing a high-dimensional characterization of the lungs of COVID-19 convalescent subjects found an enrichment of T and B cells in the respiratory tract compared to blood levels (110). Additionally, it was observed that the gastrointestinal manifestations of long COVID were linked to the expansion of SARS-CoV-2-specific CD8⁺ and CD4⁺ T cell populations (41).

Dysregulated tissue-resident T cells have been suggested as potential drivers of chronic lung pathology post-respiratory infections (321, 322), implying that long COVID pathology may stem from a dysregulated cellular response (315). CD4⁺ T cell responses during COVID-19 are correlated with disease severity, suggesting that a more severe acute SARS-CoV-2 infection could lead to a greater degree of T cell response dysregulation, potentially explaining chronic manifestations (24). Conversely, there was no correlation between immune dysregulation and persistent viral load (24), indicating that COVID-19 induces alterations in cell immunity regardless of chronic viral load, which could be a key pathophysiological trigger of long COVID (320, 323).

On the other hand, studies have shown that COVID-19 can induce significant decreases in several components of the cellular immune response, including cytokines, complements, and immune cells (303, 324, 325). Recent research showed marked reductions in counts and percentages of total lymphocytes, total T cells, CD4⁺ T cells, CD8⁺ T cells, B cells, and natural killer cells (NK) without changes in the typical TCD4:TCD8 ratio of approximately 1:1 in healthy subjects whether vaccinated or unvaccinated, who are COVID-19 survivors (324) ( Figure 1 ). Substantial dysregulations in CD8⁺ T cells expressing degranulation markers have been reported after SARS-CoV-2 infection (24). Furthermore, a machine-learning-assisted clinical characterization of the immune response of healthy volunteers, COVID-19 patients, and long COVID patients revealed significantly elevated B cell and CD14⁺ CD16⁺ CCR5⁺ monocyte levels, along with reduced T regulatory cells (Treg) and programmed cell death protein 1(PD-1)-expressing CD4⁺ and CD8⁺ T cells in the long COVID group compared to healthy controls (325). Moreover, immunological characterization of long COVID patients found a persistent increase of CD16⁺ monocyte levels and sustained expression of the SARS-CoV-2 S1 protein in CD14lo, CD16⁺ monocytes (326). While the precise role of this expression remains uncertain, it is speculated that it could contribute to chronic vascular inflammation (326). These observations may suggest that if these alterations in cellular immunity persist, they could at least partially contribute to the symptoms present in long COVID. Consistent with this, significantly higher SARS-CoV-2-specific IFN-γ-producing CD4⁺ and CD8⁺ T cells were found in subjects with prior pulmonary disease, indicating that this condition may lead to a higher likelihood of future persistent cellular immune dysregulation after experiencing COVID-19 (24). Furthermore, a study found increased levels of activated CD4⁺ and CD8⁺ T-cells after 3 months of recovery from mild, moderate, and severe COVID-19. Higher plasma levels of T-cell-related IL-4, IL-7, IL-17, and tumor necrosis factor-alpha (TNF-α) were observed to compared mild and moderate patients (327). Despite all this evidence, a study evaluating SARS-CoV-2 cellular immunity in health workers with confirmed infection, with or without persistent symptoms, found no differences in viral neutralization or T-cell responses (328). Recently, it was observed that T cells from COVID-19 patients exhibited significantly elevated levels of IL-2 production in response to stimulation with SARS-CoV-2 peptides compared to an unexposed control group (329).

SARS-CoV-2 infection triggers a strong induction of virus-specific B cells, resulting in abundant production of IgG antibodies primarily targeting the receptor-binding domain of the spike protein (S-RBD) and the nucleocapsid protein (NP) (308, 317, 330). Studies of individuals recovering from COVID-19 consistently show elevated IgG levels persisting for up to 24 weeks post-infection (315, 320). These humoral responses correlated with disease severity and the number of post-acute symptoms (20, 320, 331). Similar patterns emerge in cellular immunity. However, the precise implications of the upregulation of both humoral and cellular responses in the pathogenesis of long COVID remain unclear. Notably, some studies find no clear correlation between the humoral response and the incidence and severity of long COVID manifestations (108, 328). It is crucial to note that elevated antibody titers do not always indicate the presence of symptoms. COVID-19 vaccinations have been associated with a sustained upregulation of both humoral and cellular immune responses, with a notable absence of chronic adverse effects in most cases (54, 78, 80, 96, 332–338). Interestingly, comorbidities, particularly diabetes, chronic heart disease, and hypertension, correlate with higher convalescent antibody titers after COVID-19 (20).

On the other hand, alterations have been observed in the development of B cells, wherein antibody-secreting cells are produced extrafollicularly (339, 340). This pathway has been previously described in individuals with lupus (341). While responses directed against the virus are initiated, they can also give rise to autoreactive humoral responses (autoantibodies), which persist for months in individuals experiencing post-COVID-19 sequelae (339, 340). Autoantibodies have emerged as potentially significant contributors to COVID-19 severity (41). Reports suggest these molecules might be responsible for up to a fifth of COVID-19-related deaths (342). Autoantibody concentrations have been positively correlated with age and the male sex, potentially explaining the higher severity and case-fatality ratio observed in these (342, 343). Additionally, 10% of individuals with acute COVID-19 infections had significant concentrations of autoantibodies that directly inhibit type-I IFN (342), but these antibodies were not found in significant concentrations in asymptomatic COVID-19 patients (343).

Like in the acute phase of COVID-19, autoantibodies in long COVID patients have been reported (344). A comprehensive multi-omics study reported the presence of autoantibodies predate SARS-CoV-2 infection and can be one of many factors predicting the incidence of long COVID ( Figure 1 ) (40). Recent multiparameter analyses of long COVID highlight the significance of specific autoantibody production as a predictor among various risk factors for long COVID incidence (40). Furthermore, persistent circulation of the SARS-CoV-2 spike protein has been reported, potentially serving as a mechanistic link to long COVID symptoms (65, 67). Another category of autoantibodies targets G-protein coupled receptors (GPCRs), which have been implicated in cardiovascular and neurological development (345). In long COVID patients, α1 adrenergic receptor (α₁ AdR), β₁ AdR, and β₂ AdR and the muscarinic acetylcholine receptors M₂ (M₂ AChR), M₃ AChR, and M₄ AChR were the most found and correlates with the severity of the neurological symptoms (345–347).

Despite these findings, available data on the humoral response during long COVID fail to provide conclusive evidence that can significantly contribute to our understanding of the pathophysiological mechanisms underlying this condition, underscoring the need for further research.

Long COVID is a newly recognized clinical condition, and numerous uncertainties persist. Consequently, investigations into this emerging condition are only beginning to uncover potential underlying mechanisms (23, 24, 65, 67, 110, 112, 266, 302, 308, 315, 316, 323, 348). Public health authorities like the CDC actively conduct short-term and multi-year studies to enhance our understanding of this condition. Available data underscores that this clinical phenomenon is intricate and diverse, affecting multiple bodily systems and exhibiting persistence over months to years in some instances, summarized in Table 1 (23, 49, 139, 151, 164, 320, 350). As mentioned earlier, the definition of persistent symptoms for the post-COVID diagnosis is crucial in discerning whether they are indicative of long COVID or if the recovery process is simply slower than anticipated. Prolonged inflammation has been proposed as a potential driver of long-term manifestations following COVID-19. Indeed, the role of sustained inflammation in developing cardiovascular, respiratory, immunological, and neurological complications after COVID-19 has been elucidated (23, 91, 110, 112, 155, 355). National healthcare systems should be understanding the likelihood that some COVID-19 survivors may transition into patients with chronic disabilities. Simultaneously, the possibility of chronically ill COVID-19 survivors potentially contributing to the emergence of novel variants of concern due to persistent viral loads necessitates careful attention (66, 71). Current evidence on the existence of different subtypes of long COVID remains inconclusive. However, two studies have progressed in subtyping this condition (339, 358). Using semantic phenotypic grouping, the first study successfully stratified the disease into six distinct groups (358). These groups exhibit unique profiles of phenotypic abnormalities, encompassing specific pulmonary, neuropsychiatric, and cardiovascular manifestations, with one group exhibiting extensive and severe symptoms correlated with increased mortality (358). The second study, employing proteomic techniques, further subclassifies long COVID into two conditions. These conditions are characterized by the presence or absence of broad inflammatory signatures indicating increased neutrophil activity and qualitative changes in memory and B cell responses (339). Characterizing and subclassifying long COVID can potentially improve the diagnosis and treatment strategies for this ailment. Therefore, long-term studies must delve into the epidemiology, mechanisms, pathophysiology, and possible management of long COVID to address this emerging crisis with the utmost diligence from healthcare institutions. Concurrently, public health organizations should formulate comprehensive management strategies that recognize the diverse manifestations characteristic of it and address its manifold consequences.

KB: Conceptualization, Writing – original draft, Writing – review & editing. BD-V: Conceptualization, Writing – original draft, Writing – review & editing. LR-G: Writing – review & editing. TR: Writing – review & editing. CR: Writing – review & editing. PG: Writing – review & editing. AK: Conceptualization, Writing – review & editing.