Multiple studies have shown that chronic fatigue is the underlying symptom in L-C19 (30–35). This led to significant interest in understanding the mechanisms and develop appropriate treatment strategies. It is known that chronic fatigue syndrome and depression are immune, oxidative and nitrosative stress-related disorders. These are significantly correlated with increased levels of inflammatory mediators such as C-reactive protein, increased aldehyde formation due to oxidative damage, increased nitric oxide production and hyper nityrosylation and low antioxidant levels (zinc, selenium, glutathione SH groups, glutathione peroxidase, total antioxidant capacity) (36). Several studies have suggested that certain vaccines such as those produced by Astra Zeneca and Pfizer may trigger the neuropsychiatric symptoms, especially somatic symptoms of Hamilton Depression and Anxiety. They concluded that these vaccines may be associated with some L-C19 symptoms such as anxiety, depression, fatigue, autoimmune response, and increased production of spike protein (36). Since fatigue is a general characteristic of L-C19, Twomey et al. suggested that measurement of fatigue level should be considered and a fatigue scale (such as FACIT-F) should be applied, especially because a validated treatment for L-C19 fatigue is not known and exercise therapy is generally not beneficial (37). L-C19 fatigue was strongly linked with comorbidities such as high blood pressure, high cholesterol, rheumatoid arthritis, diabetes, previous blood clots, cardiovascular diseases, auto immune disease. Elevated levels of anti-nuclear/extractable-nuclear antibodies are strongly correlated with higher level of TNF-α and are linked to fatigue in various diseases including chronic fatigue syndrome and rheumatoid arthritis (38). Negative psychological and social factors have also been associated with chronic fatigue (39, 40). To establish the true effects of L-C19’s chronic fatigue, it is thus necessary to identify and eliminate other common causes of chronic fatigue, such as anemia, hyperglycemia, thyroid disorders, dehydration or diabetes (41).

Cognitive dysfunction is a main L-C19 symptom occurring in approximately 70% of patients (42). The most representative symptoms are concentration difficulties, brain fog, forgetfulness, semantic disfluency, or tip-of-the-tongue (ToT) word-finding problems. According to Guo et al., chronic fatigue and neurological symptoms observed in the first three weeks of illness can be a predictive factor for cognitive disorders (43). Most of these clinical manifestations are identified in patients who experienced severe C-19 illness and were hospitalized (42). Although brain fog has been reported after ordinary upper respiratory tract infections, its prevalence is significantly higher after C19, with 17.8% prevalence 2 months following acute C19 (44, 45). Using Montreal Cognitive Assessment (MoCA) score, Alemano et al. showed that more than 80% of patients with severe C-19 developed cognitive deficits later (memory, executive function, and language). It is interesting that patients who underwent sedation and ventilation presented fewer cognitive disorders, an effect attributed to reduction of stress by sedation and/or increased oxygenation due to ventilation (46). Several mechanisms have been proposed in these neurological disorders that include neuroinflammation, aberrant immune response between SARS-CoV-2 and body antigens, residual virus particle, metabolic brain disorders, and activation of peripheral trigeminal nerve roots (47). Other factors are structural or volumetric vascularization disorders, with high blood pressure or high cholesterol. Unfortunately, these comorbidities and C19’s cognitive disorders are strongly associated with loss of grey matter within the temporal lobe which, along with reduced memory performance, may be an increased risk for neurodegeneration or dementia (48). This hypothesis was confirmed by Hugon et al. who observed abnormal hypometabolic area after cerebral FDG PET scans of L-C19’ patients. Thus, the abnormal neurological functions may be attributed to deficient brain connections between the anterior and posterior cingulate cortex. The cingulate cortex is involved in memory, emotions, depression, or action decision, and its hypometabolism have been observed in neurological and psychiatric diseases, such as Alzheimer, depression or internet gaming disorder (49). The neurocognitive and neuropsychiatric deficits change CNS immune and glial cells and the negative effect on neuronal pathophysiology is mainly due to myelin homeostasis and plasticity disturbance, hippocampal neurogenesis impairment with neurotoxic astrocyte reactivity (50). The differences in white matter were observed only three months after acute phase and completely recovered after 10 months. After 3 months, a self-recovery mechanism of neuroplasticity was observed (51). These effects were mainly observed in females, patients with respiratory problems or those who needed ICU interventions (52).

Some of the medications received in C-19 acute infection may also affect the neurological system of patients as well. Thus, the neurological side effects of drugs such as lopinavir-ritonavir and corticosteroids should be considered when assessing L-C19 effects (28). More recent studies suggested that brain fog in L-C19 patients may be caused by the presence of blood clots in the cerebral or pulmonary circulation (53) and were associated with increased serum ferritin levels during C19 hospitalization (45). Since cognitive disorders are difficult to manage and treat, many patients with cognitive impairments, require long-term psychological support and treatment. Unfortunately, cognitive dysfunction led to reduced work capacity, prolonged time of normal activities, difficult work ability, mental exertion, stress and loss of employment, thus having a severe impact on the quality of life (54).

It is one of the earliest and most common symptoms of L-C19 and it is usually accompanied by hyposmia, fatigue, dyspnea, myalgia, and cough. It is influenced by C-19 acute phase severity and the use of analgesics, genetic predisposition to migraine due to trigeminovascular system activation, and systemic immune response at viral infection (55). Without a specific clinical phenotype, the headache topography is predominantly bilateral, with frontal or periocular presence, and the pain is felt like a tension-type headache, usually without any symptoms, or migraine-type headache, accompanied by vomiting or nausea (56). The presence of headache in C-19 acute phase have been considered a positive prognosis, being associated with lower severity, lower mortality, and lower need of ICU interventions (57). Some symptoms, such as headaches, continue to persist to a significant extent in the long term. For example, 16.5% of patients continue to experience headaches after 60 days from the start of the disease, of which 8.4% reported significant headaches even after 180 days post COVID-19 (58, 59). Thus, symptoms such as headaches can persist to a significant extent even months after the onset of the disease, highlighting the importance of a holistic approach and continued research to better understand the long-term health impact of this disease.

Depression and anxiety are found in over 50% of patients with L-C19, especially due to hospitalization or cognitive disorders (60). Even if these symptoms were not identified in the first phase, they are usually found in patients with certain difficulties, being part of the long-term symptoms category. The first psychiatric sequelae were noticed 14-90 days after C-19 and the estimated probability to develop new sequelae after 90 days was 5-8%. The anxiety disorders are shown to be more prevalent than mood disorders (53). Some authors suggested that depression and anxiety may be a result of disease severity and trauma of hospitalization rather than of the viral infection (61). Due to individuality of each patient, presentation can vary which makes the treatment challenging (62) thus early diagnosis and close follow-up is critical. Unfortunately, depression and anxiety are difficult to identify since they are intrinsically related to patients’ overall health and life quality. When comparing COVID infected patients with or without symptoms of depression and anxiety, imaging tests via MRI showed atrophy of the brain areas responsible for processing emotions and memory. Thus, it is clear that the anxiety and depression caused by this virus have significant long-term consequences (63).

Sleep disorders and fatigue are the most persistent symptoms that affect the daily life of L-C19 patients (64). More than 40% of patients experienced insomnia, however, the symptoms gradually improved after 3 months. When tested with wearable health devices, L-C19 patients reported decreased total sleep and light or deep sleep time leading to related health issues (65). In some patients, sleep disturbances were present even after 12-month post C-19, with negative impact on patients’ quality of life. This, along with fatigue, altered respiratory functions, stomach burn, or abdominal pain add to the significant burden of L-C19 patients (66, 67).

Most patients seem to return to normal life after infection with C-19, but many remain with mild symptoms that are often attributed to other daily factors such as fatigue, memory problems, and loss of attention, without realizing that these symptoms may be long-term symptoms caused by C-19 infection (68). Research shows that 1 in 8 patients may receive a neurological diagnosis after C-19, even after 6 months post SARS-2 infection (69). Several biomarkers have been used to differentiate between LC-19 and other causes of cognitive disorders symptomatology; however, research thus far is relatively scarce. One promising study analyzed fibrinogen and D-dimer compared to C-Reactive Protein (CRP) levels in more than 1830 hospitalized patients and found positive correlations between cognitive impairment and COVID-19 infection (70). Subjective as well as objective cognitive deficits were analyzed, considering occupational effects. Using canonical correlation (CCA) methodology to assess associations between sets of variables, it was shown that increased fibrinogen was correlated with both objective as well as subjective cognitive deficits at 6 and 12 post COVID (70). Fibrinogen has a direct effect on blood clotting, but it also fulfils site-binding functions that could affect axon binding or even have effects that degrade the β-amyloid protein (71, 72). High levels of D-dimer were associated with subjective cognitive difficulties and occupational effects (69). An increased level of D-dimer has been associated with a risk of pulmonary thromboembolism, which may be related to poor oxygenation of the brain, with direct implications for cognitive impairment (73). Determination of cognitive impairments after C-19 infection is a complex process and requires identification of factors and mechanisms of action of different biomarkers, including correlation with brain imaging.

Smell and taste dysfunctions are the most prevalent symptoms in L-C19, after fatigue (74, 75). Anosmia was more frequent present in patients with mild C-19 forms and less reported in patients with severe C-19, eye, nose and throat complaints. Initial studies demonstrated that, in mild C-19 cases, patients might have had stronger local immunity and the virus replicated in the mucosa (76). Persistent olfactory dysfunction has been associated with poorer emotion recognition in patients who experienced mild C-19 (77). The persistence of anosmia or ageusia in L-C19 patients has been attributed to injuries in the olfactory neuronal pathways or persistence of neuroepithelium inflammation (47). However, in patients with previous mild SARS-CoV-19 infection, the 3-year prevalence and recovery rate of COVID-19-related alteration in sense of smell or taste was 5% and 92%, respectively. In patients experiencing chemosensory dysfunction still 2 years after COVID-19, a delayed complete or partial recovery has been observed even after 3 years, while some patients continue to have unchanged persistent chemosensory alteration (78). Gene expression profiling of olfactory epithelium of patients with persistent olfactory symptoms showed changes in the expression levels of miRNAs involved in neural development and immune response. Further, overexpression of metallothioneins, in response to increased inflammation of the olfactory epithelium may results in decreased zinc levels and subsequent loss of smell and taste (79). L-C19 chemosensory disfunction significantly reduces quality of life, with negative implications in mental health: anxiety, depression, loss of appetite, weight changes, even work and study difficulties or social and interpersonal limitations (80).

Among LC-19 sequelae related to the renal system were acute kidney injury or renal failure, mainly due to high abundance of pf ACE2 expression in kidneys, with declined glomerular filtration rate or kidney infarction, mainly due to thromboembolism. The prognosis is associated with significant risks of mortality or morbidity. Acute kidney injury was observed mainly in non-survivors and in 1% of survivors, with renal function restauration. Therefore, investigation tools should include early recognition of kidney functional impairments or injury through urine analysis, glomerular filtration rate, ultrasound scanning or renal biopsy (81–83).

The main gastrointestinal (GI) symptoms shown to persist even six months after C-19 acute phase are constipation, diarrhea, abdominal pain, nausea/vomiting, and heartburn. Patients who reported L-C19 anxiety or sadness were more prone to present GI symptoms (55% vs. 14%) and conversely, GI symptoms lead to anxiety/sadness (84). The possible mechanisms involve the abundance in ACE2 and furin expression, fecal-oral transmission, lymphocytic infiltrations into intestinal tissues’ lamina propria, intestinal dysbiosis, or high cytokine levels (81). Inflammation and intestinal metabolites dysfunction are influenced by nutrition, diet, malnutrition, old age or diabetes and obesity (85). Further, gut microbiota dysbiosis, GI peripheral tissue damage and altered immune status have been reported six months after the infection (86). The investigation tools should include colorectal transit observations, CT scan, defecography and swallowing studies (81).

Approximately half of patients with L-C19 reported incomplete recovery, with shortness of breath and other respiratory problems (37, 87), that included chest pain, cough, or sputum production (88). The breathing discomfort has been attributed to chronic changes in breathing pattern and persisting inflammation in lungs or mediastinal lymph nodes, as well as association of metabolic abnormalities with lung sequelae. These pulmonary vascular network abnormalities have been the cause for pulmonary hypertension and damaged respiratory reflexes due to intrathoracic receptors destruction (47). L-C19 patients developed endothelial dysfunction which, even if it had progressively improved after 6 months, the risk for thrombotic or cardiovascular events remained high. Usually, endothelial dysfunctions develop in the acute phase of the disease and were responsible for atherosclerosis. These symptoms persisted even 6-months after C-19 in 58% of patients. There was a negative correlation between IL-6 levels and brachial artery flow-mediated dilation, an effect that was improved by treatment with tocilizumab, an IL-6 inhibitor. Patients hospitalized in a medical ward recovered faster than those hospitalized in ICU (89, 90). The presence of microclots associated with insoluble inflammatory molecules, antibodies and immunoglobulins were present not only in the acute phase of C-19, but also played a critical role in the development of L-C19 symptoms and other auto-immune pathologies. For example, increased level of galectin-3-binding protein (responsible for cancer development, progression and metastasis) inflammatory markers (IFN-α, IFN-β, IFN-γ, TNF-α), trombospondin-1(increased in tumors and associated with thrombosis), α-1-acid glycoprotein-2 (associated with demyelinating diseases), and reduced levels of long palate, lung and nasal epithelium carcinoma-associated protein 1, lactotransferrin, adiponectin and α-1-acid glycoprotein-1 may be the result of immunosuppression similar to that of sepsis. Evidence suggested that if these microclots resolved in the first phase of the disease, hypoxia could be avoided. This is an important finding, especially because hypoxia led to irreversible tissue damage and can be life threatening for patients with diabetes 2 or cardiovascular co-morbidities (91). For example, fibrin amyloid microclots blocked capillaries and impeded O2 to be transported to the tissues, leading to thrombotic events, myocardial infarction, strokes, kidney disfunction, or neurological disorders. Thus, their removal could be a potential therapeutic strategy which may allow the body the possibility to self-repair (92, 93). The presence of ‘amyloid’ microclots and platelet hyperactivation has prompted some research groups to propose a triple anticoagulant therapy as a potential treatment of L-C19, though this needs to be further assessed (27, 92). Furthermore, studies showed an increase in thrombin generation in patients with L-C19 (26, 94), in line with the presence of a hypercoagulable state in these patients. Persistently raised D-dimers and sustained inflammation has also been identified in convalescing C-19 patients who were not hospitalized during acute infection (24, 95, 96). More recently, a study using microfluidic strategies to reflect the physiological conditions of the vasculature, revealed that patients suffering from L-C19 have higher thrombogenicity under flow, with increased platelet capture and larger thrombi compared to matched healthy controls. These patients had been suffering of L-C19 for an average of 23 months, suggesting that this emerging disease might cause long-term thrombogenicity. These findings were correlated with levels of Von Willebrand Factor (VWF) or ADAMTS13 activity, involved in arterial thrombotic pathologies (26). An increased VWF concentrations and decreased ADAMTS13 activity were correlated with a higher risk for myocardial infections (97). Indeed, patients with L-C19 were also found to have an increased VWF : ADAMTS13 ratio, above 1.5, which was associated with impaired exercise capacity (98, 99).

Comorbidities such as high blood pressure, high cholesterol, rheumatoid arthritis, or cardiovascular diseases can lead to respiratory system symptoms. NICE recommends that breathlessness should be auto identified through simple tolerance test exercises and blood oxygen levels with pulse oximeter. For example, Mayo Clinic suggests that smoking, pollutants and extreme temperature may contribute to L-C19 pulmonary symptoms’ persistence (39). WHO rehabilitation guidelines include precautions regarding gradual return of daily activities of L-C19 patients and recommends that physical exercise must be adapted in order to prevent fatigue and patients’ activity must be in accordance with their symptoms (98). Other L-C19 symptoms are presented in Table 2 .

All studies indicate that regardless of the severity of C-19, women are more likely to develop L-C19. Although the precise mechanisms for sex differences are not completely elucidated, the faster immune response of women, which protect them from initial infection and severity might be one important factor. Unfortunately, this makes females more vulnerable to prolonged autoimmune related diseases. Other sex differences include different sex hormones, high exposure and high psychological stress occupation. Furthermore, women have been shown to be diagnosed later than men (133) and are more likely to develop L-19 cognitive disorders, anosmia, dysgeusia, respiratory and rheumatological sequelae (134–137). On the other hand, men are more exposed to renal sequelae and endothelium disfunction (138–140). Other findings suggest that women had lower mortality and lower levels of inflammation than men (141) which may be due to the immunomodulatory effects of estradiol in females and higher antiplatelet and vasodilatory activity (142, 143). Conversely, men have higher risk of inflammation or tissue damage due to higher amount of cytokines and chemokines like IL-2, TNFα, IL-7, IL10, IL-18, CCL14, or CCL23 (144). Furthermore, it has been shown that production of IL-6 inflammatory marker is lower after viral infection in women which has been associated with a higher risk of developing L-C19 symptoms (145). In a meta-analysis study, Notarte et al. showed that females presented a higher risk of developing L-C19 symptoms such as dyspnea, fatigue, breathlessness, chest pain, palpitations, depression, sleep disorders, hair loss, ocular problems, and GI-related problems than men (146).

In pregnant women, C19 had more serious consequences in the acute phase, with premature births and even deaths among both mothers and newborns. In terms of the long-term effects of the virus on pregnant women, research shows a similarity between the symptoms of the general population and pregnant women (147, 148). For example, in their study conducted on 99 pregnant women, Zhou et al. demonstrated that 74.75% exhibited at least one symptom of L-C19 (presumably referring to a condition related to COVID-19), with the most common symptoms being fatigue, myalgia, and anosmia/ageusia (148). The same symptoms, to which difficulty in concentration and hair loss were added, have also been described by Vásconez-González et al. Most symptoms were initiated with infection (42.4%) and 3-5 weeks after infection (35.5%), which lasted between 3 and 6 months (21.2%), more than two months (18.6%) or between 4 and 8 weeks (17.8%) (149). Antenatal depression (25.2%) and antenatal anxiety (27.9%) were the most common symptoms observed in post-epidemic period among pregnant women. The prevalence of these symptoms were lower than those during pandemic, but higher than those from pre COVID period. The factors that most influenced the physiological state were psychiatric treatment history, psychological counseling before pregnancy, age, education, access to information, financial instability, trimester, pregnancy complications, number of hospital stays and poor marital relationship. Financial security and high levels of social support have led to a reduction in anxiety and depression among pregnant women (150–152).

Although C-19 is less common in children than adults, L-C19 and multisystem inflammatory syndrome (MIS-C) are long-term consequences observed in asymptomatic patients (153, 154). Like adults, adolescent girls are also more prone to L-C19 than boys (155, 156). The main L-C19 symptoms reported in children and adolescents were neuropsychiatric: mood, fatigue, sleep disorder, headache, cognition, dizziness, neurological abnormalities (pins, tremor), balance problems; cardiorespiratory: respiratory symptoms, sputum/nasal congestion. orthostatic intolerance, exercise intolerance, chest pain, rhinorrhea, cough, sore throat, chest tightness, variation in heart rate, palpitations; dermatologic/teguments: hyperhidrosis, dermatologic (dry skin, rashes, hives), hair loss; gastrointestinal: abdominal pain, constipation, diarrhea, vomiting/nausea; and other: loss of appetite, altered smell, body weight variations, myalgia, altered smell, otalgia, ophthalmologic (conjunctivitis, dry eyes), fever, changes in menstruation, urinary symptoms, dysphagia, speech disturbances (157–159).

The quality of life of children and adolescents was not as impacted by L-C19 as that of adults. A small proportion reported feeling scared and worried and experienced a lack of friendship. School absence due to ill period affected their general wellbeing and it was a disturbance factor for both children and parents (160, 161). Buonsenso et al. reported that L-C19 greatly influenced the quality of life of children that included energy level (83.3%), mood (58.8%), sleep (56.3%), appetite (49.6%) and lack of concentration (60.6%). The authors concluded that most children had worse activity level than before infection and almost half of them experienced recovery from L-C19 symptoms’ cycles with 25% of them presenting constant symptoms) (162). The treatment strategy for these children should be multidisciplinary and the conventional approaches should be accompanied by changes in dietary habits (163). It is recommended that every affected child to be monitored by a primary care pediatrician four months after C-19 acute phase to check the presence of symptoms and development of new ones. The presence of L-C19 symptoms must be immediately considered and in absence of any doubt, the visit should be rescheduled after three months (164). Children with neuropsychiatric disorders must be followed up by mental health experts, pediatricians and must be supported by family and friends (165). An important issue that should be addressed is that during the pandemic, many children without C-19 experienced similar L-C19 symptoms with those infected: headaches, fatigue, sleep disturbance, and concentration difficulties. Several studies showed that almost all symptoms reported by SARS-CoV-2 infected children were also present in patients with negative test (145, 166).

L-C19 symptoms are more prevalent in individuals with underlying diseases, such as diabetes, obesity, cardiovascular or neuropsychiatric related disorders (167). Functional impairments of one or more organs due to C-19 acute phase was also strongly associated with L-C19 symptoms. Thus, coagulation issues, reactivation of some existing viruses (i.e., herpesviruses), dysfunctional nerve signaling, or autoimmunity are considered potential contributors of C-19 sequelae (168, 169). Asthma (39, 170), hyperthyroidism (171), hyperglycemia and dyslipidemia (172) have all been considered high risks for L-C19 development at old age patients. These pathologies degrade ACE2, leading to increase activation of the ACE2 receptors, virus entry and persistence of inflammatory cytokine storm or oxidative stress (145).

Many L-C19 sequelae have been observed after C-19 patients’ hospitalization. At 6-months after hospitalization, 90% of patients presented anxiety, depression, and sleep disorders (173), and the most prevalent symptoms reported at 12 months after discharge were anxiety, dyspnea, and fatigue (174). Evidence shows that individuals hospitalized for C-19 were more predisposed to develop anxiety than those hospitalized for other causes. Furthermore, hospitalized older patients were more predisposed to memory loss or confusion (175). The symptoms attributed to hospitalization are strongly correlated with other factors or comorbidities. For example, women with obesity were more predisposed to severe L-C19 at one year after discharging due to hormonal, pro-inflammatory and metabolic state (176).

When comparing hospitalized with non-hospitalized patients, O’Mahoney et al. reported that the five most common symptoms of hospitalized patients were fatigue (28.4%), pain/discomfort (27.9%), sleep difficulties (23.5%), breathlessness (22.6%), and limited regular activity (22.3%). Other symptoms included changes in lung structure/function, ground glass opacification, fibrotic changes, and reticular patterns. The non-hospitalized patients presented similar symptoms, however, with less incidence: fatigue (34.8%), breathless (20.4%), muscle pain/myalgia (17.0%), sleep disorders (15.3%), and loss of smell (12.7%) (177). Other symptoms observed in non-hospitalized patients were pneumonia, chest pain, palpitation, diabetes mellitus, and alopecia (178).

Reinfection was defined as the presence of new C-19 symptoms that occur more than 90 days after the previous diagnosis of confirmed SARS-CoV-2 infection (179). The severity of reinfection depends on the severity of the initial episode and is strongly correlated with genetic factors particularly related to the innate immune response and pathogenicity of the specific variant. Reinfections increased the development of L-C19, but were less identified in mild or asymptomatic patients, children and adolescents (180, 181). The most vulnerable to reinfections were healthcare workers who have been predisposed to C-19 infection since the beginning of the pandemic. The most frequent reported symptoms of L-C19 were asthenia (14.2%), cough (8.9%), myalgia (3.0%), dyspnea (2.0%), anosmia (1.8%), concentration deficit (1.5%), and headache (1.4%). When there were two symptoms, fatigue was always one of them. Other symptoms were related to gastroenteric and pulmonary dysfunctions. The most persistent symptoms were those related to neurological (23.3%) and psychological symptoms (18.2%), even after 61 days since the first negative swab (182). Reinfections of healthcare workers led to mild L-C19 symptoms, since most were younger than 65 (179).

In addition to host factors such as immunity status, comorbidities, vaccination status etc., Long COVID is also influenced by the virus, including strain/variant (180). Therefore, it is important to distinguish between long COVID infections with the wild type virus and subsequent variants. For instance, a significant decrease in cardiac symptoms, such as chest pain and palpitations were observed during Variant of Concern (VOC) infections periods, compared with wild-type virus infections. This decrease was sufficiently robust in adjusted statistical models, suggesting that this change occurred as a result of different infecting variants. However, the broad spectrum of symptoms belonging to either musculoskeletal or cardiorespiratory symptom clusters was similar in both wild-type and VOC infections, though more studies with higher number of observations/patients are needed to confirm the effects (183). Other studies reported differences in clinical symptoms between viral variants. For instance, most severe symptoms were observed in wild-type, during early waves of COVID, when most symptoms affected upper respiratory and central neurological systems, while anosmia, abdominal symptoms and a vast array of other symptoms were observed in alpha and delta variant infections (184). Similar findings point to the fact that wildtype SARS-CoV-2 infections had the highest post COVID condition (PCC) risks, with 6.44 times higher than subsequent variants. It has been suggested that previous natural infections, rather than vaccination, reduced the PCC risk, implying that natural immunity does not wane and is efficient for protection, including post COVID conditions. Another explanation is the possibility that individuals who did not develop PCC after the first infection, have specific traits that lower the risk of developing the condition after subsequent infections (185). The later variants, such as Omicron or Epsilon, were associated with reduced risk of developing long COVID (186). The fact that initial infections, due to more virulent strains such as the original Wuhan strain and the Alpha variant, are associated with a higher risk of long COVID may be due to an erratic and overwhelmed immune response following SARS-CoV-2. Thus, the possibility of developing severe symptoms is more likely. Also, the immunity status developed due to previous infections could play a role. However, factors such as vaccination, subsequent infection waves or social influences, such as post-traumatic stress disorder, physical inactivity, and lack of exercise during lockdowns may have confounded reports of emotional or cognitive symptoms, which may not be a true reflection of post-C OVID conditions (187). Notwithstanding, there is a general consensus that large cohort studies are needed to better discriminate between the factors leading to post COVID occurrence.

Several studies have shown that more than half of the vaccinated individuals have fewer symptoms than those who were not immunized by vaccination (188, 189). The most notable differences were observed in fatigue, brain fog, myalgia, and shortness of breath. It seems that these differences were strongly correlated with vaccine type. In their study on 812 L-C19 vaccinated participants, Strain et al. showed that the average symptoms score was greatly improved after vaccination with Astra Zeneca/Oxford vaccine being more efficient only for the fever. The mRNA Moderna vaccine was the best in reducing fatigue, brain-fog, myalgia, gastro-intestinal symptoms and autonomic dysfunction of L-C19. The average symptoms improvement score was 22.6% after Astra Zeneca/Oxford vaccine, 24.4% after the Pfizer/BioNTech vaccine, and 31% after Moderna vaccine. The authors concluded that mRNA Moderna and Pfizer vaccines presented more advantages compared to the modified adenoviral vector vaccine from Astra Zeneca (190). A similar pattern was observed by Notarte et al. in their meta-analysis of the effect of vaccination against L-C10 symptomatology. In addition, the latter study reported that two doses of vaccine were more effective to reduce the risk of L-C19 than a single dose, which was in line with other studies (191, 192). The time of vaccination was also very important, suggesting that individuals who were vaccinated a month before getting infected had reduced risk of experiencing L-C19 symptoms (193). By contrast, Ayoubkhani et al. showed that L-C19 symptoms decreased after the second dose of vaccine, regardless of the type and the time of immunization. If after the first dose, the loss of smell and taste, and trouble sleeping were reduced, after the second dose, the main decrease were observed for fatigue and headache (194). The incidence rate for L-C19 was lowest in individuals vaccinated with the third dose and the symptoms were more persistent in infection with delta and omicron SARS-CoV-2 variant (195–197). Norway national health care programs suggested that vaccination should be considered especially for non-hospitalized patients who experienced mild C-19 because they did not completely recover even eight months after infection (198). Similar results have been reported by Yelin et al. who concluded that almost 60% of individuals with mild or moderate C-19 experienced L-C19 symptoms, with difficulties in returning to the previous way of life (199). Irrespective of the type of vaccine and number of doses, the immunized patients presented an overall improvement in L-C19 symptoms, especially fatigue, breathless or insomnia, quality of life and wellbeing (200, 201).

The lifestyle before the acute C-19 phase is also important in the development of symptoms associated with L-C19. For example, L-C19 symptoms were common in smokers and in individuals who worked from home and used car or public transportation instead of walking or cycling (202). This was also confirmed by Wright et al. who showed that physical activity improved mental health and improved quality of life, although it increased fatigue. These results are in line with NICE recommendations that limits graded exercise therapy due to the possibility of symptoms worsening (203). Air pollution has also been associated with L-C19 symptoms’ persistence with patients’ exposure to pollutants being strongly correlated with increased levels of inflammatory cytokines and proteins. Furthermore, the virulence was higher in air polluted areas, with adverse effects on respiratory diseases (204).