COVID-19 is a multisystem disease with severe symptoms following infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With the spread of COVID-19, some symptoms persist beyond recovery from the acute stage and become chronic (1,2). Symptoms following illness due to COVID-19 (sequelae) include both those that persist from the period soon after COVID-19 was contracted and new symptoms that appear after recovery. These symptoms continue despite the disappearance of infectiousness following COVID-19. A Delphi consensus has been used as a definition of long COVID (LC) as a post-COVID-19 condition. According to this consensus definition, LC is a post-COVID-19 condition that occurs in individuals with SARS-CoV-2 infection, usually 3 months from onset, with symptoms that last for at least 2 months with no other explanation (1). These symptoms include, but are not limited to, disorders of the respiratory, cardiovascular, musculoskeletal, skin and nervous systems, and LC is considered a multisystem disease with a wide range of symptoms. In reports to date, the percentage of patients with post-COVID symptoms has been considered to range from 10% to ~60% (3-6).

Typical LC presents with fatigue/malaise, joint pain, myalgia, cough, sputum, dyspnea, chest pain, alopecia, memory disorders, loss of ability to concentrate, headaches, depressed mood, olfactory disorder, dysgeusia, palpitations, diarrhea, abdominal pain, sleeplessness, muscle weakness and skin rash. Previous studies have noted that LC may severely affect the daily lives of affected individuals (2-5,7-9). The precise pathogenic mechanisms of the condition are not yet fully understood; however, multiple factors, such as direct organ damage, autoimmune reactions, inflammatory reactions and mental disorders from SARS-CoV-2 infection, appear to be involved (10).

Reports of post-COVID-19 symptoms are increasing globally; however, survey results differ greatly depending on differences in settings for the patient population, including patient background, particularly the presence or absence of a definitive diagnosis, the age of the infected person, the severity of the disease, and whether they are inpatients or outpatients. Bias may also occur, for example, in data collection methods. Differences may also arise from the COVID-19 infection strain. The omicron strain is generally considered to have fewer sequelae than earlier strains (11-14).

Moreover, the weakness that is sometimes observed following the treatment of severe acute diseases not limited to COVID-19, underlying conditions from before a person became ill with COVID-19, and the mental and physical effects from changes in lifestyle due to the pandemic may render the clinical picture of post-COVID-19 symptoms more complex and difficult to analyze (15).

In general, a number of these post-COVID-19 symptoms tend to improve with time (16); however, the transition of these symptoms over a long-term period, the extent to which there are differences from the different infecting strains, and the exact risk factors involved in the development of post-COVID-19 symptoms are not yet fully understood.

In the present study, to clarify the actual incidence of and risk factors for LC in patients with COVID-19 with both pre-omicron variant and omicron variant in the community, and to establish strategies for the prevention of LC, a questionnaire survey of patients with COVID-19 in multiple facilities, including a regional hospital and associated clinics, was conducted.

In the present study, a questionnaire survey of community-dwelling patients with COVID-19, including patients admitted to the hospital and those observed as outpatients in multiple institutions, was conducted. The prevalences of symptoms and sequelae were investigated, comparing cases that occurred during the omicron epidemic period (omicron group) and those that occurred earlier (pre-omicron group).

Of the symptoms at onset, there were significantly more cases of sore throat in the omicron group and significantly more cases of dysgeusia and olfactory disorder in the pre-omicron group. In a previous study, loss of smell and infiltration of the lower respiratory tract were less common in participants infected during the omicron pandemic than in those infected during the delta pandemic (20). In addition, sore throat was known to have been more common in patients during the omicron pandemic than during the delta pandemic. Furthermore, the hospitalization rate was reported to have been lower during the omicron period than during the delta period (20). The omicron variant is also markedly more transmissible than previous variants; however, in groups that have been vaccinated, the severity has been shown to be lower (21). A similar finding was observed in the present study. These findings suggest that different SARS-CoV-2 subtypes have different associations with symptoms and severity, and they also affect the frequency of LC (15).

In line with the definition of LC, in the present study, sequelae of some kind were confirmed in 37% of the pre-omicron group and 12% of the omicron group at 3 months. As for the prevalence of LC, there is a possibility of a lower risk of developing LC symptoms when infected with the omicron strain than when infected with the delta variant or other earlier variants (7,11,15). However, it should be noted that these studies were historical case-control studies.

The results of the present study are in agreement with these reports. That is, in the area in which the study was conducted, initial symptoms and the frequency of LC were low during the omicron pandemic. Of the LC symptoms, numerous patients experienced fatigue in particular; this was observed in >10% of patients in the pre-omicron group, and in only ~3% of the omicron group. A number of other symptoms, for example, loss of concentration, dyspnea, muscle weakness and memory loss, had lower frequencies in the omicron group; however, the frequencies of alopecia and olfactory disorders in particular were markedly lower in the omicron group. In previous studies as well, tiredness and fatigue were the LC symptoms with the highest frequencies (15,22-25). Fatigue is observed at even 100 days following the initial symptoms of acute COVID-19. Moreover, in syndromes, such as acute respiratory distress syndrome, it has been observed that more than two-thirds of patients report clinically significant fatigue symptoms after 1 year (3,26). The symptoms observed in patients who have suffered from COVID-19 are considered to resemble those of chronic fatigue syndrome, and exacerbations of severe incapacitating fatigue, pain, neurocognitive disability, compromised sleep and symptoms suggestive of autonomic dysfunction are also observed (3,27). The etiology of neuropsychiatric symptoms in patients with COVID-19 is complex and multifactorial. These symptoms may be related to the direct effect of the infection, as well as to cerebrovascular disease (including hypercoagulation) (3). In fact, the loss of concentration, memory disorder, sleeplessness, depressed mood and various neuropsychiatric symptoms were also reported in the present study, and measures for their diagnosis and treatment are desired.

The question remains regarding which types of patients are at a high risk of developing LC. In the present study, underlying disease, the number of vaccine doses (≤1), oxygen administration and hospitalization were related to the risk of developing LC. By age, the highest numbers of patients were in their fifties. In previous studies, an older age, the female sex, a high body mass index, complications, hospital admission or a large number of symptoms in the acute stage and disease severity were identified (4,9,10,24,28-29). In a previous study on adults in the UK, the female sex, an older age, obesity, smoking, vaping, hospitalization with COVID-19, poverty and being a healthcare worker were associated with a higher probability of persistent symptoms following COVID-19 infection (30). An Asian ethnicity was associated with a lower probability (30).

In the present study as well, which is considered to reflect the infection status in a region in Japan, the risk of LC was similarly increased with more severe symptoms in the early stage. This suggests that attention should be paid to LC in individuals with factors for more severe disease and patients with severe symptoms in the early stage. The risk of developing LC was also higher in patients with the underlying diseases, such as hypertension, diabetes mellitus, hyperlipidemia, bronchial asthma, emphysema, chronic kidney disease, hypertension and rheumatoid or collagen disease. These are also factors related to a greater severity of COVID-19(31), and they are considered to be related to LC.

Suggested mechanisms for LC include direct tissue damage from SARS-CoV-2 infection, constitutive inflammatory responses including autoimmunity and microvascular coagulation disorders with endothelial dysfunction (2,32). In addition, SARS-CoV-2 is neurotropic, and viral RNA and protein can be detected persistently in multiple organs including the brain, suggesting deep involvement in the pathology (33,34). The consideration of LC as a systemic disease, in addition to viral eradication in the early stage, and the handling of immune and coagulation disorders may also be required.

Individuals with a history of ≥2 vaccine doses in the present study had a lower risk of developing LC. In fact, this is supported by evidence which indicates that vaccination prior to infection lowers the risk of developing LC (35). Individuals who have had two vaccine doses have also been reported to have a significantly lower likelihood of developing long-duration symptoms (≥28 days) than unvaccinated individuals (10). In individuals who are vaccinated prior to acute infection or after infection, the risk of LC symptoms, such as sleeping disturbances, myalgia, renal injury and cognitive deficits has been reported to be lower with vaccination, and there is increasing evidence to suggest that lasting improvements are observed following a second vaccine dose (10,36). These findings suggest that vaccination contributes to mitigating the development of LC and symptoms; however, further clinical research on the effects of vaccination is required.

In addition to vaccines, the control of underlying disease symptoms is also considered to be critical in preventing LC. Early antiviral therapy has been reported to be associated with a decreased risk of developing LC, associated hospitalization and mortality. Therefore, early antiviral therapy is recommended for individuals who are at risk (37,38).

The present study has several limitations and biases, which should be mentioned. These include the fact that there are two methods of data collection, the fact that the infecting strain was determined according to the time of infection, the fact that the effect of treatment was not taken into account, the relatively low response rate, the non-response bias, and the fact that the accuracy of the answers was not guaranteed. Furthermore, the sample size may not have been sufficient to reach conclusions regarding the risk of developing LC. It was also not possible to objectively evaluate each symptom.

In conclusion, in the present study, a questionnaire survey of Japanese community-dwelling individuals who had been ill with COVID-19 was conducted. LC was found in >10% of the omicron group, although this was lower in patients in the pre-omicron group. These results demonstrate that this could have a notable impact on healthcare in the community. Risk factors for LC were found to include disease severity in the acute stage and underlying diseases, especially pulmonary diseases. Research on this topic is associated various issues in terms of methodology, and there is marked variability between studies in risk factors, definitions, follow-up duration and other matters. However, a notable number of patients require long-term care following infection even with the omicron variant. Clinically, it will be crucial to establish a medical strategy by predicting the progression to LC based on the background characteristics of patients with COVID-19.