A cross-sectional, multicenter survey of Long COVID prevalence and risk factors

To date, only one small survey has investigated the actual status of the sequelae of Long COVID or COVID-19 in the Japanese population.¹⁹, and Long COVID is misunderstood in Japan. Additionally, to our knowledge, only a few studies have conducted a large-scale, global investigation of the sequelae of COVID-19, and no study has examined risk factors for each persistent symptom separately. We assessed the duration and severity of each persistent symptom; and identified sequelae that have long-term effects on quality of life.

Among the study participants, 56.1% had one or more sequelae at the time of completing the questionnaire, approximately 1 year (median) after infection. According to an Italian report, 87.4% of infected people had one or more sequelae 2 months after infection¹⁶. Similarly, a Chinese report suggested that some symptoms persisted in 76% of infected people 6 months after infection.¹⁸. Given the long duration of symptoms in our study compared to those studies, a slightly lower prevalence of sequelae may be reasonable. If symptom severity is not taken into account, even > 50% of participants infected with mild COVID-19 have one or more sequelae (table 2). Moreover, the prevalence of Long COVID was similar in the Mild and Severe groups, showing that Long COVID does not depend on the initial disease severity. The distribution of symptoms differed between the acute phase and 1 year after infection. This trend was similar regardless of COVID-19 severity. By comparing the distribution of sequelae at the time of answering the questionnaire in the Mild group, the Severe group and overall, the distribution was similar; fatigue, alopecia, concentration problems, memory problems, and insomnia persisted in ≥ 10% of participants. In a previous report, fatigue, cough, red eyes, and dyspnea were observed in >30% of participants 2-3 weeks after onset of COVID-19¹⁵. Similarly, in a survey conducted 4 to 8 weeks after the onset of COVID-19, fatigue, dyspnea, post-traumatic stress disorder (PTSD), anxiety and depression, and problems concentrating persisted in > 30% of patients in the intensive care unit and headquarters¹⁷. Additionally, in a study of patients 6 months after onset of COVID-19, fatigue was the most common persistent symptom, persisting in ≥60% of participants, and sleep disturbance and alopecia persisting in ≥ 20% of participants¹⁸. Consistent with previous studies^16,22,23, fatigue was the most common persistent symptom in our study. Other symptoms varied between studies – they could be influenced by time of study, epidemic strain of SARS-CoV-2, and ethnicity.

Regarding the effects of each persistent symptom on quality of life, we considered the symptom severity score of 3 to 4 to be the most influential. In the mild and severe groups, many participants had severe symptoms of alopecia, trouble concentrating, memory problems, insomnia, and joint pain (Supplementary Tables S2 and S3). Symptoms that were strongly exhibited in the Mild group were also strongly exhibited in the Severe group. Additionally, in the severe group, persistent cough, sputum production, fatigue, dyspnea, lack of appetite, red eyes, and diarrhea affected quality of life. Thus, a more severe COVID-19 is associated with a greater diversity of sequelae affecting quality of life.

Moreno-Perez et al.²² analyzed the risk factors for the sequelae of COVID-19 and did not detect any significant risk factors. This may be because investigators did not consider risk factors separately for each symptom. Therefore, we analyzed the factors related to each persistent symptom. Persistent sputum production and dyspnea were strongly related to COVID-19 severity (Fig. 3). Additionally, although the OR was low for cough, it was one of the most common respiratory symptoms of COVID-19 and was associated with disease severity. The higher the severity of COVID-19, the greater the organic damage to the lungs, and the severity may be strongly associated with these respiratory sequelae. According to previous studies, more severe COVID-19 is associated with decreased residual air volume and diffusivity¹⁸. In addition, people with dyspnea have low forced vital capacity, low forced expiratory volume in 1 s and carbon monoxide diffusing capacity, as well as restrictive ventilation patterns.²⁴. Greater severity and severe acute organic lung injury may result in persistence of respiratory symptoms. Besides respiratory symptoms, chest pain, sore throat and diarrhea were strongly associated with the severity and sequelae of COVID-19. Association between gastrointestinal symptoms and COVID-19 may be due to disturbances in the immune system and gut flora²⁵and diarrhea has previously been reported to be associated with severity of COVID-19²⁶. Patients with more severe COVID-19 may develop sequelae due to long-term activation of the immune system and disturbances in the gut flora. Myocardial inflammation has been reported to persist for up to 71 days after COVID-19 and may be associated with long-term chest pain²⁷. It is not known if the sore throat is caused by Long COVID. Therefore, further research is needed to explain the direct causal relationship between diarrhea and sore throat as sequelae and severity of COVID-19.

Fatigue, dysgeusia, anosmia, alopecia, and insomnia as sequelae were not related to COVID-19 severity. It has previously been reported that fatigue is not associated with the severity of COVID-19²⁸. Thus, people such as young people, people without underlying disease, vaccinated people and those with a history of COVID-19 may experience these sequelae, although they are at low risk of developing severe disease. Therefore, prevention of infection is important until treatment is available for the specific sequelae of COVID-19.

In the context of recovery time from symptoms of fatigue, alopecia and insomnia, it was observed that many patients (more than 50%) did not recover from their symptoms even after ≥ 1 year of infection with SARS-CoV-2. These symptoms were not related to the severity of COVID-19, suggesting that even mildly ill people can experience sequelae over a long period. Therefore, attention should be paid to the sequelae of the Omicron variant of SARS-CoV-2, which was dominant in 2022 and is considered highly infectious and mildly severe.^29,30,31.

Our study has certain limitations. First, it was a cross-sectional study; thus, the time from disease onset to investigation varied among patients, and patients may have been infected with different virus strains or variants. We were unable to search for the infecting strain in each patient. Second, selection bias could affect the participant’s willingness to participate, and recall bias may be involved in the severity of sequelae symptoms.³². People with long COVID are more likely to participate in questionnaire studies of COVID-19 sequelae. Conversely, people without sequelae are more likely not to be interested in the study and, therefore, not to have participated. Additionally, we may have overestimated the prevalence of COVID-19 sequelae. Memory and recall accuracy may also vary between participants for acute symptoms. Finally, although we have obtained new findings on the risk factors for sequelae of COVID-19, it is difficult to propose countermeasures to prevent sequelae of COVID-19 in addition to infection prevention and control.

In conclusion, this study revealed a high prevalence of sequelae approximately 1 year after COVID-19. Fatigue, dysgeusia, anosmia, alopecia, and insomnia as sequelae of COVID-19 can affect quality of life even in people with asymptomatic or mild disease, and sequelae are prolonged . Thus, prevention of COVID-19 is important even in people who are not at risk of severe disease.