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Original article

Factors associated with the subjective feeling of fatigue three months after COVID-19

Dejan Mihajlović1,2, Mirjana Virijević2, Ana Radovanović2
  • University of Priština with a temporary seat in Kosovska Mitrovica, Faculty of Medicine, Kosovska Mitrovica, Serbia
  • Health Center "Kosovska Mitrovica", Kosovska Mitrovica, Serbia

ABSTRACT

Introduction: The subjective feeling of fatigue is one of the most common post-COVID-19 manifestations. It is characterized by intolerance to physical and cognitive effort that the individual previously tolerated well, accompanied by weakness and other symptoms.

Aim: The aim of this study was to examine the frequency of the subjective feeling of fatigue, three months after recovery from the infection, amongst patients who had been infected with COVID-19, as well as to analyze correlated factors.

Methods: This cross-sectional study included 110 patients who had previously contracted COVID-19, and who came for a regular follow-up examination at the Health Center Kosovska Mitrovica, 3 months after recovery from acute infection. A specially designed questionnaire was used, which consisted of the segment with sociodemographic data, the segment with the data on the patient’s health status and the course of their COVID-19 infection, as well as the segment of the questionnaire related to self-assessment of the patient’s health status after the COVID-19 infection.

Results: In our sample, out of 110 respondents, as many as 52 felt fatigue. Factors that were statistically significantly associated with the subjective feeling of fatigue, three months after treatment, were the age of the subject and the presence of chronic disease (p < 0.05). The presence of fever and pneumonia during infection were statistically significantly associated with the presence of the subjective feeling of fatigue, three months after treatment (p < 0.05). Hospitalized patients and those who were hospitalized for a longer period of time were also more likely to feel fatigue three months after recovering from the infection (p < 0.05).

Conclusion: The subjective feeling of fatigue, as one of post-COVID manifestations, as well as the consequent inability of the patient to resume work-related and personal tasks and responsibilities, can be a serious individual and public health problem, which is why it is necessary to appropriately recognize and treat it.


INTRODUCTION

In December 2019, in the city of Wuhan, in China, a new coronavirus strain emerged. It was named SARSCoV-2, and it spread very quickly to almost all parts of the globe [1]. The emergence of this virus brought the world into the state of a new pandemic, caused by a virus of which little was known [2]. At the beginning, COVID-19 was categorized as: mild, moderate, severe, and critical cases, and later, asymptomatic patients were added to this categorization, and they have proven to be of great significance in virus transmission [3].

As time went by, the symptomatology of the virus changed, but the symptoms that remain characteristic of this infection are as follows: elevated body temperature, weakness, malaise, cough, myalgia, as well as loss of the sense of smell and taste. Amongst nonspecific symptoms, the ones most commonly present are gastrointestinal symptoms [4]. Pneumonia was the most common cause of hospitalization; due to the unpredictable course it may take [5].

For certain patients, recovering from acute COVID-19 infection was just one step towards complete recovery. We have witnessed a variety of possible complications, precisely due to the heterogenous clinical presentation of the disease. This is why the term post-COVID-19 syndrome, or long COVID, which entails a cluster of physical and psychological symptoms, was introduced [6]. It is believed that prolonged inflammation plays a significant role in the pathogenesis of neurological, cognitive and many other symptoms [7].

Fatigue occurs as a frequent complication within long COVID, but also in other viral infections. Fatigue is characterized by intolerance to effort, with the presence of pathological fatigue which does not pass after rest, weakness, and other symptoms, exacerbated by physical or mental strain, at intensities previously well tolerated by the individual [8]. Etiopathogenesis of chronic fatigue has as yet not been sufficiently elucidated. It is believed that proinflammatory cytokines – interleukin-1 and interferon alpha, play a significant role [9],[10].

What is certain is that the subjective feeling of fatigue greatly impacts the everyday life of the individual to such an extent that the person may spend most of their day in bed, unable to function normally [11],[12].

The aim of the paper is to analyze the frequency of the subjective feeling of fatigue, three months after acute infection, in patients who had had COVID-19, as well as to examine correlated factors.

MATERIALS AND METHODS

The research was carried out as a cross-sectional study, in the period between May and June 2021. The study included patients who came in for a regular follow-up examination to the Health Center Kosovska Mitrovica, three months after recovering from acute COVID-19 infection. The follow-up examinations had been scheduled according to the assessment made by the physicians treating the patients during the infection, based on clinical presentation in the acute phase of the disease. Bearing in mind that, in our region, the period with the highest incidence of the infection was between February and March 2021, the study was performed three months after acute infection, at scheduled follow-up examinations.

The inclusion criteria for the study were the following:

  1. Adult respondents
  2. COVID-19 diagnosis confirmed with a positive PCR test during the acute phase of infection
  3. Follow-up examination scheduled by attending physician during treatment of the COVID-19 infection.

The exclusion criteria for the study were the following:

  1. Testimony of the patient that in the period of February – May 2021 they had had symptoms of the COVID-19 infection, which was not confirmed with a PCR test
  2. Patients who had COVID-19 after March 31, 2021
  3. Patients declining to enter the study. (There were no such patients).

All patients were informed that the results of the study would be used exclusively for research purposes and that, at any moment, if they chose to do so, the patients could withdraw from participating in the study. After receiving information related to the questionnaire, all of the patients gave their written consent to be included in the research process. After the follow-up examination had been completed, the patients filled out the questionnaire on their own.

A questionnaire specially designed for this study was used. It consisted of 18 questions divided into three sections. The first section consisted of 7 questions, which related to sociodemographic data (age, sex, place of residence, education level, employment status, smoker status, alcohol intake). The second section of the questionnaire related to the health status of the respondent and consisted of 4 questions, which were in relation to the following: whether the patient suffered from any chronic illness; if they did, which diseases these were; whether the patient was on any drugs and which ones. The third section of the questionnaire consisted of 5 questions on COVID-19. Within this section, the respondents were asked to state the COVID-19 symptoms they had experienced; whether they had had pneumonia; whether they had been hospitalized; and if so, what was their length of stay, as well as which therapy they had been treated with.

The last section of the questionnaire was made up of two questions related to fatigue.

  1. In the previous three months have you felt fatigue that did not pass after sleep and rest?
  2. Has the fatigue prevented you from performing everyday duties?

The study was approved by the Chair of the Hospital Ethics Committee (Decision No. 4866/21). Descriptive statistical methods were used for data analysis, as were methods for testing statistical hypotheses. The following descriptive statistical methods were applied: arithmetic mean, median, range (min - max), absolute and relative numbers.

The chi-square test was used for testing the hypothesis on the difference in frequency. Of the nonparametric methods for data deviating from the normal distribution, the Mann-Whitney U test, i.e., Rank Sum Test, was used. The criterion of statistical significance was p < 0.05.

The SPSS Statistics 22 software was used for statistical processing of the results.

RESULTS

The study included 110 patients, aged 21 – 72 years. The average age was 48.2 ± 14.1 years. Of the total number of patients, 54 (49.1%) were male, while 56 (50.0%) were female.

The subjective feeling of fatigue, three months after recovery from acute COVID-19 infection, was felt by as many as 52 respondents, which makes up for almost half of the sample (48,0%) (Figure 1).

03 01

Figure 1. Frequency of the subjective feeling of fatigue in patients who had had COVID-19

Sociodemographic variables, such as: sex, place of residence, marital, employment, and smoker status, alcohol intake, did not show statistically significant association to the occurrence of the subjective feeling of fatigue, three months after recovery from acute COVID-19 infection, which is shown in Table 1.

Table 1. The effect of sociodemographic variables on the occurrence of the subjective feeling of fatigue

03 02

Of the sociodemographic variables, only the respondent age demonstrated statistical significance in relation to the feeling of chronic fatigue. The median age of the respondents experiencing fatigue was 59 years (range 34 – 76 years), while, for those who did not experience fatigue, the median age was 42 years (range 21 – 78 years). Subjects experiencing fatigue were statistically significantly older than those who did not experience fatigue (p = 0.004) (Figure 2).

03 03

Figure 2. Effect of age on the subjective feeling of fatigue

In the second section of the questionnaire, which contained questions related to health status and data on the COVID-19 infection, the factors that were statistically significantly associated with the feeling of fatigue were the following: chronic diseases, elevated body temperature as a symptom of acute infection, pneumonia, hospitalization, as well as the length of hospital stay.

The frequency of chronic diseases in patients who experienced fatigue was 38 cases (73.1%), while it was 20 cases (34.5%) in the group of patients who did not experience fatigue.

The subjective feeling of fatigue, three months after recovering from the infection, was statistically significantly more frequently present in subjects with chronic diseases (p = 0.004) (Table 2).

Table 2. The effect of health status and the characteristics of the COVID-19 infection on the occurrence of the subjective feeling of fatigue

03 04

In the group of patients with the subjective feeling of fatigue, three months after COVID-19, as many as 40 (76.9%) of them had elevated body temperature during the acute infection, while in the group of patients who did not experience fatigue, 28 (48.3%) of them had the same symptom. Elevated body temperature in the acute phase of COVID-19 was statistically significantly more frequent in the category of patients experiencing fatigue three months after recovering from acute COVID-19 (p = 0.029) (Table 2).

In the acute phase of disease, 26 (50%) patients with the subjective feeling of fatigue, three months after recovering from acute COVID-19, had had pneumonia, while in the group of patients not experiencing fatigue, 10 (17.2%) patients had had pneumonia.

The subjective feeling of fatigue, three months after recovering from acute COVID-19, occurred statistically significantly more often in the category of patients who had had pneumonia in the acute phase of the disease (p = 0.010) (Table 2).

In the group of patients with the subjective feeling of fatigue three months after recovery from acute COVID-19, 24 (46.2%) patients had been hospitalized, while in the group of patients without this symptom, only 8 (13.8%) patients had been hospitalized.

The subjective feeling of fatigue occurred statistically significantly more often in the category of patients who had been hospitalized during acute COVID-19 infection (p < 0.008) (Table 2).

In patients who experienced fatigue, the median length of hospital stay during acute COVID-19 infection was 15 days (range 9 – 21), while in patients who did not experience fatigue, the median hospital stay was 5 days (range 3 – 6). The subjective feeling of fatigue, three months after recovery from acute COVID-19, occurred statistically significantly more often in respondents who had been hospitalized longer (p = 0.012) (Figure 3).

03 05

Figure 3. Analysis of the effect of the length of hospital stay on the occurrence of the subjective feeling of fatigue

Statistically significant association was not found between the feeling of fatigue and vitamin supplementation (p = 0.378), nor was it established between the feeling of fatigue and the loss of the sense of smell and taste (p = 0.352) (Table 2).

DISCUSSION

According to data found in literature, around 10% – 30 % of patients worldwide exhibit signs of prolonged illness after acute COVID-19 infection and long after a negative COVID-19 test [13]. As stated in the results, fatigue was experienced by almost half of the respondents. The results related to the incidence of chronic fatigue are different from study to study, and range from 35% in the American study, to 53% in the Irish study, to as many as 87% in the Italian multicentric study, carried out two months after the acute phase of the disease [14],[15],[16].

The largest follow-up study, carried out by Huang et al., which included more than 2,000 subjects, showed that 63% of the respondents felt fatigue [17], which is somewhat more than in our study. In the same study [17], age, as well as existing chronic diseases, showed significant association to the occurrence of the subjective feeling of fatigue, which is in keeping with our results. The results of an American multicentric study, involving a population of 582 subjects, showed fatigue to be the symptom that was most commonly present in the 35 – 49 age group, while, in our study, the incidence of fatigue rose with age. According to our results, elevated body temperature, pneumonia, hospitalization, and length of hospital stay were significantly associated to the occurrence of this symptom, three months after recovery from acute infection.

In their study carried out by telephone conversations with patients, 30 and 60 days after initial infection, Carvalho-Schneider et al. obtained results that an auscultatory finding indicating pneumonia as well as hospitalization were associated with the presence of the feeling of fatigue, 60 days after initial infection [18]. Also, through multivariate regression, a cross-sectional study conducted last year in Norway obtained results indicating that the presence of a greater number of symptoms during acute infection was a positive predictor of the occurrence of fatigue [19]. A systematic meta-analysis, which included around 40 studies, also indicated similar results, but, at the same time, it showed the heterogeneity of results, due to the differing study designs, different samples in different time intervals, and different modes of obtaining results (through questionnaires, insight into patient histories, and through telephone conversations). Heterogeneity is also present due to the use of various validated and non-validated questionnaires [20].

The limitation of our study is reflected in the short follow-up period, which does not allow for generalization of data so as to apply to all patients who had suffered from COVID-19. In future research, it is necessary to lengthen the time of research and consequently increase the number of subjects, in order to confirm or supplement the findings from this study. The best solution would be to carry out a methodologically well-designed cohort study which would determine other symptoms in the post-COVID period, but also overcome the limitations typical of cross-sectional studies.

Just like other cross-sectional studies, this study also lacks the capacity to demonstrate cause-and effect relationships, merely correlation. The findings from this study may be used merely as a reference for future similar studies. In further research, other factors potentially associated with fatigue need to be excluded, i.e., their confounding effect must be taken into consideration before conclusions are drawn.

Also, a very frequent limitation in questionnaire-based studies is the issue of understanding the questions, as well as the issue of motivation for providing candid answers, which is why there is a possibility of bias, in the sense of exaggerated or insufficient feedback. The questionnaire in our study was not standardized, as this was a pilot study, whose purpose was to correct the flaws and weaknesses of the items themselves, as well as the method of questionnaire distribution. Nevertheless, a high percentage of patients experiencing a subjective feeling of fatigue, three months after recovery from acute COVID-19 infection, is a testimony of the significance of this study.

CONCLUSION

The subjective feeling of fatigue is present in a high percentage of subjects, not only in our study, but in other studies as well. This symptom is connected to age, chronic diseases, elevated body temperature, pneumonia, hospitalization, as well as to the length of hospital stay, during the acute phase of the infection. The subjective feeling of fatigue, three months after recovery from acute COVID-19, as a frequent post-COVID manifestation, as well as the consequent inability of the patient to return to their work-related and personal tasks and responsibilities, may represent a serious public health problem, which is why it is necessary to appropriately recognize and treat the subjective feeling of fatigue.

  • Conflict of interest:
    None declared.

Informations

Volume 3 No 1

Volume 3 No 1

March 2022

Pages 26-34
  • Received:
    22 November 2021
  • Revised:
    05 January 2022
  • Accepted:
    23 February 2022
  • Online first:
    14 March 2022
  • DOI:
Corresponding author

Dejan Mihajlović
Faculty of Medicine, University of Priština with a temporary seat in Kosovska Mitrovica
15/11 Čika Jovina Street, 38210 Kosovska Mitrovica, Serbia
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.


  • 1. Ahn DG, Shin HJ, Kim MH, Lee S, Kim HS, Myoung J, et al. Current Status of Epidemiology, Diagnosis, Therapeutics, and Vaccines for Novel Coronavirus Disease 2019 (COVID-19). J Microbiol Biotechnol. 2020 Mar 28;30(3):313-24. doi: 10.4014/jmb.2003.03011.[CROSSREF]

    2. Atzrodt CL, Maknojia I, McCarthy RDP, Oldfield TM, Po J, Ta KTL, et al. A Guide to COVID-19: a global pandemic caused by the novel coronavirus SARS-CoV-2. FEBS J. 2020 Sep;287(17):3633-50. doi: 10.1111/febs.15375.[CROSSREF]

    3. Gao Z, Xu Y, Sun C, Wang X, Guo Y, Qiu S, et al. A systematic review of asymptomatic infections with COVID-19. J Microbiol Immunol Infect. 2021 Feb;54(1):12-6. doi: 10.1016/j.jmii.2020.05.001.[CROSSREF]

    4. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020 Aug 25;324(8):782-793. doi: 10.1001/jama.2020.12839.[CROSSREF]

    5. Attaway AH, Scheraga RG, Bhimraj A, Biehl M, Hatipoğlu U. Severe covid-19 pneumonia: pathogenesis and clinical management. BMJ. 2021 Mar 10;372:n436. doi: 10.1136/bmj.n436.[CROSSREF]

    6. Lamprecht B. Gibt es ein Post-COVID-Syndrom? [Is there a post-COVID syndrome?]. Pneumologe (Berl). 2020;17(6):398-405. German. doi: 10.1007/s10405-020-00347-0.[CROSSREF]

    7. Maltezou HC, Pavli A, Tsakris A. Post-COVID Syndrome: An Insight on Its Pathogenesis. Vaccines (Basel). 2021 May 12;9(5):497. doi: 10.3390/vaccines9050497.[CROSSREF]

    8. Nacul L, Authier FJ, Scheibenbogen C, Lorusso L, Helland IB, Martin JA, et al. European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE): Expert Consensus on the Diagnosis, Service Provision, and Care of People with ME/CFS in Europe. Medicina (Kaunas). 2021 May 19;57(5):510. doi: 10.3390/medicina57050510.[CROSSREF]

    9. Roerink ME, van der Schaaf ME, Dinarello CA, Knoop H, van der Meer JW. Interleukin-1 as a mediator of fatigue in disease: a narrative review. J Neuroinflammation. 2017 Jan 21;14(1):16. doi: 10.1186/s12974-017-0796-7.[CROSSREF]

    10. Russell A, Hepgul N, Nikkheslat N, Borsini A, Zajkowska Z, Moll N, et al. Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome. Psychoneuroendocrinology. 2019 Feb;100:276-85. doi: 10.1016/j.psyneuen.2018.11.032.[CROSSREF]

    11. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A: The International Chronic Fatigue Syndrome Study Group. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine. 1994, 121 (12): 953-959. https://doi.org/10.7326/0003-4819-121-12-199412150-00009 [HTTP]

    12. Ross SD, Estok RP, Frame D, Stone LR, Ludensky V, Levine CB. Disability and chronic fatigue syndrome: a focus on function. Arch Intern Med. 2004 May 24;164(10):1098-107. doi: 10.1001/archinte.164.10.1098.[CROSSREF]

    13. Mackay A. A Paradigm for Post-Covid-19 Fatigue Syndrome Analogous to ME/ CFS. Front Neurol. 2021 Aug 2;12:701419. doi: 10.3389/fneur.2021.701419.[CROSSREF]

    14. Tenforde MW, Kim SS, Lindsell CJ, Billig Rose E, Shapiro NI, Files DC, et al.; IVY Network Investigators; CDC COVID-19 Response Team; IVY Network Investigators. Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network - United States, March-June 2020. MMWR Morb Mortal Wkly Rep. 2020 Jul 31;69(30):993-8. doi: 10.15585/mmwr.mm6930e1.[CROSSREF]

    15. Carfì A, Bernabei R, Landi F; Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent Symptoms in Patients After Acute COVID-19. JAMA. 2020 Aug 11;324(6):603-5. doi: 10.1001/jama.2020.12603.[CROSSREF]

    16. Townsend L, Dyer AH, Jones K, Dunne J, Mooney A, Gaffney F, et al. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS One. 2020 Nov 9;15(11):e0240784. doi: 10.1371/journal.pone.0240784.[CROSSREF]

    17. Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021 Jan 16;397(10270):220-232. doi: 10.1016/S0140-6736(20)32656-8.[CROSSREF]

    18. Carvalho-Schneider C, Laurent E, Lemaignen A, Beaufils E, Bourbao-Tournois C, Laribi S, et al. Follow-up of adults with noncritical COVID-19 two months after symptom onset. Clin Microbiol Infect. 2021 Feb;27(2):258-63. doi: 10.1016/j.cmi.2020.09.052.[CROSSREF]

    19. Stavem K, Ghanima W, Olsen MK, Gilboe HM, Einvik G. Prevalence and Determinants of Fatigue after COVID-19 in Non-Hospitalized Subjects: A Population-Based Study. Int J Environ Res Public Health. 2021 Feb 19;18(4):2030. doi: 10.3390/ijerph18042030.[CROSSREF]

    20. Iqbal FM, Lam K, Sounderajah V, Clarke JM, Ashrafian H, Darzi A. Characteristics and predictors of acute and chronic post-COVID syndrome: A systematic review and meta-analysis. EClinicalMedicine. 2021 May 24;36:100899. doi: 10.1016/j.eclinm.2021.100899.[CROSSREF]


References

1. Ahn DG, Shin HJ, Kim MH, Lee S, Kim HS, Myoung J, et al. Current Status of Epidemiology, Diagnosis, Therapeutics, and Vaccines for Novel Coronavirus Disease 2019 (COVID-19). J Microbiol Biotechnol. 2020 Mar 28;30(3):313-24. doi: 10.4014/jmb.2003.03011.[CROSSREF]

2. Atzrodt CL, Maknojia I, McCarthy RDP, Oldfield TM, Po J, Ta KTL, et al. A Guide to COVID-19: a global pandemic caused by the novel coronavirus SARS-CoV-2. FEBS J. 2020 Sep;287(17):3633-50. doi: 10.1111/febs.15375.[CROSSREF]

3. Gao Z, Xu Y, Sun C, Wang X, Guo Y, Qiu S, et al. A systematic review of asymptomatic infections with COVID-19. J Microbiol Immunol Infect. 2021 Feb;54(1):12-6. doi: 10.1016/j.jmii.2020.05.001.[CROSSREF]

4. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020 Aug 25;324(8):782-793. doi: 10.1001/jama.2020.12839.[CROSSREF]

5. Attaway AH, Scheraga RG, Bhimraj A, Biehl M, Hatipoğlu U. Severe covid-19 pneumonia: pathogenesis and clinical management. BMJ. 2021 Mar 10;372:n436. doi: 10.1136/bmj.n436.[CROSSREF]

6. Lamprecht B. Gibt es ein Post-COVID-Syndrom? [Is there a post-COVID syndrome?]. Pneumologe (Berl). 2020;17(6):398-405. German. doi: 10.1007/s10405-020-00347-0.[CROSSREF]

7. Maltezou HC, Pavli A, Tsakris A. Post-COVID Syndrome: An Insight on Its Pathogenesis. Vaccines (Basel). 2021 May 12;9(5):497. doi: 10.3390/vaccines9050497.[CROSSREF]

8. Nacul L, Authier FJ, Scheibenbogen C, Lorusso L, Helland IB, Martin JA, et al. European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE): Expert Consensus on the Diagnosis, Service Provision, and Care of People with ME/CFS in Europe. Medicina (Kaunas). 2021 May 19;57(5):510. doi: 10.3390/medicina57050510.[CROSSREF]

9. Roerink ME, van der Schaaf ME, Dinarello CA, Knoop H, van der Meer JW. Interleukin-1 as a mediator of fatigue in disease: a narrative review. J Neuroinflammation. 2017 Jan 21;14(1):16. doi: 10.1186/s12974-017-0796-7.[CROSSREF]

10. Russell A, Hepgul N, Nikkheslat N, Borsini A, Zajkowska Z, Moll N, et al. Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome. Psychoneuroendocrinology. 2019 Feb;100:276-85. doi: 10.1016/j.psyneuen.2018.11.032.[CROSSREF]

11. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A: The International Chronic Fatigue Syndrome Study Group. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine. 1994, 121 (12): 953-959. https://doi.org/10.7326/0003-4819-121-12-199412150-00009 [HTTP]

12. Ross SD, Estok RP, Frame D, Stone LR, Ludensky V, Levine CB. Disability and chronic fatigue syndrome: a focus on function. Arch Intern Med. 2004 May 24;164(10):1098-107. doi: 10.1001/archinte.164.10.1098.[CROSSREF]

13. Mackay A. A Paradigm for Post-Covid-19 Fatigue Syndrome Analogous to ME/ CFS. Front Neurol. 2021 Aug 2;12:701419. doi: 10.3389/fneur.2021.701419.[CROSSREF]

14. Tenforde MW, Kim SS, Lindsell CJ, Billig Rose E, Shapiro NI, Files DC, et al.; IVY Network Investigators; CDC COVID-19 Response Team; IVY Network Investigators. Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network - United States, March-June 2020. MMWR Morb Mortal Wkly Rep. 2020 Jul 31;69(30):993-8. doi: 10.15585/mmwr.mm6930e1.[CROSSREF]

15. Carfì A, Bernabei R, Landi F; Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent Symptoms in Patients After Acute COVID-19. JAMA. 2020 Aug 11;324(6):603-5. doi: 10.1001/jama.2020.12603.[CROSSREF]

16. Townsend L, Dyer AH, Jones K, Dunne J, Mooney A, Gaffney F, et al. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS One. 2020 Nov 9;15(11):e0240784. doi: 10.1371/journal.pone.0240784.[CROSSREF]

17. Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021 Jan 16;397(10270):220-232. doi: 10.1016/S0140-6736(20)32656-8.[CROSSREF]

18. Carvalho-Schneider C, Laurent E, Lemaignen A, Beaufils E, Bourbao-Tournois C, Laribi S, et al. Follow-up of adults with noncritical COVID-19 two months after symptom onset. Clin Microbiol Infect. 2021 Feb;27(2):258-63. doi: 10.1016/j.cmi.2020.09.052.[CROSSREF]

19. Stavem K, Ghanima W, Olsen MK, Gilboe HM, Einvik G. Prevalence and Determinants of Fatigue after COVID-19 in Non-Hospitalized Subjects: A Population-Based Study. Int J Environ Res Public Health. 2021 Feb 19;18(4):2030. doi: 10.3390/ijerph18042030.[CROSSREF]

20. Iqbal FM, Lam K, Sounderajah V, Clarke JM, Ashrafian H, Darzi A. Characteristics and predictors of acute and chronic post-COVID syndrome: A systematic review and meta-analysis. EClinicalMedicine. 2021 May 24;36:100899. doi: 10.1016/j.eclinm.2021.100899.[CROSSREF]

1. Ahn DG, Shin HJ, Kim MH, Lee S, Kim HS, Myoung J, et al. Current Status of Epidemiology, Diagnosis, Therapeutics, and Vaccines for Novel Coronavirus Disease 2019 (COVID-19). J Microbiol Biotechnol. 2020 Mar 28;30(3):313-24. doi: 10.4014/jmb.2003.03011.[CROSSREF]

2. Atzrodt CL, Maknojia I, McCarthy RDP, Oldfield TM, Po J, Ta KTL, et al. A Guide to COVID-19: a global pandemic caused by the novel coronavirus SARS-CoV-2. FEBS J. 2020 Sep;287(17):3633-50. doi: 10.1111/febs.15375.[CROSSREF]

3. Gao Z, Xu Y, Sun C, Wang X, Guo Y, Qiu S, et al. A systematic review of asymptomatic infections with COVID-19. J Microbiol Immunol Infect. 2021 Feb;54(1):12-6. doi: 10.1016/j.jmii.2020.05.001.[CROSSREF]

4. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020 Aug 25;324(8):782-793. doi: 10.1001/jama.2020.12839.[CROSSREF]

5. Attaway AH, Scheraga RG, Bhimraj A, Biehl M, Hatipoğlu U. Severe covid-19 pneumonia: pathogenesis and clinical management. BMJ. 2021 Mar 10;372:n436. doi: 10.1136/bmj.n436.[CROSSREF]

6. Lamprecht B. Gibt es ein Post-COVID-Syndrom? [Is there a post-COVID syndrome?]. Pneumologe (Berl). 2020;17(6):398-405. German. doi: 10.1007/s10405-020-00347-0.[CROSSREF]

7. Maltezou HC, Pavli A, Tsakris A. Post-COVID Syndrome: An Insight on Its Pathogenesis. Vaccines (Basel). 2021 May 12;9(5):497. doi: 10.3390/vaccines9050497.[CROSSREF]

8. Nacul L, Authier FJ, Scheibenbogen C, Lorusso L, Helland IB, Martin JA, et al. European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE): Expert Consensus on the Diagnosis, Service Provision, and Care of People with ME/CFS in Europe. Medicina (Kaunas). 2021 May 19;57(5):510. doi: 10.3390/medicina57050510.[CROSSREF]

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