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Short and long-term trajectories of the post COVID-19 condition: Results from the EuCARE POSTCOVID study

BMC Infectious Diseases volume 25, Article number: 625 (2025) Cite this article

Abstract

Background

Post COVID-19 condition (PCC) affects 10–40% of patients and is characterized by persisting symptoms at ≥ 4 weeks after SARS-CoV-2 infection. Symptoms can last 7 or even more months. How long PCC persists and any changes in its clinical phenotypes over time require further investigation. We investigated PCC trajectories and factors associated with PCC persistence.

Material and methods

We included both hospitalized COVID-19 patients and outpatients from February 2020 to June 2023, who underwent at least one follow-up visit after acute infection at San Paolo Hospital, University of Milan. Follow-up visits were conducted at the post COVID-19 clinic or via telemedicine. During each follow-up examination, patients completed a short version of the World Health Organization (WHO) Case Report Form (CRF) for ongoing symptoms, the Hospital Anxiety and Depression Scale (HADS), and a screening tool for Post-Traumatic Stress Disorder (PTSD). Statistical analyses involved Chi-square, Mann–Whitney, Kruskal–Wallis tests, and logistic regression analysis.

Results

We enrolled 853 patients (median age 62, IQR 52–73; 41% females). 551/853 (64.6%), 152/418 (36.4%) and 21/69 (30.4%) presented PCC at median follow up of 3 (IQR 2–3), 7 (IQR 6–10) and 26 (IQR 20–33) months, respectively (p < 0.001). The main clinical phenotypes were fatigue, respiratory sequelae, brain fog and chronic pain; anosmia/dysgeusia was observed mostly in the first post-acute period. Female sex, acute disease in 2020, a longer hospital stay and no COVID-19 vaccination were associated with persistence or resolution of PCC compared to never having had PCC. Anxiety, depression and PTSD were more common in PCC patients. By fitting a logistic regression analysis, acute infection in 2020 remained independently associated with persistent PCC, adjusting for age, sex, preexisting comorbidities and disease severity (AOR 0.479 for 2021 vs 2020, 95%CI 0.253–0.908, p = 0.024; AOR 0.771 for 2022 vs 2020, 95%CI 0.259–2.297, p = 0.641; AOR 0.086 for 2023 vs 2020, 95%CI 0.086–3.830, p = 0.565).

Conclusions

There was a reduction in the PCC burden 7 months following the acute phase; still, one third of patients experienced long-lasting symptoms. The main clinical presentations of PCC remain fatigue, respiratory symptoms, brain fog, and chronic pain. Having had SARS-CoV-2 infection during the first pandemic phases appears to be associated with persistent PCC.

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Background

Long COVID, also referred to as Post-COVID-19 Condition (PCC), is defined by the Center for Disease Control and Prevention (CDC) as the presence of persisting symptoms four weeks after the acute SARS-CoV-2 infection [1, 2]. It is estimated that PCC affects a substantial proportion of patients, ranging from 10 to 40%, placing a heavy burden on already stressed health systems [3,4,5,6]. Symptoms can last for months, with many studies following patients for up to one year since the acute phase, and a few others suggesting symptoms may last even longer [7,8,9].

For the sake of simplicity, symptoms can be grouped in clusters in order to identify different PCC phenotypes [10, 11]. One study found shortness of breath and chronic fatigue as the most frequent long COVID manifestations, while female sex and severe COVID-19 infection during the acute phase were the main risk factors for developing PCC [12,13,14]. Evidence indicates a decline in PCC incidence following the surge of the Omicron variant compared to the wild-type virus, while incidence was higher with the Alpha and Delta variants [15,16,17,18]. A follow-up study on long-term outcomes in 242,712 COVID-19 patients showed patients infected with the Omicron variant were 88% less likely to experience lingering symptoms compared to the original viral strain [15]. Preliminary data suggest a reduction in the risk of developing long-term cardiorespiratory sequelae after Omicron infection compared to the wild-type virus, while neurological symptoms, such as depression and anxiety, continue to be prevalent [8, 15]. It is currently unclear how long this condition persists, and whether clinical phenotypes change over time.

Many factors have been associated with PCC development, most notably older age, female sex, the severity of acute infection, and prior comorbidities. In contrast, vaccination appears to offer protective benefits, and while evidence remains limited, emerging data suggests that antiviral and anti-inflammatory agents during the acute phase may have a preventive effect, with stronger support for oral nirmatrelvir/ritonavir in particular. No treatment for PCC is currently available. [17,18,19,20,21,22,23,24,25]. Several authors have suggested a possible role of psychological factors in the development of PCC, especially during the initial waves of the pandemic (2020–2021) due to isolation during lockdowns and fear of a new, previously unknown disease [26, 27]. One study measured depression and anxiety levels during lockdowns, which resulted to be at quasi-clinical levels [21]. Evidence for a possible reduction in psychological symptoms with later variants is currently limited.

Since the onset of the ongoing COVID-19 pandemic, healthcare professionals have encountered unprecedented challenges in the management and follow-up of patients. The implementation of lockdown measures, coupled with the surge in patient numbers and the resulting strain on health systems, necessitated novel approaches to follow-up care and the optimization of hospital resources. Additionally, the prevalence of old age and comorbidities, common characteristics in COVID-19 patients, heightened the risk of loss to follow-up. In response to these challenges, new methods of patient re-evaluation, such as telemedicine, have been introduced, benefiting both patients and healthcare providers [20]. Telemedicine employs audio and/or visual devices to facilitate communication between patients and healthcare professionals.

This study presents the outcomes of a follow-up program designed for COVID-19 patients from the EuCARE POSTCOVID cohort [28], conducted from January 2020 to June 2023, employing in person evaluations and telemedicine. Our aim was to examine the trajectories of PCC and clinical outcomes over time, as well as to identify potential factors associated with PCC persistence in a cohort of both hospitalized and non-hospitalized patients.

Materials and methods

Study design and population

The EuCARE POSTCOVID study is a retrospective cohort study including patients with at least one follow-up examination at 2–3, 6–10 and ≥ 12 months after an acute SARS-CoV-2 infection. It includes 6 centers in over 3 continents and aims to investigate the long-term outcome of SARS-CoV-2 infection; the study protocol has already been described elsewhere [28]. Patients included in this study have been evaluated at the post COVID service of the Clinic of Infectious Diseases, San Paolo Hospital, ASST Santi Paolo e Carlo, Milan, Italy or by telemedicine from February 2020 to June 2023. We included both hospitalized COVID-19 patients and outpatients with milder disease who were not hospitalized during the acute phase. The study flow chart is depicted in Fig. 1.

Fig. 1
figure 1

Study flow chart. Legend: 853 patients were followed up at 3, 2–3 months after acute COVID-19 disease. Of these, 418 patients were followed up also at 7, IQR 6–10 months and 69 patients also at 26, IQR 20–33 months. Loss to follow up: patients that didn’t keep an appointment or didn’t answer to phone call to schedule next appointments; to be contacted/ongoing: patients with a next scheduled appointment or patients still to be phone contacted. PCC, post COVID-19 condition

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Study procedures

At each visit, patients underwent blood exams and completed a condensed version of the post-COVID-19 WHO Case Report Form (CRF) to document symptoms. Following the acute phase and/or hospital discharge, we gathered data on persistent symptoms not previously experienced before COVID-19 infection. If any symptoms were reported, we investigated whether they persisted, their frequency, or if they had already resolved. Additionally, patients completed the Hospital Anxiety and Depression Scale (HADS-A/D) to assess symptoms of anxiety and depression and a screening tool for Post-Traumatic Stress Disorder (PTSD).

The HADS-A/D includes 7 questions each for anxiety and depression. A total HADS score between 8 and 10 indicates “possible” cases, while scores of 11 or more denote “probable” cases for both anxiety and depression. Scores higher than 10 were utilized to identify symptoms of anxiety and depression. The Post-traumatic Stress Disorder Checklist-5 (PCL-5) is a 20-item self-report measure assessing the 20 DSM-5 symptoms of PTSD, with a 5-point scale for each symptom. A total symptom severity score ranging from 0 to 80 can be obtained, and a cut-off of 33 was considered indicative of PTSD [29,30,31].

The primary outcome was the proportion of participants who were diagnosed with PCC, as defined by the CDC definition: the presence of ≥ 1 symptom 4 or more weeks after the acute infection, either at entry in the cohort (2–3 months after the acute infection) or at any of the follow-up visits. We also focused on the main symptoms clusters of PCC as previously identified [11, 32]: fatigue, respiratory symptoms, brain fog/central nervous symptoms, chronic pain and anosmia/dysgeusia. A list of symptoms included in each PCC phenotype is provided in Supplementary Table 1.

This study has been approved by the Ethics Committee Milano Area 1 (n 1869, 01/08/2022) and all patients have signed an informed consent.

Statistical analyses

Categorical variables are presented as absolute numbers and percentages, quantitative variables as median and interquartile range (IQR). The proportion of patients diagnosed with PCC and the main PCC phenotypes at each time point have been compared by Chi-square test. Among patients with at least two follow up examinations, we compared those who had never experienced PCC, those who resolved PCC, and those with persistent PCC at the last available follow-up using Chi-square test and non-parametric Kruskal–Wallis test. For patients diagnosed with PCC at the first follow-up (2–3 months post-acute phase), we examined factors associated with the persistence of PCC versus its resolution using Chi-square test and non-parametric Mann–Whitney test. Finally, by fitting a multivariable logistic regression analysis adjusted for possible confounders (age, sex, comorbidities, and calendar time of infection) we explored factors associated with ongoing PCC at the last available follow-up in comparison to those who had never experienced PCC or had recovered from it. Age and sex influence both susceptibility to and recovery from PCC, comorbidities may independently affect both the risk of exposure and the outcome, and calendar time of infection accounts for new viral variants and treatment options that could impact the outcome. Statistical analyses were performed by SPSS (version 29) and STATA software (version 14).

Results

Study population

Three medical evaluations were conducted in total (Fig. 1). Patients were evaluated at 2–3 months after the acute phase and then followed up at 6–10 months and more than 12 months. Initially, 853 patients underwent a first follow-up assessment at 3 months post-acute phase (IQR 2–3), and thus were included in our study. The median age was 62 years (IQR 52–73), with the majority being men (59% males, 41% females). Most patients were evaluated in 2020 and 2021 (66.7% and 19.3% respectively). Accordingly, only 12.5% of the cohort had received at least two doses of the vaccine prior to SARS-CoV-2 infection, as the majority of patients were enrolled before vaccination became widely available. All enrolled patients had a primary SARS-CoV-2 infection, with no documented cases of reinfection.

The cohort includes 766 hospitalized COVID-19 patients (89.8%) and a smaller subset of individuals (87, 10.2%) who experienced a mild acute illness and were not hospitalized. Regarding disease severity during the acute phase, approximately one third of patients received treatment with a reservoir mask (RM), high-flow nasal cannula (HFNC), or continuous positive airway pressure (CPAP), while 8% of patients required admission to the intensive care unit (ICU) (Table 1).

Table 1 Study population characteristics
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Of 853 patients, 418 individuals (49%) also completed follow-up evaluations at 7 months (IQR 6–10); 69 patients (17%) were followed up at a median of 26 months (IQR 20–33). 26/853 (3%), 218/418 (52%) and 58/59 (98%) evaluations were performed by telemedicine. The missing patients included those lost to follow-up (18 at the second follow-up visit, 157 at the third), those with ongoing scheduled appointments who were in the process of completing their long-term follow-up, and those yet to be contacted to arrange subsequent evaluations. Challenges in maintaining follow-up included patients not responding to phone calls, refusing further evaluations, logistical difficulties such as travel constraints for older patients, and others who dropped out of the study. Additionally, 3 patients (0.35%) died after the first evaluation.

PCC and main phenotypes over time

Interestingly, we observed a reduction in the proportion of symptomatic patients over time: PCC was present in 551 out of 853 patients (64.6%) at the first medical evaluation; at the second visit, 152 out of 418 patients (36.4%) still had PCC symptoms, and finally, PCC persisted in 21 out of 69 patients (30.4%) at the third medical evaluation (p < 0.001).

In our cohort of patients, we identified five main clinical phenotypes of PCC: fatigue, respiratory sequelae, brain fog, chronic pain, and anosmia/dysgeusia (Table 2). The clinical presentation of PCC varied through time: while anosmia/dysgeusia was the most prominent symptom at the first follow-up (211/853 patients, 24.7%; 211/551 PCC patients, 38.3%), it became less common at the second evaluation and was only reported once at the third follow up (1/69 patients, 1.4%; 1/21 PCC patients, 4.8%), making it the less represented symptom cluster in the long term.

Table 2 PCC phenotypes over time
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Fatigue and respiratory symptoms were present in approximately 1 in 4 PCC patients at the first follow-up visit (123/853, 14.4%; 123/551 PCC patients, 22.3% for fatigue, and 143/853, 16.8%; 143/551 PCC patients, 25.9% for respiratory symptoms). The frequency of these symptoms increased with each subsequent evaluation in PCC patients. For fatigue, it was present in 62/418 total patients (14.8%; 62/152 PCC patients, 40.7%) at the second visit and in 13/69 total patients (18.8%; 13/21 PCC patients, 61.9%) at the third visit. Similarly, respiratory sequelae were found in 75/418 total patients (17.9%; 75/152 PCC patients, 49.3%) at the second visit and in 11/69 total patients (15.9%; 11/21 PCC patients, 52.4%) at the third visit, making them the most common manifestations of PCC after long-term follow-up.

The percentage of PCC patients suffering from chronic pain and brain fog, which were relatively uncommon manifestations 3 months after the acute phase (49/853, 5.7%; 49/551 PCC patients, 8.9% for chronic pain, and 29/853, 3.4%; 29/551 PCC patients, 5.3% for brain fog), increased significantly at the last evaluation (10/69 total patients, 14.5%; 10/21 PCC patients, 47.6% for chronic pain, and 5/69 total patients, 7.2%; 5/21 PCC patients, 23.8% for brain fog).

Comparison among patients who had never had PCC, patients who had recovered from PCC and patients with ongoing PCC

A total of 418 patients, representing 49% of the initial 853-patient cohort, underwent a second medical evaluation. Subsequently, we proceeded to compare patients who had never developed PCC, patients who had recovered from PCC symptoms, and patients with persistent PCC at the last available follow-up (Table 3).

Table 3 Comparison among patients who had never had PCC, patients with resolved and patients with persistent PCC
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Female sex, having had the acute infection in 2020, a longer hospital stay, and lack of COVID-19 vaccination were positively associated with PCC (either persistent or resolved) when compared to patients who never developed PCC. Additionally, psychological symptoms such as anxiety, depression, and PTSD were more common among patients with PCC, with PTSD reaching statistical significance.

Notably, no statistically significant association was found between PCC and other commonly cited risk factors in current literature, such as obesity, the number of preexisting comorbidities and the maximum grade of oxygen therapy during the acute phase.

Comparison between patients with resolved PCC and ongoing PCC

We also analyzed a total of 308 patients who were diagnosed with PCC at the entry in the cohort and had at least two follow-up visits. Among these, 198/308 (64.3%) no longer had PCC symptoms at subsequent evaluations, while 110/308 (35.7%) had persistent PCC at a median follow up of 8 months (IQR 6–15) (Table 4). We compared these two groups to identify factors associated with PCC persistence over time. We observed that female sex and lack of COVID-19 vaccination were positively associated with PCC persistence. Additionally, while not reaching statistical significance, psychological symptoms such as anxiety, depression, and PTSD were also observed more frequently in patients with persistent PCC.

Table 4 Factors associated with PCC persistence
Full size table

Factors associated with PCC persistence over time

Finally, we examined factors associated with ongoing PCC (compared to those who never had PCC or had resolved symptoms at the last available follow-up) using logistic regression analysis. Having had acute SARS-CoV-2 infection in 2020 remained independently associated with persistent PCC, even after adjusting for age, sex, preexisting comorbidities, and the severity of acute disease (AOR 0.479 for 2021 vs 2020, 95%CI 0.253–0.908, p = 0.024; AOR 0.771 for 2022 vs 2020, 95%CI 0.259–2.297, p = 0.641; AOR 0.086 for 2023 vs 2020, 95%CI 0.086–3.830, p = 0.565).

Discussion

This study stands out as one of the first comprehensive, ongoing, large-scale investigations to extend follow-up for PCC patients beyond the first year post-diagnosis, offering insights into both short- and long-term changes in the overall burden of PCC and the evolution of clinical phenotypes.

In our cohort, primarily consisting of unvaccinated hospitalized patients and a smaller sample of outpatients during the early stages of the pandemic, we observed a preliminary reduction in the percentage of PCC over the follow-up period. However, the significant proportion of missing outcomes at the second and third follow-up visits prevents us from drawing definitive conclusions regarding the initial cohort and limits the generalizability of these findings. According to the CDC definition [1], over two-thirds of patients in our cohort exhibited PCC symptoms at the initial 2–3-month follow-up, a proportion that decreased progressively with subsequent visits, with one-third of patients still experiencing PCC at a long follow-up of 2 years or more.

While anosmia/dysgeusia is prevalent in the first post-acute period, fatigue, respiratory sequelae, and to a lesser extent, brain fog emerged as the predominant long-term PCC phenotypes, in accordance with what described in other cohorts [33,34,35,36]. Similar data have already been published showing a reduction of ear, nose and throat (ENT) symptoms over time but a possible long-term persistence of chronic fatigue [3, 37, 38]. Fatigue, observed in half of our patients, shares several similarities with myalgic encephalomyelitis [39], a condition that follows several infections, defined by chronic fatigue that lasts at least six months and is associated with brain fog, sleep disorders, post-exertional malaise and orthostatic intolerance [40, 41].

Similar to PCC, the diagnosis of myalgic encephalomyelitis is primarily clinical and requires the exclusion of differential diagnoses. Thus far, the pathogenetic mechanisms of myalgic encephalomyelitis remain poorly understood, and there is no specific treatment available apart from cognitive and motor rehabilitation therapies, which have been extensively studied [42]. Due to the overlap in symptoms and therapeutic approaches, myalgic encephalomyelitis is now acknowledged as one of the potential manifestations of PCC. Accurate identification and management of these patients could significantly improve their quality of life [43].

While these findings underscore the ongoing significance of PCC, with potentially millions of people still suffering from it, delineating whether these symptoms are exclusively attributable to long COVID remains complex [23, 44]. While certain manifestations may have a clear correlation with acute SARS-CoV-2 infection in the early post-acute phase, numerous confounding factors may emerge over time. For example, factors such as fatigue, cognitive difficulties, and anxiety tend to increase with age, as do comorbidities. This complicates the attribution of PCC outcomes solely to the viral infection rather than to other ensuing concomitant factors. Moreover, many PCC symptoms closely resemble those of other post-viral syndromes and poorly defined conditions like chronic fatigue syndrome, underscoring the imperative for a more precise and concise definition of long-term PCC [45].

Consistent with existing literature, female sex, prolonged hospitalization, and lack of COVID-19 vaccination were positively associated with PCC among patients with at least two follow-up visits [13, 14, 19,20,21, 46,47,48]. In our unadjusted analysis and in almost all previous studies investigating long COVID, females were characterized by a higher risk of PCC, possibly due to a higher prevalence of psychological issues and/or hormonal factors yet to be understood [46, 49, 50]. A recent study investigated the impact of sex and gender on PCC and found that socio-economic factors, as well as stress levels, income, being females and living alone and lower education, were predictors of PCC and may partially explain the higher incidence of PCC in women [12].

Even though few of the patients in our cohort had been vaccinated before infection, unvaccinated patients were found to be at higher risk of PCC, as well documented by various observational studies and meta-analyses [19, 20, 48].

We also observed that PCC persists over time, particularly among patients infected in the first waves of the pandemic. The reduction in PCC persistence was displayed only for the comparison between the two first calendar period (2021 vs 2020), while we didn’t observe any reduction in most recent years (2022 and 2023) compared to 2020; this could be due to different reasons, including the small sample size mainly in the last years, the possible protective effect of COVID-19 vaccination in reducing the burden of PCC symptoms [51, 52], but also the reduction in PCC incidence following the infection with most recent variants. In fact, a reduction of PCC after Omicron infection compared to the Wuhan strain has also been reported by other authors and by other analyses in the EuCARE POSTCOVID study [15, 16, 53].

This study has some limitations. Our study design may introduce a possible selection bias that precludes definitive conclusions regarding PCC incidence rates, as patients returning for follow-up visits inherently have a higher risk of exhibiting PCC symptoms, while many others, who were lost to follow-up, were likely asymptomatic or followed up in other long COVID centers. Similarly, our study is unable to definitively ascertain the potential protective effects of vaccines and antiviral therapies, as they were introduced after the majority of our patients were enrolled, and the small sample of patients receiving specific treatments limits our ability to draw definitive conclusions. Given that most of our patients were unvaccinated, hospitalized during the acute phase and with mild to moderate symptoms, the generalizability of our findings might be limited. Finally, we haven’t a control group of patients without COVID-19 to be followed up over time to ascertain the incidence of symptoms associated with PCC; this will be the focus of our future.

Despite the limitations due to incomplete follow-up data, which warrant caution in the generalizability of our results, our findings suggest a trend toward a potential decrease in the burden of PCC over time, with an evolving clinical phenotype characterized by prominent fatigue and respiratory sequelae, alongside, to a lesser extent, anxiety and depression-related symptoms. This underscores the potential role of psychological support in managing these patients and highlights the necessity for further long-term investigations.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

PCC:

Post-COVID-19 Condition

CDC:

Center for Disease Control and Prevention

WHO:

World Health Organization

CRF:

Case Report Form

HADS:

Hospital Anxiety and Depression Scale

PTSD:

Post Traumatic Stress Disorder

PCL-5:

Post-traumatic Stress Disorder Checklist-5

DSM-5:

Diagnostic and Statistical Manual of Mental Disorders

IQR:

Interquartile Range

RM:

Reservoir mask

HFNC:

High-flow nasal cannula

CPAP:

Continuous positive airway pressure

ICU:

Intensive care unit

ENT:

Ear, nose and throat

References

  1. CDC: Long-term effects of COVID-19. Centers for Disease Control and Prevention. 2020. Available at https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects.html.

  2. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV. Condition WCCDWGoP-C-: A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022;22(4):e102–7.

    Article  CAS  PubMed  Google Scholar 

  3. Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re'em Y, Redfield S, Austin JP, Akrami A. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021;38:101019. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.eclinm.2021.101019. Epub 2021 Jul 15. PMID: 34308300; PMCID: PMC8280690.

  4. Nguyen KH, Bao Y, Mortazavi J, Allen JD, Chocano-Bedoya PO, Corlin L. Prevalence and factors associated with long COVID symptoms among US adults, 2022. Vaccines (Basel). 2024;12(1):99.

    Article  PubMed  Google Scholar 

  5. Van Herck M, Pagen DME, van Bilsen CJA, Brinkhues S, Konings K, den Heijer CDJ, Mujakovic S, Ter Waarbeek HLG, Burtin C, Janssen DJA, et al. Impact of post-COVID-19 condition on health status and activities of daily living: the PRIME post-COVID study. Thorax. 2024;79(5):457–64.

    Article  PubMed  Google Scholar 

  6. Mehandru S, Merad M. Pathological sequelae of long-haul COVID. Nat Immunol. 2022;23(2):194–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Salmon D, Slama D, Linard F, Dumesges N, Le Baut V, Hakim F, Oustric P, Seyrat E, Thoreux P, Marshall E. Patients with Long COVID continue to experience significant symptoms at 12 months and factors associated with improvement: A prospective cohort study in France (PERSICOR). Int J Infect Dis. 2024;140:9–16.

    Article  PubMed  Google Scholar 

  8. Fernandez-de-Las-Peñas C, Notarte KI, Macasaet R, Velasco JV, Catahay JA, Ver AT, Chung W, Valera-Calero JA, Navarro-Santana M. Persistence of post-COVID symptoms in the general population two years after SARS-CoV-2 infection: A systematic review and meta-analysis. J Infect. 2024;88(2):77–88.

    Article  PubMed  Google Scholar 

  9. Iversen A, Blomberg B, Haug K, Kittang B, Özgümüs T, Cox RJ, Langeland N. Symptom trajectories of post-COVID sequelae in patients with acute Delta or Omicron infection in Bergen. Norway Front Public Health. 2024;12:1320059.

    Article  PubMed  Google Scholar 

  10. Hampshire A, Azor A, Atchison C, Trender W, Hellyer PJ, Giunchiglia V, Husain M, Cooke GS, Cooper E, Lound A, et al. Cognition and Memory after Covid-19 in a Large Community Sample. N Engl J Med. 2024;390(9):806–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gentilotti E, Górska A, Tami A, Gusinow R, Mirandola M, Rodríguez Baño J, Palacios Baena ZR, Rossi E, Hasenauer J, Lopes-Rafegas I, et al. Clinical phenotypes and quality of life to define post-COVID-19 syndrome: a cluster analysis of the multinational, prospective ORCHESTRA cohort. EClinicalMedicine. 2023;62: 102107.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Gebhard CE, Sütsch C, Gebert P, Gysi B, Bengs S, Todorov A, Deforth M, Buehler PK, Meisel A, Schuepbach RA, et al. Impact of sex and gender on post-COVID-19 syndrome, Switzerland, 2020. Euro Surveill. 2024;29(2):2300200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hill EL, Mehta HB, Sharma S, Mane K, Singh SK, Xie C, Cathey E, Loomba J, Russell S, Spratt H, et al. Risk factors associated with post-acute sequelae of SARS-CoV-2: an N3C and NIH RECOVER study. BMC Public Health. 2023;23(1):2103.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Luo D, Mei B, Wang P, Li X, Chen X, Wei G, Kuang F, Li B, Su S. Prevalence and risk factors for persistent symptoms after COVID-19: a systematic review and meta-analysis. Clin Microbiol Infect. 2024;30(3):328–35.

    Article  PubMed  Google Scholar 

  15. Bai F, Cozzi-Lepri A, Hedberg P, Santoro A, Marchetti G et al, Reduction of post COVID-19 condition during the Omicron wave: results from the EuCARE POSTCOVID Study. Accepted and rated as Top Poster at the 34th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID). Barcelona: 2024.

  16. Antonelli M, Pujol JC, Spector TD, Ourselin S, Steves CJ. Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2. Lancet. 2022;399(10343):2263–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hernández-Aceituno A, García-Hernández A, Larumbe-Zabala E. COVID-19 long-term sequelae: Omicron versus Alpha and Delta variants. Infect Dis Now. 2023;53(5): 104688.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Du M, Ma Y, Deng J, Liu M, Liu J. Comparison of long COVID-19 caused by different SARS-CoV-2 strains: a systematic review and meta-analysis. Int J Environ Res Public Health. 2022;19(23):16010.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Grady CB, Bhattacharjee B, Silva J, Jaycox J, Lee LW, Monteiro VS, Sawano M, Massey D, Caraballo C, Gehlhausen JR, Tabachnikova A, Mao T, Lucas C, Peña-Hernandez MA, Xu L, Tzeng TJ, Takahashi T, Herrin J, Güthe DB, Akrami A, Assaf G, Davis H, Harris K, McCorkell L, Schulz WL, Grffin D, Wei H, Ring AM, Guan L, Cruz CD, Iwasaki A, Krumholz HM. Impact of COVID-19 vaccination on symptoms and immune phenotypes in vaccine-naïve individuals with Long COVID. medRxiv [Preprint]. 2024:2024.01.11.24300929. https://doiorg.publicaciones.saludcastillayleon.es/10.1101/2024.01.11.24300929. PMID: 38260484; PMCID: PMC10802754.

  20. Man MA, Rosca D, Bratosin F, Fira-Mladinescu O, Ilie AC Burtic SR, Fildan AP, Fizedean CM, Jianu AM, Negrean RA, et al. Impact of Pre-Infection COVID-19 Vaccination on the Incidence and Severity of Post-COVID Syndrome: A Systematic Review and Meta-Analysis. Vaccines. 2024;12:189. https://doiorg.publicaciones.saludcastillayleon.es/10.3390/vaccines12020189.

  21. Trinh NT, Jödicke AM, Català M, Mercadé-Besora N, Hayati S, Lupattelli A, Prieto-Alhambra D, Nordeng HM. Effectiveness of COVID-19 vaccines to prevent long COVID: data from Norway. Lancet Respir Med. 2024;12(5):e33–4.

    Article  PubMed  Google Scholar 

  22. Suran M. VA Finds Nirmatrelvir Associated With Lower Risk of Long COVID. JAMA. 2022;328(24):2386.

    PubMed  Google Scholar 

  23. Al-Aly Z, Topol E. Solving the puzzle of Long Covid. Science. 2024;383(6685):830–2.

    Article  CAS  PubMed  Google Scholar 

  24. Ayoubkhani D, Bosworth ML, King S, Pouwels KB, Glickman M, Nafilyan V, Zaccardi F, Khunti K, Alwan NA, Walker AS. Risk of Long COVID in People Infected With Severe Acute Respiratory Syndrome Coronavirus 2 After 2 Doses of a Coronavirus Disease 2019 Vaccine: Community-Based, Matched Cohort Study. Open Forum Infect Dis. 2022;9(9):ofac464.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Byambasuren O, Stehlik P, Clark J, Alcorn K, Glasziou P. Effect of covid-19 vaccination on long covid: systematic review. BMJ Med. 2023;2(1): e000385.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Tomasoni D, Bai F, Castoldi R, Barbanotti D, Falcinella C, Mulè G, Mondatore D, Tavelli A, Vegni E, Marchetti G, d'Arminio Monforte A. Anxiety and depression symptoms after virological clearance of COVID-19: A cross-sectional study in Milan, Italy. J Med Virol. 2021;93(2):1175–9. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/jmv.26459. Epub 2020 Sep 30. PMID: 32841387; PMCID: PMC7461061.

  27. Rudenstine S, Schulder T, Bhatt KJ, McNeal K, Ettman CK, Galea S. Long-COVID and comorbid depression and anxiety two years into the COVID-19 pandemic. Psychiatry Res. 2022;317: 114924.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Varisco B, Bai F, De Benedittis S, Tavelli A, Cozzi-Lepri A, Sala M, Miraglia FG, Santoro MM, Ceccherini-Silberstein F, Shimoni Y, et al. EuCARE-POSTCOVID Study: a multicentre cohort study on long-term post-COVID-19 manifestations. BMC Infect Dis. 2023;23(1):684.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bonazza F, Luridiana Battistini C, Fior G, Bergamelli E, Wiedenmann F, D’Agostino A, Sferrazza Papa GF, Borghi L, Piscopo K, Vegni E, et al. Recovering from COVID-19: psychological sequelae and post-traumatic growth six months after discharge. Eur J Psychotraumatol. 2022;13(1): 2095133.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hattori Y, Katayama M, Kida D, Kaneko A. Hospital Anxiety and Depression Scale Score Is an Independent Factor Associated With the EuroQoL 5-Dimensional Descriptive System in Patients With Rheumatoid Arthritis. J Clin Rheumatol. 2018;24(6):308–12.

    Article  PubMed  Google Scholar 

  31. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361–70.

    Article  CAS  PubMed  Google Scholar 

  32. Reese JT, Blau H, Casiraghi E, Bergquist T, Loomba JJ, Callahan TJ, Laraway B, Antonescu C, Coleman B, Gargano M, et al. Generalisable long COVID subtypes: findings from the NIH N3C and RECOVER programmes. EBioMedicine. 2023;87: 104413.

    Article  PubMed  Google Scholar 

  33. Ballering AV, van Zon SKR, Olde Hartman TC, Rosmalen JGM, Initiative LCR. Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study. Lancet. 2022;400(10350):452–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Seeßle J, Waterboer T, Hippchen T, Simon J, Kirchner M, Lim A, Müller B, Merle U. Persistent Symptoms in Adult Patients 1 Year After Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study. Clin Infect Dis. 2022;74(7):1191–8.

    Article  PubMed  Google Scholar 

  35. Tran VT, Porcher R, Pane I, Ravaud P. Course of post COVID-19 disease symptoms over time in the ComPaRe long COVID prospective e-cohort. Nat Commun. 2022;13(1):1812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wulf Hanson S, Abbafati C, Aerts JG, Al-Aly Z, Ashbaugh C, Ballouz T, Blyuss O, Bobkova P, Bonsel G, Borzakova S, et al. Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021. JAMA. 2022;328(16):1604–15.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Han Q, Zheng B, Daines L, Sheikh A. Long-term sequelae of COVID-19: a systematic review and meta-analysis of one-year follow-up studies on post-COVID symptoms. Pathogens. 2022;11(2):269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mizrahi B, Sudry T, Flaks-Manov N, Yehezkelli Y, Kalkstein N, Akiva P, Ekka-Zohar A, Ben David SS, Lerner U, Bivas-Benita M, et al. Long covid outcomes at one year after mild SARS-CoV-2 infection: nationwide cohort study. BMJ. 2023;380: e072529.

    Article  PubMed  Google Scholar 

  39. Nacul L, Authier FJ, Scheibenbogen C, Lorusso L, Helland IB, Martin JA, Sirbu CA, Mengshoel AM, Polo O, Behrends U, 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;57(5):510.

    Article  PubMed  Google Scholar 

  40. Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management. London: National Institute for Health and Care Excellence (NICE); 2021. PMID: 35438859.

  41. Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles AC, Speight N, Vallings R, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 2011;270(4):327–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bateman L, Bested AC, Bonilla HF, Chheda BV, Chu L, Curtin JM, Dempsey TT, Dimmock ME, Dowell TG, Felsenstein D, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management. Mayo Clin Proc. 2021;96(11):2861–78.

    Article  PubMed  Google Scholar 

  43. Deumer US, Varesi A, Floris V, Savioli G, Mantovani E, López-Carrasco P, Rosati GM, Prasad S, Ricevuti G. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): an overview. J Clin Med. 2021;10(20):4786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(3):133–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Choutka J, Jansari V, Hornig M, Iwasaki A. Author Correction: Unexplained post-acute infection syndromes. Nat Med. 2022;28(8):1723.

    Article  CAS  PubMed  Google Scholar 

  46. Bai F, Tomasoni D, Falcinella C, Barbanotti D, Castoldi R, Mulè G, Augello M, Mondatore D, Allegrini M, Cona A, et al. Female gender is associated with long COVID syndrome: a prospective cohort study. Clin Microbiol Infect. 2022;28(4):611.e619–611.e616.

    Article  Google Scholar 

  47. Perlis RH, Santillana M, Ognyanova K, Safarpour A, Lunz Trujillo K, Simonson MD, Green J, Quintana A, Druckman J, Baum MA, et al. Prevalence and Correlates of Long COVID Symptoms Among US Adults. JAMA Netw Open. 2022;5(10): e2238804.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Català M, Mercadé-Besora N, Kolde R, Trinh NTH, Roel E, Burn E, Rathod-Mistry T, Kostka K, Man WY, Delmestri A, et al. The effectiveness of COVID-19 vaccines to prevent long COVID symptoms: staggered cohort study of data from the UK, Spain, and Estonia. Lancet Respir Med. 2024;12(3):225–36.

    Article  PubMed  Google Scholar 

  49. Subramanian A, Nirantharakumar K, Hughes S, Myles P, Williams T, Gokhale KM, Taverner T, Chandan JS, Brown K, Simms-Williams N, et al. Symptoms and risk factors for long COVID in non-hospitalized adults. Nat Med. 2022;28(8):1706–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kedor C, Freitag H, Meyer-Arndt L, Wittke K, Hanitsch LG, Zoller T, Steinbeis F, Haffke M, Rudolf G, Heidecker B, et al. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nat Commun. 2022;13(1):5104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ceban F, Kulzhabayeva D, Rodrigues NB, Di Vincenzo JD, Gill H, Subramaniapillai M, Lui LMW, Cao B, Mansur RB, Ho RC, et al. COVID-19 vaccination for the prevention and treatment of long COVID: A systematic review and meta-analysis. Brain Behav Immun. 2023;111:211–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Azzolini E, Levi R, Sarti R, Pozzi C, Mollura M, Mantovani A, Rescigno M. Association Between BNT162b2 Vaccination and Long COVID After Infections Not Requiring Hospitalization in Health Care Workers. JAMA. 2022;328(7):676–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hedberg P, Nauclér P. Post-COVID-19 Condition After SARS-CoV-2 Infections During the Omicron Surge vs the Delta, Alpha, and Wild Type Periods in Stockholm. Sweden J Infect Dis. 2024;229(1):133–6.

    Article  PubMed  Google Scholar 

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Acknowledgements

We are thankful to all the patients who participated in the study and their families. We would like to thank all the staff of the Clinic of Infectious Diseases and Tropical Medicine, San Paolo Hospital, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan who cared for the patients and all the colleagues involved in the EuCARE project. The preliminary results will be presented as oral communication at the 16th Italian Conference on AIDS and Antiviral Research (ICAR). The authors acknowledge support from the University of Milan through the APC initiative. The authors thank Dr. Gibran Horemheb Rubio Quintanares for his contributions to the study.

Funding

This research received the contribution of the EuCARE Project funded by the European Union´s Horizon Europe Research and Innovation Programme under Grant Agreement No 101046016.

Author information

Authors and Affiliations

  1. Department of Health Sciences, Clinic of Infectious Diseases, San Paolo Hospital, ASST Santi Paolo E Carlo, University of Milan, Milan, Italy

    Andrea Santoro, Francesca Bai, Maria Francesca Greco, Roberta Rovito, Matteo Sala & Giulia Marchetti

  2. Department of Health Sciences, Unit of Clinical Psychology, San Paolo Hospital, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy

    Lidia Borghi, Kyrie Piscopo & Elena Vegni

  3. School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil

    Julia Fonseca de Morais Caporali, Carolina Coimbra Marinho & Arnaldo Santos Leite

  4. Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy

    Maria Mercedes Santoro, Francesca Ceccherini Silberstein, Marco Iannetta & Luca Carioti

  5. Vilnius Santaros Klinikos Biobank, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania

    Dovile Juozapaite

  6. Clinic of Infectious Diseases and Dermatovenerology, Institute of Clinical Medicine, Medical Faculty, Vilnius University, Vilnius, Lithuania

    Edita Strumiliene

  7. Department of Internal Medicine 4, Centro Hospitalar Universitário de Lisboa Central, Centro Clínico Académico de Lisboa, Lisbon, Portugal

    André Almeida

  8. Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal

    Cristina Toscano

  9. Hospital Juan Graham Casasus, Villahermosa, Tab, Mexico

    Jesus Arturo Ruiz Quinones

  10. EuResist Network GEIE, Rome, Italy

    Chiara Mommo, Iuri Fanti & Francesca Incardona

  11. InformaPRO S.R.L, Rome, Italy

    Francesca Incardona

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  1. Andrea Santoro
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Consortia

EuCARE POSTCOVID study

Contributions

GM and FB developed the question research and the study protocol. AS, FB and MS helped with patients’ recruitment. JFM, CCM, ASL, MMS, FCS, MI, DJ, ES, AA, CT, JARQ, CM, IF and FI participated in EuCARE POSTCOVID study. LB, KP, EV helped in psychological tests and interpretation. AS, FB, MG, RR and GM helped in analyzing and interpreting the data. AS, FB, and GM contributed to the final data interpretation and the writing of the manuscript. All authors contributed to the editing of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Giulia Marchetti.

Ethics declarations

Ethics approval and consent to participate

The study will be conducted in accordance with the Declaration of Helsinki, ICH-GCP, and relevant national legal and regulatory requirements. The Ethics Committee Area A Milan and the Ethics Committee at each clinical research site have approved the study protocol, informed consent forms, and participant information materials before the beginning of the study commences (version 1.1; 08/02/2022). Each enrolled subjects sign an informed consent for study participation and personal data handling before enrollment. The confidentiality of all study participants will be protected, and all data will be kept confidential and stored in accordance with regulatory laws. Data dissemination will only occur in anonymous form, and personal information will not be released without the patient’s written consent.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Santoro, A., Bai, F., Greco, M.F. et al. Short and long-term trajectories of the post COVID-19 condition: Results from the EuCARE POSTCOVID study. BMC Infect Dis 25, 625 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12879-025-10805-w

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BMC Infectious Diseases

ISSN: 1471-2334

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