Advertisement

Exploring the trajectory recovery curve of the number of post-COVID Symptoms: The LONG-COVID-EXP-CM Multicenter Study

Open AccessPublished:February 08, 2022DOI:https://doi.org/10.1016/j.ijid.2022.02.010

      Highlights

      • This multicenter study included 1563 hospitalized patients with COVID-19.
      • Almost 50% of patients developed ≥3 post-COVID-19 symptoms 6 months after infection.
      • A trajectory curve reveals overall decrease in the number of post-COVID-19 symptoms.

      Abstract

      Objectives

      This multicenter study investigated the recovery curve of the number of post-COVID-19 symptoms in previously hospitalized patients using an exponential decay model and mosaic plots.

      Methods

      Patients hospitalized during the first wave of the pandemic (from March 10, 2010–May 31, 2020) due to COVID-19 from 5 hospitals in Madrid, Spain were scheduled for 2 telephone interviews at 2 follow-ups with a 5-month period in between and were asked about the presence of post-COVID-19 symptoms. The total number of post-COVID-19 symptoms was monitored. Clinical features, symptoms at hospital admission, and hospitalization data were collected from medical records.

      Results

      A total of 1593 patients who had COVID-19 were assessed 8.4 (T1) and 13.2 (T2) months after hospitalization. The mean number of post-COVID-19 symptoms was 2.6 (SD 2.0) at T1 and 1.5 (SD 1.4) at T2. The trajectory curve showed a decrease in prevalence trend. The analysis also revealed that 985 (61.8%) subjects reported more (T1>T2), 549 (34.5%) equal (T1 = T2), and 59 (3.7%) fewer (T1<T2) post-COVID-19 symptoms in the first tertile (T1: 8.4 months) compared with the second tertile (T2: 13.2 months) assessment.

      Conclusions

      Current trajectory analysis revealed an overall decrease in the tendency in the number of post-COVID-19 symptoms throughout the 2 years after the infection.

      Keywords

      Introduction

      Evidence supports that between 35% to 60% of COVID-19 survivors will experience post-COVID-19 symptoms (
      • Fernández-de-las-Peñas C
      • Palacios-Ceña D
      • Gómez-Mayordomo V
      • Florencio LL
      • Cuadrado ML
      • Plaza-Manzano G
      • Navarro-Santana M.
      Prevalence of Post-COVID-19 symptoms in hospitalized and non-hospitalized COVID-19 survivors: A systematic review and meta-analysis.
      ). The presence of post-COVID-19 symptoms is associated with worse quality of life (
      • Malik P
      • Patel K
      • Pinto C
      • Jaiswal R
      • Tirupathi R
      • Pillai S
      • Patel U.
      Post-acute COVID-19 syndrome (PCS) and health-related quality of life (HRQoL): A systematic review and meta-analysis.
      ). Almost 90% of studies investigating post-COVID-19 symptoms are cross-sectional (
      • Fernández-de-las-Peñas C
      • Palacios-Ceña D
      • Gómez-Mayordomo V
      • Florencio LL
      • Cuadrado ML
      • Plaza-Manzano G
      • Navarro-Santana M.
      Prevalence of Post-COVID-19 symptoms in hospitalized and non-hospitalized COVID-19 survivors: A systematic review and meta-analysis.
      ;
      • Malik P
      • Patel K
      • Pinto C
      • Jaiswal R
      • Tirupathi R
      • Pillai S
      • Patel U.
      Post-acute COVID-19 syndrome (PCS) and health-related quality of life (HRQoL): A systematic review and meta-analysis.
      ). Longitudinal studies assessing symptoms at different follow-up up periods have provided heterogeneous results.
      • Huang L
      • Yao Q
      • Gu X
      • et al.
      1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study.
      reported a decrease of most post-COVID-19 symptoms, whereas
      • Seeßle J
      • Waterboer T
      • Hippchen T
      • et al.
      Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study.
      reported a decrease in some post-COVID-19 symptoms but an increase in others. Understanding the longitudinal evolution of post-COVID-19 symptoms could optimize patient care and public health outcomes.
      This multicenter study presents 2 approaches analyzing the trajectory recovery curve of the number of post-COVID-19 symptoms: (1) an exponential bar plot model to assess the trajectory curve of post-COVID-19 symptoms; (2) mosaic plots to investigate the patient-to-patient changes in post-COVID-19 symptoms during the first year after hospitalization.

      Methods

      The LONG-COVID-EXP-CM is a multicenter cohort study including individuals hospitalized during the first wave of the pandemic (from March 10, 2020–May 31, 2020) in 5 hospitals of Madrid, Spain due to SARS-CoV-2 infection (ICD-10 code) diagnosed using RT-PCR technique and radiological findings. From all patients hospitalized during the first wave, a sample of 400 individuals from each hospital was randomly selected by a computer software. The ethics committees of all involved hospitals approved the study (HCSC20/495E, HSO25112020, HUFA 20/126, HUIL/092-20, HUF/EC1517). Informed consent was obtained from all participants.
      Patients were scheduled for 2 telephone interviews at 2 follow-up periods with a 5-month period in between. Patients were systematically asked about a list of post-COVID-19 symptoms but were free to report any additional symptom that they experienced. We pooled the total number of post-COVID-19 symptoms. Demographic (age, gender, height, weight), clinical (medical comorbidities), and hospitalization (onset symptoms at hospital admission, days at the hospital, and intensive care unit admission) data were collected from medical records. These variables were adjusted in the analyses.
      The exponential curves were fitted to the data according to the formula y=Kect; where y represents the number of post-COVID-19 symptoms at a time t (in months), and K and c are the parameters of the model. The mosaic plots were created categorizing the number of post-COVID-19 symptoms in individuals with ≥3 post-COVID-19 symptoms.

      Results

      From 2000 patients randomly selected to participate, data from 1593 (46.4% women, age: 61 ± 16 years) were collected at hospital admission, at T1 (mean: 8.4, range 6 to 10), and T2 (mean: 13.2, range 11 to 15) months after hospital discharge.
      The mean number of post-COVID-19 symptoms was 2.6 ± 2.0 at T1 and 1.5 ± 1.4 at T2 Figure 1. graphs the fitted exponential curve showing a decrease in prevalence trend in the number of post-COVID-19 symptoms. The analysis also revealed that 985 (61.8%) subjects reported more (T1>T2), 549 (34.5%) equal (T1 = T2), and 59 (3.7%) fewer (T1<T2) post-COVID-19 symptoms at T1 compared with T2 assessment.
      Figure 1:
      Figure 1Recovery curve of the number of post-COVID-19 symptoms. Opacity indicates the sample size at that follow-up time. Asterisks represent then mean values taken at T1 and T2 follow-up periods.
      Figure 2 shows the mosaic plots according to the prevalence of individuals with ≥3 post-COVID-19 symptoms. As it can be seen, 47.8% (763/1,593) patients exhibited ≥3 post-COVID-19 symptoms at T1, whereas just 25.3% (403/1,593) at T2. Only 1 of 5 patients (n = 302, 18.9%) were free of any post-COVID-19 symptom at T1, whereas 32.1% (n = 511) were free of any post-COVID-19 symptom at T2.
      Figure 2:
      Figure 2Mosaic plot of the number of post-COVID-19 symptoms categorized (≥3 post-COVID-19 symptoms) at T1 (8.4 months after hospital discharge) versus T2 (13.2 months after hospital discharge).

      Discussion

      To the best of our knowledge, this is the first study to analyze the trajectory recovery curve of the number of post-COVID-19 symptoms in previously hospitalized COVID-19 survivors. The overall tendency was a decrease in the number of post-COVID-19 symptoms throughout the following 2 years after the infection. The mosaic plots revealed that almost 50% of patients developed ≥3 post-COVID-19 symptoms the months after infection (T1), with a decrease of 50% at 1 year (T2).
      There is evidence that long-lasting proinflammatory cytokine and interleukin storms associated with the SARS-CoV-2 virus could lead to an exaggerated immune response by inducing hyperactivation of T cells, macrophages, and natural killer cells (
      • Coomes EA
      • Haghbayan H.
      Interleukin-6 in Covid-19: A systematic review and meta-analysis.
      ,
      • Mulchandani R
      • Lyngdoh T
      • Kakkar AK.
      Deciphering the COVID-19 cytokine storm: Systematic review and meta-analysis.
      ). This immune response could promote atypical response of the mast cells (
      • Afrin LB
      • Weinstock LB
      • Molderings GJ.
      COVID-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome.
      ) and an overexpression of the angiotensin-converting enzyme II (ACE2) and transmembrane serine protease 2 (TMPRSS2) receptor at different levels (
      • Shiers S
      • Ray PR
      • Wangzhou A
      • Sankaranarayanan I
      • Tatsui CE
      • Rhines LD
      • Li Y
      • Uhelski ML
      • Dougherty PM
      • Price TJ.
      ACE2 and SCARF expression in human dorsal root ganglion nociceptors: implications for SARS-CoV-2 virus neurological effects.
      ), explaining the plethora of post-COVID-19 symptoms. The trajectory curve identified suggests that post-COVID-19 symptoms could be present up to 2 years after infection. Therefore, identifying the risk factors associated with post-COVID-19 symptomatology may help in their management (
      • Fernández-de-las-Peñas C
      • Pellicer-Valero OJ
      • Navarro-Pardo E
      • Palacios-Ceña D
      • Florencio LL
      • Guijarro C
      • Martín-Guerrero JD.
      Symptoms experienced at the acute phase of SARS-CoV-2 infection as risk factor of long-term post-COVID Symptoms: The LONG-COVID-EXP-CM Multicenter Study.
      ).
      These results should be considered according to weaknesses of the study. First, only hospitalized patients aged 60 years were included. Second, we pooled the number of post-COVID-19 symptoms. The trajectory curve of any particular post-COVID-19 symptom or those grouped by system could be different.

      Consent to participate

      Participants provided informed consent before collecting data.

      Consent for publication

      No personal info of any patient is provided in the text.

      Role of the Funding Source

      The LONG-COVID-EXP-CM is supported by a grant of Comunidad de Madrid y la Unión Europea, a través del Fondo Europeo de Desarrollo Regional (FEDER), Recursos REACT-UE del Programa Operativo de Madrid 2014-2020, financiado como parte de la respuesta de la Unión a la pandemia de COVID-19. The sponsor had no role in the design, collection, management, analysis, or interpretation of the data; and the draft, review, or approval of the manuscript or its content. The authors were responsible for the decision to submit the manuscript for publication, and the sponsor did not participate in this decision.

      Author Contributions

      Dr Fernández-de-las-Peñas and Dr. Pellicer-Valero had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: all authors. Drafting of the manuscript: all authors. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: Dr. Martín-Guerrero. Supervision: Dr. Pellicer-Valero.

      Conflict of Interest

      No conflict of interest is declared by any of the authors.

      References

        • Afrin LB
        • Weinstock LB
        • Molderings GJ.
        COVID-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome.
        Int J Infect Dis. 2020; 100: 327-332
        • Coomes EA
        • Haghbayan H.
        Interleukin-6 in Covid-19: A systematic review and meta-analysis.
        Rev Med Virol. 2020; 30: 1-9
        • Fernández-de-las-Peñas C
        • Palacios-Ceña D
        • Gómez-Mayordomo V
        • Florencio LL
        • Cuadrado ML
        • Plaza-Manzano G
        • Navarro-Santana M.
        Prevalence of Post-COVID-19 symptoms in hospitalized and non-hospitalized COVID-19 survivors: A systematic review and meta-analysis.
        Eur J Int Med. 2021; 92 (2021): 55-70
        • Fernández-de-las-Peñas C
        • Pellicer-Valero OJ
        • Navarro-Pardo E
        • Palacios-Ceña D
        • Florencio LL
        • Guijarro C
        • Martín-Guerrero JD.
        Symptoms experienced at the acute phase of SARS-CoV-2 infection as risk factor of long-term post-COVID Symptoms: The LONG-COVID-EXP-CM Multicenter Study.
        Int J Infect Dis. 2022 Jan 8; (S1201-9712(22)00007-8)
        • Huang L
        • Yao Q
        • Gu X
        • et al.
        1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study.
        Lancet. 2021; 39: 747-758
        • Malik P
        • Patel K
        • Pinto C
        • Jaiswal R
        • Tirupathi R
        • Pillai S
        • Patel U.
        Post-acute COVID-19 syndrome (PCS) and health-related quality of life (HRQoL): A systematic review and meta-analysis.
        J Med Virol. 2022; 94: 253-262
        • Mulchandani R
        • Lyngdoh T
        • Kakkar AK.
        Deciphering the COVID-19 cytokine storm: Systematic review and meta-analysis.
        Eur J Clin Invest. 2021; 51: e13429
        • Seeßle J
        • Waterboer T
        • Hippchen T
        • et al.
        Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study.
        Clin Infect Dis. 2021 Jul 5; : ciab611
        • Shiers S
        • Ray PR
        • Wangzhou A
        • Sankaranarayanan I
        • Tatsui CE
        • Rhines LD
        • Li Y
        • Uhelski ML
        • Dougherty PM
        • Price TJ.
        ACE2 and SCARF expression in human dorsal root ganglion nociceptors: implications for SARS-CoV-2 virus neurological effects.
        Pain. 2020; 161: 2494-2501