key: cord-0315587-nt7x40et authors: Anaya, J.-M.; Rojas, M.; Salinas, M. L.; Rodriguez, Y.; Roa, G.; Lozano, M.; Rodriguez-Jimenez, M.; Montoya, N.; Zapata, E.; Post-COVID study group,; Monsalve, D. M.; Acosta-Ampudia, Y.; Ramirez-Santana, C. title: Post-COVID Syndrome. A Case Series and Comprehensive Review date: 2021-07-20 journal: nan DOI: 10.1101/2021.07.17.21260655 sha: 1d0f4c92291ce5ca1d09f44b05cc19d95be7dbd0 doc_id: 315587 cord_uid: nt7x40et The existence of a variety of symptoms with a duration beyond the acute phase of COVID-19, is referred to as post-COVID syndrome (PCS). We aimed to report a series of patients with PCS attending a Post-COVID Unit and offer a comprehensive review on the topic. Adult patients with previously confirmed SARS-CoV-2 infection were systematically assessed through a semi-structured and validated survey. Total IgG, IgA and IgM serum antibodies to SARS-CoV-2 were evaluated by an electrochemiluminescence immunoassay. A systematic review of the literature and meta-analysis were conducted, following PRISMA guidelines. Univariate and multivariate methods were used to analyze data. Out of a total of 100 consecutive patients, 53 were women, the median of age was 49 years (IQR: 37.8 to 55.3), the median of post-COVID time after the first symptoms was 219 days (IQR: 143 to 258), and 65 patients were hospitalized during acute COVID-19. Musculoskeletal, digestive (i.e., diarrhea) and neurological symptoms including depression (by Zung scale) were the most frequent observed in PCS patients. A previous hospitalization was not associated with PCS manifestation. Arthralgia and diarrhea persisted in more than 40% of PCS patients. The median of anti-SARS-CoV-2 antibodies was 866.2 U/mL (IQR: 238.2 to 1681). Despite this variability, 98 patients were seropositive. Based on autonomic symptoms (by COMPASS 31) two clusters were obtained with different clinical characteristics. Levels of anti-SARS-CoV-2 antibodies were not different between clusters. A total of 40 articles (11,196 patients) were included in the meta-analysis. Fatigue/muscle weakness, dyspnea, pain and discomfort, anxiety/depression and impaired concentration were presented in more than 20% of patients reported. In conclusion, PCS is mainly characterized by musculoskeletal, pulmonary, digestive and neurological involvement including depression. PCS is independent of severity of acute illness and humoral response. Long-term antibody responses to SARS-CoV-2 infection and a high inter-individual variability were confirmed. Future studies should evaluate the mechanisms by which SARS-CoV-2 may cause PCS and the best therapeutic options. During acute infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible of the coronavirus disease 2019 (COVID-19), symptoms vary from mild forms to critical and more severe cases [1] [2] [3] . Symptoms in the mildest forms include dry cough, fatigue, anosmia, and fever. On the other hand, in the most severe forms, the symptoms can progress to respiratory failure requiring invasive mechanical ventilation [2, 4, 5] . Although most of the COVID-19 patients recover completely, without sequelae, many patients may continue experiencing COVID-19 symptoms after recovery and others may even develop new symptoms [6] . Altogether, this clinical spectrum occurring after acute infection is called post-COVID syndrome (PCS) [7] . Some authors have defined PCS as the presence of signs and symptoms after acute COVID-19 infection for more than 12 weeks [8, 9] . Among the most frequently reported PCS symptoms are fatigue, headache, attention deficit, hair loss, dyspnea, myalgia, and arthralgia [10] . However, a wide variety of symptoms have been reported within the PCS involving multiple organs and systems demanding long-term follow-up [8, 9] , and even rehospitalization due to severity of PCS. In addition, most of these patients have comorbidities such as cardiovascular diseases, diabetes mellitus, obesity, cancer, and chronic kidney diseases [8, 9] . Therefore, it is crucial to understand the heterogeneity of PCS. The objective of this work was to describe the clinical and serological characteristics (i.e., antibodies anti-SARS-CoV-2) of the first 100 consecutive post-COVID of 2012). The institutional review board of the Universidad del Rosario approved the study design. A semi-structured survey was constructed based on internationally validated questionnaires that sought information during and after COVID-19 acute infection [11] [12] [13] [14] [15] . It was validated by a consensus of expert physicians. Once validation and approval were obtained, a pilot test was done in a group of 30 volunteers. The pilot phase allowed to identify additional questions to assess systemic compromise, to organize queries, and adapt them to guarantee its interpretability by the respondent. A total of 177 questions were included in the semi-structured survey, and distributed in the following areas: identification and consent, 6; sociodemographic and epidemiological characteristics, 12; past medical history, 15 (https://forms.gle/QeD96DY6NZz53hAy7). All data were collected in an electronic and secure database as described elsewhere [16] . Depression was assessed by All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. Total IgG, IgA and IgM antibodies to SARS-CoV-2 were evaluated in serum samples through the Elecsys Anti-SARS-CoV-2 electrochemiluminescence immunoassay "ECLIA" (Roche Diagnostics International AG, Rotkreuz, Switzerland). The Elecsys anti-SARS-CoV-2 S assay detects antibodies to SARS-CoV-2 Receptor Binding Domain (RBD) in a double-antigen sandwich assay format. The protocol was followed according to manufacturer instructions. Positive results by the ECLIA require a signal-to-cut-off (S/Co) value of ≥ 0.80 U/mL. Serum samples were initially analyzed directly without dilution, in case of results >250 U/mL, the serum sample was diluted 1:10, according to manufacturer's recommendations. An internal validation procedure was performed, that included samples previously tested by enzyme-linked immunosorbent assay (ELISA, Euroimmun, Luebeck, Germany), and a neutralizing antibody assay (Supplementary material 1). A systematic review of the literature was done following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline [19] . PubMed was systematically searched for published and unpublished studies. Additional manual searches of the references cited in the articles were done. The search included articles up to May 8 th , 2021. No restrictions were placed on study period or sample size. Other information sources such as personal communications and author's repositories were included. Terms used for this search were: ("Post-COVID" OR "Long COVID") AND ("COVID-19"). Articles in Spanish and English were included. Studies meeting the following criteria were included: (a) studies describing clinical manifestations after acute COVID-19, (b) studies evaluating patients in clinical settings, (c) case series, cross-sectional, case-control, cohort, or clinical trial studies were also included, (d) studies including data from national registries or unaudited databases were excluded. Study selection was done independently by three reviewers (i.e., GR, ML, JMA) who evaluated studies for eligibility in a two-step procedure. In the first phase, all identified titles and abstracts were evaluated to ensure the relationship with PCS. The potentially relevant articles were subsequently selected and evaluated again in the second phase. Here, a full-text review was done to determine whether the studies effectively reported the data about the clinical features of PCS. Retrieved articles were rejected if the eligibility criteria were not meet, and a fourth reviewer (i.e., MRJ) was consulted in cases in which the eligibility criteria were not clear. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. To summarize the diverse information of frequencies of post-COVID manifestations, a meta-analysis approach was employed using Metafor R package (http://www.jstatsoft.org/v36/i03/). The logit transformed proportion was used to derive the weighted proportion. The overall pooled prevalence and 95% confidence intervals (CIs) were obtained using a random effect model for each clinical manifestation. Statistical heterogeneity between studies was evaluated by Cochran's Q-statistic, as well as Tau 2 and I 2 statistics. A P value > 0.10 in Qstatistics or <50% in I 2 statistic indicated a lack of heterogeneity. Next, we aimed to evaluate the likely influence of autonomic symptoms in severity of PCS, and their association with clinical phenotypes. Thus, a K-means clustering analysis based on the algorithm of Hartigan and Wong on weighted COMPASS 31 domains was conducted [20] . Shortly, the K-means method, aims to partition the points into k groups such that the sum of squares from points to the assigned cluster centers is minimized. For this analysis, 25 random sets were used, and a final optimal number of clusters were obtained based on the average silhouette width. In addition, patients were evaluated based on their clinical status during acute COVID-19. The significance level of the study was set to 0.05. Statistical analyses were done using R software version 4.0.2. General characteristics of patients are shown in Table 1 . Out of a total of 100 patients, 53 were women, the median age was 49 years (IQR: 37.8 to 55.3), the median of post-COVID time was 219 days (IQR: 143 to 258), and 65 patients were hospitalized during the acute COVID-19. Constitutional symptoms, musculoskeletal and respiratory symptoms, ageusia and anosmia were the most frequent clinical manifestations registered during the acute illness (Table 1) . Musculoskeletal, digestive (i.e., diarrhea) and neurological symptoms including depression (35%) were the most frequent observed during PCS (Table 1 - Figure 2 A-B). One-third of PCS patients present with at least one musculoskeletal, respiratory, gastrointestinal and neurological symptoms simultaneously ( Figure 2C ). Interestingly, there were a reduction in the frequency of some acute symptoms reported by patients. However, arthralgia and diarrhea persisted in more than 40% of the patients during PCS ( Figure 2D ). A median of anti-SARS-CoV-2 antibodies of 866.2 U/mL (IQR: 238.2 to 1681) was observed, indicating large inter-individual variability (Table 1) . Despite this variability, almost all patients (98.0%) presented positivity for anti-SARS-CoV-2 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. 1 4 antibodies (value of ≥ 0.80 U/mL, Figure 3 ), of whom 88 patients disclosed titles above 151.4 U/mL. Evaluation of PCS based on severity of acute illness showed that hospitalized and critically ill patients were older, more likely to exhibit elevated body mass index, higher frequency of hypertension, fatigue, and fever on admission that ambulatory patients (Table 2) . Noteworthy, during the PCS a previous hospitalization was not associated with any clinical manifestation. The levels of antibodies anti-SARS-CoV-2 were lower in patients who were not previously hospitalized (Table 2) . However, ambulatory patients were evaluated in earlier phases of PCS than hospitalized and critically ill patients (Kruskal-Wallis test, P<0.0001). Initially, 1222 records were found through the database search. After duplicate studies were excluded, a total of 1208 studies were obtained. After the first records were screened by title and abstract, 42 articles were fully assessed for eligibility. Of these, 2 articles were excluded, since they reported PCS clinical manifestations but not patient data. This procedure left 40 articles (11,196 patients) that fulfilled the inclusion criteria, and they were included in the quantitative and qualitative synthesis ( Figure 1 and Supplementary Material 2) All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Out of 40 studies included in the systematic review [7,10,21-58], 30 were cohort studies, 5 cross-sectional, 3 case series, and 2 case-control studies. No clinical trials were included in the systematic review and meta-analysis. Pooled prevalence of PCS manifestations is summarized in Table 3 . Fatigue/muscle weakness, dyspnea, pain and discomfort, anxiety/depression and impaired concentration were presented in more than 20% of patients included in the meta-analysis ( Figure 4 ). These symptoms were reported in more than five manuscripts in the literature review. In addition, high methodological and statistical heterogeneity was found in this analysis, accounting for most of the imprecision detected by the Q and I 2 statistics. Based on autonomic symptoms (by COMPASS 31) two clusters were obtained (Table 4 - Figure 5A ). Impaired visual acuity and blurry vision were more frequently registered during the acute phase in patients belonging to cluster 2 that cluster 1 ( Figure 5B ), while depression, chills, weakness, diarrhea, musculoskeletal, palpitations/tachycardia, dryness, cognitive involvement, headache, dizziness, and tinnitus were more frequently observed in the post-COVID cluster 2 ( Figure 5C ). As expected, COMPASS 31 score was higher in cluster 2 than in cluster 1, as were the median Zung scores. Levels of antibodies were not different between clusters (Table 4 ). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. ; https://doi.org/10.1101/2021.07.17.21260655 doi: medRxiv preprint This study indicates that a significant number of patients present with a clinical spectrum after SARS-CoV-2 infection recovery, affecting the quality of life and requiring interdisciplinary approach. Although the cases series do not evaluate incidence nor prevalence, musculoskeletal, digestive (i.e., diarrhea) and neurological symptoms including depression were the most frequent observed in our PCS patients. Arthralgia and diarrhea were the two more frequent acute clinical manifestations persisting during the PCS. Our results were consistent with the meta-analysis in which fatigue/muscle weakness, dyspnea, pain and discomfort, anxiety/depression and impaired concentration were presented in more than 20% of patients. Noteworthy, PCS was independent of severity of acute illness and the humoral response to RBD SARS-CoV-2. The causes of PCS are under study, however the main hypotheses include a persisting chronic inflammatory process, an autoimmune phenomenon or even a hormonal imbalance as a consequence of an alteration in the hypothalamicpituitary-adrenal axis [59] . In this line, a study on COVID-19 patients at 3-6 months of convalescence showed that patients with PCS exhibit high levels of CD27 -IgD -B cells (which have been associated with autoimmune diseases such as multiple sclerosis [60]), CD8+ T cells, as well as elevated production of Th1 and Th17 cytokines, thus favoring a hyperinflammatory milieu. In addition, patients showed B cell impaired response given by IL-6/IL-10 imbalance [61] . In a similar study, All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. Persistence of symptoms has been evaluated in PCS. Moreno-Perez et al. [65] , reported that up to 50.9% of the patients considered "recovered" persisted with symptoms similar to those experienced during the acute phase. Moreover, other studies showed that the reported duration of musculoskeletal symptoms varies widely depending on duration of patients follow-up [35, [66] [67] [68] . Different protocols All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. and populations as well as the preexistence of musculoskeletal symptoms, which were not evaluated in all the studies, preclude a comparative analysis. Nevertheless, early identification would allow to focus the therapeutic management of these patients [69] . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. ; https://doi.org/10.1101/2021.07.17.21260655 doi: medRxiv preprint The mechanisms behind autonomic dysfunction are not clear. However, autoimmune phenomena could be associated with its appearance [82] . Production of autoantibodies against Some symptoms during acute COVID-19 have been reported to be predictors of PCS, including diarrhea, anosmia, dyspnea, pleurisy, skin sensitivity, and A blood type [15] . A lower SARS-CoV-2 IgG titer at the beginning of the observation period was associated with a higher frequency of PCS [94] . Severity of acute COVID-19 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. ; https://doi.org/10.1101/2021.07.17.21260655 doi: medRxiv preprint 0 suggests that convalescent critically ill patients commonly experience long-lasting mental health illness. Anxiety, depression, post-traumatic stress disorder, memory and attention disorders are common [95] . However, in our case series severity of acute disease was not associated with PCS. As expected, the levels of anti-SARS-CoV2 antibodies were lower in patients who were not previously hospitalized [96] . Our results confirm the heterogeneous but long-lasting humoral response to SARS-CoV-2 infection [97, 98] . Other PCS is mainly characterized by musculoskeletal, pulmonary, digestive and neurological involvement including depression. PCS is independent of severity of acute illness and humoral response. Our study confirms the long-term immunity for SARS-CoV-2 but also the inter-individual variability of the immune response. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. ; https://doi.org/10.1101/2021.07.17.21260655 doi: medRxiv preprint The funders had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. [26] Ordinola Navarro A, Cervantes-Bojalil J, Cobos Quevedo O de J, Avila All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. [32] Arjmand P, Murtaza F, Eshtiaghi A, Popovic MM, Kertes PJ, Eng KT. Impact of the COVID-19 pandemic on characteristics of retinal detachments: the All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. [77] Thieben MJ, Sandroni P, Sletten DM, Benrud-Larson LM, Fealey RD, All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. μ IU /mL. a P values for categorical variables were obtained by Fisher's exact test. Quantitative variables were analyzed by Kruskal-Wallis test. b A linear regression model including total SARS-CoV-2 antibodies as dependent variable was conducted. Sex, age, body mass index, clinical management, and post-COVID time were included as covariates. Linear model confirmed that post-COVID time was a confounding factor for the difference of total SARS-CoV-2 antibodies among groups (β= 4.36, P= 0.0126). In addition, significant interactions for ICU management confirmed this result (β= -5.65, P= 0.0221). * Statistically significant after Bonferroni correction. P value threshold for acute COVID-19 symptoms: 0.05/18= 0.0028; P value threshold for post-COVID symptoms: 0.05/47= 0.0011. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. ; https://doi.org/10.1101/2021.07.17.21260655 doi: medRxiv preprint Table 3 . Clinical features of post-COVID-19 patients (systematic review and metaanalysis). Male (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. NA Tau 2 is the variance of the effect size parameters across the population of studies, and it reflects the variance of the true effect size (i.e., heterogeneity among studies). I 2 refers to the percentage of heterogenetic among the included studies. NA: Not applicable/available; Estimation was done assuming a random effects model. a Results were ordered according to the number of articles included in each meta-analysis. b COVID-19 represents the total of patients reported in selected articles. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. ; https://doi.org/10.1101/2021.07.17.21260655 doi: medRxiv preprint r = 0.72, P = 2.5e−08 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. ; https://doi.org/10.1101/2021.07.17.21260655 doi: medRxiv preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 20, 2021. ; https://doi.org/10.1101/2021.07.17.21260655 doi: medRxiv preprint National Institute for Health and Care Excellence. 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(which was not certified by peer review) is the author/funder The authors would like to thank all the members of the CREA and Elizabeth T.Cirulli for their contributions and fruitful discussions during the preparation of the manuscript.