key: cord-0935029-hrn7ziyf authors: Anaya, Juan-Manuel; Rojas, Manuel; Salinas, Martha L.; Rodríguez, Yhojan; Roa, Geraldine; Lozano, Marcela; Rodríguez-Jiménez, Mónica; Montoya, Norma; Zapata, Elizabeth; Monsalve, Diana M.; Acosta-Ampudia, Yeny; Ramírez-Santana, Carolina title: Post-COVID syndrome. A case series and comprehensive review date: 2021-09-10 journal: Autoimmun Rev DOI: 10.1016/j.autrev.2021.102947 sha: 39e6bfc229dec732d752c680fa3f02496d7351ec doc_id: 935029 cord_uid: hrn7ziyf 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: 37.8–55.3), the median of post-COVID time after the first symptoms was 219 days (IQR: 143–258), 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: 238.2–1681). 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 infection 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 for their consent and were informed about the Colombian data protection law (1581 of 2012). 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 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. J o u r n a l P r e -p r o o f General characteristics of patients are shown in Table 1 Musculoskeletal, digestive (i.e., diarrhea) and neurological symptoms including depression were the most frequent observed during PCS (Table 1 - Figure 2 A-B). 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 2C ). 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 antibodies (value of ≥0.80 U/mL, Figure 3 ). 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 (11196 patients) that fulfilled the inclusion criteria, and they were included in the quantitative and qualitative synthesis ( Figure 1 and Supplementary Material 2) 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. J o u r n a l P r e -p r o o f 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) . 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, convalescent patients yielded high levels of tumor necrosis factor (TNF) and IL-1β [62] . Recovered patients showed high levels of endothelial activation markers and pro-inflammatory mediators such as growth factors platelet-derived growth factor, vascular endothelial growth factor, MIP-1β, eotaxin, IL-12p70, and IL-17A [63] . Thus, suggesting that clinical manifestations in PCS could be associated to 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] . Persistent elevation of IL-6 levels, an increase of the angiotensin-converting enzyme 2 in the peripheral nervous system and mast cell participation have been considered to explain the musculoskeletal symptoms in PCS [70] [71] [72] . Similarly, over-activation of nociceptive neurons, secondary to neurotropism of the virus, may cause prolongation of symptoms [73] . It is possible that most of the inflammatory response caused by the virus affects the integrity of the central and peripheral nervous system, which promotes the perpetuation of pain after the acute illness [74] . On the other hand, inflammatory damage, triggered by acute infection, would cause psychiatric disorders in predisposed individuals. These symptoms include depression, anxiety and, in worse situations, suicidal behavior [75] . Autonomic dysfunction was confirmed in our study. Orthostatic symptoms and hyperhidrosis have been described [56] . To date, it is unknown if a pre-existing history of minor autonomic symptoms may have some type of relation with autonomic disorders in PCS [76] . These results are relevant since disorders such as postural orthostatic tachycardia syndrome (POTS) and other autonomic dysfunctions may emerge after infectious triggers such as SARS-CoV-2 [77] [78] [79] [80] [81] . The mechanisms behind autonomic dysfunction are not clear. However, autoimmune phenomena could be associated with its appearance [82] . Production of autoantibodies against α1, β1 and β2 receptors, angiotensin II receptor type 1, opioids 1, acetylcholine, M2 and M4S receptors are associated with development of POTS [36, [83] [84] [85] . This immune mechanism, secondary to SARS-CoV2, could be triggered through molecular mimicry between antigens of autonomic nerve J o u r n a l P r e -p r o o f fibers, autonomic ganglia, and SARS-CoV2 antigens, as described in some autoimmune conditions. Respiratory symptoms in PCS are common. The meta-analysis indicated that up to 48% of patients with PCS persisted with respiratory symptoms. Some studies have shown the persistence of pulmonary radiological and functional changes after acute infection [53] . Among the main respiratory functional changes, alteration in gas transfer measured by diffusing capacity for carbon monoxide (D LCO ) has been documented up to 12 weeks of follow-up [13, [86] [87] [88] . D LCO alteration could be associated with interstitial and vascular damage, secondary to acute infection [89, 90] . These features may depend on the severity of the disease during the acute COVID-19 [91] [92] [93] . Pulmonary radiological alterations have been documented after 12 months post-infection [53] . 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 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. J o u r n a l P r e -p r o o f 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 mechanisms beyond the humoral immune response can influence the persistence and/or triggering of PCS, such as viral shedding, therapy, clinical management, immune response, social isolation, comorbidities, age, sex, among others [54] . In terms of viral shedding, some studies have shown that persistent fragments of viral genes, including in feces though not infectious, could induce a hyperimmune response that explaining the persistence of symptoms in post-COVID patients [99, 100] . Moreover, even if the virus is cleared, and there are high neutralizing antibody titers, the immune system could continue to be overactive, thus inducing PCS [99] . 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. 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A Systematic Review of the Current Data 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.