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Background: At least 10% of SARS-CoV-2 infected patients suffer from persistent symptoms for >12 weeks, known as post-COVID-19 condition (PCC) or Long Covid. Reported symptomatology is diverse with >200 physical and neurological debilitating symptoms. Here, we analyzed pro-inflammatory cytokine levels as a potential mechanism underlying persistent symptomatology. Method(s): Clinical data and samples used belong to the KING cohort extension, which includes clinically well characterized PCC (N=358, 59 persistent symptoms evaluated), COVID-19 recovered and uninfected subjects. We used Gower distances to calculate symptom's similarity between PCC and Ward's hierarchical clustering method to identify different symptom patterns among PCC patients. Cytokine levels of randomly selected PCC, recovered and uninfected subjects (N=193) were measured on plasma samples collected >6 months after acute infection using the 30-Plex Panel for Luminex. Mann- Whitney t-test was used to compare PCC vs recovered groups and Kruskal-Wallis t-test for >2 groups comparisons (PCC vs recovered vs Uninfected and within PCC clusters). FDR correction was applied for statistical significance (p-adj). Result(s): Hierarchical clustering identified 5 different PCC clusters according to their symptomatology, where PCC3 and PCC5 clusters showed higher prevalence of women ( >80%) and more persistent symptoms, while acute COVID-19 was mild in >80% of the patients. We selected 91 PCC (belonging to each cluster), 57 recovered and 45 uninfected subjects for cytokine profiling (Table 1). 13 soluble markers were significantly elevated (IL-1beta, Eotaxin, MIP-1beta, MCP-1, IL-15, IL-5, HGF, IFN-alpha, IL-1RA, IL-7, MIG, IL-4 and IL-8) in PCC and recovered groups compared to uninfected subjects (all p-adj< 0.04). In addition, PCC subjects tended towards higher levels of IL-1RA compared to recovered group (padj= 0.071). Within PCC clusters, FGF-basic and RANTES were elevated while IL-2 and MIG were decreased in PCC3 and PCC5 compared to the other PCC clusters (all p-adj< 0.04). TNF-alpha, IP-10, G-CSF and MIP-1alpha were decreased in PCC3 and PCC5 not reaching statistical significance (all p-adj=0.07). Conclusion(s): Some cytokines remained altered in all SARS-CoV-2 infected subjects independently of persistent symptoms after 6 months from acute infection. Differences between PCC and recovered individuals are limited after correction. Importantly, PCC cytokine profiles showed differences between clusters, which suggests different PCC subsyndromes with distinct etiology. Subjects Characteristics (Table Presented).
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Background: Over 600 million of COVID-19 cases have been reported. A remarkable fragment of these cases are reinfections, which are mostly explained by the genomic variability of the SARS-CoV-2 variants. However, little is known about other factors fostering these reinfections. Method(s): We recorded clinical and demographic data from subjects (N=3303, March 2020 - March 2022) with at least 2 PCR+ events separated by >=90 days, analyzed by the Microbiology Department, Northern Metropolitan Clinical Laboratory from Germans Trias i Pujol Hospital (Spain). Data collected included: age, sex, comorbidities, adjusted morbidity group (GMA), hospitalization, symptomatology, NAAT (PCR, TMA) tests, antigen tests, serology, and vaccination. Temporal data was encoded using Python, and demographic characterization was performed under R. Result(s): We identified 2344 cases of confirmed reinfections, where the 2 PCR+ events were separated by >=90 days and a negative test was obtained between episodes. 72.2% of reinfected subjects were females with a median age of 45 IQR [28-63] years. Age density analysis showed three peaks at 24, 45, and 85 years, probably mostly composed of young people, who usually are less cautious, healthcare workers, and people living in nursing homes, respectively, being all of them groups prone to be tested. Regarding health status, 86.2% of participants had at least one chronic condition, with 40.5% of patients having chronic conditions in >=4 systems based on GMA assessment. Interestingly, 75.2% of reinfected subjects < 26 years had at least one chronic condition. 121 (4.2%) participants were hospitalized during a COVID-19 episode, highlighting 8.3% (N=10) of them hospitalized during the reinfection (half of them vaccinated before hospitalization), and 5% (N=6) of them during both infections. The severity of the second infection may be caused by a diminished acquired immunity after the first infection. Time between reinfections density analysis provided three peaks at ~200, ~400, and ~600 days, corresponding with time between waves. A decrease of reinfections was observed between 40 and 100 days after vaccination, which would be the period of highest protection against reinfection. Conclusion(s): SARS-CoV-2 reinfections are more prevalent among women. Importantly, people with an undermined health status, independently of age, are more sensitive to reinfections, but in most of the cases no hospitalization was required. Finally, vaccination seems to have a short protective effect on reinfection.
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Background: The Post-COVID-19 Condition (PCC) is a novel, long-lasting, poorly understood and highly disabling post-viral syndrome, which poses enormous healthcare, economic and socio-political challenges. Lack of validated biomarkers forces clinical management to be based on clinical definitions, which are imprecise. In the clinic, symptoms tend to present in clusters, which have yet to be properly defined. Also, it is unclear how often PCC resolves, and which factors influence PCC resolution. Method(s): To delineate PCC presentation clusters and explore factors related with PCC resolution, we performed a 2-year prospective cohort study in individuals who recovered from acute COVID-19 regardless of its acute and post-acute severity. All subjects were systematically followed in the outpatient post-COVID-19 clinic of a tertiary care hospital in Spain. PCC was defined as per the WHO 2021 definition. Persistent symptoms were those present >3 months after acute COVID-19, and lasting for >2 consecutive months. PCC recovery was the absence of PCC symptoms during >3 consecutive months. Symptom clusters were identified using Gower's distance matrices, dendograms, PCA and Silhouette techniques. Factors associated with PCC recovery were identified using a directed acyclic graph approach. Result(s): 548 subjects were included;341 (62%) had PCC. The latter were mostly females (69.8%) with mean age of 47.9 (SD 12.2) years. Only 38.1% required hospitalization and 9% required high-flow oxygen during acute COVID-19. Their most frequent comorbidities were allergy (31.4%), obesity (24.8%), dyslipidemia (24.0%) and hypertension (19.6%). At least 3 symptom clusters with additive symptoms were identified: considering only symptoms present in >35% of subjects, Cluster A was enriched in fatigue and dyspnea;Cluster B had Cluster A symptoms plus headache, arthralgia and neurocognitive complains;Cluster C had Cluster B symptoms plus chest pain and tachycardia. PCC recovery was achieved by 26 (7.6%) individuals over 2 years. Male sex (RR 3.01;CI 1.4-6.3), ICU admission (RR 7.85;CI 2.6-23.2), metabolic comorbidity (RR 2.07;CI 1.1-4.1), and mild acute COVID-19 (RR 2.70;CI 1.1-4.6) increased the likelihood of PCC recovery. Conversely, subjects with muscle pain, impaired attention, dyspnea, and tachycardia were less likely to recover from PCC (RR 0.26;CI 0.13-0.52). Conclusion(s): At least 3 severity clusters can be identified in the PCC. Over the first 2 years, only a minority of subjects fully recover from PCC.
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Introduction: Rehabilitation in subjects with severe coronavirus disease 2019 (COVID-19) pneumonia has been widely recommended. However, data regarding the starting time of rehabilitation, subjects and healthcare workers safety are limited. We aimed to assess the safety and characterize the effect of early and non-early physiotherapy on severe COVID-19 pneumonia subjects. Method(s): Retrospective cohort study including a consecutive sample of surviving subjects admitted to an acute care hospital due to severe COVID-19 pneumonia from March 13th to May 15th of 2020. Subjects were separated into three groups: non-physical therapy, early physiotherapy (onset <7 days of admission), and non-early physiotherapy. Subject and therapist safety, and length of hospital stay were the main evaluated outcomes. Result(s): A total of 159 subjects were included (72% male;median age 62 years). Rehabilitation was performed on 108 subjects (32 early and 76 non-early physiotherapy). The length of hospital stay was 19 (IQR 36.25) and 34 days (IQR 27.25) (p=0.001) for early and non-early physiotherapy groups, respectively. No physiotherapist was infected and no subject adverse effect was identified. Multivariate analysis of subjects receiving physiotherapy during admission identified obesity (Odds ratio [OR] 3.21;p-value 0.028), invasive mechanical ventilation (OR 6.25;p-value <0.001) and non-early physiotherapy (OR 3.54;p-value 0.017) as independent factors associated with a higher risk of prolonged hospital stay. Conclusion(s): Rehabilitation in acute severe COVID-19 pneumonia is safe for subjects and healthcare workers, and could reduce the length of hospitalization stay, especially in those that may start early.
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Background. There are few real-world data on the use of remdesivir (RDV) looking at timing of initiation in relation to symptom onset and severity of presenting disease. Methods. We conducted multi-country retrospective study of clinical practice and use of RDV in COVID-19 patients. De-identified medical records data were entered into an e-CRF. Primary endpoints were all-cause mortality at day 28 and hospitalization duration. We assessed time from symptom onset to RDV start and re-admission. We included adults with PCR-confirmed symptomatic COVID-19 who were hospitalized after Aug 31, 2020 and received at least 1 dose of RDV. Descriptive analyses were conducted. Kaplan-Meier methods were used to calculate the mortality rate, LogRank test to compare groups defined by severity of disease. Competing risk regression with discharge and death as competing events was used to estimate duration of hospitalization, and Gray's test to compare the groups. Results. 448 patients in 5 countries (12 sites) were included. Demographics are summarized (table) by 3 disease severity groups at baseline: no supplemental oxygen (NSO), low flow oxygen ≤6 L/min (LFO), and high-flow oxygen > 6L/min (HFO). No demographic differences were found between groups except for the higher percentage of cancer/chemotherapy patients in NSO group. Corticosteroids use was HFO 73.6%, LFO 62.7%, NSO 58.0%. Mortality rate was significantly lower in NSO, and LFO groups compared with HFO (6.2%, 10.2%, 23.6%, respectively;Fig1). Median duration of hospitalization was 9 (95%CI 8-10), 9 (8-9), 13 (10-15) days, respectively (Fig2). Median time from first symptom to RDV start was 7 days in all 3 groups. Patients started RDV on day 1 of hospitalization in HFO and LFO and day 2 on NSO groups. And received a 5 day course (median). Readmission within 28-days of discharge was < 5% and similar across all 3 groups. Conclusion. In this real-world cohort of COVID-19 positive hospitalized patients, RDV use was consistent across countries. RDV was started within a median of 7 days from symptom within 2 days of admission and given for a median of 5 days. Higher mortality rate and duration of hospitalization was seen in the HFO group and similar rates seen in the LFO and NSO groups. Readmission was consistently low across all 3 groups.
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Background: Persistent symptoms after the acute SARS-CoV-2 infection are referred to as post-COVID-19 syndrome(PCS). Fatigue, palpitations and exercise intolerance are common complains among PCS patients in whom unexplained sinus tachycardia is a frequent observation. Objective: To evaluate the prevalence and the pathophysiological mechanisms of IST in a consecutive and prospective population of patients with PCS. Methods: Consecutive patients with persistent symptoms 3 months after an acute COVID-19 were prospectively evaluated at a multi-disciplinary PCS unit. All patients were screened for IST and those with confirmed criteria underwent comprehensive CV examination: ECO, 24h Holter (assessment of the cardiac autonomic function), QoL Questionnaire (MLHFQ), six-min walking test (6MWT) and blood sample with inflammation and myocardial biomarkers. Two control patients, matched by age and gender, were assigned to each case: one with previous SARS-CoV-2 infection without PCS (group 2,recovered asymptomatic) and one without prior COVID (group 3,uninfected). Results: IST were met in 43/200 PCS patients (21%) being more common in young (mean age 39y) woman (91%) without clinical history and with mild COVID (not requiring hospital admission during the acute phase). Mean HR 96±3 (supine) and 112±17 (upright position), with 8 patients fulfilling diagnostic of POTS. No underlying structural heart disease, proinflammatory state, myocyte injury or hypoxia were identified 6MWT showed a significantly diminished exercise capacity(59% of the estimated distance). An impaired QoL was also identified. Regarding the 24h Holter, all HRV parameters were significantly deteriorated in IST patients compared with control groups (significantly decrease in time and frequency domain parameters). The most reduced components were those related with the cardiovagal tone: PNN50 4±4 in group 1 (vs 11±9 in group 2 and 18±9 in group 3;p<0 002);HF band 336±280 (vs 823±1200 in group 2 and 1229±630 in group 3;p=0 01). Conclusion: IST is a prevalent condition among PCS patients and may at least partially explain the prevalent symptoms of fatigue, impaired exercise, and palpitations, Cardiac ANS imbalance with decreased parasympathetic activity may account as a plausible explanation.
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Background: Persistent symptoms after the acute phase of SARS-CoV-2 infection are referred to as 'post-COVID-19 syndrome' (PCS), with a reported incidence ranging between 35% and 87%. Fatigue, palpitations and exercise intolerance are common complains among PCS patients in whom unexplained sinus tachycardia, occasionally exacerbated by postural changes, is a frequent observation that remains poorly characterized. Purpose: We sought to characterize the prevalence of inappropriate sinus tachycardia (IST) and postural orthostatic tachycardia (POTS) in a consecutive and prospective population of patients with PCS. Methods: Consecutive patients with persistent symptoms 3 months after an acute SARS-CoV-2 infection were prospectively evaluated at a multi-disciplinary PCS unit. All patients were screened for IST or POTS and those with confirmed criteria underwent comprehensive cardiovascular examination including echocardiography, 24-hour Holter, Minnesota Living with Heart Failure Questionnaire (MLHFQ), six-minute walking test (6MWT) and inflammation and myocardial biomarkers. Two control patients, matched by age and gender, were assigned to each case: one with previous SARS-CoV-2 infection without PCS (group 2) and one without prior SARS-CoV-2 infection (group 3). Results: IST or POTS criteria were met in 34 out of the 200 PCS patients (17%). The mean age was 39 ± 10 years, with 29 women (91%). The interval from the index COVID-19 disease to the PCS diagnosis was 71 ± 17 days, with a majority of patients (n = 29,85%) not requiring hospital admission during the acute phase. At physical examination, the mean heart rate was 96 ± 3bpm at supine and 112 ± 17bpm at the upright position, with 8 patients fulfilling diagnostic criteria of POTS. No underlying structural heart disease, pro-inflammatory state, myocyte injury or hypoxia were identified among our patient population. The 6MWT showed a significantly diminished exercise capacity with a 59% of the estimated distance after adjustment by age, sex and body mass index;an impaired quality of life was also identified, as suggested by a median MLFHQ total score of 67 out of 105 points. The 24-hour Holter showed an increase in HR predominantly during daytime in group 1 (mean daytime HR of 94 ± 3bpm), an altered heart rate variability with a decrease in time domain parameters [PNN50 4 ± 4 in group 1 (vs. 11 ± 9 in group 2 and 18 ± 9 in group 3;p < 0.002)respectively;SD 100 ± 20 (vs. 127 ± 38 and 136 ± 13;p = 0.009) and a decrease in frequency domain parameters [LF 751 ± 450 (vs. 1721 ± 1009 and 2199 ± 920;p = 0.01), HF 336 ± 280 (vs. 823 ± 1200 and 1229 ± 630;p = 0.01)]. Conclusions: IST and its POTS variant are a prevalent condition among PCS patients and may at least partially explain the common symptoms of fatigue, impaired exercise and palpitations that characterize the PCS. Cardiac autonomic nervous system imbalance may account as a plausible pathophysiological mechanism of IST in PCS patients.
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Background: One of the fundamental pillars of SARS-CoV-2 pandemic control and vaccine development is understanding mid-and long-term immunity. Early humoral response has been extensively studied, however data on what recovered individuals are still scarce and the most recent studies are based on few time points over time, which limits the comprehension of the longitudinal pattern of the potential changes. In this study we have evaluated the neutralizing activity and IgG antibody titer against SARS-CoV-2 in mild/ asymptomatic and hospitalized COVID-19 individuals, over a 6-month period. Methods: We have evaluated the kinetics of the humoral immune response in 210 individuals infected by SARS-CoV-2 covering the first and second waves of COVID-19 outbreak in Catalonia (Spain). IgG antibody titer was evaluated with an in-house sandwich ELISA against the S2 subunit, the binding domain receptor (RBD) and the nucleoprotein (NP) and the neutralizing activity was evaluated by a neutralization assay with HIV reporter pseudoviruses expressing SARS-CoV-2 S protein. Statistical analyses were carried out using mixed-effects non-linear and linear models. Results: Most study participants developed a neutralizing humoral response against SARS-CoV-2, however the maximum neutralization titer was 10-fold lower in mild/asymptomatic individuals compared to those with a more severe illness. We observed a slow and progressive decay of neutralizing activity in individuals with mild or asymptomatic disease throughout the 6-month period. In hospitalized individuals, half maximal neutralization activity was achieved on day 10 and showed an initial rapid decline that significantly slowed and remained nearly flat after day 80. Despite this, activity at six months remained higher in hospitalized individuals compared to mild symptomatic participants. On the other hand, we observed that IgG antibody titers against S2, RBD and NP had a more marked fall without showing differences in the decay pattern between individuals with different degree of severity of the disease. Conclusion: Our data suggest that the neutralizing activity remains relatively stable for more than 6 months despite the decline in IgG antibodies, suggesting that the quality of immune response evolves and allows maintaining the neutralizing activity despite the decay in antibody titers. Our results provide a more detailed picture of the behavior of the natural humoral immune response over time that complements the current evidence on mid-term immunity.
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Background: Many immune studies of SARS-CoV-2 (CoV-2) infection have focused on the generation of virus-specific as a means of protection. However, a small group of CoV-2 infected individuals called Non-seroconverters (NSC), do not generate antibodies but experience a mild or moderate disease course. Identifying mechanism of CoV-2 control in NSC may inform the development of novel therapeutics and vaccines approaches. Methods: We identified eleven CoV-2 NSC (3.6%) from the King-cohort study (PI-20-217). NSC were defined by a positive CoV-2 PCR at the time of diagnosis in the absence of IgG, IgA and IgM in serum and plasma measured by two independent ELISA techniques. For comparison, we identify groups of CoV-2 convalescent (n=15) and low-neutralizers (n=15). We measured T-cell responses to the CoV-2 Spike (S) and Nucleocapsid (NP) recombinant proteins in PBMCs by ELISPOT and flow cytometry. We combined T-cell surface and lineage markers together with PD-1, functional (TNF, IFN-y, and IL-2) and activation induced markers (AIM: CD25, CD137 and OX40). Results: We identified CoV-2 specific CD4+ and CD8+ T-cells against the S and the NP in NSC individuals. All NSC responded to S by production of one or more cytokine in either CD4+ or CD8+ T-cells, and 57% responded to NP. Specific-CD8+ T cells against S in NSC were characterized by IFN-y, and TNF production, and we observed higher levels of TNF production as compared to low neutralizers (p=0.02). No differences were found in IFN-y, IL-2 and TNF production in S-specific CD4+ T cells between groups, nor in NP CD8+ or CD4+ T-cell responses. The levels of CD137/OX40 in CD8+ and CD4+ T cells were significantly lower in NSC in response to S (p=0.006, and p=0.012). Also, lower levels of PD-1 were observed in CD8+ T cells in response to NP in NSC (p=0.017). Conclusion: We provide evidence of SARS-CoV2 cellular immunity in NSC individuals despite the absence of humoral neutralizing responses. CD8+ and CD4+ T cells against the S and NP were present in NSC and characterized by TNF production in CD8+ T-cells in responses to S when compared to low neutralizers. Decreased levels of activation markers were observed in NSCs following S and NP stimulation. We propose a protective role of cellular immunity in NSC potentially driven by preexisting cellular responses.