ABSTRACT
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).
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.