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Objective: To assess risk factors for persistence vs improvement and to describe clinical characteristics and diagnostic evaluation of subjects with post-acute sequelae of COVID-19/post-COVID-19 syndrome (PCS) persisting for more than one year. Design: Nested population-based case-control study. Setting: Comprehensive outpatient assessment, including neurocognitive, cardiopulmonary exercise, and laboratory testing in four university health centres in southwestern Germany (2022). Participants: PCS cases aged 18 to 65 years with (n=982) and age and sex-matched controls without PCS (n=576) according to an earlier population-based questionnaire study (six to 12 months after acute infection, phase 1) consenting to provide follow-up information and to undergo clinical diagnostic assessment (phase 2, another 8.5 months [median] after phase 1). Main outcome measures: Relative frequencies of symptoms and health problems and distribution of symptom scores and diagnostic test results between persistent cases and controls. Additional analysis included predictors of changing case or control status over time with adjustments for potentially confounding variables. Results: At the time of clinical examination (phase 2), 67.6% of the initial cases (phase 1) remained cases, whereas 78.5% of the controls continued to report no health problems related to PCS. In adjusted analyses, predictors of improvement among cases were mild acute index infection, previous full-time employment, educational status, and no specialist consultation and not attending a rehabilitation programme. Among controls, predictors of new symptoms or worsening with PCS development were an intercurrent secondary SARS-CoV-2 infection and educational status. At phase 2, persistent cases were less frequently never smokers, had higher values for BMI and body fat, and had lower educational status than controls. Fatigue/exhaustion, neurocognitive disturbance, chest symptoms/breathlessness and anxiety/depression/sleep problems remained the predominant symptom clusters, and exercise intolerance with post-exertional malaise for >14 h (PEM) and symptoms compatible with ME/CFS (according to Canadian consensus criteria) were reported by 35.6% and 11.6% of persistent cases, respectively. In adjusted analyses, significant differences between persistent cases and stable controls (at phase 2) were observed for neurocognitive test performances, scores for perceived stress and subjective cognitive disturbances, symptoms indicating dysautonomia, depression and anxiety, sleep quality, fatigue, and quality of life. In persistent cases, handgrip strength, maximal oxygen consumption, and ventilator efficiency were significantly reduced. However, there were no differences in measures of systolic and diastolic cardiac function, in the level of pro-BNP blood levels or other laboratory measurements (including complement activity, serological markers of EBV reactivation, inflammatory and coagulation markers, cortisol, ACTH and DHEA-S serum levels). Screening for viral persistence (based on PCR in stool samples and SARS-CoV-2 spike antigen levels in plasma in a subgroup of the cases) was negative. Sensitivity analyses (pre-existing illness/comorbidity, obesity, PEM, medical care of the index acute infection) revealed similar findings and showed that persistent cases with PEM reported more pain symptoms and had worse results in almost all tests. Conclusions: This nested population-based case-control study demonstrates that the majority of PCS cases do not recover in the second year of their illness, with patterns of reported symptoms remaining essentially similar, nonspecific and dominated by fatigue, exercise intolerance and cognitive complaints. We found objective signs of cognitive deficits and reduced exercise capacity likely to be unrelated to primary cardiac or pulmonary dysfunction in some of the cases, but there was no major pathology in laboratory investigations. A history of PEM >14 h which was associated with more severe symptoms as well as with more objective signs of disease may be a pragmatic means to stratify cases for disease severity.
Objective: To assess risk factors for persistence vs improvement and to describe clinical characteristics and diagnostic evaluation of subjects with post-acute sequelae of COVID-19/post-COVID-19 syndrome (PCS) persisting for more than one year. Design: Nested population-based case-control study. Setting: Comprehensive outpatient assessment, including neurocognitive, cardiopulmonary exercise, and laboratory testing in four university health centres in southwestern Germany (2022). Participants: PCS cases aged 18 to 65 years with (n=982) and age and sex-matched controls without PCS (n=576) according to an earlier population-based questionnaire study (six to 12 months after acute infection, phase 1) consenting to provide follow-up information and to undergo clinical diagnostic assessment (phase 2, another 8.5 months [median] after phase 1). Main outcome measures: Relative frequencies of symptoms and health problems and distribution of symptom scores and diagnostic test results between persistent cases and controls. Additional analysis included predictors of changing case or control status over time with adjustments for potentially confounding variables. Results: At the time of clinical examination (phase 2), 67.6% of the initial cases (phase 1) remained cases, whereas 78.5% of the controls continued to report no health problems related to PCS. In adjusted analyses, predictors of improvement among cases were mild acute index infection, previous full-time employment, educational status, and no specialist consultation and not attending a rehabilitation programme. Among controls, predictors of new symptoms or worsening with PCS development were an intercurrent secondary SARS-CoV-2 infection and educational status. At phase 2, persistent cases were less frequently never smokers, had higher values for BMI and body fat, and had lower educational status than controls. Fatigue/exhaustion, neurocognitive disturbance, chest symptoms/breathlessness and anxiety/depression/sleep problems remained the predominant symptom clusters, and exercise intolerance with post-exertional malaise for >14 h (PEM) and symptoms compatible with ME/CFS (according to Canadian consensus criteria) were reported by 35.6% and 11.6% of persistent cases, respectively. In adjusted analyses, significant differences between persistent cases and stable controls (at phase 2) were observed for neurocognitive test performances, scores for perceived stress and subjective cognitive disturbances, symptoms indicating dysautonomia, depression and anxiety, sleep quality, fatigue, and quality of life. In persistent cases, handgrip strength, maximal oxygen consumption, and ventilator efficiency were significantly reduced. However, there were no differences in measures of systolic and diastolic cardiac function, in the level of pro-BNP blood levels or other laboratory measurements (including complement activity, serological markers of EBV reactivation, inflammatory and coagulation markers, cortisol, ACTH and DHEA-S serum levels). Screening for viral persistence (based on PCR in stool samples and SARS-CoV-2 spike antigen levels in plasma in a subgroup of the cases) was negative. Sensitivity analyses (pre-existing illness/comorbidity, obesity, PEM, medical care of the index acute infection) revealed similar findings and showed that persistent cases with PEM reported more pain symptoms and had worse results in almost all tests. Conclusions: This nested population-based case-control study demonstrates that the majority of PCS cases do not recover in the second year of their illness, with patterns of reported symptoms remaining essentially similar, nonspecific and dominated by fatigue, exercise intolerance and cognitive complaints. We found objective signs of cognitive deficits and reduced exercise capacity likely to be unrelated to primary cardiac or pulmonary dysfunction in some of the cases, but there was no major pathology in laboratory investigations. A history of PEM >14 h which was associated with more severe symptoms as well as with more objective signs of disease may be a pragmatic means to stratify cases for disease severity.
Background After COVID-19 infection, 10–20% of patients suffer from varying symptoms lasting more than 12 weeks (Long COVID, LC). Exercise intolerance and fatigue are common in LC. The aim was to measure the maximal exercise capacity of the LC patients with these symptoms and to analyze whether this capacity was related to heart rate (HR) responses at rest and during exercise and recovery, to find out possible sympathetic overactivity, dysautonomia or chronotropic incompetence. Methods Cardiopulmonary exercise test was conducted on 101 LC patients, who were admitted to exercise testing. The majority of them (86%) had been treated at home during their acute COVID-19 infection. Peak oxygen uptake (VO2peak), maximal power during the last 4 min of exercise (Wlast4), HRs, and other exercise test variables were compared between those with or without subjective exercise intolerance, fatigue, or both. Results The measurements were performed in mean 12.7 months (SD 5.75) after COVID-19 infection in patients with exercise intolerance (group EI, 19 patients), fatigue (group F, 31 patients), their combination (group EI + F, 37 patients), or neither (group N, 14 patients). Exercise capacity was, in the mean, normal in all symptom groups and did not significantly differ among them. HRs were higher in group EI + F than in group N at maximum exercise (169/min vs. 158/min, p = 0.034) and 10 min after exercise (104/min vs. 87/min, p = 0.028). Independent of symptoms, 12 patients filled the criteria of dysautonomia associated with slightly decreased Wlast4 (73% vs. 91% of sex, age, height, and weight-based reference values p = 0.017) and 13 filled the criteria of chronotropic incompetence with the lowest Wlast4 (63% vs. 93%, p < 0.001), VO2peak (70% vs. 94%, p < 0.001), the lowest increase of systolic blood pressure (50 mmHg vs. 67 mmHg, p = 0.001), and the greatest prevalence of slight ECG-findings (p = 0.017) compared to patients without these features. The highest prevalence of chronotropic incompetence was seen in the group N (p = 0.022). Conclusions This study on LC patients with different symptoms showed that cardiopulmonary exercise capacity was in mean normal, with increased sympathetic activity in most patients. However, we identified subgroups with dysautonomia or chronotropic incompetence with a lowered exercise capacity as measured by Wlast4 or VO2peak. Subjective exercise intolerance and fatigue poorly foresaw the level of exercise capacity. The results could be used to plan the rehabilitation from LC and for selection of the patients suitable for it.
Aim: (I) to verify if there are sex differences in respiratory function, respiratory muscle strength, and effort limitation in individuals recovered from severe acute COVID-19 30 months after the initial infection, and (II) to evaluate the influence of length of stay on cardiorespiratory capacity among men and women. Methods: Cross-sectional observational multicentric study with participants from five Brazilian states (São Paulo, Amazonas, Minas Gerais, Bahia, and Brasília). We assessed lung function and respiratory muscle strength by maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), and cardiorespiratory fitness by cardiopulmonary exercise test (CPET). Results: 86 individuals were stratified by sex (48 women and 38 men). Females had significantly longer hospitalization for acute COVID-19 (p < 0.05) and showed a marked reduction in MIP (cmH2O and % predicted). Regarding the CPET, women presented lower V˙O2% predicted, O2 pulse, and oxygen uptake efficiency slope (OUES, % predicted) (p < 0.05). In addition, women also had greater abnormal combinations between RER < 1.10, OUES < 80% predicted, VE/VVM < 15% [3 (6.2%)] and V˙O2% predicted < 80%, V˙E/V˙CO2 slope and V˙O2/workload < 8.4 mL/min/W [8 (17%)]. The regression analysis showed a significant influence of age, length of hospitalization (< and >10 days), and FEV1/FVC (%) on the V˙O2 peak (mL·kg−1·min−1). Secondarily, we found that women hospitalized for more than 10 days had worse O2 pulse (p = 0.03), OUES % predicted (p < 0.001), and worse V˙O2% predicted (p < 0.009). Conclusion: Women exhibited more pronounced impairments in several key indicators of cardiopulmonary function 30 months post-infection.
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