Persistent symptoms and clinical findings in adults with post-acute sequelae of COVID-19/post-COVID-19 syndrome in the second year after acute infection: population-based, nested case-control study

Raphael S. Peter, Alexandra Nieters, Siri Göpel, et. al.,doi:


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.

What is already known on this topic Self-reported health problems following SARS-CoV-2 infection have commonly been described and may persist for months. They typically include relatively non-specific complaints such as fatigue, exertional dyspnoea, concentration or memory disturbance and sleep problems. The incidence of this post-COVID-19 syndrome (PCS) is varying and associated with sociodemographic variables, pre-existing disease and comorbidities, the severity of the acute SARS-CoV-2 index infection, and some other factors. The long-term prognosis is unknown and may differ for different symptoms or symptom clusters. Evidence of measurable single or multiple organ dysfunction and pathology and their correlation with self-reported symptoms in patients with non-recovery from PCS for more than a year have not been well described.

What this study adds The study describes the severity of the index infection, lower educational status, no previous full-time employment, and (need for) specialist consultation or a rehabilitation programme (the latter probably due to reverse causation) as factors for non-recovery from PCS, and found no major changes in symptom clusters among PCS cases persisting for more than a year. After a comprehensive medical evaluation of cases and controls and adjusted analyses, objective signs of organ dysfunction and pathology among persistent PCS cases correlated with self-reported symptoms, were detected more often among cases with longer lasting post-exertional malaise, and included both reduced physical exercise capacity (diminished handgrip strength, maximal oxygen consumption and ventilatory efficiency), and reduced cognitive test performances while there were no differences in the results of multiple laboratory investigations after adjustment for possible confounders.

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