Neurocognitive Sequelae of COVID-19 After Acute Infection

The study covered in this summary was published in as a preprint and has not yet been peer reviewed.

Key Takeaways

  • The burden of self-reported post-acute symptoms and possible sequelae, particularly fatigue and neurocognitive impairment, remains significant 6 to 12 months after acute, even among young and middle-aged adults after mild acute SARS-CoV-2 infection, and affects overall health and working capacity.

  • Considering the burden of post-COVID sequelae on individuals and society, it is important to urgently clarify the underlying biologic abnormalities and causes to determine adequate treatment options and develop effective rehabilitation measures.

Why This Matters

  • Prior research has revealed that post-acute sequelae of COVID-19 are common, especially among patients who were hospitalized for COVID-19.

  • However, so far, very few larger-scale studies have delved into the symptomatology and prevalence of post-COVID syndrome beyond 6 months after acute infection and its association with health-related quality of life, well-being, and working capacity in a population -based, nonclinical sample.

  • Post-acute self-reported complaints and symptoms vary. They are nonspecific and sometimes of unknown and functional relevance.

  • With this extensive population-based study, the researchers show evidence of persistent new symptom clusters (nonexisting before acute infection), such as fatigue, neurocognitive impairment, chest symptoms, smell or taste disorder, and anxiety/depression that occur longer than 6 months after acute infection. The prevalence of each of these five clusters is >20%.

  • The researchers also demonstrate that the three most prevalent symptoms (fatigue, neurocognitive impairment, and chest symptoms) often disrupt daily life and activities. These symptoms frequently occur together. Fatigue and neurocognitive impairments have the greatest impact on working capacity.

  • Long-term smell and taste disorders are documented independently of other complaints.

  • In this cohort, age was not a major determinant of symptom prevalence. Initial severity and female sex were consistent risk factors for various manifestations of medium-term post-COVID syndrome. In addition, age was a risk factor for self-reported decreased working capacity, which overall and at population level surpassed 10%.

Study Design

  • The researchers conducted a population-based retrospective cohort study in four geographically defined regions in southern Germany.

  • They included individuals between the ages of 18 and 65 who had PCR-confirmed SARS-CoV-2 infection between October 2020 and March 2021.

  • The investigators analyzed symptom frequencies — 6 to 12 months after acute infection, vs before acute infection — expressed as prevalence differences (PDs) and prevalence ratios (PRs).

  • The investigators measured symptom severity and clustering, risk factors, associations with general health recovery, and working capacity.

Key Results

  • Among 11,710 patients (mean age, 44.1 years; 59.8% women; 3.5% previously admitted with COVID-19; mean follow-up time, 8.5 months), the most frequent symptoms with PDs >20% and PRs >5% were rapid physical exhaustion, shortness of breath, concentration difficulties, chronic fatigue, memory disturbance, and altered sense of smell.

  • The main risk factors were female sex and severity of the initial infection.

  • Prevalence rates were considerable among both men and women who had a mild course of acute infection, and PCS markedly affected younger patients.

  • As symptom clusters, fatigue (PD, 37.2%) and neurocognitive impairment (PD, 31.3%) most contributed to reduced health recovery and working capacity.

  • Commonly occurring and relevant for working capacity were chest symptoms, anxiety/depression, headache/dizziness and pain syndromes. There was some variation with respect to sex and age.

  • When factoring in new symptoms with at least moderate impairment of daily life and ≤80% recovered general health or working capacity, the overall estimate for post-COVID syndrome was 28.5% (age- and sex-standardized rate, 26.5%).


  • The self-reported nature of symptoms and sequelae without medical validation is among the limitations.

  • Reporting bias may play a role when individuals describe symptoms from the past, particularly if they have neurocognitive sequelae.

  • There was a limited response with some overrepresentation of older persons and women.

  • The study regions were situated around medium-sized university cities, and respondents had completed more education than the general population, so this may limit generalizability.

  • Because the researchers only undertook a before-after comparison within infected patients, they are unable to distinguish between the impact of the pandemic itself and its consequences. Nonpharmaceutical and public health interventions on symptoms and symptom reporting may affect the results.

  • The authors utilized only one method for symptom clustering, and it is possible that other approaches would characterize different and presumably larger clusters.

Study Disclosures

This is a summary of a preprint research study, “Prevalence, Determinants, and Impact on General Health and Working Capacity of Post-Acute Sequelae of COVID-19 Six to 12 Months After Infection: A Population-Based Retrospective Cohort Study From Southern Germany, ” written by Raphael S. Peter from Ulm University in Ulm, Germany, published on medRxiv, and provided to you by Medscape. This study has not yet been reviewed. The full text of the study can be found on

For more news, follow Medscape on Facebook, TwitterInstagram, and YouTube.


Leave a Comment