In a recent study published in Nature, researchers determined symptoms and risk factors present beyond 12 weeks in non-hospitalized adults with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Post-acute sequelae of coronavirus disease 2019 [COVID-19] (PASC) or long COVID is the persistence of symptoms, including fatigue, muscle & joint pain, shortness of breath, headache, chest pain, cough, altered smell & taste, and diarrhea in previously SARS-CoV-2 infected individuals.
Several systematic reviews have shown the prevalence of long COVID often based on a patient's self-reported symptoms. These studies also typically lack a control group, making it challenging to infer whether the reported symptoms were due to a previous SARS-CoV-2 infection, pre-existing health conditions, or social effects of the pandemic. Furthermore, these studies examined only hospitalized cohorts, missing population-level data on symptoms experienced by non-hospitalized individuals.
Therefore, there is an unmet need for large-scale studies using healthcare data of COVID-19 patients and closely matched control populations to elucidate symptoms independently associated with long COVID. Additionally, studies should reveal demographic and clinical risk factors in non-hospitalized individuals to assess symptoms specific to long COVID.
About the study
In the present study, researchers selected 486,149 adults with confirmed SARS-CoV-2 infection from a United Kingdom (UK)-based primary care database, Clinical Practice Research Datalink (CPRD) Aurum. They also created a control group comprised of 1,944,580 propensity score-matched adults who never had SARS-CoV-2 infection.
The composite study outcome covered all long COVID symptoms per the World Health Organization (WHO) clinical case definition. For study analysis, long COVID was pre-defined as the presence of at least one WHO criteria-based symptom ≥12 weeks after infection. The researchers identified 115 relevant symptoms coded within primary care records and grouped them into 15 domains. Additionally, they extracted data for 87 chronic health conditions and the demographic characteristics of patients.
Consolidating all 115 symptoms into 50 distinct symptoms filtered out commonly occurring symptoms unrelated to COVID-19, symptoms with mutually inclusive SNOMED clinical term (CT) codes (e.g., pain and chest pain), and symptoms that appear together (e.g., vomiting).
The researchers used Cox proportional hazards models to estimate adjusted hazard ratios (aHRs) for all the identified symptoms, and a p-value <0.05 for any covariate was statistically significant. They also identified, clustered, and characterized dominant symptom clusters. Likewise, the researchers used a multinomial logistic regression model to identify demographic features associated with the latent long COVID classes. The study period ending April 15, 2021, was split into three time periods from the index date as per the National Institute for Health & Care Excellence (NICE) guidelines on managing the long-term effects of COVID-19.
The authors observed that 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks. Also, COVID-19 increased the risk of reporting at least one of the symptoms included in the WHO case definition for long COVID by 26%.
The study results pointed at multiple factors, including female sex, decreasing age, smoking, high body mass index, and belonging to Black or other ethnic minority groups, which increased the risk of symptoms included in the WHO definition of long COVID. The researchers also observed a wide range of comorbidities were associated with an increased risk of long COVID. Further, the researchers observed three distinct clusters of phenotypes of long COVID. These included 80% of patients with fatigue, rash, and pain, and barely 5.8% of them had respiratory symptoms, including cough, phlegm, and shortness of breath. The remaining 14.2% suffered from mental health-related and cognitive symptoms, including anxiety, insomnia, brain fog, and depression. Interestingly, the current review also identified new long COVID-related symptoms, such as hair loss, sneezing, sexual dysfunction (e.g., reduced libido), fever, and hoarse voice.
As per the current review, as of 7 April 2022, 2.7% of the UK population was experiencing symptoms persisting beyond four weeks from SARS-CoV-2 infection, with 70% experiencing symptoms beyond 12 weeks. The main symptoms in all such individuals were shortness of breath, fatigue, anosmia, and difficulty concentrating. Moreover, long COVID was most prevalent in females and individuals with pre-existing comorbidities and disabilities.
Further research should investigate the underlying pathophysiology and clinical outcomes between the three phenotypic subgroups to inform the development of targeted therapies. Further, studies should investigate the association between symptom burden, life quality, and professional capability to assess which symptoms have the greatest impact.