Long COVID: which symptoms can be attributed to SARS-CoV-2 infection?

Mortality rates following SARS-CoV-2 infection have decreased as a consequence of public health policies, vaccination, and acute antiviral and anti-inflammatory therapies. However, in the wake of the pandemic, post-acute sequelae of COVID-19, or long COVID, has emerged: a chronic illness in people who have ongoing multidimensional symptomatology and disability weeks to years after the initial infection. Early reports of long COVID prevalence, summarised in a systematic review examining the frequency and variety of persistent symptoms after COVID-19, found that the median proportion of people who had at least one persistent symptom 60 days or more after diagnosis or at least 30 days after recovery from COVID-19 infection was 73%. However, the estimated prevalence depends on the duration, population, and symptoms used to define long COVID. More recently, community-based studies have suggested a lower prevalence of persistent symptoms; whereas among people who were hospitalised following COVID-19 infection, a high proportion do not fully recover (50–70%).5, 6, 7

The number of COVID-19 cases continues to rise and now exceeds 500 million worldwide. Consequently, the number of people with long COVID is similarly increasing. Indeed, the UK Office for National Statistics (ONS) survey up to May, 2022 estimated that 2 million people in the UK had self-reported long COVID. Of these people, 72% reported having long COVID for at least 12 weeks, 42% for at least 1 year, and 19% for at least 2 years. Consistent with other studies, fatigue was the most common symptom in the ONS survey, followed by breathlessness, cough, and muscle ache.4, 5, 6, 7, 8 Risk factors for long COVID are female sex, obesity, middle age (35–65 years), living in areas of greater socioeconomic deprivation, and the presence of another activity-limiting health condition.1, 5, 6 Importantly, health-care use is increased in those with long COVID, with increased general practitioner consultation rates.

How many of the symptoms currently attributed to long COVID actually represent pre-existent disease or are unrelated to COVID-19 is uncertain. Symptoms that were present before SARS-CoV-2 infection are often not recorded or assessed by recall. In The Lancet, Aranka V Ballering and colleagues report the findings of a longitudinal cohort study conducted in the north of the Netherlands between April, 2020, and August, 2021, where 23 somatic symptoms were assessed using 24 repeated measurements in digital COVID-19 questionnaires. The study was embedded within the large, population-based Lifelines COVID-19 cohort. The main strengths of this study were that participants were their own control, with the pattern and severity of symptoms assessed before and 3–5 months after SARS-CoV-2 infection, and were also compared with a matched control group of COVID-19-negative participants. Of the 76 422 participants, 4231 (5·5%) had COVID-19 and were compared with 8462 matched controls. Participants had a mean age of 53·7 years (SD 12·9), 46 329 (60·8%) were female, and nearly all were of White ethnicity. The proportion of participants who had at least one core symptom of substantially increased severity to at least moderate was 21·4% (381 of 1782) in COVID-19-positive participants versus 8·7% (361 of 4130) in COVID-19-negative controls. Thus, this study found that core symptoms were attributed to COVID-19 in 12·7% of participants, or approximately one in eight. This is a major advance on previous long COVID prevalence estimates, as it includes a matched control group without SARS-CoV-2 infection and accounts for symptoms that were present before infection.

The pattern of symptomatology observed by Ballering and colleagues was similar to previous reports, with fatigue and breathlessness among the most common symptoms, but other symptoms such as chest pain were more common in people who had COVID-19 than in COVID-19-negative controls. Ballering and colleagues propose a core symptom set to be considered as part of the case definition for long COVID. Although an agreed diagnostic core symptom set would inform clinical pathways and research, the study by Ballering and colleagues did not fully consider the impact on mental health, it was conducted in one region in the Netherlands, and it did not include an ethnically diverse population; thus the concept of a core symptom set will require further validation.

Importantly, the study by Ballering and colleagues does not provide new mechanistic insights, which are key to uncovering new therapeutic targets. In other studies, clustering of patient-reported outcomes has identified different severity groups of long COVID and identified increased systemic inflammation in people with very severe long COVID.5, 6 How patient-centred outcomes, together with biomarkers, can further refine long COVID diagnosis and inform precision medicine approaches warrants further consideration.

Encouragingly, emerging data from other studies suggest that the proportion of newly infected people developing long COVID is reduced in people who have received vaccination before SARS-CoV-2 infection, and might be lower in people infected with the omicron variant than those infected with earlier variants. Findings from the ONS survey suggested that vaccination following infection might reduce the symptom burden of long COVID after the first dose, with sustained improvement after a second dose. Whether acute treatments for COVID-19 affect the likelihood of developing long COVID or its severity is unknown.

Current evidence supports the view that long COVID is common and can persist for at least 2 years after SARS-CoV-2 infection, although severe debilitating disease is present in a minority. The long COVID case definition needs to be further improved, potentially to describe different types of long COVID, of which better mechanistic understanding is crucial. This will lead to personalised multimodality treatments that can be implemented to manage the increasingly high number of people with long COVID.