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37% of COVID-19 Patients Diagnosed With A Long-COVID Symptom

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A retrospective study conducted by the University of Oxford in collaboration with the National Institute for Health Research (NIHR) and the Oxford Health Biomedical Research Centre (BRC) has explored the instance, co-occurrence and evolution of long-COVID symptoms in a cohort of 270,000 people diagnosed with COVID-19. The study findings are published in PLoS Medicine.

Why do some patients experience long-COVID symptoms?

The COVID-19 global pandemic has presented many challenges to science and society. Arguably one of the greatest difficulties – from a clinical perspective – has been the huge variability in illness severity. While some patients have presented as completely asymptomatic, for others, COVID-19 has led to severe illness or death. Furthermore, while the majority of people recover fairly quickly from the disease, a proportion of the population experience persistent symptoms that continue for weeks – or even months – after the infection has cleared, a phenomenon often referred to as "long-COVID".

"It [long-COVID] is not well defined either in terms of what it is or when it occurs. It is used loosely to refer to symptoms affecting people many weeks (or longer) after COVID infection," Paul Harrison, professor of psychiatry at the University of Oxford and first author of the study told Technology Networks.

The jury is still out on why some patients recover quickly and others develop long-COVID symptoms, as the biological processes underpinning long-COVID remain to be fully understood. However, gathering data on the type of long-COVID symptoms that occur in different individuals, the number of symptoms and how they evolve over time is important for understanding who might be at greater risk.

US-based electronic health records used for the study

The researchers behind the new study utilized a US-based electronic health record network, TriNetX, to conduct a large-scale study of ~270,000 people that were recovering from COVID-19. Their work aimed to provide answers to four key questions, NIHR Academic Clinical Fellow Dr. Max Taquet, who led the analyses, explained in a press briefing: "Our questions [for this research] were: how common were symptoms of long-COVID? Does age, sex, severity of infection or race affect the incidence of long-COVID symptoms? Do the symptoms co-occur? And how do the rate of the symptoms compare after COVID-19 vs influenza?"

The researchers calculated the incidence of nine core symptoms of long-COVID three to six months after diagnosis. These core features included: abnormal breathing, abdominal symptoms, anxiety/depression, chest/throat pain, cognitive symptoms ("brain fog"), fatigue, headache, myalgia (muscle pain) and other pain. 

The primary cohort of the study included individuals that had received a confirmed diagnosis of COVID-19 on or after January 20, 2020, and that were still alive by the end of follow-up (December 16, 2020). This cohort was matched to a second cohort of patients that had been diagnosed with influenza in the same time frame, and that had not received a confirmed diagnosis of COVID-19.

Over one third diagnosed with at least one long-COVID symptom

The data show that 37% of the primary study cohort received a diagnosis of at least one long-COVID symptom in the 3–6-month period after the initial COVID-19 diagnosis. The percentage incidence for each of the individual symptoms diagnosed were as follows:

  • Abnormal breathing – 8%

  • Abdominal symptoms – 8%

  • Anxiety/depression – 15%

  • Chest/throat pain – 6%

  • Cognitive symptoms ("brain fog") – 4%

  • Fatigue – 6%

  • Headache – 5%

  • Myalgia (muscle pain) – 1.5%

  • Other pain – 7%

Long-COVID symptoms occurred most often in individuals that had been hospitalized and were diagnosed at a higher rate in women. When asked if these particular findings were concurrent with previous studies exploring long-COVID symptoms, Professor Harrison said: "We did not find such a clear female excess as some prior studies, but we did find a marked relationship to the severity of the infection." He added, "The data don’t directly inform treatment strategies, but they do highlight those who may be at greater risk."

"The results confirm that a significant proportion of people, of all ages, can be affected by a range of symptoms and difficulties in the six months after COVID-19 infection. These data complement findings from self-report surveys, and show that clinicians are diagnosing patients with these symptoms. We need appropriately configured services to deal with the current and future clinical need," Taquet said in a press release.

Individual factors, such as age, sex and severity of illness were also found to influence which symptoms were reported. Older members of the cohort and males were found to experience more breathing difficulties and cognitive issues. In contrast, younger individuals and women reported headaches, abdominal symptoms and anxiety or depression.

As for co-occurrence of symptoms, Taquet said, "Many individuals [after a diagnosis of COVID-19] only experience one symptom. However, what we see clearly [in the data] is that the likelihood for symptoms to co-occur increases with time."

From the matched group data, the researchers identified that some of the same symptoms occur in influenza patients, but at a lower rate. "This shows that patients with influenza also experience some of those symptoms, which is worth keeping in mind," noted Taquet. The fact that the symptoms occurred at a significantly higher rate in those recovering from COVID-19 vs influenza is important, as it implies that the cause of the symptoms is directly linked to SARS-CoV-2 infection, rather than a generic response to a viral infection. However, it should be considered that for individuals to be included in the control (influenza) cohort, they had to have visited a healthcare provider to receive a diagnosis; this might suggest that they had a more severe form of influenza.

How can we use this data?

The researchers stress that this work does not provide an explanation as to why long-COVID occurs. It also does not provide guidance on how to treat these symptoms.

There are a number of limitations to the research that the authors highlight, including: the findings do not apply to individuals that were infected with SARS-CoV-2 but did not receive a diagnosis (i.e., individuals that were asymptomatic), and it cannot provide information relating to how long the long-COVID symptoms persisted in each participant.

Nonetheless, the authors believe that the work could potentially highlight members of the population that are at a greater risk of experiencing long-COVID symptoms. "We have no treatments for long-COVID, only treatment of some of the symptoms (which may or may not prove to be effective). The key need is for studies that show the biological basis of the symptoms, since then treatments can be targeted at the underlying mechanism."

As for next steps, Harrison emphasized that the following will be important: "Longer follow up (and larger samples), replication in other datasets, study of severity and outcome of symptoms and study of causes."

Paul Harrison was speaking to Molly Campbell, Science Writer for Technology Networks.

Reference: Taquet M et al. Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19. PLoS Med. 2021. 18(9): e1003773. doi: 10.1371/journal.pmed.1003773