New Study on the Long-Term Symptoms Related to COVID-19

The large new study recently published in The Lancet suggests that one in eight adults (12.7%) who are infected with SARS-CoV-2 experience long-term symptoms and is one of the first comparison studies of long COVID that included the uninfected population. The inclusion of uninfected population enables a more accurate prediction of long-term COVID-19 symptom prevalence as well as improved identification of the core symptoms of 'long COVID'.

What is Long COVID?

'Long COVID', aka 'Post-COVID conditions' are a wide range of new, returning, or ongoing health problems that people experience after being infected with the SARS-CoV-2 virus that causes COVID-19.

The CDC identified some of the people who are more at risk than others for developing 'long COVID':

• People who have experienced more severe COVID-19 illness, especially those who were hospitalized or needed intensive care,
• People who had underlying health conditions prior to COVID-19,
• People who did not get a COVID-19 vaccine,
• People who experience multisystem inflammatory syndrome (MIS) during or after COVID-19 illness.

Despite widespread suffering from 'long COVID', effective treatments have yet to be discovered and implemented. Data on the magnitude and breadth of the long-term symptoms experienced by long COVID patients are imperative. However, many prior studies on long COVID failed to examine the prevalence of these symptoms in people who had not received a COVID-19 diagnosis or consider the symptoms of specific patients prior to being diagnosed.

Study Results

The study measured symptoms in individuals both pre- and post-COVID infection, as well as in uninfected population. There was a total of 76 422 participants (46 329 female and 30 093 male).

The researchers collected data by periodically asking patients to complete questionnaires on 23 symptoms commonly associated with long COVID:

headache, dizziness, chest pain, back pain, nausea, painful muscles, difficulties with breathing, feeling hot and cold alternately, tingling extremities, lump in the throat, general tiredness, heavy arms or legs, pain when breathing, runny nose, sore throat, dry cough, wet cough, fever, diarrhea, stomach pain, ageusia or anosmia, sneezing, and itchy eyes.

Between March 2020 and August 2021, the same patients were given the questionnaire 24 times, a total of 883 973 questionnaires.

Questionnaires helped indicate participants who contracted COVID-19 (at this time infected with the SARS-CoV-2 alpha-variant or earlier versions). Most of the data was gathered before the Dutch COVID-19 vaccine deployment, hence there were insufficient participants who had received the vaccine for this study's analysis.

Out of the total number of participants, 4231 participants were COVID-19 positive (2 770 female and 1 461 male).

The maximum follow-up time was 484 days after COVID-19 diagnosis. COVID-19 positive participants were matched to 8 462 COVID-19 negative participants. The maximum follow-up time of control participants was 481 days after their matched timepoint.

Men were more frequently hospitalized due to COVID-19 than women (5.0% of male vs 2.5% of female COVID-19 positive participants).

When compared to symptoms before a COVID-19 diagnosis and to the control group, the researchers discovered that several symptoms were either new or worse three to five months after being diagnosed.

This finding suggests that these symptoms can be seen as the primary indications/core symptoms of long COVID. These core symptoms include:

• chest pain,
• breathing problems/pain,
• muscle aches,
• loss of taste/smell,
• tingling hands/feet,
• lump in throat,
• alternately feeling hot and cold,
• heavy arms/legs, and
• general exhaustion.

The first author of the study, Aranka Ballering says:

"These core symptoms have major implications for future research, as these symptoms can be used to distinguish between post COVID-19 condition and non-COVID-19-related symptoms. By looking at symptoms in an uninfected control group and in individuals both before and after SARS-CoV-2 infection, we were able to account for symptoms which may have been a result of non-infectious disease health aspects of the pandemic, such as stress caused by restrictions and uncertainty."

Three months after infection, the intensity of these symptoms reached a peak and did not subsequently diminish. Three to five months following a COVID-19 diagnosis, other symptoms such as headaches, itchy eyes, dizziness, back pain, and nausea did not dramatically worsen.

Ms. Ballering rightly concluded:

"Post-COVID-19 condition, otherwise known as long COVID, is an urgent problem with a mounting human toll. Understanding the core symptoms and the prevalence of post-COVID-19 in the general population represents a major step forward for our ability to design studies that can ultimately inform successful healthcare responses to the long-term symptoms of COVID-19."

Study Limitations

The authors acknowledge some limitations in the study:

• The study included patients infected with the alpha variant or earlier variants of SARS-CoV-2 and has no data from people infected during the period when the delta or omicron variants were causing most infections.
• Due to asymptomatic infection, the prevalence of COVID-19 in this study may be underestimated.
• Since the beginning of data collection other symptoms, such as brain-fog, have been identified as potentially relevant for a definition of long COVID but this study did not look at these symptoms.
• The study was undertaken in one region and did not include and ethnically diverse population.

Suggested Future Research

Prof Judith Rosmalen, the Study Lead Author and Professor and the University of Groningen, The Netherlands suggests that the future research should include mental health symptoms (e.g. depression and anxiety symptoms), along with additional post-infectious symptoms that they could not assess in this study (such as brain fog, insomnia, and post-exertional malaise).

Prof. Rosmalen explained: "We were unable to investigate what might cause any of the symptoms observed after COVID-19 in this study, but we hope future research will be able to give insights into the mechanisms involved. Furthermore, due to the timing of this study we were unable to assess the effect of COVID-19 vaccination and different SARS-CoV-2 variants on long COVID symptoms. We hope future studies will provide answers on the impacts of these factors."

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