Studies elucidate poorly understood long COVID

Young woman with headache
Young woman with headache

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Three new studies detail "long-haul" COVID-19, one finding 203 symptoms involving 10 organ systems, another showing that more than five coronavirus symptoms in the first week of infection portends a long disease course, and one finding few long-haul–like symptoms in children.

Average of 55.9 lingering symptoms

In the first study, published yesterday in the Lancet's EClinicalMedicine, a team led by University College London scientists analyzed survey responses from 3,762 COVID-19 survivors from 56 countries who still had symptoms 28 days after becoming ill.

Respondents had begun experiencing symptoms before June 2020 and were surveyed from Sep 6 to Nov 25, 2020. It is the largest international study of COVID-19 long-haulers to date, according to the authors, who tracked 66 symptoms for 7 months.

More than 91% of participants reported having, on average, 55.9 COVID-19 symptoms involving a mean of 9.1 organ systems for more than 35 weeks. Affected organ systems included systemic; neuropsychiatric; cardiovascular; dermatologic; gastrointestinal; pulmonary and respiratory; immunologic and autoimmune; musculoskeletal; reproductive, genitourinary, and endocrine; and head, ear, eye, nose, and throat.

After 6 months, the most common symptoms included fatigue, malaise after exertion, and cognitive problems, or "brain fog." A third to a half of respondents reported insomnia and other sleep problems, heart palpitations and rapid heartbeat, muscle aches and joint pain, shortness of breath, and dizziness and vertigo. The most debilitating symptoms were fatigue, breathing problems, and cognitive issues.

While symptoms varied in prevalence over time, three symptom combinations (or clusters) surfaced, each of them with its own unique temporal profile. Overall, 85.9% of participants had relapses, mainly triggered by exercise, physical or mental activity, and stress, and 86.7% reported fatigue, compared with 44.7% of recovered respondents. Cognitive or memory problems affected about 88% of participants.

With the exception of the loss of taste and smell, the prevalence and trajectory of all symptoms were comparable between participants with confirmed COVID-19 and those suspected of having it. The probability of severe and very severe symptoms was highest during the first 28 days of infection, while the likelihood of mild and moderate symptoms rose gradually after that, the researchers wrote.

In total, 1,700 participants (45.2%) had to reduce their work hours as a result of their illness, and another 839 (22.3%) were unable to work at all.

National screening program urged

The researchers, who have all had or still have long COVID-19, are recommending the broadening of clinical guidelines for evaluating lingering symptoms beyond cardiovascular and respiratory function tests. Specifically, they are calling for inclusion of neuropsychiatric, neurological, and activity intolerance as symptoms.

They also advise the creation of a national screening program in the United Kingdom for anyone who suspects that they have long COVID-19 to ensure that patients get appropriate treatment.

Senior author Athena Akrami, PhD, said in a University College London news release that clinicians need to evaluate a far wider range of symptoms when diagnosing long COVID-19.

"There are likely to be tens of thousands of long COVID patients suffering in silence, unsure that their symptoms are connected to COVID-19," she said. "Building on the network of long COVID clinics, which take [general practice] referrals, we now believe a national programme could be rolled out into communities able to screen, diagnose and treat all those suspected of [having] long COVID symptoms."

More initial symptoms, longer illness

The second study, a review led by University of Birmingham researchers in the United Kingdom, was published yesterday in the Journal of the Royal Society of Medicine. The team analyzed pooled prevalence data from the Living Systematic Review database, which suggested patients with five or more coronavirus symptoms in the first week of infection are significantly more likely than others to develop long COVID-19.

The most common symptoms were fatigue, shortness of breath, muscle and joint pain, headache, altered smell and taste, chest pain, cough, and diarrhea. Other symptoms included cognitive dysfunction, memory loss, sleep disorders, and anxiety.

One of two symptom clusters consisted of fatigue, headache, and upper respiratory issues, and the other was made up of multisystem symptoms of fever and gastroenterologic problems.

People with long COVID-19 reported lower quality of life, mental illness, and employment problems. "These individuals may require multidisciplinary care involving the long-term monitoring of symptoms, to identify potential complications, physical rehabilitation, mental health and social services support," the authors wrote. "Resilient healthcare systems are needed to ensure efficient and effective responses to future health challenges."

Condition needs more attention, study

In a Sage press release, lead author Olalekan Lee Aiyegbusi, MBChB, PhD, said that long-haulers often suffer in silence. "People living with long COVID generally feel abandoned and dismissed by healthcare providers and receive limited or conflicting advice," he said. "More than one-third of the patients in one of the studies included in the review reported they still felt ill or in a worse clinical condition at eight weeks than at the onset of COVID-19."

Coauthor Shamil Haroon called for future research into the long-haul phenomenon. "Neither the biological or immunological mechanisms of long COVID, nor the rationale for why certain people are more susceptible to these effects, are yet clear, limiting development of therapies," he said in the release. "It is essential we act quickly to address these issues."

The authors suggested that long COVID-19 may follow a disease course similar to that of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), because previous research showed that about 25% of patients with those syndromes still had reduced lung function and exercise capacity 6 months after they were released from the hospital.

"The wide range of potential symptoms and complications patients with long COVID may experience highlights the need for a deeper understanding of the clinical course of the condition," study co-principal investigator Melanie Calvert, PhD, said in the release. "There is an urgent need for better, more integrated care models to support and manage patients with long COVID to improve clinical outcomes."

Uncommon in kids and teens

In the third study, published yesterday in JAMA, University of Zurich researchers compared symptoms compatible with long COVID-19 in 1,355 children and teens attending one of 55 randomly selected Swiss schools who had undergone serologic COVID-19 testing no more than 6 months before.

The researchers conducted serologic testing and analyzed online questionnaire responses from the children from June 2020 to April 2021. Median participant age was 11 years, and 54% were girls. Parents reported their children's symptoms since October 2020 that lasted for at least 4 weeks and whether the symptoms lingered longer than 12 weeks.

Of the 109 children who had coronavirus antibodies but were never hospitalized, 4% experienced one or more symptoms lasting more than 12 weeks, as did 2% of children without antibodies. The most common symptoms lasting beyond 12 weeks in seropositive children were tiredness (3%), concentration problems (2%), and need for more sleep (2%). Comparable proportions of seropositive and seronegative participants said they were in excellent or good health.

"This study found a low prevalence of symptoms compatible with long COVID in a randomly selected cohort of children assessed 6 months after serologic testing," the researchers wrote.

They added that although some children develop long COVID-19, the few prevalence estimates in the scientific literature range from 0% to 27%. "Initial SARS-CoV-2 infection severity, different methodological approaches (clinical assessment vs self-report), definition of cases (diagnosed vs suspected), variable follow-up times, and prevalence of preexisting clinical conditions likely contribute to the variability in prevalence estimates," they concluded.

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