By Deborah Borfitz

October 19, 2021 | By the end of this year, consensus by a global coalition of researchers, healthcare providers, and patients on a core set of outcomes that should be included in all future studies of post-COVID syndrome—so-called “long COVID”—are expected to be publicly released. A core outcome set (COS) is urgently needed to optimize and standardize clinical data collection and reporting across clinical trials for the condition, says Daniel Munblit, professor in the department of pediatrics & pediatric infectious diseases at Sechenov University (Moscow) and honorary senior lecturer in the Inflammation, Repair and Development Section of the National Heart and Lung Institute at Imperial College London.

A significant but indefinite portion of people diagnosed with COVID-19 subsequently experience lasting symptoms, including fatigue, breathlessness, and neurological complications. One recent study, published in PLOS Medicine (DOI: 10.1371/journal.pmed.1003773), estimated lingering post-COVID symptoms in about 36% of patients.

The study compared patients with a confirmed diagnosis of COVID-19 to a matched cohort of COVID-free patients diagnosed with influenza and, unlike most previous studies of the condition, included a control group (incidence of atopic dermatitis). But in the absence of agreement on what constitutes long COVID, the researchers arbitrarily if pragmatically looked at nine commonly described clinical features.

When the pandemic struck, and the daily death toll began quickly mounting, everyone was understandably focused on the acute stage of COVID-19, says Munblit. Afflicted patients were the first to draw attention to long COVID last summer and many physicians doubted its existence until they started experiencing the condition themselves.

Being a new and unknown COVID-related condition, investigators began measuring literally hundreds of different outcomes in hundreds of different ways, he says. All the heterogenous data generated was impossible to integrate and analyze in a meaningful way.

The condition is commonly associated with the persistence of a range of heterogeneous signs and symptoms—some of which may be due to other problems—for more than 12 weeks. But until this week, there was not a common international definition of long COVID, he adds.

On October 6, the World Health Organization (WHO) announced it had reached a consensus on the clinical definition of post COVID-19 condition. It reads as follows:

Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time.

Minimum Set

Global response to the need for a COS for long COVID is being led by international researchers, in collaboration with the WHO, healthcare professionals, patient representatives, the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC), and experts in COS methodology such as leaders of the COMET (Core Outcome Measures in Effectiveness Trials) initiative, says Munblit. The project began over the summer with the first round of a special “Delphi” type of survey asking key stakeholder groups (people living with post-COVID condition, researchers and healthcare professionals) to assess which outcomes matter to them most.

The survey had over 1,500 respondents from over 70 countries. Most participants were from Europe and North America, but Africa, South America, Asia, and Australia were also represented to ensure global input into the process and, hopefully, optimize global uptake of its recommendations, he says.

The second round of the survey, where participants get to see how others rated outcomes and can adjust their own ratings, is now underway. A consensus-building meeting will likely be held in early November to finalize the list of core outcomes that should be measured, says Munblit.

In the next phase of the project, to be completed as soon as possible in 2022, all potential measurement tools will be assessed for each core outcome before the Delphi process gets repeated to reach consensus on how to measure those outcomes, he says. This work is being funded by the National Institute for Health Research in the U.K.

The COS is only the minimum set of outcomes that should be examined in long COVID clinical trials, he stresses. “If researchers want to measure more outcomes, they are more than welcome to do so.”

The long COVID initiative is being co-led by Tim Nicholson, a clinical lecturer at the Institute of Psychiatry Psychology & Neuroscience at King’s College London, together with colleagues at King’s, Imperial College London, and the University of Liverpool. These include Paula Williamson, professor of medical statistics at the University of Liverpool, who leads the COMET initiative.

The long COVID COS is being developed in parallel with ongoing clinical studies into the condition, which are not being held up during the consensus-building exercise. “We are in touch with a number of researchers globally, so they are aware of the work we are doing [and the timeline],” Munblit says.

Before long COVID was broadly described, the National Institutes of Health (NIH) came up with a minimal set of common outcome measures for COVID trials in general. The set includes a measure of viral burden (quantitative PCR or cycle threshold), patient survival (mortality at hospital discharge or at 60 days), and patient progression through the healthcare system (based on the WHO Clinical Progression Scale), as reported last year in Lancet Infectious Diseases (DOI: 10.1016/S1473-3099(20)30483-7).

The NIH has more recently funneled $1.15 billion in funding toward studies examining how COVID-19 may lead to widespread and lasting symptoms. In doing so, the agency refers to the constellation of symptoms self-reported by patients in the U.K. as “Post-Acute Sequelae of SARS-CoV-2 infection.”

Future Work

A living systematic review recently published in BMJ Global Health (DOI: 10.1136/bmjgh-2021-005427) identifies weakness, general malaise, fatigue, concentration impairment, and breathlessness as the five most common symptoms of long COVID. Findings were based on 39 studies, few of which included children.

Regardless of the lingering health problems, long COVID is “much more prevalent in adults than children,” says Munblit. Further research will be needed to assess the health impacts in kids. In its clinical case definition, the WHO also says a separate definition of long COVID may be applicable for children.

The COS will almost certainly need refining as knowledge accumulates on the complex and poorly understood disorder, he adds. The work is critical to optimizing how clinical data gets measured in trials, and other research and clinical services globally, as well as bringing a wide spectrum of resources from specialist centers in the developed world to low-resource settings in the developing world.