Long COVID: Definitions, Diagnosis, and Developments

Everything you need to know about long COVID symptoms, mechanisms, and diagnostic testing opportunities

Michael Schubert, PhD

Michael Schubert, PhD, is a veteran science and medicine communicator. He holds graduate degrees in biochemistry and molecular biology with a research focus on chromatin structure and function and has written on subjects from subspeciality pathology to fictional science. In addition to writing and editing, he is co-director of the Digital Communications Fellowship in Pathology and professor of professional practice in academic writing at ThinkSpace Education, the University of Chichester.

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Published:Jan 23, 2024
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As early as spring 2020, people who had survived COVID-19 began publicly sharing their ongoing symptoms and struggles to recover. Originally driven almost entirely by patients, researchers and clinicians eventually responded to the push to investigate these reports, ultimately publishing a study showing that only one in eight participants were symptom-free two months after infection. From that point, research into the post-viral condition, popularly termed “long COVID,” accelerated—from 105 articles published on the topic in 2020 to nearly 5,000 in 2023.

          Graph illustrating the annual number of PubMed-indexed publications on common terms for long COVID over the last five years from 105 in 2020 to 4,665 in 2023.

Figure 1. Annual PubMed-indexed publications on common terms for long COVID over the last five years.

Today's Clinical Lab, PubMed

But what defines long COVID—and how can it be assessed in the clinical laboratory? The question remains under debate, but evidence of multi-organ impacts and a significant immune system component is mounting.

What is long COVID?

Many symptoms of post-viral conditions are nonspecific, and long COVID is no different. 

The National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) study examined nearly 10,000 participants to identify 12 signature symptoms of the condition: postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, altered sexual desire or capacity, altered or absent smell or taste, thirst, chronic cough, chest pain, and abnormal movements, such as tics or tremors.

Another study found seven distinct symptoms, adding hair loss, chest and joint pain, dyspnea, and obesity to the list.

As the debate around the nature of long COVID and its associated symptoms continues, new research suggests it may not be just one condition. 

In fact, symptom clustering suggests four general phenotypes that highlight the syndrome’s complexity:

  • minimal symptoms 
  • tiredness/headache/musculoskeletal symptoms 
  • tiredness/headache/musculoskeletal symptoms accompanied by loss of taste or smell
  • many symptoms across multiple systems

Symptoms have also been found to differ between populations, with race, gender, and socioeconomic conditions affecting patients’ symptom profiles.

Currently, fatigue is a hot topic in long COVID research, with similarities identified between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID symptoms and pathophysiology.

Another area of interest includes SARS-CoV-2’s lasting effects on the brain; with the knowledge that the virus can fuse neurons and change the structure of the brain, researchers are seeking explanations for long COVID-associated cognitive and psychiatric changes. Additional studies are exploring the pathophysiology of the chronic pain, cardiovascular complications, immune system issues, and even mitochondrial dysfunction reported in long COVID patients.

Prevalence and persistence of long COVID

Large-scale studies demonstrate that long COVID is a widespread phenomenon, with approximately one in seven US residents having experienced the condition. A smaller cross-sectional study demonstrated that over half of all COVID-19 patients report long COVID symptoms one year post-infection. 

But how reliable are these numbers? People who had COVID-19 before definitive testing was available may be overlooked in the data—and in research and clinical care—due to their lack of a confirmed diagnosis. Studies may also be flawed, where meta-analysis has highlighted methodological issues, such as missing or inappropriate control groups, poor or inconsistent definitions, and sampling bias.

More robust studies that steer clear of these pitfalls estimate a lower prevalence of long COVID—and the Omicron variant of SARS-CoV-2 also appears less likely to induce long COVID symptoms.

For some, the symptoms of long COVID linger for months; others face complications for years. An examination of almost two million electronic health records in Israel revealed that, in people with mild COVID-19 infections, most chronic symptoms resolve within one year. In Singapore, a cluster of patients experienced long COVID-associated inflammation, but saw their inflammatory biomarker levels return to baseline within two years.

In contrast, data from the Centers for Disease Control and Prevention has shown that long COVID symptoms may fluctuate, with some emerging or recurring months after the initial infection. Analyzing the health insurance records of over 40,000 people showed elevated rates of adverse outcomes from asthma to arrhythmias in people with long COVID.

And, in terms of specific symptoms, a study of 331 long COVID patients showed ongoing organ impairment in 59 percent of participants at the one-year mark as demonstrated by physical examination, imaging, and laboratory studies. Patients with cognitive and neuropsychiatric effects reported similar experiences; deficits were measurable up to two years after infection with little evidence of change over time, and brain activation patterns indicated the development of compensatory processes

Ultimately, long COVID remains a matter of significant concern to patients and healthcare providers alike.

How to diagnose long COVID

Laboratory testing for long COVID typically includes blood counts, metabolic panels, inflammatory markers, vitamin levels, and organ function testing. However, as understanding of the condition grows, more definitive testing is on the way. 

Immune dysregulation

Transcriptomic analysis has revealed molecular characteristics associated with distinct symptom clusters—higher immunoglobulin-related gene expression in patients with ongoing pulmonary issues and lower expression in those with other symptoms.

Another study found differences in the neutrophils and plasma proteome of patients with and without long COVID. Many investigations have focused on the immune system and, in particular, the inflammatory response; notably, a Nature study of 268 individuals identified a range of immune features specific to long COVID, including the following:

  • elevated nonconventional monocytes
  • elevated activated and double-negative B cells
  • elevated interleukin-4/6-secreting CD4+ T cells
  • lower circulating conventional type 1 dendritic cells
  • lower central memory CD4+ T cells
  • lower circulating cortisol
  • increases in a range of circulating hormones and immune modulators
  • increased humoral responses to SARS-CoV-2, Epstein-Barr, and Varicella zoster viruses

These findings build on previous studies that showed increased antibody response to COVID-19 vaccination in long COVID patients, changes in B and T cell levels, persistent inflammation in the brain and body, and systemic anti-inflammatory processes

Though these results show promise for diagnostic testing, experts acknowledge that immune profiling is not a simple process: “If you are a doctor doing routine lab work on these patients, you are not going to find these signals,” said Akiko Iwasaki, PhD, lead author of the Nature study. Co-author David Putrino, PhD, added, “These findings show us that people with long COVID are living with a disease process that is observable using the blood testing protocols laid out in the study, but also varies from patient to patient depending on their specific medical history. This means that physicians must listen to their patients and perform a wide variety of physiological and lab tests.”

Complement biomarkers

Complement dysregulation offers another potential opportunity for lab-based diagnosis. Researchers investigating complement protein levels in people with and without long COVID found significant differences in nine markers, concluding that only four of them—Ba, iC3b, C5a, and TCC—together had a predictive power of 0.785 for long COVID. “These findings suggest that complement biomarkers could facilitate the diagnosis of long COVID,” the authors concluded, further proposing that appropriate selection of complement inhibitors might also offer new therapeutic options.

Computational biology

Taking a different tack, computational biology company PrecisionLife sought to examine similarities between genes associated with ME/CFS and those associated with severe or fatigue-dominant long COVID. Via combinatorial and genotype analysis, researchers identified 73 long COVID-associated genes, 14 of which were differentially expressed in transcriptomic analysis and may therefore offer a route to molecular diagnostic testing. 

Additionally, because 13 of the 73 genes are targeted by drugs already in development, and a further 42 have potential for future targeting, the development of long COVID therapeutics may be closer than they seem. PrecisionLife CEO Steve Gardner, PhD said, “Understanding the complex biology of heterogeneous diseases is key to creating better diagnostic and treatment options for patients . . . Using combinatorial analytics to gain unprecedented insight into the drivers of disease biology, we can make a real impact for millions of patients who are desperately seeking accurate diagnosis and better treatments.”

Commercial long COVID tests

The first commercially available long COVID test, IncellDX’s incellKINE Long COVID In Vitro Diagnostic, received CE-IVD approval in Europe in August 2022; since then, IGeneX has also launched a blood test based on the incellKINE assay for use in Australia.

 Although no such tests are approved for commercial use in North America, the U.S. Department of Health and Human Services (HHS) has established a National Research Action Plan on Long COVID to prioritize the need for reliable, effective diagnostic testing and treatment.

The enduring impacts of long COVID

“Long COVID will be around long after the pandemic subsides, impacting our communities, our healthcare system, our economy, and the well-being of future generations,” concludes the HHS-commissioned Health+ Long COVID Report. “We can reduce the severity and breadth of that impact, however, if we act collectively and urgently . . . It starts with listening to and working as partners with those impacted by long COVID and will take concerted, immediate action from many.”


Michael Schubert, PhD

Michael Schubert, PhD, is a veteran science and medicine communicator. He holds graduate degrees in biochemistry and molecular biology with a research focus on chromatin structure and function and has written on subjects from subspeciality pathology to fictional science. In addition to writing and editing, he is co-director of the Digital Communications Fellowship in Pathology and professor of professional practice in academic writing at ThinkSpace Education, the University of Chichester.


Tags:

DiagnosticsImmune SystemVirusesInfectious DiseaseCoronavirus
Top Image:
Research into “long COVID” has quickly accelerated—from 105 articles published on the topic in 2020 to nearly 5,000 in 2023.
iStock, filo