Is There a Long COVID Phenotype?

By Chuck Dinerstein, MD, MBA — Jul 07, 2023
Long COVID remains chimeric, more a litany of symptoms than a clearcut “disease.” Perhaps a clustering of symptoms might reveal the underlying picture. Researchers using lots of data and statistical analysis identify some patterns.
Image by Gordon Johnson from Pixabay

The study reported in the Open Forum of Infectious Diseases is based on data contained within the Innovative Support For Patients with SARS-Co-V-2 Infectious Registry (INSPIRE), containing patient self-reported symptoms within a few weeks of a COVID test; those individuals could be COVID positive or negative. There were roughly 6,000 participants, 75% of whom had a positive test for COVID before the onset of their symptoms. The self-reported symptoms were gathered from a survey done at entry into the registry and 3 and 6 months.

The statistical search for clustering of symptoms using a technique called latent class analysis initiated by identifying possible “domains” of symptoms, e.g., muscle aches, joint pain, and fatigue. With this symptoms anchor, the frequency of other symptoms is measured, and clusters are identified. The researchers focused most specifically on the fatigue-related.


ACE-HEENT is a cluster with aches, cough, tiredness, and head, eye, ear, nose, and throat symptoms. LOST is loss of smell and taste.

At three and six months, the number of those with minimal symptoms, consider them the asymptomatic, had risen to 72% in those COVID positive and 75% in those COVID negative – for most individuals, their acute symptoms resolve, and Long COVID is not an issue.

For those with persistent symptoms, the symptom clusters changed. Of the remaining 28% of those COVID positive, 50% had a different cluster of symptoms at three and six months; for the 25% COVID negative, the change was about 30% - COVID’s symptoms change over time, making a disease, defined by symptoms, highly dependent on when we look.

Fatigue is extreme tiredness or a lack of energy and motivation. It can manifest itself in many ways; it is one of the most frequent symptoms attributed to COVID acutely and in the long term. Here is what the researchers found when focusing on fatigue.

At three and six months, many more patients had minimal symptoms, as did those with maximal symptoms. As before, symptoms experienced by patients continued to change; for 40% of those COVID positive and 47% of those COVID negative, their initial symptoms were not the same as those at three or six months.

“…the similarities of the positive and negative cohorts suggest that many of the symptoms may not be unique to SARSCoV-2 infection and result from disruptive effects of the pandemic or post-infectious symptoms from other illnesses.”

This is an especially important conclusion. If you look back across those tables and consider the difference between those COVID positive and those COVID negative, which we might think of as the “controls,” nearly all of the symptom clusters we associate with “Long COVID” are found in similar, if not more significant proportions in the control group. Without either a unique diagnostic biomarker for Long COVID or a readily identified symptomatic pattern (phenotype), identifying those with Long COVID is difficult at best and a fool’s errand at worst.

A second important insight is that Long COVID’s symptoms are protean, like the Greek god Proteus, able to change shape at will—many of the symptomatic, COVID positive or negative, have overlapping symptoms. But the researchers did find that cognitive problems, loss of taste and smell were only found in the group COVID positive and persisted over time. So perhaps we may use this cluster as a more defining criterion of Long COVID.

As with all studies, there are strengths and limitations. It was prospective and included a valuable control of those COVID negative. On the other hand, it was self-reported survey data requiring Internet access and without any measure of severity. Additionally, given the changeability of COVID-19 and the length of the study, the post-infection symptoms reflect differing variants and may further confound our counting of symptoms. 

The researchers' final thought.

“This [study] provides further evidence that there is not a singular Long COVID, and that people’s experiences can vary.”

That is why medicine is art as well as science.

Source: Long COVID Clinical Phenotypes Up to Six Months After Infection Identified by Latent Class Analysis of Self-Reported Symptoms Open Forum of Infectious Diseases DOI: 10.1093/ofid/ofad277 


Chuck Dinerstein, MD, MBA

Director of Medicine

Dr. Charles Dinerstein, M.D., MBA, FACS is Director of Medicine at the American Council on Science and Health. He has over 25 years of experience as a vascular surgeon.

Recent articles by this author: