Could Cortisol Confirm Long COVID Diagnosis?

Medically reviewed by Ioana Bina, MD, PhD

Background Long COVID

Long COVID manifests itself as new or worsening chronic health problems that continue or start 4 weeks or more after the initial infection (symptomatic or asymptomatic) and may be relapsing and remitting.

Roughly twenty percent of patients report long COVID with symptoms like chronic fatigue, shortness of breath, sleep abnormalities, headache, brain fog, joint pains, nausea, cough, and abdominal pain. This means tens of millions of people are affected. In the U.S. alone, 4 million people are out of work because of long COVID, which represents 2.4% of the working population.

The cause of long COVID remains unclear but some hypotheses are: persistence of virus or viral remnants, autoimmunity, dysbiosis, latent virus reactivation, and tissue damage caused by lingering inflammation.

Earlier scientific papers have linked cortisol with long COVID: Long COVID symptoms can be explained by low cortisol due to SARS CoV2 action on the HPA axis and adrenal glands. Depression and fatigue are positively correlated with cortisol in long COVID.

Breakthrough

On August 10, 2022, a breakthrough Yale University study was pre-published by Jon Klein et al. The Yale immunology lab led by Professor Akiko Iwasaki has been at the forefront of COVID research. And even though there are the necessary caveats – it has to go through peer review and should not be used to guide clinical practice (yet) – this new study is significant because it builds on the cortisol papers referenced above.

Bloomberg and Fortune amongst others have promptly covered the breakthrough.

In 2004, after the SARS outbreak in Hong Kong, scientists noticed that SARS patients with lymphopenia and neutrophilia had significantly higher cortisol than those without, questioning the use of high-dose glucocorticoid medication as treatment. Autopsies revealed that cortisol-producing adrenal glands showed degeneration and necrosis.

In fact, SARS (the first COVID strain) uses molecular mimicry, a strategy to evade and misdirect the host's immune response, to break down the cortisol response by itself. Our bodies produce antibodies to counter the virus but they react with our own hormone ACTH which looks similar. So instead of attacking the virus, our antibodies are binding with ACTH which happens to be the releasing hormone leading to the production of cortisol. This is one possible explanation why our cortisol levels drop in long COVID. We end up destroying cortisol production which would modulate our immune system response.

As you can see in the graph, Long COVID (LC) shows a 50% drop vs. normal cortisol levels (HC) in the morning. This could potentially confirm cortisol as the predictor for those who develop long COVID but also diagnose whether someone has long COVID or not. While this is great progress, more studies are needed to validate these learnings.

Source: Distinguishing features of Long COVID identified through immune profiling

Salivary cortisol determination has been described as helpful and effective for establishing and monitoring a proper recovery plan for long COVID. Next year, Pardigm.com will allow consumers to test their cortisol levels at home, from saliva, and get results with the Paradigm app within minutes. However, more studies are needed to validate whether cortisol is correlated with long COVID and whether home testing is a reliable marker. For example, we need to understand at what time of day – wake-up? – you need to measure and how many tests are required on the first day. We would welcome a dialogue with the FDA and other governmental bodies on these studies.

Long COVID Symptoms Same As Hypocortisolism

Hypocortisolism, a state of paradoxically low cortisol, due to HPA axis maladaptation and incompletely understood, shares the same symptoms as long COVID. An article published in Nature in May 2022 alluded to adrenal gland insufficiency developing weeks later in patients with COVID-19, induced through different mechanisms, including vascular damage, viral replication, inflammatory factors and improper tapering off of long-term corticosteroid medication. Further studies are needed to define the role of the adrenal gland in long COVID and the potential benefit of low dose glucocorticoid replacement.

Cortisol as The Chicken And The Egg

It seems cortisol is both the chicken and the egg with high cortisol increasing the risk of attracting COVID as well as low cortisol involved in long COVID symptoms.

We’ve written before about how cortisol increases the risk of catching COVID. Several scientific papers have been published about cortisol and COVID in 2020 and 2021:

• High Cortisol increases the risk of attracting COVID
• High Cortisol increases mortality after attracting COVID
• Cortisol as an Independent Predictor of Unfavorable Outcomes in Hospitalized COVID Patients

Bottom line, it’s too early to say for sure that cortisol confirms a long COVID diagnosis, but for now cortisol seems to be the biomarker that’s showing a clear difference as compared to healthy people. That’s progress and we’re anxious to see further studies confirming this breakthrough.

Before you go, we have one more question for you: How can we get better? Here at Pardigm.com, our goal is to gather the best information to help you understand the science of stress. If you think we missed anything in our research, please let us know here.

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