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Long COVID Mystery Has Doctors in the Dark

March 23, 2023 — This month, I took care of a patient who recently contracted COVID-19 and was complaining of chest pain. After ruling out the possibility of a heart attack, pulmonary embolism, or pneumonia, I concluded that this was a residual symptom of COVID. 

Chest pain is a common lingering symptom of COVID. However, because of the scarcity of knowledge regarding these post-acute symptoms, I was unable to counsel my patient on how long this symptom would last, why he was experiencing it, or what its actual cause was. 

Such is the state of knowledge on long COVID. That informational vacuum is why we’re struggling and doctors are in a tough spot when it comes to diagnosing and treating patients with the condition.

Almost daily, new studies are published about long COVID (technically known as post-acute sequelae of COVID-19 [PASC]) and its societal impacts. These studies often calculate various statistics regarding the prevalence of this condition, its duration, and its scope. 

However, many of these studies do not provide the complete picture — and they certainly do not when they are interpreted by t

he lay press and turned into clickbait. 

Long COVID is real, but there is a lot of context that is omitted in many of the discussions that surround it. Unpacking this condition and situating it in the larger context is an important means of gaining traction on this condition. 

And that’s critical for doctors who are seeing patients with symptoms.

Long COVID: What Is It?   

The CDC considers long COVID to be an umbrella term for “health consequences” that are present at least 4 weeks after an acute infection. This condition can be considered “a lack of return to the usual state of health following COVID,” according to the CDC.

Common symptoms include fatigue, shortness of breath, exercise intolerance, “brain fog,” chest pain, cough, and loss of taste/smell. Note that it’s not a requirement that that symptoms be severe enough that they interfere with activities of daily living, just that they are present.

There is no diagnostic test or criteria that confirms this diagnosis. Therefore, the symptoms and definitions above are vague and make it difficult to gauge prevalence of the disease. Hence, the varying estimates that range from 5% to 30%, depending on the study. 

Indeed, when one does routine blood work or imaging on these patients, it is unlikely that any abnormality is found. Some individuals, however, have met diagnostic criteria and have been diagnosed with postural orthostatic tachycardia syndrome (POTS). POTS is a disorder commonly found in long COVID patients that causes problems in how the autonomic nervous system regulates heart rate when moving from sitting to standing, during which blood pressure changes occur. 

How to Distinguish Long COVID From Other Conditions

There are important conditions that should be ruled out in the evaluation of someone with long COVID. First, any undiagnosed condition or change in an underlying condition that could explain the symptoms should be considered and ruled out. 

Secondly, it is critical to recognize that those who were in the intensive care unit or even hospitalized with COVID should not really be grouped together with those who had uncomplicated COVID that did not require medical attention. 

One reason for this is a condition known as post-ICU syndrome or PICS. PICS can occur in anyone who is admitted to the ICU for any reason and is likely the result of many factors common to ICU patients. They include immobility, severe disruption of sleep/wake cycles, exposure to sedatives and paralytics, and critical illness. 

Those individuals are not expected to recover quickly and may have residual health problems that persist for years, depending on the nature of their illness. They even have heightened mortality

The same is true, to a lesser extent, to those hospitalized whose “post-hospital” syndrome places them at higher risk for experiencing ongoing symptoms. 

To be clear, this is not to say that long COVID does not occur in the more severely ill patients, just that it must be distinguished from these conditions. In the early stages of trying to define the condition, it is more difficult if these categories are all grouped together. The CDC definition and many studies do not draw this important distinction and may confuse long COVID with PICS and post-hospital syndrome.

Control Groups in Studies Are Key

Another important means to understand this condition is to conduct studies with control groups, directly comparing those who had COVID with those that did not. 

Such a study design allows researchers to isolate the impact of COVID and separate it from other factors that could be playing a role in the symptoms. When researchers conduct studies with control arms, the prevalence of the condition is always lower than without. 

In fact, one notable study demonstrated comparable prevalence of long COVID symptoms in those who had COVID versus those that believe they had COVID. 

Identifying Risk Factors

Several studies have suggested certain individuals may be overrepresented among long COVID patients. These risk factors for long COVID include women, those who are older, those with preexisting psychiatric illness (depression/anxiety), and those who are obese. 

Additionally, other factors associated with long COVID include reactivation of Epstein-Barr virus (EBV), abnormal cortisol levels, and high viral loads of the coronavirus during acute infection. 

None of these factors has been shown to play a causal role, but they are clues for an underlying cause. However, it is not clear that long COVID is monolithic — there may be subtypes or more than one condition underlying the symptoms. 

Lastly, long COVID also appears to be only associated with infection by the non-Omicron variants of COVID.

Role of Antivirals and Vaccines 

The use of vaccines has been shown to lower, but not entirely eliminate, the risk of long COVID. This is a reason why low-risk individuals benefit from COVID vaccination. Some have also reported a therapeutic benefit of vaccination on long COVID patients. 

Similarly, there are indications that antivirals may also diminish the risk for long COVID, presumably by influencing viral load kinetics. It will be important, as newer antivirals are developed, to think about the role of antivirals not just in the prevention of severe disease but also as a mechanism to lower the risk of developing persistent symptoms. 

There may also be a role for other anti-inflammatory medications and other drugs such as metformin.

 Long COVID and Other Infectious Diseases 

The recognition of long COVID has prompted many to wonder if it occurs with other infectious diseases. Those in my field of infectious disease have routinely been referred patients with persistent symptoms after treatment for Lyme disease or after recovery from the infectious mononucleosis. 

Individuals with influenza may cough for weeks post-recovery, and even patients with Ebola may have persistent symptoms (though the severity of most Ebola causes makes it difficult to include). 

Some experts suspect an individual human’s immune response may influence the development of post-acute symptoms. The fact that so many people were sickened with COVID at once allowed a rare phenomenon that always existed with many types of infections to become more visible.

Where to Go From Here: A Research Agenda

Before anything can be definitely said about long COVID, fundamental scientific questions must be answered. 

Without an understanding of the biological basis of this condition, it becomes impossible to diagnose patients, development treatment regimens, or to prognosticate (though symptoms seem to dissipate over time). 

It was recently said that unraveling the intricacies of this condition will lead to many new insights about how the immune system works — an exciting prospect in and of itself that will advance science and human health.

Armed with that information, the next time clinicians see a patient such as the one I did, we will be in a much better position to explain to a patient why they are experiencing such symptoms, provide treatment recommendations, and offer prognosis. 

Amesh A. Adalja, MD, is an infectious disease, critical care, and emergency medicine specialist in Pittsburgh, and senior scholar with the Johns Hopkins Center for Health Security.

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