Articles & Experts

The Long Haul: Possible New Explanation for Long COVID

Tuesday, October 31, 2023

by Aaron Medaris

Yes, we’re still talking about COVID. We wish we didn’t have to, but the fact is, COVID is here to stay and it’s something we’re going to have to deal with. Luckily for us, the past 3.5 years have been filled with technological advancements that help us better test, prevent, and treat this cruel illness; allowing many people who contract COVID-19 to recover in a matter of days or weeks. However, there are some people who have been infected that experience long-term effects from their infection, known as Long COVID. Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), is a term used to describe a range of symptoms that persist for weeks, months, or years after the acute phase of a COVID-19 infection. Though Long COVID occurs more often in people who had severe cases, people who had a mild or asymptomatic case can also experience a variety of symptoms long after their initial infection has resolved. In this article, we will explore the various and wide-reaching symptoms of Long COVID, assessing and testing patients exhibiting symptoms, and the latest scientific findings of Long COVID. 

Symptoms of Long COVID 

As of today, there are no diagnostic tests that determine if a patient’s symptoms or conditions are due to Long COVID. Symptoms and conditions can be wide and far reaching and, in some cases, they can even go away and then come back. Common symptoms associated with Long COVID can include:

  • Fatigue: Persistent and often debilitating tiredness or weakness.
  • Shortness of Breath: Difficulty breathing or breathlessness, even during mild physical activity.
  • Cognitive Issues: Often referred to as "brain fog," which can involve difficulties with concentration, memory, and mental clarity.
  • Muscle and Joint Pain: Widespread or localized muscle and joint aches or discomfort.
  • Chest Pain: Discomfort or pain in the chest, which may be associated with breathing difficulties.
  • Headaches: Frequent or severe headaches.
  • Loss of Taste or Smell: Anosmia (loss of smell) or ageusia (loss of taste).
  • Sleep Disturbances: Problems with sleep, including insomnia or excessive fatigue.
  • Heart Palpitations: Irregular or rapid heartbeats.
  • Gastrointestinal Symptoms: Digestive problems, such as diarrhea or abdominal pain.
  • Skin Rashes: Skin issues or unexplained rashes.
  • Dizziness: Feeling lightheaded, dizzy, or experiencing vertigo.
  • Mood Changes: Emotional and psychological symptoms, such as depression, anxiety, or mood swings.
  • Fever: Occasional or persistent low-grade fevers.
  • Post-Exertional Malaise: Severe fatigue or worsening of symptoms after physical or mental exertion. 

It's important to note that the duration and severity of these symptoms can also vary widely. Some people experience mild, manageable symptoms, while others may have more severe and debilitating symptoms that last for months. Additionally, new symptoms may emerge over time, making long COVID a complex and challenging condition to manage. 

Assessing and caring for those with Long COVID

Many Long COVID conditions can be diagnosed clinically based on history and findings on physical examination. Others might require directed diagnostic testing, however it is important as a healthcare provider, to help the patient understand that such clinical assessments might be uninformative. Because Long COVID conditions involve multiple organ systems, a thorough physical exam should be considered. In addition to blood pressure, heart rate, respiratory rate, pulse oximetry, body temperature, and body mass index, healthcare providers should evaluate ambulatory pulse-oximetry for patients with respiratory symptoms, fatigue, or malaise. For patients experiencing postural symptoms such as dizziness, fatigue, or cognitive impairment, Orthostatic vital signs should be evaluated. 

Utilizing laboratory tests can be informative, but again it’s important for the patient to understand that there is no “one” test that will determine if they are experiencing Long COVID. However, because Long COVID affects multiple organ systems, laboratory tests may be able to help you as a provider better understand how Long COVID may be affecting your patient. 

Basic Laboratory Tests to Consider with Long COVID patients include: 


Laboratory Tests

Blood count, electrolytes, and renal function

CBC with possible iron studies, basic metabolic panel, urinalysis

Liver Function

Liver function tests or CMP

Inflammatory Markers

C-reactive protein, erythrocyte sedimentation rate, ferritin

Thyroid Function

TSH and free T4

Vitamin Deficiencies

Vitamin D, vitamin B12


 Specialized Diagnostic Laboratory Tests to Consider with Long COVID patients include:



Laboratory Tests

Rheumatological Conditions

Antinuclear antibody, rheumatoid factor, creatine phosphokinase, anti-cardiolipin, anti-cyclic citrullinated peptide

Coagulation Disorders

D-dimer, fibrinogen

Myocardial Injury


Differentiate symptoms of cardiac vs. pulmonary origin

B-type natriuretic peptide

Other assessment tools can be utilized for evaluation of patients with Long COVID conditions. Testing should be adjusted to fit the patients symptoms and presentation. Those assessments can include the following: 

Functional status or quality of life

  • Patient Reported Outcomes Measurement Information System
  • Post COVID Functional Status Scale
  • EuroQol-5D 

Respiratory Conditions

  • Modified Meical Research Council Dyspnea Scale 

Neurologic Conditions

  • Montreal Cognitive Assessment
  • Mini Mental Status Examination
  • Compass31
  • Neurobehavioral Symptom Inventory 

Psychiatric Conditions

  • Generalized Anxiety Disorder-7
  • Patient Health Questionnaire-9
  • PTSD Symptom Scale 

Latest Findings on Long COVID

In a recent study published in the journal Cell, scientists from the University of Pennsylvania discovered that serotonin levels were lower in people with symptoms of Long COVID. These researchers are suggesting that lingering effects of the COVID-19 virus reduce the amount serotonin the body produces. 

In this study, researchers analyzed the blood of 58 patients dealing with Long COVID symptoms between 3 and 22 months since infection of the virus. That blood was then compared to 30 people who experienced no Long COVID symptoms in addition to 60 patients in the early stages of a COVID-19 infection.

 One finding that stood out to Maayan Levy, a lead author on the study and professor at Perelman School of Medicine, was that levels of serotonin and other metabolites were altered right after a COVID-19 infection, something that also happens immediately after other viral infections. However, in patients with Long COVID, serotonin was the only significant molecule that did not recover to pre-infection levels. 

The researchers also analyzed stool samples from some of the Long COVID subjects and found that they contained remaining viral particles. Utilizing this knowledge, researchers turned to miniature models of the human gut, knowing that this is where more serotonin is produced, and were able to identify a pathway that could underlie some cases for Long COVID. The thought behind this pathway is that viral remnants prompt the immune system to produce interferons. These interferons cause inflammation which inhibits the body’s ability to absorb tryptophan (amino acid that helps produce serotonin). This can trigger blood clots after a COVID-19 infection and could impair the body’s ability to circulate serotonin. With lower levels of serotonin within the body, the vagus nerve is disrupted and therefore the parasympathetic nervous system is also disrupted. 

Scientists also proposed that patients exhibiting symptoms of Long COVID due to lower levels of serotonin could also be an explanation of why they experience problems with short-term memory, as serotonin plays an important role with memory. 

Though this study shows promise, researchers understand that this study needs to be enlarged to be more definitive in its results. An expansion of this study will most likely focus on the three biomarkers presented in this study: the presence of viral COVID remnants in stool, low serotonin, and high levels of interferons. 

“All these different hypotheses might be connected through the serotonin pathway,” said Christoph Thaiss, lead author of the study. “Second of all, even if not everybody experiences difficulties in the serotonin pathway, at least a subset might respond to therapies that activate this pathway,” he went on to say. 

Dr. Levy and Dr. Thaiss, both researchers in this study said they would begin clinical trails to test the effectiveness of fluoxetine (Prozac) which is a selective serotonin reuptake inhibitor to see if they can restore some of the vagal signals to improve memory and cognition. 

Time will tell what the results of the clinical trials will be. Until then, it’s important as a healthcare professional to listen with compassion and support your patients that struggle with Long COVID. Assess, diagnose, and provide them with the resources that can help them through this difficult time. 



Long COVID or Post-COVID Conditions 

Caring for People with Long COVID 

Post-COVID Conditions: Information for Healthcare Providers 

Viral Persistence and Serotonin Reduction Can Cause Long COVID Symptoms, Penn Medicine Research Finds 

Scientists Offer a New Explanation for Long Covid