Non-Respiratory Symptoms of COVID-19

The truth is that much of what we were told in the early days of the COVID-19 pandemic was not entirely accurate. Many of the messages in the United States and other countries implied that the disease was “mild” for anyone who was not elderly or did not have a pre-existing respiratory condition. We were told the main symptoms were fever, coughing and difficulty breathing. It would be like a bad cold.

None of that is false. Data still shows that elderly individuals and those with pre-existing conditions are the most likely to experience severe disease. However, over the past few months we have seen how the SARS-CoV-2 virus can present serious complications in almost every organ system, and how its effects aren’t limited to the most vulnerable populations. We have also seen a growing number of cases where individuals are still experiencing life-altering symptoms for months after their supposed recovery.

To gain a full understanding of SARS-CoV-2 and COVID-19, we have to explore every system in the body and track down the causes of all the unexpected clinical presentations of the disease.  

How does COVID-19 affect other body systems?

COVID-19 is primarily a respiratory disease. The most common symptoms are fever, coughing and difficulty breathing. Some people have described it as a bad cold, while many have required hospitalization or ventilators. CDC lists several non-respiratory symptoms such fatigue, muscle/body aches, sore throat, congestion, and several digestive issues. The loss of taste and smell has also been a widely discussed symptom.

The SARS-CoV-2 virus gains access to cells by binding to the ACE2 receptor. This receptor normally binds an enzyme responsible for lowering blood pressure. It’s highly expressed in many parts of the respiratory system, but also in many other tissues throughout the body. This widespread distribution of ACE2 is one of the reasons why COVID-19 can cause so many different symptoms. If the virus manages to bind ACE2 in other tissues—the β cells of the pancreas, for example—it can disrupt a wide variety of bodily functions.

The other major factor in severe COVID-19 is the irregular immune response provoked by SARS-CoV-2. The infection is closely associated with a decrease in circulating immune cells such as CD4+ and CD8+ T cells, as well as an increase in inflammatory markers. Inflammatory cytokines such as IL-6 are released by the innate immune system in response to an infection. In some cases of COVID-19, cytokine production spirals out of control into a condition called a “cytokine storm.” This triggers extreme inflammation, causing immune cells to damage our own cells. In many cases, the cytokine storm causes more harm than the original infection. Cytokine storm is one of the key triggers of acute respiratory distress syndrome (ARDS) in COVID-19 patients, and it is suspected to cause many of the other life-threatening symptoms associated with COVID-19.

Are these symptoms actually more common with COVID-19 than other viruses or emerging infectious diseases such as SARS or MERS? It’s hard to tell. Many of the non-respiratory symptoms also occur with these other diseases, but the circumstances of the COVID-19 pandemic make it difficult to compare frequency. For example, there have only been around 8,400 cases of SARS worldwide since 2003. According to Johns Hopkins, there have been over 59 million cases of COVID-19 (as of November 24, 2020). A single doctor may see dozens of complex COVID-19 cases with multiple systems affected, while the case numbers of SARS are low enough that reports of unique symptoms are scarce.

Overall, the complexity of COVID-19 is a reminder that this is a novel disease caused by a previously unknown virus. Our understanding of the infection has progressed at an amazing rate since it was first reported, but we still have so much more to learn.

Cardiovascular System

Cardiovascular COVID-19 symptoms

Outside of the lungs, the cardiovascular system is possibly the most impacted by COVID-19. Inflammation and cytokine storm are the most likely cause of many of these clinical presentations, but data on ACE2 expression in cardiac cells suggests that direct viral attack is also a factor. 

Patients with “severe” COVID-19 have significant rates of major cardiac events such as cardiac arrest. An early study from Wuhan, China, the first epicenter of the pandemic, found that 22% of ICU patients showed signs of acute damage to the heart muscle, while another recent study estimated as high as 36%. A different Wuhan study found that 23% of hospitalized patients experienced heart failure. There are also reports of new-onset atrial fibrillation, an irregular heart rate that occurs when the upper and lower chambers of the heart beat out of sync.

Myocarditis, a common feature of viral infections, has also been reported with many COVID-19 cases. This inflammation of the heart muscle often results in chest pains, shortness of breath, and arrhythmia. If blood clots begin to form, it can also lead to a heart attack or stroke.

Blood clot formation is also a risk with COVID-19, as the virus has been shown to influence several factors involved in coagulation. By disrupting the normal coagulation cascade, the virus induces a high risk of blood clots, including venous thromboembolism and ischemic stroke. This is likely related to hypoxia caused by a decrease in respiratory function, as well as general inflammation, but platelet hyperactivity as a result of ACE2 binding has also been implicated.

Nervous System

Neurological COVID-19 symptoms

Headaches and dizziness have been documented in COVID-19 patients of every level of disease severity, with some frequency estimates as high as 42%.

Some of the more serious symptoms, however, involve SARS-CoV-2 entering nervous tissue. ACE2 is found on neurons, and direct entry of the virus into structures such as the brain stem can cause the loss of autonomic control over breathing. Other symptoms are similar to meningoencephalitis, an inflammation of the brain that can lead to altered mental states. One case study describes a patient who developed delusions and the inability to walk, among other serious neurological symptoms. This patient tested negative for COVID-19 via nasopharyngeal swabs, but antibodies for SARS-CoV-2 were found in his cerebrospinal fluid.

As mentioned earlier, there are many reports of COVID-19 leading to ischemic stroke, especially among older patients and those with cardiovascular risk factors. Cerebral hemorrhage can also occur if the virus binding to ACE2 causes a breakdown of the blood brain barrier.

One interesting symptom that seems to be widespread is the loss of taste and smell. Patients describe the complete inability taste or smell anything, sometimes continuing for several days or weeks after recovery. ACE2 is expressed in cells of the olfactory bulb, and invasion of those cells by SARS-CoV-2 could lead to a disruption of those senses.

Kidneys

Renal COVID-19 symptoms

Acute kidney injury (AKI, or acute renal failure) is one of the most fatal complications of COVID-19, and it occurs in a high proportion of hospitalized patients. One study in New York City hospitals found that 37% of patients were diagnosed with AKI, and 14% required dialysis. In a different study, up to 87% of critically ill patients showed blood or protein in their urine, which can also indicate damage to the kidneys. Histopathological studies have shown damage to kidney tubules that suggests direct infection of renal cells by SARS-CoV-2.

Liver and Pancreas

COVID-19 symptoms in the liver and pancreas

Diabetes has long been understood as a risk factor for developing severe COVID-19, but even non-diabetic COVID-19 patients have shown abnormal glucose metabolism. These symptoms include hyperglycemia, ketosis and ketoacidosis. Inflammation from cytokines may affect the β-cells in the pancreas, which are responsible for producing insulin. β-cells also express ACE2, so it is possible that the virus is directly attacking these cells, resulting in a decrease in insulin production. This has not yet been demonstrated in published literature, but previous research on SARS-CoV showed evidence of ACE2 binding in the pancreas.

Liver failure is the fourth most fatal complication of COVID-19, after ARDS, heart failure and renal failure. Liver injury is most common in COVID-19 cases that are otherwise considered severe, but it can be a major complication on its own. Hyperinflammation and metabolic damage are likely causes of liver damage, but ACE2 expression on the cells lining the bile duct in the liver suggests that direct binding may be a factor.

Digestive System

Many people diagnosed with COVID-19 report diarrhea, nausea, vomiting and abdominal pain during their illness. These can occur at any level of disease severity, and while they’re unlikely to be life-threatening on their own, they represent another potential mode of transmission. Live SARS-CoV-2 viral particles have been detected in human feces, even after symptoms have gone away. While there are currently no reports of transmission via feces, this brings up an important piece of the pandemic response. Wastewater monitoring can help predict where outbreaks are about to occur by detecting a rise in the level of viral particles or RNA present in sewage.

Long-Term COVID-19

There is little research at this point about the long-term effects of COVID-19, but there are thousands of patients who continue to struggle with mild to life-changing symptoms long after their “recovery.” These symptoms include pain, numbness, and chronic fatigue. Ed Yong writes in The Atlantic about patients who wake up in the night gasping for breath or experience debilitating headaches. Some of these symptoms overlap with conditions such as chronic fatigue syndrome and dysautonomia, which is a disturbance of the autonomic nervous system. Many of these patients are still unable to return to “normal life” six or more months later.

The sheer numbers of these “long-haulers” contradicts the idea that COVID-19 is a “mild” infection that lasts 14 days. While extensive resources have been funneled into understanding the virus and developing drugs and vaccines, chronic COVID-19 is an area that will require much of its own research. In the meantime, changing the narrative around the severity of COVID-19 could influence how seriously people take precautions. As public health professor Nisreen Alwan tells Ed Yong, the definition of recovery must be expanded beyond life and death. “Death is not the only thing that counts. We must also count lives changed.”

There is no dichotomy between death and a “mild” infection. Many of the non-respiratory symptoms can be life-changing, even without the unique symptoms experienced by long-haulers. COVID-19 symptoms are complex and surprising, and we must continue to work towards solutions while protecting ourselves and everyone around us.


Resources

  1. Gupta A, et al. 2020. Extrapulmonary manifestations of COVID-19. Nat Med. 26(7)
  2. AlSamman M, et al. 2020. Non-respiratory presentations of COVID-19, a clinical review. Am J Emerg Med. S0735-6757(20)30847-0.

Young Scientist Discovers Potential Anti-SARS-CoV-2 Drug Molecule

3d model of coronavirus SARS-CoV-2

14-year-old Anika Chebrolu spent the early months of the COVID-19 pandemic identifying a potential anti-SARS-CoV-2 drug candidate. Originally, she was screening potential anti-influenza treatments, but as she watched COVID-19 case numbers rising around the world, she pivoted to focus instead on the SARS-CoV-2 virus. Several months later, Anika not only discovered a strong candidate for further testing, but she earned the title of 2020 Top Young Scientist in a competition sponsored by 3M.

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A Closer Look at C. difficile Biology with Luminescent Tagging

Clostridium difficile is a bacterium that infects around half a million people per year in the United States. The infection causes symptoms ranging from diarrhea to severe colitis, and it’s one of the most common infections contracted while staying in the hospital. As the global incidence of C. diff infection has risen over the past decade, so has the pressure to develop novel therapeutic strategies. This requires a thorough exploration of all aspects of C. difficile biology.

Two recent papers published by researchers at the University of Leiden have shed light on C. difficile physiology using HiBiT protein tagging. The HiBiT system allows detection of proteins in live cells using an 11 amino acid tag. The HiBiT tag binds to the complementary LgBiT polypeptide to reconstitute the luminescent NanoBiT® enzyme. The resulting luminescence is proportional to the amount of HiBiT-tagged protein that is present.

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Rapid COVID-19 Testing, International Collaboration, and a Family Favor

When the COVID-19 pandemic descended on New York in March 2020, Christopher Mason, PhD, knew he was in a unique position to contribute. The Mason Lab specializes in sequencing and computational methods in functional genomics – valuable expertise for addressing an emerging infectious disease. Within days, Chris and his team were helping to analyze patient data, as well as developing new tests and detection methods for the SARS-CoV-2 virus.

3d model of coronavirus covid-19

The Mason Lab developed protocols for a simple COVID-19 detection test that requires less time and equipment than common PCR methods. Their subsequent preprint detailing these methods quickly gained widespread attention, and Chris found himself fielding an endless stream of questions and requests.

During the frenzy, Chris received a call from his older brother. Cory Mason is the mayor of Racine, Wisconsin, the brothers’ hometown.

“He said he saw me tweeting about our new test,” Chris says. “Then he asked me, ‘What if we set it up here in Wisconsin?’’

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Capillary Electrophoresis On Your Benchtop

Spectrum Compact CE System

Here’s the good news: The Spectrum Compact CE System is now available from Promega. 

Here’s the better news: Labs of all sizes now have the opportunity to perform Sanger sequencing and fragment analysis with a personal, benchtop instrument. 

There is no bad news. 

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What We Know About the COVID-19 and the SARS-CoV-2 Virus

David Goodsell image of SARS-2-CoV
Image by David Goodsell

In the nine months since the first cases of COVID-19 were noticed in Wuhan, China, the virus has spread around the globe and infected over 22 million people. As with all emerging infectious diseases, we often find ourselves with more questions than answers. However, through the tireless work of researchers, doctors and public health officials worldwide, we have learned a lot about the virus, how it spreads and how to contain it.

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A Virtual Visit with the National Young Researcher of the Year

Gayetri Ramachandran taught her first university class during the COVID-19 pandemic. While the online course was successful overall, it was a strange experience to teach without being able to see the students.

Gayetri Ramachandran, the first recipient of the National Young Researchers Prize by Promega France

“If you’re giving a seminar and you can’t see the other person, it’s extremely difficult,” says Gayetri, a postdoctoral researcher at the Institut Necker Enfants Malades in Paris, France. “If they’re sleeping, I can’t see them. It’s fine, you can sleep, but if I can’t see that you’re sleeping, then I can’t get that feedback in real time.”

Earlier this summer, Gayetri had another opportunity to give an online presentation. Before the COVID-19 pandemic disrupted travel plans, she was scheduled to visit the Promega Headquarters in Madison, WI, to tour the facilities and meet with R&D scientists. Instead, Gayetri presented her research to a group of Promega scientists in the first Promega Virtual Customer Experience Visit.

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How To Reopen Your Lab With Sustainability In Mind

If you’re preparing to return to the lab for the first time in months, there’s never been a better time to make your lab more sustainable.

Earlier this year, the COVID-19 pandemic forced thousands of labs to temporarily shut down. As restrictions are lifted in many areas, scientists are slowly resuming research. However, reopening a lab after months of closure will require a lot of cleaning and organizing, much like a fresh start. This presents a valuable opportunity to evaluate your lab’s practices and identify ways that you can reduce your environmental impact.

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Connecting and Collaborating: How Scientists Across the Globe are Supporting Each Other During The COVID-19 Pandemic

Many research labs around the world have temporarily closed their doors in response to the COVID-19 pandemic, while others are experiencing unprecedented need for reagents to perform viral testing. This urgency has led many scientists to make new connections and build creative, collaborative solutions.

“In labs that are still open for testing or other purposes, there’s certainly heightened anxiety,” says Tony Vanden Bush, Client Support Specialist. “I feel that right now, I need to help them deal with that stress however possible.”

Last week, Tony was contacted by a lab at the University of Minnesota that was preparing to serve as a secondary COVID-19 testing facility for a nearby hospital lab. The two labs needed to process up to 6,000 samples per day, and the university lab was far short of that capacity.

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Jon Campbell Is Challenging Classic Models of Metabolic Disease

Jonathan Campbell, PhD, asked me to write that he is taller and a bit more handsome than most scientists. I will neither confirm nor deny those assertions, but I will acknowledge that Dr. Campbell has a unique way of describing his recent collaborations and research on metabolism and Type 2 diabetes.

“The rest of the world has been thinking that it’s almost like the emperor has no clothes,” he says. “But we’re the guys who came right in and said ‘Hm, that dude’s naked.’”

Lumit Immunoassays give Jon Campbell's lab better results with an easier workflow.

On March 13, only a few days before the COVID-19 pandemic caused widespread shutdowns in Wisconsin, Jon visited the Promega headquarters in Madison, Wisconsin to meet with R&D scientists and discuss opportunities for new technologies. Over the course of a few hours, Jon and his collaborator Matthew Merrins, PhD, demonstrated how their research challenges dogma and could fundamentally change our understanding of postprandial metabolism. For five decades, the paradigm of glucose control focused on a model that positioned insulin and glucagon as diametrically opposing forces to raise or lower glycemia. As Jon states, things did not always add up.

“For years, everybody has been saying ‘Glucagon is the antithesis of insulin,’ right? Insulin is a good guy. It makes glucose come down. Glucagon is a bad guy. It makes glucose go up. And these two are in this cosmic battle against each other over the control of glycemia. Well, we asked, ‘Why do the beta cells that secrete insulin have glucagon receptors?’ And as you follow the breadcrumbs, you find that these two things are actually working in cooperation. Without that cooperation, the whole thing falls apart,” Jon says.

The Incretin Effect

In addition to exploring the complex biology of glucagon, Jon’s lab studies the Incretin Effect, a mechanism by which the gut influences the secretion of insulin in the pancreas. Past research revealed that rises in blood-glucose matched closely whether glucose was administered orally or intravenously. However, the amount of insulin secreted was 3—4 times higher following oral intake. This is a result of the actions of GLP1 and GIP, the two major human incretins. GLP1 and GIP bind to G-protein coupled receptors in the beta cells of the pancreas to induce insulin secretion. Insulin then acts to promote glucose uptake, reducing glycemia. Many researchers believe that dysfunction of the incretin mechanisms contributes to the reduced insulin secretion seen in individuals with Type 2 diabetes.

“If we can understand the mechanisms of the incretin effect,” Jon says, “We may be able to understand the pathophysiology driving Type 2 diabetes. My hope is that people are going to realize that diabetes is not just a glucose disease. Maybe we have been looking at this too much from a glucose-centric viewpoint. Clearly, glucose is a big problem with diabetes, but it’s not just glucose. This is a metabolic disease, and in order to understand how to fix a metabolic disease, you need to look at all the metabolites and the way overall metabolism is dysregulated.”

Research on the incretin effect has already supported the development of two new classes of drugs for Type 2 diabetes: GLP1R agonists and DPP4 inhibitors (DPP4 is an enzyme that degrades GLP1).

“We collaborate with industry quite a bit, especially pharmaceuticals. We are helping them understand the mechanism of action by which their drugs may work, and that funding has allowed us to expand and grow our program a lot in our first five years. I like to bridge that line between basic and translational science—translating basic science into the clinic.”

The Search for New Technology

Jon wasn’t visiting Promega in mid-March with the goal of seeing the world before COVID-19-related travel restrictions were announced. He’s constantly looking for new collaborations in which both parties can bring something unique to the table. Jon was one of the first to try the new Lumit™ Insulin and Glucagon Immunoassays, which he says are easier to use and have produced better results in his work with glucagon than radioimmunoassays or ELISAs.

“People like Promega scientists say they have a new technology, and they’re looking for someone to try it out it in real-world situations. I don’t have that kind of technology, but I know how to apply it, so there’s a lot of value there. It’s a no-brainer to talk to people about how we can find synergy when the two of us both bring something like that to the table. For some applications, the Lumit™ assays are blowing out whatever we can do, and they’re also incredibly easy to use. So that was a significant improvement in our workflow.”

When asked what he hopes to accomplish in the next few years, Jon similarly points to innovative technology and techniques.

“We have to say, ‘What’s the next innovative step forward, and what new tools can we bring?’ We need to figure out new ways to interrogate the systems that we’re interested in. Then we can start to strip away new biology. If we ask the right question and we answer definitively, we’ll end up with three more questions. Which is great, because we’ll always have more work to do.”


Lumit™ Immunoassays provide a simple and fast alternative to conventional immunoassay methods including sandwich ELISAs and Western blots. Learn more here.

Working on diabetes research? Read more about Promega assays to measure insulin activity in real time.