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.

Three Pillars of ESI Mastery: Part Two

Today’s blog is written by Malynn Utzinger, Director of Integrative Practices, and Tim Weitzel, ESI Architect.

Last month we wrote about the first of three pillars of ESI Self-Mastery: Recognizing and Owning What You Already Have/Are/Do. In this blog, we offer some thoughts on the second pillar: continuously growing our ESI knowledge and skill.

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mRNA Vaccines for COVID-19: The Promise and Pitfalls

Multiple battles are being fought in the war against the SARS-CoV-2 coronavirus that causes COVID-19. Currently, there are nearly 3,000 clinical trials listed in the World Health Organization (WHO) database, either underway or in the recruiting stage, for vaccines and antiviral drugs. Two recent announcements of data from phase 3 vaccine trials, by Pfizer/BioNTech and Moderna, have offered some hope for global efforts to fight the pandemic. At the time of writing, Pfizer and BioNTech had submitted an application for emergency use authorization (EUA) to the Food and Drug Administration (FDA), and Moderna had planned to do so shortly.

mrna vaccines and coronavirus covid-19

Both vaccines are mRNA-based, as opposed to most conventional vaccines against established diseases that are protein-based. Typically, the key ingredient in viral vaccines is either part of an inactivated virus, or one or more expressed proteins (antigens) that are a part of the virus. These protein antigens are responsible for eliciting an immune response that will fight future infection by the actual virus. Another approach is to use a replication-deficient viral vector (such as adenovirus) to deliver the gene encoding the antigen into human cells. This method was used for the coronavirus vaccine developed by Oxford University in collaboration with AstraZeneca; phase 3 interim data were announced on the heels of the Pfizer/BioNTech and Moderna announcements. All three vaccines target the SARS-CoV-2 spike protein, because it is the key that unlocks a path of entry into the host cell.

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Supporting Caregivers, Colleagues, and Neighbors

“Oh, I get by with a little help from my friends.” – The Beatles

And don’t forget family, colleagues, neighbors. And, these days, the chatty checker at the grocery store, the postal carrier who offers a wave, even the guy who makes oh-so-brief eye contact at a stoplight. We’re all getting by with a little help from anyone who will offer it.   

two people wearing masks and social distancing give waves in the subway station

Care. Support. Help! We provide and receive these gifts throughout our entire lives. The pandemic, however, has prompted many of us to feel the weight of their importance more than ever. We simply need one another to get by. Lending someone a helping hand can be tremendous therapy, too. Today we pause to appreciate three distinct ways our Promega community is supporting colleagues in times of need.     

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Finding a Cure for COVID-19: Spotlight on Virologist Dr. Colleen Jonsson

Photograph of Dr. Jonsson of UTSHC who works on small molecule SARS-CoV-2 theraupeutics
Dr. Colleen Jonsson, UTHSC

Since the COVID-19 pandemic swept the world in early 2020, many scientists in the viral research community have shifted their focus to study the SARS-CoV-2 coronavirus. Dr. Colleen Jonsson is one of them. She’s the Director of the Regional Biocontainment Laboratory, and Director of the Institute for the Study of Host-Pathogen Systems at the University of Tennessee Health Science Center (UTHSC) in Memphis.

Dr. Jonsson has been studying highly pathogenic human viruses for more than three decades. She has led several cross-institutional projects using high-throughput screens to discover small molecules that could be used as antiviral drugs. And now, she’s using that experience to find an antiviral therapeutic against SARS-CoV-2.

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The Gift that Keeps on Giving: Reduce, Reuse, and Recycle this Holiday Season

It’s finally the holiday season, the most wonderful time of the year! Although we’d love to gather with family and friends as usual, times are different. COVID-19 may have presented its challenges, but that surely won’t stop us from connecting with one another to spread love and holiday cheer!  

With the holiday season comes lots of gifts, packages, and deliveries. One of the best ways we can connect and support one another through this is by reducing, reusing, and recycling our material. Doing so will benefit humanity’s most precious gift that keeps on giving: Mother Earth.

The question is, how can we put our best efforts towards reducing, reusing, and recycling our materials used for gifting? First, it’s important to remind ourselves of gifting material that is recyclable and not recyclable. 

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Biotechnology Teaching Online: A New Way to Look at Scientific Notebooks

This post is written by guest blogger, Peter Kritsch MS, Adjunct Instructor BTC Institute.

When I was in the middle of my junior year in high school, my family moved. We had lived in the first state for 12 years. I had gone to school there since kindergarten. Although it wasn’t a small district, I knew everybody and, for better or worse, everybody knew me. Often the first reaction I get when I tell people when we moved is that it must have been hard to move so close to graduation. The reality is . . . it really wasn’t. In fact, it was quite liberating. See, I didn’t have to live up to anybody else’s expectations of who I was based on some shared experience in 2nd grade. I had the opportunity to be who I wanted to be, to try new things without feeling like I couldn’t because that wasn’t who I was supposed to be. 

As long as I refrained from beginning too many sentences with “Well at my old school . . . “ people had to accept me for who I was in that moment, not for who they perceived me to be for the previous 12 years. Now, the new activities were not radically different. I still played baseball and still geeked out taking AP science classes, but I picked up new activities like golf, playing basketball with my friends, and even joined the yearbook. I know . . . “radically different.”  The point is that the new situation allowed me to try something new without worrying about what had always been. 

Peter teaches about biofuels in his virtual classroom.

The pandemic has forced a lot of us to move our classrooms online. In a short period of time, everything changed about how education was done. Our prior teaching experience, including the experience I had with doing blended learning (ooops . . . “back at my old school”), was helpful to a point.  But we quickly found out that being completely virtual was different. And as science teachers, how do you do more than just teach concepts when online? How do you help students to continue engaging in the crucial parts of science – observing, questioning, designing, analyzing, and communicating?

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Mass Spec for Glycosylation Analysis of SARS-CoV-2 Proteins Implicated in Host-Cell Entry

The spike protein of the SARS-CoV-2 virus is a very commonly researched target in COVID-19 vaccine and therapeutic studies because it is an integral part of host cell entry through interactions between the S1 subunit of the spike protein with the ACE2 protein on the target cell surface. Viral proteins important in host cell entry are typically highly glycosylated. Looking at the sequence of the SARS-CoV-2 virus, researchers predict that the spike protein is highly glycosylated. In a recent study, spike proteins of SARS-CoV-2 were analyzed using mass spec analysis to determine the N-glycosylation profile of the subunits that make up the spike protein.

3d model of coronavirus covid-19

Glycans assist in protein folding and help the virus avoid immune recognition by the host. Glycosylation can also have an impact on the antigenicity of the virus, as well as potential effects on vaccine safety and efficacy. Mass spectrometry is widely used for viral characterization studies of influenza viruses. Specifically, mass spec has been used to study influenza protein glycosylation, antigen quantification, and determination of vaccine potency.

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Reflections on Virtual Conference Life: Can You Hear Me?

Today’s guest blog is written by Research Scientist Danette Daniels, PhD.

Virtual Conference Presentation

One of my favorite things about being a scientist is attending conferences. They are an opportunity to connect with the broader community, share ideas, talk about the future, and get inspired. After a conference I would return to my lab feeling so energized and excited, being motivated to push the research forward and work on the next stories we could share.

In March of this year, I remember my shock of watching the conferences slowly getting canceled one by one. First, it was everything in March and April, then May, then through to August.  I was in denial at the time, thinking this would be temporary and that we would all be back together in person in a few months. Then it became quite clear this would not be the case and events were transitioning to a virtual format.

Virtual! I was so skeptical. How could you connect with anyone at a virtual conference? How are people going to ask questions after a talk? How will it be to give a talk basically to your computer, not knowing who is listening, or more importantly for me, not being able to read the audience? I was not looking forward to it, but the alternative, no conferences at all, I thought was worse.

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3 Tips for Preserving Muscle and Joint Health at Work

Today’s guest blog was written by Claire Checovich, Exercise & Ergonomics Specialist in the Promega Wellness Center.

The human body is amazing – it can climb towering cliffs, run hundreds of miles, and move many times its own weight.

It can also be annoying – how many of us have been injured just by sleeping or sitting in a funny position?

We’ve almost certainly all experienced the latter, whether we’re hunched over books and papers or staring at a computer for hours on end. That’s where ergonomics and biomechanics comes in.

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