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A Neuroimmunological Approach to Understanding SARS-CoV-2

July 2, 2021

By Parmida Pajouhesh, Neurobiology, Physiology & Behavior ‘23

Author’s Note: The Coronavirus Disease has undoubtedly affected us in many sectors of our lives. There has been a lot of discussion surrounding the respiratory symptoms induced by the disease but less focus on how contracting the disease can result in long-term suffering. As someone who is fascinated by the brain, I wanted to investigate how COVID-19 survivors have been neurologically impacted post-recovery and what insight it can provide on more severe neurological disorders. 

 

The Coronavirus Disease (COVID-19) has drastically changed our lives over the past fifteen months. The viral disease produces mild to severe symptoms, including fever, chills, and nausea. There are individual differences in the length of recovery, typically ranging from 1-2 weeks after contraction [1]. Once recovered, those infected are assumed to be healthy and “back to normal,” but data shows that this is not the case for some COVID-19 survivors. COVID-19 has resulted in more severe long-term effects for patients, greatly affecting their ability to perform daily tasks. Taking a deeper look into the neuroimmunological side effects of COVID-19 can help explain the long-term symptoms experienced by survivors. 

Developing our knowledge of long-term neurological effects on COVID-19 survivors is crucial in understanding the risk of cognitive impairments, including dementia and Alzheimer’s disease [2].

A team led by Dr. Alessandro Padovani at the University of Brescia recruited COVID-19 survivors with no previous neurological disease or cognitive impairment for check-ins six months after infection [3]. The exam assessed motor and sensory cranial nerves and global cognitive function. The results showed that the most prominent symptoms were fatigue, memory complaints, and sleep disorder.  Notably, these symptoms were reported much more frequently in patients who were older in age and hospitalized for a longer period of time [3]. 

Other symptoms reported include “brain fog,” a loss of taste or smell, and brain inflammation [2]. Researchers hypothesize that the virus does not necessarily need to make its way inside neurons to result in “brain fog” but instead claim that it is an attack on the sensory neurons, the nerves that extend from the spinal cord throughout the body to gather information from the external environment. When the virus hijacks nociceptors, neurons that are specifically responsible for sensing pain, symptoms like brain fog can follow [4].

Theodore Price, a neuroscientist at the University of Texas at Dallas, investigated the relationship between nociceptors and angiotensin-converting enzyme 2 (ACE2), a protein embedded in cell membranes that allows for viral entry when the spike protein of SARS-CoV-2 binds to it [4, 5]. The nociceptors live in clusters around the spinal cord, which are called dorsal root ganglia (DRG). Price determined that a set of DRG neurons did contain ACE2, enabling the virus to enter the cells. The DRG neurons that contained ACE2 had messenger RNA for the sensory protein MRGPRD, which marks neurons with axons concentrated at the skin, inner organs and lungs. If sensory neurons are infected with the virus, it can result in long-term consequences. It might not be the case that the virus is directly entering the brain and infecting the sensory neurons. Alternatively, it is the immune response triggering an effect on the brain, which leads to the breakdown of the blood-brain barrier surrounding the brain [6]. While this area of research is still under investigation, studies have shown that the breakdown of the blood-brain barrier and lack of oxygen to the brain are hallmarks of Alzheimer’s disease and dementia. Scientists are tracking global function to further understand the impact of COVID-19 treatments and vaccines on these neurological disorders. 

Understanding whether the cause of neurological symptoms is viral brain infection or immune activity is important to clinicians who provide intensive care and prescribe treatments [2, 6]. With future studies, researchers plan to further examine the causes of these symptoms. This knowledge will hopefully provide COVID-19 survivors with adequate support to combat these difficulties and reduce their risk of developing a more severe neurological disorder in the future.

 

References :

  1. Sissons, Beth. 2021. “What to Know about Long COVID.” Medical News Today. www.medicalnewstoday.com/articles/long-covid#diagnosis
  2. Rocheleau, Jackie. 2021. “Researchers Are Tracking Covid-19’s Long-Term Effects On Brain Health.” Forbes. www.forbes.com/sites/jackierocheleau/2021/01/29/researchers-are-tracking-covid-19s-long-term-effects-on-brain-health/?sh=59a0bb284303
  3. George, Judy. 2021. “Long-Term Neurologic Symptoms Emerge in COVID-19.” MedPage Today. www.medpagetoday.com/infectiousdisease/covid19/90587
  4. Sutherland, Stephani. 2020. “What We Know So Far about How COVID Affects the Nervous System.” Scientific American. www.scientificamerican.com/article/what-we-know-so-far-about-how-covid-affects-the-nervous-system
  5. Erausquin, Gabriel A et al. 2021. “The Chronic Neuropsychiatric Sequelae of COVID‐19: The Need for a Prospective Study of Viral Impact on Brain Functioning.” Alzheimer’s & Dementia. Crossref, doi:10.1002/alz.12255  
  6. Marshall, Michael. 2020. “How COVID-19 Can Damage the Brain.” Nature. www.nature.com/articles/d41586-020-02599-5?error=cookies_not_supported&code=5b856480-d7e8-4a22-9353-9000e12a8962  

The Human-Animal Interface: Exploring the Origin, Present, and Future of COVID-19

June 16, 2021

By Tammie Tam, Microbiology ‘22

Author’s Note: Since taking the class One Health Fundamentals (PMI 129Y), I have been acutely aware of this One Health idea that the health of humankind is deeply intertwined with the health of animals and our planet. This COVID-19 pandemic has been a perfect model as a One Health issue. Through this article, I hope to introduce readers to a fuller perspective of COVID-19 as a zoonotic disease. 

 

The COVID-19 pandemic has escalated into a human tragedy, measured daily by an increasing number of infection cases and a piling death toll. Yet, to understand the current and future risks of the SARS-CoV-2 virus, one must account for the virus’s relationship with animals in the context of its zoonotic nature, as the transmission between animals and humans is often overlooked. Uncovering the range of intermediary hosts of the virus may provide clues to the virus’s origin, point to potential reservoirs for a mutating virus, and help inform future public health policies. As a result, a small but growing body of researchers is working to predict and confirm potential human-animal transmission models.

The origin of the SARS-CoV-2

Currently, the World Health Organization (WHO) and other disease detectives are still working to unravel the complete origin of the virus. Scientists have narrowed down the primary animal reservoir for the virus through viral genomic analysis, between strains of human and animal coronaviruses [1]. They suspect bats to be the most likely primary source of the virus because the SARS-CoV-2 strain is a 96.2 percent match for a bat coronavirus, bat-nCoV RaTG13 [1]. Despite the close match, the differences in key surface proteins between the two viruses are distinct enough to suggest that the bat coronavirus had to have undergone mutations through one or more intermediary hosts in order to infect humans [2]. 

To identify potential intermediate hosts, scientists are examining coronaviruses specific to different animal species [1]. If SARS-CoV-2 is genetically similar to another animal-specific coronavirus, SARS-CoV-2 may also possess similar viral proteins to the animal-specific coronaviruses. With similar proteins, similar host-virus interactions can theoretically take place, allowing for SARS-CoV-2 to infect the animal in question. For example, besides bats, a pangolin coronavirus, pangolin-nCoV, has the second highest genetic similarity to SARS-CoV-2, which positions the pangolin as a possible intermediate host [3]. Because of the similarity, viral proteins of the pangolin coronavirus can interact with shared key host proteins in humans just as strongly as in pangolin [4]. However, more epidemiological research is needed to determine whether a pangolin had contracted coronavirus from a human or a human had contracted coronavirus from a pangolin. Alternatively, the intermediate host could have been another animal, but there are still no clear leads [1]. 

What it takes to be a host for SARS-CoV-2

In any viable host, the SARS-CoV-2 virus operates by sneaking past immune defenses, forcing its way into cells, and co-opting the cell’s machinery for viral replication [5]. Along the way, the virus may acquire mutations—some deadly and some harmless. Eventually, the virus has propagated in a high enough quantity to jump from its current host to the next [5].

Most importantly for the virus to infect a host properly, the virus must recognize the entranceway into cells quickly enough before the host immune system catches on to the intruder and mounts an attack [5]. SARS-CoV-2’s key into the cell is through its spike glycoproteins found on the outer envelope of the virus. Once the spike glycoproteins interact with an appropriate angiotensin-converting enzyme 2 (ACE2) receptor found on the host cell surfaces, the virus blocks the regular functions of the ACE2 receptor, such as regulating blood pressure and local inflammation [6,7]. At the same time, the interaction triggers the cell to take in the virus [5]. 

Since the gene encoding for the ACE2 receptor is relatively similar among humans, the virus can travel and infect the human population easily. Likewise, most animals closely related to humans like great apes possess a similar ACE2 receptor in terms of structure and function, which allows SARS-CoV-2 a path to hijack the cells of certain non-human animals [8]. Despite the overall similar structure and function, the ACE2 receptor varies between animal species at key interaction sites with the spike glycoproteins due to natural mutations that are kept to make the ACE2 receptor the most efficient in the respective animal. Thus, while there are other proteins involved in viral entry into the host cells, the ACE2 receptor is the one that varies between animals and most likely modulates susceptibility to COVID-19 [9]. 

As a result, scientists are particularly interested in the binding of the ACE2 receptor with the viral spike glycoprotein because of its implications for an organism’s susceptibility to COVID-19. Dr. Xuesen Zhao and their team from Capital Medical University examined the sequence identities and interaction patterns of the binding site between ACE2 receptors of different animals and the spike glycoproteins of the SARS-CoV-2 [10]. They reasoned that the more similar the ACE2 receptor of an animal is to humans, the more likely the virus could infect the animal. For example, they found ACE2 receptors of rhesus monkeys, a closely related primate, had similar interaction patterns as humans [10]. Meanwhile, they found rats and mice to have dissimilar ACE2 receptors and poor viral entry [10].

While entrance into the cell is a major part of infection, there are other factors to also consider, such as the ability for viral replication to subsequently take place [11]. With so many different organisms on the planet, the models simply provide a direction for where to look next. SARS-CoV-2 is unable to replicate efficiently in certain animals despite having the entrance key to get in. For example, the virus is able to replicate well in ferrets and cats, making them susceptible to the virus [12]. In dogs, the virus can only weakly replicate. Meanwhile in pigs, chickens, and ducks, the virus is unable to replicate [12]. Outside of the laboratory, confirmed cases in animals include farm animals such as minks; zoo animals such as gorillas, tigers, lions, and snow leopards; and domestic animals such as cats and dogs [13].

The future for SARS-CoV-2

Due to the multitude of intermediary hosts, COVID-19 is unlikely to disappear for good even if every person is vaccinated [14]. Viral spillover from human to animal can spill back to humans. Often, as the virus travels through a new animal population, the virus population will be subjected to slightly different pressures and selected for mutations that will confer a favorable advantage for virus survival and transmission within the current host population [15]. Sometimes, this could make the virus weaker in humans. However, there are times when the virus becomes more virulent and dangerous to humans if it spills back over from the animal reservoir [15]. Consequently, it is important to understand the full range of hosts in order to put in place preventative measures against viral spillover. 

As of now, most of the known susceptible animals usually do not get severely sick with some known exceptions like minks [1]. Nevertheless, people must take precautions when interacting with animals, since research into this area is still developing and there are many unknown factors involved. This is especially important for endangered species to not become sick, because they already face other threats that make them vulnerable to extinction [8]. As a result, some researchers are taking it into their own hands to keep certain animals safe. For example, after the San Diego Zoo’s resident gorillas contracted COVID-19 in January, the zoo proactively began using the experimental Zoetis vaccine to vaccinate their orangutans and bonobos, which are great apes that are considered closely related to humans and susceptible to COVID-19 [16]. Due to an assumed COVID-19 immunity in the gorillas and a limited supply of the Zoetis vaccines, they decided to not vaccinate the gorillas [16]. Now, scientists are trying to modify the Zoetis vaccine for minks, because minks are very susceptible to severe symptoms from COVID-19 and have shown to be able to transmit the virus back to humans [17]. 

Besides the virus mutating into different variants through basic genetic mutations, people must be cautious of potential new coronaviruses which can infect humans [18]. The human population has encountered other novel coronaviruses over the past several years, so it is not out of the question. In animals, if two coronaviruses of a human and an animal infect the same animal host, it could cause a recombination event and create a new hybrid coronavirus [19]. 

For the SARS-CoV-2 virus, Dr. Maya Wardeh and their team at the University of Liverpool found over 100 possible host species where recombination events could take place [18]. These hosts are animals who can contract two or more coronaviruses with one of them being the SARS-CoV-2 virus. For instance, the lesser Asiatic yellow bat, a well-known host of several coronaviruses, is predicted to be one of these recombination hosts [18]. Also, species closer to home such as the domestic cat is another possible recombination host [18]. While it will take many different rare events, from co-infection to human interaction with the particular animal for recombination to be possible, scientists are on the lookout.

Even without a full picture, the Center for Disease Control (CDC) understands the potential risks of animal reservoirs and advises COVID-19-infected patients to stay away from animals—wildlife or domestic—to prevent spillover [20]. COVID-19 has also brought to light zoonotic disease risks from illegal animal trades and wet markets. Once research into the human-animal transmission model becomes more well-developed, public health officials will have a clearer picture as to how the pandemic spiraled to its current state and help develop policies to prevent it from happening again. 

 

References: 

  1. Zhao J, Cui W, Tian BP. 2020. The Potential Intermediate Hosts for SARS-CoV-2. Frontiers in Microbiology 11 (September): 580137. https://doi.org/10.3389/fmicb.2020.580137. 
  2. Friend T, Stebbing J. 2021. What Is the Intermediate Host Species of SARS-CoV-2? Future Virology 16 (3): 153–56. https://doi.org/10.2217/fvl-2020-0390.
  3. Lam TT, Jia N,  Zhang YW, Shum MH, Jiang JF,  Zhu HC,  Tong YG, et al. 2020. Identifying SARS-CoV-2-Related Coronaviruses in Malayan Pangolins. Nature 583 (7815): 282–85. https://doi.org/10.1038/s41586-020-2169-0. 
  4. Wrobel AG, Benton DJ, Xu P, Calder LJ, Borg A, Roustan C, Martin SR, Rosenthal PB, Skehel JJ, Gamblin SJ. 2021. Structure and Binding Properties of Pangolin-CoV Spike Glycoprotein Inform the Evolution of SARS-CoV-2. Nature Communications 12 (1): 837. https://doi.org/10.1038/s41467-021-21006-9. 
  5. Harrison AG, Lin T, Wang P. 2020. Mechanisms of SARS-CoV-2 Transmission and Pathogenesis. Trends in Immunology 41 (12): 1100–1115. https://doi.org/10.1016/j.it.2020.10.004. 
  6. Hamming I, Cooper ME, Haagmans BL, Hooper NM,Korstanje R, Osterhaus  ADME, Timens  W, Turner  AJ, Navis G, van Goor H. 2007. The Emerging Role of ACE2 in Physiology and Disease. The Journal of Pathology 212 (1): 1–11. https://doi.org/10.1002/path.2162.
  7. Sriram K, Insel PA. 2020. A Hypothesis for Pathobiology and Treatment of COVID‐19 : The Centrality of ACE1 / ACE2 Imbalance. British Journal of Pharmacology 177 (21): 4825–44. https://doi.org/10.1111/bph.15082. 
  8. Melin AD, Janiak MC, Marrone F, Arora PS, Higham JP. 2020. Comparative ACE2 Variation and Primate COVID-19 Risk. Communications Biology 3 (1): 641. https://doi.org/10.1038/s42003-020-01370-w. 
  9. Brooke GN, Prischi F. 2020. Structural and Functional Modelling of SARS-CoV-2 Entry in Animal Models. Scientific Reports 10 (1): 15917. https://doi.org/10.1038/s41598-020-72528-z.
  10. Zhao X, Chen D, Szabla R, Zheng M, Li G, Du P, Zheng S, et al. 2020. Broad and Differential Animal Angiotensin-Converting Enzyme 2 Receptor Usage by SARS-CoV-2. Journal of Virology 94 (18). https://doi.org/10.1128/JVI.00940-20.
  11. Manjarrez-Zavala MA, Rosete-Olvera DP, Gutiérrez-González LH, Ocadiz-Delgado R, Cabello-Gutiérrez C. 2013. Pathogenesis of Viral Respiratory Infection. IntechOpen. https://doi.org/10.5772/54287. 
  12. Shi J, Wen Z, Zhong G, Yang H, Wang C, Huang B, Liu R, et al. 2020. Susceptibility of Ferrets, Cats, Dogs, and Other Domesticated Animals to SARS–Coronavirus 2. Science 368 (6494): 1016–20. https://doi.org/10.1126/science.abb7015.
  13. Quammen D. And Then the Gorillas Started Coughing. The New York Times. Accessed February 19, 2021. Available from: https://www.nytimes.com/2021/02/19/opinion/covid-symptoms-gorillas.html. 
  14. Phillips N. 2021. The Coronavirus Is Here to Stay — Here’s What That Means. Nature 590 (7846): 382–84. https://doi.org/10.1038/d41586-021-00396-2. 
  15. Geoghegan JL, Holmes EC. 2018. The Phylogenomics of Evolving Virus Virulence. Nature Reviews Genetics 19 (12): 756–69. https://doi.org/10.1038/s41576-018-0055-5. 
  16. Chan S, Andrew S. 2021. Great Apes at the San Diego Zoo Receive a Covid-19 Vaccine for Animals. CNN. Accessed March 5, 2021. Available from: https://www.cnn.com/2021/03/05/us/great-apes-coronavirus-vaccine-san-diego-zoo-trnd/index.html. 
  17. Greenfield P. 2021. Covid Vaccine Used on Apes at San Diego Zoo Trialled on Mink. The Guardian.Accessed March 23, 2021. Available from: http://www.theguardian.com/environment/2021/mar/23/covid-vaccine-used-great-apes-san-diego-zoo-trialled-mink. 
  18. Wardeh M, Baylis M, Blagrove MSC. 2021. Predicting Mammalian Hosts in Which Novel Coronaviruses Can Be Generated. Nature Communications 12 (1): 780. https://doi.org/10.1038/s41467-021-21034-5.
  19. Pérez-Losada M, Arenas M, Galán JC, Palero F, González-Candelas F. 2015. Recombination in Viruses: Mechanisms, Methods of Study, and Evolutionary Consequences. Infection, Genetics and Evolution 30 (March): 296–307. https://doi.org/10.1016/j.meegid.2014.12.022.
  20. Centers for Disease Control and Prevention. 2020. COVID-19 and Your Health. Accessed February 11, 2020. Available from: https://www.cdc.gov/coronavirus/2019-ncov/daily-life-coping/animals.html.

Unnoticed Adverse Childhood Experiences in COVID-19

May 21, 2021

By Vishwanath Prathikanti, Political Science ‘23

Author’s Note: While doing research for a paper on the mental decline in adults during the pandemic, I discovered something alarming occurring in younger people. While young adults are still the most susceptible to acquire depression in the pandemic, an unprecedented number of K-12 students were as well. Furthermore, K-12 students facing parental abuse were not being recognized as often as before due to the new virtual learning environment they are in. In this paper, I identify what this can lead to, and why we should be doing a better job protecting our younger students.

As college students, we often take for granted the fact that, if we do not have a positive relationship with our parents, many of us can live on campus during the pandemic. Children do not have this luxury, and in fact, the pandemic has made the threat of child abuse arguably even more dangerous.

 

Part 1: Adverse Childhood Experiences and their effect on the biological development of adolescents.

An Adverse Childhood Experience (ACE) can be any traumatic experience in a child’s life from the ages of 0-17, ranging from the death of a family member to abuse or neglect [1]. ACE’s are relatively common in the US, with around 61% of adults reporting to have experienced some form of an ACE in their lifetime [1]. Apart from the psychological damage, chronic stress caused by ACE’s has a number of harmful effects on a biological level, including a weakened immune system, which can result in premature death [2]. 

First and foremost, ACE’s cause a fear response in multiple parts of the brain; the amygdala mediates the response, the prefrontal cortex is involved with the cognitive response, and the hypothalamic-pituitary-adrenal (HPA) axis is critical in the stress response [3]. In a developing brain, extra stressors can cause dysregulation of the HPA system, which inhibits hippocampal neurogenesis, or the growth of new neurons [3]. These stressors have been found to cause cognitive defects in children resulting in lower attention span, lower scores in problem-solving, and lower scores on the California Verbal Learning Test long delay-free recall, which tests learning and memory [4]. Children who suffer from these stressors are often diagnosed with PTSD as a result of the ACE.

Part 2: How COVID-19 makes these situations more difficult to notice and likely more frequent

An important fact to note is that child abuse is more likely to occur in households with parentswho are chronically stressed or have mental illnesses such as depression [1]. COVID-19 has seen a general rise in mental illnesses and general stress across the world, with one study reporting a rise in depression from 14.6 percent to 48.3 percent and stress increasing from 8.1 percent to 81.9 percent [5]. Unsurprisingly, experts are concerned that this has resulted in a surge in domestic abuse. It is important to note is that while reports of child abuse have gone down by 20-70 percent (depending on the area), it is very likely that this is because the primary reporters were teachers, doctors, and social workers who had higher access to children before the pandemic [6, 7]. Furthermore, while the visits themselves have decreased, visits that result in hospitalization increased from 2.1 to 3.2 percent, suggesting that injury severity is getting worse [6].

Normally, teachers are one of the most important ways of identifying and reporting child abuse. Rashes and bruises are easily identifiable by teachers when a child is at school for the majority of the day. On the less physical side of things, when a student is distressed or is showing signs of poor mental health, such as inattentiveness or stress, teachers will address it with a personal conversation with the student. However, it is much more difficult to observe these signs of abuse over online platforms, such as Zoom. Rashes and bruises are much harder to detect due to limited to no visibility of a child’s body, and when students mute themselves or turn off their camera, it is extremely difficult to gauge attention and recognize when there is a problem. The zoom format of group meetings is also naturally less conducive to one-on-one meetings with teachers and students that would normally be very flexible and easy to conduct in person. 

Dr. Kevin Gee from the UC Davis School of Education spoke about K-12 education and dealing with the challenges COVID has posed for this age group during a UC Davis live event. According to Gee, the more support schools can provide to kids the better. “I know of schools that did one-on-one home visits; socially distanced with masks just to check in on how kids are doing,” Gee said [8]. Gee went on to further explain how schools often have many strategies for recovering “academic learning losses, but we still don’t know a lot about how one goes about recovering socio-emotional losses that have been incurred over the past year and a half” [8].

Part 3: Implications for adults

In abuse-related PTSD specifically, adults have been shown to have smaller hippocampal volumes after experiencing an ACE followed by chronic stressors [3, 9]. This smaller volume results in a myriad of memory-related effects. The most significant were deficits in verbal short-term memory, or the ability to remember words that were just spoken, and a failure to activate the hippocampus during memory tasks, leading to poor memory or the inability to make new memories [3]. This reduction in volume can be seen in the other aspects of the brain that contribute to a fear response, including the prefrontal and frontal cortices, cerebellum, and corpus callosum [3]. Neuronal survival and synaptic connectivity generally decreased, resulting in abnormalities in brain structure, possibly leading to psychotic disorders such as schizophrenia and bipolar disorder [10, 11].

The implications of this data are grim, indicating that COVID-19 may produce a generation suffering from mental illness brought on by ACE’s on a scale never before seen. With no way of knowing exactly how many children are affected, it is crucial to focus on preventing abuse rather than intervening when signs appear. This shift can be seen in the passing of the Family First Prevention Services Act of 2018, which is still being updated and improved today. The act focuses on giving states the option to spend money on “prevention services that would allow ‘candidates for foster care’ to stay with their parents or relatives” given the candidates create a “written, trauma-informed prevention plan” that is evidence-based [12]. So far the process for actually implementing these changes has been slow, and not all states have approved the reimbursement of medical charges for families [13]. It’s a relatively small step, and many more must be made to prevent a rise in ACE’s and the health detriments that accompany them in COVID-19.

 

References:

  1. “Adverse Childhood Experiences” CDC. https://www.cdc.gov/violenceprevention/aces/fastfact.html#:~:text=Adverse%20 childhood%20experiences%2C%20or%20ACEs,in%20the%20home%20or%20community 
  2. Bellis et al. “Adverse childhood experiences and sources of childhood resilience: a retrospective study of their combined relationships with child health and educational attendance.” BMC Public Health. 2018; 18: 792. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020215/#CR2 
  3. Anda, et al. “The enduring effects of abuse and related adverse experiences in childhood” Eur Arch Psychiatry Clin Neurosci. 2006 Apr; 256(3): 174–186. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232061/ 
  4. Beers, Sue R. and De Bellis, Michael D. “Neuropsychological Function in Children With Maltreatment-Related Posttraumatic Stress Disorder.” The American Journal of Psychiatry. March 2002. 159(3): 483-486. https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.159.3.483 
  5. Xiong, J. et al. “Impact of COVID-19 pandemic on mental health in the general population: A systematic review.” Journal of Affective Disorders. December 2020. 277(1): 55-64. https://www.sciencedirect.com/science/article/pii/S0165032720325891 
  6. “Trends in U.S. Emergency Department Visits Related to Suspected or Confirmed Child Abuse and Neglect Among Children and Adolescents Aged <18 Years Before and During the COVID-19 Pandemic — United States, January 2019–September 2020” CDC. https://www.cdc.gov/mmwr/volumes/69/wr/mm6949a1.htm#:~:text=During%20the% 20COVID%2D19%20pandemic%2C%20the%20total%20number%20of%20emergency, hospitalization%20increased%2C%20compared%20with%202019. 
  7. Eberman, Sarah. “Identifying and Addressing Child Abuse During the Coronavirus Pandemic.” Hackensack Meridian Health. April 23, 2020. https://www.hackensackmeridianhealth.org/HealthU/2020/04/23/identifying-and-addressing-child-abuse-during-the-coronavirus-pandemic/ 
  8. “UC Davis LIVE: Covid’s Impact on Education” https://m.facebook.com/events/2815426028773876
  9. Bremner, J.Douglas. “Long-term effects of childhood abuse on brain and neurobiology.” Child and Adolescent Psychiatric Clinics of North America. April 2003. 12(2): 271-292. https://www.sciencedirect.com/science/article/abs/pii/S1056499302000986?via%3Dihub 
  10. Read, J. et al. “The contribution of early traumatic events to schizophrenia in some patients: a traumagenic neurodevelopmental model.” Psychiatry. Winter 2001;64(4):319-45. https://pubmed.ncbi.nlm.nih.gov/11822210/ 
  11. Aas, et al. “The role of childhood trauma in bipolar disorders.” Int J Bipolar Disord. 2016; 4: 2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712184/#:~:text=Childhood%20 traumatic%20events%20are%20risk,suicide%20attempt%20and%20substance%20misuse). 
  12. National Conference of State Legislatures. “Family First Prevention Services Act.” Accessed 4/12/2021. https://www.ncsl.org/research/human-services/family-first-prevention-services-act-ffpsa.aspx 
  13. National Conference of State Legislatures. “Family First Legislation.” Accessed 4/12/2021. https://www.ncsl.org/research/human-services/family-first-updates-and-new-legislation.aspx
  14. Centers for Disease Control and Prevention. “Data Visualizations: Adverse Childhood Experiences (ACEs).” Accessed 5/18/21. https://www.cdc.gov/vitalsigns/aces/data-visualization.html#info2

COVID-19 Testing: Three Tools for Public Health

April 23, 2021

By Jessica Lee, Biochemistry & Molecular Biology ‘21

Author’s Note: Inspired by the success of the asymptomatic testing at UC Davis, I wrote this article exploring the different types of diagnostic and antibody tests for SARS-CoV-2, focusing on mechanisms and relative sensitivities and specificities. 

 

The COVID-19 pandemic has demonstrated the importance of widespread and accurate diagnostic testing in controlling community spread. Together with mask mandates, social distancing, and quarantining, COVID-19 testing can slow the spread of a disease that has killed over 2.5 million people [1]. Approximately 80 million COVID-19 tests have been reported at this time, and yet, many people are confused as to how COVID-19 tests work and how each type of test differs in mechanism, sensitivity, and specificity [2]. 

Depending on the type of COVID-19 diagnostic test, they will either detect SARS-CoV-2 nucleic acid, protein, or antibodies generated as a consequence of infection [3]. Samples can be collected from patients via nasal swab, saliva collection, or blood collection [3]. This article will review current COVID-19 tests as well as address potential confusion arising from false negative and false positive results. 

 

Diagnostic Tests

Diagnostic tests are administered to patients to determine if they are infected with SARS-CoV-2 at time of sampling. Such tests may be administered to either symptomatic or asymptomatic patients as a diagnostic tool or preventative public health measure. Various types of diagnostic tests have been developed since the emergence of SARS-CoV-2 as an infectious agent; however, all tests rely on one of two underlying technologies [4]. Molecular tests detect segments of the viral genome while antigen tests detect the presence of viral proteins [4]. However, both molecular tests and antigen tests differ from antibody tests which detect previous SARS-CoV-2 infections. 

 

Molecular Tests

Molecular tests primarily rely on polymerase chain reaction (PCR) technology to detect relatively low quantities of SARS-CoV-2 genome [4]. A PCR has four primary components: DNA template, DNA-dependent DNA polymerase, primers, and nucleotides [5]. SARS-CoV-2 has a positive-sense single stranded RNA genome meaning the genome can directly be translated into protein by host translation machinery [6]. However, since PCRs require a DNA template, the genome must be converted from RNA to DNA via the enzyme reverse transcriptase [5]. Due to this reverse transcription step, this specific type PCR is called reverse transcription, or RT-qPCR. The resulting DNA product then serves as the template for PCR during which a DNA-dependent DNA polymerase recognizes the template and synthesizes the complementary strand via incorporation of nucleotides. The primers, short DNA fragments about 20 nucleotides in length, are the component of PCR that confers specificity to the assay through their complementarity to a specific region in the DNA template [5]. When all reaction components are combined and cycled through specific temperatures, the result is the exponential increase in the number of copies of the target DNA [5]. Thus, the assay can produce a positive result with very small quantities of original template. 

The U.S. Centers for Disease Control (CDC) has established two sets of oligonucleotide primers for the detection of the nucleocapsid (N) gene of SARS-CoV-2 [7]. Thus, if SARS-CoV-2 genome is present in a sample, the primers will hybridize to the N gene, resulting in the amplification of the region and yielding a positive result. Other primers for the detection of the RNA-dependent RNA polymerase and envelope genes have also been developed by the World Health Organization (WHO) [7]. Since the primers are essential to establishing high specificity, it is important that the primers only bind to the intended target. If the primer is too promiscuous, the assay might produce a false positive. Alternatively, if the primer is too stringent, the assay might produce a false negative. There is also concern that if the region in which the primers bind mutates, the assay may no longer consistently detect such mutants [7].

Samples for molecular tests may be collected via nasal swab or saliva and may be pooled for more efficient testing [8]. If a sample pool is positive for SARS-CoV-2, the individual samples are then tested to determine which individuals are positive. Care must be taken, however, with pooled sampling because samples with low viral loads may not be detected due to decreased sensitivity [8]. 

Molecular tests are generally characterized by high sensitivity, high specificity, and moderate price (~$100/test), earning their status as the “gold standard” of COVID-19 testing [9]. However, depending on the laboratory, results may take up to a week to be returned to the patient [3].

 

Antigen Tests

Antigen tests are immunoassays that detect viral proteins by binding viral protein to SARS-CoV-2 antibodies [10]. Generally, antibodies specific to the N protein are produced and purified for use in antigen tests [10]. There is more variation in how antigen tests work as compared to molecular tests; however, generally, the antibodies are conjugated to a tag which can either be read by a machine or is visible to the naked eye. The Abbott BinaxNow COVID-19 Ag Card is even similar to an over-the-counter pregnancy test–a positive result is indicated by a line in a test window [10]. Samples are collected via nasal or nasopharyngeal swab and are flowed over test strips loaded with conjugated antibodies [3,9]. 

Antigen tests often produce results within 15-30 minutes–much faster than many of the molecular tests [3]. Thus, many health care providers use antigen tests as point-of-care “rapid” tests [9]. Although antigen tests are generally cheaper than molecular tests at about $5-50 per test and are highly specific, they are moderately less sensitive than molecular tests [9]. If the antigen level of a specimen is low due to collection before symptom onset or in late infection, a false negative may be more likely than if a molecular test was administered [9]. However, for both molecular and antigen tests, the probability of a false positive is low due to their high specificity [9]. 

 

Antibody Tests

Instead of diagnosing active SARS-CoV-2 infections, antibody tests indicate if the patient has an adaptive immune response to a SARS-CoV-2 infection [3]. Samples are collected via fingerstick–a device which pricks the finger to produce a few drops of blood–or blood draw and detect the presence of antibodies generated by SARS-CoV-2 infection [3]. There are many different types of antibody tests, but all can be sorted into two categories: binding antibody detection or neutralizing antibody detection tests [11]. Assays that detect antibodies through binding of an antigen use purified spike or nucleocapsid protein from SARS-CoV-2 to determine if the patient has previously been infected [11]. The mechanism of these tests is very similar to antigen tests which also depend on the selective binding of antibodies to antigens. Neutralizing antibody detection tests determine the ability of antibodies in a sample to prevent infection in cell culture [11]. This category of tests give a more accurate assessment of a patient to resist reinfection.    

 The CDC’s binding antibody test uses purified spike protein for the detection of IgG and IgM antibodies [12, 13]. While both IgG and IgM antibodies are usually generated 1-3 weeks after exposure to an antigen, IgG antibodies persist longer–often months post infection [11]. Due to the lag between peak viral production and peak antibody production, antibody tests cannot be used as diagnostic tools; however, they are useful for identifying recovered individuals for surveillance purposes[13]. Furthermore, widespread serology surveillance allows public health officials to monitor where COVID-19 cases are concentrated and inform public health policy [14].  

Some antibody tests have high specificity and sensitivity; although, this is highly dependent on the type of test and period of time post infection. Tests may result in a false negative if there has not been sufficient antibody production or if antibody levels have decreased below the limit of detection [13,11]. For example, if one compares a test that only detects IgM antibodies to a test that only detects IgG antibodies, one might see differential results if administered months after infection. Some antibody tests have a slight cross-reactivity with SARS1 and MERS-CoV sera which could result in false positives; however, there is minimal cross-reactivity with commonly circulating coronaviruses [15]. While nucleic acid detection tests remain the gold standard for diagnosis of acute SARS-CoV-2 infection, antibody tests can be valuable tools for clinical and surveillance efforts [12]. 

 

Asymptomatic Testing 

Many U.S. colleges have implemented regular, asymptomatic testing of their students and employee populations [16]. Regular testing can allow early cases of COVID-19 to be identified and allow for efficient contact tracing, limiting the spread of COVID-19. At UC Davis, students and employees who go on campus are required to get tested at least every week at the free asymptomatic testing clinic [17]. With the ability to screen thousands of samples each day, UC Davis has expanded its saliva testing program to include the greater Davis community, catching at least 850 asymptomatic cases that otherwise might have spread to other individuals [17]. 

Clearly, the importance of widespread testing of both symptomatic and asymptomatic individuals cannot be understated. Testing is one of the most important tools public health officials have to monitor and control the ongoing pandemic.

 

References

  1. World Health Organization. WHO Coronavirus (COVID-19) Dashboard. Accessed April 13, 2021. Available from: https://covid19.who.int/. 
  2. Centers for Disease Control and Prevention. COVID Data Tracker: United States Laboratory Testing. Accessed April 13, 2021. Available from: https://covid.cdc.gov/covid-data-tracker/#testing_totalpositivity.
  3. U.S. Food and Drug Administration. Coronavirus Disease 2019 Testing Basics. Accessed April 13, 2021. Available from: https://www.fda.gov/consumers/consumer-updates/coronavirus-disease-2019-testing-basics#:~:text=There%20are%20two%20different%20types,tests%20and%20antibody%20tests.
  4. U.S. Food and Drug Administration. A Closer Look at COVID-19 Diagnostic Testing. Accessed April 13, 2021. Available from: https://www.fda.gov/health-professionals/closer-look-covid-19-diagnostic-testing.
  5. NCBI. Polymerase Chain Reaction (PCR). Accessed April 13, 2021. Available from: https://www.ncbi.nlm.nih.gov/probe/docs/techpcr/.
  6. Ahlquist P, Noueiry AO, Lee WM, Kushner DB, Dye BT. 2003. Host factors in positive-strand RNA virus genome replication. J Virol [Internet]. 77(15), 8181–8186. https://doi.org/10.1128/jvi.77.15.8181-8186.2003.
  7. Wang R, Hozumi Y, Yin C, Wei GW. 2020. Mutations on COVID-19 diagnostic targets. Genomics [Internet]. 112(6):5204-5213. doi:10.1016/j.ygeno.2020.09.028.
  8. Centers for Disease Control and Prevention. 2020. CDC 2019-Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel. Available from: https://www.fda.gov/media/134922/download.
  9. Centers for Disease Control and Prevention. 2020. Interim Guidance for Antigen Testing for SARS-CoV-2. Available from: https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antigen-tests-guidelines.html.
  10. Andrea Prinzi, MPH. 2020. How the SARS-CoV-2 EUA Antigen Tests Work. American Society for Microbiology. Available from: https://asm.org/Articles/2020/August/How-the-SARS-CoV-2-EUA-Antigen-Tests-Work.
  11. Centers for Disease Control and Prevention. 2021. Interim Guidelines for COVID-19 Antibody Testing. Available from: https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antibody-tests-guidelines.html.
  12. Centers for Disease Control and Prevention. 2020. Serology Testing for COVID-19 at CDC. Available from: https://www.cdc.gov/coronavirus/2019-ncov/lab/serology-testing.html. 
  13. U.S. Food and Drug Administration. 2020. Serology/Antibody Tests: FAQs on Testing for SARS-CoV-2. Available from: https://www.fda.gov/medical-devices/coronavirus-covid-19-and-medical-devices/serologyantibody-tests-faqs-testing-sars-cov-2. 
  14. Centers for Disease Control and Prevention. 2021. COVID-19 Serology Surveillance Strategy. Available from: https://www.cdc.gov/coronavirus/2019-ncov/covid-data/serology-surveillance/index.html.
  15. Freeman B, Lester S, Mills L, et al. 2020. Validation of a SARS-CoV-2 spike protein ELISA for use in contact investigations and serosurveillance. Preprint. bioRxiv. 2020;2020.04.24.057323. doi:10.1101/2020.04.24.057323.
  16. Anderson, N. 2020. Welcome to college. Now get tested for the coronavirus — again and again. The Washington Post. Available from: https://www.washingtonpost.com/local/education/welcome-to-college-now-get-tested-for-the-coronavirus–again-and-again/2020/09/04/2d087722-ed2f-11ea-b4bc-3a2098fc73d4_story.html.
  17. Hubler, S. 2021. A California University Tries to Shield an Entire City From Coronavirus. The New York Times. Available from:  https://www.nytimes.com/2021/01/30/us/college-coronavirus-california.html.

 

Online References

  1. World Health Organization. WHO Coronavirus (COVID-19) Dashboard. Accessed 2021. 
  2. Centers for Disease Control and Prevention. COVID Data Tracker: United States Laboratory Testing. Accessed 2021. 
  3. U.S. Food and Drug Administration. Coronavirus Disease 2019 Testing Basics. Accessed 2021.
  4. U.S. Food and Drug Administration. A Closer Look at COVID-19 Diagnostic Testing. Accessed 2021. 
  5. NCBI. Polymerase Chain Reaction (PCR). Accessed 2021. 
  6. Ahlquist P, et al. 2003. J Virol [Internet]. 77(15), 8181–8186. 
  7. Wang R, et al. 2020. Genomics [Internet]. 112(6):5204-5213. 
  8. Centers for Disease Control and Prevention. 2020. CDC 2019-Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel. 
  9. Centers for Disease Control and Prevention. 2020. Interim Guidance for Antigen Testing for SARS-CoV-2. 
  10. Andrea Prinzi, MPH. 2020. American Society for Microbiology. 
  11. Centers for Disease Control and Prevention. 2021. Interim Guidelines for COVID-19 Antibody Testing. 
  12. Centers for Disease Control and Prevention. 2020. Serology Testing for COVID-19 at CDC. 
  13. U.S. Food and Drug Administration. 2020. Serology/Antibody Tests: FAQs on Testing for SARS-CoV-2. 
  14. Centers for Disease Control and Prevention. 2021. COVID-19 Serology Surveillance Strategy. 
  15. Freeman B, et al. 2020. Preprint. bioRxiv. 2020;2020.04.24.057323. 
  16. Anderson, N. 2020. The Washington Post.
  17. Hubler, S. 2021. The New York Times.

Talking with a pediatric oncology nurse about COVID-19 and how it has forever changed the culture of oncology healthcare

April 16, 2021

By Grace Wensley, Biological Sciences ‘21

Author’s Note: As I saw how the COVID-19 pandemic has so greatly affected the elderly population and immunocompromised adults, I wondered why there wasn’t as much as a conversation about immunocompromised children. I interviewed a pediatric oncology nurse working at Children’s Hospital in Oakland, California, and discovered how difficult the pandemic has been on pediatric oncology patients and the healthcare culture shift that has emerged from it. 

This pandemic has taken quite a toll on the healthcare system, and this interview displayed the hardships faced among the pediatric oncology sector. Nurse Kelli Hemmingsen-Smith  discusses how various COVID-related protocols can disrupt pediatric oncology patients’ treatments. Additionally, she describes the emotional impact of the pandemic from limited visitors allowed, a scary environment due to all doctors and nurses wearing masks, and extended inpatient stays for some patients.

 

This interview has been lightly edited for clarity and brevity.

 

Health Care Practices Pre-COVID-19

Grace Wensley: When would your oncology patients wear masks prior to COVID?

Kelli Hemmingsen-Smith, RN: I’m trying to remember what life was like before we wore masks. Normally we would ask them to wear a mask any time they were neutropenic—so any time their absolute neutrophil count (ANC), the amount of white blood cells that are actually neutrophils, was under 500. Part of wearing a mask is for [going] outside because of the spores found in the dirt, on top of sick contacts. We try to be a bit more lenient so that kids can have somewhat of a normal life. But, 99 percent of kids have a central line (a catheter placed in a large vein for fast blood draws and drug administering) so what happens at our hospital is if you have a fever and you have a central line, you have to come to the hospital, get a dose of antibiotics that last for 24 hours and then wait. If you get another fever you do the same thing again. If you get to the hospital and you have a fever, and you’re neutropenic, you have to be admitted and stay until your fever resolves and your counts recover which could take weeks. So while we aren’t requiring kids to wear masks in certain situations [prior to COVID] a lot of family members will enforce mask-wearing because if your kid gets a fever, we know it’s probably a virus, but we can’t risk it so this is how we treat it. If it’s not a virus though, kids go septic really fast so they’ve kind of taken it into their own for mask-wearing.

GW: When these patients are neutropenic is that usually due to their chemotherapy? 

KH: Yes, pretty much all the time. Kids get their chemo. About 7-10 days later, they reach the nadir, which is where your white blood cell counts are at the lowest that they should be, and then they slowly start to recover after that. Also, if they’re sick, that can also cause them to be neutropenic because their immune systems are non-functioning, especially in the beginning days of leukemia, a cancer of your immune system. We can have kids who are waiting for their counts to recover before they start certain chemo, and they can be delayed because their counts aren’t recovering. Sometimes, it can just be because they have a cold. 

GW: Do patients’ counts have to recover between each dose of chemo? 

KH: Depends on the chemo. Not always. Depending on where they are in their cycles. 

GW: If their counts aren’t recovering, and they keep getting sick and can’t recover, does their treatment get delayed? 

KH: Yes. So mask-wearing is a big deal. Like I said, although we required [mask wearing] only for certain instances, kids getting sick that are in treatment is a huge deal and parents are very aware of that.

GW: In these situations of patients being required to wear masks pre-COVID, would their doctors and nurses also be wearing masks? 

KH: Pre-COVID, never. I would actually be very surprised if our culture didn’t change in the fact that we always wear a mask to be perfectly honest, because when you really think about it, it does make sense. When they are neutropenic in the hospital, they get a private room. Our unit has an entire HEPA-filtered unit, so instead of them having to stay in their rooms they can come out, and there is a playroom. Prior to COVID, the only thing that changed from a nursing standpoint if the kid was neutropenic was what room they were put in and that was it. 

 

Healthcare Practices During COVID-19

GW: Has there been a big delay in cancer treatment schedules due to how the hospital has had to adjust infrastructure with COVID? 

KH: We never limited anything. But the only way that it has really impacted our kid’s treatment is when they are getting procedures. They have to have been tested for COVID within four days of their procedure, and for a lot of our patients, it is hard to get to us twice—it is hard enough to get to us once. We do have a lot more people missing procedures, or we don’t get the results of the COVID tests back fast enough. Now, it’s a little different, because we have a rapid in-house test that takes 2-3 hours. Now, if you missed [the test] and didn’t come, we can usually make it work, but in the beginning, that wasn’t always the case. 

I think where we see the delay the most is if a kid’s family gets COVID. In that case, we hold [off on] chemo because the patient could then test positive for COVID. We automatically hold chemo, get a COVID test, and while they are doing the quarantine we are still holding chemo because we just don’t know. That is 14 days. Then if they get it, that’s another 14 days that we are on hold. These are kids that are usually at the end of their treatments [in clinic] which is what we call the maintenance phase which is where you take oral chemo every day. So a month of not taking it is a lot. How does that affect survival, relapse? We don’t know.

GW: Have there been instances where you admit a patient from the clinic to inpatient out of fear that by going home, they could potentially get COVID?

KH: Yes. We had a kid whose housing situation doesn’t allow them to fully quarantine so he just stayed inpatient until we could find a safe place for him to go. We had another patient who was going for a bone marrow transplant, and her family got COVID. We had to hold her marrow transplant until we knew that she had been away from them long enough. She stayed inpatient, and no one could come to visit. But what was really interesting, was once they did the transplant, she got COVID. So we don’t know if it was just “chilling” and when we blasted her immune system it came on. So there is a lot that we don’t know. Would it be fine for the kids to take oral chemo the whole time until their ANC dropped? Maybe. But nobody knows.

GW: Have any of your patients had COVID?

KH: Yes, and what is very interesting about the kids who have gotten it is that the younger kids have had pretty much zero symptoms, and the only reason we know that they have it is because they have to be tested prior to anesthesia. They get anesthesia a lot because they get chemo through lumbar punctures [spinal tap] which we administer anesthesia for. We automatically hold chemo when they test positive. When their symptoms resolve we restart chemo. A lot of time during that time, their ANC will drop due to the virus, and then we wait longer if their ANC did drop to restart the chemo until it was at the right numbers. They haven’t really been super symptomatic.  I’ve noticed that a couple of the kids that have been getting it have elevated liver enzymes, but that can be caused by chemo too, so it’s kind of one of those where there isn’t really a correlation. I’ve noticed it with two kids. 

GW: What is the visitor policy currently? 

KH: Inpatient is one person per patient, and that person can alternate and stay overnight with them. In the clinic, we only allow one parent at a time. Before COVID, anyone could come—we couldn’t care less. Now in the clinic, it’s no siblings and only one parent, unless it’s a consent conference or a diagnosis, then we make allowances. 

GW: Do you think the strict visitor policy will remain post-COVID?

KH: I would hope that would change because that’s a big hardship. If you have a kid that’s young, and can’t really be left alone, then the parents don’t ever get an overlap period to communicate things like, “Hey this cup is what he’s been taking his medicine in.” I would hope that would change. They can’t see their siblings and that’s a big deal for kids.

GW: How have wearing masks affected patient and provider care? 

KH: Even now, anytime an employee is in their room, they all have to put masks on. Us being in masks and gaining rapport with children who are really scared of us is really hard. It’s such a simple thing, but we give a lot of toys now. They can’t go in the playroom. There are no volunteers. When kids are awaiting COVID results prior to surgery, it sometimes takes hours to get them back and that whole time they are fasting. Kids get grumpy. While waiting for surgeries, a lot of the time one parent is outside sitting in the car all day on speaker. It’s hard. 

 

Conclusion:

The feeling I observed from the entire interview was that many of these hardships related to COVID-19 will in time go away, but mask-wearing is here to stay. It took a global pandemic to make light of it, but any type of illness can significantly affect the trajectory of a patients’ treatment and masks can help prevent this, so as Hemmingsen-Smith said, “It just makes sense.”

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