Categories
COVID-19

The Physiology and Anatomy Behind Viruses Ft. COVID-19

Viruses are mainly thought to be infectious diseases that spread easily, originating from a cough or sneeze, or even out of nowhere. Although this is partially true, there is much more behind the development of a virus. Tracing the origins of viruses can be quite difficult because they do not necessarily leave behind any ‘fossils.’ Rather, they only make copies of themselves which means studying their ancestry requires pinpointing the host cell and trying to deduce its origins.

A virus is a non-living microscopic agent that has attachment proteins that act as receptors. Viruses are extremely small, approximately 20 to 400 nanometers in diameter. By comparison, a human red blood cell is about 6,000 to 8,000 nanometers in diameter. The structure of a virus has a center of nucleic acid (either DNA or RNA), and is enclosed in a defensive layer of protein called the capsid. A capsid is composed of protein subunits also known as capsomeres. Its envelope and the cell membrane are also made up of similar material. 

Viruses have either single-stranded DNA, single-stranded RNA, double-stranded DNA, or double-stranded RNA. The type of genetic material found in a particular virus depends on the nature and function of the specific virus. The viral genome can consist of very few genes or up to hundreds of genes depending on the type of virus. The genetic material is not typically exposed but is covered by the capsid in order to be protected from damage.

Scientists have been able to theorize how viruses may develop based on the fact that the genes of many viruses, like those that cause herpes, share similar characteristics with the genes from cells. This theory is known as the Cellular Theory. This theory implies that viruses first started as big pieces of cellular DNA and eventually became independent. Others speculate that viruses came along very early in evolution, and some of their DNA stayed in cells’ genomes. This is known as the Theory of Evolution for Viruses. The fact that viruses infecting humans share similar structural features with viruses could mean that all of these viruses have a common origin, dating back billions of years.

Not all viruses look exactly the same in appearance, but they all share a similar structure. The shape of viruses varies widely. In general, viruses fit usually into two different visual categories. Viruses of humans, animals, and plants are typically spherical and rod-shaped, sometimes consisting of many sides. Viruses of bacteria (bacteriophages) are often shaped almost like a spaceship.

Figure 2: Visual of the structure of a virus that has a “spaceship” appearance.

Because viruses can not exist independently, they must take over a living cell in order to survive and reproduce. When a virus comes into contact with a susceptible host cell, it will latch itself onto the surface using its receptors. The virus will then inject its nucleic acid into the host cell. After, the virus will enter the cell in order to take control of the host by using the protoplasm,the living part of a cell that is surrounded by a plasma membrane, inside of it to create new viruses. Once these new virus particles assemble, they will leave the original host cell and find new host cells and repeat the same process, called the lytic cycle. There is no cell division within the development and replication of viruses. Viruses are only able to be replicated through the chemical synthesis of viral nucleic acid and capsid proteins. In the ending stage of virus replication, host cells that have been attacked may be completely destroyed or suffer little or no harm.

Few viruses go through an additional phase before replication, known as the lysogenic or dormant phase. During this phase, the virus can remain inside the host cell for extended periods of time without causing any changes to the cell. Once activated, however, these viruses can immediately enter into the lytic cycle.

Figure 3: Diagram of a lytic cycle, the process of virus replication.

Viruses cause a number of diseases in the organisms they infect. Human infections and diseases caused by viruses include Ebola fever, chickenpox, influenza, AIDS, and herpes. Plant diseases include mosaic disease, ringspot, leaf curl, and leafroll. Viruses known as bacteriophages cause disease in bacteria and archaeans. Humans can contract viruses through ingestion, sexual transmission, from the air, and many other ways.

Figure 4: Illustration of how airborne diseases can spread.

Vaccines have been effective in preventing some types of viral infections, such as smallpox and the flu. They work by helping the body build an immune system response against these specific viruses. However, it is important not to forget that many viruses can still cause serious damage to living things, and some can actually be fatal. Viruses like COVID-19, are examples of diseases that morphed into a strong and deadly virus that attacks the body and has the ability to kill.

Coronaviruses are a family of viruses that can cause illnesses such as the common cold and it is essentially made up of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). However, the newly discovered coronavirus, COVID-19 or SARS-CO-V-2, became so severe that it caused a worldwide pandemic and has resulted in hundreds of thousands of deaths. Experts say SARS-CoV-2 originated in China and was passed from bats to humans. 

Figure 5: Diagram depicting the human-to-human transmission of coronavirus and its effects on the body.

The name “coronavirus” is derived from Latin: corona, meaning “crown” or “wreath.” Coined by June Almeida and David Tyrrell who studied the human coronavirus, the name was meant to refer to the appearance of the virus. Coronaviruses are large, roughly spherical shaped particles with viral spike peplomers which are actually proteins that lie on the surface of the virus. On average a coronavirus particle has 74 surface spikes all around. The average diameter of a virus particle is around 125 nm (.125 μm). They also contain a positive-sense, single-stranded RNA genome. 

Figure 6: Image depicts the COVID-19 virus and its anatomy.

Inside their envelope lies the nucleocapsid, which is formed from multiple copies of nucleocapsid protein. They are bound to the positive-sense single-stranded RNA genome in a “continuous beads-on-a-string type conformation.” The lipid bilayer envelope, membrane proteins, and nucleocapsid protect the virus when it is outside the host cell.

Figure 7: Infographic detailing the structure and makeup of a COVID-19 virus particle.

A virus infects the body by entering healthy cells and going through the lytic cycle. There, the infector makes copies of itself and multiplies throughout the body. The new coronavirus would then latch its spiky surface proteins to receptors on healthy cells, especially those in the lungs, and this is why those who have contracted the coronavirus experience respiratory issues. Eventually, the virus kills off some of the healthy cells.

COVID-19 begins with droplets from an infected person’s cough, sneeze, or breath. They could travel through the air or be on a surface that someone may touch before touching the eyes, nose, or mouth. That gives the virus a passage into the mucous membranes and allows it to segway into the throat. Within 2 to 14 days, the immune system may respond with symptoms including a fever, cough, body aches, headaches, shortness of breath, chills, loss of taste, loss of smell, nausea, and other symptoms. The virus moves down into the respiratory tract, the airway that is connected to the mouth, nose, throat, and lungs. Because the lower airways have more ACE2 receptors compared to the respiratory tract, COVID-19 is more likely to travel deeper than the average cold.

Viruses are very complex in the way they manifest, and there is still much research that has yet to be discovered about viral infections. Doctors are continuously working close with researchers to develop stronger and more efficient ways of combating these infections. Currently, there are different vaccines being made in order to eventually fight COVID-19 virus cases.

Figure 8: A visual referencing the symptoms that may come with COVID-19.

Citations

“2-13. MORPHOLOGY AND PHYSIOLOGY OF VIRUSES “. Nursing411.Org, 2020, http://nursing411.org/Courses/MD0151_Principals_Epidem_Micro/2-13_Principals_Epidem_Micro.html. Accessed 20 Aug 2020.

“Bacteriophage Life Cycle Animation”. Thoughtco, 2020, https://www.thoughtco.com/bacteriophage-life-cycle-animation-373884. Accessed 1 Sept 2020.

Baines, Luara. “Virus Notes.” Physiology/Anatomy, 30 Aug 2020. Pioneer Valley High School.

“Coronavirus”. En.Wikipedia.Org, 2020, https://en.wikipedia.org/wiki/Coronavirus. Accessed 1 Sept 2020.

“Coronavirus Disease 2019 (COVID-19) – Symptoms And Causes”. Mayo Clinic, 2020, https://www.mayoclinic.org/diseases-conditions/coronavirus/symptoms-causes/syc-20479963. Accessed 1 Sept 2020.

“Learn How Virus Replication Occurs With This Detailed Primer”. Thoughtco, 2020, https://www.thoughtco.com/virus-replication-373889. Accessed 20 Aug 2020.

Alexis Dehorta, Youth Medical Journal 2020

Categories
COVID-19

The Impact of COVID-19 on Pre-Diabetic Patients

Introduction

The COVID-19 pandemic is taking a great toll globally. To control the situation effectively, measures to lower the death rate have to be taken. Doctors have already stated that people with comorbidities like diabetes are at a higher risk of getting severe symptoms of COVID-19 infection.

Increase in Risk

The fluid and electrolyte balance of the body is maintained with the help of the renin-angiotensin system. When a person complains of low blood pressure, the renin (present in the kidney) forms angiotensin I by breaking down the enzyme angiotensinogen. Angiotensin-converting enzyme(ACE) converts angiotensin I into angiotensin II to activate it.
This Angiotensin-converting enzyme (usually present on the lungs, kidney, and heart) binds to the Angiotensin-converting enzyme receptors and squeezes the blood vessels, thus raising the blood pressure of the body. Then the Angiotensin-converting enzyme-2 (ACE-2) breaks down the angiotensin II into molecules that neutralize its harmful effects.

SARS-CoV-2 has a high affinity for ACE-2 receptors present on the surface of healthy cells. Thus it attaches itself to the ACE-2 and attacks the lungs, kidney, and heart.
The levels of ACE-2 increase in a diabetic person (a condition with high blood glucose levels, hyperglycemia) allowing the virus to attack the organs of the diabetic person more disastrously. Acute hyperglycemia upregulates ACE-2 expression on cells which might facilitate viral cell entry. Chronic hyperglycemia downregulates ACE-2 expression making the cells vulnerable to the inflammatory and damaging effects of the virus.

Link Between COVID-19 and Diabetes

COVID-19 is an acute respiratory infection caused by a coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and is spread through air droplets or close contact with an infected person. Often older people(above 65 years of age) & people with pre-existing diabetic conditions are affected.

The risk of a fatal outcome from COVID-19 is up to 50% higher in patients with diabetes. When diabetic patients develop a viral infection it can increase inflammation and the treatment is hard because of fluctuations in blood glucose levels and the presence of diabetic complications. This is because of the compromised immune systems making it difficult to fight with the virus leading to a longer recovery period.

Linked Complications & Risk Factors

Complications like Acute respiratory distress syndrome (ARDS) & multi-organ failure are prevalent in prediabetic Covid-19 patients. It involves the lower respiratory tract which can offset pneumonia, rapidly progressing to ARDS associated with multi-organ failure.
Acute respiratory distress syndrome (ARDS) is a severe lung condition causing fluid accumulation in the alveoli, progressive fibrosis which comprises the gas exchange. The type 1 & 2 pneumocytes lining the alveoli become dysfunctional leading to a decrease in surfactant levels & the ability of lungs to expand causing Sepsis (a serious infection which causes the immune system to attack the body) and Severe pneumonia (Pus collection in air sacs).

COVID-19 prediabetic patients have direct viral invasion which causes functional immune deficiency and directly reduces immune cell function. This leads to diminished bactericidal clearance, increased infectious complications, and protracted sepsis mortality. Thus they may develop pneumonia leading to sepsis.
SARS-CoV-2 infects the upper respiratory tract & circulating immune cells (CD3, CD4, and CD8 T cells) inducing lymphocyte apoptosis with elevated inflammatory biomarkers such as C-reactive protein, serum ferritin, and IL-6. The T cells inhibit the overactivation of innate immunity resulting in lymphocytopenia, which suppresses the innate immune system and enhances the cytokine secretion resulting in a cytokine storm causing a multi-organ failure.

Body mass index (BMI) in obesity of 30 or above increases the risk. Abdominal obesity is associated with a higher risk involving abnormal secretions of adipokines and cytokines like TNF-alpha and interferon which may induce an impaired immune response. Obese people also experience mechanical respiratory problems, with reduced ventilation of the basal lung sections increasing the risk of pneumonia.

If a person with diabetes has a fever from COVID-19, they lose additional fluids. This can lead to dehydration, which may require intravenous fluids.

Diabetes damages arteries with fatty material deposition on their inner walls (atherosclerosis) which can cause Hypertension. Arterial hypertension is also highly prevalent in Covid19 patients due to the use of ACE inhibitors since SARS-CoV-2 binds to ACE2 to enter target cells. ACE inhibitors and angiotensin receptor blockers increase the expression of ACE2 which facilitates target organ infection and promote the progression of the disease.

Management of Diabetes in Patients with COVID-19

In COVID-19 the endothelial dysfunction associated with hypoxia causes intravascular disseminated coagulation. It involves the formation of abnormal clumps of thickened blood clots inside the blood vessels, leading to massive bleeding in other places causing inflammation & infection. Diabetes is associated with a pro-thrombotic state, which plays a key role in blood clotting with an imbalance between clotting factors and fibrinolysis. Pre-Diabetic patients with COVID-19 have a longer prothrombin time and higher concentrations of D-dimer(a small protein fragment in the blood after a blood clot). Other risk factors such as obesity, older age, and being admitted to the hospital could increase the pro-coagulative state and the risk of thrombotic complications.

Diabetes causes disturbance of glucose homeostasis and worsening of hyperglycemia(a characteristic of Diabetic Ketoacidosis). In diabetic patients with Covid-19, there is a direct effect of SARS-CoV-2 binding to ACE receptors expressed in pancreatic tissue and β-cells harming the β-cell function. Therefore there is an acute loss of insulin secretory capacity, stress condition, and a cytokine storm resulting in Diabetic Ketoacidosis (DKA).

Figure 1 : Synopsis of reciprocal effects of diabetes and COVID-19

Poor glycemic control is a risk factor for serious infections but is useful in some conditions like bacterial pneumonia. To maintain optimal glycaemic control it requires frequent blood glucose monitoring and continuous change in anti-diabetic treatment after the measured glucose levels.

Pre-Diabetic patients with COVID-19 infection should have regular blood glucose monitoring and adequate glycemic control which might reduce the risk of this severe infection. Special considerations to avoid certain antihyperglycemic agents should be noted. In Type 2 diabetes, Metformin (initial drug of choice) possesses a risk of dehydration & lactic acidosis hence should be avoided in patients who have greater potential to progress to severe COVID-19. Dipeptidyl peptidase (DPP)-4 inhibitors are well tolerated & can be used as an alternative to Metformin. Sodium-glucose cotransporter-2 inhibitors have risks of dehydration & Diabetic Ketoacidosis which is one of the complications hence avoided. Similarly, Glucagon-like peptide 1 receptor (GLP-1) agonists have a risk of dehydration so patients on these medications should be closely monitored. If any anti-hyperglycemic drugs are discontinued alternate treatment is usually Insulin and it should be continued if it is already ongoing in a patient.

In type1 diabetes frequent blood glucose monitoring every 3-4hrs & adjustments of insulin dose based on blood glucose values is needed. Urine ketones along with blood glucose should be monitored if fever with hyperglycemia occurs. Systematic screening for pre-diabetes in patients with proven COVID-19 infection is advisable.

Conclusion

There is a bidirectional relationship between Covid-19 and diabetes. On one hand, diabetes is associated with an increased risk of severe Covid-19 while on the other hand new-onset diabetes and severe metabolic complications of preexisting diabetes, including diabetic ketoacidosis and hyperosmolar for which exceptionally high doses of insulin are warranted, have been observed in patients with Covid-19.

It is important to recognize the importance of diabetes as a vital comorbidity in patients with COVID-19. Any prediabetic patient who develops COVID-19 symptoms should contact their healthcare provider as soon as possible. Although people with diabetes are at a risk of more serious complications from COVID-19, it is possible to reduce the risk by maintaining ideal blood sugar levels and following infection prevention measures.

References

https://www.firstpost.com/health/diabetic-pre-diabetic-patients-and-those-with-high-fasting-blood-sugar-at-higher-risk-of-fatality-due-to-covid-19-8591451.html

Ceriello, A., Stoian, A., & Rizzo, M. (2020, May). COVID-19 and diabetes management: What should be considered? Retrieved September 05, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162752/

COVID-19 Infection in People with Diabetes. (2020, March 30). Retrieved September 05, 2020, from https://www.touchendocrinology.com/insight/covid-19-infection-in-people-with-diabetes/


Diabetic, pre-diabetic patients and those with high fasting blood sugar at higher risk of fatality due to COVID-19 – Health News , Firstpost. (2020, July 13). Retrieved September 05, 2020, from https://www.firstpost.com/health/diabetic-pre-diabetic-patients-and-those-with-high-fasting-blood-sugar-at-higher-risk-of-fatality-due-to-covid-19-8591451.html


Diabetic, pre-diabetic patients and those with high fasting blood sugar at higher risk of fatality due to COVID-19 – Health News , Firstpost. (2020, July 13). Retrieved September 05, 2020, from https://www.firstpost.com/health/diabetic-pre-diabetic-patients-and-those-with-high-fasting-blood-sugar-at-higher-risk-of-fatality-due-to-covid-19-8591451.html


Home. (n.d.). Retrieved September 05, 2020, from https://www.idf.org/aboutdiabetes/what-is-diabetes/covid-19-and-diabetes/1-covid-19-and-diabetes.html


N. Zhu, D., J. Hellewell, S., C. Huang, Y., W. Guan, Z., D. Wang, B., J. Yang, Y., . . . M. Shyamsundar, S. (1970, January 01). SARS-CoV-2 disease severity and diabetes: Why the connection and what is to be done? Retrieved September 05, 2020, from https://immunityageing.biomedcentral.com/articles/10.1186/s12979-020-00192-y
S, K., H, A., & S, A. (2020, May 15).

Multi-Organ Failure in a Patient With Diabetes due to COVID-19 With Clear Lungs. Retrieved September 05, 2020, from https://www.cureus.com/articles/32094-multi-organ-failure-in-a-patient-with-diabetes-due-to-covid-19-with-clear-lungs

Pratiksha Baliga, Youth Medical Journal 2020

Categories
COVID-19

The Process of Coronavirus Detection

This article will be examining and summarizing two forms of Coronavirus detection. This information was gathered and analyzed using the CDC’s official website and other trusted webpages. This information was analyzed in a way for the average person to understand.

I preface by giving a warning that the FDA has seen multiple unauthorized testing kits for COVID-19 sold online. These kits can conclude to be hazardous and you should always just go to your local testing site.

The most common testing method in the United States consists of a healthcare worker using a long swab to grab a sample which will then be sent out for testing. Other countries may use blood samples. Both Blood and the swab sample take up to a week for results.

Tests using Q-tips are known as molecular tests. These molecular tests detect active infection. In other words, it checks for the presence of coronavirus. The tests are run through what is known as Real-time reverse-transcription polymerase chain reaction, or rRT-PCR. Currently, laboratories are required to have a positive result from the rRT-PCR assay in at least two specific genomic targets (an assay is essentially an analytic procedure completed in laboratories). Laboratories check for a single positive target with sequencing of a second target to get confirmation that coronavirus is present in the sample. 

Overall, the success of the molecular test relies on many factors. That is why the CDC has strict guidelines for how to handle and work with molecular test samples. To get a more accurate result scientists are recommended to get multiple samples. These samples are various types of respiratory samples, serum, and stool specimens. A single negative result for coronavirus does not result in the guarantee that a person does not have coronavirus, so they are put “under investigation”.  This test only takes a couple of hours to run.

Tests using blood samples are called a serology test. These tests look for previous infection or antibodies for coronavirus. The presence of these antibodies tells the scientists that person had the virus and developed an immune response to it. These tests are not flawlessly accurate but scientists are working to make them precise, using information on how the virus is transmitted. The CDC requires a two phase approach for these serology tests. Phase one uses two screening tests while phase two uses one confirmatory test to detect coronavirus antibodies. 

Phase one includes the enzyme-linked immunosorbent assay and the microneutralization assay. The enzyme-linked immunosorbent assay is also known as ELISA. This test is used to discover whether there is concentration of specific antibodies. The microneutralization assay is used to measure antibodies that can neutralize the virus. This test takes a minimum of 5 days to find results.

The following are how the CDC determines the results of the serology tests:

  • If a clinical sample is positive by either ELISA, or positive by micro neutralization, the specimen is determined to be confirmed positive.
  • If a clinical sample is positive by both ELISAs, and negative by micro neutralization, the sample is determined to be indeterminate.
  • If a clinical sample is positive by only one ELISA, and negative by micro neutralization, the sample is determined to be negative.
  • If a clinical sample is negative by both ELISAS, the sample is determined negative.

The differences between the two tests are, a serological test can detect antibodies even if a patient has recovered, whereas a molecular test can detect the virus only if the person is currently infected. Both the molecular tests and the serological tests are risk free, but you may feel some discomfort or pain while someone is getting a sample.

The tests I did not discuss are Nasal aspirate, Tracheal aspirate, and the Sputum Test. These tests are less common, but you are encouraged to research them.

Some hospitals and various agencies have set up Drive-through coronavirus testing centers. Be sure to do your own research on these.

Rapid PCR tests are currently being developed. Scientists are working very hard to find a more convenient and less cost effective way to detect coronavirus. Currently, the coronavirus tests developed by the CDC, Washington, and New York are PCR tests.

Some good information to know:

  1. COVID-19 tests are very new and false negatives can occur. 
  2. At home tests are to be used with precaution as the quality of the specimen is largely unknown.
Categories
COVID-19

Combination Ab/Ag Paper-Based Lateral Flow Assay for COVID-19

Problem Investigated:

As of the beginning of June, there have been over 3.5 million cases of infection and roughly 250,000 deaths due to COVID-19.  It is crucial to pinpoint the whereabouts of the virus in terms of rates and progression in individuals.  The only way to do this is via testing.  Yet this is an aspect that has failed, time and time again.  Developed countries despite having some of the strongest healthcare systems have the highest numbers of cases due to lack of effective and efficient testing and developing countries too face this very uncertainty due to the scarcity of cheap point of care testing kits.  With this lack of resources, even those working on the frontline, such as healthcare workers, have very little access to tests, let alone the general public. Hence, in order to reduce the high levels of uncertainty, to plan how to eventually lift lockdowns, and ultimately overcome this pandemic, developing effective and affordable testing kits is quintessential.

Our aims and hypothesis:

Through our test, we aim to significantly increase testing capacity globally and make testing more inclusive so that people, especially those in developing nations, are not deprived of the resources necessary to combat COVID-19.  Our hypothesis states that with our combination of antibody-antigen tests, we can provide researchers, labs, and hospitals a ‘truer’ value and indication of the severity and extent of the virus outbreak so that the strain on the healthcare system can be reduced.

Our solution:

We have designed a combination antibody/antigen (Ab/Ag) paper-based lateral flow assay that is sustainable, easily manufactured, and easy to utilize as a point-of-care (POC) device.  Integrating QR codes onto our tests, which would be connected to an app, we can connect researchers to non-personal data to track the virus and provide users a platform to assess their own progress.

Our prototype:

Diagnosis is the primary strategy towards the overarching goal of virus control and elimination, which would be effective ultimately everywhere to detect active cases, but mainly in developing countries and those with currently low numbers of cases as it may give those countries a chance to thoroughly control and prevent the outbreak from growing.  Testing for antibodies would be more effective in countries and regions where the virus has spread to a much wider vicinity.  Such tests can give an indication of historical infection and as many have debated, a possible sign of immunity, which can be used to slowly lift lockdown restrictions, however that is to be further explored.

Ultimately to get the fullest and the most accurate picture, both tests are needed simultaneously.

Our test is a double-sided combination Ab/Ag paper-based lateral flow assay, which on one side, can detect the presence of the COVID-19 virus itself, and on the other, both IgM and IgG antibodies from blood, urine, serum, plasma, saliva, and sputum samples [1].

FIGURE 1: A schematic representation of the appearance of our test.  Both sides of the paper will have this structure and appearance.

The standard method of diagnosis so far throughout this current pandemic has been through polymerase chain reaction(PCR) and serological tests.  PCR tests detect viral RNA, thus can only determine who has an active case of COVID-19.  Serological tests, on the other hand, can only reveal if an individual has previously been exposed to the virus and developed antibodies as a natural immune response.  Though these two forms of diagnostics respectively have their benefits such as high sensitivity and accuracy, they are constantly challenged by many quality assurance issues.  This includes but is not limited to: cross-reactivity of used antibodies in ELISA specifically, virus stability, reagent storage, equipment performance, and staff competency just to name a few [2].  Furthermore, with PCR and serology, there are high risks of false-positives from contamination and transcription errors, or false-negative results from malfunctioning equipment and degraded samples and reagents [2, 3].  Currently, these tests are administered separately, should an individual have the rare privilege to have access to both forms.

Dr James Gill, Locum GP & Honorary Clinical Lecturer at Warwick Medical school has stated, “The best test for early detection is combining the antibody test AND  the PCR swab taken from the patient.  Then we have a 98.6% detection rate within the first 5.5 days of infection.”

The timing of diagnosis has proven to be crucial in outbreak response in order to mitigate and track the virus not just for an entire country but for an individual’s health too.  Currently, PCR takes a few hours to run and prospective serology tests claim to show results in 15-30 minutes, however, on their own they do not normally benefit patients as immune responses can only be detected for a period of time after initial viral infection [1].  Studies have shown that within the first week of infection, PCR tests can detect covid-19 from nasal swabs with ~95% accuracy, in which gradually after that, the percentage decreases [4].  However at the moment of writing there seems to be a range of PCR detection rates according to many factors such as where the sample was taken from, lab and clinical settings and different protocols for different countries [5].

As stated before, both tests are clearly needed simultaneously therefore we believe our combination Ab/Ag test can possibly override the separate tests.  This has been proven possible in diagnosing HIV through 4th generation combination tests, which have overtaken the market.  This combination test is one of the most preferred and recommended methods of diagnosis for HIV, approved by authorities [6].

Unlike the traditional diagnostic methods like PCR, a paper-based platform provides a basis for point-of-care (POC) diagnosis in resource-limited settings, and removes the necessity for any heavy machinery or professional to administer the tests, whilst maintaining the high sensitivity and accuracy as diagnostic tests should.  In addition, they have numerous advantages including: affordability, sustainability, portability, disposability, and the ability to handle small volumes of unprocessed samples of biofluids such as blood, urine, saliva, sputum or plasma [1].  Paper is an inexpensive, lightweight, easy to functionalize and versatile material.  The most common kinds of paper used for POC devices are filter paper and chromatography paper [7].  Due to its 3D, porous, heterogeneous morphology, paper most often have the ability to store reagents and samples without the use of refrigeration, which would be especially useful in developing countries where there is often a lack of accessibility to electricity, and given the contagious nature of the samples, our paper-based assay should be able to protect users from even more exposure to other biohazards [1, 8].

FIGURE 2: A more in-depth representation as to how each side of the paper functions, and how the detection is carried out via bioconjugated AuNPs.  Top: Covid-19 detection.  Bottom: IgM and IgG detection.

How our test works:

Our test is a lateral flow assay thus functions quite similarly to pregnancy tests.  The user will put a sample of blood, urine, saliva, sputum, serum or plasma on to the sample pad.  Due to capillary force, the cellulose fibers of the paper allows for the biofluids to penetrate the hydrophilic matrix and flow up the test without external power [9].  As the sample rehydrates the conjugated pad, the target will bind to the bioconjugated gold nanoparticles on either side(AuNPs).  As studies have found that covid-19 enters host cells by using their spike glycoprotein (S-protein), on the top layer of the assay we have placed AuNP’s that are functionalised with a complementary antibody to that of the s-protein in order for only the virus to attach to it and aggregate the nanoparticles.  In addition, on the bottom layer, in order to only attach to the desired IgM and IgG antibodies, we functionalised the AuNP’s with dead or inactive covid-19 antigens.  The sample will continue to flow up the paper by capillary action.  As the sample reaches the detection zone and the control line,  there are capture reagents allocated in certain regions, overall forming a QR code image.  Should the test turn out to be positive, the conjugated AuNPs will bind to the capture reagents, causing a visible color change on the QR code to the naked eye, indicating positive for the biomarker detected.  Should the test be negative, no binding will be initiated, causing no color change.  We would expect our test to be able to show results within 5-10 minutes.  Once results have been processed, the user should scan the QR code, connected to our app, which would be able to recognize the different colored QR codes.  The app has an option by which the users would be able to report any symptoms should they have any, indicating their progress, and non-personal data such as how many are positive for COVID-19 can be sent easily to researchers, hospitals, and authorities.  Should the user report severe symptoms we will allow them to contact nearby hospitals, which will allow for hospitals to capacity plan a lot better, without further risk of being overwhelmed and will allow for those who really require intensive care, the opportunity to receive the help they need.

FIGURE 3: A depiction of the color changes of the QR code detection zone upon aggregation with different biomarkers. Top left: Red QR code contains unaggregated AuNPs indicating Negative results for both COVID-19 and IgM and IgG antibodies.  Top right: Deep blue QR code as a result of positive detection for COVID-19.  Bottom left: Light blue QR code as a result of positive for ONLY IgG antibodies.  Bottom centre: Light pink QR code as a result of positive for ONLY IgM antibodies.  Bottom right: Purple QR code as a result of positive for BOTH IgM and IgG antibodies.

In order to detect the presence of COVID-19 and IgG and IgM antibodies at the detection zone, we have decided to use gold nanoparticles (AuNPs) in order to efficiently provide results in a short time period.

Coronaviruses are enveloped positive single-stranded RNA (+ssRNA) viruses which are round, elliptical and often pleomorphic in their form [10].  They have a crown-like appearance under electron microscopes due to the spike glycoproteins (S-proteins) on the envelope, hence the name of coronavirus.  There are two main biorecognition strategies: directly detecting the pathogen, in this case, it would be through the viral RNA or detecting biomarkers, such as antigens like the S-proteins.  Traditionally, PCR directly detects nucleic acids, however, recent innovations in detecting biomarkers for many diseases and conditions have been proven to be faster and more robust [11].  In order to detect the virus, we wanted to use a particle or similar sized material which could detect the S-proteins.  In the case of COVID-19, the virus is 60-140nm in diameter, thus we found it most suitable to integrate nanotechnology and nanomaterials to be able to track the virus from the same scale, hence using APS.

AuNPs are a leading class of metal nanostructures that are widely known for their versatile traits such as chemical inertness, water-solubility, high electron density, and strong optical absorption [12, 13].  They have such broad size and shape controllability, ranging from 1 to 800nm in size and have different morphological shapes from spheres, cubes, rods, dog bones, shells, crystals and even hollow structures[12].  Abundant in characteristics, AuNPs have in recent decades been applied in genomics, clinical chemistry, vaccine development, microorganisms control, cancer-cell imaging, and drug delivery, but have also been recognized to constitute ideal tools in virus detection [13, 14].  AuNPs as labeling agents and bioconjugates are easily visualized to the naked eye due to their intense colors, thus would contribute to the simplicity and portability of our prototype, making it an ideal POC platform, whilst maintaining high levels of sensitivity and accuracy.

To be able to visually and easily present test results, the QR code detection zone relies on the colorimetric changes of AuNP solutions upon aggregation, which can be mediated upon the recognition of COVID-19 antigens and IgM and IgG antibodies which are complementary to the bioconjugated AuNPs [15].

When aiming to use AuNPs in biomedicine as a diagnostic or therapeutic tool, it is necessary to rightly choose the targeting component such as a monoclonal antibody (mAb), and attach it on to the surface of the nanoparticle [16].  Sole AuNPs are ‘blind’ with respect to sensing COVID-19 or antibodies, so the bioconjugation of specific biomolecules to their surfaces is a crucial process.  There have been many successful examples of various AuNP bioconjugates being employed in colorimetric systems to detect well-known human viruses such as Dengue virus; Ebola virus; Hepatitis; HIV; Human Papillomavirus; Herpes; West Nile Virus and even SARS [3, 17].

As stated before, we believe our test would be able to present results within 5 minutes without compensating the accuracy and quality.  This contrasts previous attempts to employ efficiency to detect COVID-19 but with inaccuracy, as shown by the UK government using £3.5million to purchase faulty tests from China.  The technique of using bioconjugated AuNPs has exhibited very promising statistics when detecting SARS in the 2003 pandemic, with a sensitivity limit of 100fM, thus with SARS-CoV-2, we would expect it to show similar prospects [18].

Due to the need for easy and rapid access to data, for researchers, hospitals and authorities, and a platform to report symptoms and progress, we decided to integrate the use of smartphones and diagnosis through the detection zone for our test forming a QR code.  Upon aggregation of the AuNPs, the QR code on each side will change colors according to the sample contents [19].  As shown in figure 3, should the test be negative on each side, the QR codes will remain red.  Should the test show positive for COVID-19, the QR code on the antigen detection side will change into a deep blue color.  If positive for IgM antibodies the QR code will turn light pink, if only positive for IgG antibodies the QR will turn light blue, and if both are present the QR code will be purple.

According to Statista, the current number of smartphone users in the world today is 3.5 billion (45.04% of the current population) and these numbers are growing ever so fast in this day and age.  Aligning this to our aim of inclusivity in terms of availability to testing, we wanted to connect smartphone devices to the tests in a simple manner.  The first smartphone approaches for POC diagnostics have usually involved additional attachment parts, or very specific post-treatment of the used tests: Zangheri et al. described a lateral flow assay which required the use of an accessory lens [20], Mudanyali et Al. reported a smartphone-based platform with a 3D printed accessory with LED [21], You et Al. and Lee et Al. both used smartphone readers [22, 23].  These approaches all use customized add-ons and excessive resources, bringing down the people reached drastically.  In more recent attempts to make it easier to analyse or record data from lateral flow assays, Yang et Al. have innovated a way to integrate barcode on to the assay in order to be read by inexpensive barcode scanners similar to those used in supermarkets [9].  But yet again that lacks inclusivity as we don’t all have barcode scanners lying around hence QR codes seems to be the most effective.

Utilizing paper as the main material for our assay, functionalizing AuNPs for detection, and integrating QR codes as a mean of recording and analyzing data, we have considered the manufacturing process, how the tests will be utilized and the sustainability of our test, all in order to maximize the potential for our test to not be harmful to any party involved.  The materials for our test for COVID-19 can be easily synthesized, made, found, and disposed of, and show little to no toxicity in the case of AuNPs [13, 17].

Accessibility was a big motivation for us whilst designing the test.   Upon our research, we noticed that at the time of writing, out of the 50 countries with the lowest GDP per capita at nominal value in US dollars in 2019 according to the International Monetary Fund, 15 are in the lowest 50 nations in terms of numbers of cases and 13 are in the lowest 50 in terms of death from COVID-19.   But most of all, out of the 50 countries with the lowest recorded numbers of testing, there are 22 of those countries with the lowest GDP per capita.  With even more uncertainty as to how far and wide the disease has spread in these countries, it was our concern that we should not neglect them in our idea of how we should combat COVID-19.  Which raises the question: do these developing countries genuinely not have as many cases, or is it just due to a lack of testing, resources, and knowledge that has caused their data to appear the way that it does?  The only way to find out is through testing.  Testing as many people worldwide as possible.  And through our tests, we may find an answer.

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Categories
COVID-19

The Impact of COVID-19 on the American Healthcare System

ABSTRACT:

The prevalence and impact of COVID-19, or the novel Coronavirus, is unprecedented in modern history and unparalleled in the clinical and healthcare communities in the world. Millions of people across the world have been forced to completely alter their lifestyles, while sacrificing critical components of their livelihoods ranging from education, income and career stability. Out of this crisis, however, the flaws and shortcomings of one institution in the United States has become evident: an unjust, woefully unprepared, and indifferent healthcare system. Across the country, the serious shortcomings associated with the realities of health insurance coverage, clinical and laboratory innovation, and patient care are made evident and are thereby intensified by COVID-19.

INTRODUCTION:

On December 31, 2019, Chinese authorities alerted the World Health Organization (WHO) of an outbreak of a novel strain of coronavirus causing severe illness, which was subsequently named SARS-CoV-2, and later named COVID-19 (Anderson, 2020). Thereupon, as of 29 March 2020, the highly transmissible and fatal virus has infected 638,146 people and caused 30,105 deaths in 203 countries, areas or territories globally (WHO, 2020). As a result, the American healthcare system, in particular, is being directly jeopardized as a collective result of its deficient primary care capability, lack of reserve capacity to handle health care crises such as COVID-19, and weak private-public partnerships with regard to government, the economy, and academic institutions (Blumenthal and Seervai, 2020). In addition, the biomedical, clinical, and virus-based statistics and scientific patterns of COVID-19 indeed directly undermine conventional healthcare practices in the U.S., while presenting unprecedented respiratory and airborne threats (Annals of Internal Medicine, 2020).

SCIENTIFIC ANALYSIS OF COVID-19:

Coronaviruses are a type of virus. The term encompasses a wide range of respiratory-related viruses, and some may cause disease. A newly identified type, COVID-19, serves as a highly transmissible and lethal respiratory illness—now considered a pandemic globally. Common clinical products and representations of COVID-19 include fever, cough, shortness of breath, myalgia, and fatigue (Qin et al., 2020). In rare cases, these symptoms and clinical difficulties may cause severe respiratory problems, kidney failure, or death (Sauer, 2020).

Although the initial source and cause in formation of the novel Coronavirus are unknown, scientific data supports the comprehensive theory linked to direct the animal-to-human transmission mechanism centered around the Huanan Seafood Wholesale Market of Wuhan (Cascella et al., 2020). The CoVs have become the major pathogens of emerging respiratory disease outbreaks in recent decades—prevalent across global health realities and occurrences. They are a large family of single-stranded RNA viruses (+ssRNA) that can be isolated in different animal species; for unknown reasons, these viruses can cross species barriers and can cause illness ranging from the common ‘cold’ to more severe diseases such as MERS and SARS (Cascella et al., 2020).

Genetic scientific evidence and research has indicated that the genome of the new HCoV, isolated from a cluster-patient with atypical pneumonia after visiting Wuhan, had 89% nucleotide identity with bat SARS-like-CoVZXC21 and 82% with that of human SARS-CoV; its single-stranded RNA genome contains 29891 nucleotides or 9860 amino acids (Chan et al., 2020). Although its origins are not entirely understood, these genomic summaries imply that SARS-CoV-2 probably evolved from a strain found in bats (Cascella et al., 2020). 

CoVs are enveloped, positive-stranded RNA viruses with nucleocapsid. Transcription termination occurs at transcription regulatory sequences, specifically located between the so-called open reading frames (ORFs) that work as templates for the production of subgenomic mRNAs; many ORFs encode for structural proteins, including spike, membrane, envelope, and nucleocapsid proteins (Perlman and Netland, 2009). For example, research highlighted how nsp is able to block the host innate immune response; in retrospect with functions of structural proteins, the envelope has a crucial role in virus pathogenicity as it promotes viral assembly and release, one instance portraying the clinical and biochemistry complexities of the virus (Lei et al., 2018). 

Figure 1. This figure illustrates the basic genome associated with COVID-19. It incorporates several genetic structures including Spike Glycoproteins (S) and Nucleoproteins (N), critical elements in immune reactions and viral assembly.

CLINICAL AND HUMAN HEALTH IMPLICATIONS OF COVID-19:

Ultimately, as a result of the given genome sequence and protein structure of COVID-19, respiratory, cardiac, and nearby organ function was significantly reduced. Based on biopsies of virus patients, it has been confirmed that the alveolar structure relative to pulmonary tissue can be destroyed to varying degrees, while a small amount of serous exudation may be seen in the alveolar cavity paired with the formation of a transparent membrane (Xiaohong, et al., 2020).

Figure 2. This figure demonstrates histologic changes evident in pulmonary tissue: proteinaceous exudates in alveolar spaces, with granules; (B) scattered large protein globules (arrows); (C) intra-alveolar fibrin with early organization, mononuclear inflammatory cells, and multinucleated giant cells; (D) hyperplastic pneumocytes, some with suspected viral inclusions (arrow).

 In addition, “hypertrophy of cardiomyocytes, degeneration and necrosis of some cardiomyocytes, mild hyperemia and edema of interstitial cells, and infiltration of a small amount of lymphocytes, monocytes and neutrophils” were seen in numerous studies conducted under different conditions and clinical settings (Xiaohong, et al., 2020). Significant tissue damage to the heart is mostly evident in older populations, signifying the epidemiologic and policy-oriented attention given towards the demographic of senior citizens.

Figure 3. This figure illustrates HE staining and immunohistochemical staining of punctured heart tissue for testing purposes; shows cardiomyocyte hypertrophy, degeneration, necrosis, scattered inflammatory cell infiltration, and related cardiac issues.

Ultimately, as reinforced by current research being conducted globally, COVID-19 may manifest itself in distinctly differing manners among the general population. It may manifest itself in mild, moderate, or severe illness; among the clinical manifestations, there may be prevalence of severe pneumonia, ARDS, sepsis, and septic shock (Wu and McGoogan, 2019). As a result of these unparalleled and highly dynamic bodily conditions and reactions, public health institutions and systems find great challenge in productively and effectively addressing the health and well-being of the general population.

PUBLIC HEALTH CONCERNS ASSOCIATED WITH COVID-19:

COVID-19 poses an unprecedented public health threat as a result of its unique clinical properties and evident parameters of lethality and impact, including: highly transmissible properties, progressive respiratory and pathologic impact in vulnerable individuals, concealed or asymptomatic conditions for large portion of general population, long virus life, and relatively high mortality rate. 

According to research conducted by the National Institutes of Health (NIH), Centers for Disease Control (CDC), UCLA, and Princeton University, COVID-19 is detectable in aerosols for up to three hours, copper up to four hours, cardboard up to 24 hours, and plastic and stainless steel for up to two to three days (Katella, 2019). The virus on materials apparent in frequently-touched surfaces poses a serious threat—forcing the general population to practice new forms of personal hygiene, interactions, and cleaning protocol.

Moreover, the modes of transmission for novel Coronavirus remain open-ended, forcing the general population and healthcare providers to maximize all possible precautions—often involving shutting down of schools and work facilities, public attractions and spaces, and other institutions—leaving profound impacts on the economy and productivity of society. According to current clinical evidence, COVID-19 is primarily transmitted between people through respiratory droplets and contact routes, not involving any airborne path (WHO, 2020). Droplet transmission occurs when a person is in in close contact (within 1 m) with someone who has respiratory symptoms (e.g., coughing or sneezing) and is therefore at risk of having his/her mucosae (mouth and nose) or conjunctiva (eyes) exposed to potentially infective respiratory droplets (of COVID-19); therefore, transmission of the COVID-19 can occur by direct contact with infected people and indirect contact with surfaces in the immediate environment or with objects used on the infected person (Ong et al., 2020). On the other hand, aerosol or airborne transmission (defined by presence of microbes within droplet nuclei, which are generally considered to be particles <5μm in diameter) is possible under specific circumstances and settings in which procedures or support treatments that generate aerosols are performed; examples may include non-invasive positive-pressure ventilation and cardiopulmonary resuscitation (Cheng et al., 2020).

Figure 4. This figure demonstrates common paths of transmission for COVID-19. Evidence suggests that the virus is mostly transmitted through droplet form, but can be dangerous under certain circumstances (evident in aerosol form).

Lastly, numerous studies have documented SARS-CoV-2 infection in patients who never develop symptoms (asymptomatic) and in patients not yet symptomatic (pre-symptomatic). One study found that as many as 13% of RT-PCR-confirmed cases of SARS-CoV-2 infection in children were asymptomatic (Dong et al., 2020). Another report concluded that half of (50%) nursing facility residents infected with SARS-CoV-2 from a frontline healthcare worker were asymptomatic or pre-symptomatic at the time of contact tracing evaluation and testing (Kimball et al., 2020). As a result of common reports of asymptomatic behavior, transmission can be intensified through individuals unsure of their carrier status, and able to infect others if not in compliance with basic social distancing or cleaning measures.

COVID-19 TESTING:

The medical and biochemical properties of COVID-19 have created a pandemic which has resulted in a national testing crisis—one major impact on the American healthcare system and providers across the nation. In a time of unprecedented crisis, it is critical that the federal government maintains transparency, effective communication, and an environment for creative collaboration. As a result of policy and structural failures, COVID-19 testing across the U.S. has been limited and in short supply to those in most need of testing. 

As a result of a limited testing range, the scientific data that can be compiled, analyzed, and integrated at the highest levels of policy-making is severely skewed. Invalid and misleading data can increase stress on healthcare providers and hospitals (no clarity), and possibly produce scientific and clinical results which are inaccurate or nonfactual (CDP, 2020). The crucial purpose for testing a wide range of communities—regardless of socioeconomic status or resources—is to support the government in understanding how prevalent the disease is and how it is evolving; tracking positive test results helps authorities make evidence-based decisions to try to slow the spread of the disease (Wood, 2020).

Ultimately, the testing crisis in the U.S. has shown one critical shortcoming: the healthcare institutions and individual, private companies/laboratories are not properly regulated, oversawn, or incentivized to handle crisis situations or support citizens when most in need.

COVID-19 TREATMENT AND HEALTHCARE FRAMEWORK:

Hospitals, clinics, and healthcare providers across the nation are suffering the dire consequences of such a pressing crisis—an accumulation of fear, anxiety, lack of resources, and alienation concerning basic conditions of support and assistance. As found in a multitude of research studies, compared to most similarly large and wealthy countries, the U.S. has fewer practicing physicians per capita but has a similar number of licensed nurses per capita; the U.S. also has more hospital-based employees per capita than most other comparable countries, but nearly half of these hospital workers are non-clinical staff (Kamal et al., 2020). A large portion of hospital staff across the country are administrative or non-clinical (especially as compared to comparable nations), leaving a serious burden on nurses, physicians, and other providers in the form of long hours and increased exposure to the virus.

In addition, beyond the lack of personnel throughout facilities in the nation, a vast majority of these institutions lack the necessary precautionary materials, resources, and PPE to protect themselves, patients, and the integrity of hygiene in facilities. The majority of workers who keep America’s hospitals operational do not have the salary to afford extra bedrooms, much less extra properties. For technicians, respiratory therapists, first responders, and cleaning staff—individuals on the frontlines—doing their job is an act of moral conflict; without adequate PPE and resources, they’re putting their own health at risk every time they report for duty, as well as that of their families (Hamblin, 2020). In addition, as made evident in a study conducted by Peterson-KFF Health System Tracker, the U.S. has fewer hospitals and hospital beds per capita compared to other similar countries.

Figure 5. This figure illustrates the U.S.’ hospital density. The U.S. had 17.1 hospitals per million people in 2016, which is significantly fewer than most other comparable countries.

Collectively, critical equipment such as ventilators and beds are also in short supply, with the U.S. having a national supply of 160,000 ventilators and 45,000 intensive care unit (ICU) beds (Blumenthal and Seervai, 2020). In a severe outbreak of respiratory illness like COVID-19, as many as 2.9 million Americans might need ICU care. These issues will be particularly acute in rural areas, where shortages of health professionals and emergency facilities are evident in non-emergency conditions as well.

APPROPRIATE SYSTEMATIC HEALTHCARE CHANGES NEEDED:

In order to prepare the American healthcare system for more inevitable medical disasters, as well as average care, serious reforms in the scope of policy, clinical innovation, and private-public partnerships must be analyzed and improved. In 2018, 8.5 percent of the American population, or 27.5 million, did not have health insurance at any point during the year, approximately a seven percent increase from the previous year (Berchick et al., 2019). The American healthcare system has long neglected to serve the interests of ordinary citizens—unfortunately serving as the embodiment of corporate greed, high insurance premiums and additional costs, and lack of accountability and oversight on part of government. It is undeniable that private industry and enterprise is the greatest source of innovation and creativity in an economy and collective society. However, with that ideology in mind, COVID-19 has profoundly exposed the lack of emphasis on premium care, the abuse and wastefulness of major corporations and insurance companies, and the severe lack of government accountability in the face of emergency and concerning hospital personnel and resources.

It is essential for the government to take a more hands-on approach in serving the American people’s healthcare needs, instituting definite policy oriented towards ensuring market equality, affordability, and access for all citizens; incentivizing clinical research and disaster preparedness; and puttinge more explicit and thorough disaster/emergency mechanisms into place. Private industries and clinical innovation are the heart of American democracy and ingenuity, but a stronger public-private partnership, paired with explicit preparedness and collaboration protocol among federal, state, and local agencies, undoubtedly serve the best interests of the American people.

CONCLUSION:

The public health crisis of COVID-19 has demonstrated both unprecedented clinical and policy adversity and challenges to the general population. As the scientific research and medical studies progress, it is undeniable that the effects of COVID-19—based on its unparalleled scientific qualities and traits—serve as a key moment in time to comprehensively and thoroughly analyze the inefficacy of the American healthcare system and the changes that need to be made. Regardless of those specific policy decisions, it must be made clear at the highest levels of government and public policy, that the health and well-being of the American people is the first and foremost priority. The science and medicine is clear; however, the framework to which these critical disciplines of STEM can operate within for generations to come is going to be determined during the 21st century—a moment defined by crisis and adversity—but designed for national and global improvement.

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