Dr. Brechot’s Health Research & Care Blog – August 5, 2020

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August 5, 2020

Cleaning, sanitizing and disinfecting against COVID-19: What’s the difference?

Nearly a half million COVID-19 cases were confirmed in Florida as of Aug. 4. By now, we hope everyone understands the importance of wearing face masks, maintaining social distancing, and practicing good personal hygiene in controlling the spread of SARS-CoV-2 and containing the pandemic. Over the past few months you have no doubt practiced at least one, if not all, of the following three processes: cleaning, sanitizing and disinfecting. So, what are the differences and how can each be used to help prevent COVID-19 infection?

In this context, we don’t intend to recommend any products or teach you how to make homemade solutions, but to explain the differences.

Based on Centers for Disease Control and Prevention (CDC) guidelines, cleaning means to remove the germs, dusts or dirt from surfaces or objects through scrubbing, rubbing or washing. Sanitizing significantly reduces the growth of viruses, bacteria or germs on surfaces or objects. Sanitizers are referred to by the U.S. Environmental Protection Agency (EPA) as antimicrobial solutions or devices that can reduce microbiological contamination to meet the public health standards or requirements.

Disinfecting kills or inactivates bacteria, germs or viruses on surfaces or objects. Disinfectants are more effective than sanitizing or cleaning products, so they must meet more rigorous EPA testing standards. Both sanitizing and disinfecting processes can be used after the cleaning process to further lower the risk of spreading infection. For example, during influenza season, it’s highly recommended that schools or communities clean, sanitize and disinfect their facilities daily to reduce the spread of flu.

Let’s be clear; disinfection is not a panacea. Sometimes, disinfecting is not as good as a simple cleaning or sanitizing process. Before deciding which is applicable or more efficient, you need to evaluate your situation. The CDC has issued a guidance for Cleaning and Disinfecting Public Spaces, Workplaces, Businesses, Schools, and Homes.

Cleaning

Regardless of the presence of the pandemic, every person, household and community should maintain a good cleaning routine. Thoroughly cleaning your home or work environment can provide many benefits, such as reducing allergies and stress. Regular cleaning is enough for infrequently touched surfaces or objects, and unoccupied rooms, sidewalks, parks or other spaces.

Sanitizing

Surfaces, such as kitchen countertops and cutting boards, that come into contact with food (especially raw meat) and beverages, should be sanitized using appropriate methods. Chemicals are not necessary for some sanitizing processes.  For example, steamed heat can reduce or kill certain germs and bacteria. Some products work as both sanitizer and disinfectant. Be sure read the label before using.

Disinfecting

Frequently touched surfaces should be disinfected routinely. These include light switches, door handles, handrails, elevator buttons, faucet handles, tables, cell phones, laptops and other electronic devices. Even when social distancing is applied, shared spaces or those occupied by many people — hospitals, clinics or homes with sick patients, for example — should also be disinfected regularly. The Global Virus Network recently published an important update about disinfection strategies against COVID-19.  Interestingly, a paper published 15 years ago concluded that commonly used disinfectants, such as isopropyl alcohol (rubbing alcohol) with concentrations of 60% or more, could inactivate SARS-CoV-1; this is also effective for SARS-CoV-2. However, before using any disinfecting products, please check whether the product is included in EPA List N, an updated list of more than 400 surface disinfectants that meet the agency’s criteria for use against SARS-CoV-2.  

Different voices

Recently, different voices have been raised regarding cleaning, sanitization and disinfection in stopping the spread of COVID-19 virus. A Comment recently published in The Lancet stated that contaminated objects that have not been in contact with an infected carrier for many hours do not pose a measurable risk of transmission in non-hospital settings. In other words, surface transmission seems rare in COVID-19 cases. The paper also suggested peer-reviewed studies are needed to determine the COVID-19 virus’s survival rate on different types of surfaces in real-life settings. Yet, we still must be careful and pay attention to surface transmission.

Whatever product or process you decide to use to reduce your risk of COVID-19 viral infection, remember safety. Always wear proper protective equipment when working with chemicals, follow the label instructions, avoid mixing chemicals, safely store the products/devices, properly handle waste, and last, but not least, never eat, drink or inject any of the products.

Finally, please do not let cleaning, sanitizing and disinfecting give you a false sense of security. To fully minimize our risk, we must remain diligent about wearing masks, keeping social distancing and avoiding crowds.

 

Christian Brèchot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

Linman Li, MBA, MPH, PMP, CPH
Director, USF- GVN Center
USF Health Morsani College of Medicine
Vice President, Global Virus Network

 

 

 

July 22, 2020

Is it time to shift to a saliva test for COVID-19?

As COVID-19 continues to spread in most U.S. states, the 7-day moving average daily percent of positive tests in Florida has reached 18.7%. Months after the first outbreak of this pandemic, we all know SARS-COV-2 diagnostic tests are vital for immediately identifying an infectious cluster, tracking transmission, and managing treatment and overall prevention of the virus’s spread.

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In our April 1 blog, we described the standard SARS-COV-2 diagnostic test — real time reverse transcription-polymerase chain reaction (rRT-PCR) detection of the COVID-19 virus from a nasal or throat swab. A 6-inch-long swab is inserted into the nose or throat to collect samples for analysis. The whole process should take no more than 15-20 seconds if performed correctly. Does the test hurt? Not necessarily, but the process can be uncomfortable. Are any other tests available? Yes, we also have another test method called the antibody test. Blood needs to be drawn and analyzed for antibody response to the virus.

A health care worker collects a specimen using a nasal swab at a COVID-19 mobile testing site.

How reliable is saliva for detecting SARS-CoV-2?

In this blog, we’d like to review a new diagnostic test based on saliva samples. Like nasal swab testing, it is an alternative way to collect specimens and detect the presence of SARS-CoV-2, rather than checking for antibodies against the virus. Like many DNA tests self-administered at home, the saliva sample is collected by spitting into a test tube and mailed to a laboratory for testing. The test uses a method similar to the rRT-PCR nasal swab test, which converts the specimen’s RNA into DNA and rapidly amplifies it to detect tiny genetic pieces of the virus. If genetic material of pathogen SARS-CoV-2 is present, the patient is diagnosed with COVID-19.

Is the saliva test reliable? Saliva has been shown in several studies to be a promising specimen for diagnosis, surveillance and prevention of COVID-19. For example, a study published in Clinical Infectious Diseases demonstrated that 91.7% of patients detected COVID-19 virus in their own saliva. Another study, later published in the Journal of Infection, confirmed that saliva samples from 25 COIVD-19 patients tested positive for SARS-COV-2. Further study at Yale University found that saliva was more sensitive than nasopharyngeal swabs. Saliva is a common agent for transmitting viruses, such as SARS-CoV-1, MERS and Ebola. Different sizes of saliva droplets are generated by sneezing, talking, or even breathing. Overall, saliva tests have yielded many accurate results for SARS-CoV-2 RNA detection.

Several studies have shown saliva to be a promising specimen for COVID-19 diagnosis, surveillance and prevention.

Advantages of the saliva test

Saliva testing has many benefits:

  1. It is noninvasive and more comfortable. Samples are easier to collect compared to nasal swab and antibody blood tests. States are being urged to reopen their schools, so saliva might play a very important role in testing populations of children because the process is not as scary for them. Children up to 10 years old are less likely to develop severe illness from SARS-CoV-2 and less likely to transmit the virus; yet, those older than age 10 (i.e., in middle and high schools) were recently shown to potentially transmit the virus, especially in the context of a high-virus circulation level. Thus, the risk of transmitting the virus to other vulnerable family members, such as grandparents, should not be underappreciated, and children should be extensively tested to better contain the pandemic.

  2. With appropriate guidance, the collection and screening of saliva samples can be managed at home and repeated multiple times. That significantly reduces the risk of infection among health care workers who administer nasal swab or antibody tests. In May, under an emergency use authorization, the U.S. Food & Drug Administration approved the first diagnostic test with the option of using home-collected saliva samples for COVID-19 testing.

  3. The diagnostic test is less costly due to its simple process, allowing health care personnel and protective equipment to be saved for when they are most needed.

  4. Test volume can be easily increased compared to other methods. Saliva collection and screening can scale up without the need for fully functioning testing centers.

Saliva-based COVID-19 testing — with a simpler, more comfortable, and less costly collection process than nasal swab or antibody testing — may offer an option for timely testing of students when schools reopen. Studies continue to evaluate the reliability of this test method.

Even though many studies have shown reliable results, it is still uncertain whether the saliva test is as sensitive, if not more sensitive, than the nasal swab method in correctly generating a positive result for people who have COVID-19.  Several institutions across the globe are conducting ongoing studies testing the reliability of saliva tests to detect COVID-19 virus. No firm conclusions should be drawn until the peer-reviewed studies are complete.

Christian Brèchot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

Linman Li, MBA, MPH, PMP, CPH
Director, USF- GVN Center
USF Health Morsani College of Medicine
Vice President, Global Virus Network

 

 

 

July 8, 2020

Can SARS-CoV-2 be spread by floating airborne particles?

Over the past few weeks, the spread of COVID-19 in geographic areas such as Latin America, the U.S. and India, has been rather daunting. Has the second wave arrived, or has the first wave never left? The COVID-19 case reports from the three countries mentioned all show an ascending curve. So, the first wave of COVID-19 is far from over in these countries. While we have learned a lot about the current pandemic, much remains uncertain. For example, one hot topic is whether SARS-CoV-2 is airborne.   239 scientists worldwide supported a recent Clinical Infectious Diseases commentary recommending precautions against potential airborne transmission of SARS-COV-2 to control the increase in cases as countries reopen.

What is airborne transmission?

Airborne coronavirus has been a bone of contention for many scientists since this pandemic started. As mentioned in our May 13 blog, the two major routes for transmission of the COVID-19 virus are person-to-person through respiratory droplets and by direct contact. Today what worries us most, however, is potential spread of infection from microscopic droplets (aerosols) exhaled by contagious people without symptoms.  

According to the World Health Organization, airborne transmission occurs when infectious agents, contained within droplet nuclei in aerosols, persist long enough for others to inhale the virus particles. It is important to understand that many public health agency recommendations are based on older studies. In fact, a perspective published in Science noted that in still air, a 100-μm droplet will settle to the ground from 8 feet in 4.6 seconds, whereas a 1-μm aerosol particle will take 12.4 hours. Also, droplets produced by coughing or sneezing can be aerosolized and travel across an enclosed space. 

The perspective also suggested that the CDC’s 6-feet-apart social distancing guideline may not be enough in many indoor environments. In spaces with inadequate ventilation aerosols can stay suspended in the air for hours, accumulate over time, and move more than 6 feet with the air flow. That means that by talking, or even breathing normally, you can get infected with airborne diseases, such as tuberculosis and measles. Interestingly, an article published 16 years ago in the New England Journal of Medicine cited SARS-CoV-1 investigations that concluded only airborne transmission appeared to explain the large community outbreak at the Amoy Garden in Hong Kong.

So, is SARS-CoV-2 airborne?

The simple answer is that it is too early to either draw a solid conclusion or to rule out reasonable doubt. Based on a study published in Nature, scientists in China measured the viral RNA of SARS-CoV-2 in two Wuhan hospitals in February and March this year. Their analysis identified the spread of viral RNA in aerosols in isolation wards and ventilated patient rooms. The good news is that the amount was very low when proper sanitization and ventilation was performed. Also, after thorough sanitization, previously high concentrations of aerosolized SARS-CoV-2 RNA in some medical worker areas were reduced to undetectable levels. Of note, the researchers did detect higher concentrations of SARS-CoV-2 RNA in aerosols in patients’ toilet areas.

However, detecting viral RNA does not automatically imply the presence of infectious viral particles. More studies need to be done worldwide on the circulation of viral infectious particles, investigating different doses and sizes of droplets. Such research could help define how many aerosolized SARS-CoV-2 particles must be inhaled to get infected.

 

What should we do?

Although current scientific evidence is insufficient to conclude that SARS-CoV-2 can be transmitted through aerosols, we fully support the recommended precautions, recently published in scientific journals, to address potential airborne spread of COVID-19. Good indoor ventilation, avoidance of crowds, proper household disinfection, and open spaces can limit the risk of airborne transmission. These protective measures are simple and inexpensive to implement.

Also, never forget to wear face masks. Masks provide a critical barrier and reduce the likelihood and severity of COVID-19 by significantly reducing the concentration of the virus in the air. The aerosol filtering efficiency of homemade masks using different materials, thicknesses, and layers was recently found to be similar to that of tested surgical masks. Thus, it comes as no surprise that countries implementing universal masking, such as Taiwan, Japan, Hong Kong, Singapore, and South Korea, have been most effective in reducing the spread of COVID-19.

By combining methods to reduce the risk of airborne COVID-19 virus transmission indoors with wearing masks, social distancing and good personal hygiene, we can all do our part to curb the pandemic.

Christian Brèchot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

Linman Li, MBA, MPH, PMP, CPH
Director, USF- GVN Center
USF Health Morsani College of Medicine
Vice President, Global Virus Network

 

 

June 24, 2020

Dexamethasone: Has an old drug ushered in a new era?

With total COVID-19 deaths surging past 469,000 this week, an old drug called dexamethasone continues to capture the worldwide attention of media and clinical literature. Almost every major news outlet has published, or broadcast stories related to this common steroid medication that has been on the market for over 60 years.

What prompted all the enthusiasm?

It all started with the news release reporting initial results of a randomized, controlled clinical trial from the University of Oxford. According to the release, more than 2,000 COVID-19 patients received randomized low-dose dexamethasone treatment. This treatment group was compared with over 4,000 patients who received routine care only. Dexamethasone administered either orally or by intravenous injection was found to reduce the number of deaths by one-third, one-fifth and zero, respectively, in patients on ventilators, on oxygen, and without any respiratory support.

These initial findings have shown dexamethasone to be the first drug to reduce deaths among COVID-19 patients. The World Health Organization welcomed the preliminary results and the lifesaving scientific breakthrough for coronavirus patients with severe respiratory complications.

What is dexamethasone and how does it work?

Dexamethasone is a long-acting corticosteroid used to treat numerous health conditions, including severe allergies, arthritis, asthma, skin conditions, inflammation, and adrenal insufficiency. Although the drug is widely prescribed for many different diseases, the effectiveness and safety of corticosteroids to treat COVID-19 patients remains highly controversial. As mentioned in our May 20 blog, SARS-CoV-2 can trigger hyperinflammation in the lungs and lung lesions in about 5-10% of patients with clinical symptoms. This is linked to a major overreaction of the immune response, called the cytokine storm.”  It can cause acute respiratory distress syndrome (ARDS) and multiple-organ failure in infected patients, leading to severe illness or death.

Steroids, like dexamethasone, prevent the release of inflammation-causing substances in the body. In other words, the drug does not target the viral infection but suppresses the body’s immune response. Well-established research indicates that the immune system should not be inhibited when the body is fighting against infection.

So, why does dexamethasone still work? We do not exactly know; the balance between stimulating and inhibiting the immune response to the virus is very delicate. One possible explanation is that the benefits of steroid treatment outweigh its potential harm in patients experiencing a critical medical condition. Indeed, the drug produced more promising results in patients on ventilators or receiving supplemental oxygen; there was no benefit for those who did not require respiratory support, that is, they had less severe disease. Clearly, more studies are needed on the immune profiling of such patients.

The benefits and limitations

No doubt, initial results reporting that dexamethasone cuts the risk of death in the sickest patients with coronavirus infection are remarkable. Another significant benefit is the low cost of the drug, which is widely produced in many countries. Last week, both the British government and South Africa Health Ministry approved dexamethasone to treat severely ill COVID-19 patients. Dexamethasone could also open a door for treatment of non-COVID-19 patients who have severe respiratory failure— although anti-inflammatory drugs were initially considered toxic, based on previous experience with influenza.

This clinical trial also has limitations. Modifying immune response must be carefully evaluated.  We have learned how difficult it can be to control potential side effects when treating patients with sepsis. Although the Oxford study states that dexamethasone had no adverse effects, the research needs to be peer-reviewed and reproduced to reach full conclusions.

In addition, it would be interesting to evaluate the effectiveness of dexamethasone in combination with antiviral drugs like remdesivir to treat SARS-CoV-2. Peer-reviewed data shows that remdesivir — which directly targets the virus itself by blocking a key enzyme it needs to replicate — shortens hospital stays for COVID-19 patients. Further studies should carefully investigate whether these two therapies could improve outcomes jointly, rather than using each separately.

Dexamethasone illustrates the impact of an unbiased drug repurposing strategy. More definitive data are needed to make this old drug a new standard of care for critically ill COVID-19 patients.

Christian Brèchot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

Linman Li, MBA, MPH, PMP, CPH
Director, USF- GVN Center
USF Health Morsani College of Medicine
Vice President, Global Virus Network

 

 

 

June 17, 2020

Risk of COVID-19 transmission by presymptomatic vs. asymptomatic patients

Whether or not COVID-19 infected patients with no apparent symptoms (asymptomatic) can transmit the virus tremendously impacts the global public health strategy against SARS-CoV-2 infection. In this week’s blog, we wish to clarify the distinction between asymptomatic and presymptomatic carriers of COVID-19, their risk of transmitting the virus and the critical need to identify a testing method before symptoms appear. We support the World Health Organization’s recent clarification and thank them for raising awareness of this critical issue.

What is presymptomatic?

We understand that distinguishing between asymptomatic and presymptomatic cases can be confusing. Asymptomatic was discussed many times in our previous blogs. But, what does presymptomatic mean? Presymptomatic transmission is the spread of SARS-CoV-2 from an infected person to another person before the source has developed symptoms. A recently published study in Nature has shown substantial transmission of COVID-19 before symptom onset. Shedding of the virus—the point at which an individual becomes contagious– may begin two to three days before the appearance of the first symptoms. This contrasts with what was observed with SARS-CoV-1 in 2003. A recently published editorial in The New England Journal of Medicine states that, although virus shedding was not quantitatively analyzed, 71% of samples cultured from patients at a skilled nursing facility yielded live viruses one to six days before symptom onset. After symptoms appear, the viral load decreases gradually. In general, as expected, higher rates of presymptomatic transmission were reported in geographic areas where SARS-COV-2 diagnostic tests have been widely used.

According to an article in Emerging Infectious Diseases, presymptomatic transmission occurs through generation of respiratory droplets as well as, possibly, aerosol or indirect transmission. It has been more challenging to quantify how asymptomatic individuals contribute to the transmission of SARS-CoV-2. Lack of quantitative analysis of viral shedding has hindered evaluating the role of “asymptomatic” individuals, those who are infected but display no symptoms. However, a recent study in Clinical Infectious Diseases reported that asymptomatic individuals may also show substantial viral shedding for potential transmission. More comprehensive studies are needed to draw a solid conclusion about the risk of COVID-19 transmission when comparing asymptomatic and presymptomatic individuals.

Challenge to identify infections before symptoms

Unfortunately, the COVID-19 pandemic is expanding because it remains difficult to trace mild or presymptomatic infections. We have learned a very important lesson from the initial response to the SARS-CoV-2 outbreaks. For instance, most countries worldwide delayed state and local responses, thus allowing SARS-CoV-2 to spread rapidly. A key issue has been testing. Symptom-based screening alone fails to detect a high proportion of infectious cases and is not enough to control overall transmission. Consequently, many countries have been locked down to prevent the rapid spread of COVID-19, because simply isolating patients may not be enough to contain the outbreak. Conversely, several countries, such as Australia, South Korea, Germany, Singapore, and Taiwan, managed to contain the virus early and have worked hard to keep it suppressed with efficient testing and a contact tracing system.

Until a reliable vaccine is widely available, or we develop effective screening to identify presymptomatic or asymptomatic virus carriers who are unknowingly contagious, we suggest the following:

  • Make sure to wear face masks, maintain social distancing of 6 feet or more, and practice good hygiene.
  • Young people at not invulnerable. SARS-CoV-2 is a highly contagious virus that can infect anyone, and even those without apparent symptoms can accelerate its spread to family, friends or others.
  • Governments and communities should embrace new technologies to efficiently trace previous contacts of patients diagnosed as contagious COVID carriers, regardless of the presence or absence of symptoms.

Christian Brèchot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

Linman Li, MBA, MPH, PMP, CPH
Director, USF- GVN Center
USF Health Morsani College of Medicine
Vice President, Global Virus Network

 

 

 

June 10, 2020

The 1918 flu pandemic vs. COVID-19: What have we learned?

Many studies and articles have compared the flu pandemic of 1918-1919 to the COVID-19 outbreak that began in December 2019 (maybe even earlier).  We are witnessing a very uncertain time with a flattening of the coronavirus curve in most but, by far, not all geographic areas. While many countries report a sharp decrease in cases and deaths, the pandemic persists in South America, India, and other areas. In fact, the number of infections is still increasing in Florida, although at a slow pace. Thus, we all wonder what will happen next. As with the 1918 flu pandemic, will a second, or even third, more deadly wave occur or will this latest pandemic end soon? First, let’s look back at what happened during the 1918 influenza pandemic.

Notice of the influenza epidemic of 1918 lying on the laboratory table of a medical research scientist studying the virus.

A brief history of the 1918 influenza pandemic

From 1918 to 1919, a devastating pandemic infected more than 500 million people worldwide (almost one third of the total population), and about 10% died. The disease was caused by an HIN1 virus that originated in birds. It was called the 1918 Influenza pandemic, also known as the Spanish flu. Ironically, the pandemic was not first detected in Spain. During World War I, unlike most other countries that fought in the war, Spain was a neutral zone. Without a wartime news blackout by Spain’s government, Spanish media reported freely on the severity of the illness and the country became associated with the origin of the pandemic!

According to an article published in the journal Emerging Infectious Diseases, the case-fatality rate was more than 2.5% worldwide (compared to less than 0.1% in other flu pandemics). In the U.S, the first case was identified among military personnel in spring 1918. Many American soldiers gathered before being deployed to Europe by ship. Air travel was not available at that time. Many soldiers developed “flu-like” symptoms, but most recovered rapidly. The more deadly wave struck in fall 1918. This second wave lasted six weeks and followed the troops from Sierra Leone to the U.S, spreading to almost all Europe and later Asia.  By the end of the pandemic, more than 675,000 people had died in the U.S. and 50 million globally. Half of all the deaths occurred in the second wave. Many researchers believe this was caused by a mutated strain of the virus. The third wave in spring 1919 led to the end of the pandemic that summer due to herd immunity and massive deaths.

A century has passed since the 1918 influenza pandemic. Are there any significant similarities or differences to the current COVID-19 pandemic we are fighting? The answer is yes to both.

The similarities

Both viruses are transmitted via respiratory droplets. This means that the old- fashioned social distancing and quarantine measures that worked during the 1918 flu pandemic will work now as well.  For example, an article in PNAS, reported that St. Louis, Missouri was one of the U.S. cities with the most effective public health interventions against the 1918 flu pandemic. The transmission rate was reduced around 30- 50%.  The mortality rate was reduced only about 10%, because the measures were introduced too late and lifted too early. Conversely, Philadelphia was badly hurt because the city did not cancel massive gatherings. Does that sound like the current situation? We are not at war now. However, just as troops traveled worldwide during the 1918 flu pandemic, nowadays “global citizens” taking advantage of our more convenient transportation systems have contributed significantly to the spread of the COVID-19 virus between countries. 

The white crosses of an historic graveyard cemetery in Norway, built  after miners died during the 1918 influenza pandemic.

The white crosses of an historic graveyard cemetery in Norway, built after miners died during the 1918 influenza pandemic.

Furthermore, people living in poverty were more vulnerable to the 1918 flu pandemic virus, because they didn’t receive proper medical care or pay sufficient attention to personal hygiene. Low-income people in U.S. and in developing countries are also suffering disproportionately during the current pandemic.  In the absence of vaccines and treatments, surveillance and contract tracing was implemented to contain the spread of the 1918 flu pandemic. Just like we are doing right now.  

The differences

While many similarities can be drawn between two pandemics, there are also important differences. The most noticeable difference involves individuals at greatest risk. The elderly and those with underlying diseases are the most vulnerable to SARS-COV-2. In contrast, during the 1918 flu pandemic, young healthy people died at a higher rate. Why? One hypothesis proposed that the elderly people in 1918 had already encountered similar viruses in previous years and therefore were partly protected against infection. It is a good example of the “cross-immunity” phenomenon explained in our June 3 blog.

Another notable difference is today’s immersive improvements in data sharing. A century ago, the lack of health care infrastructures and providers made reporting cases difficult.  The same was true for the development of new diagnostic tests, treatments and vaccines. In 1918, we did not have the technology or the capability to accelerate pandemic-related research that we can achieve today.

An elderly woman sitting in her home tries out the face mask she has handmade to wear during the 1918 influenza pandemic.

An elderly woman sitting in her home tries out the face mask she has handmade to wear during the 1918 influenza pandemic.

What have we learned?

Pandemics have rewritten the course of human history in their own unique ways. Is there going to be a second, or even third, wave of COVID-19? Maybe. However, we live in extraordinary times so we should keep our hopes up. This pandemic has been devastating for many, but we are witnessing the development of diagnostic tests, treatments and vaccines faster than ever before. Many organizations and institutions, including the Global Virus Network, continue devoting 100% of their efforts toward curbing the current pandemic. While we wait patiently for more promising results, make sure to wear your face masks, maintain social distance, and practice good hygiene.

Christian Brèchot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

Linman Li, MBA, MPH, PMP, CPH
Director, USF- GVN Center
USF Health Morsani College of Medicine
Vice President, Global Virus Network

 

 

June 3, 2020

The implications of  COVID-19 cross immunity

What is immunity?

Knowing how immunity works against SARS-CoV-2 is critical for understanding the pathogenesis of COVID-19; developing diagnostics tests, neutralizing antibody-based therapies and vaccines; and standardizing protective and preventive measures.

Immunity is a state in which the body recognizes and resist to invading viruses, bacteria or other pathogens, mitigating their harmful effects. It prevents infection and maintains the integrity of the body by fighting, neutralizing and removing the pathogens. Most COVID-19 patients (symptomatic or asymptomatic) produce IgM and IgG antibodies within days to weeks of infection with SARS-CoV-2. The virus also induces a cellular immune response based on T cells, but we are still in the early days of understanding this T cell-mediated immunity.

However, an article recently published in the journal Cell by La Jolla Institute for Immunology at the University of California San Diego, a Global Virus Network (GVN) Center of Excellence, found that 40-60% of unexposed, healthy individuals developed T-cell immune responses to SARS-CoV-2 proteins. Blood specimens were collected from these study participants between 2015 and 2018, before the outbreak of COVID-19. That means although they had not been exposed to the new coronavirus, it appears that a good percentage had already raised an immune response, which could be partially protective against SARS-CoV-2!

One plausible explanation for this finding is cross-immunity.

What is cross-immunity?

Cross-immunity, or cross-reactivity, means that an antibody can recognize multiple structurally similar parts of pathogen proteins known as epitopes, even though they are located on different viruses. That enables the human host to efficiently defend itself against many potentially-threatening pathogens. The smallpox vaccine, for example, was developed after British doctor Edward Jenner observed that milkmaids infected with cowpox did not show any symptoms of smallpox; this led to administering as a vaccine material from smallpox sores (a process known as variolation).

Returning to the Cell article, individuals never exposed to SARS-COV-2 might show a cross-reactivity between SARS-CoV-2 and the other coronaviruses that cause the common cold. Similarly, another GVN Center of Excellence, Duke-NUS Medical School in Singapore, published a preprint on BioRxiv last week. The researchers noted that T cells reacting to SARS-CoV-2 epitopes were detected in nine out of 18 blood donors (50%) although they had neither been exposed to the first SARS virus (2003) nor SARS-CoV-2.

Understanding the mechanism of cross-immunity is increasingly important because antibodies are actively developed for diagnostics, vaccines, or treatment for various diseases. Indeed, a very important implication is that we might use cross-immunity to existing vaccines to reinforce protection against SARS-CoV-2. With this in mind, several studies are now evaluating the potential protective effect of the Bacille Calmette Guerin (BCG) vaccine, used to prevent tuberculosis. And the Institute of Human Virology at the University of Maryland, the first GVN Center of Excellence, leads a clinical trial testing whether the polio vaccine can induce innate immunity against SARS-CoV-2, and, possibly, interfere with its replication.

Human immunity to SARS-CoV-2 may be more widely distributed than we thought. According to an article posted by the American Society for Microbiology, 60-75% of children have antibodies to at least one coronavirus, and 90% of adults over age 50 years have antibodies to all coronaviruses causing the common cold. This may also have important implications for the mortality (deaths) caused by COVID-19. Is it plausible that different levels of cross-reactivity with coronaviruses explain why certain countries, regions or individuals would be more susceptible to SARS-CoV-2 or may experience higher morbidity and mortality rates even with social isolation and other protective measures?  Yet, while cross-immunity is a very appealing concept, many other factors need to be considered. For instance, we know that age, gender, health status, diet, behaviors and other factors play a very important role in contributing to the severity of COVID-19 symptoms.

Cross-immunity may induce challenges as well as potential benefits. For example, we must ensure that cross-immunity with other coronaviruses does not cause COVID-19 diagnostic tests to show false positive results. Finally, cross-immunity might in theory contribute to what we call “antibody-dependent enhancement (ADE),” a phenomenon that generates vaccine side-effects. So far, no evidence exists that any of the vaccines in development worsen a COVID-19 virus infection, but we need to remain mindful of ADE as we monitor vaccine progress.  

Clearly, more studies are needed, but cross-immunity remains an important field of research to decipher.

Christian Brèchot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

Linman Li, MBA, MPH, PMP, CPH
Associate Director, USF Medicine International
USF Health Morsani College of Medicine
Vice President, Global Virus Network

 

 

May 27, 2020

Where do we stand in the fight against COVID-19?

Did the curve really flatten?

Nearly five months after the first cluster of pneumonia cases (later identified as COVID-19) was reported on Dec. 31, 2019, has the curve really flattened?

As mentioned in our April 22 blog, there are many prediction models. In the U.S., for example, the Centers for Disease Control and Prevention cites 19 individual forecasts. All suggest that the number of deaths will continue to rise in the coming weeks, but at a much slower pace. Many states continue to loosen their restrictions.  At the same time, coming off a long Memorial Day weekend, unfortunately the U.S. death toll approached 100,000. This accounts for almost 30% of all COVID-19 related deaths worldwide. At the same time, the situation is particularly alarming in South America. 

While waiting for vaccines and treatments, we must innovate and identify more preventive solutions

According to the  World Health Organization, we still have a long way to go in the COVID-19 pandemic. Last week, Spain extended its state of emergency for the fifth time until June 6. Meanwhile, Spain has announced it will reopen its borders to foreign tourists in July.  This capricious pattern has repeated during the pandemic. Ironically, while we cannot fully foresee the course of the pandemic, we can certainly predict that the situation’s unpredictability will continue until a vaccine or treatment becomes available.

A new study published last week in The Lancet found that hydroxychloroquine or chloroquine may not help treat COVID-19 as has been claimed, but instead the drug may lead to a decreased hospital survival rate and an increased frequency of ventricular arrhythmias. However, the authors of this large retrospective analysis acknowledge that randomized prospective studies, such as those conducted at Tampa General Hospital, are still needed. Also, hydroxychloroquine is likely to be effective in the early stages of infection, rather than in critically ill pneumonia patients. Overall, these debates point to the importance of evaluating drugs that might prevent, not only treat, COVID-19. The FDA, for example, has approved two clinical trials to assess the potential of using the repurposed drug nitazoxanide, widely prescribed to treat intestinal parasites, to prevent COVID19 in nursing homes and among health care workers. These nitazoxanide trials are being initiated in Tampa Bay.  Finally, identifying optimal ways to improve the effectiveness of masks and disinfecting solutions should also have a significant impact, and several teams at USF are working along these lines.

As with treatments, we have seen very promising, but still early results in vaccine development. So far, the interpretation of the studies is limited by the small size of the cohorts, short follow-up time, and the absence of randomized control groups. Two weeks ago, the company Moderna announced encouraging early results from a Phase 1 trial of its messenger RNA vaccine against the novel coronavirus. And last week, the The Lancet published a paper based on data from the COVID-19 vaccine developed by Cansino Biologics. This platform uses genetic material from a live but weakened human cold virus, adenovirus 5(Ad5), and SARS-COV-2 coronavirus, incorporating the latter into the Ad5 virus. The results appear promising, because antibodies and neutralizing antibodies increased significantly at day 14 after inoculation and peaked 28 days after inoculation in the three dose groups. Yet, does previous immunity against colds decrease the effectiveness of such viral vectored vaccines? In addition, we need to ensure not only effectiveness, but also safety of the vaccines.

Another question to be addressed: When a vaccine is available who, or which groups, should receive it first? It will be impossible to produce enough doses in a short time to protect the world’s population, so vaccination priorities must be determined. The principles established for distributing and implementing the use of COVID-19 testing kits should also apply to the vaccine. High-risk groups — including the elderly, people with underlying medical conditions, health care providers, and underserved populations — should be vaccinated before others. Standard protocols must be developed to meet the expected high demand but initially low supply of vaccines.

 

Summer is here, which means flu season is not far away. By fall, we may have to fight both COVID-19 and influenza. Please do not take the current ease of restrictions for granted. Continue to be diligent about social distancing and personal hygiene to protect your loved ones and yourself.

Christian Brèchot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

Linman Li, MBA, MPH, PMP, CPH
Associate Director, USF Medicine International
USF Health Morsani College of Medicine
Vice President, Global Virus Network

 

 

May 20, 2020

COVID-19: A perverse respiratory virus that attacks beyond the lungs

The overall COVID-19 mortality (death) rate is not known, but given the estimated number of asymptomatic infections it will not be very high, maybe about 0.3%. However, the highly contagious virus has had devastating consequences as it spread across the world. The mortality rate is much higher in older populations (10-15%) and in people with pre-existing conditions, such as diabetes, obesity, and chronic cardiovascular or pulmonary diseases.

This virus is so unusual and, in fact, perverse!

Each week we learn more about its capacity to damage the organs of infected patients who become critically ill. SARS-CoV-2 can trigger lung lesions in about 5-10% of patients with clinical symptoms. This is known to be associated with a major overactive immune response, known as the cytokine storm,” which causes extensive inflammation in the lungs. We now also know that the virus can cause a loss of smell and taste (anosmia) and infect the brain with significant neurological consequences (see our April 29 blog on nicotine).

Lately, another deadly feature of the virus has emerged. That is, its ability to infect the endothelial cells that line blood vessels. These cells have very important functions in our body, including maintaining a proper cardiovascular balance. They also contribute to our immune status and defense against infections. Therefore, infection of endothelial cells and resulting inflammation of blood vessels may lead to severe dysfunction of vital organs, such as the heart, lungs, brain and kidneys.  It may also be associated with thrombotic complications observed in many patients with COVID-10  (primarily embolisms caused by a blood clot blocking an artery in the lungs), as well as breakaway blood clots leading to unexpected stroke in some young and middle-aged adults.

There is more. The U.S. and several European countries have reported rare cases of a pediatric inflammatory disorder that shares features of Kawasaki disease (KD) and may be linked to the virus.

Described in our May 6 blog, KD is a very rare acute vascular inflammation almost exclusively affecting children. The prognosis is generally good, but the condition is clearly still a serious threat. One of KD’s most severe complications is coronary artery aneurysm. Although the cause of KD remains unclear, researchers hypothesize that a viral trigger may play a role in some genetically susceptible children because KD is associated with some viral respiratory infections, including seasonal coronavirus.

The annual incidence of KD is highest in Japan, at more than 300 per 100,000 children under the age of 4, compared with 25 per 100,000 children under age 5 in the U.S. Now some recent reports indicate a link between KD with SARS-CoV-2. In particular, a recent study published in The Lancet shows that the ongoing COVID-19 epidemic in Italy resulted in an increased monthly KD incidence at least 30 times greater than the monthly incidence of the previous five years. Moreover, there was a clear starting point after the first case of COVID-19 was diagnosed in North Italy. Similar observations were made in France, in the UK and now also in the U.S.

But let’s be clear. Although we need to pay attention to these findings, it does not change the fact that KD is a very rare condition, and the vast majority of children experience very mild COVID-19 symptoms when they are infected.

So, what does COVID-19’s growing list of apparent complications mean?

It means we are still at the beginning of our journey to fully understand the physiological effects of this vexing virus. And, it emphasizes the distinctiveness of a new respiratory virus that can ravage many parts of the body — and why we must persist in protecting ourselves.

Christian Brèchot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

Linman Li, MBA, MPH, PMP, CPH
Associate Director, USF Medicine International
USF Health Morsani College of Medicine
Vice President, Global Virus Network

 

 

To view Dr. Brechot’s recent interview with Rolling Stone, Click Here.  He discusses the origins of COVID-19, and how the virology and wider scientific communities are working together for solutions.

May 13, 2020

Q & A: What you need to know about COVID-19

We have now entered the era of “containment relaxation.” This is a new chapter, an unprecedented situation. Two months have passed since we launched this blog, so let’s sum up some top public concerns and questions about COVID-19 in everyday life. Throughout our busy work and study days, we are bombarded with countless pieces of information about the new coronavirus, many of which are unconfirmed.

Clearly, many mysteries about COVID-19 remain. Yet, the one thing confirmed by all studies is that effective prevention of COVID-19 transmission should be based upon well-known public health measures: wearing a mask as soon as you leave your house, washing your hands frequently with soap and hydroalcoholic solutions, and respecting the social distance of at least six feet. This is key!

1. How is COVID-19 transmitted? Will I get infected if I go grocery shopping?

The predominant routes for human-to-human COVID-19 transmission are through respiratory droplets (from coughing, sneezing, talking) or by fomites: i.e., touching a surface or object contaminated by an infected person and then touching your nose, mouth or eyes. It is important to keep a social distance while at the grocery store. You must wear your mask. You should make a list of things that you need for at least a week or two. If possible, only one household member should go shopping to minimize unnecessary exposure. Before entering the home, try to leave your shoes outside and make sure all the products are thoroughly cleaned and disinfected. If possible, use gloves but make sure to minimize cross-contamination. Most importantly, don’t forget to wash your hands before touching anything in the house. You can clean and disinfect households as recommended by the Centers for Disease Control and Prevention.

2. Is a vaccine available?

Testing of vaccine candidates continues globally but, unfortunately, no vaccine is available yet. We have to wait. Safety is the primary goal for seeking approved vaccines. Many researchers have stepped up to develop vaccines against COVID-19. According to a recent published perspective in Science, new manufacturing platforms, structure-based antigen design, computational biology, protein engineering, and gene synthesis now provide tools for making vaccines quickly and precisely. The Global Virus Network recently published a scientific column about COVID-19 vaccines; please read it here

3. Has the U.S. Food and Drug Administration (FDA) approved any drug to treat COVID-19?

A huge worldwide effort is focused on developing treatments to fight COVID-19 on many fronts. Several are very interesting candidates, including for preventive therapy. Yet, at this stage, the FDA has yet to approve any drugs to treat COVID-19. However, the agency created a Coronavirus Treatment Acceleration Program to speed up the development of treatments. For example, on May 1, 2020, the FDA issued an emergency use authorization (EUA) allowing the investigative antiviral drug remdesivir to be used in treating suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease. However, the effectiveness of this drug must be confirmed. In addition, new immunomodulatory molecules have shown a lot of promise for combatting the acute respiratory syndrome, which affects about 5 to 10% of patients with COVID-19-related disease. 

4. I keep hearing that the U.S. doesn’t do enough testing? Why?

At this point, we all know the importance of viral RNA testing and antibody testing. The main reason we do not conduct enough tests is that the supply of resources required for testing, including the swabs, reagents, and personal protective equipment, is still far below the demand. In addition, some people are reluctant to get tested because they fear discrimination associated with COVID-19. When capacity is sufficient to test for SARS-CoV-2 antibodies, such testing will help reveal the true scale of the population already exposed to the virus (particularly who experienced no or mild symptoms). Moreover, diagnostic testing for viral RNA should be mandatory. If you have been exposed to a confirmed case or experience any of the listed symptoms, please call your health care provider or county health department to schedule a test.

5. Should I stop seeing my doctors about my underlying health conditions during the pandemic?

No, you should keep up with all routine doctor appointments, including annual examinations. Most health care providers are available through telemedicine or are developing this technology to accommodate standard doctor appointments. Please check with your health care provider about what they can do for you. If you are a USF Health patient, please review this page for detailed information.

6. If I have recovered from COVID-19, can I be re-infected? How long does immunity last?

The presence of antibodies to COVID-19 does reflect elimination of the virus and protection, at least for most patients. But is too early to tell how long protective immunity may last. The levels of neutralizing antibodies from recovered COVID-19 patients vary from case to case. According to the World Health Organization, detection of antibodies suggested by some governments as a basis for an “immunity passport” does not guarantee protection against COVID-19 re-infection. Additionally, a viewpoint from JAMA Network suggests that the “immunity passport“ needs to be implemented with caution.

7. The weather is getting warmer. Is there any correlation between COVID-19 infection rate/mortality and weather?

According to several papers, including one recently published paper in Science of The Total Environment, the average temperature in each country negatively correlated with the number of SARS-COV-2 infections. However, no significant association was found between COVID-19 mortality and temperature. In fact, humidity seems to be a more important parameter. In the laboratory, the virus showed sensitivity to temperature. However, it is too early to predict whether seasonal changes will really affect the outcome of COVID-19 epidemics. More data are needed to draw reliable conclusions.

8. Are my pets safe?

Some SARS-CoV-2 cases have been confirmed in pet cats and dogs in Hong Kong and the U.S. However, not enough evidence exists to show that your pets can transmit the virus to you. If you are sick, limit your contact with your pets. If you suspect your pet is infected with COVID-19, consult your veterinarian. Here is a resource for COVID-19 in animals.     

9. How can I maintain a healthy relationship with my family or other household members?

It is very challenging to work and live at home every day especially if your roommate, children and/or significant other are present at the same time. Here are some tips from Johns Hopkins University to help improve your relationship during this pandemic. Keep in mind that mental health problems should not be trivialized. When you need help, don’t wait.

10. When will it be over?

Of course, the sooner the better. But without a vaccine and/or therapeutic treatments, it is difficult to predict when this pandemic will end or possibly recur. All we can do is maintain our role as good citizens— be diligent about social distancing and personal hygiene. One day, we will emerge from this global health crisis and look back proudly at what we have done together to curb COVID-19.

Christian Brèchot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

Linman Li, MBA, MPH, PMP, CPH
Associate Director, USF Medicine International
USF Health Morsani College of Medicine
Vice President, Global Virus Network

 

 

May 6, 2020

Children and COVID-19: How infectious are they?

How many children have been infected with SARS-CoV-2?  Are they contagious? Which treatments should we contemplate for them? These are all key questions to answer if we want to successfully implement our public health strategies in the coming months. Unfortunately, more studies are required to provide the information we need.

To date, the pediatric population accounts for only  1 to 5 percent of the reported infected patients worldwide. In most cases, the course of the disease is much milder in children than in adults. A few newborns have been infected, but the evidence for intrauterine transmission from mother to fetus is so far scarce. Kawasaki disease, a rare but serious inflammatory vascular disorder, has been potentially linked to COVID-19 in some children in the UK and in France. Such reported cases of this syndrome are unusual, but they indicate the need for caution and continued investigation.

What about children’s capacity to spread the virus, not only to other children but also to their parents and more vulnerable grandparents? While still controversial, most studies to date emphasize a lower viral load (amount of virus in the blood) and low transmission rates in children. Yet, a recent study from Germany suggests that the viral loads for children can be comparable to those seen in adults — but does this mean that children show the same potential for transmitting the virus? Fortunately, the answer appears to be no. In fact, the virus can be more easily transmitted from adults to children than from children to adults. This points to the complexity of viral transmission, which does not depend solely on the viral load.

Overall, growing evidence indicates that children yield less impact than adult populations in disseminating COVID-19 infection. This is key information for making decisions about sending the kids back to school. Again, we still need much more information about the impact of the new coronavirus on children – and hope to soon see some comprehensive studies on this topic in the U.S. and in Florida.

What can we expect when countries reopen?

After several months of battling the COVID-19 virus, at least 12 countries are preparing to reopen or lift some restrictions in certain parts of their countries.  Florida was among the states in the U.S. to begin a  phase 1 reopening this week. In New York, the epicenter for COVID-19, as the weather warmed up, many people rushed to parks over the weekend to breathe fresh air, the New York Times reported.  You may wonder: Does reopening put more people at risk? Will the curve continue to flatten, or will we experience a second wave?

Without sufficient data, it is too early to draw conclusions. While many questions remain uncertain or unanswered, people’s lives here will slowly return to normal, as they have been in China. In the process, the following strategies and measures should be taken into account.

Increase testing capacity and volume

As emphasized many times in our previous posts, testing-identifying-tracing-isolating, testing and more testing are vital. Extensive tests (both for viral RNA and antibodies to the virus) are needed to reveal the true scale of this pandemic. Many diagnostic kits are now provided by various companies. We need to evaluate them carefully and standardize the results nationally and internationally. The University of South Florida is leading efforts to develop novel test kits and test the residents in our community.

Enhance and improve contact tracing

Contact tracing identifies and follow ups with individuals who may have been in contact with confirmed COVID-19 cases during the time when those patients were infectious. The Centers for Disease Control and Prevention advises contacts to stay home and to maintain social distance from others until 14 days after their last exposure in case they also become ill. Contact tracing is critical in fighting COVID-19 and other infectious diseases, such as Ebola. Based on a recently published article in the journal Lancet, isolation and contact tracing can reduce the spread of infection within the community.  However, contact tracing is labor intensive and can be greatly enhanced by innovative technologies, such as smart phone/device applications.

The GPS and Bluetooth functions built into most people’s smartphones can be used to track contacts. Many countries, including China, Singapore and Australia, rely heavily on smartphone tracing apps to prevent COVID-19 from spreading further in their regions. Last week, Apple and Googlereleased virus contact tracing tools to public health organizations so agencies can build and test their own apps.

An editorial in Nature points out many challenges of relying on the smart phone apps for contact tracing. First, no global standards exist among different countries. Moreover, many users will question whether their data is stored safely, and whether the privacy of app users sharing the information is effectively protected. The contact tracing app sends you an alert when you are in close contact with a confirmed case. Based on the data received and your social circle, the infected individual who is supposed to remain anonymous may be easy to identify.  An original investigation published in JAMA Internal Medicine suggests that the maximum benefit from contact tracing can be achieved only while following other measures such as testing and social distancing.

Maintain protective measures

As we try to strike a balance between protecting ourselves and restoring our lives, keep some principles in mind. First, a recent journal article in Mathematical Biosciences, reports that early termination of social distancing may trigger a second wave of COVID-19. So, wearing face masks and maintaining social distancing practices are highly recommended, and these measures will be the new normal until a vaccine is eventually available. Secondly, everyone must continue to practice good personal hygiene: wash your hands frequently, avoid touching your face, and cover your mouth when coughing or sneezing. Lastly, remain positive and safely maintain daily physical activities. Physical and mental health are equally important during this time.  Remember, we are all in this together, and we will fight this pandemic together.

Christian Brèchot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

Linman Li, MBA, MPH, PMP, CPH
Associate Director, USF Medicine International
USF Health Morsani College of Medicine
Vice President, Global Virus Network

 

 

April 29, 2020

Basic research meets epidemiology: Can nicotine patches prevent SARS-CoV-2 infection?

Let’s be clear: this is still a hypothesis. But a great paper recently published by the French National Academy of Science proposes, with substantial rationale, that controlled nicotinic agents may efficiently prevent or control infection by the COVID-19 virus. Here’s how that might work:

We know that SARS-CoV-2, like other human coronaviruses (SARS-CoV-1, MERS-CoV) and some animal coronaviruses), infects the central nervous system (CNS). In fact, several clinical observations indicate that patients with COVID-19 experience neurological dysfunction, and this may play a role in the respiratory failure of some. Moreover, loss of the sense of taste and/or smell (anosmia) is quite frequently observed and might even correlate to the severity of the infection. Those with anosmia may possibly experience less severe courses of infection, but this needs to be confirmed.  

We have also learned that SARS-CoV-2, such as several other viruses including coronaviruses, enters the olfactory epithelium and progresses into the brain to the olfactory bulbs. But how does the virus enter neural (nerve) cells? It has been well established that angiotensin converting enzyme II (ACEII), acting synergistically with a cellular serine protease (TRMPSS2), is a major receptor used by the virus to enter targeted cells. But could the virus enter through additional receptors?

This is where serendipity, or “open thinking,” comes into play. Scientists have long known that the rabies virus infects neurons by binding its envelope protein to the nicotinic acetylcholine receptor (nAChR). In fact, nAChR  plays a critical role in the host-pathogen interaction by down-regulating inflammation (the so-called cholinergic anti-inflammatory pathway), and the rabies envelope inhibits nAChR activity. So, the virus not only uses the receptor to enter the brain; it also inhibits the receptor’s anti-inflammatory potential. These nicotinic receptors are also present in cells lining the interior surface of blood vessels in the lungs (lung epithelium).

A nicotinic treatment might compete with the viral envelope for binding to the nAChR, decrease entry of the virus, and partially restore the anti-inflammatory activity of the receptor.  Why? 

That’s where basic research and structural biology come in.  A study was conducted based on very sophisticated electron microscopy (cryo-EM) of the SARS-CoV-2 spike (S) protein, the envelope protein that binds to the cell surface. The advanced microcopy demonstrated that SARS-CoV-2 and rabies viral envelopes share similarities. Thus, SARS-CoV-2 might also bind to the nicotinic receptor to enter cells and block nAChR.

Now, add epidemiology and clinical observations to that structural biology discovery. Recent solid evidence indicates that the COVID-19 rate among smokers is less than that of nonsmokers — even after taking into account potential confounding factors of smoking, such as age and sex.

Overall, epidemiological, clinical and basic research evidence suggests that Covid-19 infection may be prevented and controlled by nicotine. With this in mind, French clinicians have begun testing whether COVID-19 can be effectively treated by administering nicotine through skin patches, or other methods like nasal spray or chewing gum. Let’s wait and see, but, if successful, this bold and simple approach would be quite a breakthrough!

At the same time, infected individuals who smoke have a worse prognosis than those who do not. So let’s be clear. This new COVID-19 clinical research evaluating nicotine substitutes — which contain small amounts of nicotine without other harmful chemicals found in tobacco — is not an encouragement to smoke.

COVID-19 antibody therapy: convalescent plasma transfusions

While we wait for clear COVID-19 drugs or a vaccine to provide widespread immunity, the population is still vulnerable. In the meantime, many researchers and health care providers are leaning towards the historical, experimental treatment commonly called “convalescent plasma.”

What is convalescent plasma?

Plasma makes up 55% of your blood in the form of liquid. The rest is comprised of red blood cells, whites blood cells, and platelets. Plasma contains immune-boosting antibodies that help your body fight off viruses, bacteria and other pathogens. Convalescent plasma (CP) is a post-infection potential therapy identified for viral diseases. The treatment collects plasma containing antibodies from the blood of recovered COVI-19 patients (donors) and then transfuses those potentially antibodies into infected patients to neutralize the virus. The purpose, when no other treatment or vaccine exists, is to improve survival rates.

CP therapy is not a new concept and can be traced back to a century ago. Its effectiveness was evident during the outbreak of H1N1 virus in 1918, SARS in 2003, as well as in the H1N1 pandemic in 2009. Most recently, it was used to treat Middle East Respiratory Syndrome and Ebolapatients.

Physicians from many countries, including India, China, South Korea, Italy and the U.S are all enthusiastic about using CP therapy to help severely ill COVID-19 patients recover more rapidly. The MayoClinic, working with 56 other institutions, leads the U.S. project investigating this antibody therapy for hospitalized patients with severe or life-threatening COVID-19, or those at high risk of serious disease progression. The U.S. Food and Drug Administration has published recommendations for using COVID-19 CP in clinical trials and for emergency purposes.

Promising early results, but challenges remain

Apreliminary communicationon JAMA Network reports an uncontrolled case series in which the clinical status of five severely ill COVID-19 patients improved after they received CP therapy. A study published in the Journal of Medical Virology demonstrates a similar finding.

As promising as CP therapy may be, many challenges lie ahead in proving its effectiveness.

First, the FDA recommends that patients with severe or immediately life-threatening disease meet criteria for the use of COVID-19 CP therapy, but the optimal dosage and timing of the therapy remains unclear. That will be important to know, because CP transfusions carry the risk of a damaging immune reaction. Instead of being defended against the virus, patients could suffer a “cytokine storm” driven by inflammation in overdrive. A studyreporting on CP therapy for H1N1 influenza, suggested that a single dose of CP with neutralizing antibodies titers of greater than 1:160 effectively reduced mortality and the respiratory viral load..

Secondly, although COVID-19 positive cases now surpass 3 million, not enough people qualify as CP donors. According to FDA guidelines, CP donors must completely recover from the COVID-19 infection and have undergone an initial positive diagnostic test. If a diagnostic test was not performed, then patients are required to obtain a positive antibody test. Before donating plasma, they must either be asymptomatic for 28 days, or be at least 14 days asymptomatic and have a negative diagnostic test. All CP donors must also meet minimum eligibility criteria to donate blood. All these requirements can exclude many potential donors.

Finally, tests are available to identify recovered patients with high levels of antibody response; however, standard guidelines for use of these antibody tests still must be developed.

Despite the challenges, CP is worth studying as a therapy that may limit the loss of life during this COVID-19 pandemic. Further published data is needed to prove its benefit.

 

Christian Brèchot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

Linman Li, MBA, MPH, PMP, CPH
Associate Director, USF Medicine International
USF Health Morsani College of Medicine
Vice President, Global Virus Network

 

 

 

April 22, 2020

Collaboration more important than ever to curb a pandemic characterized by uncertainties

The pandemic caused by SARS-CoV-2 is less than two months old, yet seems longer. Scientists face extraordinary challenges, particularly when it comes to balancing the understandable urgency of the public expectations for immediate research outcomes with the reality of science, which requires time to avoid mistakes, hasty conclusions and misleading announcements.

The discussion on antibody testing is a good illustration of this dilemma. We need widespread use of diagnostic kits as soon as possible, but must also standardize testing and choose the right kitsto obtain the best results (as mentioned in previous blogs). At the same time, we now face the reality of coronaviruses infections. Antibodies do not last very long, maybe a few months. Some neutralize (defend against) viral invaders – but others may facilitate adverse immune reactions, such as a subsequent infection.

Scientists are tackling the challenge of balancing the demand for rapid COVID-19 research outcomes with the need for accurate and clinically meaningful diagnostics and therapeutics.

To cope with these challenges, we need to organize prospective cohorts of patients infected with SARS-CoV-2, evaluating the outcomes of those treated with the investigational therapies, and those not treated. This is the only way to truly understand immunological responses to the virus, design robust vaccines, investigate the extent and effects of viral genetic variability, and evaluate the interplay between genetic variations and the genetic profile of infected patients. The scientific method takes time, and it won’t allow us to draw useful conclusions for this first round of epidemics. But, it is the way to get meaningful results.

Meanwhile, we must encourage transdisciplinary efforts to find rapid solutions as well as engage in the more long-term research efforts. This is exactly what the University of South Florida has initiated, and I am proud to participate with so many colleagues and friends. The task force launched by USF President Steve Currall and Senior Vice President Paul Sanberg has attracted many research ideas and proposals that will be extremely useful; USF Health clinical studies at Tampa General Hospital will facilitate prospective follow-up of patients with COVID-19; and the university’s partnership with the GlobalVirus Network will allow us to integrate the results in an international context.

While I have led many large and renowned research institutions, I’ve never witnessed such rapid mobilization as achieved both here at USF and by the entire international community. That’s why I remain optimistic that, beyond all the struggles and uncertainties, the overwhelming response to this pandemic will lead to meaningful discoveries in the fight against COVID-19 and future emerging infectious diseases.

Predictive models for COVID-19 are critical, but interpret with caution

As COVID-19 continues to spread worldwide, predictive models have increasingly drawn the attention of the news media and of policymakers. The Institute for Health Metrics and Evaluation (IHME) model has gained the most attention and generated debate in the U.S. In this blog, we will not attempt to evaluate which models are more valid, but to share how such mathematical models may be useful as the pandemic evolves.

What are predictive infectious disease models?

Predictive modeling uses available data and reasonable assumptions to predict how an infectious disease spreads in the real world. All models are simplifications of reality. Many different kinds of predictive models exist to simulate the outbreak. The most common is the Susceptible-Infectious-Recovered (SIR) predictive model. The population can be the host of disease (susceptible); infected by the disease and show symptoms (Infectious); or recovered or naturally immune from the disease (Recovered). The model demonstrates how individuals move from one stage to another. By adding populations who experience a long incubation period (Exposed), you get a more advanced model known as Susceptible-Exposed-Infectious-Recovered (SEIR). Using different variables and equations, the model can calculate when COVID-19 cases will peak under certain circumstances. Many parameters affect the accuracy of a predictive model.

Predictive modeling uses existing data and reasonable assumptions to forecast how an infectious disease spreads in the real world.  As more data becomes available, it triggers adjustment of the model, resulting in different outcomes.

How can modeling help us?

A viewpoint recently published in JAMA indicates the primary purpose of predictive models is to assess the relative effect of interventions in reducing health care burden, rather than to forecast the exact number and duration of cases. Nevertheless, in early March, a paper based on the transmission of COVID-19 in Hubei, China, was published by a group of Chinese scholars. Their aim was to help the rest the world understand the predictability of virus spread and make proper decisions to help prevent or slow the outbreak. The predictive values of these models are only useful when compared under different intervention scenarios. For example, by computing the effects of different potential measures such as social distancing, wearing face masks or home isolation, the simulations can guide government leaders’ decisions during the pandemic. According to an article in Nature, many countries, like the U.K. and the U.S, are using the predictive models as their “wind indicator” to implement preventive infection control measures to curb the pandemic and to put in place certain economic policies to support their citizens. 

What are the drawbacks of predictive modeling?

Improper estimation and prediction based on inadequate forecasting models will affect the resilience of the national health care system and could have adverse consequences. For instance, not every state or region implements social distancing the same way. Also, as more data becomes available daily, it triggers the adjustment of the predictive model, resulting in different outcomes. Moreover, infection rates, disease incubation period, case-fatality ratios, comorbidities, age distributions, and the correct number of asymptomatic individuals must be taken into account for the accuracy of projections. Unfortunately, during this current pandemic driven by a new virus, reliable data is very challenging to collect.

What course should we follow?

Based on the analysis report of Imperial College London’s model, a combination of mitigation measures, such as home isolation, home quarantine and social distancing, may reduce the peak medical demands by two-thirds and deaths by half. So far, the lockdowns in Europe and social distancing in the U.S. seems to be working as expected. However, the question remains: When these can these measures safely be lifted or relaxed? Will reopening certain areas lead to a second wave of COVID-19? Without standard COVID-19 drugs or other treatments, as well as the absence of a vaccine, the population is still vulnerable to COVID-19. Policymakers should exercise caution in relying solely on predictive models to make decisions about bringing people back to school and work, and resuming the normal activities of life. More data are needed for further actions.

 

Christian Bréchot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

Linman Li, MBA, MPH, PMP, CPH
Associate Director, USF Medicine International
USF Health Morsani College of Medicine
Vice President, Global Virus Network

 

 

 

April 15, 2020

Importance of COVID-19 diagnostics and lessons for future pandemics

Diagnostic tests are at the heart of the fight against infectious diseases — something not fully appreciated by governments, national and international institutions, or venture funds (when it comes to financing biotech companies).

We need treatments and vaccines, but the key to containing a new pathogen that threatens the world is early detection of infected individuals and immediate contact tracing. This is exactly what has not happened for SARS-CoV-2 in most countries, with the notable exceptions of South Korea, Taiwan and Germany. Now, it is possible to use serology-based assays (antibody blood tests) to evaluate how extensively populations have been exposed to the virus, key information to help us figure out how to ease out of containment, return to a more normal life, reinvigorate the economy, and take care of patients who suffer from other diseases and cannot be properly treated in the present context. Indeed, dealing with a general population massively exposed to the virus (about 50-60%), a level that offers protection against a “second episode” of epidemics, differs from managing more limited population exposure (around 5-10%). Unfortunately, the more likely smaller exposure percentage can sustain the risk of reinfection upon containment relaxation. So, again, diagnostics will be at the heart of any strategy in the coming months.

COVID-19 nasal swab laboratory test

Before drawing shaky conclusions that could lead to another crisis, we should keep a few things in mind. First, a series of diagnostic tests have been proposed by biotechnology companies and academia. However, their sensitivity-specificity and reliability-reproducibility markedly differ, so we need standardization and thorough evaluation. This can be performed rapidly but must be done carefully, not only by national agencies but also at the international level. (The Global Virus Network will contribute to this assessment, incorporating its experience in 50 centers around the world.)

Secondly, an academic community cannot design diagnostic tests without the support of industry partners. The academic scholars can generate the concept, the bold and smart ideas, and this is how we make progress. But, then, industry must drive large-scale development – attaining a robust, easy-to-use test that can be massively produced and distributed. I see too many academics who believe they can do the entire job themselves.

Finally, how can we better prepare for future pandemics? The Coalition for Epidemics Preparedness Innovations (CEPI), set up after the Ebola crisis in 2014, has made real progress in developing standby vaccines against known viruses and in responding quickly to new ones, such as the current SARS-COV-2 virus. The creation of CEPI, a consortium of large foundations (Bill and Melinda Gates, Wellcome Trust), large pharmaceutical companies involved in vaccine development, the World Health Organization, the National Institutes of Health, governments, and other organizations, is clearly useful in preparing for prevention and treatment.

We should do the same for diagnostics, building upon the resources of existing institutions such as the Foundation for Innovative Diagnostics (FIND), based in Geneva and supported by the Bill and Melinda Gates and Wellcome Trust foundations. Only through close collaborations among academics, industrial partners, nonprofit foundations and research agencies can we outsmart our common invisible enemy, the viruses.

Psychological well-being during the COVID-19 pandemic

With the dramatic daily rise of COVID-19 cases, the rapidly emerging COVID-19 pandemic has affected our psychological well-being as well as physical health.

Over100 countries – representing one third of the world’s population — are either completely or partially locked down, according to the data. Escalating levels of anxiety, stress, sadness, anger, guilt, or post-traumatic stress are common during outbreaks, coinciding with daily reports of cases and deaths, quarantine and stay-at-home orders, overwhelming news coverage, and lack of social interaction caused by social distancing.  In many countries, including China, Italy, the U.K. and the U.S., the mental health of frontline health workers is more fragile than ever as they struggle to balance the responsibilities of caring for patients, family, friends and, above all, themselves. Not surprisingly, health care groups that combated previous outbreaks of Ebola, H1N1, and 2003 SARS, experienced similar mood swings.

Based on recent psychiatry research, health care professionals working in intensive care units, emergency departments or infectious disease departments are twice as likely to suffer from anxiety or depression as those not directly exposed to  COVID-19 patients. Due to the increase in cases and the shortage of resources, many medical staff members are severely overworked. As a result, they are under constant pressure to provide adequate care to patients without standard COVID-19 drugs or other treatments. They do this while enduring the loss of their patients and colleagues, fully realizing their risk of becoming infected or infecting others (including their own loved ones), and experiencing stigmatization as caregivers for COVID-19 patients.

A new study in Psychiatry Research reports that health care professionals in ICUs, emergency departments, and infectious diseases departments are twice as likely to suffer from anxiety or depression as those not directly exposed to  COVID-19 patients.

Psychological intervention and prevention is critical to maintain the mental health of frontline healthcare professionals as well as the “health” of the medical system. We need to ensure that  basic needs are met; for example, reasonable working hours, access to physical activities and healthy, balanced diets. Appropriate precautions such as personal protective equipment (PPE) should be taken. Furthermore, effective communication among health care team members, and tremendous support from leadership and family will help providers cope with the mental stress.

We must also address the mental well-being of other vulnerable groups, such as recovered COVID-19 patients, children, the elderly, pregnant women, the Asian population (a special case in this pandemic), and last, but not least, frontline COVID-19 workers, including first responders, cashiers, gas station attendants, restaurant workers, and delivery personnel. Take children, for example; most don’t understand why they can no longer go to school or gather with friends for social activities. Many schools in different countries have implemented virtual classrooms, resulting in more screen time and less physical activity. Adults need to set good examples to guide children in their lives through the stressful time of home confinement.

During this pandemic, the general public should remain aware of potential psychological reactions, maintain a positive attitude, be selective in determining what information to rely upon, take preventive measures to protect themselves and others from infection, and use online networks or cell phones to reach out to family members and the community. Most importantly, seek appropriate help when needed, through telemedicine and social support resources.   

In short, collective and individual psychological effects can last long after the outbreak ceases. The emotional well-being of health care professionals and entire communities must be addressed both during and after any disaster, including pandemics. Appropriate approaches should be implemented to overcome the impact of psychological distress on various target groups.

Christian Bréchot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

Linman Li, MBA, MPH, PMP, CPH
Associate Director, USF Medicine International
USF Health Morsani College of Medicine
Vice President, Global Virus Network

 

 

 

April 8, 2020

Vaccine development challenges and the debate over masks

When and how will a vaccine to prevent COVID-19 happen?

As the SARS-CoV-2 pandemic continues, we already must think about the possibility that the virus may “return” next year and in the future. That means we must meet the urgent need for safe vaccines to protect against COVID-19 – and that takes time. Some phase I clinical trials to assess the tolerance of vaccine candidates in healthy individuals have already started. Several companies are even planning phase 2 trials with larger groups of people to determine effectiveness and further evaluate safety. Finally, phase 3 studies will test whether the vaccine works well in a “real world” context. So, we may have to wait 15 to 18 months for a vaccine ready for widespread use – and that estimate encompasses a very fast track record. Several scientists, including myself, co-signed a letter urging regulatory agencies to shorten the process. We will see.

What are some coronavirus vaccine approaches being tested?

At least 30 companies and academic groups are working on various approaches, and the competition has already shown promise. To induce an immune response, some vaccine platforms use direct injection of mRNA encoding for the viral proteins, in particular those shaping the “spikes” of the coronavirus. Others deploy viral vectors — such as measles, lentiviruses, adenoviruses or others — to carry a synthesized fragment of SARS-CoV-2 encoding the coronavirus spike protein for expression in the cell and presentation to the immune system. Finally, other groups work directly with viral peptide sequences chosen from structural analyses-derived studies and then injected into consenting study participants.

What will be the criteria for success?

First, let’s not forget that no one has yet successfully developed an efficient vaccine against a human coronavirus. We have no vaccines against SARS-CoV-1 or MERS-CoV. The major challenges to address include:

–Should we rely solely on generating a humoral immune response, indicated by the appearance of antibodies to specific viral proteins, or should we also rely on a cellular immune response in which T-cells (a type of immune cell) destroys infected cells? We know that COVID-19 produces protective antibodies, including neutralizing antibodies that block infection, but for how long? What is the real proportion of patients who get such neutralizing antibodies? The capacity of a vaccine to generate cellular immune response will likely be very important.

–What is the impact of the viral genetic variability? Should we worry that certain variants will “escape” from the vaccines we are preparing now? We really don’t know. So far (see our April 1 blog), no evidence exists for such evolution of the virus, but we should remain prudent.

–Would attempts to prepare vaccines with a “common core component” for all coronaviruses, be feasible?

Overall, these challenges imply that, concurrent with vaccine development, we must extensively analyze the immunological parameters during carefully designed follow-up of patients with COVID-19. We need to speed up carefully and spend time evaluating investigational vaccines in animal models. These models only partially recapitulate what happens in humans, but at least we minimize the risks. This would be particularly relevant to rule out inducing harmful “antibody dependent enhancement.” This is a phenomenon (as described for the dengue fever virus, for example) in which antibodies generated by the first infection do not protect against the virus, but actually enhance the second infection.

Can we identify other paths to eradicate COVID-19?

An interesting, complementary approach for vaccines recently emerged. Several studies reveal that some live vaccines, such as those administered for measles, bacillus Calmette-Guérin (BCG), pertussis and other diseases, produce pronounced nonspecific protective effects, while inactivated (or killed pathogen) vaccines do not. In fact, some strains of BCG vaccine not only confer protection against disseminated forms of tuberculosis, but also induce immunity against infections caused by nonrelated pathogens. Along these lines, a highly provocative new study found that countries without universal policies of BCG vaccination (Italy, the Netherlands, U.S.) have been more severely affected by SARS-CoV-2 than countries with universal and longstanding BCG policies. The authors also argue that BCG vaccination reduced the number of reported COVID-19 cases in a country. Related hypotheses have been proposed about the capacity of oral polio vaccines to stimulate such “cross-protection.” Can we take advantage of such bold approaches? We must be cautious, but this also needs to be explored. Ultimately, only extensive international cooperation and more flexible intellectual property and regulatory regulations will allow us to rapidly embrace so many scientific and development challenges.

How is the COVID-19 virus transmitted?

A recent World Health Organization scientific briefing, reported that the predominant route for COVID-19 transmission is human to human through respiratory particles known as droplets (>5-10 μm), which are emitted during sneezing or coughing. The second mode of transmission is through direct contact: transfer of the viral pathogen from a contaminated surface/environment to the mouth, nose or eyes. What worries us most is a potential third mode of transmission — that aerosolized viral particles may be spread through the air by talking, or even normal breathing.

Recent correspondence from the New England Journal of Medicine noted that the virus remained in aerosols as the infection titer decreased throughout a three-hour experiment. Also, the 7th version of the guidelines for diagnosis and treatment of COVID-19 in China indicates that especially in relatively closed environments (such as elevators and stairwells), the virus may spread with prolonged exposure to high concentrations of viral particles suspended in air. Conversely, another study from Singapore, found no transmission through aerosol had been reported. Since we lack efficient research and valid data, it’s still debatable whether the COVID-19 virus can be spread by aerosol.

So, should a face mask be used?

According to a review in The Lancet, after the outbreak of SARS-CoV-2, many countries implemented their own recommendations about the use of face masks. In countries like China and Japan, wearing face masks in public has become a daily routine to stop transmission of the virus. Last week, the U.S. Centers for Disease Control and Prevention also issued recommendations for wearing cloth masks in public areas. People may still be unclear about the need for and effectiveness of the measure.

Keep in mind that the most effective way to contain a pandemic is not to cure all the sick patients, but to stop the spread of the infection. Without cutting off the source of transmission, anyone in the community can become infected to the extent that no health system in the world can absorb all the cases.

When should a mask be worn?

A recent study in Nature Medicine concluded that surgical face masks can prevent transmission of human coronaviruses and influenza viruses from both larger respiratory droplets and aerosol exhaled by symptomatic individuals. More studies are needed to determine whether this also applies to COVID-19 but, in the absence of treatments or a vaccine, wearing a mask during this pandemic should be a universal precaution. Masks should especially be worn in public, because a yet unidentified asymptomatic population of SARS-CoV-2 infected patients has the potential to shed the virus.

N95 respirators are designed to block 95% of small particles (0.3 micron), including airborne particles, when properly fitted to the face. They are commonly used in industrial or health care settings and are not recommended for use by the general public. Surgical masks are disposable and can block large droplets from sneezing, coughing, or talking. They should be worn by people with COVID-19 related symptoms to prevent spreading infection to healthy people. However, used surgical masks must be properly disposed; otherwise, they pose a potential health hazard for others.

Cloth masks, which can be made at home, washed regularly and reused, are suitable for people showing no symptoms to wear in public. Their widespread use is a good way to slow the asymptomatic population from unknowingly infecting others.

It is vital to ensure that those at high risk – health care providers, nursing home workers, sick patients and the people caring for them — have an adequate supply of N95 respirators and surgical masks. There is no need for the general public to hoard these types of masks.

In summary, a face mask of any kind can only help reduce the risk of infection. These coverings will not make you invincible against the virus. Nor are they an alternative to washing your hands or following appropriate physical distancing measures. For optimal prevention, wear your masks in public areas, maintain good hand hygiene, and keep a safe physical distance.

Christian Bréchot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

Linman Li, MBA, MPH, PMP, CPH
Associate Director, USF Medicine International
USF Health Morsani College of Medicine
Vice President, Global Virus Network

 

 

 

April 1, 2020

Antibody tests: The only reliable approach to reveal true scale of the SARS-CoV-2 pandemic

While we were preparing this week’s blog, the U.S. surpassed China and Italy as the worldwide leader in confirmed coronavirus cases. New York, for example, became the new epicenter of the current pandemic as the number of confirmed cases surged each day.

What is COVID-19 testing?

According to World Health Organization, when a patient meets the suspect case criteria, upper and/or lower respiratory tract specimens, such as a nasal or throat swab, sputum, and/or endotracheal aspirate, should be collected from the suspected cases and screened for the virus. They are screened using a nucleic acid amplification test (NAAT), such as real-time reverse transcription-polymerase chain reaction (rRT-PCR). This molecular technology converts the specimen’s RNA into DNA, which is rapidly amplified to detect tiny genetic pieces of the virus. If genetic material of pathogen SARS-CoV-2 is present, the patient is diagnosed with COVID-19.

Rapid diagnostic tests have been needed to decentralize testing capacity and help make up for lags in current testing.  Now, we will have the possibility to perform rapid testing, with results being available in around 5 to 10 minutes. The specificity of these tests still must be evaluated, but this is real progress.

However, the real question now, in addition to increasing NAAT test capacity, is does NAAT provide enough data to help reach the ultimate goal of curbing this pandemic?  We expect the best epidemiological data yet to be provided by upcoming antibody blood tests.

What is an antibody test?

Unlike the current tests collected primarily by nose or throat swab, the antibody test (known as a serological assay) relies on drawn blood. This blood test detects whether people have developed antibodies, molecules made by the immune system to attack disease-causing organisms (pathogens) and the level of antibodies in their blood. Many countries including France, the Netherlands, UK, Germany, China, and Singapore, as well as certain states in the U.S., are working rapidly to produce and promote the test, which can provide a bigger picture of populations infected and the full scope of immunity to COVID-19 within communities.

Dr. Florian Krammer, professor of microbiology at the Icahn School of Medicine at Mount Sinai in New York City, a center affiliated with the Global Virus Network (GVN), developed a similar test: the serological enzyme-linked immunosorbent assay (ELISA) test. According to the medRxiv preprint, the assay was created using recombinant antigen extracted from the spike protein (S protein) of SARS-CoV-2. The S protein conveys the virus to receptors on the host cell surface and helps the virus invade the human cell where it replicates. When infected with COVID-19, the body produces antibodies that recognize the “foreign” S protein and destroy the virus.

What is the difference between NAAT and the serological assay test?

While NAAT checks whether someone is currently infected, a serological assay identifies whether an individual has been infected in the past and if their immune system mounted an antibody response to the virus. It can identify even asymptomatic people (those who were infected without showing any apparent symptoms) —  a mystery yet to be solved in this pandemic.

The antibody test offers several other advantages: it can demonstrate the true prevalence of SARS-CoV-2 infection within the population, and it’s simple and affordable. Blood from a finger prick is sufficient to generate the test result.

Most countries are implementing social distancing to flatten the pandemic’s curve. At some point, the population will need to resume normal life. Large-scale antibody testing can help officials determine when it’s safe to limit social distancing and allow people to return to work and public activities. In particular, the test can help determine which frontline health care providers were infected and developed immunity to the virus, so they can continue fighting the virus without endangering patients or their health.

Finally, antibody tests can identify recovered patients with high levels of antibody response. The antibodies in their blood can be harnessed through “convalescent plasma” to potentially treat patients with severe COVID-19. This investigational treatment may lead to the end of the pandemic, but further research is needed.

The tests have limits. Negative antibody test results cannot rule out infection with COVID-19 since immunity typically occurs after a few days of infection. Furthermore, NAAT testing is required to confirm the infection. Little data exists on how long antibody-mediated immunity lasts. Last, but not least, the reliability of the test must be proven. How do we know that patients are not responding to other kinds of coronavirus? Are laboratories in different countries using the same standard to design the antibody test and evaluate its results? Standard protocols need to be developedand are currently being assessed, in particular by the Foundation for Innovative New Diagnostics (FIND) jointly supported by WHO and the Bill and Melinda Gates Foundation. Future research and clinical trials must support the use of antibody blood tests.

Why are there big differences in mortality rates for this new coronavirus from one country to another; what is the contribution of virus genetic variability?

Keep in mind that we do not know the actual mortality rates of COVID-19, because the number of all infected individuals is still unknown. Yet, the number of confirmed deaths do seem to vary widely among countries, ranging from 0.7% in Germany to as much as 10% in Italy and Spain. We do not precisely know why — but clearly, the age of infected populations and testing strategies are key. SARS-CoV-2 appears to have targeted a group of young adults in Germany (in particular contaminated when skiing) versus an elderly population in Italy. Moreover, Germany immediately recognized the need to test individuals with mild symptoms and their contacts, not just focus on those with pneumonia.

Are some genetic variants of SARS-CoV-2 associated with higher mortality?

We do not know for sure, but this is emerging as an important issue to solve. Keep in mind that any virus, especially an RNA virus, generates a large number of genetic variations, or mutations, when multiplying due to “errors” in replication of the viral RNA polymerase. Moreover, such mutations can induce selective advantage or disadvantage to the virus and thus be selected or counter-selected as a result of natural evolution of the infection – but also in response to treatments and/or containment measures.

So, mutations will be detected. The more pertinent question is how relevant are they are to the clinical, virological and biological patterns of the COVID-19? The impact of the mutations will depend on which viral genes are affected by the mutations. For instance, changes in the “spike” encoding proteins may influence how the virus binds to its cellular receptor and, therefore, the type of cells infected by the virus (known as cellular tropism). Mutations in the viral polymerase may change the level of viral multiplication, while other mutations in viral proteins might affect immune response to the virus.

We are still at the early stages of this global pandemic, but the overall genetic variability of the virus seems low. If this holds true, it may markedly benefit the effectiveness of treatments and the future success of vaccines.

Two intriguing studies from China – one an accepted paper and the second a preprint – are based on variations in functional sites of the receptor-binding domain (the spike viral proteins). The researchers suggest that at least two major forms of the virus have been circulating. These two “genotypes” are very closely related. One study refers to the two genotypes as “Types I and II” and the other study refers to the “S and L” forms. The researchers suggest that L (or Type II) was more prevalent during the burst of the aggressive epidemics in Wuhan, while the S (or Type I) form induces less severe infection and may spread more quickly worldwide. This observation may help explain severity of the COVID-19.

But, even more provocative, the researchers hypothesize that the S strain might have preexisted in China in humans before the epidemics were identified and that the more recent L strain appeared through mutations and selection of the variant. If confirmed, this observation might also have a big impact on vaccination-based strategies. It raises the theoretical possibility of antibody-dependent enhancement whereby (as with dengue fever) antibodies to the virus induced by the first infection would not protect against a second infection, but actually make it worse. This hypothesis has already been brought up for other coronaviruses, such as MERS-CoV. In any case, some GVN members have emphasized the need for prudence before vaccinating the general population.

Other studies have described mutations in other regions of the SARS-CoV-2 genome, particularly in genes affecting the structure of the viral particles. Observations from GVN centers in Italy indicate the presence of mutations in the viral RNA polymerase that may lead to increased rates of viral replication.

All these observations still need to be proven. As we read the research literature on COVID-19, it is important to remember the evidence we still need — mutations in cultured cells to demonstrate their effect on viral multiplication and good, methodical clinical studies to determine if and how the mutations affect humans. This will only be achieved through international collaboration, data sharing, and the simultaneous study of host and viral genomes.

Christian Brechot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

Linman Li, MBA, MPH, PMP, CPH
Associate Director, USF Medicine International
USF Health Morsani College of Medicine
Vice President, Global Virus Network

 

 

 

 

March 25, 2020

“Invulnerable” young adults not only contribute to pandemic’s spread; substantial numbers suffer respiratory distress

As of March 24, over 375,000 coronavirus cases and more than 16,300 deaths were reported from 196 countries, according to the World Health Organization. Last week, China reported no new cases from Wuhan, the epicenter of the outbreak. In contrast, Italy had exceeded the total number of deaths in China. It has been clear from the beginning of this pandemic that the death rate increases very significantly in old and fragile individuals. This led many to consider that young infected patients are primarily “carriers” of the virus, contributing only to transmission of the infection and suffering few ill effects themselves.

Many young adults still believe that they are invulnerable or even immune to the virus (currently no vaccine against the respiratory illness COVID-19 exists), and they tend to ignore social isolation or physical distancing. But a more disturbing reality is emerging as the pandemic evolves; a significant number of infected young persons have been hospitalized for respiratory distress, including many requiring critical care in ICUs.

Indeed, the most recent Epidemiology Report from Australian Government Department of Health indicates that the highest proportion of the country’s 295 confirmed coronavirus cases affect people ages 20 to 49. Also, 47.5% of hospitalized patients in Australia are people ages 20 to 49.  In Italy, 50% of those hospitalized in ICUs were younger than age 50 – and in France as well.  Similarly, in the U.S. more than half of all confirmed cases in New York are in people younger than age 49.

The most recent study from the U.S Centers for Disease Control and Prevention shows that about 20% of hospitalized patients are ages 20 to 44. Although the study has limitations, such as not identifying whether these young patients had underlying conditions, the risk of getting sick or even dying should be highly considered by all ages.

Some may argue that the chance of otherwise healthy young adults developing severe symptoms is still relatively low — but is this a risk young adults are willing to take?  Even if they are unconcerned about their own susceptibility, it’s important for young people to recognize that this highly contagious respiratory virus can infect anyone and even those without apparent symptoms can accelerate its spread to family, friends or others. Ignorance of social distancing puts other vulnerable groups at risk. This pandemic has become the touchstone to test individuals’ values, principles and social responsibilities. We’re all in this together, so let’s all stay socially isolated to protect the medically vulnerable, help limit disease spread and reduce the strain on our health care system.

An all-out scientific push to find drugs and a preventive vaccine to treat SARS-CoV-2

No current treatment specifically targets this new coronavirus, SARS-CoV-2, or the closely related SARS-CoV-1 virus. We remain hopeful that the huge drug discovery effort underway will lead to new compounds. However, given the time required to develop safe and effective new drugs, such compounds will not be available in time to curb the present pandemic. Also, despite fantastic work being done to design vaccines against SARS-CoV-2, this form of immunotherapy will, at best, take around 18 months to become available. In fact, several scientists with the Global Virus Network have pledged to take the time needed to evaluate any promising vaccine candidates in animal models before vaccinating humans. This preclinical testing is critical to avoid severe vaccine side effects, such as those encountered with dengue virus – namely, the generation of antibody-dependent enhancement that can lead to increased infection. In this context, repurposing drugspreviously FDA-approved for other diseases or pathogens is our best chance.

Here’s the good news. We can use existing antiviral drugs that directly inhibit the replication machinery of the virus, such as remdesivir, faviparavir, lopinavir, or others. Several of these have been used to treat HIV. Some limited studies suggest that remdesivir works in COVID-19 patients with severe respiratory distress.

We can also investigate new uses for old drugs that target infected human cells, limiting the ability of the virus to enter and replicate in the cells. Chloroquine and its derivative hydroxychloroquine – extensively used in the past to treat malaria – are at the forefront of this class of molecule. Several small studies point to chloroquine’s effectiveness in reducing the concentration of viral particles (viral load) and how long the virus stays in the bloodstream (viremia) – both key to controlling the disease and the pandemic. One highly referenced, but very small, French clinical trialcombined hydroxychloroquine with an antibiotic to treat patients with COVID-19, and reported promising preliminary results. Some controversy continues about possible side effects. Chloroquine has accrued a very good safety profile in combatting malaria over many years; however, most treated populations have been young. Could the antimalarial drug cause toxicity in elderly persons (in particular those with cardiac arrhythmias), especially when a high dose is needed to efficiently control viral multiplication? The U.S. and several other countries are launching randomized controlled studies to carefully answer this question.

It may be too late in the disease process if we only aim to target the virus. Solid evidence now indicates that immune response and associated inflammation generated by the coronavirus play a major role in the so-called “cytokine storm,” an immune system overreaction driving lung pathology and acute respiratory distress. The interleukin 6 (IL6) cytokine has been identified as an important driver of this harmful inflammation. Also, the risk of long-term respiratory sequelae, such as lung tissue damage and scarring, following apparent recovery has become a concern, although not yet well documented. Interestingly, some studies suggest that monoclonal antibodies inhibiting the activity of the IL6 receptor (i.e., the immunosuppressant tocilizumab) might very significantly benefit those patients with respiratory distress. These drugs have so far been used to treat polyarthritis and an acute systemic inflammatory syndrome (called cytokine release syndrome) caused by CAR-T cell therapy, illustrating the impact of an unbiased repurposing strategy.

Clearly modifying immune response must be carefully evaluated.  We have learned when treating patients with sepsis how difficult it can be to control potential side effects. It’s worth noting that preliminary evidence indicates corticosteroids may help those patients with severe respiratory failure — although these inflammation-lowering drugs were initially thought to be toxic, based on previous experience with influenza.

In addition, more upstream research is being conducted to neutralize the virus through antibodies obtained either by molecular biology or even from blood plasma of recovered patients; it is still too early to evaluate the benefits and risks of this approach. (Yesterday, the FDA announced it would expedite treatment of seriously ill COVID-19 patients with this “convalescent plasma.)

Beyond therapeutics against coronavirus, it would be great to provide preventive therapies (prophylaxis) to those with a high risk of infection (such as health care workers) and/or with a high risk of very severe disease (such as nursing home residents). But more data needs to be obtained for prophylactic therapies; with this view, and with further testing, chloroquine and hydroxychloroquine may offer an interesting opportunity, as well as nitazoxanide, a widely used antiparasitic drug with an excellent safety profile and laboratory (in vitro) evidence of its effectiveness against coronaviruses and SARS-CoV-2.

Overall, we have many therapeutic options to pursue with a real chance of success in saving COVID-19 patients from serious harm or death. And, any molecules proven effective will likely need to be combined – attacking the virus on multiple fronts — for optimal treatment of COVID-19.

Christian Brechot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine
President, Global Virus Network

 

 

 

 

 

March 18, 2020

New Findings on Coronavirus

The pandemic caused by SARS-associated coronavirus 2 (SARS-CoV-2) has become a stark reality, and the University of South Florida remains at the forefront of measures aimed at curbing its rapid spread. Leadership continues to closely monitor the evolving coronavirus (COVID-19) outbreak and to provide excellent ongoing communication on the crisis.

In my role as USF Professor and President of the Global Virus Network (GVN), a network of around 50 research centers worldwide, I will work with Linman Li of USF Medicine International (now being recruited as GVN Vice-President) to update you weekly on new findings about the coronavirus pandemic disrupting our lives. Our comments are not intended to replace documents and information issued by USF and USF Health on COVID-19, including the expertise shared by our USF Health Department of Internal Medicine infectious disease colleagues (Seetha Lakshmi, John Sinnott, Asa Oxner, and Kami Kim). Also, with the situation rapidly changing, we wish to emphasize that there is still much to learn about the epidemiology of this virus and how it causes infection.

USF Health’s Christian Brechot, MD, PhD, is president of the Global Virus Network

Epidemiology: Getting the “denominator” right in mortality rates

The mortality rate of this novel coronavirus infection will clearly be lower than estimates currently reported when we actually identify the overwhelming number of infected individuals. That’s because many with very mild or no clinical symptoms will then be counted and added to the overall number of cases encompassed in the “denominator” used to calculate a coronavirus mortality rate. (The numerator is the number of coronavirus deaths reported.)

Yet, recent information indicates that SARS-CoV-2 is highly contagious, with an R0 number (average number of individuals contaminated from a single case) possibly as high as 5 or 6. Under these circumstances, even though mortality rates may be lower than 0.4-0.5% overall, the dissemination of the virus worldwide (with potentially hundreds of millions of cases) will could have a massive casualty rate. COVID-19 will mostly kill old and fragile individuals (present estimates climb from around 2-3% after age 65 to 10% after age 80) — but a number of younger and apparently healthy persons will also die from the virus.

The pandemic threatens to completely overwhelm our health systems and lead to many uncounted side effects for patients with unrelated diseases who will not be correctly treated. This is why we must curb the pandemic now, and there is only one way — social isolation, that is, separating infected people from healthy people. The good news is that this method works: China has obtained a massive reduction of new infections. And in Codogno, the city where a coronavirus epidemic initiated in Northern Italy, a drastic lockdown has led to a very significant reduction of new infections after three weeks. How long should a lockdown last? This is a difficult questions, but governments should consider at least maintaining aggressive measures for about two months.

Linman Li of USF Medicine International

Pursuing treatment options

Several coronavirus vaccines are in different stages of development. When proven successful and approved, a vaccine will be very useful in combating any reemergence of SARS-CoV-2 — but it is not available to help us now. The scientific community worldwide is stepping up both to develop new therapeutic molecules and to repurpose drugs currently used for other diseases. The Global Virus Network is at the forefront of this ambitious task, synergizing the activities of the GVN centers and providing input to complement the efforts of national and international research agencies.

No antiviral therapy exists specific to either this new coronavirus, SARS-CoV-2, or the original SARS virus, SARS-CoV, which caused a swift global outbreak in 2003. That is why some clinical studies are testing antivirals proven to be effective for other viruses, in particular, retroviruses such as HIV. A complementary approach is to target the immune response, which clearly plays a critical role in the development of an acute respiratory syndrome in certain patients (to be further explained in the next blog).

Earlier this month, an international preclinical study published in Cell offered some good news. Researchers already knew that SARS-CoV uses the angiotensin-converting enzyme 2 (ACE2) to enter cells. A complex and multistep process allows SARS-CoV cell entry and infection to happen. It involves binding of the “spike” of the coronavirus (the viral S protein) to the ACE molecule and then cleavage of this S protein by a cellular serine protease known as TMPRSS2. The new study shows the same process holds true for SARS-CoV-2.  Most importantly, the researchers demonstrated that a molecule inhibiting TMPRSS2 activity – a protease inhibitor previously used for another clinical indication in Japan — can block the infection of human lung cells. Also, antibodies obtained from patients who recovered from SARS-CoV-2 infection can block entry of the virus, thus providing a neutralizing action. This promising work defines potential treatment targets that may protect against SARS CoV-2 infection.

Christian Brechot, MD, PhD
Senior Associate Dean for Research in Global Affairs, USF Health Morsani College of Medicine
Associate Vice President for International Partnerships and Innovation, USF
Professor, Department of Internal Medicine

Dr. Brechot has served as president of the Global Virus Network since 2017, and is past president of the world-renowned Pasteur Institute.