Bringing Clinics and Hospitals Up to Speed: Why the right testing strategy will help us reopen our medical facilities amidst COVID-19 pandemic

By Rashid A. Chotani

To meet COVID-19 head-on, the American medical community has had no choice but to make the pandemic our primary focus. We have been forced to retool our hospitals by opening more beds, canceling elective procedures (including non-emergent surgeries), converting operating rooms for intensive care units, and a whole lot more.

But we are beginning to see that turning our attention away from other illnesses and conditions comes at a serious cost; an analysis by The New York Times demonstrates that more Americans have died of non-COVID-19 causes in the first one-third of 2020 than in the first one-third of 2019. Were these deaths also the result of COVID-19, and simply not recorded as such? Or have we been paying so much attention to COVID-19 that we have neglected other threats?

 

As we continue our fight against this pandemic, we must adapt to meet the needs not only of those infected with SARS-CoV-2 (the coronavirus that causes COVID-19), but also of those Americans who necessitate medical help unrelated to the pandemic.

A vital step forward is reopening our hospitals and clinics for elective surgeries and other procedures that cannot be handled via telemedicine. But is this a step we can safely take? A recent report from Nature suggests that as many as 40% of infections occur in the days before patients become symptomatic themselves; in order to safely reopen our hospitals, we need to make sure that doing so won’t precipitate the resurgence of the disease.

 

We argue that a vital approach to keep this risk down is to adopt an intelligent testing strategy for SARS-CoV-2. This strategy must achieve two goals: We must test patients to keep our hospital staff safe, and test hospital staff to ensure infection does not transmit from the hospital back into the community.

 

The first challenge is to reduce the risk that an asymptomatic patient will accidentally spread the virus when coming in for an elective procedure. The currently available tests will not catch every such case, but they can identify the vast majority. When coupled with the use of personal protective equipment (PPE) – which is no longer as scarce as before – such screenings could make a considerable difference in our ability to reopen.

 

Testing asymptomatic patients requires that we use different types of tests and interpret them together to achieve higher accuracies. The Polymerase Chain Reaction (PCR) testing for viral RNA is the first test to become positive, doing so around 4-5 days after infection, but it also has a high false negative rate and becomes less accurate over time. By contrast, antibody testing typically starts to catch positive cases by day 7 after infection, but becomes increasingly accurate over time. By testing patients on the day before or day of their procedures, we are more likely to catch asymptomatic cases.

 

Testing medical staff represents a different challenge. Regular testing of large asymptomatic groups can entail a logistical and financial burden upon the hospital or clinic. To meet this challenge, two plausible solutions are point-of-care antibody testing and pooled testing.

 

The point-of-care (POC) antibody testing approach has the ability to test large numbers of suspected cases even without swift access to a central laboratory. Although positive POC antibody test results would require confirmation by PCR or laboratory testing, the team can take provisional protective actions while awaiting those results. Additionally, antibody screening can reveal the prevalence of prior infections and shed light on the prevalence of SARS-CoV-2 in the overall population being examined.

 

The alternative solution entails the use of “pooled testing” that enables the testing of large groups with relatively few tests. The concept is simple: instead of testing each individual separately, the samples from a large number of individuals are divided into a few groups, so that fewer need to be run. If the test is negative, the entire group is considered free of the virus; if the group is positive, subgroups are then tested until the positive individual or individuals are successfully identified.

Recent experience shows that a single positive result from RNA testing will still test positive after the addition of 63 negative samples. Once we have tested enough to understand which populations are at a higher or lower risk, we can then tailor the size of each testing group accordingly, thereby further minimizing the number of tests. The use of pooled testing shall enormously reduce the burden on healthcare amidst this pandemic.

There is no doubt that for our health system to work, it must not only meet the demands of COVID-19 patients, but concurrently be able to continue to treat other unrelated illnesses and injuries. Hospitals and clinics must reopen. But to reopen safely, they must employ intelligent testing strategies that embrace both viral RNA and antibody testing. Only then can we provide great care that defies SARS-CoV-2.

Dr. Rashid A. Chotani is a physician scientist and infectious disease epidemiologist. He holds appointments as the Medical Director at IEM and VP Medical Affairs at CareLife Medical, with extensive experience in outbreaks, epidemics and pandemics. Contributing Team:

Syed S. Ashraf, Charlie Maze, Faisal H. Cheema, & Terry Clark Dr. Syed S. Ashraf is a Board-Certified Internist and Managing Partner at Carelife Medical in Northern Virginia providing clinical guidance and expertise for COVID-19 screening process. Dr. Charles Mize is the Chief Medical Officer for U.S. Health Defense and is an Emergency Medicine specialist with extensive international and medical policy experience. Currently he is providing emergency medicine care in Alaska and is actively involved in developing COVID-19 treatment protocols for different organizations.

Dr. Faisal H. Cheema is a physician scientist, specializing in basic sciences and transitional & clinical research. He holds a research leadership position in a large health system and also has a faculty appointment at the University of Houston College of Medicine Dr. Terry Clark is a General Surgeon, Fulbright Scholar, Executive VP, & Chief Medical Officer for Boston Biopharma. Boston Biopharma is providing point of care antibody testing test-kits for COVID-19.

'Immunity passport' key to containing spread of coronavirus 

By Rashid A. Chotani & Syed S. Ashraf & Charlie Mize & Terry Clark 

April 30 (UPI) -- Imagine yourself in one of these scenarios. First: you direct a food preparation and delivery service. You know that some of your employees have likely had COVID-19 in the past but many have not. Would it be safer to send out on delivery those who have recovered from infection and are no longer infectious? If so, how do you determine who they are? 

Second: You are in charge of immigration and tourism for an island country. You would love to have visitors, but not those that are going to bring the virus back on shore. How can you prove that those entering are not infected? Or are immune to infection? 

Last: You and your team of doctors and nurses need to treat highly contagious COVID-19 patients requiring life support. You know some of your team has likely had the infection and recovered. Would it be safer for the doctors and nurses who have recovered from infection to treat those who severely ill and contagious? And if so, how do you find them? 

The solution to these problems and others like them is an "immunity passport," the demonstrated proof of immunity to SARS-CoV-2 by either recovery or vaccination. To find this proof, we need a test for both the virus and for immunity. The ideal test would be one that detected disease shortly after infection but before a patient became contagious -- and one that could demonstrate whether a patient had recovered from infection and was now immune. 

There are several tests available for COVID-19 and in isolation all of them fall short of this ideal. However, we get much closer when we look at each test and fit them into a diagnostic framework built upon our growing understanding of the coronavirus and our immune response to it. What's more, joining different types of tests into a single approach provides us new insights into how COVID-19 behaves -- and how we can fight it. 

The first available test and the test recommended by the Centers for Disease Control and Prevention and the World Health Organization is called Polymerase Chain Reaction testing. This testing -- also called antigen testing -- detects the virus' genetic code, or RNA, in a patient's nose or saliva. It is a simple concept and positive results are generally true. 

But the test is far from perfect. It requires special training to perform, special equipment to process and exposes those conducting the test to the virus. Then there's the question of its accuracy. If we test too early or too late, the test can miss the virus. Perhaps the immune system has removed enough of the virus to make it hard to detect, or maybe the amount of virus during the days after infection is too low to detect. 

Sometimes the test isn't performed just right and so the results are less accurate. When we receive a negative test, it isn't clear what to do. Is the test a true negative or an error? And if accurate, that negative does not tell us if a patient has been infected and recovered or if the patient has never been infected at all. Without that knowledge, it is impossible to know how much of the population has been infected and recovered, and if enough of the population is recovered to provide "herd immunity." Clearly, we need more than this PCR RNA testing if we are to move forward. 

The other class of COVID-19 tests look for human antibodies to the coronavirus. Antibodies are proteins made by the human body to target and neutralize the virus. There are different types of antibodies, but most tests look for an antibody called IgM, which the body produces first, during active infection, and IgG, which the body creates later as part of a sustained, long-term immune response. These tests have the benefit of being easy to perform, fast, and in many cases can be more accurate than PCR RNA. 

The human body builds more and more antibodies as infection continues, which means that antibody testing becomes more accurate as time passes, unlike PCR. There's also the ability to demonstrate immunity. In the case of many other infections, the identification of IgG in the blood indicates that a person is immune. For example, with varicella zoster, the virus that causes chickenpox and shingles, as well as measles, mumps, rubella and hepatitis A (just to name a few diseases) the detection of IgG antibodies is proof of immunity. In the case of COVID-19, it is very likely, but not yet proven, that IgG will similarly demonstrate immunity. We do not know how long that immunity will last, or whether the virus' mutations will allow it to escape the immune system, like influenza does. But the only way to know is to use these tests and study them. 

Some have dismissed antibody testing as insufficiently accurate, with no role other than general population surveillance. They have deferred wholesale to antigen testing. The assumption of RT-PCR as being a "gold standard" must be clarified. PCR technology is well established, but PCR nasal or oral swab for COVID-19 diagnosis is new and authorized under emergency like the serologic antibody tests. 

However, the ability of either test to predict disease will vary on the prevalence of COVID-19 in the community, no matter how it is conducted. Moreover, we have seen that testing for viral RNA alone has severe drawbacks -- a limited accuracy that can diminish over the course of illness and an inability to reveal anything about immune response. 

Antibody response is also imperfect, but the caliber of antibody testing is improving, and when combined with RNA testing and clinical judgment, we can advance an understanding of the coronavirus impossible with the use of either test in isolation. But antibody testing is key. Only through a study of the body's antibody response and through continued use of antibody testing will we answer the important questions: Can we become immune? And can 

we prove immunity through intelligent testing? The right solution under the present crisis is to gain as much insight so we can make better informed decision. 

Dr. Rashid A. Chotani is an infectious disease epidemiologist and chief science officer at CareLife Medical. Dr. Syed S. Ashraf is a board-certified internist and managing partner at Carelife Medical. Dr. Charles Mize is the chief medical officer for U.S. health defense and is an emergency medicine specialist. Dr. Terry Clark is a general surgeon, Fulbright scholar, executive vice president and chief medical officer for Boston Biopharma. 

 

 

Source: 

https://www.upi.com/Top_News/Voices/2020/04/30/Immunity-passport-key-to-containing-spread-of-coronavirus/1961588246960/?upi_ss=Chotani 

Position Paper 

The Testing Debate for COVID-19: PCR vs. Rapid Antibody Test: How Rapid Antibody Testing can Identify Potential Immune Patients Quickly 

 

Rashid A. Chotani, MD, MPH, FRCPH, Chief Science Officer & VP Medical Affairs, Carelife Medical 

Syed S. Ashraf, MD, FHM, Chief Administrative Officer, Carelife Medical 

Fatima Aziz, MD, Senior Medical Director, Carelife Medical 

Terry Clark, MD, Executive VP & Chief Medical Officer, Boston Biopharma 

Charles Haviland Mize, MD, Bear/Badger Expeditionary and Retrieval Medicine 

 Knowledge and clarity empower rational action. The COVID-19 pandemic demands a powerful response, but the absence of a clear understanding of the virus has hamstrung governments' ability to act. The COVID-19 pandemic has now affected over 200 hundred countries and caused disease in over one million, resulting in close to 53,000 deaths. According to the Johns Hopkins Coronavirus Resource Center, United States has the largest number of cases (over 245,000) with close to 6,000 deaths and an epicenter of the disease in New York State (~ 93,000 cases and over 2,500 deaths). The quarantine, staying-home and social-distancing measures instituted throughout the states will help curb the epidemic. These measures are important and powerful tools to slow viral transmission. In of themselves, however, they do not help decision-makers determine the true extent and spread of the disease, nor how best to prepare to meet it. Rapid screening for disease is the cornerstone of curbing an outbreak, because such screening affords an understanding the epidemiology of the virus. Armed with this knowledge, public health policymakers are in a stronger position to more accurately assess and implement strategically meaningful interventions. 

 

The nation struggles with the question “To Test or Not” for COVID-19. Testing for SAR-CoV-2 in the US appears to be controversial. The concerns arise from a poor understanding of the testing process and the consequences test results may have on staffing and employment. Fundamentally, however, the implications of testing are far-reaching and concern more than the single individual and a single test. Widespread testing is what enables us to discern disease incidence and prevalence, and to determine who has recovered from infection and is now immune. The faster we can clear individuals from active disease state, the faster we can mitigate the socio-economic downturn and social disruption. In order to do so, we need the ability to clearly identity the following categories of patients: 

1. Exposed and now infected (at risk) 

2. Infected but asymptomatic (infectious to others) 

3. Infected and symptomatic (sick and infectious) 

4. Infected and recovered (developed immunity) 

Testing that can place patients into one of these categories will allow us to understand if someone is contagious (shedding virus) or non-contagious (not shedding virus). Furthermore, such testing will inform us if an individual has developed a certain level of immunity. 

Multiple testing modalities are being used or have recently been developed, to include RT-PCR for viral RNA and rapid antibody testing. Neither of these tests are perfect; alone can provide neither 100% sensitivity nor specificity. PCR tests for viral presence, which can vary between patients depending viral load and the patient’s degree of exposure. Variability in viral load as well as poor swab technique during testing can lead to false negatives. Administration of the test puts staff at risk because it requires removal of a patient’s mask and can cause the patient to sneeze or cough. Furthermore, recent studies have demonstrated that PCR, which has been considered the “Gold Standard,” has a high false negative rate, up to 30%. This false negative rate suggests that a third of covid-19 suspected individuals tested negative by PCR may continue to carry and transmit COVID-19 unaware of the risk they pose to others. Moreover, PCR testing requires special equipment and special training, and can provide results only days after testing. By contrast, serologic immunoassay via IgM/IgG is a simple point-of-care, cost-effective test using a finger-stick blood drop. It provides results within minutes and can be used to conduct serial monitoring of populace to see who has been exposed to COVID-19. Importantly, antibody testing allows clinical decision makers to determine who is now clear of active disease and can return to work. 

We have been using a rapid antibody IgM/IgG test by Boston Biopharma that has been FDA-approved for sale and is under evaluation for emergency use authorization like most rapid tests available currently. After consideration of the sensitivity/specificity of the PCR test, the inherent danger of spreading the virus during the nasal swabbing, and the test’s cost and inconsistent turnaround time, we believe that a rapid antibody test is the better tool to empower our public health. The antibody test for IgM and IgG detects the humoral response (in immuno-competent people) and exposure prevalence. Known immunologic graphs correlate IgM rise with symptom development in covid-19 patients (roughly ~4-7 days since exposure event) and, additionally, the IgM response may be present in asymptomatic patients. IgG indicates longer-term immune response. 

It is important to note that no test on its own can determine patient infectious status. To be effective, testing must be conducted within a clinical screening and evaluation process. Based on our experience, antibody testing is easier to administer, is a better point-of-care (POC) tool, and adds further critical information to that of RT-PCR alone. 

Disagreement over testing methodology stems from the evolving understanding of COVID-19 and the varying knowledge of virology by those crafting the public response. It is clear that a stay-home policy without a means to survey the US population and “clear” individuals of active disease state would be detrimental to the American economy and would create further social disruption and anxiety. This toll on staffing is especially important in the healthcare setting. The use of social distancing and isolation measures in democratic nations have yielded favorable outcomes and have been able to “flatten the curve.” However, the ability to identify individuals who are IgM (-) and IgG (+) is critical if we are to return to some normalcy and reassure labor force mobility. Table 1 describes the various scenarios and the potential outcomes.

 

At present, there are no definitive nor specific therapeutic agents or vaccines, despite the tremendous commitment to their research and development. While we wait, the disease continues to cause significant morbidity and mortality. Antibody testing affords another benefit: the identification of patients who have recovered from the infection and who are able to provide their own antibodies to others in the form of convalescent plasma. During the 2014 Ebola outbreak, convalescent plasma was recommended as an empirical treatment, and a protocol for treatment of Middle East Respiratory Syndrome (MERS) coronavirus with convalescent plasma was established in 2015. Other studies for viruses such as SARS-CoV, H5N1 avian influenza, and H1N1 influenza suggest the effectiveness of transfusion of convalescent plasma. (1,2,3,4,5) A recent uncontrolled case series of 5 critically ill patients study published by Chenguang Shen et al in JAMA suggests that convalescent plasma transfusion may help in the treatment of critically-ill patients with COVID-19. While awaiting confirmation in randomized clinical trials, the approach continues to hold much promise. (6) 

Conclusion: 

Rapid POC antibody COVID-19 specific testing is the best means at our disposal to improve our epidemiologic understanding of the virus and to empower a robust public health response. The ability to determine immunity will enable us to safely restore our economy. This will further permit safe and cost-effective way to create a registry of immune individuals whereby enabling collection of convalescent plasma, a possible treatment for patients critically ill with COVID-19. 

References: 

1. Kraft CS, Hewlett AL, Koepsell S, et al; Nebraska Biocontainment Unit and the Emory Serious Communicable Diseases Unit. The use of TKM-100802 and convalescent plasma in 2 patients with Ebola virus disease in the United States. Clin Infect Dis. 2015;61(4):496-502. 

2. van Griensven J, Edwards T, de Lamballerie X, et al; Ebola-Tx Consortium. Evaluation of convalescent plasma for Ebola virus disease in Guinea. N Engl J Med. 2016;374(1):33-42. 

3. Florescu DF, Kalil AC, Hewlett AL, et al. Administration of brincidofovir and convalescent plasma in a patient with Ebola virus disease. Clin Infect Dis. 2015;61(6):969-973. 

4. Zhou B, Zhong N, Guan Y. Treatment with convalescent plasma for influenza A (H5N1) infection. N Engl J Med. 2007;357(14):1450-1451. 

5. Hung IF, To KK, Lee CK, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011;52(4):447-456. 

6. Chenguang Shene et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. Published online March 27, 2020. doi:10.1001/jama.2020.4783. 

Rashid A. Chotani, MD, MPH rashid@carelife.md | Office: 703-854-1298 | Mobile: 571-425-9730 

Boston Biopharma. March, 2020.

COVID-19 is spreading at a rapid pace throughout the United States and Western Europe. Fragmented strategies of banning travel, social distancing, and quarantine have provided little avail in slowing the steep upward trajectory of daily exponential growth rates. Waiting for a vaccine to become available or for the majority of the population to develop herd immunity, characterized by 70-80% infected and recovered, are the pivotal turning points we strive for in the fight against COVID-19. With positive cases dispersed geographically throughout the world, completely stopping the infection is highly improbable. Efforts to slow transmission in an attempt to prevent overwhelm of our healthcare systems is the primary plan of action for developed countries. 

 

Finding a balance between our current methodology of testing, performed in the laboratory and rapid tests capable of producing real time results in the field, will allow for a broad spectrum COVID-19 testing. Current testing takes a few hours to be completed per sample, but backlogs of tests has shifted time estimates for results to a few days following initial sample collection. Additionally, shortages in testing kits has resulted in a formalized symptom-driven guidance as to which patients can be tested. Test kits are being rationed for those presenting with acute respiratory distress, fever, and associated severe clinical sequeale. Testing only those exhibiting substantial symptoms not only negatively skews overall infection rates, but prevents classification of asymptomatic individuals capable of transmitting the virus to the surrounding population without detection. As a means of augmenting the bottleneck of testing required to support largescale population testing, BB has developed a rapid test kit available for use by clinicians and medical staff. 

 

Finding alternative testing options that allow for rapid and on the spot results can allow Physicians to implement broad spectrum testing to individuals both asymptomatic and those actively exhibiting symptoms associated with COVID-19. Rapid tests for SARS-CoV-2 specific IgM and IgG using immunohistochemistry via whole blood, plasma, or serum sample analysis are currently in development. This rapid testing platform can be implemented for screening at border crossings, and pop-up medical testing facilities in order to screen mass numbers of potentially infected individuals. 

 

BB COVID-19 test kits applied will assist in decreasing the total morbidity and mortality suffered by society in this global pandemic. Flattening the curve using rapid clinical testing side by side with the current standard laboratory test can help to shape a new reality of hope that we are all desperately searching for.