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SARS-CoV-2 (COVID-19) RESEARCH ARTICLES
CONTENTS
JOURNAL EDITORIAL STAFF
EDITOR D. Luke Glancy, MD
ASSOCIATE EDITOR L.W. Johnson, MD
CHIEF EXECUTIVE OFFICER JeffWilliams
3 EDITORIAL: COVID-19
JOURNAL EDITORIAL BOARD Vice Chair, K. Barton Farris, MD Secretary/Treasurer, Richard Paddock, MD
4 THE RESILIENCE OF OUR STATE
Anthony Blalock, MD D. Luke Glancy, MD L.W. Johnson, MD Fred A. Lopez, MD
5 COVID-19 : EPIDEMIOLOGY, CLINICAL PRESENTATION AND PROGNOSIS
LSMS 2021 BOARD OF GOVERNORS OFFICERS President, William Freeman, MD Past President, Katherine Williams, MD President-Elect, John Noble, Jr., MD Vice President, George Ellis, Jr., MD Speaker of the House, T. Steen Trawick, MD Vice Speaker, R. Reece Newsome, MD Secretary/Treasurer, Richard Paddock, MD Chair, COL, David Broussard, MD
12 DIAGNOSTIC APPROACH TO COVID-19
16 PREVENTIONAND TREATMENT OF SARS-CoV-2: ANUPDATE
24 COVID-19 AND CARDIOVASCULAR DISEASE
31 THE EFFECTS OF THE COVID-19 PANDEMIC ON THE UNDERGRADUATE MEDICAL EDUCATION EXPERIENCE AT LOUISIANA STATE UNIVERSITY SCHOOL OF MEDICINE IN NEW ORLEANS
COUNCILORS District 1 Member, Vacant
District 1 Alternate, Maurice Sholas, MD District 2 Member, Robert Chugden, MD District 3 Member, Allen Vander, MD District 4 Member, Richard “Rick”Michael, MD District 5 Member, Gwenn Jackson, MD District 6 Member, Michael Roppolo, MD District 7 Member, Brian Gamborg, MD District 8 Member, Lance Templeton, MD District 9 Member, Andy Blalock, MD District 10 Member, Nicholas Viviano, MD District 10 Alternate, James Connolly, MD SECTION REPRESENTATIVES Senior Physician Member, Marcus Pittman, III, MD Senior Physician Alternate, Donnie Batie, MD Young Physician Member, Amberly Nunez, MD Resident/Fellow Member, Blake Denley, MD Medical Student Member, Brittany Wagner Employed Physician Member, Bennett Schmidt, MD Private Practice Physician Member, Vicki Steen, MD
36 AN INTERNAL MEDICINE RESIDENCY RESPONSE TO THE COVID-19 PANDEMIC IN LOUISIANA
44 LEADERSHIP IN THE TIME OF COVID
EDITORIAL: COVID-19 TheCOVID-19pandemichasdisruptedvirtuallyall aspectsofhumanactivityworldwidemore than any other catastrophes in the past 100 years, with the possible exception of the two world wars. COVID-19 is a viral disease that is highly contagious and often lethal, especially to elderly persons with underlying disease. Because little is known about many aspects of the disease, Jeff Williams and I decided to devote an entire issue of the Journal of the Louisiana State Medical Society to COVID-19. Fortunately, Fred Lopez, M.D.
of the LSU Health Sciences Center in New Orleans, an internationally recognized expert in infectious diseases, agreed to be the editor of this issue, and he has assembled other experts to contribute. All of us, regardless of our medical specialty, need to know more about COVID-19, and this issue of the Journal provides a good starting point in this endeavor.
D. Luke Glancy, M.D. Editor-in-Chief
3
THE RESILIENCE OF OUR STATE Fred A. Lopez, MD, MACP
Several years ago, I wrote a guest editorial entitled “Infectious Diseases in the 21 st Century: No End in Sight.” 1 In it I quoted Dr. Robert Petersdorf, a legend in the field of infectious diseases, who wrote in the late 1970s, when referring to graduating fellows in infectious diseases: “Even with my great personal loyalty to [the discipline of] infectious diseases, I cannot conceive of a need for 309 more infectious diseases experts unless they spend their time culturing each other.” 2 Times have definitely changed. Over the past four decades or so, the advent of AIDS and hepatitis C, enhanced vaccine development, the impact of multidrug-resistant bacteria, foodborne epidemics, the emergence of infections due to pathogens such as the Zika and Ebola viruses, and our perpetual struggle withmutating influenza viruses have increasingly positioned the field of infectious diseases at the forefront of medicine and public health. And now, of course, the world is grappling with SARS-CoV-2, the virus responsible for COVID-19, causing the general population to think more about infectious diseases than it ever has before—or ever wanted to. Because of the significance of the global pandemic, the Journal of the Louisiana State Medical Society , a vanguard of the medical community in our state since 1844, is providing an update on COVID-19 in this issue. Articles written by various medical professionals address the disease’s clinical aspects (epidemiology, diagnostics, therapeutics, complications, and prevention); its impact on student and resident training; and the challenges associated with leading a Department of Medicine during a pandemic. Hurricane Katrina or COVID-19? As a Louisiana native, I have often asked myself which has proven more formidable, having lived through the experience of caring for patients during the former at the iconic Charity Hospital and now caring for patients with the latter at our university teaching hospital. 3 For many involved in healthcare in this state, Hurricane Katrina has provided a referential point to affix experiences in time (i.e., “pre-Katrina” or “post-Katrina”), but with the novel coronavirus reaching its toxic tentacles into seemingly every aspect of our lives for such a protracted period, it may well become the new chronological marker in Louisiana. I do not view either disaster as an exclusive holder of this mantle but rather consider both to be examples of the resilience of our state in addressing some of its greatest recent challenges. We hope that you find this issue helpful in your understanding of COVID-19 and its collateral effects, a pandemic whose vast impact will be felt for many years to come.
Fred A. Lopez, MD, MACP Richard Vial Professor LSU School of Medicine-New Orleans
REFERENCES 1. Lopez FA. Infectious diseases in the 21 st century: No end in sight. Emergency Medicine 2009;41:8. 2. Petersdorf RG. The doctors’ dilemma. N Engl J Med . 1978;299(12):628-634. 3. Lopez FA. In the Eye of the Storm: Charity Hospital and Hurricane Katrina. The Pharos Winter 2006; 4-10. I would like to thank Michelle Holt, M.Ed., M.F.A., Managing Editor for the LSU Department of Medicine, for her assistance.
4
COVID-19 : EPIDEMIOLOGY, CLINICAL PRESENTATION AND PROGNOSIS Logan S. Ledet, MD, Fred A. Lopez, MD, MACP
Dr. Ledet is a Fellow in the Section of Infectious Diseases, Department of Internal Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA Dr. Lopez is the Richard Vial Professor and Vice Chair of Education in the Department of Internal Medicine, Louisiana State University Health Sciences Center, New w, LA, USA
ABSTRACT Since the first case of COVID-19 was reported inWuhan City, Hubei Province, China, in December 2019, an ensuing pandemic has challenged public health infrastructure around the world. During this time, scientists and clinicians have been striving to understand, prevent, and treat this disease, generating an enormously robust amount of data in the process. This article aims to provide clinicians with up-to-date, useful and accurate information regarding the virus’s origins, transmission dynamics, clinical presentation, and prognosis that can help inform their practice in this challenging, and constantly evolving health crisis.
HISTORY AND EPIDEMIOLOGY Throughout human history, society has been shaped by intermittent outbreaks of infectious diseases described as “plagues” and/or “pandemics.” Outbreaks of infectious diseases have changed the course of history, transforming economies and affecting the outcomes of wars, causing devastation but also leading to amazing advancements in public health and medicine. Since the beginning of the 21st century, some of the most notable outbreaks of infectious diseases have been due to novel viruses from the family Coronaviridae. The 2003 outbreak of Severe Acute Respiratory Syndrome (SARS) ultimately resulted in more than 8,000 cases with an approximate 10% mortality rate. The disease, first documented in Hong Kong, spread rapidly over multiple continents, sparking worldwide fear and causing disastrous economic impacts 1 . No cases have been reported since 2004. Again, in 2012, a SARS-like coronavirus illness emerged in Saudi Arabia. Deemed Middle East Respiratory Syndrome (MERS), this outbreak led to more than 1,000 cases with an even higher mortality rate estimated at almost 35% (2). In both instances, these viruses emerged in areas with dense human populations where there exist so-called “wet markets.” In these markets, fresh meat, fish, and produce are sold, allowing for frequent mixing of different animal species in close contact with human patrons. SARS-CoV and MERS-CoV originated from animal reservoirs. The SARS virus was originally traced to wildlife market civets, which likely acted as an amplifying intermediate animal host, and ultimately to bats. Likewise, MERS was traced to bats, with
dromedary camels acting as intermediate hosts. These viruses gained the ability to not only infect humans, but also achieve human-to-human transmission. The resulting illnesses included severe lower respiratory tract infections with extra-pulmonarymanifestations due to viruses abilities to infect a broad range of cell types while simultaneously evading host immune response and triggering cytokine dysregulation 1,2 . SARS-CoV and MERS-CoV served as harbingers of the pandemic we find ourselves in today, fully realized in COVID-19 caused by SARS-CoV-2. In December 2019, a cluster of severe pneumonia cases were described inWuhan City, Hubei Province, China. It was noted that a number of the patients affected had either visited or worked in the same local seafood market prior to becoming ill. Shortly thereafter, a novel coronavirus, now called SARS- CoV-2, was isolated via PCR from bronchoalveolar lavage fluid collected from infected patients 3 . Since isolation of the virus, much work has been done to determine its animal origins. Like SARS and MERS, this virus likely originated in bats. SARS-CoV-2 shares 96.2% sequence identity with a bat coronavirus, BatCoV RaTG13, first isolated from Rhinolophus affinis (intermediate horseshoe bat) in Yunnan province. Though a number of intermediate animal hosts have been proposed, including the pangolin, thus far the intermediate host or hosts have not been definitively identified. A WHO task force continues to investigate this issue 4 . SARS-CoV-2 spread rapidly thereafter, with the first case on US soil being reported on January 19, 2020, in Washington state 5 . Eleven days later, on January 30th, the WHO declared 5
a Public Health Emergency of International Concern (PHEIC), the organization’s highest level of alarm. Ultimately, on March 11, 2020, the COVID-19 was declared a pandemic by the WHO 6 . The incubation period for SARS-CoV-2 is estimated to be 2-14 days, with a mean of approximately 5-6 days 7,8 , prompting the widespread recommendation of a 14-day self-quarantine for patients exposed to or diagnosed with infection. The median time from illness onset to hospital admission is estimated to be 4 days, and median time from illness onset to death in patients who ultimately succumb to infection is estimated at 13 days 7 . SARS-CoV-2 respiratory droplets are primarily transmitted via close person-to-person contact (including being within 6 feet of an infected person). Airborne transmission by smaller droplets and particles that remain suspended in air and travel further than 6 feet can sometimes occur. Fecal aerosol transmission may also be possible. Contact transmission seems to be a less frequent contributor. While the virus can persist on an inanimate surface for multiple days 9 , there have been studies that showed difficulty in actually culturing live virus from these surfaces 10 . Droplet transmission via larger respiratory particles (greater than 5 μm in diameter) has been the most widely accepted mode of transmission of SARS-CoV-2 by most public health organizations 11 , and is the basis of the at least 6-foot separation recommendation for social distancing. However, our understanding of transmission is evolving, including several, well-documented instances of COVID spread, where the most plausible explanation is under favorable conditions (i.e. poor ventilation, high concentration of particles, and extended exposure) airborne transmission is possible 12, 13, 14 . Symptomatic patients are contagious. Though asymptomatic transmission has been well described, including early in the pandemic aboard the Diamond Princess cruise ship 15 , exactly when a patient becomes contagious in asymptomatic infection or in the pre- symptomatic phase of infection is more difficult to establish. While PCR testing provides evidence that SARS- CoV-2 is present, it does not necessarily translate to being contagious. Infectivity in viral culture is the gold standard for determining presence of live virus, and such data does not exist for the vast majority of patients. Viral load or cycle threshold in RT-PCR has been used as a surrogate marker for infectivity in culture in many studies, and it does appear that viral load is highest within the first week of symptoms 16, 17 . One recently published decision analytical model by Johansson et al., assesses the proportion of transmission from pre-symptomatic individuals (18). Applying a mean incubation period of 5 days, they estimate that 59% of
COVID-19 transmission is from asymptomatic patients, 35% from pre-symptomatic and 24% from never symptomatic patients. The basic reproduction number, R0 (“R naught”), is the average number of secondary cases generated by one infected individual in a totally susceptible population. R0 greater than 1 means that human to human transmission can occur and persist; an R0 less than 1 means transmission will decline and eventually be extinguished 19 . A meta- analysis of 12 studies by Liu et al. determined the average estimate of the R0 of SARS-CoV0-2 is 3.28 with a median of 2.79 20 . As a point of comparison, the R0 of measles is widely cited to be 12-18, and the R0 of influenza is approximately 1.3 21 . This number declines as the number of immune individuals in a population increases, through natural infection or vaccination. However, it is important to note that while first generation of COVID-19 vaccines have been shown todecrease severity of illness, their ability togenerate sterilizing immunity in the upper respiratory tract continues to be evaluated 22 . Thus, their effect on COVID transmission is not yet known and investigations into this issue are ongoing. It is imperative that other mitigation measures be continued (social distancing, mask wearing, hand washing, etc.) while vaccinations are being carried out. As of February 14, 2021, there have been an estimated 108.7 million cases and 2.39 million deaths worldwide, with 27.6 million cases and over 485,000 deaths in the U.S., and over 380,000 confirmed cases and 9,292 confirmed deaths in Louisiana 23 . This equates to approximately 8.3% of the population of Louisiana having been infected with COVID-19. CLINICAL PRESENTATION One of the most challenging aspects of the pandemic has been the wide range of illness severity seen in affected patients. In particular, asymptomatic patients, those who will never develop symptoms in the course of their infection, and pre-symptomatic patients, who will eventually develop symptoms, have made containment of spread challenging. In a review of populations with broad testing, for example Iceland and Vo’, Italy, approximately 40-50%of patientswere asymptomatic at the time of testing positive (24). A large meta-analysis by Byambasuren et al. published inDecember 2020 looked at studies which followed patients for at least 14 days to assess whether they remain asymptomatic or are merely pre-symptomatic at the time of positive testing 25 . By their estimate, approximately one in five patients are never symptomatic. Numerous studies have attempted to determine clinical characteristics of asymptomatic patients; however, a significant number of asymptomatic cases have been 6
reported in all age groups, both genders, and a variety of co-morbid conditions 26 . Our understanding of why certain patients will remain asymptomatic or have longer pre- symptomatic phases of infection remains unclear. Acutely symptomatic patients can present with a variety of symptoms, owing to the ACE2 receptor utilized by the virus to enter cells being expressed on tissues in nearly all organ systems of the body 19 . The most commonly reported include fever (77.4%-98.5%), cough (59.4%-81.8%), malaise (38.1%-69%), dyspnea (3.2%-55.0%), myalgia (11.1%-34.8%), sputum production (28.2%-56.5%), anosmia (25%), and headache (6.5%-33.9%) 27 . To a lesser extent sore throat (12%), arthralgia (11%), confusion (11%), dizziness (11%), and diarrhea (10%) have also been reported 27 . The prevalence of certain symptoms has evolved during the pandemic. For example, gastrointestinal symptoms including not only diarrhea, but also nausea, vomiting, and elevated liver function tests seem to have become more commonly reported in later phases of the outbreak 28 . When present, symptoms on average last approximately 8 days 27 . In patients with respiratory complaints, abnormalities on chest imaging are common. CT findings associated with COVID-19 are especially well described. Findings are typically bilateral, although unilateral abnormalities have been described particularly in mild cases or early in a patient’s course. Ground glass opacities and consolidation are the most common finding (94.5%); less common, but still frequently described findings include air bronchograms, linear opacities, interlobular septal thickening, bronchiectasis, pleural effusion, and nodules 29 . It is notable that these findings are non-specific and can be associated with a variety of disease processes, particularly other viral pneumonias. For this reason, the American College of Radiology does not recommend using CT as a first-line or diagnostic test for COVID-19 30 . As per NIH treatment guidelines 31 , moderate illness is defined as lower respiratory disease based on clinical assessment or imaging, but with SpO2 of greater than 94% on room air. Severe illness is defined as SpO2 <94% on room air, a respiratory rate of greater than 30 breaths per minute, PaO2/FiO2 of less than 300 mm Hg, or infiltrates in greater than 50% of the lung on imaging. Individuals who are aged 65 years or older or with comorbidities such as cardiovascular disease, chronic lung disease, chronic kidney disease, or diseases that affect the immunesystem(including diabetes) are considered at high risk for developing more severe illness 32 . One study estimates that 1 in 5 people of the global population, or 1.6 billion people, have at least one of these underlying conditions and are therefore at increased risk 33 . An updated list of medical conditions that increase risk or might increase risk for severe illness from COVID-19 is maintained by the CDC on its website 32 .
Furthermore, disparity among U.S. ethnic groups is also present withCOVID-19. AfricanAmerican/Black andHispanic populations are at higher risk of SARS-CoV-2 infection and COVID-19-related death. Though further study is needed to conclusively determine a cause, current data suggests this disparity is due to increased exposure risk and/or limited access to healthcare rather than increased susceptibility 34 . Numerous existing severity scores for community acquired pneumonia have been evaluated to assess their ability to accurately risk stratify patients with COVID-19. One retrospective study by Fan et al. compared A-DROP, CURB- 65, PSI, SMART-COP, NEWS2, CRB-65, and qSOFA, with the A-DROP scoring system being most accurate in predicting in-hospital death 35 . Modified severity scores have also been proposed to include expanded versions of A-DROP 36 , as well as entirely novel scoring systems such as the 4C Mortality Score or the COVID Inpatient Risk Calculator (CIRC). The 4C Mortality Score was developed in the UK, and includes 8 variables: age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, level of consciousness, urea level, and C reactive protein. A score of 15 points or higher was associated with a mortality rate of 62%, and a score of less than 3 carried a mortality rate of 1%. The scoring system showed excellent discrimination and calibration, and by the authors’ analysis this system out performed previously developed CAP severity scores 37 . The COVID Inpatient Risk Calculator (CIRC) was developed by researchers at Johns Hopkins 38 . This model uses demographics, comorbidities, symptoms, vital signs, and a range of lab values todetermine the likelihood of a patient progressing to severe disease or death within 7 days of admission. For example, using CIRC, a 78-year-old Black man, with a history of MI and stroke, admitted from a nursing home with a fever, respiratory and constitutional symptoms, has an 18% chance of progressing to severe disease or death by day 4 of his hospital admission, and a 22% chance of progressing to severe illness or death by day 7 38 . A rare complication of COVID-19 has been Multisystem Inflammatory Syndrome in both children and adults, known as MIS-C and MIS-A respectively. This syndrome was first described in the UK when a small cluster of children began returning to the hospital 2-4weeks after initial infectionwith what appeared to be Kawasaki’s disease or toxic shock-like syndrome 39 . A broad range of symptoms were described, but most cases were associated with shock, cardiac dysfunction, gastrointestinal symptoms, and markedly elevated inflammatory markers. There were also reported cases that occurred during acute infection with COVID-19, and these patients tended to have milder associated symptoms 40 . Though fewer in number, similar cases have been described in adults. Similarly, adult cases tended to include shock, cardiovascular dysfunction, gastrointestinal symptoms, dermatologic, and neurologic manifestations. 7
Respiratory involvement was rare (41). This appears to be a post-infectious phenomenon, as the majority of both pediatric and adult patients had negative RT-PCR studies, but had positive serology for antibodies against SARS- CoV-2 40,41 . The mechanism is not fully understood, but a proposed etiology is endothelial inflammation caused by acute infection which results in immune dysregulation 42 . Other patients who have recovered from COVID-19, develop “postacute COVID-19 syndrome.” Symptoms are typically nonspecific, and most commonly include fatigue and dyspnea. Other symptoms include joint and chest pain as well as “brain fog.” As the SARS-CoV-2 outbreak is relatively new, investigations into better understanding this phenomenon are ongoing 43 . One recently published study by Chaolin Huang and colleagues, followed a cohort of 1733 patients in Wuhan, China, for 6 months following discharge from the hospital for COVID-19 44 . At 6 months post-discharge, the most common symptoms reported by patients were anxiety and depression, sleep disturbances, fatigue, and muscle weakness. Patients who had more severe disease had a higher likelihood of abnormal oxygen diffusion on pulmonary function testing and persistent
second 142 days later, the Nevada patient experienced an increase in symptom severity during his second infection whichoccurred48days after his first infection 48,49 . It is known that neutralizing antibodies are generated in response to COVID-19; however, the durability of this response is not yet known, but is likely within the range of 5-7 months 50, 51 . EMERGENCE OF SARS-CoV-2 VARIANTS Variant strains of SARS-Cov-2 have evolved by mutation during the course of this pandemic. Investigations of these variants will need to address questions regarding transmissibility, virulence, accuracy of diagnostic testing, efficacy of antibody-based treatments and vaccinations, and ability to reinfect individuals with prior infection. One such variant emerged in the UK in the fall of 2020, and is associated with multiple mutations including a spike protein-associated receptor binding domain mutation at position 501 where asparagine has been replaced by tyrosine, i.e., N501Y. The strain is known as B.1.1.7. and it is estimated to be approximately 50% more transmissible than the Wuhan reference strain 52 . This variant may also be associated with an increased risk for severe disease 53 . The UK variant does not appear to have an effect on current vaccine efficacy 54 . However, both currently available vaccine-generated antibodies and COVID-19 antibodies from early natural infections may have decreased efficacy against two additional emerging variants from South Africa (known as B.1.351) and Brazil (known as P.1) due to additional mutations in the spike protein including one at position 484 where glutamic acid is replaced by lysine (i.e., E484K) 55, 56, 57, 58 . By late January 2021, the UK, South African, and Brazilian variants had been detected in the United States. Even with ongoing vaccination efforts, increased vigilance and mitigation measures will be crucial to prevent surges in cases. REFERENCES 1. LeDuc JW, Barry MA. SARS, the first pandemic of the 21st century. Emerg Infect Dis [serial on the Internet]. 2004 Nov [Nov 28 2020] http://dx.doi.org/10.3201/eid1011.040797_02 2. Chan JF, Lau SK, To KK, Cheng VC, Woo PC, Yuen KY. Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease. Clin Microbiol Rev. 2015;28(2):465-522. doi:10.1128/CMR.00102-14 3. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China. N Engl J Med 2020;382:727-33. DOI: 10.1056/NEJMoa2001017 4. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020). https://doi.org/10.1038/ s41586-020-2012-7 5. Bhatraju PK, Ghassemieh BJ, Nichols M, et al. Covid-19 in Critically Ill Patients in the Seattle Region – Case Series. N Engl J Med 2020;382:2012-22. DOI: 10.1056/NEJMoa2004500 6. WHO: WHO Director-General speeches [Internet]. Geneva, 8
abnormalities on high resolution chest CT. MORTALITY AND REINFECTION
As of February 14, 2021, the current case fatality ratio of COVID-19 in the United States is 1.8%, with 148.00 deaths per 100,000 persons 23 . Though numbers of cases and deaths continue to rise, there have been numerous reports that the mortality rate has been decreasing. One study in England confirmed that patients admitted to hospital with COVID-19 in mid-April and May had a significantly lower mortality rate than patients admitted earlier in the pandemic. Their analysis included adjustments for patient demographics and comorbidities which did not seem to account for the change 45 . Proposed reasons for this decline include widespread use of corticosteroids which demonstrated a mortality benefit in the RECOVERY trial 46 , better healthcare provider understanding of the disease process, as well as decreased healthcare burden as mitigation measures have been introduced 45, 47 . Numerous groups around the world are investigating whether this decline is real, or merely due to changes in testing and case reporting, particularly on a country-to-country basis. Confirmed cases of reinfection have been reported. Two such instances are the case of a 33-year-old man in Hong Kong and a 25-year-old man in Nevada. In each case, genomic analysis of the virus isolated from the patient in each infection was performed, and the isolates were genetically distinct. An importance difference between the cases is that while the Hong Kong patient was mildly symptomatic in his first infection and asymptomatic in his
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DIAGNOSTIC APPROACH TO COVID-19 Mohammed Ziada MD, Infectious Diseases Fellow
Victoria Burke MD, Assistant Professor of Clinical Medicine Department of Medicine — Section of Infectious Diseases LSU Health Sciences Center, New Orleans, LA
ABSTRACT INTRODUCTION
Accurate and timely diagnosis of SARS-CoV-2 infection is essential to control viral spread.
METHODS
In this article, we review the indications for SARS-CoV-2 testing among both symptomatic and asymptomatic individuals, as well as the general characteristics, indications, and interpretation of the three major classes of COVID-19 diagnostics: nucleic acid amplification testing (NAAT), antigen testing, and antibody testing. In general, NAAT and antigen tests are utilized to make a diagnosis of acute infection. Antibody tests are serologic assays that measure the immune response to SARS-CoV-2 infection and can confirm prior recent infection. They have limited utility in confirming active infection and commercially available assays cannot confirm immunity to SARS-CoV-2.
CONCLUSION
NAAT assays and antigen testing are the major diagnostics utilized to confirm active infection with SARS-CoV-2, whereas, antibody testing is used to confirm prior recent infection.
INTRODUCTION The COVID-19 global pandemic has impacted the entire world over the past year, accounting for over 100 million cases and greater than 2 million deaths worldwide. Accurate and timely diagnosis of SARS-CoV-2 infection is essential to control viral spread to limit further morbidity and mortality from this illness. In this article, we review the indications for SARS-CoV-2 testing among both symptomatic and asymptomatic individuals, as well as the general characteristics, indications, and interpretation of the three major classes of COVID-19 diagnostics: nucleic acid amplification testing (NAAT), antigen testing, and antibody testing. INDICATIONS FOR SARS-COV-2 TESTING There are no specific clinical features that can reliably distinguish COVID-19 fromother respiratory viral infections 1 . Providers should, therefore, have a low threshold for suspicion of COVID-19 in patients with any concerning symptoms, particularly if they have spent time in an area with community transmission or have a close contact with confirmed or suspected COVID-19 in the preceding 14 days. If possible, it is recommended that all symptomatic patients with suspected infection undergo testing for
acute infection.
The Infectious Diseases Society of America (IDSA) has suggested priorities for testing when diagnostic capacity is limited. High-priority individuals include hospitalized patients (especially critically ill patients with unexplained respiratory illness) and symptomatic individuals who are health care workers or first responders, work or reside in congregate living settings, or have risk factors for severe disease 2 . Testing certain asymptomatic individuals may also be important for public health or infection control purposes. Situations where testing of asymptomatic individuals is recommended include the following instances: 2,3
• Following close contact with an individual with COVID-19 without full PPE (this includes neonates born to mothers with active or recent COVID-19). The optimal time to test for COVID-19 following exposure remains uncertain but five to seven days post exposure is largely recommended based on the average incubation period. • Screening residents of congregate living facilities that house individuals at risk for severe disease (e.g., long- 12
term care facilities, correctional and detention facilities, homeless shelters).
• Nucleic acid amplification testing (NAAT) of viral RNA, most commonly reverse-transcription polymerase chain reaction (RT-PCR) testing (detects viral nucleic acid).
• Screening hospitalized patients at locations where prevalence is moderate or high (e.g., ≥10 percent PCR positivity in the community).
• SARS-CoV-2 antigen testing (detects a specific viral antigen).
• Prior to time-sensitive surgical procedures or aerosol- generating procedures.
• Antibody testing (detects antibody to spike or nucleocapsid proteins).
• Prior to receiving immunosuppressive therapy including prior to transplantation. OVERVIEW OF DIAGNOSTIC TESTS FOR SARS-COV-2 There are 3 classes of tests available to diagnose active or prior COVID-19:
Authorized assays for acute viral testing include those that detect SARS-CoV-2 nucleic acid or antigens. These viral specific tests detect viral nucleic acid or antigens from respiratory tract samples (including nasal, nasopharyngeal, oral, or oropharyngeal swabs or saliva samples) to diagnose active infection with SARS-CoV-2. In contrast, serologic assays detect antibodies in the blood that indicate prior infection with SARS-CoV-2. A summary of SARS-CoV-2 diagnostics is detailed below.
Table1: Summary of Diagnostic Tests for SARS-CoV-2 (4) table 1 NAAT Antigen Test
Antibody Test
Intended use
• Detect current infection • Detect current infection • Prior infection (usually >3-4 weeks)
Analyte detected • Viral RNA
• Viral Antigen
• Antibodies to spike and nucleocapsid proteins
Specimen type(s)
• Nasal, Nasopharyngeal, Sputum, Saliva
• Nasal, Nasopharyngeal
• Blood
Sensitivity
• Varies by test, but gen- erally high
• Moderate
• Variable
Specificity
• High
• High
• Variable
Test complexity
• Varies by test
• Relatively easy to use • Relatively easy to use
Authorized use at Point-of-Care
• Most are not, some are not
• Most are, some are not
• N/A
Turnaround time
• 15 mins to >2 days
• Less than 1 hour
• 15 mins to 2 hours
Cost
• Moderate (~$100/test)
• Low (~$5-50/test)
• Low (~$40/test)
Adapted from CDC Guidance.
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NAAT TESTING Nucleic acid amplification testing (NAAT) to detect SARS- CoV-2 RNA from the upper respiratory tract is the preferred initial diagnostic test for COVID-19 when available 3 . Among the available classes of diagnostic tests, NAAT has the highest sensitivity and specificity for acute COVID-19, although variability exists amongst different NAAT testing platforms. Rapid NAAT assays, defined as those assays that generate results in under an hour including the Abbott ID NOW and Cepheid GeneXpert Xpress Assays, are generally less sensitive and specific thanmore time-intensive standard laboratory-based NAAT methods, including RT-PCR or transcription mediated amplification (TMA) assays, which yield results within 8 to 48 hours 3 . A positive NAAT PCR for SARS-CoV-2 in a symptomatic patient generally confirms the diagnosis of COVID-19 with no additional diagnostic testing required. In some cases, an inconclusive or indeterminate result indicates that only one of the two or more genes targeted by NAAT testing was identified. These results can be considered presumptive positive results, given the high specificity of NAAT assays. In a symptomatic patient where suspicion for COVID-19 is low, a single negative rapid or standard NAAT assay is sufficient to exclude the diagnosis. In a symptomatic patient where suspicion for COVID-19 is high or the prevalence is >10% in the general population, testing should be repeated between 24-48 hours later with a standard NAAT assay such as RT-PCR if the initial rapid diagnostic is negative 3 . Of note, detectable virus in asymptomatic patients following resolved infection does not usually indicate relapsed or new infection. Patients with COVID-19 can shed detectable SARS-CoV-2 RNA either continuously or intermittently in upper respiratory tract specimens for weeks after the resolution of symptoms (5). Prolonged viral RNA detection after symptom resolution does not indicate that a patient is contagious as this virus shed is unlikely to still be transmissible 6 . ANTIGEN TESTING Antigen tests are immunoassays that detect the presence of a specific viral antigen, which implies active viral infection. They are usually rapid, inexpensive, and can be performed at the point of care, yielding greater accessibility with a faster turnaround time than most NAAT assays. Antigen tests are typically less sensitive than NAAT assays and are most accurate in confirming a diagnosis in the early stages of infection when viral replication is high. Given their rapid turnaround time, low cost, and high specificity, antigen testing is often utilized in serial screening of congregate settings or other sites of localized outbreaks. When used in clinical diagnosis in symptomatic patients, positive antigen tests can be interpreted as indicative of SARS-
CoV-2 infection. Negative antigen tests could represent a false negative given their reduced sensitivity and should generally be confirmed using a more sensitive NAAT RT- PCR assay if clinical suspicion is high. When used for serial testing in congregate settings, negative antigen tests do not need to be confirmed 4 . In general, antigen tests should be used in settings where prevalence is moderate and early in disease onset to yield the most accurate results. SEROLOGIC (ANTIBODY) TESTING Serologic tests detect antibodies to either the SARS- CoV-2 spike protein or nucleocapsid in the blood. They identify patients who have been previously infected with SARS-CoV-2 as well as patients with active infection with prolonged symptoms that extend for enough time to generate a humoral immune response (i.e., typically about three weeks). False positive serologic testing was described early in the pandemic due to cross-reactivity with other human coronaviruses when using low specificity assays in low prevalence areas 7 . Therefore, to be of value, FDA- approved anti-SARS-CoV-2 antibody tests are required to have high sensitivity and specificity (i.e., >99.5%) and should be used in areas of moderate to high prevalence. Because serologic tests are less likely tobe reactive in thefirst several days to weeks of infection while the host humoral response is generated, they have very limited utility in the diagnosis of acute infection 8 . As such, the IDSA discourages their use for confirmation of infection in the first two weeks following symptom onset 7 . Checking serologic testing with IgG or total antibody (rather than IgM, IgA or IgG/IgMassays) three to four weeks after the onset of symptoms optimizes the accuracy of testing for evidence of recent infection (7).
Commercially approved antibody assays detect both neutralizing antibodies that confer active immunity to repeat SARS-CoV-2 infection and binding antibodies that lack this protective ability. Therefore, current commercially available serologic assays cannot determine whether antibodies detected are protective against future SARS- CoV-2 infection. Confirmed and suspected cases of reinfection with the virus in seropositive patients, although rare, have been reported, confirming that these assays should not be used to demonstrate immunity 4 . The CDC recommends that results of antibody testing not be used to determine housing arrangements in congregate settings such as dormitories or prisons, to make decisions about returning to work, or to alter work and personal protective equipment requirements for health care workers and first responders 4 . Additionally, the effectiveness and durability of anti-SARS-CoV-2 antibody responses have not yet been defined. As such, serologic testing cannot be used to determine immune status since they are unable to define whether detectable antibody is able to effectively neutralize 14
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