The novel coronavirus, SARS-CoV-2, and its infection, COVID-19, has quickly become a worldwide threat to health, travel, and commerce. It is essential for emergency clinicians to learn as much as possible about this pandemic to manage the unprecedented burdens on healthcare providers and hospital systems. This review analyzes information from worldwide research and experience on the epidemiology, prevention, and treatment of COVID-19, and offers links to the most reliable and trustworthy resources to help equip healthcare professionals in managing this public health challenge. As the pandemic sweeps the United States, lessons learned from early centers of infection, notably New York and Northern Italy, can help localities to prepare.
A 42-year-old man presents to your ED triage area with a high-grade fever (39.6°C [103.3°F]), cough, and fatigue for 1 week. He said that the week prior, he was at an emergency medicine conference in New York City, and took the subway with some people who were coughing excessively. The triage nurses immediately recognize the infectious risk, place a mask on the patient, place him in a negative pressure room, and inform you that the patient is ready to be seen. You wonder what to do with the other 10 individuals who were sitting near the patient while he was waiting to be triaged, and what you should do next... Later in your shift, a steady flow of patients with varying degrees of upper and lower respiratory symptoms arrive. Additionally, there are several “worried well” patients without symptoms, who are requesting testing for COVID-19, based on varying degrees of perceived exposures. What do you tell them? How do you handle the throngs of patients now potentially contaminating higherrisk patients?
Coronaviruses earn their name from the characteristic crown-like viral particles (virions) that dot their surface. This family of viruses infects a wide range of vertebrates, most notably mammals and birds, and are considered to be a major cause of viral respiratory infections worldwide.3,4 With the recent detection of the 2019 novel coronavirus (SARS-CoV-2), and the resultant disease that has been given the name, coronavirus disease 2019 (COVID-19), there are now a total of 7 coronaviruses known to infect humans:
Prior to the global outbreak of SARS-CoV-1 in 2003, HCoV-229E and HCoV-OC43 were the only coronaviruses known to infect humans. Following the SARS-CoV-1 outbreak, 5 additional coronaviruses have been discovered in humans, most recently the novel coronavirus SARS-CoV-2, believed to have originated in Wuhan, Hubei Province, China. SARS-CoV-1 and MERS-CoV are particularly pathogenic in humans and are associated with high mortality. In this article, the epidemiology, pathophysiology, and management of COVID-19 are reviewed, with a focus on best practices and public health implications.
PubMed, ISI Web of Knowledge, and the Cochrane Database of Systematic Reviews resources from 2012 to 2020 were accessed using the keywords emergency department, epidemic, pandemic, coronavirus, SARS-CoV-2, and COVID-19. The websites of the United States Centers for Disease Control and Prevention (CDC); the World Health Organization (WHO); Japan’s National Ministry of Health, Labor, and Welfare; and EMCrit were also accessed.
As of March 27, 2020, there have been 566,269 confirmed cases of COVID-19 globally, with the majority of new cases now occurring outside of mainland China. There have been 25,423 confirmed deaths.1 For up-to-date numbers on global confirmed cases/deaths from COVID-19, go to the Johns Hopkins University online tracker. At the time of this printing, confirmed cases span 176 countries across all continents except Antarctica, prompting the WHO to declare the SARS-CoV-2 infection a pandemic. Of the deaths, over half have now occurred outside of China, led by Italy (8215 deaths), and Iran (2378 deaths). The current global case fatality rate is 4.38%. With the outbreak of COVID-19 coinciding with the celebration of the Chinese Lunar New Year in late January 2020 and an associated approximately 15 million visits to Wuhan City, the efforts to contain the outbreak to mainland China were ultimately unsuccessful. Initial reports from affected patient populations in hospitals in China indicated that the majority of those infected with severe disease and poor outcomes (as measured by intensive care unit [ICU]-level care and mortality) tended to be patients with comorbid conditions such as hypertension, diabetes, obesity, asthma, chronic obstructive pulmonary disease, or advanced age.2,6
In epidemiology, the R0 value (pronounced “R-naught”) is known as the basic reproduction number and can be thought of as the expected number of cases generated directly by 1 case in a population, where all individuals are susceptible to infection. Early epidemiologic studies in the case of COVID-19 estimated an R0 value of 2.2 (90% high density interval: 1.4-3.8), a value similar to SARS-CoV-1 and pandemic influenza, suggesting the potential for sustained human-to-human transmission and a global pandemic.7 As will be discussed in more detail in the “Prevention” section, R0 is a reflection of both virus behavior and human behavior, so with the correct societal and behavioral interventions, this R0 value can be reduced.
With just mere months since the first case, the death toll from SARS-CoV-2 has far exceeded that of both MERS-CoV and SARS-CoV combined.1 The true mortality rate is believed to be lower than the case fatality rate, due to selection bias, as only those with symptomatology severe enough to prompt emergency evaluation and/or hospitalization are being tested for COVID-19.8 Data from the Diamond Princess cruise ship outbreak provides a unique snapshot of the true mortality and symptomatology of the disease, given that everyone on board was tested, regardless of symptoms. Based on this data, unpublished analyses at the London School of Hygiene and Tropical Medicine have estimated an age-adjusted case fatality rate of 0.5%. This would still rank COVID-19 as deadlier than pandemic influenza, while maintaining a similar infectious profile.9 Additionally, according to Japan’s National Ministry of Health, Labor, and Welfare, 327 of the 697 people aboard the ship who tested positive for COVID-19 never showed symptoms, even up to a month after the initial positive test.10
We are fortunate to provide a first-hand perspective to the COVID-19 crisis in Italy, which occurred a few weeks after Washington state’s first reported case (January 21), and what epidemiologists have estimated is about 2 to 3 weeks ahead of the New York metropolitan area outbreak. Andrea Duca, MD is an emergency medicine physician and member of the Editorial Board of Emergency Medicine Practice based in Northern Italy, an area which bore the initial brunt of COVID-19. He reports that the rapid spread of SARS-CoV-2 overwhelmed most hospitals, which were unprepared to deal with the sudden influx of patients requiring ventilatory support. To date (as of March 18, 2020), Italy has a case fatality rate of 8.37%, which should serve as a warning to other healthcare systems around the world preparing to deal with patients with severe COVID-19 in the upcoming weeks. See Table 1 for Dr. Andrea Duca’s summary of lessons learned managing the SARS-CoV-2 outbreak in his ED in Bergamo, Italy. Additional data from that hospital are included in Figures 1, 2, 3, and 4. Figure 1 presents a timeline of COVID-19 cases in the Lombardy region, February 20 to March 17, 2020; Figure 2 lists the percentage of daily census admissions and discharges of COVID-19 patients, February 29 to March 10, 2020; Figure 3 presents the total daily census admissions and discharges of COVID-19 patients; Figure 4 presents a graphic display of the disposition of COVID-19 patients, February 29 to March 10, 2020.
Coronaviruses are in the order Nidovirales, in the family Coronaviridae, and subfamily Orthocoronavirinae. Coronaviruses are enveloped with positive-sense single-stranded RNA, and possess the largest genome of all RNA viruses. Two-thirds of the coronavirus genome at the 5’ terminus encodes viral proteins involved in transcribing viral RNA and replication, while one-third at the 3’ terminus encodes viral structural and group-specific accessory proteins.4 Our current understanding highlights 4 major proteins in coronaviruses: S (spike), E (envelope), M (membrane), and N (nucleocapsid) proteins. These biomarkers play a central role not just in how we diagnose the disease, but how we will come to understand its pathogenicity profile, and ultimately any options for a vaccine and/or direct antiviral treatment targeted to dismantle the viral life cycle. (See Figure 5.)
The SARS-CoV-1 and MERS-CoV viruses were both believed to have resulted from zoonotic spread from the bat population.11 Naming the virus causing the current pandemic “SARS-CoV-2” is a result of its genetic similarity to the virus that caused the outbreak in 2003, which is now called “SARS-CoV-1.” While coronaviruses likely evolved over thousands of years remaining confined to bat populations, intermediate mammalian hosts (such as civet cats in the case of SARS-CoV-1 and dromedary camels in the case of MERS-CoV) have been implicated and likely played a role in the ultimate transmission of these novel coronaviruses to humans.12,13 The outbreak of COVID-19 is suspected to have originated in the Huanan Seafood Wholesale Market in Wuhan City; however, other researchers have suggested that this market may not be the original source of viral transmission to humans.2,14 Bats are rare in markets in China, but they are hunted and sold directly to restaurants for food.15
Coronaviruses primarily infect the upper respiratory and gastrointestinal tracts of birds and mammals. The surface spike glycoprotein (S-protein) is a key factor in the virulence of coronaviruses, as it enables it to attach to host cells. MERS-CoV has been shown to bind to dipeptidyl-peptidase 4 (DPP4), a protein that has been conserved across species known to harbor this strain of coronavirus. While most respiratory viruses infect ciliated cells, DPP4 is expressed in nonciliated cells in human airways, which is believed to be an important factor in its zoonotic transmission and high case fatality rate.16 In SARS-CoV-1, human angiotensin-converting enzyme 2 (ACE2) was the primary cellular receptor to which the virus attached, and is believed to have played a role in the ability of SARS-CoV-1 to produce infections of both the upper and lower respiratory tracts, contributing to its infectivity and .lethality.17
Previous studies have suggested that immunopathogenesis, also referred to as “cytokine storm,” leads to the deterioration of patients dealing with various respiratory viruses, including SARS-CoV-1 and avian influenza.18,19 A number of studies support the theory that the rapid deterioration of COVID-19 patients is driven by immunopathogenesis, whereby release of inflammatory markers initiates a positive feedback loop that leads to ARDS, multiorgan failure, and death.20 A cohort of 41 laboratory-confirmed COVID-19 patients in China found that ICU patients had significantly higher levels of inflammatory markers (IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1, and TNF-alpha) than non-ICU patients.21 A recent study conducted in China provides a detailed immunopathology report on SARS-CoV-2, suggesting patients with severe COVID-19 express an “…excessive activated immune response…by pathogenic Th1 cells and inflammatory monocytes,” findings that are additionally supported by immunohistochemical analysis of postmortem lung biopsies of COVID-19 patients.22,23 A growing body of literature suggests secondary or virus-induced hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory syndrome, to be the underlying cause of deterioration in these patients. This disease process carries a similar cytokine profile to patients with COVID-19, and includes cardinal clinical features of unremitting fever, cytopenias, hyperferritinemia, and pulmonary involvement.24,25 Immunomodulatory therapies that are being considered in the treatment of COVID-19 will be discussed in the “Management” section.
SARS-CoV-2 enters type 2 pneumocytes in humans via the same ACE2 receptor as SARS-CoV-1.26 A multicenter retrospective cohort study examining risk factors associated with inhospital death found hypertension to be the most common comorbidity in COVID-19-diagnosed patients requiring admission (30%), followed by diabetes (19%).27
Much has been made in recent weeks of the potential link between the commonly used antihypertensives, ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), and elevated risk for severe COVID-19 infection based on the binding of SARS-CoV-2 on ACE2 receptors. At this time, the official recommendations by the European Society of Cardiology, the American College of Cardiology, American Heart Failure Society, and the Heart Failure Society of America collectively state that patients on ACEIs and ARBs should continue their medications. The European Society of Cardiology stated, “there is no clinical or scientific evidence to suggest that treatment with ACEIs and ARBs should be discontinued because of the COVID-19 infection,”28 and the joint HFSA/ACC/AHA statement noted, "there are no experimental or clinical data demonstrating beneficial or adverse outcomes among COVID-19 patients using ACEI or ARB medications.”29
Similar concerns over the use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, have been raised based on postulated interactions with SARS-CoV-2 binding to ACE2 receptors. There is currently no scientific evidence to suggest that taking NSAIDs worsens COVID-19. Clearly, prospective multicenter trials should be conducted to investigate this issue further. A full discussion of the theoretical benefits and harms to patients on these medications can be found in the "Nephrology Journal Club"
Much can be learned from the change in the dynamics of transmission following implementation of strict travel restrictions and quarantining measures in mainland China. A mathematical modeling study published in The Lancet estimated that the median daily reproduction number (Rt) in Wuhan declined from 2.35 (95% confidence interval [CI], 1.15–4.77) 1 week before travel restrictions were introduced on January 23, 2020, to 1.05 (0.41–2.39) 1 week after.30 The effectiveness of broad governmental and societal interventions has been documented by multiple data-driven analyses, and should prompt all governments to act accordingly to prioritize early detection, isolation, and treatment; to supply adequate medical supplies; and to establish a system in which patients are admitted to designated hospitals with a comprehensive therapeutic strategy.30,31 Utilizing a stochastic transmission model parameterized to the COVID-19 outbreak, Hellewell et al concluded that “highly effective contact tracing and case isolation is enough to control a new outbreak of COVID-19 within 3 months.”32
A study published on March 16, 2020 by the Imperial College of London and WHO compared 2 fundamental policy strategies to reduce the rate of spread of SARS-CoV-2: “(a) mitigation, which focuses on slowing but not necessarily stopping epidemic spread – reducing peak healthcare demand while protecting those most at risk of severe disease from infection, and (b) suppression, which aims to reverse epidemic growth, reducing case numbers to low levels and maintaining that situation indefinitely.” The study found that “…optimal mitigation policies (combining home isolation of suspect cases, home quarantine of those living in the same household as suspect cases, and social distancing of the elderly and others at most risk of severe disease) might reduce peak healthcare demand by two-thirds, and deaths by half. However, the resulting mitigated epidemic would still result in hundreds of thousands of deaths and health systems (most notably intensive care units) being overwhelmed.”33 This explains and lends support to the aggressive measures taken by countries in recent days to battle the spread of the SARS-CoV-2 pandemic.
Reports from Italy suggest that up to 20% of healthcare professionals dealing with COVID-19 patients became infected with the virus, with some reported deaths.34 Losing healthcare workers to illness at a time when they are needed the most can be the tipping point for healthcare systems that are already stretched to the breaking point by high volumes of sick patients. Recognition of the crisis in Italy underscores the importance of strictly enforcing preventive measures to all healthcare professionals. This has been accomplished in some systems by assigning one person to monitor compliance in the ED at all times.
Based on the transmission specifications of coronaviruses as a class, and documented transmission patterns of the SARS-CoV-1 and MERS-CoV outbreaks, the transmission of SARS-CoV-2 is presumed to be primarily through droplets and fomites, although viral particles have also been found in feces of seropositive patients. A preprint article published in The New England Journal of Medicine by researchers at the United States National Institutes of Health, Princeton University, and the University of California Los Angeles, found estimated half-lives for SARS-CoV-2 virus on various surfaces as follows: 1.1 hours in aerosols, 0.77 hours on copper, 3.46 hours on cardboard, 5.46 hours on steel, and 6.81 hours on plastic. These results indicated a plausible likelihood of aerosol and fomite transmission of SARS-CoV-2, and lend credence to its reported high rate of spread.35
Both the WHO and CDC guidelines for infection control emphasize the importance of strict hand hygiene in curtailing SARS-CoV-2 transmission. This stems from the uncertainty surrounding the transmission vectors aboard the quarantined Diamond Princess cruise ship off the coastal waters of Japan, as well as increasing reports from around the world of COVID-19 appearing in people who had not had direct contact with known or suspected carrier(s) or traveler(s) to an endemic area.36,37 Given the reports from the Chinese CDC of SARS-CoV-2 virus being found in the feces of seropositive patients, the likelihood of fecal-oral and, hence, hand transmission is very high.38 Healthcare professionals and patients should follow standard hand-washing techniques: wash hands with soap and water for at least 20 seconds, especially after going to the bathroom; before and after eating; and after blowing the nose, coughing, or sneezing. If soap and water are not available, one should use an alcohol-based sanitizer with at least 60% alcohol.5
Additional guidelines for those with close contacts and suspicious exposures include “strong recommendations” for immediate medical attention, an observation period of 14 days, wearing of a facemask if coughing or with URI symptoms, prioritizing private transportation over public, prenotification of the hospital (or clinic) prior to patient arrival, and cleansing of the transport vehicle with 500 mg/L chlorine-containing disinfectant, with open ventilation.39 Note that the recommended observation period may soon be modified, given recent case reports and studies suggesting incubation periods from 0 to 24 days.40,41
Given the recent shortages of N95 respirator masks and other PPE, there is an increased need to follow current recommendations to account for changing availability of these necessary supplies. These can and should be followed in real time using the links supplied in Table 3. Additionally, recent considerations include recommendations to designate entire units within the facility with dedicated healthcare personnel to care for known or suspected COVID-19 patients, along with need for airborne infection isolation rooms (AIIRs).2
Doffing of personal protective equipment (PPE) is often the highest-risk procedure during the patient-physician interaction, in terms of spread of SARS-CoV-2. Below is a simple step-by-step approach put together by emergency clinicians at EMCrit on the proper doffing of PPE after evaluation of a suspected or confirmed COVID-19 patient.42 (See Table 2.)
A video of the correct procedures for donning and doffing PPE is available in youtube
Experience from Bergamo, in the region of Lombardia in Northern Italy, provides a model of response that may help other systems prepare. That region’s EDs encountered an overwhelming volume of patients in severe respiratory distress over short periods of time which required immediate adjustments to flow and throughput. A summary of these changes and recommendations are listed in Table 1. Of note, much of the data are estimates based on preliminary data collection.
ED staff must maintain a high index of suspicion when evaluating all patients, but especially those with fever, cough, dyspnea, or signs of a respiratory illness. The CDC had initially focused their travel warnings and epidemiological risks on those with recent travel or contact with a traveler to Wuhan City, Hubei province, China; however, having reached pandemic status with significant community spread, the connection to China is no longer relevant as a criterion to rule out SARS-CoV-2 infection.
In late January 2020, the first data detailing the clinical features, course, and prognosis from infection with SARS-CoV-2 relative to the previous 2 deadly coronavirus outbreaks (MERS-CoV and SARS-CoV-1) were published in The Lancet.21,43 Since then, a multicenter retrospective cohort analysis of 1099 patients was published in The New England Journal of Medicine, which provides an updated glimpse of demographic and clinical characteristics of COVID-19.41 Table 3 differentiates symptomatology in patients with severe versus nonsevere disease, as defined by the American Thoracic Society guidelines for community-acquired pneumonia.44 Patients with severe disease were older than those with nonsevere disease by a median of 7 years, and had much higher rates of comorbidity, namely hypertension (23.7% vs 13.4%, respectively) and diabetes (16.2% vs 5.7%, respectively). This table and article can be viewed in The New England Journal of Medicine. Table 3 summarizes the early characteristics of SARS-CoV-2 compared to MERS-CoV and SARS-CoV-1.
On March 18, 2020 the American Journal of Gastroenterology published a new study from the Wuhan Medical Treatment Expert Group for COVID-19 in China revealing that GI symptoms, such as diarrhea, are common in SARS-CoV-2 infection.46 In 204 patients confirmed to have SARS-CoV-2, 99 (48.5%) had GI symptoms, and 7 of the patients with GI symptoms had no respiratory symptoms whatsoever. This is clearly a departure from the purely respiratory disease current guidance has provided, but consistent with the observed fecal-oral transmission patterns noted in earlier cited Chinese studies. Furthermore, the prognosis of patients with GI symptoms was worse than for those with purely respiratory symptoms. They found that patients without digestive symptoms were more likely to be cured and discharged than patients with digestive symptoms (60% vs 34.3%). The authors failed to ascertain the etiology of the mortality and morbidity difference between COVID-19, and recommend further studies.46
It should be noted that in the initial data from Bergamo, Italy described by Dr. Andrea Duca, there is a reported association of obesity with disease severity and need for intubation/critical care. From the same data, the rates of patients needing NIV or intubation in the ED are similar to data from Wu et al,45 accounting for up to 31% of suspected COVID-19 patients admitted to the hospital. It is still too early to know how many patients who were started on NIV in the ED will be converted to invasive ventilation during the hospital stay and how many on oxygen will deteriorate and need to be ventilated. These data are still being collected and analyzed, and will soon be available for analysis and publication.
Within 1 month of initial reports detailing the SARS-CoV-2 outbreak, the CDC developed a real-time reverse transcription-polymerase chain reaction (rRT-PCR) test to detect SARS-CoV-2. While diagnostic testing in the United States was available initially only through the CDC, this assay is now being made available at the state level with the use of the International Reagent Resource (IRR). The IRR was initially established by the CDC for the study and detection of influenza, but it has been expanded to include newly discovered influenza and coronaviruses.47,48 It should be noted that widely available respiratory viral panels test only for the earlier forms of human coronavirus, namely human coronaviruses 229E, NL63, OC43, and HKU1.49 The SARS-CoV-1, MERS-CoV, and SARS-CoV-2 strains require specialized assays that are becoming increasingly available. Unfortunately, the initial United States testing efforts were hampered by faulty initial test kits (due to problems with the reagent), and as a result, there was a lack of testing available for the majority of the country. Table 4 summarizes the current recommendations for SARS-CoV-2 testing.
In what has become a controversial policy reversal as the outbreak increases in the United States, there is a significant departure from previous guidance of testing any persons, including healthcare personnel who have had close contact with a suspected or laboratory-confirmed COVID-19 patient, or who have a history of travel from endemic areas within 14 days of their symptom onset. At the time of this publication, the current recommendation is to not test the asymptomatic healthcare workers who have known exposures, or other asymptomatic individuals with concerning exposures and/or travel history. There is also a pedaling back of recommendations to test any persons who do not need to be admitted to the hospital. It is unclear at this point whether these recommendations will change again.
There are additional epidemiologic factors that may also help guide decisions about SARS-CoV-2 testing. Documentation of COVID-19 in a locality with known community transmission may assist with the epidemiologic risk assessment to guide testing decisions. However, the inability of many locales and hospitals to test all persons has led to a rescinding of this recommendation. Given the increasing concern about the availability and reliability of SARS-CoV-2 testing, there is varying guidance provided at the federal, state, and local levels. Nonetheless, when clinicians decide to test, they should recall that in cases of high suspicion and based on early research in China (as well as reported by Duca in Italy, two negative tests repeated at least 24 hours apart (3 days in Italy), are needed to exclude COVID-19 as a diagnosis.51
Given this information, emergency clinicians should re-emphasize to the lay public what we already know of viral respiratory infections: that seeking treatment in a hospital setting for mild symptoms, fever, mild diarrhea, or cough alone likely carries with it more risk than benefit, both to themselves and to vulnerable patients around them. Patients experiencing severe symptoms such as difficulty breathing, high fever (>39°C), and an inability to tolerate oral hydration should seek emergency evaluation. For those who are concerned about their symptoms or concerned about spreading the infection to vulnerable family members, care should be taken to practice social distancing, self-quarantining, and utilization of telehealth and drive-through screening clinics to receive medical evaluation and testing (if warranted) while minimizing risk of infectious spread. Though beyond the scope of this review, further discussions regarding institutional and departmental policies that weigh the need to protect the health of medical staff and care for patients versus the need to minimize nosocomial spread from asymptomatic healthcare workers who may infect patients, will need to continue.
In the initial onset of SARS-CoV-2 outbreak in the United States, many clinicians were encouraged to test for other causes of respiratory illness (eg, influenza), based on recommendations from their infectious disease and infection prevention services. However, there has been ongoing debate regarding the testing and evaluation for COVID-19 in relation to co-infections with other viruses.
After an exhaustive search of the literature, interviews with several infectious disease physicians, consultation of several national and international forums dedicated to both emergency medicine and COVID-19, we were able to find only a single non-peer reviewed Chinese study of 8274 specimens collected and analyzed for SARS-CoV-2 and other viral species. (Note that the publisher states, “This article is a preprint and has not been peer reviewed. It reports medical research that has yet to be evaluated and so should not be used to guide clinical practice.”) In this study, they found that 5.8% of COVID-19 patients had co-infections with other viruses, and that 18.4% of other (non-SARS-CoV-2) infections had other co-infectants.52 The authors acknowledged the unreliability of their tests for both SARS-CoV-2 and other viruses, which may underreport the actual co-infection rate. Furthermore, in some preliminary data reported by Stanford Medicine Data scientists, and immediately available to the public online at the behest of the California Department of Public Health, researchers found that in the 49 positive SARS-CoV-2 results, 11 (22.4%) also had co-infection with another virus.53 We anticipate that a large, validated study will help to shed further light on the rate of co-infection with SARS-CoV-2. In the meantime, we must recommend that clinicians maintain a high index of suspicion for SARS-CoV-2, regardless of the presence of other viruses.
As illustrated in Table 1 of a recent study published in The Lancet, univariate analyses of the following patient characteristics and laboratory markers were associated with increased mortality: increased age, lymphopenia, leukocytosis, and elevations in ALT, lactate dehydrogenase, high-sensitivity cardiac troponin I, creatine kinase, D-dimer, serum ferritin, IL-6, prothrombin time, creatinine, and procalcitonin.27 Multivariate regression models showed increasing odds of in-hospital death associated with older age (odds ratio [OR], 1.10; 95% CI,1.03-1.17 per year increase, P = .0043), higher sequential organ failure assessment (SOFA) score (5.65, 2.61-12.23; P < .0001), and D-dimer > 1 mcg/mL (18.42, 2.64–128.55; P = .0033) on admission.27 This table can be found at The Lancet
A recently published meta-analysis on procalcitonin in COVID-19 patients suggests that procalcitonin levels should remain in the reference range in patients with noncomplicated COVID-19, and that an elevation in procalcitonin may reflect bacterial co-infection in patients developing a severe form of COVID-19.54 A meta-analysis of platelet counts in COVID-19 patients found that thrombocytopenia is associated with increased risk of severe disease, and that a substantial decrease in platelet count should serve as a clinical indicator of worsening illness in patients hospitalized with COVID-19.55 See Table 5 for laboratory markers correlating with disease severity and clinical management for patients with COVID-19 pneumonia.
Data from the CDC released on March 17, 2020 shows a disconcerting trend in hospitalization rates in the younger-age demographic. Table 6 shows the latest rates, with an alarming rate of hospitalization of up to 20% in individuals aged 20 to 44 years. The good news for the pediatric population is that there have been no deaths reported in the United States at the time of publication. (See the “Pediatric Population” section.)
Findings on chest imaging in COVID-19 have been similar to findings seen in previous years from the SARS-CoV-1 and MERS-CoV outbreaks. A cohort analysis of 41 COVID-19 patients found all but 1 with bilateral lung involvement.21,59 A study of computed tomography (CT) scans of 21 COVID-19 patients showed 3 (21%) with normal CT scans; 12 (57%) with ground-glass opacity only; 6 (29%) with ground-glass opacity and consolidation at presentation; and interestingly, 3 (14%) with normal scans at diagnosis. Fifteen patients (71%) had 2 or more lobes involved, and 16 (76%) had bilateral disease.60 Of the 18 patients with positive findings on chest CT, all had the presence of ground-glass opacities, with 12 of the 18 having concomitant lobar consolidations.60
Data on 101 cases of COVID-19 pneumonia analyzed retrospectively from 4 institutions in Hunan, China found lesions present on CT were more likely to show a peripheral distribution (87.1%), bilateral involvement (82.2%), lower lung predominant (54.5%), and multifocal (54.5%).61 These findings, specifically the peripheral distribution of lesions, reflect positively on the ability of lung ultrasound to detect COVID-19 pneumonia.
Given the rate of nosocomial spread of the virus, the resource-intensive nature of obtaining CT scans in these patients, and the risk of transporting unstable hypoxemic patients, routine CT scans are not recommended in COVID-19 patients, as it rarely leads to a change in management. The American College of Radiology supports the use of CT sparingly, mainly in hospitalized symptomatic patients who may have other pathologies that need to be considered.62 Figure 6 presents a schema for imaging in patients with suspected COVID-19 pneumonia.
Recent literature as well as anecdotal reports from Italy offer support for using lung ultrasound as a way to screen patients with suspected COVID-19 pneumonia. For evaluation of pneumonia and/or adult respiratory distress syndrome (ARDS), lung ultrasound gives results that are similar to chest CT and are superior to standard chest radiography, with the added advantage of ease of use at point of care, repeatability, absence of radiation exposure, and low cost.63 Table 7 details findings on lung ultrasound as they correlate to findings on chest CT, with COVID-19 commonly resulting in lung pathology in the posterior lobes.64 In Italy, this has proven to be a useful screening tool. (See Table 1.)
With increasing disease severity, an evolution of findings on lung ultrasound may be seen.64 (See Figure 7.)
A YouTube video of an ultrasound scan of a patient with COVID-19 pneumonia [Courtesy Giovanni Volpicelli, MD]
Healthcare providers interested in receiving training to spot characteristic changes in the lung parenchyma in patients with COVID-19 can reference a recently published article by Huang et al, which has multiple examples of ultrasound images correlated to findings on high-resolution chest CT.65 This article and the images can be seen in Research Square
The article, “A Rapid Advice Guideline for the Diagnosis and Treatment of 2019 Novel Coronavirus (2019-nCoV)-Infected Pneumonia (standard version),” published in the journal, Military Medical Research, provides rapid advice guidelines and diagnostic imaging of several cases.39 Figure 8 presents a typical x-ray and CT images of a patient with COVID-19.
The article, “Evolution of CT Manifestations in a Patient Recovered from 2019 Novel Coronavirus (2019-nCoV) Pneumonia in Wuhan, China,” published in the journal Radiology, published 6 images of the evolution of chest imaging of a 42-year-old male patient infected with COVID-19 who recovered over 31 days.66
In the case of infection with any of the coronavirus strains, there is no approved treatment specific to the virus. Many patients with confirmed COVID-19 pneumonia in a recent JAMA study received broad-spectrum antibacterial therapy (moxifloxacin, 89 [64.4%]; ceftriaxone, 34 [24.6%]; azithromycin, 25 [18.1%]) with most receiving anti-influenza therapy (oseltamivir, 124 [89.9%]), and some additionally receiving steroids (glucocorticoid therapy, 62 [44.9%]).2 Given the evolving nature of this pandemic, clinicians may be well served by seeking the guidance of nations or health systems that have implemented proven treatment and management protocols. One such guidance from Belgium, entitled “Interim Clinical Guidance For Patients Suspected Of/Confirmed With Covid-19 In Belgium”. Recommendations from the Italian Society of Infectious and Tropical Diseases can be found here (published in Italian)
For an additional example, see Figure 9 for the Boston Medical Center’s COVID-19 treatment protocol.
Considering the lack of direct evidence with regard to treatment of COVID-19, recently proposed guidelines have been built largely on treatment guidelines for SARS-CoV, MERS-CoV, and influenza infections. Currently, there are weak recommendations for alpha-interferon atomization inhalation twice/day, and lopinavir/ritonavir orally twice/day; however, evidence supporting these in reducing the incidence and mortality of ARDS in patients infected with SARS-CoV-1 and MERS-CoV are limited to case series and case reports.39 A recent systematic review showed that lopinavir/ritonavir’s anticoronavirus effect was seen mainly in its early application, and no significant effect was seen in late application of therapy.67 A recently published randomized controlled trial in The New England Journal of Medicine on 199 hospitalized COVID-19 patients found no benefit to mortality or time to clinical improvement with lopinavir-ritonavir treatment. Positive trends in nonprimary outcomes, such as complications of acute kidney injury, serious infections, and rate of noninvasive or invasive mechanical ventilation were noted; however, the study ended enrollment as another study using remdesivir became available.68 At this time, the use of combination antivirals in the treatment of COVID-19 is controversial, as there are currently no randomized controlled trials in humans to support their use.69,70
Remdesivir has recently been recognized as a promising antiviral drug against a wide array of RNA viruses, including SARS-CoV-1 and MERS-CoV infection in vitro and in nonhuman primate models.71 Recent in vitro studies conducted on COVID-19 have found that remdesivir and chloroquine inhibit viral infection of cells with low micromolar concentration with a high selectivity index.72 There are ongoing clinical trials in multiple countries testing the efficacy of remdesivir, though at this time this drug is available only for compassionate use in severe COVID-19 cases, and is not available commercially.
A recent open-label non-randomized control study between treatment with favipiravir and interferon-alpha (treatment group) and lopinavir/ritonavir and interferon-alpha (control group) found significant reduction in the time to viral clearance (median 4 versus 11 days, P < .001) and improvement rate on chest CT scan at day 14 (91.4% to 62.2%, P = 0.004); it should be noted, severely ill patients were excluded from this study.73
In a systematic review in the Chinese literature of treatments for SARS-CoV-1, 14 studies were identified in which steroids were used. Twelve studies were inconclusive and 2 showed potential harm. One study reported diabetes onset associated with methylprednisolone treatment.74 Another uncontrolled, retrospective study of 40 SARS patients reported avascular necrosis and osteoporosis among corticosteroid-treated SARS patients.59 A randomized, double-blind, placebo-controlled trial measured SARS-CoV-1 plasma viral load across time after fever onset and found corticosteroid use within the first week of illness was associated with delayed viral clearance.75
However, a recent study performed in China examining risk factors associated with the development of ARDS in COVID-19 patients found that treatment with methylprednisolone decreased the risk of death among patients with ARDS (hazard ratio, 0.38; 95% CI, 0.20-0.72).45 These data lend support to the theory that deterioration in COVID-19 patients occurs secondary to an immunopathogenesis and development of a “cytokine storm,” which can be mitigated by administration of glucocorticoids in patients with severe ARDS.
Cytokine storm is being increasingly examined as a culprit behind the rapid deterioration of COVID-19 patients several days to weeks after initial infection by SARS-CoV-2, which raises the possibility of utilizing inflammatory cell receptor blockers and stem cell therapy as potential therapeutic agents. Multicenter clinical trials are underway investigating tocilizumab (IL-6 receptor blocker) in the treatment of COVID-19 pneumonia.20 A more comprehensive list of ongoing investigations and trials into novel therapies against SARS-CoV-2 can be found in Monthly Prescribing Reference.
A considerable amount of literature has attributed a variety of antiviral and immunomodulatory effects to chloroquine, including the suppression of IL-6, a cytokine believed to play a significant role in the deterioration of COVID-19 patients into severe ARDS.20,76 Chloroquine has also been shown to act as an effective antiviral medication in animal models infected with avian influenza and SARS-CoV-1.77,78 Unpublished data emerging from China suggest that chloroquine has been studied as a treatment for COVID-19, with favorable results.79 The Guangdong Provincial Department of Science and Technology and the Guangdong Provincial Health Commission recently submitted an expert consensus report that recommended chloroquine treatment of new coronavirus pneumonia with a treatment regimen of 500 mg orally twice daily for patients without contraindications.80 A recent study published in Clinical Infectious Diseases, using physiologically based pharmacokinetic models, found increased potency of hydroxychloroquine over chloroquine (EC50 = 0.72 μM vs 5.47 μM, respectively) in lung tissue. This study recommends a 400 mg loading dose twice daily for 1 day, followed by a 200 mg maintenance dose twice daily for 4 days.81 Clinical trials are underway to formally investigate the use of these medications both as a therapeutic and prophylactic agent against COVID-19 in humans.82 A recent nonrandomized clinical trial of 20 patients found hydroxychloroquine treatment to be significantly associated with viral load reduction and disappearance in COVID-19 patients, with this effect increased by the addition of azithromycin. Hydroxychloroquine dosing was 600 mg daily, and azithromycin was 500 mg on the first day followed by 250 mg daily for 4 days.83 (Note that the publisher states, “This article is a preprint and has not been peer reviewed. It reports medical research that has yet to be evaluated and so should not be used to guide clinical practice.”) Clinical trials are underway to formally investigate the use of these medications both as a therapeutic and prophylactic agent against COVID-19 in humans
There is no significant literature at present on optimal fluid management in patients with COVID-19, nor is there literature that describes new-onset congestive heart failure secondary to the virus. As previously described, a leading theory in the pathophysiology of rapidly deteriorating COVID-19 patients is that ARDS (noncardiogenic pulmonary edema) is brought on by a hyperinflammatory state. Given that this is not a form of distributive or hypovolemic shock that is seen in bacterial sepsis and the resulting pulmonary edema is the primary life-threat to those with severe COVID-19, the authors recommend a judicious approach to fluid resuscitation on a case-by-case basis.
In patients who deteriorate and require ICU-level care, clinicians should consider noninvasive ventilation (NIV), mechanical ventilation, or extracorporeal life support, if necessary.39 The development of ARDS and respiratory decompensation plays a central role in the pathogenesis of COVID-19. In this sense, the following treatment principles are key in managing COVID-19 patients:
Preliminary unpublished data from Andrea Duca, MD in an ED in Bergamo, Italy shows that from February 29 to March 10, 2020, the rate of patients presenting to the ED with suspected COVID-19 who needed admission for oxygen therapy increased by 138%. Among those admitted patients, 31% were still hypoxic on maximal oxygen therapy and started on ventilatory support in the ED (81% CPAP, 7% NIV, 12% invasive ventilation), with 82% showing criteria for moderate to severe ARDS.
Data from China and Italy suggest that COVID-19 patients who are hypoxemic respond well to PEEP, indicating a crucial role for NIV as a therapeutic and stopgap measure to prevent intubation.45 The statistics from retrospective analyses in China indicate that up to 30% of admitted patients required NIV,84 while early reports from Italy indicate figures approaching 31%. Given current epidemiological trends, these requirements are likely to outpace the current capacity of most, if not all, hospitals if aggressive preparatory measures are not taken. Based on the current data from China and Italy, we recommend the following:
See Figures 10, 11, and 12 for image of single-limb NIV device, demonstration of wear, and a helmet CPAP with viral filter before PEEP valve .
In the event a patient presents in severe respiratory distress or fails prior use of NIV, the clinician must prepare for invasive ventilation and endotracheal tube intubation. See Table 8 for rapid sequence intubation (RSI) steps.
There is ongoing controversy as to the role of preoxygenation and the possible spread of viral particles while utilizing the typical techniques. A review on this subject can be found in EMcrit. In the meantime, the commonly utilized choices are:
For a brief synopsis on the indications, principles, and various types of mechanical ventilation, please see Hickey et al. For COVID-19 patients, special emphasis should be placed on the “Lung Protective Strategy” section, based on the ARDSnet trials, which showed that low tidal volume ventilation in patients with ARDS improved mortality.85 Briefly:
Tidal volume (TV) should be initially set at 6 mL/kg based upon ideal body weight. As patients develop acute lung injury and progress into ARDS, their lungs become progressively recruited and develop shunts, which leads to decreased functional lung volume. A low tidal volume strategy offsets the decreased functional lung volume. Tidal volume should not be adjusted based on minute ventilation goals. Respiratory rate is adjusted based upon minute ventilation goals and the acid-base status of the patient. An initial rate of 16 breaths/min is appropriate for most patients to achieve normocapnia.86
In disaster situations when the number of patients requiring mechanical ventilation outpaces the number of available ventilators, ventilators can be rigged to split airflow to multiple patients. Click here for a video tutorial on how to accomplish.
The key take-aways for this maneuver include the following:
Children seem to have been relatively spared from the worst complications and mortality of this disease, as noted in the CDC rates of hospitalization per age group. (See Table 6.) To date in the United States, and from our co-author’s experience in Northern Italy, there have been no reported deaths in children. However, in a prepublication paper released on March 16, 2020 in the Journal of Pediatrics, Dong et al analyzed 2143 children in China with suspected and confirmed SARS-CoV-2 infection and found that almost “4% of children were asymptomatic, 51% had mild illness and 39% had moderate illness. About 6% had severe or critical illness, compared to 18.5% of adults. One child, a 14-year-old boy, died.”87 The study also found that infants had higher rates of serious illness when compared with older children. Approximately 11% of infants had severe or critical cases compared to 7% of children ages 1 to 5 years; 4% of those 6 to 10 years; 4% of those 11 to 15 years; and 3% of those aged 16 years and older. There are several theories speculating on the vast differences between adults and children, such as “higher levels of antibodies against viruses or different responses from their developing immune systems.”87 Another theory is related to the relative lack of or poorly developed ACE2 receptors in children, which prevents the virus from being able to bind as well to children’s cells. Wu et al reported in their Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention of approximately 1000 children under the age of 19, no reported deaths in children younger than 9 years of age.84 In a recent correspondence to the New England Journal of Medicine, researchers from China found that of the 171 cases confirmed to have SARS-CoV-2, there was only 1 death in a 10-month old child, who had multiple co-morbidities.88
In a small retrospective study in China, 20 confirmed SARS-CoV-2-positive pediatric patients were analyzed with CT scans of their chests as well as laboratory markers, including procalcitonin. The authors found that procalcitonin was elevated in 16/20 patients, chest CTs showed consolidation with surrounding halo signs in 10/20 patients, and 12/20 showed ground-glass opacities. It was also suggested that underlying co-infection may be more common in children (8/20), and a consolidation with surrounding halo sign is considered a typical sign for this population.58 Even though the pediatric population may be spared the morbidity and mortality seen in adults, clinicians should be aware that they may infect more vulnerable populations and should encourage social distancing. Further research in the American pediatric population will better help the understanding and management of severe disease presentations in children in the United States.
The data on pregnant patients with COVID-19 still remains sparse.89 Generally, pregnant women with SARS-CoV-2 infection share the same characteristics of nonpregnant women with the virus. In a retrospective review of 9 patients, Chen et al analyzed the risk of maternal-fetal transmission of SARS-CoV-2 and found that intrauterine transmission from SARS-CoV-2-positive mothers was shown to be unlikely.90 Additionally, in those patients, they found very few complications related to pregnancy, unlike the complications that were characteristic of pregnant women with SARS.91,92 . Clearly, larger studies will need to be conducted to better evaluate the risk of vertical transmission between mother and fetus with SARS-CoV-2 infection.
Shared decision-making is a collaborative process in which patients and providers make healthcare decisions together, taking into account scientific evidence, the clinician’s experience, as well as the patient's values and preferences. Although the scientific evidence underlying the testing and treatment of SARS-CoV-2 infection is nascent and evolving rapidly, certain knowledge is known and extrapolation from other serious infectious diseases is justified. There are at least 2 clinical scenarios related to COVID-19 that may be appropriate for SDM: (1) testing for SARS-CoV-2 in mildly symptomatic patients and (2) goals-of-care discussion in critically ill patients.
Given that there are no treatments proven to be beneficial for COVID-19 at the time of this writing, making the diagnosis of this disease in mildly symptomatic patients may not change clinical management. Standard supportive care, as is used for typical viral upper respiratory infections, can be recommended for patients, without testing for SARS-CoV-2. These would include over-the-counter antipyretics, antitussives, decongestants, analgesics, oral fluids, and rest. Patients would also be instructed to practice self-isolation to prevent spread of COVID19 to other individuals. The current tests for SARS-CoV-2, using RT-PCR, has a sensitivity between 60% and 90% and can generate false-positive or false-negative results. Given the real possibility of a limitation in testing resources, it may be reasonable for patients with possible COVID-19 to forgo testing, assume that they have the virus, and take the socially responsible precautions. Given the rapidly changing guidance around testing from institutions and government health agencies, adherence to your hospital, state, or local policies should be followed and explained to the patient.
Another clinical scenario that would be appropriate for shared decision-making would be endotracheal intubation for a patient in respiratory failure with a poor prognosis, either due to advanced age or severe comorbidities. This decision will be frequently encountered since ARDS is a common final pathway for many patients with COVID-19. Early studies have demonstrated high mortality rates for older patients, particularly those over age 80. In this scenario, providers could potentially engage in shared decision-making with patients or their surrogates to collaboratively decide whether or not intubation is justified. This is similar to other goals-of-care discussion around code status for patients with advanced age and/or end-stage diseases.
In our first iteration, we speculated on the future of what was not yet a pandemic. Unfortunately, the future is here, and we are in the midst of a growing pandemic that has shut down cities, nations, and continents. We may be best served to look at past events to learn from others’ missteps and seek opportunities to improve for the regions of the world not yet inundated with COVID-19.
“Community spread,” “stealth transmission,” “social distancing,” and “flattening the curve” have become common parlance as the public and medical societies attempt to understand and control COVID-19. With an R0 value mimicking pandemic influenza, the spread and containment of SARS-CoV-2 faces unprecedented challenges.93 We continue to find that constantly changing daily information (and misinformation) have added to the challenges to the general public as well as the medical community. The Lancet published an online editorial, which appeals to the medical community and the public alike to seek verified information through the CDC or WHO and avoid social media and other unverified sources for information. Many worried well patients will show up in the ED, taxing already overburdened systems. This is an opportunity for hospital leadership to develop and/or expand their telehealth options, to minimize the numbers of worried well or low-risk patients with mild symptoms overwhelming local EDs.
There are now several biotech and pharmaceutical companies racing for a vaccine for SARS-CoV-2, and although studies are promising, widespread availability and use are at least 18 months away (summer of 2021). A DNA vaccine candidate for SARS-CoV-2 has entered into human clinical trials, while 2 vector-based candidates have begun human trials; protein-based vaccines are still at the preclinical stage.72 There are still challenges to the successful development of a vaccine due to incomplete understanding of viral transmission, pathogenesis, and immune response; and lack of optimal animal challenge models and standardized immunological assays.
We believe China, Washington state, Italy, and now the New York metropolitan area should serve as examples for the rest of the world not yet inundated with SARS-CoV-2. Being prepared for an onslaught of cases is the first step all healthcare systems need to accept. Testing and isolating infected or suspected persons early has shown benefit in China, South Korea, and elsewhere, and locales such as New York City can attest to the negative effect of being unprepared for mass testing and expeditious containment of spread on its populations.
In the event of a mass influx of patients with exposure to SARS-CoV-2 or symptoms concerning for COVID-19, immediate isolation is required. If 1 infected person presents to a busy ED triage area, there is a high likelihood of spreading the virus and potentially contaminating others. The CDC recommends placing ample touchless hand sanitizer stations and easy-to-dispense boxes of face masks at entrances to the ED and hospital. They also recommend placing signs that advise anyone entering the facility to “immediately put on a mask and keep it on during their assessment; cover their mouth/nose when coughing or sneezing; use and dispose of tissues carefully; and perform hand hygiene after contact with respiratory secretions.”94 The authors recommend hospital and departmental leadership pursue the following directives:
The single best way to save the most people and reduce morbidity is to be proactive and not reactive. Those of us in the midst of this crisis wish we could have done things differently and implemented the above recommendations from the moment we encountered patient zero. Our lack of early testing and strict isolation run counter to what epidemiologists recommend to control infectious outbreaks. Please learn from our mistakes.
You recognized the need for immediate and proper donning of personal protective equipment. You and a nurse put on your complete PPE and obtained the patient’s vital signs, which confirmed a temperature of 39.6°C [103.3°F], pulse of 106 beats/min, respirations of 22 breaths/min, blood pressure 102/68 mm Hg, and pulse oximetry 89% on room air. You performed bedside lung ultrasound using the “lawnmower” technique to visualize as much lung as possible, which confirmed bilateral B-lines in the posterior lungs with confluence producing a characteristic “waterfall sign.” You placed him in a negative pressure isolation room, starting him immediately on supplemental oxygen, and confirmed his travel history and possible contacts with people who may have been exposed to COVID-19. After careful, proper doffing of your PPE, you contacted your hospital infectious disease and infection prevention team, who directed you to also contact your local department of public health, who then sent a representative to find out his possible contacts. You deferred obtaining a CT, as it would not have changed this patient’s management. You sent a battery of lab tests, including a D-dimer, procalcitonin, and LDH, started empirical coverage for bacterial pneumonia, consulted the CDC and WHO for up-to-date guidance on additional treatment recommendations, and remembered to consider steroids only if the patient’s condition deteriorated and he developed ARDS.
The remaining “worried well” and otherwise clinically stable patients were given the current recommendations of the CDC and, based on their respective risk profiles, offered symptomatic treatment or outpatient testing of COVID-19 with mandatory isolation for 14 days and symptom monitoring. Consultation with your local Department of Health and Infection Prevention department for the current testing and treatment protocols will help guide the management for those well enough to self-isolate at home.
|Table 9. Helpful Resources for COVID-19|
|United States Centers for Disease Control and Prevention||Coronavirus Disease 2019 (COVID-19)|
|World Health Organization||Coronavirus disease (COVID-19) outbreak|
|Johns Hopkins University||COVID-19 Global Case Tracker|
|United States Department of Labor, Occupational Safety and Health Administration||COVID-19 Additional Resources|
|American College of Emergency Physicians||COVID-19 Clinical Alert|
|The Lancet||COVID-19 Resource Centre|
Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.
To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study will be included in bold type following the references, where available.