Beating the Pandemic: What Emergency Providers Should Know About COVID-19

The disease associated with the 2019 novel coronavirus (COVID-19) is now a significant event in world history, with uncertain but likely major consequences for individuals, families, healthcare workers, health systems, and the global economy. There still is a great deal to be learned. Although COVID-19 appears to pose only a limited danger to children, older adults face the possibility of much more serious manifestations. In addition, healthcare professionals and systems are under serious threat of being overwhelmed. Staff may be in shortage because of illness or the need for isolation. Hospital systems may need to divert resources from areas and specialties under less strain than others. In short, at this time it seems COVID-19 will demand the attention of most practitioners and allied health providers over the next year. Thus, familiarization with what is known so far about its pathophysiology, epidemiologic risk factors, treatment, and future directions for research is important as we face and fight this crisis united as healthcare providers.

Terminology

During crisis situations, accurate communication is vital to ensure healthcare providers and the public are properly informed. Thus, consistent terminology should be used when discussing COVID-19. Because of the novel character of this virus and to ensure the proper epidemiologic terms are employed, the following definitions may be helpful:

Severe acute respiratory syndrome (SARS): The infectious disease caused by a zoonotic coronavirus (SARS-CoV) that spread between multiple countries in East Asia and Canada in 2002-2003.¹

Middle East respiratory syndrome (MERS): The infectious disease caused by a zoonotic coronavirus (MERS-CoV) that spread between multiple countries in the Middle East and South Korea from 2012 to the present.²

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): The currently proposed name of the virus related to the December 2019 outbreak in Wuhan, China.¹ The name is proposed by the Coronavirus Study Group of the International Committee on the Taxonomy of Viruses. In materials distributed for the public, the World Health Organization (WHO) also will refer to the virus as “COVID-19 virus” to avoid confusion.³

Coronavirus Disease 2019 (COVID-19): The currently accepted name by WHO for the disease caused by SARS-CoV-2.³ The name was chosen following international guidelines to avoid stigmatizing any particular location, region, animals, or food items.⁴

Endemic: A disease that is constantly present, prevalent, and expected in a given area.⁵

Epidemic: A sudden rise in the cases of a disease beyond what normally is expected.⁵

Outbreak: The same definition as epidemic, but generally in a more limited area (such as a city or province).⁵

Pandemic: An epidemic that has spread across multiple countries.⁵

Microbiology of Coronaviruses

Coronaviruses are named for the club-like projections of surface proteins from the virus particle that appear to create a crown, or “corona,” on electron micrographs.⁶ (See Figures 1 and 2.) Coronaviruses are enveloped, nonsegmented, single-stranded, positive-sense ribonucleic acid (RNA) viruses, with the largest known genome among all viruses (approximately 30 kb).^6,7

Numerous coronaviruses are known to cause diverse clinical syndromes in humans and animals, including mild to severe disease in such species as bats, rats, mice, chickens, turkeys, cattle, beluga whales, dogs, cats, rabbits, livestock, and pigs.⁷ In these animals, disease can manifest in the central nervous system, the respiratory tract, the gastrointestinal (GI) tract, the hepatobiliary system, and the renal system.⁷

Pathogenic human coronaviruses (HCoVs) were identified first in the 1960s.⁸ Four strains of community-
transmitted, seasonal HCoVs now have been identified: HCoV 229E, OC43, NL63, and HKU1. Each of these coronaviruses is an endemic cause of generally mild, self-limited respiratory infections in children and adults. Notably, 60% to 90% of adults will become seropositive for at least one of these viruses in their lifetime.⁶

The novel coronaviruses SARS-CoV and MERS-CoV emerged in 2003 and 2012, respectively, causing major epidemics of severe respiratory illnesses. SARS-CoV was determined to have a natural reservoir in horseshoe bats, supported by findings of highly conserved SARS-related CoVs in bats that use the same cellular receptor as the human virus.⁹ There also were findings of similar viruses in palm civets and other mammals that were postulated to act as intermediate animal hosts in the “wet markets” (exotic animal and seafood markets) of China. MERS-CoV also has been linked to previously identified bat coronaviruses, with the dromedary camel acting as an intermediate host.¹⁰ After containment of both of these outbreaks, it was suggested that new, zoonotic coronaviruses would continue to emerge in the future, causing novel human and animal diseases through their ability to recombine and infect multiple species and cell types.⁷

Novel 2019 Coronavirus

In December 2019, an outbreak of pneumonia of unknown etiology emerged in Wuhan, China, with a case cluster apparently linked to the Huanan Seafood Wholesale Market — a marketplace for seafood and various animals from regions throughout East and Southeast Asia.¹¹ These cases were identified using a reporting mechanism for “pneumonia of unknown etiology” that originally had been developed in the wake of the previous SARS epidemic.¹² Although retrospective case identification was able to pinpoint cases of pneumonia associated with the Huanan Seafood Wholesale Market as early as Dec. 13, 2019, further cases with no clear epidemiologic link were identified as early as Dec. 1, 2019.¹³ This suggested that transmission potentially had occurred as early as November 2019, but had been undetected.

The China Center for Disease Control and Prevention (China CDC) conducted initial viral studies, which included lower respiratory tract samples, in four of the known patients from the December 2019 cluster. In these patients, no specific pathogens could be identified by the RespiFinderSmart22kit (including known HCoVs).¹¹ Further genomic sequencing of extracted RNA revealed sequences that matched with betacoronavirus lineage genomes, including > 85% identity with a previously published bat SARS-like CoV. Later confirmed by whole genome sequencing and viral culture, the newly isolated virus initially was named 2019-nCoV. ^11,14 Although genetically distinct from SARS-CoV and MERS-CoV, it fell within the same genus. These studies were repeated and confirmed in samples from additional patients from hospitals in Wuhan, with continued phylogenetic analysis providing further evidence that 2019-nCOV was more similar to bat-derived coronavirus strains than strains known to infect humans.^15,16 The data suggested a bat reservoir for coronaviruses in general, including 2019-nCoV; however, the data also suggested that an intermediate animal (not a bat) may have been infected and amplified the virus in the Huanan Seafood Wholesale Market, although this remains incompletely understood.¹⁶ Similarly, SARS-CoV and MERS-CoV were believed to pass through other intermediate host animals.^17,18 This raised further questions about the transmission of 2019-nCoV and its emergence as a human pathogen. One study suggested that a snake species may have been an intermediate host (based on similar codon usage) and two others implicated pangolins; however, neither hypothesis has been widely accepted, and further research is needed.^19,20,21

Ultimately, by Dec. 31, 2019, the China CDC announced an outbreak investigation was underway, and by Jan. 1, 2020, it had closed the Huanan Seafood Wholesale Market.¹² This was followed by case investigation and contact tracing by the China CDC. By mid-January 2020, as cases accrued and the natural history of the pneumonia of unknown etiology became clear, the China CDC announced the outbreak response had been upgraded to “Level 1,” the highest designation for such measures.¹² Meanwhile, the China CDC also had developed primers for molecular identification of the novel coronavirus disease and released the virus’s genetic sequence for distribution to health authorities globally. This ultimately served as a significant step forward for other nations to rapidly develop their own molecular identification assays.

Nevertheless, human-to-human spread was well underway, as cases in other provinces in China were reported by the end of January, and cases associated with travel to Wuhan were reported abroad in Southeast Asia.¹² On Jan. 22, 2020, the Chinese government issued a quarantine notice for the entire city of Wuhan, the center of the epidemic.²² However, at this point, outbreak containment was complicated by the Chinese New Year travel plans of many Chinese citizens, many of whom had traveled before the quarantine went into effect, as well as likely asymptomatic or mildly symptomatic spread of the virus among the population at large.^23-25

Several initial case series regarding the virus were published by late January 2020, providing the global community with a view into the epidemic and better delineating rates of severe disease, complications, and mortality among patients with confirmed infection.^12,13,26 These studies emphasized that the burden of severe disease rested in particular with the elderly and those with comorbid conditions, but also provided early hints of the strain that healthcare facilities would face because of the need for drastic infection prevention measures, intensive care unit (ICU) support, and intensive ventilatory support measures, including extracorporeal membrane oxygenation. To alleviate these strains on the healthcare system, Chinese authorities undertook emergency measures of creating multiple facilities strictly dedicated to cohorting hundreds to thousands of COVID-19 patients, some of which were field hospitals constructed within days.²⁷

The number of confirmed cases rose rapidly throughout February 2020, with Chinese cases numbering into the tens of thousands. WHO member states discovered and reported cases in rapid succession, frequently associated with travel from East Asia, but with many indicative of community spread within their borders. On Feb. 11, 2020, WHO announced that the label “COVID-19” should be applied to the new disease in an effort to avoid stigmatizing regions where it had been first identified.³ By Feb. 29, 2020, more than 85,000 cases had been identified between 54 countries, with the vast majority of confirmed cases (79,000) within China.²⁸

Although sporadic clusters had appeared globally up to this point, Iran and Northern Italy faced sudden surges of COVID-19 patients in late February and early March 2020.²⁹ Italian ICUs reported attempts to cohort hundreds of COVID-19 cases, but still were forced to transfer patients to unaffected regions to cope with the massive numbers of critically ill patients.³⁰ Within the first two weeks of March 2020, COVID-19 patients were estimated to occupy more than 1,000 ICU beds out of a total of 5,200 in Italy, and intensivists were left to consider implementing triage principles (denying lifesaving care to the sickest and least likely to survive) when allocating ventilatory support.^31,32 In the meantime, multiple European countries reported increasing numbers of COVID-19 patients, while China’s extreme efforts at containment and quarantine had interrupted community transmission of new cases, thus shifting the center of the epidemic to the Western hemisphere.³³ On March 11, 2020, WHO elevated COVID-19 to “pandemic” status.³⁴

The United States began to see widespread community transmission in mid-March 2020, as patients began to number into the thousands and every state and U.S. territory reported cases.³⁵ Mirroring European and Chinese efforts to curtail community transmission, U.S. authorities enacted closures of universities, school districts, bars, restaurants, gyms, and other locations of public gathering, while millions of Americans were asked to work from home or to forsake working altogether.³⁶ At the time of this writing, the number of documented cases outside of China has overtaken those reported from within China, and global spread is recorded in more than 150 countries, with the number of new cases rising exponentially each day.³⁷

Epidemiology and Risk Factors

The epidemiology and risk factors for COVID-19 are evolving. Providers, healthcare systems, and governments are attempting to elucidate this information as the number of cases continues to rise.

Initially, the risk factors for acquisition of the disease were understood to be focused around exposure to a possible mammalian host at the Huanan Seafood Wholesale Market; however, later investigation questioned whether the disease may have presented first in the community, because neither the first identified case nor 13 other initial patients visited the market in question.¹³ As the infection spread, it became clear that epidemiologic exposure to the seafood market alone could not explain all cases. Initial concern for human-to-human transmission was noted in the same study, based on known characteristics of the coronavirus group. Further studies described transmission of the virus among close contacts, including both family clusters and business contacts, suggesting the potential for index cases to transmit the disease asymptomatically.^23,38 Since then, SARS-CoV-2 has been detected widely in individuals with no travel history or known contact with other individuals who have tested positive, confirming community spread of the virus. In addition, it is estimated that upward of 86% of cases in Wuhan prior to Jan. 23, 2020, were undetected, suggesting the pandemic is driven largely by asymptomatic spread or is spread by those with mild symptoms.²⁵

It also should be noted that some data have suggested that healthcare workers can become disproportionately represented among COVID-19 cases, likely due to the virus’s potential for nosocomial spread.^39,40

The incubation period, defined as the period between exposure to the infection and the appearance of first symptoms, has been suggested as an average of five to six days, based on initial reports from SARS-CoV-2 and mirrored by other coronavirus diseases, including SARS and MERS.⁴¹ The range may extend to two to 14 days.

Disease severity and mortality are highest among the elderly.^40,42 Individuals with comorbidities like hypertension, diabetes, and heart disease tend to be overrepresented among confirmed cases.^12,13,26,43 U.S. data have estimated mortality rates to be highest among those older than 85 years of age (10% to 27%), followed by those aged 65 to 84 years (3% to 11%), those aged 55 to 64 years (1% to 3%), and least among those aged 20 to 54 years (< 1%).⁴² Providers should take note that even among nongeriatric adults, hospitalizations and ICU admissions still are common, especially among those with underlying conditions. (See Figure 3 and Table 1.)

Overall disease incidence among pediatric patients has been difficult to assess, as each affected region has followed different approaches to testing populations. In one of the largest datasets from China (including 72,314 patients), only about 2% of documented cases occurred in patients younger than 19 years of age (965 patients).⁴⁴ Initial reports from Italy demonstrated that out of 22,512 cases, only 1.2% (70 cases) were documented among patients younger than 18 years of age, and there were no reported deaths in this age group.⁴⁰ Recent data described 4,226 cases in the United States and noted that only 5% of documented cases occurred in patients younger than 19 years of age (123 cases).⁴²

Further features of identified pediatric patients have been reported variably. The China CDC detailed features of 2,143 cases, of which 34% had a positive real-time polymerase chain reaction (RT-PCR) test and 66% were suspected cases (high risk by exposure to a known COVID-19 case with clinical symptoms, laboratory features, or imaging findings).⁴⁵ However, these data were limited somewhat because of the overrepresentation of suspected cases, especially since this time period overlapped with influenza and respiratory syncytial virus season. Among these children, the median age was 7 years, with the age range from 1 day to 18 years. Biological males and females were represented equally. The majority of cases (> 90%) were asymptomatic or of mild to moderate severity; however, it was observed that more critical features were observed in children younger than 1 year of age (involving acute respiratory distress syndrome or respiratory failure with possible additional features of end organ dysfunction). There are no current comprehensive data to suggest which comorbidities in children increase the risk of severe disease. The authors of one study found that those who required an ICU stay and mechanical ventilation had coexisting conditions, such as hydronephrosis, leukemia, and complicated intussusception.⁴⁶

Pathophysiology and Transmission

The pathophysiology of coronavirus infections has been characterized largely by studies of the milder human coronaviruses and SARS-CoV. Human coronaviruses HCoV-NL63 and SARS-CoV both enter host cells through interaction with human angiotensin-converting enzyme 2 (ACE2), which is found throughout the body, including the respiratory and GI tracts. It is thought that ACE2 normally has a protective role in the inflamed lung, and as such, SARS-CoV’s interaction with this may contribute to disease severity.⁴⁷ The newly identified coronavirus, SARS-CoV-2, shows structural similarity to SARS-CoV in the receptor binding domains, which suggests that this new virus also binds at ACE2 sites.¹⁵ ACE2 is found primarily in the lower respiratory tract instead of the upper, which may account for why proportionally fewer patients have presented with symptoms of typical upper respiratory tract infection.⁴⁸ Upon infection of alveolar epithelial cells, the virus may cause cell lysis and sloughing of the respiratory epithelium. Similar to other viral infections, it is thought that the host response is responsible for many of the disease manifestations. In studies of SARS-CoV, researchers have suggested that damage to the lungs of infected patients occurs both directly, by viral destruction of alveolar and bronchial epithelial cells and macrophages, and indirectly, through production of immune mediators, although the exact role of these mechanisms remains controversial.⁴⁹

Viral transmission of the known human coronaviruses (HCoVs 229E, OC43, NL63, and HKU1) has not been well studied. Based on the behavior of other respiratory tract viruses, coronaviruses are believed to spread mainly through respiratory droplets, along with direct and indirect contact with infected persons.⁶ SARS-CoV primarily was transmitted directly through mucous membrane contact with infectious respiratory droplets, as well as through exposure to fomites, with most cases occurring in people who had close contact with those affected by the illness.⁵⁰ It has been established previously that both SARS-CoV and SARS-CoV-2 use ACE2 to enter cells; the presence of the receptor in the GI tract has led to questions regarding fecal-oral spread of the virus. In a study of 73 patients hospitalized with COVID-19 (ages 10 months to 78 years), investigators found that 53% of patients had a stool positive for SARS-CoV-2 RNA. Notably, 17 patients continued to demonstrate positive stool RNA after developing negative respiratory samples.⁵¹ Further studies have looked for evidence of live virus in stool samples with mixed results.^52,53 The Report of the WHO-China Joint Mission on COVID-19 did not identify the fecal-oral route as a main driver of SARS-CoV-2 transmission.⁵⁴

Airborne spread has not yet been reported; however, the authors of one study in laboratory conditions suggested that aerosol transmission of the virus is plausible, with a similar aerosolized stability to that of SARS-CoV.⁵⁵ In addition, fomite transmission via contaminated surfaces is believed to be a potential route of transmission, with results of one study demonstrating stability of potentially viable virus on surfaces like plastic and stainless steel for up to 72 hours.⁵⁶

There have been concerns about vertical transmission of infection, especially after reports of infection detected in a 36-hour-old infant in China. This child’s mother had tested positive by nasopharyngeal swab, but cord blood, placental specimens, and breast milk did not have the virus present.⁵⁷ In a later case series of nine pregnant women who tested positive for SARS-CoV-2 late in pregnancy, all delivered healthy infants via cesarean delivery and had negative testing of throat swabs, cord blood, amniotic fluid, and breast milk.⁵⁸ These findings were repeated in a larger series of 38 pregnant women and infants.⁵⁹ One case report has suggested that a neonate born to a mother with active COVID-19 developed an elevated immunoglobulin M (IgM) response to SARS-CoV-2, which is suggestive of vertical transmission because maternal IgM is not passed through the placenta, although the infant’s nasopharyngeal RT-PCR results for the virus remained repeatedly negative.⁶⁰ Elevations in immunoglobulin G and IgM also have been reported among other newborns of mothers with COVID-19.⁶¹ Further investigation is warranted, but it remains unclear if vertical transmission is a significant mechanism of infection of neonates at this time.⁶²

Clinical Manifestations

The first described manifestations of COVID-19 in hospitalized adult patients were reported as “pneumonia of unknown cause.”¹³ This was defined as an illness without a causative pathogen with clinical features of fever (≥ 38° C), radiographic evidence of pneumonia, low or normal white-cell count or low lymphocyte count, and no symptomatic improvement after antimicrobial treatment for three to five days following standard clinical guidelines; or as the first three criteria, plus an epidemiologic link to the Huanan Seafood Wholesale Market or a sick contact with similar symptoms.⁶³ Later reports described the most prominent early symptoms as fever (98% of patients), cough (76%), and myalgia/fatigue (44%).⁶³ Laboratory findings among adult patients included lymphopenia (83.2%), thrombocytopenia (36.2%), elevated C-reactive protein (60.7%), elevated lactate dehydrogenase (41%), and elevated aminotransferases (AST/ALT, 22.2% and 21.3%, respectively). More than 23% of patients had at least one coexisting illness. The presence of coexisting illness was more common among patients with severe disease than among those with non-severe disease (38.7% vs. 21%). Age also was a predictor of disease severity; patients with severe disease were a median of seven years older than those with non-severe disease.

Pediatric patients diagnosed with COVID-19 have had somewhat more diverse clinical presentations, with a significant number of patients remaining asymptomatic, and far fewer patients with severe disease. It is important to note that the bulk of data describing clinical symptoms in pediatric populations are from hospitalized children in China. Fever has been reported in 41% to 65% of cases and cough in 38% to 65% of cases.^41,46,64,65 Features of upper respiratory infection have been less prevalent, reported at 15% to 19%, with pharyngeal erythema specifically identified in 46% of cases.^46,65 As noted previously, the virus has the ability to infect the GI tract; however, few pediatric patients presented with GI symptoms: 8% to 15% were noted to develop diarrhea and 6% to 10% to develop vomiting.^46,64,65

Few pediatric patients have severe manifestations. Three severe cases were described in one large review of 171 children with COVID-19; all three had coexisting conditions (hydronephrosis, leukemia on maintenance chemotherapy, and intussusception), and ultimately the child with intussusception had multi-organ failure, which resulted in death.⁴⁶ Although further pediatric deaths have been reported, details of the patients have not been adequately clarified to determine if specific risk factors were present.

There have been several additional reports focusing on infants and neonates. A case series of hospitalized infants only included nine cases in China (age 28 days to 1 year), with the youngest being just
1 month of age. All had a sick family contact, and none experienced severe complications or required intensive care treatment. Of these cases, four had fever, three others had mild disease or no symptoms, and the last two had an unknown presentation.⁶⁶ A later case series of four neonates born to mothers with known COVID-19 showed no manifestations of disease in any neonate. Three of the four patients’ parents consented to testing and tested negative.⁶⁷ One of the largest studies on pediatric patients described an increased severity of disease in infants younger than 1 year of age; however, more than 70% of these patients were diagnosed on clinical symptoms alone, without SARS-CoV-2 testing to verify suspected COVID-19 disease.⁴⁵

Rates of asymptomatic infection have been reported as high as 13% to 23%.^46,64 It is likely that early in the epidemic’s investigation, many children who were tested were known contacts of a positive case. Of children represented in the data, 65% to 90% had a close contact who tested positive or were part of a family cluster.^46,64,65,68

Laboratory findings among pediatric patients have been variable. The authors of a review article focused on pediatric laboratory findings in COVID-19 found a normal leukocyte count in almost 70% of patients, while only 15% of patients mounted leukocytosis.⁶⁹ Leukopenia is more variable, reported in 5% to 26% of cases.^46,69 Procalcitonin was found to be elevated in 64% of patients in one large case series of SARS-CoV-2 positive children (n = 171).⁴⁶ However, smaller studies have demonstrated lower percentages of children with elevated procalcitonin.

Radiographic findings on chest X-ray or chest computed tomography (CT) are common among individuals with COVID-19, and even those with asymptomatic or mild disease may have abnormalities suggestive of infection. Among adult and pediatric patients with disease, 75% to 98% are reported to have evidence of pneumonia on imaging, particularly with bilateral lobular and subsegmental consolidations described on CT scans, as well as multifocal ground glass opacities.^12,26,65 Pediatric patients also may demonstrate consolidation with a surrounding halo sign.⁶⁵ Overall, pediatric patients with COVID-19 are less likely to have fewer findings on CT, and lesser extent of disease on radiography.⁷⁰

Diagnosis and Testing

In mid-January 2020, the China CDC developed primers for molecular identification of the novel coronavirus disease and released the virus’s genetic sequence for distribution to global health authorities.¹² This was an important contribution to the global health community, allowing other nations to rapidly develop their own molecular identification assays to track and control new cases abroad.

Using these sequencing data, new cases in the United States are diagnosed primarily based on RT-PCR testing, available through multiple commercial laboratory suppliers under the Emergency Use Authorization of the Food and Drug Administration (FDA).⁷¹ Viral genetic material has been detected in bronchoalveolar lavage fluid, sputum, nasal and pharyngeal swabs, bronchoscope brush biopsies, feces, and blood, while urine appears to be routinely negative.⁵³ For the time being, the U.S. Centers for Disease Control and Prevention (U.S. CDC) recommends collecting nasopharyngeal swabs as the preferred choice for initial diagnostic testing, with oropharyngeal, nasal mid-turbinate, and anterior nare swabs as acceptable alternatives.⁷² Collection of sputum is an option for patients with productive cough, although sputum induction is not recommended.

Local and national test reagents and infrastructure have been outpaced by spreading community transmission and local surges of cases. Although tests remain scarce, the U.S. CDC recommends prioritizing testing according to the following categories of patients:⁷³

• hospitalized patients and symptomatic healthcare workers;
• symptomatic patients in long-term care facilities, symptomatic patients aged 65 years and older, symptomatic patients with underlying conditions, and symptomatic first responders;
• symptomatic critical infrastructure workers; individuals who are not any of the above but present with symptoms; and mildly symptomatic individuals in communities with high COVID-19 hospitalizations.

Testing for other pathogens also should be performed during initial evaluation, but codetection between SARS-CoV-2 and other respiratory viruses has been reported.⁷⁴ In one small study of pediatric patients with SARS-CoV-2, coinfection with other respiratory pathogens (namely influenza A and B, mycoplasma, respiratory syncytial virus, and cytomegalovirus) was found in 40% of patients.⁶⁵ Thus, the presence of influenza or other respiratory pathogens does not rule out COVID-19, and the U.S. CDC recommends that specific testing for SARS-CoV-2 should not be delayed.⁷²

In one analysis of patients who underwent serial RT-PCR tests and serial chest CT scans, the sensitivity of an initial CT scan at presentation was estimated to be upward of 97%, albeit with greater accuracy in patients older than 60 years of age.⁷⁵

Management

At the time of this writing, there is no FDA-approved drug specific for treating COVID-19.⁷⁵ Emphasis currently is placed on supportive care of complications, as well as strict infection control practices. Many individuals with COVID-19 will be able to manage their illness on their own at home, which may be preferable as a means of case isolation. However, some patients may have progression of symptoms to moderate or severe disease, especially older individuals with cardiovascular disease, renal disease, diabetes, or immunocompromising conditions. The decision to admit and monitor patients at higher risk for severe complications must be made at the discretion of the provider on a case-by-case basis. Patients with COVID-19 who are discharged home should be warned that increasing shortness of breath or worsening symptoms may require re-evaluation by a healthcare provider.

Current guidelines from the U.S. CDC emphasize that corticosteroids may be harmful and should not be given when managing COVID-19 infections, unless otherwise indicated by another condition.⁷⁵ This recommendation is based on data from other coronavirus outbreaks (SARS and MERS) and influenza studies that demonstrated that corticosteroid use could prolong viral replication in patients and ostensibly delay or hamper recovery.^75,76

Multiple other medications are under investigation or consideration as potential therapies for COVID-19 infection. Recently, chloroquine and hydroxychloroquine (already approved by the U.S. FDA for other uses) have been cited as promising therapies, although their ultimate benefit remains unknown.⁷⁷ Their method of action is believed to be based on alteration of phagolysosome pH in human cells, thus interfering with SARS-CoV-2’s (or any intracellular organism’s) ability to reproduce within host cells.⁷⁸ In vitro testing supported this rationale, and 20 clinical studies were launched at multiple Chinese hospitals to evaluate the efficacy of chloroquine in COVID-19.^78,79 Some investigators have claimed the initial data demonstrated that chloroquine may reduce patients’ length of stay and ameliorate the progression of COVID-19 pneumonia,^78,79 but this remains controversial. In another study, investigators claimed that the combination of hydroxychloroquine and azithromycin led to a reduction of viral load in COVID-19 patients, but this study was nonrandomized and extremely small.⁸⁰ Thus, there are no U.S. recommendations at the time of this writing to use these agents in COVID-19 patients.

Several other medications already marketed as antivirals also are under consideration for the treatment of COVID-19. Remdesivir is a nucleoside analogue previously used in Ebola treatment (albeit with no improvement in outcomes compared to placebo), but in vitro data support its efficacy against a variety of coronaviruses.^81,82,83 Lopinavir and ritonavir (Kaletra) are protease inhibitors with some data supporting their efficacy against SARS and MERS, but recent data in the current COVID-19 pandemic suggest they are not useful.^84,85,86 Darunavir/cobicistat also are protease inhibitors considered in the treatment of COVID-19, but there are no in vitro or clinical data to support their use at this time.⁸⁷ Ribavirin is another nucleoside analogue that has been considered; however, it was found to have little effect on outcomes in SARS and MERS.^84,88

Other therapies considered in the treatment of COVID-19 include tocilizumab (interleukin-6 inhibitor)⁸⁹ and aerosolized alpha-interferon,⁹⁰ but there are no recommendations from the U.S. CDC to use these therapies. The FDA is facilitating access to convalescent serum/plasma (antibodies harvested from COVID-19 survivors) as an investigational therapy,⁹¹ but with significant side effects and no firm evidence to support its efficacy against COVID-19, there is no recommendation for its use at this time.

Recently, there has been discussion of whether angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) increase the risk of infection and severity of COVID-19, primarily because of SARS-CoV-2’s previously described mechanism of binding to ACE2 to facilitate cell entry.⁹² No evidence has been found to support this hypothesis, and on the contrary, some animal studies suggest these medications actually may be protective against severe disease. At this time, discontinuation of these medications in COVID-19 disease is not recommended.

Likewise, because SARS-CoV-2 binds to ACE2, some have suggested that medications that lead to upregulation of this enzyme, such as nonsteroidal anti-inflammatory drugs (NSAIDs), could lead to more severe disease.⁹³ This supposition was followed by statements from the French Ministry of Health that patients with COVID-19 should avoid NSAIDs.⁹⁴ However, at this time there is no published clinical evidence to recommend discontinuation or avoidance of NSAIDs in COVID-19 patients.⁹⁵

Infection Prevention and Precautions

Strategies to prevent community and nosocomial spread of COVID-19, as well as to minimize exposure of at-risk populations, are paramount. The U.S. CDC has provided comprehensive, updated recommendations for community mitigation strategies aimed at slowing the transmission of COVID-19 and reducing illness and death, while minimizing social and economic impacts.⁹⁶ For all individuals, it is recommended people avoid close contact with others; avoid touching the eyes, nose, and mouth; and clean hands frequently, either using soap and water for 20 seconds or using hand sanitizer that is at least 60% alcohol.⁹⁷

Because of the known problem of asymptomatic spread, recommendations have expanded beyond the simple message of staying home when symptomatic to practicing “social isolation.” On an individual level, this includes encouraging individuals to maintain a distance of three to six feet apart from each other. On a larger scale, this has led to the systematic closure of schools, businesses, gymnasiums, restaurants, and bars, and the cancellation of large community events. There have been calls for widespread community quarantine, recommending that all individuals “shelter in place” and avoid all possible interaction with others.

The U.S. CDC recommends minimizing potential healthcare exposures to contagious cases of COVID-19 through a variety of tactics, ⁹⁸ including the following:

• asking patients with symptoms of cough, sore throat, or fever to reschedule appointments for routine care;
• using telehealth and telephone triage protocols to determine if symptomatic patients can be managed from home;
• requesting patient transport and emergency medical services to contact receiving emergency departments on transport protocols of symptomatic patients;
• limiting points of entry to healthcare facilities, and posting visual materials and handwashing/sanitizer stations at these points, as well as throughout hallways;
• enforcing cough etiquette and studious masking of all symptomatic patients;
• designating separate waiting areas for patients with respiratory symptoms in coordination with the facility’s infection prevention specialists;
• ensuring patients in such waiting areas are separated by at least six feet;
• ensuring patients with respiratory symptoms (including suspected or confirmed COVID-19) are transported and triaged efficiently and quickly through specially designated areas.

There is no approved vaccine available for the prevention of COVID-19 at this time. The discovery and production of such a vaccine is a national and international public health priority to control the pandemic. Recently, the U.S. National Institutes of Health has initiated a Phase I clinical trial of an investigational vaccine.⁹⁹ Efforts to produce a vaccine also are underway in China and Europe.¹⁰⁰

Personal Protective Equipment

As in all situations in which a patient presents with a potentially contagious infectious disease, practitioners confronting potential cases of COVID-19 should contact their institutional infection prevention specialists for specific guidance. In general, the U.S. CDC recommends that all healthcare personnel entering the room of a patient with known or suspected COVID-19 use a respirator or facemask, gown, gloves, and eye protection.⁹⁸ Staff should ensure they follow personal protective equipment (PPE) donning and doffing procedures correctly to ensure contaminated droplets are not passed onto the hands, face, or eyes.¹⁰¹ (See Figures 4-6.)

When possible, and when supplies are adequate, respirators designated for airborne precautions are preferred. Understandably, these may become scarce in surge scenarios, and still may need to be prioritized for other patients with conditions that absolutely demand airborne precautions (such as varicella, tuberculosis, etc.). If respirators are scarce in the event of a surge scenario, facemasks are believed to be acceptable for all non-aerosol-generating situations among COVID-19 patients.⁹⁸ In surge scenarios, institutions may choose to prioritize disposable and reusable respirators only for aerosol-generating procedures, such as intubation and bronchoscopy, among others. For a standardized list of all aerosol-generating procedures, providers should contact their facility’s infection prevention specialist.

In the event of a surge scenario, when community-transmitted cases of COVID-19 threaten to overwhelm the healthcare system, tactics must be employed to conserve PPE. Respirators should be prioritized for known aerosol-generating procedures and patients with a clearly delineated need for airborne precautions.⁹⁸ Similarly, gowns should be prioritized. The U.S. CDC provides multiple suggestions for using and reusing respirators and facemasks in crisis scenarios:^102,103

• using respirators that have exceeded the manufacturer’s expiration date for fit-testing and training when supplies must be conserved;
• following limited reuse policies of face masks and respirators between COVID-19 patients in crisis situations;
• designating convalescent healthcare personnel (providers who have already been sick with, recovered, and ostensibly gained immunity to SARS-CoV-2) to provide care to COVID-19 patients.

In crisis situations, the creation of facemasks from available materials (such as paper, cloth, or plastic) may be necessary. These clearly are not up to ordinary national standards of care, do not qualify as true PPE, and should be employed only as a last resort. In these situations, the U.S. CDC recommends combining their use with a face shield when possible.¹⁰²

Conclusion

The final costs and outcomes of the COVID-19 pandemic cannot be predicted, but its current implications are historic in scope. Some efforts at modeling the pandemic have predicted that without appropriate action, millions of lives could be lost in the United States and Europe.¹⁰⁴ Healthcare workers already are tasked with extremely high patient volumes in heavily impacted regions, and many have become separated from their families for the sake of isolation and protecting the vulnerable. There are few, if any, individuals in the world who will not have some personal connection to this pandemic.

However, while anxieties and doubts multiply in the face of such grave predictions, providers should remind themselves that this pandemic ultimately will pass. Although the immediate effects of COVID-19 may seem overwhelming, the courage and efforts of healthcare workers will outlast the disease. Indeed, the day may not be so distant when this pandemic is relegated to mere historical interest, and humanity will have learned an essential lesson in vigilance against infectious diseases.

Acknowledgement

The authors would like to extend their appreciation to Anne Blaschke-Bonkowsky, MD, PhD, for her support and advice throughout the writing of this manuscript.

REFERENCES

1. Gorbalenya AE, Baker SC, Baric RS, et al. Severe acute respiratory syndrome-related coronavirus: Accessed on March 3, 2020. The species and its viruses – a statement of the Coronavirus Study Group. https://www.biorxiv.org/content/10.1101/2020.02.07.937862v1.full.pdf
2. de Groot RJ, Baker SC, Baric RS, et al. Middle East Respiratory Syndrome Coronavirus (MERS-CoV): Announcement of the Coronavirus Study Group. J Virol 2013;87:7790-7792.
3. World Health Organization. Naming the coronavirus disease (COVID-19) and the virus that causes it. Accessed March 3, 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it
4. World Health Organization. World Health Organization Best Practices for the Naming of New Human Infectious Diseases. Published May 2015. Accessed March 3, 2020. https://apps.who.int/iris/bitstream/handle/10665/163636/WHO_HSE_FOS_15.1_eng.pdf;jsessionid=157DE29B674AD1593D61F717AB52AFA8?sequence=1
5. Centers for Disease Control and Prevention. Epidemic disease occurrence. In: Principles of Epidemiology in Public Health Practice. 3rd ed. US Department of Health and Human Services; 2012.
6. Coronaviruses, including SARS and MERS. In: Red Book 2018, American Academy of Pediatrics Committee on Infectious Diseases. 31st ed. American Academy of Pediatrics; 2018.
7. Fehr AR, Perlman S. Coronaviruses: An overview of their replication and pathogenesis. Methods Mol Biol 2015;1282:1-23. doi:10.1007/978-1-4939-2438-7_1
8. Bradburne AF, Bynoe ML, Tyrrell DA. Effects of a “new” human respiratory virus in volunteers. Br Med J 1967;3:767–769. doi:10.1136/bmj.3.5568.767
9. Ge XY, Li JL, Yang XL, et al. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature 2013;503:535-538. doi:10.1038/nature12711
10. Azhar EI, El Kafrawy SA, Farraj SA, et al. Evidence for camel-to-human transmission of MERS coronavirus. N Engl J Med 2014;370:2499-2505. doi: 10.1056/NEJMoa1401505
11. Zhu N, Zhang D, Wang W, et al; China Novel Coronavirus Investigating and Research Team. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727-733. doi:10.1056/NEJMoa2001017
12. Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med 2020;382:1199-1207. doi:10.1056/NEJMoa2001316
13. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. doi:10.1016/S0140-6736(20)30183-5
14. Tan W, Zhao X, Ma X, et al. A novel coronavirus genome identified in a cluster of pneumonia cases — Wuhan, China 2019-2020. China CDC Weekly 2020;2:61-62.
15. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020;395:565-574.
16. Chan JF, Kok KH, Zhu Z, et al. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect 2020;9:221-236. doi:10.1080/22221751.2020.1719902
17. Guan Y, Zheng BJ, He YQ, et al. Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China. Science 2003;302:276-278.
18. Alagaili AN, Briese T, Mishra N, et al. Middle East respiratory syndrome coronavirus infection in dromedary camels in Saudi Arabia. mBio 2014;5:e00884-e00914. doi:10.1128/mBio.00884-14
19. Ji W, Wang W, Zhao X, et al. Cross-species transmission of the newly identified coronavirus 2019-nCoV. J Med Virol 2020;92:433-440. doi:10.1002/jmv.25682
20. Callaway E, Cyranoski D. Why snakes probably aren’t spreading the new China virus. Nature News. Published Jan. 23, 2020. Accessed March 22, 2020. www.nature.com/articles/d41586-020-00180-8
21. Cyranoski D. Mystery deepens over animal source of coronavirus. Nature News. Published Feb. 26, 2020. Accessed March 22, 2020. www.nature.com/articles/d41586-020-00548-w#ref-CR5
22. Qin A, Wang V. Wuhan, center of coronavirus outbreak, is being cut off by Chinese authorities. The New York Times. Updated Jan. 24, 2020. Accessed March 14, 2020. https://www.nytimes.com/2020/01/22/world/asia/china-coronavirus-travel.html
23. Rothe C, Schunk M, Sothmann P, et al. Transmission of 2019-nCoV infection from an asymptomatic contact in Germany. N Engl J Med 2020;382:970-971. doi:10.1056/NEJMc2001468
24. Bai Y, Yao L, Wei T, et al. Presumed asymptomatic carrier transmission of COVID-19. JAMA 2020; Feb 21. doi:10.1001/jama.2020.2565
25. Li R, Pei S, Chen B, et al. Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2). Science 2020; Mar 16. doi:10.1126/science.abb3221 [Epub ahead of print].
26. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020;395:507-513. doi:10.1016/S0140-6736(20)30211-7
27. Wang J, Zhu E, Umlauf T. How China can build a coronavirus hospital in 10 days. The Wall Street Journal. Updated Feb. 6, 2020. Accessed March 17, 2020. https://www.wsj.com/articles/how-china-can-build-a-coronavirus-hospital-in-10-days-11580397751
28. World Health Organization. COVID-19 Situation Report - 40. Published Feb. 29, 2020. Accessed March 14, 2020. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200229-sitrep-40-covid-19.pdf?sfvrsn=7203e653_2
29. World Health Organization. COVID-19 Situation Report - 47. Published March 7, 2020. Accessed March 17, 2020. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200307-sitrep-47-covid-19.pdf?sfvrsn=27c364a4_2
30. Grasselli G, Pesenti A, Cecconi M. Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: Early experience and forecast during an emergency response. JAMA 2020; Mar 13. doi:10.1001/jama.2020.4031 [Epub ahead of print].
31. Remuzzi A, Remuzzi G. COVID-19 and Italy: What next? Lancet 2020;Mar 13. doi:10.1016/S0140-6736(20)30627-9 [Epub ahead of print].
32. Vergano M, Bertolini G, Giannini A, et al. Raccomandazioni di etica clinica per l’ammissione a trattamenti intensivi e per la loro sospensione, in condizioni eccezionali di squilibrio tra necessità e risorse disponibili. Società Italiana di Anestesia, Analgesia, Rianimazione e Terapia Intensiva. March 6, 2020. Accessed March 20, 2020. http://www.siaarti.it/SiteAssets/News/COVID19%20-%20documenti%20SIAARTI/SIAARTI%20-%20Covid19%20-%20Raccomandazioni%20di%20etica%20clinica.pdf
33. Nebehay S. Europe is epicenter of coronavirus pandemic: WHO. Reuters. Published March 13, 2020. Accessed March 17, 2020. https://www.reuters.com/article/us-health-coronavirus-who/europe-is-epicenter-of-coronavirus-pandemic-who-idUSKBN2102Q0
34. World Health Organization. WHO Director-General’s opening remarks at the media briefing on COVID-19 - 11 March 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020
35. CDC. Coronavirus disease 2019 (COVID-19): Cases in U.S. March 16, 2020. Accessed March 17, 2020. https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html
36. Chappell B. Coronavirus: U.S. urges Americans to home-school; The WHO says: ‘Test, test, test.’ National Public Radio. Published March 16, 2020. Accessed March 17, 2020. https://www.npr.org/sections/health-shots/2020/03/16/816428320/coronavirus-u-s-enters-quarantine-life-as-many-schools-and-businesses-close
37. World Health Organization. COVID-19 Situation Report - 56. Published March 16, 2020. Accessed March 17, 2020. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200316-sitrep-56-covid-19.pdf?sfvrsn=9fda7db2_2
38. Chan JF, Yuan S, Kok KH, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person to person transmission: A study of a family cluster. Lancet 2020;395:514-523. doi:10.1016/S0140-6736(20)30154-9
39. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020; Feb 7. doi:10.1001/jama.2020.1585 [Epub ahead of print].
40. Livingston E, Bucher K. Coronavirus disease 2019 (COVID-19) in Italy. JAMA 2020; Mar 17. doi:10.1001/jama.2020.4344 [Epub ahead of print].
41. Zimmerman P, Curtis N. Coronavirus infections in children including COVID-19: An overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children. Pediatr Infect Dis J 2020;Mar 12. doi:10.1097/INF.0000000000002660
42. Centers for Disease Control and Prevention. Severe outcomes among patients with coronavirus disease 2019 (COVID-19) — United States, February 12–March 16, 2020. MMWR Morb Mortal Wkly Rep 2020;69:343-346. http://dx.doi.org/10.15585/mmwr.mm6912e2
43. Centers for Disease Control and Prevention. Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 — United States, February 12–March 28, 2020. MMWR Morb Mortal Wkly Rep 2020; Mar 31. http://dx.doi.org/10.15585/mmwr.mm6913e2
44. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020; Feb 24. doi:10.1001/jama.2020.2648 [Epub ahead of print].
45. Dong Y, Mo X, Hu Y, et al. Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China. Pediatrics 2020; Mar 16. doi:10.1542/peds.2020-0702 [Epub ahead of print]..
46. Lu X, Zhang L, Du H, et al. SARS-CoV-2 infection in children. N Engl J Med 2020; Mar 18. doi:10.1056/NEJMc2005073
47. Perlman S, Netland J. Coronaviruses post-SARS: Update on replication and pathogenesis. Nat Rev Microbiol 2009;7:439-450. doi:10.1038/nrmicro2147
48. Paules CI, Marston HD, Fauci AS. Coronavirus infections — More than just the common cold. JAMA 2020; Jan 23. doi:10.1001/jama.2020.0757 [Epub ahead of print].
49. Perlman S, Dandekar A. Immunopathogenesis of coronavirus infections: Implications for SARS. Nat Rev Immunol 2005;5:917-927.
50. WHO. Consensus document on the epidemiology of severe acute respiratory syndrome (SARS). 2003. https://www.who.int/csr/sars/en/WHOconsensus.pdf
51. Xiao F, Tang M, Zheng X, et al. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology 2020; Mar 3. doi:10.1053/j.gastro.2020.02.055 [Epub ahead of print].
52. Woelfel R, Corman V, Guggemos W, et al. Clinical presentation and virological assessment of hospitalized cases of coronavirus disease 2019 in a travel-associated transmission cluster. medRxiv 2020; Mar 8. doi:https://doi.org/10.1101/2020.03.05.20030502
53. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 2020; Mar 11. doi:10.1001/jama.2020.3786 [Epub ahead of print].
54. WHO. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19) 16-24 February 2020. https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf
55. Yu IT, Li Y, Wong TW, et al. Evidence of airborne transmission of the severe acute respiratory syndrome virus. N Engl J Med 2004;350:1731-1739. doi:10.1056/NEJMoa032867
56. van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med 2020; Mar 17. doi:10.1056/NEJMc2004973 [Epub ahead of print].
57. Wang S, Guo L, Chen L, et al. A case report of neonatal COVID-19 infection in China. Clin Infect Dis 2020; Mar 12. doi:10.1093/cid/ciaa225 [Epub ahead of print].
58. Chen H, Guo J, Wang C, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records. Lancet 2020;395:809-815. doi:10.1016/S0140-6736(20)30360-3
59. Schwartz D. An analysis of 38 pregnant women with COVID-19, their newborn infants, and maternal-fetal transmission of SARS-CoV-2: Maternal coronavirus infections and pregnancy outcomes. Arch Path Lab Med 2020. https://doi.org/10.5858/arpa.2020-0901-SA
60. Dong L, Tian J, He S, et al. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA 2020; Mar 26. doi:10.1001/jama.2020.4621 [Epub ahead of print].
61. Zeng H, Xu C, Fan J, et al. Antibodies in infants born to mothers with COVID-19 pneumonia. JAMA 2020; Mar 26. doi:10.1001/jama.2020.4861 [Epub ahead of print].
62. Kimberlin DW, Stagno S. Can SARS-CoV-2 infection be acquired in utero?: More definitive evidence is needed. JAMA 2020; Mar 26. doi:10.1001/jama.2020.4868 [Epub ahead of print].
63. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; Feb 28. doi:10.1056/NEJMoa2002032
64. Wang D, Ju XL, Xie F, et al. Clinical analysis of 31 cases of 2019 novel coronavirus infection in children from six provinces (autonomous region) of Northern China Zhonghua Er Ke Za Zhi. 2020;58:E011. doi:10.3760/cma.j.cn112140-20200225-00138
65. Xia W, Shao J, Guo Y, et al. Clinical and CT features in pediatric patients with COVID-19 infection: Different points from adults. Pediatr Pulmonol 2020; Mar 5. doi:10.1002/ppul.24718
66. Wei M, Yuan J, Liu Y, et al. Novel coronavirus infection in hospitalized infants under 1 year of age in China. JAMA 2020; Feb 14. doi:10.1001/jama.2020.2131 [Epub ahead of print].
67. Chen Y, Peng H, Wang L, et al. Infants born to mothers with a new coronavirus (COVID-19). Front Pediatr 2020; Mar 16. https://doi.org/10.3389/fped.2020.00104
68. Cai J, Xu J, Lin D, et al. A case series of children with 2019 novel coronavirus infection: clinical and epidemiological features. Clin Infect Dis 2020; Feb 28. doi:10.1093/cid/ciaa198 [Epub ahead of print].
69. Henry BM, Lippi G, Plebani M. Laboratory abnormalities in children with novel coronavirus disease 2019. Clin Chem Lab Med 2020; Mar 16. doi:10.1515/cclm-2020-0272
70. Chen A, Huang J, Liao Y, et al. Differences in clinical and imaging presentation of pediatric patients with COVID-19 in comparison with adults. Rad Cardiothorac Imag 2020;2. https://doi.org/10.1148/ryct.2020200117 [Epub ahead of print].
71. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): Information for laboratories. Updated Feb. 20, 2020. Accessed Mar. 17, 2020. https://www.cdc.gov/coronavirus/2019-ncov/lab/index.html
72. CDC. Coronavirus disease 2019 (COVID-19): Interim guidelines for collecting, handling, and testing clinical specimens from persons for coronavirus disease 2019 (COVID-19). Updated March 24, 2020. Accessed April 2, 2020. https://www.cdc.gov/coronavirus/2019-nCoV/lab/guidelines-clinical-specimens.html
73. CDC. Evaluating and testing persons for coronavirus disease 2019 (COVID-19). Updated March 24, 2020. Accessed April 1, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-criteria.html
74. Wu X, Cai Y, Huang X, et al. Co-infection with SARS-CoV-2 and influenza A virus in patient with pneumonia, China. Emerg Infect Dis 2020; Mar 11. doi:10.3201/eid2606.200299 [Epub ahead of print].
75. Coronavirus Disease 2019 (COVID-19): Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19). Centers for Disease Control and Prevention. Accessed March 20, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html
76. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020;Feb 15. doi:10.1016/S0140-6736(20)30317-2
77. Grady D, Thomas K. With minimal evidence, Trump asks F.D.A. to study malaria drugs for coronavirus. The New York Times. Published March 19, 2020. Accessed March 20, 2020. https://www.nytimes.com/2020/03/19/health/coronavirus-drugs-chloroquine.html?te=1&nl=morning-briefing&emc=edit_NN_p_20200320&section=topNews&campaign_id=9&instance_id=16929&segment_id=22414&user_id=7ee3c92df43705d56c8e392cd928cda9&regi_id=117612452tion=topNews
78. Colson P, Rolain JM, Lagier JC, et al. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents 2020; Mar 4. https://doi.org/10.1016/j.ijantimicag.2020.105932
79. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020;14:72-73. Epub 2020 Feb 19. doi:10.5582/bst.2020.01047
80. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020; Mar 20:105949. doi: 10.1016/j.ijantimicag.2020.105949 [Epub ahead of print].
81. Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 2020;11:222. doi:10.1038/s41467-019-13940-6
82. Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med 2017;9. doi:10.1126/scitranslmed.aal3653
83. Martinez MA. Compounds with therapeutic potential against novel respiratory 2019 coronavirus. Antimicrob Agents Chemother 2020; Mar 9. pii: AAC.00399-20. doi:10.1128/AAC.00399-20 [Epub ahead of print].
84. Stockman LJ, Bellamy R, Garner P. SARS: Systematic review of treatment effects. PLoS Med 2006;3:e343.
85. Chan JF, Yao Y, Yeung ML, et al. Treatment with lopinavir/ritonavir or interferon-B1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis 2015;212:1904-1913.
86. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020; Mar 18. doi:10.1056/NEJMoa2001282 [Epub ahead of print].
87. Lack of evidence to support use of darunavir-based treatments for SARS-CoV-2. Johnson and Johnson. Accessed March 20, 2020. https://www.jnj.com/lack-of-evidence-to-support-darunavir-based-hiv-treatments-for-coronavirus
88. Omrani AS, Saad MM, Baig K, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: A retrospective cohort study. Lancet Infect Dis 2014;14:1090-1095.
89. [No authors listed.] A multicenter, randomized controlled trial for the efficacy and safety of tocilizumab in the treatment of new coronavirus pneumonia (COVID-19). ChiCTR2000029765. Chinese Clinical Trial Registry. Accessed March 20, 2020. http://www.chictr.org.cn/showprojen.aspx?proj=49409
90. Jin YH, Cai L, Cheng ZS, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res 2020;7:1-23.
91. Investigational COVID-19 convalescent plasma - Emergency INDs. U.S. Food and Drug Administration. Published March 26, 2020. Accessed March 31, 2020. https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/investigational-covid-19-convalescent-plasma-emergency-inds
92. European Society of Cardiology. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers. Published March 13, 2020. Accessed March 20, 2020. https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang
93. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020; Mar 11. doi: 10.1016/S2213-2600(20)30116-8 [Epub ahead of print].
94. Direction générale de la Santé. Actualisation recommandations Covid 19. Published March 14, 2020. Accessed March 23, 2020. https://dgs-urgent.sante.gouv.fr/dgsurgent/inter/detailsMessageBuilder.do?id=30500&cmd=visualiserMessage
95. European Medicines Agency. EMA gives advice on the use of non-steroidal anti-inflammatories for COVID-19. Published March 18, 2020. Accessed March 23, 2020. https://www.ema.europa.eu/en/news/ema-gives-advice-use-non-steroidal-anti-inflammatories-covid-19
96. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19). Schools, workplaces & community locations. Updated March 21, 2020. Accessed March 21, 2020. https://www.cdc.gov/coronavirus/2019-ncov/community/index.html
97. World Health Organization. Coronavirus disease (COVID-19) advice for the public. Updated March 18, 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public
98. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): Interim infection prevention and control recommendations for patients with suspected or confirmed coronavirus disease 2019 (COVID-19) in healthcare settings. Updated March 19, 2020. Accessed March 20, 2020. https://www.cdc.gov/coronavirus/2019-ncov/infection-control/control-recommendations.html
99. National Institutes of Health. NIH clinical trial of investigational vaccine for COVID-19 begins. Published March 16, 2020. Accessed March 23, 2020. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-investigational-vaccine-covid-19-begins
100. Gander K. 3 countries starting coronavirus vaccine trials in global race to stop COVID-19 before end of year. Newsweek. Published March 20, 2020. Accessed March 23, 2020. https://www.newsweek.com/countries-coronavirus-vaccine-trials-covid-19-before-end-year-1493362
101. Centers for Disease Control and Prevention. Healthcare-associated infections: Protecting healthcare personnel. Updated August 18, 2014. Accessed March 23, 2020. https://www.cdc.gov/hai/prevent/ppe.html
102. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): Strategies for optimizing the supply of facemasks. Updated March 17, 2020. Accessed March 20, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/ppe-strategy/face-masks.html#crisis-capacity
103. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): Strategies for optimizing the supply of N95 respirators: Crisis/alternate strategies. Updated March 17, 2020. Accessed March 20, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/respirators-strategy/crisis-alternate-strategies.html
104. Ferguson NM, Laydon D, Nedjati-Gilani G, et al. Impact of non-pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand. Imperial College COVID-19 Response Team. Published March 16, 2020. Accessed March 23, 2020. https://www.imperial.ac.uk/media/imperial-college/medicine/sph/ide/gida-fellowships/Imperial-College-COVID19-NPI-modelling-16-03-2020.pdf?fbclid=IwAR2eVXFfU1I5LmkRH5NVaf9K1srb8L4Riznpmywq8IFeT-qzKaUPTHiuUlo