Pandemic 2020: History, Spread, and Treatment of COVID-19

Earn 1.5 credit hours with this CE course

*Note: As COVID-19 research continues, our understanding of the virus will continue to broaden. This course is based on information available in mid-2020 and focuses on the history of the virus, with some information provided about management of cases. Management recommendations are changing rapidly, so it is important that nurses remain informed of the most recent recommendations from the NIH and CDC.

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By James Wilde, MD, FAAP, and Dean Winslow, MD
This course is 1.5 contact hours
Course must be completed by September 30, 2023
Course Objectives:
Upon completion of this course, participants should be able to:
  1. Recognize specific conditions in patients presenting to the emergency department.
  2. Apply state-of-the-art diagnostic and therapeutic techniques to patients with the particular medical problems.
  3. Discuss the differential diagnosis of the particular medical problems.
  4. Explain both the likely and rare complications that may be associated with the particular medical problems.
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Executive Summary
Coronavirus disease 2019 (COVID-19) is caused by a coronavirus, which is responsible for diseases such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), but also for the common cold.
Many patients with COVID-19 may be asymptomatic but capable of spreading the disease. Older patients and those with comorbidities are at risk for more severe disease and death. Healthcare workers tend to get more severe disease as well. Children do not seem to be as susceptible to the disease, but there are reports of a Kawasaki-like illness associated with COVID.

To date, there is no effective treatment for the disease other than supportive care. There are many different presentations of the disease, not just respiratory. Therefore, precautions should be taken to protect oneself during the pandemic.
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Background
The world is in the midst of a pandemic caused by a novel coronavirus. The pathogen, now named severe acute respiratory syndrome coronavirus-2, or SARS-CoV-2, came to world attention in January 2020. Initial reports used the term “Wuhan coronavirus” to designate the new virus. The disease it causes has come to be known as COVID-19, short for coronavirus disease 2019.
When the first human cases were identified in Wuhan, China, in December 2019, the virus likely moved from its animal reservoir in late November and crept silently into Wuhan hospitals over the next few weeks. The alarm was sounded by several brave Chinese physicians in December, when they started noting unusual cases of pneumonia marked by acute respiratory distress syndrome (ARDS).
On Dec. 31, Chinese authorities alerted the World Health Organization (WHO) China Country office that 27 cases of pneumonia of unknown origin had been detected in and around Wuhan. By Jan. 9, Chinese researchers announced that they had mapped the new coronavirus’s genome, which appeared to match the genome of a coronavirus previously isolated from bats.
As of Jan. 20, there were 278 cases reported in China, mostly in and around Wuhan, and four cases outside of China, with an apparent case fatality rate of 2%. The first case of this novel coronavirus was identified in Thailand on Jan. 13, in Japan on Jan. 15, and in South Korea on Jan. 20. WHO started the first of their daily updates on the progress of COVID-19 on Jan. 20.
By Jan. 26, a total of 2,014 cases had been confirmed globally, including 29 cases from 10 countries outside of China. In 26 of those 29 cases, there was a travel history from Wuhan City, China. On Jan. 17, the Centers for Disease Control and Prevention (CDC) began public health entry screening at three U.S. international airports that received the largest number of travelers from Wuhan.

On Jan. 21, the CDC activated its emergency operations center, and on Jan. 31, President Trump declared a public health emergency and announced restrictions on travel from China.
The initial report concerned 44 patients who were identified with pneumonia of initially unknown etiology from Dec. 16, 2019, to Jan. 2, 2020, in Wuhan City, China, a city of more than 11 million people in Hubei Province.

Origins of COVID-19

The first Situation Update from WHO regarding COVID-19 was published online on Jan. 20. In that update, the events surrounding the origins of the outbreak were summarized. The initial report concerned 44 patients who were identified with pneumonia of initially unknown etiology from Dec. 16, 2019, to Jan. 2, 2020, in Wuhan City, China, a city of more than 11 million people in Hubei Province.
On Jan. 11, WHO received further information from Chinese authorities that the outbreak was associated with an outdoor seafood market in Wuhan City that featured assorted live animals for sale.
Specimens obtained from patients admitted to a Wuhan hospital on Dec. 27 were analyzed by a team from the Chinese Center for Disease Control and Prevention and were found to contain a novel virus with 86.9% sequence identity to a previously published SARS-like coronavirus. Electron micrographs of infected cells showed a virion with distinctive spikes consistent with the Coronaviridae family.
Investigators from the Wuhan Institute of Virology examined samples from seven patients with severe pneumonia and found a coronavirus with 96% identity at the whole-genome level to bat coronavirus. Although it appears that this virus was originally derived from bats, there is speculation about an as-yet unconfirmed intermediate host that allowed it to pass into humans. One prime candidate for the intermediate host is the pangolin, an animal that is sold for medicinal purposes and as a culinary delicacy in China.
There also has been speculation on social media and in common print media that the virus originated from the Wuhan Institute of Virology as a pathogen that had been engineered to become infectious for humans. There is no conclusive proof for this hypothesis.
Detailed analysis of the genome by researchers at the Scripps Research Institute concluded that SARSCoV-2 “is not the product of purposeful manipulation.” An April 30 news release from the Office of the Director of National Intelligence stated, “The Intelligence Community also concurs with the wide scientific consensus that the COVID-19 virus was not manmade or genetically modified.”
The Virus
Coronaviruses are single-stranded zoonotic RNA viruses that have many hosts in the animal kingdom. Prior to the identification of SARS-CoV-2, there were six coronaviruses known to infect humans. Four of these coronaviruses are common causes of upper respiratory infections in children and tend to circulate in humans in a seasonal pattern between December and May.
Coronaviruses can mutate and recombine, and occasionally those mutated strains can spread from animals to humans. This is what happened in the case of both SARS-CoV, which emerged briefly in 2002 and disappeared by 2003, and MERS-CoV, which emerged in 2013 and is still circulating in parts of the Middle East.
Infections due to SARSCoV and MERS-CoV both caused high mortality in victims, with death rates of approximately 10% and 30%, respectively. Both are beta coronaviruses, like SARS-CoV-2.
An interesting paper in 2007 discussed the ability of viruses to mutate and jump species and even speculated that, “The presence of a large reservoir of SARSCoV like viruses, in horseshoe bats together with the culture of eating exotic animals in southern China, is a time bomb. The possibility of the reemergence of SARS and other novel viruses from animals or laboratories and therefore the need for preparedness, should not be ignored.”
Early studies showed that the SARSCoV-2 virus uses S-proteins on the surface of the virion to bind to host receptors, and that these proteins have a high affinity for human angiotensin converting-enzyme 2 (ACE2) receptors. These receptors are the primary binding site used by SARSCoV-2 to gain access to human cells during infection.
ACE2 receptors are found in many human cell types, including in the lungs, heart, kidneys, and intestines. They are found throughout epithelial cells of the nose, mouth, and lungs. They are particularly abundant on type 2 pneumocytes in the alveoli. The pathophysiology of SARS-CoV-2 might be explained in part by interference with ACE2 receptors.
The reninangiotensin system is a biochemical pathway that converts angiotensin I to angiotensin II (ANG II). It is an important mechanism for the regulation of blood pressure. ANG II increases blood pressure, but it also can lead to inflammation. Left unchecked, it actually may cause damage to human tissues. ACE2 helps to modulate that effect by breaking down ANG II. When SARS-CoV-2 binds to ACE2 receptors, it leads to decreased activity of the enzyme, which leaves ANG II relatively unchecked and, thus, able to cause higher degrees of inflammation.
Research is ongoing to determine whether manipulation of the interaction between ACE2 and SARS-CoV-2 might lead to prophylactic or therapeutic interventions.
Transmission, Incubation, Period, Contagion, and Viral Shedding
The CDC has summarized the data on transmission of the virus in their Interim Infection Prevention and Control Recommendations. The available evidence indicates that SARS-CoV-2 is spread primarily by respiratory droplets after a cough or sneeze. These droplets may gain access to an uninfected person by inhalation or by landing in the mouth, nose, or eyes. The degree of transmission from contaminated surfaces is not clear. Another report from the CDC provides evidence for transmission from singing during a choir practice.
Early in the pandemic, the incubation period was estimated to be five to 14 days, with a median of 5.1 days, based on cases with clearly identified exposure and symptom onset. The mathematical model used to calculate this interval also indicates that 97.5% of people will have symptoms by day 11, and 99% of people will have symptoms by day 14.
This and other similar estimations of the incubation period are the basis for the current length of quarantine periods for patients with known exposures to COVID-19.
The period of contagion for respiratory infections, such as influenza, are well known to start before the actual onset of symptoms in the index patient. COVID-19 also appears to be transmissible before the onset of symptoms. One report from China evaluating a family cluster clearly documented transmission during the incubation period.
Another Chinese study showed that 12.6% of transmission may be pre-symptomatic. A study from Singapore very early in the outbreak in that country showed that pre-symptomatic transmission had occurred in at least 6.4% of the first 157 locally acquired infections.
A study in a U.S. skilled nursing facility demonstrated a mean duration of three days from a positive test for COVID to the onset of symptoms. The testing cycle thresholds (Ct) for the real-time polymerase chain reaction (RT-PCR) results in that study were no different between COVID-19-positive patients who were symptomatic, pre-symptomatic, and asymptomatic, suggesting that the viral load is similar for all groups and, thus, all are potentially infectious.
An early report from China demonstrated that the highest viral load was detected in the nasopharynx at the time of symptom onset, with levels dropping sharply by day 10 of illness. This is in sharp contrast to SARS-CoV, which was notable for increased levels of infectiousness at seven to 10 days after the onset of illness, making containment of that 2003 outbreak much more practical.
Another group from China looked at temporal patterns of viral shedding in 94 patients and found a similar pattern of high viral load in throat swabs at the onset of symptoms, declining rapidly over 10 days, but remaining detectable for up to three weeks. Based on an analysis of 77 transmission pairs, the researchers inferred that infectiousness actually may peak zero to two days before symptom onset, with as much as 44% of secondary cases becoming infected before symptom onset in the index case.
Another group from Hong Kong tested sputum rather than nasopharyngeal swabs and again found a high viral load at presentation. Of interest, that group also detected SARS-CoV-2 in blood in 22% of patients tested and in rectal swabs in 27%. No patients had virus detected in urine. This group also demonstrated serum antibodies to two different COVID-19 proteins in 88% to 100% of patients 10 days or later after symptom onset.
Data on viral load and communicability helps to inform recommendations for discontinuing isolation of patients with documented COVID-19 infection. The current recommendation from the CDC is to discontinue isolation 10 days after the onset of symptoms if the symptoms are improving and at least three days have passed since the last fever. In that recommendation, CDC experts acknowledge that low-level viral shedding or residual particles of viral RNA may continue for as long as six weeks after infection.
It is not known if PCR-positive samples beyond day 10 of illness represent infectious virus, but once patients are clinically recovered, they are “likely no longer infectious.”
Estimates of Basic Reproduction Number
One of the early priorities in studying the transmission of COVID-19 was to calculate a basic reproduction number, also known as R0. This number provides an estimate of the transmissibility of a virus, or how many additional new infections can be expected in a naïve population after exposure to an infectious person.
There are several different methods for calculating the R0, which can change based on actions taken to protect the uninfected, such as isolation of infected individuals and social distancing. The first estimate was based on data obtained from China from Dec. 31 to Jan. 28, the first month of the outbreak and before travel to other provinces was restricted.
These authors estimated an R0 of 2.68. Since then, many other authors have calculated an R0 for COVID-19 based on varying patient populations. One summary of 12 different estimates found a median of 2.78 and a range of 1.5 to 6.49.29 An R0 greater than 1 indicates that the number infected is likely to increase, while an R0 less than 1 indicates that the number of infected will decrease.
Outbreak in China
When the world first learned about the novel coronavirus in Wuhan in mid-January, the outbreak was still relatively small. By Jan. 20, there were only 278 confirmed cases inside China, and six deaths. On Jan. 23, the Chinese government instituted a quarantine and halted all train and air travel from Wuhan City to other parts of China in an effort to contain the spread of the virus.
Two days later, all of Hubei province was placed under quarantine. However, by that time, a large and rapidly growing number of infections had already been detected in China outside of Hubei province, including at least 10 in Beijing and Shanghai. On Jan. 31, both Italy and the United States halted all airline flights between their countries and China. By that same date, two cases had already been detected in Italy and six cases had been detected in the United States. The number of infected patients rose rapidly in China during the next five weeks.
Some perspective is helpful in looking at these statistics. Even as late as Feb. 15, when China reported more than 66,000 infections and 1,524 deaths, the world outside of China had 526 total cases of COVID-19 and only two deaths. No country outside of China had yet reached a total of 100 cases. Further analysis of the data available on the WHO website shows that as of Feb. 15, more than 80% of the cases reported in China were in Hubei province, the home province of Wuhan. This is despite the fact that Hubei accounts for less than 5% of the total population of China.
Why the infection was so much more concentrated in Hubei (and remains so to this day) is difficult to explain, but it might explain why extreme measures regarding social distancing and sheltering in place had not yet been undertaken outside of China.
Several early reports from China described the characteristics of COVID-19 infections. One report described 99 patients recruited from a single center from Jan. 1 to Jan. 20 in Wuhan. In this study, 49% of patients were said to have a history of exposure to the seafood market in Wuhan. The mean age was 55.5 years, and COVID-19 was confirmed by RT-PCR in all.
The primary symptoms were fever (83%), cough (82%), and shortness of breath (31%). A small minority had sore throat (5%), rhinorrhea (4%), and diarrhea (2%). Two-thirds of patients had markedly increased erythrocyte sedimentation rate, ferritin level, and C-reactive protein. All had evidence for pneumonia, and at the time of publication, 11% had died and 62% were still in the hospital.
Another study looked at 1,099 patients infected with SARS-CoV-2 in 30 provinces in China. All patients had laboratory proven COVID-19. Forty-three percent of the patients were from Wuhan, and 72% of the remainder had contact with residents of Wuhan. Nine hundred twenty-six of 1,099 patients were classified as having “non-severe” disease. The mean incubation period was four days, and the mean age of the patients was 43 years.
Fever was present in 43% at the time of admission, but fever was noted in 89% at some time during the hospital stay. Nine hundred seventy-five chest computed tomography (CT) scans were performed, and 86% showed abnormal results, including ground glass opacities in 56%. Eighteen percent of patients with non-severe disease had no abnormalities on chest radiograph or chest CT scan. Lymphopenia was present in 83%, and most of the patients had elevations of C-reactive protein.
Overall, severe illness occurred in 16% after admission to the hospital, and only five patients died. The median duration of hospitalization was 12 days.
The largest case series to date described the epidemiology of the outbreak as of Feb. 11. At that point, there were 44,672 confirmed cases in China, and another 28,000 suspected cases. Analysis of the confirmed cases showed only 1% were younger than 10 years of age, another 1% were 10-19 years of age, and 87% were older than 30 years of age. Mild cases accounted for 81% of patients, severe for 14%, and critical for 5%. The overall case fatality rate was 2.3%.
A plateau in the number of infected patients appeared to be reached in China by the beginning of March, two months after the outbreak was first identified. After March 1, the total number of infected has risen by only about 5%, and few new infections have been detected in China since May 1.
As of June 1, the total number of deaths in China was just under 5,000, for an overall case fatality rate of 5.5%. But just as China appeared to be reaching the end of its outbreak, events took a marked turn for the worse in the rest of the world.
The Diamond Princess Outbreak
The largest cluster of COVID-19 infections outside of mainland China during the month of February occurred from Feb. 3 to Feb. 23 aboard the Diamond Princess cruise ship. The ship was quarantined in Yokohama, Japan, on Feb. 3 after returning from a two-week cruise to three countries.
The quarantine was ordered when authorities in Japan learned that a passenger had departed the ship in Hong Kong on Jan. 25 and subsequently was found to have COVID-19 infection. The ship had approximately 3,700 passengers and crew. The median age of the passengers was 69 years. On Feb. 5, passengers were quarantined in their cabins, but crew members continued to work. Initial testing focused on passengers with fever or respiratory symptoms as well as their close contacts.
All those with positive tests were taken off the ship and hospitalized. After this cohort, testing was expanded to allow phased disembarkation of passengers. Eventually, those without symptoms or close contacts were required to complete a 14-day quarantine on board the ship before they could depart.
A total of 712 passengers and crew (19.2%) had positive tests for SARSCoV-2. More than 46% of positive patients were asymptomatic at the time of the test. Among 381 symptomatic patients, 9.7% required intensive care, and nine died (1.3%). As of March 13, 11 symptomatic U.S. passengers remained in the hospital in Japan.
This outbreak represented an interesting case study in the early stages of the COVID pandemic. It demonstrated that the disease is highly communicable, but infection is not inevitable, especially if uninfected people are removed from sources of contagion. Eighty percent of the passengers and crew of the Diamond Princess escaped infection.
The case fatality rate of 1.3% in a largely elderly cohort of infected people also gave a glimpse into what could be expected as the infection continued to spread around the globe. The large number of asymptomatic patients who were positive for the virus provided a hint into the difficulty of containing any large outbreak.
COVID Appears in Europe
Both Iran and Italy reported marked increases in COVID-19 infections starting in the last week of February, two to three weeks before the rest of Europe and North America began to see acceleration in the number of infections. Why these countries were affected so much earlier than surrounding countries is unclear. The situation was particularly dire in Italy, with the Lombardy region being the epicenter.
The outbreak in Italy served as an illustration of what was to come to the United States. Soon after Italy was inundated, the rest of Europe began to experience high rates of infection as well. As of the end of May, infection rates were in steep decline all over Europe, but the toll was high. As of May 31, Europe had 180,000 total deaths, half the world total, and far above the 102,000 at that point in the United States.
The Seattle Nursing Home Outbreak
On Feb. 28, a case of COVID-19 was identified in a skilled nursing facility in King County, WA. This facility cared for 130 residents, with a staff of 170. At the time the index patient was identified, at least 45 residents and staff had symptoms of respiratory illness. The CDC aided local public health officials to investigate the outbreak.
By March 18, 101 residents, 50 healthcare personnel, and 16 visitors, all of whom were epidemiologically linked to the facility, were confirmed with COVID-19 infections. Most of the residents with confirmed infections had respiratory symptoms, but seven residents had no symptoms at all.
The index patient in the outbreak, a 73-year-old woman, was admitted to the hospital on Feb. 27 and died on March 2. The median age of infected facility residents was 83 years. Fifty-four percent were hospitalized, and the case fatality rate was 33.7%. Ninety-four percent of facility residents had chronic underlying health conditions.
Among the 16 infected visitors, 50% were hospitalized, but only one died (6%). The median age for this group was 62.5 years. Only three of 50 infected healthcare personnel were hospitalized, and none of them died. The median age for this group was 43.5 years.
This episode illustrated the potential for rapid spread of COVID-19 in a vulnerable population of elderly adults. Until this outbreak was identified, the primary screening algorithms focused on people with known contacts to COVID-19 patients or travelers from regions with high levels of COVID-19 activity. In response to this outbreak, on March 10, the governor of Washington ordered a policy of mandatory screening of healthcare workers and visitor restrictions for all licensed nursing homes and assisted living facilities in the state.
Another report from the same region and time period illustrated the potential benefit of social distancing. During March 5-9, two residents of a senior independent and assisted living community in Seattle were hospitalized with confirmed COVID-19 infections. On March 6, social distancing began, including isolation of residents in their rooms, with no communal meals or activities. In addition, no visitors were allowed in the facility, and staff member screening began.
Eighty residents (mean age 86 years) and 62 staff members (mean age 42 years) participated in SARS-CoV-2 testing on March 10, and again seven days later. Results were positive for SARS-CoV-2 in three residents and two staff members on the first round of testing. In the second round of testing, only one new positive result was found, in an asymptomatic resident.
Assays to Diagnose COVID-19 Testing for SARS-CoV-19 using an RT-PCR assay began in CDC labs on Jan. 18. Testing in U.S. public health labs started on Feb. 1, but because of initial problems with the test developed by the CDC for state lab use, testing outside of the CDC did not increase substantially until Feb. 27. By the middle of March, the vast majority of testing was being done at the state and local level, and by March 14, public health laboratories using the CDC assay were no longer required to submit samples to the CDC for confirmation. On March 12, Roche Molecular Systems, Inc., became the first of numerous commercial entities to obtain an emergency use authorization (EUA) to develop their own diagnostic test for COVID based on the assay developed by the CDC. Since then, EUAs have been issued to dozens of additional manufacturers. This has opened the door for testing to be done at the individual hospital level, primarily focused in academic medical centers. Virtually all of these assays are based on RT-PCR technology. On April 1, the first antibody-based assay was announced by Cellex Inc., which offered an IgG/IgM rapid test. Many more have been developed since then, but because of the urgency of making tests available, these manufacturers were not required to submit to the rigors of the Food and Drug Administration (FDA) approval process. There have been varying reports in the medical literature regarding the sensitivity of these assays. A small study in the Chinese literature examined the detection of SARS-CoV-2 by RT-PCR in various clinical specimens from patients with COVID-19 disease. In this study, 93% of bronchoalveolar lavage fluid specimens were positive for the virus. The rate of positive results was 63% for nasal swabs, and 32% for pharyngeal swabs. In a much larger study of 1,014 patients published in the Feb. 26 online journal Radiology, only 59% of patients who were diagnosed clinically with COVID-19 infection had a positive throat swab by RT-PCR.38 This study, like others in publication, was hampered by the lack of a definitive “gold standard” to determine which patients actually had confirmed COVID-19 infection. According to the Infectious Diseases Society of America (IDSA), there were at least 25 different commercially available nucleic acid amplification tests for SARS-CoV-2 as of May 6. These tests were rushed to market under an EUA, and most have no clinical performance data. While these tests are highly specific, there is little to no information on their clinical sensitivity by anatomic site or by time during the course of the disease. Moreover, the current literature does not even have a standard definition for infection with COVID-19. The IDSA statement does recommend the use of nasopharyngeal swabs over throat swabs or saliva alone to test for COVID-19. Given the poor quality of the available evidence, we are severely hampered in our ability to interpret the assays in terms of predictive value, particularly in settings where the prevalence is low. In practice, this means that a positive test is likely to represent a true positive; the patient likely has COVID. However, a negative test does not rule out infection with COVID. Much work remains to be done to assess for the accuracy of existing molecular diagnostic tests.
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About the Authors
This course was written by James Wilde, MD, FAAP, Professor of Emergency Medicine, Augusta University, Augusta, GA.
The content for this course was revised by Dean L. Winslow, MD, Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine.

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