COVID-19: Natural History and Spectrum of Disease

OUTLINE

• Short Comparison of SARS-CoV-2 With SARS-CoV-1 and MERS-CoV, 72

• Natural History, 73

  • Incubation Period, 73

• Spectrum of COVID-19, 74

  • Pathogenicity and Virulence, 74

  • Asymptomatic Disease and Carrier Status, 75

  • Asymptomatic Patient Trajectories, 75

  • Symptomatic Patient Trajectories, 76

  • Demographics, 76

• Pathogenesis, 76

• Clinical Characteristics, 76

  • Respiratory and Pulmonary Manifestations, 76

  • Cardiovascular Manifestations, 77

  • Neurological Manifestations, 77

  • Gastrointestinal Manifestations, 78

  • Renal Manifestations, 78

  • Cutaneous Manifestations, 82

  • Ocular Manifestations, 83

  • Musculoskeletal and Rheumatological Manifestations, 84

• Impact of Comorbidities, 87

• Radiology and Laboratory Features, 87

• Treatment, Clinical Course, and Outcomes, 88

• Drug Pipeline, 89

• Vaccines, 90

• Children and COVID-19, 90

• Post Recovery Symptoms and the Long-Hauler Syndrome, 90

• Racial Disparities in Susceptibility to SARS-CoV-2, 91

• Conclusion, 92

Coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first described in the city of Wuhan, China in late 2019. After infecting tens of thousands of people in Wuhan and the province of Hubei, where Wuhan is located, the disease spread to various other cities of China and internationally. With multiple surges and peaks, it has infected individuals on every continent, even Antarctica (36 people testing positive at Chilean Bernardo O’Higgins research station in December 2020). It has spread rapidly to more than 200 countries and continues to challenge the health care resources of both the developed and developing world. With a global case count in hundreds of millions and with a death toll in multimillions over an 18-month period, the COVID-19 pandemic has become the most dangerous global infectious disease of the 21st century.

Humans are susceptible to a range of microbes that include parasites, bacteria, and viruses. However, most of the newly identified emerging pathogens are viruses that are carried by vectors, or cause primary disease in animals and then “jump” to humans (zoonotic). These are opportunistic viruses that mutate at high rates, easily adapting to the new human host, thereby enabling human-to-human transmission. The most prominent of these emerging pathogens are the Zika virus and the newer zoonotic respiratory coronaviruses, ^, which also include the current pandemic-causing virus SARS-CoV-2.

Short Comparison of SARS-CoV-2 With SARS-CoV-1 and MERS-CoV

The first SARS-CoV outbreak occurred in late 2002 and soon became a pandemic in early 2003, resulting in the death of more than 700 people, with a large cluster of fatalities reported from Hong Kong. This SARS-CoV virus is thought to have originated in a single or multiple species of bats. A more recent coronavirus (CoV) pathogen is the Middle Eastern respiratory syndrome (MERS) CoV, which first emerged in 2012 in Saudi Arabia, and spread to many countries in the region. By 2018, MERS-CoV had infected more than 2000 people, causing 803 deaths, the majority of them in Saudi Arabia. Camels and bats are considered to be reservoirs of this pathogen.

Before the emergence of SARS, human coronaviruses typically caused only mild upper respiratory tract infections, resulting in the common cold. All of this changed with the emergence of SARS-CoV, MERS-CoV, and the newest member SARS-CoV-2, the causative agent of the COVID-19 pandemic.

The recently identified respiratory tract virus SARS-CoV-2 belongs to the viral family coronaviridae, also referred to as the coronavirus family. Other prominent members of the respiratory tract group of viruses are the rhinovirus, the respiratory syncytial virus (RSV), and the influenza and parainfluenza viruses. The coronaviruses are positive-sense, single-stranded RNA viruses, containing an RNA inner core with an outer oily lipid envelope from which crown-like spikes of proteins project outward. These characteristic crown-like projections on their surface give the virions the appearance of a solar corona in electron micrographs and hence the nomenclature corona . For a detailed structure and other biological characteristics of SARS-CoV-2 the reader is referred to the specific chapter on the topic in this book. The coronaviruses are heat sensitive and are susceptible to lipid solvents such as acetone, ether, and vinegar (which contains acetic acid). The lipid envelope of the virus also breaks apart on contact with soap.

The viral sequence of SARS-CoV-2 identified by Zhu et al. contains 29,892 nucleotides, and the viral genome reported by Wu et al. contains 29,903 nucleotides. Phylogenetic analysis revealed the close relationship to SARS-like coronaviruses previously found in bats in China. The pangolin, a mammal also known as the scaly anteater, may be an intermediate host and a natural reservoir of SARS-CoV-2–like coronaviruses. While initially there was the suggestion that the pangolin may be an intermediate host as it is a natural reservoir of SARS-CoV-2–like coronaviruses, it may be that in the case of SARS-CoV-2 that the raccoon dog was the critical host from which the virus spread into humans. Also, a jump from a human to a tiger in New York City at the Bronx Zoo demonstrated that this pathogen also can be a reverse zoonosis. See Fig. 4.1 for an illustration of this zoonotic transmission model of SARS-CoV-2. There are also reports of domestic pets such as cats and dogs becoming susceptible to SARS-CoV-2 infection.

Natural History

The manifestation and the course taken by the disease process without therapeutic intervention constitute the natural history of a disease. The evolution of a specific disease varies considerably based on host factors, and in the case of infectious diseases, agent characteristics can also play a major role. Agent factors are significantly more important for diseases caused by viruses that mutate rapidly with implications for pathogenicity and virulence.

The natural history of asymptomatic SARS-CoV-2 infection can be surmised from the outbreak characteristics of COVID-19 on the cruise ship Diamond Princess . Of the total number of 3711 passengers and crew members, 712 persons became infected based on the reverse transcription polymerase chain reaction (RT-PCR) test. At the time of testing, 410 did not have any symptoms. A subset of 96 persons were observed subsequently for 7 days, and 11 became symptomatic.

Incubation Period

The incubation period is the duration from the time of exposure to the pathogen to the manifestation of symptoms of the disease. The mean incubation period of SARS-CoV-2 infection is 5.5 days, with a range of 2 to 12 days. But there could be outliers, and Table 4.1 shows the number of positive cases that could be missed using a 14-day and 28-day protocol of isolation.

Table 4.1

Expected Number of Symptomatic SARS-CoV-2 Infections Missed During Active Monitoring Using 14-Day and 28-Day Protocols With Varying Risks for Infection After Exposure

	Missed Symptomatic Infections per 10,000 Monitored Persons
Isolation Period	Low Risk (1/10,000)	Medium Risk (1/1000)	High Risk (1/100)	Infected Sample (1/1)
14 days	0	0.1	1	101
28 days	0	0	0	1.4

Modified from Lauer SA, Grantz KH, Bi Q, et al. The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application. Ann Intern Med. 2020;172(9)577–582.

Transmission Characteristics SARS-CoV-2 is mainly transmitted by respiratory droplets; however, the virus also has been isolated from the patient stools, and there have been many documented cases in which contact tracing supports infection secondary to inhalation of the virus in the air farther than 6 ft (or 2 m) from the source patient. Both symptomatic patients and asymptomatic persons infected with SARS-CoV-2 can transmit the virus. The virus can remain infectious suspended in aerosols for hours, and there is described transmission through the air in closed spaces and in a crowded and congested environment.166 The virus can also remain viable for up to 72 hours on different surfaces as varied as plastic, steel, copper, and cardboard. Despite detection on surfaces, the role of contact transmission (transmission involving fomites) appears to be minimal. Fig. 4.2 provides the dynamics of infectiousness, susceptibility to infection, and disease manifestation.

Table 4.2 provides the fatality rate and reproductive rate (R ₀ ) of common and emerging virus infections. The toll and the public health impact of major viral infections during the course of the 20th and early 21st centuries can be ascertained from the statistics.

Table 4.2

Fatality Rate and Reproductive Rate (R ₀ ) of Common and Emerging Virus Infections

Virus	Fatality rate (%)	Transmissibility Factor (R 0 )	Deaths
SARS-CoV-2 (2019)	3	2.2	4.7 million + (until September, 2021)
SARS-CoV (2002)	10	2–5	700
MERS-CoV (2012)	40	<1	800
H1N1 (2009)	0.03	1.2–1.6	18,600–300,000
H1N1 (1918)	3	1.4–3.8	17–50 million (1918–1920)
Measles virus	0.3	12–18	140,000 in 2018
Seasonal flu	<0.1	1.2–2.4	0.3–0.6 million/y currently
Ebola virus (2014–2016)	40	1.5–2.5	11,300 (2014–2016)
HIV	80 (without drug therapy)	2–4	30 million total deaths till 2020
Smallpox virus	17	5–7	300 million in 20th century

Modified from Chen J. Pathogenicity and transmissibility of 2019-nCoV: a quick overview and comparison with other emerging viruses. Microbes Infect. 2020;22(2):69-71.

Spectrum of COVID-19

The spectrum of disease can vary from asymptomatic without any clinical manifestations, through minimal symptoms causing just a mild limitation in activities of daily living, to more significant symptoms requiring hospitalization resulting in a mild, moderate, or severe disease trajectory. The spectral range also includes cases of persisting symptoms—weeks, months, or possibly even years after recovering from COVID-19, the long-hauler syndrome.

Asymptomatic Patient Trajectories

Long et al. conducted a clinical and immunological study of SARS-CoV-2 RT-PCR–positive asymptomatic individuals who were isolated and hospitalized. This group of asymptomatic patients did not have any relevant clinical symptoms during the preceding 2 weeks and also during the period of hospitalization. The researchers also had two comparison groups—an age- and sex-matched control group and a symptomatic group. Fig. 4.3 summarizes the chest computed tomography (CT) and laboratory features of the asymptomatic group of 37 individuals. Of the 21 individuals with lung abnormalities based on chest CT imaging, two-thirds had unilateral radiological lung signs and in one-third the signs were bilateral. Of 16 who did not show any chest CT abnormalities, 5 developed focal ground-glass opacities or stripe shadows within 5 days of hospitalization.

Viral RNA detection was also prolonged in the asymptomatic group as measured by the median duration when compared with the symptomatic group. However, this increased viral RNA detection may not be correlated with higher infectivity of the virus. ^, The study by Long et al. also showed that 18 proinflammatory and antiinflammatory cytokines were elevated in the symptomatic group and the cytokine profiles were similar in the asymptomatic and control groups, pointing to a reduced inflammatory response in the asymptomatic group.

During the active phase of infection, the immunoglobulin (IgG) profiles in both the asymptomatic and symptomatic groups were similar. When the groups were seen 8 weeks after discharge from hospital (early convalescent phase), the IgG levels in the symptomatic group were significantly higher than those of the asymptomatic group. This finding has implications for the duration of immunity resulting from asymptomatic versus symptomatic infection from SARS-CoV-2.