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Coronavirus Disease 2019 (COVID-19): A Clinical Guide
Coronavirus Disease 2019 (COVID-19): A Clinical Guide
Edited by
Ali Gholamrezanezhad, MD
Keck School of Medicine, University of Southern California (USC)
Los Angeles, California, USA
Michael P. Dube, MD
Keck School of Medicine, University of Southern California (USC)
Los Angeles, California, USA
This edition first published 2023
© 2023 John Wiley & Sons Ltd
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The right of Ali Gholamrezanezhad and Michael P. Dube to be identified as the authors of the editorial material in this work has
been asserted in accordance with law.
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To my mother, Fatemeh
For her endless support and devotion to making my life most fulfilling . . .
my wife
for her unconditional love and patience . . .
my brother
for his support in silence!
Contents
List of Contributors x
Preface xvii
1 COVID-19: Epidemiology 1
Phillip Quiroz, George W. Rutherford, and Michael P. Dube
2 COVID-19: Virology 22
Saeideh Najafi, Salar Tofighi, and Juliana Sobczyk
28 Racial, Ethnic, and Other Disparities in the Epidemiology and Care of COVID-19 586
Liesl S. Eibschutz, Charlotte Sackett, Kalpana Dave, Sarah Cherukury, Christian Vega,
Mauricio Bueno, and Hector Flores
Index 658
x
List of Contributors
Jennifer H. Johnston, MD
Angelena Lopez, MD
Department of Radiology, McGovern School of
Department of Medicine, Division of Pulmonary and
Medicine, UT Houston, Houston, TX, USA
Critical Care Medicine, Cedars-Sinai Medical Center,
Los Angeles, CA, USA
Sean K. Johnston, MD
Department of Radiology, Keck School of
Medicine, University of Southern California, Los Stan Louie, PharmD
Angeles, CA, USA Clinical Pharmacy and Ophthalmology
Clinical Experimental Therapeutics Program,
Narges Jokar, MD Ginsburg Institute of Biomedical Technology,
Department of Molecular Imaging and Radionuclide USC School of Pharmacy,
Therapy, The Persian Gulf Nuclear Medicine USC Keck School of Medicine, University of
Research Center, Bushehr Medical University Southern California, Los Angeles, CA, USA
Hospital, Bushehr, Iran
xiv List of Contributors
Yuri Matusov, MD
Niyousha Naderi, MD
Department of Medicine, Division of Pulmonary
Keck School of Medicine, University of Southern
and Critical Care Medicine, Cedars-Sinai Medical
California, Los Angeles, CA, USA
Center, Los Angeles, CA, USA
Yasaswi V. Vengalasetti, MS
Anurag Singh, BSc Department of Epidemiology and Population
Department of Microbiology, Ram Lal Anand Health, Stanford University School of Medicine,
College, University of Delhi, New Delhi, India Stanford, CA, USA
Preface
The astounding speed and global impact of the Outpatient management and prevention of hospitaliza-
coronavirus disease 2019 (COVID-19) pandemic was tion and disease progression have made slow but steady
unforeseen when the first cases of this illness were progress, with the availability in some settings of anti-
reported in December 2019 from Wuhan, China. By SARS-CoV-2 monoclonal antibodies. Subsequently,
the end of January 2020, nearly 8000 cases had been studies of promising oral antiviral agents have reported
reported globally from 19 countries, and the World beneficial effects of preventing hospitalization with a
Health Organization declared a Public Health more generally applicable form of treatment.
Emergency of International Concern. It soon became Sadly, the pandemic has further exposed health dis-
apparent this was not going to be a focal or controlla- parities around the globe. Minority and lower-income
ble outbreak. In the more than two years that have fol- people have disproportionally borne the brunt of
lowed, the world has truly been turned upside down COVID-19 illness and mortality, the result of environ-
with countless severe disruptions to life and econo- mental and structural disadvantages and greater nonin-
mies worldwide. fectious medical comorbidity. Viral mutation has led to
The challenges to the healthcare systems in high-, emerging SARS-CoV-2 variants that have properties of
middle-, and low-income countries alike have been increased infectivity and reduced responses to vaccines
enormous. The strain on individuals and institutions and monoclonal antibodies. The Delta variant exploded
has been dealt with by interventions of varying suc- worldwide in the summer of 2021, challenging but not
cess. The mental and physical health of workers have fully overcoming current therapies. The world will con-
been a prime focus in the global response to the tinue to monitor for variants of concern, more recently
pandemic. with the Omicron variants, and science will adapt with
The scientific community has responded rapidly, if new vaccines and therapeutics as necessary.
imperfectly at times, to the death and disability imposed In spite of terrible loss of life, disabling post-COVID
by severe acute respiratory syndrome coronavirus 2 syndromes, and damage to global economies, there is
(SARS-CoV-2). Important and dramatic advances in the reason for optimism. The first-generation messenger
care of critically ill inpatients have been made, primar- RNA and viral vector vaccines appear to be maintain-
ily using potent anti-inflammatory interventions such ing protection against severe disease, and vaccines
as glucocorticoids and tocilizumab. Multiple effective promising better protection from variants are emerg-
vaccines have been developed with record speed using ing. As the world sorts out how to make vaccines more
multiple different vaccine platforms and have been dis- generally available in lower-income countries, there is
seminated globally. Much work still needs to be done in an expectation that infection with SARS-CoV-2 will
combatting vaccine hesitancy worldwide and providing eventually become a more manageable virus along the
vaccines in the developing world. lines of other respiratory viruses such as influenza.
1
COVID-19: Epidemiology
Phillip Quiroz1, George W. Rutherford2, and Michael P. Dube3
1
Keck School of Medicine at the University of Southern California, Los Angeles, California, USA
2
Department of Epidemiology and Biostatistics, School of Medicine, and Institute for Global Health Sciences, University of California San Francisco,
San Francisco, CA, USA
3
Department of Medicine, Division of Infectious Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
Coronavirus Disease 2019 (COVID-19): A Clinical Guide, First Edition. Edited by Ali Gholamrezanezhad and Michael P. Dube.
© 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd.
2 Coronavirus Disease 2019 (COVID-19)
The first death from the novel SARS coronavirus was detected in the horseshoe bat Rhinolophus affinis from
announced by Chinese health officials on 11 January Yunnan Province, more than 1500 km from Wuhan [6].
2020 [2]. The WHO named this illness coronavirus dis- In addition, similar strains of SARS-CoV-2 were found
ease 2019 (COVID-19) according to its nomenclature earlier in other regions of China. Bats are likely reser-
on 11 February 2020 and would eventually declare the voir hosts for SARS-CoV-2; however, whether bat-CoV
outbreak a pandemic on 11 March 2020 [5]. At the time RaTG13 directly jumped to humans or transmitted
of this writing in August 2021, the SARS-CoV-2 pan- to intermediate hosts to facilitate animal-to-human
demic has left entire countries crippled and in desper- transmission remains inconclusive, and epidemiologic
ate recovery. Worldwide spread has left more than investigations are still being conducted.
4 million people dead, ranking it among the top 10 most
deadly pandemic illnesses in human history.
Animal Host
Cross-Species Zoonotic
Transmission Spillover Event
2012
MERS-CoV
Human-to-
Recombination SARS-CoV-2 2019 Human Spread
Events
2002
SARS-CoV
Figure 1.1 Diagram depicting historical examples, along with the proposed mechanism for SARS-CoV-2, of other
Coronaviridae theorized recombination events leading to circulation in animals and zoonotic spillover into humans.
COVID-19: Epidemiology 3
These events, although rare, are thought to have led to infectiousness, and that the duration of viral RNA
similar outbreak-type events several times in human shedding is variable and may increase with age and ill-
history. Intermediate animal hosts of SARS-CoV and ness severity [14]. Furthermore, the short-term risk for
MERS-CoV were determined to be the masked palm reinfection (e.g. within the first several months after
civets (P. larvata) and the dromedary (Camelus drom- initial infection) is low, because prior infection has
edarius), respectively, before transmission to humans been shown to reduce the risk for infection in the sub-
occurred [8, 9]. With respect to COVID-19, genomic sequent six to seven months by 80–85% [15].
evidence has pointed to the Sunda pangolin (Manis
javanica) as a suspected intermediate host of SARS-
CoV-2. Sequence identity between pangolin-origin
coronavirus and SARS-CoV-2 is 99%, indicating that
Modes of Transmission
SARS-CoV-2 may have been passed on to humans as a
Overview
result of exposure with these mammals [10]. In addi-
tion, SARS-CoV-2 and other coronaviruses from pan- The US Centers for Disease Control and Prevention
golins use receptors (angiotensin-converting enzyme (CDC) confirmed person-to-person transmission on
2 [ACE2] receptor) with similar molecular structures 30 January 2020. Many transmission routes have been
to infect cells, bolstering the argument for the virus considered, such as surface-to-surface contact, fecal-
being enzootic in these animals. However, others oral, bloodborne, and sexual contact, but evidence points
have questioned the relationship between pangolin to droplet spread via the respiratory pathway to be the
and human infection, and this hypothesis is still being most likely principal mode of transmission [16, 17].
studied [11].
Respiratory Droplets
transmitted over such longer distances via an airborne ing, ventilation, adequate distancing, etc.) [17]. In
route, in a nonprocedural setting this would primarily addition, providers should always practice good
occur in specific scenarios where proximity and viral surface hygiene, with the precautions that evidence
load are optimized (i.e. sneezing and/or coughing in may provide different conclusions in the future. In
close contact). The precise extent to which aerosol short, collective data suggest that live virus persists
transmission has contributed to the overall pandemic transiently on surfaces, and although it is beneficial to
is uncertain and is not thought to be the major con- practice good sanitary hygiene overall, fomites are not
tributor to overall pandemic transmission [17, 20]. thought to be a major route of transmission [17].
Regardless, there are numerous examples suggesting
aerosol transmission in some settings and evidence
Fecal-Oral
supporting proximity as a key determinant of risk,
along with duration of contact, indoor settings (i.e. SARS-Cov-2 has been detected in nonrespiratory spec-
households, healthcare settings, college dormitories, imens, including stool, blood, ocular secretions, and
homeless shelters, detention facilities, superspreader semen, but their role in infection also appears to be
events), and poor ventilation [17, 19, 21]. minimal. Fecal-oral transmission was theorized early
in the outbreak because of the known high concentra-
tion of ACE2 receptors in the small bowel [25].
Direct Surface Contact and Fomites
Although viral RNA is commonly detected in stool,
Early reports of clustered infections from China raised live virus has only rarely been isolated. Currently, no
concern of possible surface contact transmission of evidence supports fecal-oral transmission in humans,
SARS-CoV-2. Although it is plausible that touching a and studies with intragastric inoculation of SARS-
contaminated surface and subsequently contacting a CoV-2 in macaques did not result in infection [17].
mucosal surface (the eyes, nose, or mouth) could lead This is supported by an official joint report released by
to infection, there is currently no conclusive evidence the WHO and China in February 2020 stating trans-
for fomite or direct contact transmission in humans. mission through the fecal-oral route did not appear to
Early concerns of events suggesting fomite transmis- be a significant contributing factor for viral spread [26].
sion were circumstantial [22, 23]. In these early
reports, individuals using shared facilities (such as
Bloodborne
elevators and restrooms) proposed either fomite or res-
piratory transmission in those settings. In a detailed Bloodborne transmission was also hypothesized early
investigation of a large nosocomial outbreak linked to on, but the proportion of persons with viral RNA
119 confirmed cases at a hospital in South Africa, detectable in blood is currently unknown and likely
fomite transmission was proposed given the separated very small. An early study found viral RNA in only 3 of
distribution of cases in multiple wards [22]. However, 307 blood specimens. However, no replication-
the hospital did not have a universal mask policy, competent virus has been isolated from blood samples
lacked adequate ventilation, and had a substantial to this date, and there have been no documented cases
burden of infection among health care workers. As a of bloodborne transmission [27]. Moreover, there have
result, respiratory transmission from infected staff been documented reports of recipients of platelets or
could not be excluded [24]. Among healthcare work- red blood cell transfusions from donors diagnosed
ers, poor hand hygiene has been shown to be associ- with SARS-CoV-2 in which the transfused individuals
ated with increased risk for infection with SARS-CoV-2. did not experience COVID-19-related symptoms, nor
Although this might suggest increased risk for con- did they test positive for SARS-CoV-2 [26, 28].
tamination via direct contact or fomite spread, it is dif-
ficult to separate this from other hygienic practices. As
Semen and Vaginal Secretions
will be discussed in subsequent sections, hand hygiene
precautions have been shown to be highly associated Sexual transmission of SARS-CoV-2 was also an initial
with practices that decrease risk overall (mask wear- concern. However, no current evidence supports
COVID-19: Epidemiology 5
s exual transmission of SARS-CoV-2 in semen or vagi- the outbreak, the CFR was much higher: 17.3% across
nal fluids. Although viral RNA has been found in China as a whole and greater than 20% in the center of
semen, infectious virus has not been isolated [29]. In the outbreak in Wuhan [35]. Underreporting of cases,
addition, vaginal fluid studies have been negative such as from failure to test individuals with mild dis-
except for a small number of case reports showing ease and asymptomatic infection, can greatly inflate
RNA with low viral levels [30]. the CFR. Conversely, there are concerns that during
the rapid spread of disease during a pandemic, the
CFR will underestimate disease, because the death
Asymptomatic Transmission counts do not account for any eventual deaths that
may occur in the overall pool of cases. Wide variations
People who express symptoms convey the highest (estimates ranging from <0.1% to >25%) in CFR can
risk for transmission. However, one of the more insidi- also arise from country to country as a result of extrin-
ous aspects of this virus is its ability to spread among sic or societal factors [36]. CFR, furthermore, does not
individuals who are minimally symptomatic or account for differences in age or sex; it is a cumulative
asymptomatic. Multiple studies have demonstrated that population at-risk metric. Nevertheless, this method,
asymptomatic or presymptomatic persons have the abil- along with others, was used to approximate disease
ity to spread infection, and this has been well docu- mortality and was consistent with the initial CFR
mented throughout the pandemic [31–33]. Some models reports released from China in the early stages of the
estimate the proportion of spread attributable to asymp- pandemic, outside of Hubei Province [36–38].
tomatic and presymptomatic transmission at greater
than 50% [34]. However, it is important to note that the
risk for transmission from an individual who is asymp- Serial Interval
tomatic appears to be less than from a presymptomatic In any infectious disease outbreak, the estimation of
individual, who also carries lesser risk than that from transmission dynamics is crucial to contain spread in a
one who is symptomatic [33]. The impact of asympto- new area. Of the tools used in such estimations, the
matic spread on the pandemic is undoubtedly consider- serial interval is one of the significant epidemiological
able and has led to difficulties in quantitatively tracking measures that help determine the spread of infectious
exposure in populations. Nevertheless, the concern for disease. It is required to understand the turnover of
undetected spread has shaped policy and national deci- case generation and transmissibility of the disease and
sions across the globe, forcing implementation of multi- is defined as the time between which the infector and
ple unprecedented global infection prevention measures the secondarily infected show the symptoms, that is,
that will be briefly discussed in later sections. the time interval between the onset of symptoms in
the primary (infector) and secondary cases (infected).
The estimated serial interval for SARS-CoV-2 is about
Virulence and Mortality 4.5–5 days [39].
estimated that R0 is higher for certain variants of con- 26 January 2020 to 27 February 2021 (Figure 1.2) [42].
cern, such as the alpha or delta variants [40]. This The percentage excess mortality is this difference in
increased transmissibility is of great concern as world- mortality for a given time period divided by the aver-
wide spread of variants of concern accelerates and age mortality in the same designated time frame dur-
more transmissible variants become the dominant cir- ing previous years. The estimated number of excess
culating strains. deaths peaked during the weeks ending 11 April 2020,
1 August 2020, and 2 January 2021 (Figure 1.2) [41],
with approximately 75–88% of excess deaths directly
Excess Mortality
associated with COVID-19 [42, 43].
Excess mortality is a measure used by epidemiologists Globally, it is difficult to accurately estimate the
and public health experts to assess the overall impact of total number of excess deaths. Not all countries have
pandemic disease. Because not all cases and deaths can the infrastructure to report nationwide mortality accu-
realistically be reported, this gives practical insight into rately and expeditiously, and representation from
overall impact. It is defined as the difference in mortal- poorer countries is underreported. Keeping in mind
ity in a given year compared with the average number these limitations, the WHO estimates, in 2020, a
of deaths over a given number of previous years. In the worldwide excess mortality of more than 1.8 million
United States, data from the National Vital Statistics deaths attributed directly to COVID-19, with unoffi-
System of the CDC estimated that 545 600–660 200 cial total pandemic deaths totaling more than 3 mil-
excess deaths occurred in the United States from lion people [43].
70,000
60,000
50,000
40,000
30,000
20,000
10,000
0
1/14/2017 7/14/2017 1/14/2017 7/14/2018 1/14/2019 7/14/2019 1/14/2020 7/14/2020 1/14/2021
Observed Count (All Causes) Observed Count (Excluding COVID-19) Average Expected Counts (All Causes)
Figure 1.2 Excess mortality counts by week for observed all-cause mortality and observed mortality excluding COVID-19
(1 January 2017 to 1 July 2021). Overlaid trend line is average expected counts based on previous year trends. Red box:
Counts may be incomplete because only 60% of death records are submitted to National Center for Health Statistics (NCHS)
within 10 days of the date of death, and completeness varied by jurisdiction (1 February 2020 to 26 June 2021). *Number of
deaths reported is the total number of deaths received and coded as of the date of analysis and does not represent all
deaths that occurred in that period. Data are possibly incomplete because of the lag in time between when the death
occurred and when the death certificate was completed, submitted to NCHS, and processed for reporting purposes. Source:
Data are from the US Centers for Disease Control and Prevention [41].
COVID-19: Epidemiology 7
20
15
10
0
0-4 Years 5-17 Years 18-29 Years 30-39 Years 40-49 Years 50-64 Years 65-74 Years 75-84 Years 85+ Years
Figure 1.3 Case and death count distribution by age with corresponding percentage of US population for each respective
age group. Source: Graph data are from the US Centers for Disease Control and Prevention [45].
Figure 1.4 US COVID-19 cases and deaths for males and females for all age groups. *Those who were listed as “other”
constituted less than 0.001% of cases, and deaths are not graphically represented here. Source: Case and mortality data from
the US Centers for Disease Control and Prevention [45]. Data are as of July 2021.
COVID-19: Epidemiology 9
2000
14 DAY CUMULATIVE*
1500
1000
500
0
1-Oct-2020 1-Nov-2020 1-Dec-2020 1-Jan-2021 1-Feb-2021 1-Mar-2021 1-Apr-2021
Figure 1.5 Los Angeles County age-adjusted COVID-19 case rate per 100 000 individuals by race/ethnicity, April 2020 to
June 2021. *Data are estimated reported data from the Los Angeles County Department of Public Health and do not
necessarily reflect exact amounts.
70
60
PER 14 DAY CUMULATIVE*
50
40
30
20
10
0
1-Oct-2020 1-Nov-2020 1-Dec-2020 1-Jan-2021 1-Feb-2021 1-Mar-2021 1-Apr-2021
Figure 1.6 Los Angeles County age-adjusted mortality rate per 100 000 individuals by race/ethnicity, April 2020 to June
2021. *Data are estimated reported data from the Los Angeles County Department of Public Health and do not necessarily
reflect exact amounts.
in 2020, COVID-19 became the leading cause of race-respective population percentages, Hispanics
death in Los Angeles for Latino/Hispanics (where and non-Hispanic Blacks have been disproportion-
they account for 49% of the total population), outpac- ately affected in terms of disease morbidity and mor-
ing mortality rates from heart disease, cancer, and tality, with both respective mortalities outpacing their
diabetes [53]. proportions of the population (Figure 1.7) [54–56].
In terms of the US population overall, crude data Furthermore, additional studies have reported that
demonstrated that non-Hispanic whites accounted American Indian or Alaska Native, non-Hispanic
for the greatest percentage of morbidity, compris- persons were also disproportionately affected and
ing approximately 50% of cases, with Hispanic and more likely to be infected, hospitalized, or die with
non-Hispanic blacks following at 29% and 11%, COVID-19 in comparison with their white counter-
respectively (Table 1.3). However, when considering parts [55–57].
10 Coronavirus Disease 2019 (COVID-19)
Data as of July 2021. Of the 27 472 068 recorded cases, race/ethnicity was available for 17 382 837 (63%) cases.
Multiple/Other Non-Hispanic
White Non-Hispanic
Black Non-Hispanic
Asian Non-Hispanic
Hispanic/Latino
0 10 20 30 40 50 60 70
Multiple/Other Non-Hispanic
White Non-Hispanic
Black Non-Hispanic
Asian Non-Hispanic
Hispanic/Latino
0 10 20 30 40 50 60 70
Figure 1.7 Case and death percentages by race/ethnicity with corresponding percentage of US population for each
respective group. Source: Data are from the US Centers for Disease Control and Prevention [45]. Data are as of July 2021.
12 Coronavirus Disease 2019 (COVID-19)
this is a relatively new method in the arsenal of vac- The importance of vaccines cannot be understated.
cine development, this technology has been studied Successful historical examples, such as the polio,
for at least a decade before this specific application, so measles-mumps-rubella, and smallpox vaccines, have
the science is well understood. mRNA segments cod- underscored the profound importance of this technol-
ing for the coronavirus spike protein are introduced ogy in achieving herd immunity. Vaccine-mediated
into the body through an intramuscular injection to herd immunity is an essential tool in public health
trigger an immune response. Using a protective lipid and directly protects vulnerable populations with
nanoparticle coating, these particles are taken up by lesser vaccine responsiveness (i.e. elderly adults, indi-
cells, processed, coded for synthesis of spike protein, viduals with chronic disease, and immunocompro-
and presented to the immune system, triggering a mised persons). The alternative “natural immunity”
humoral and a cellular immune response. The Pfizer- method would be impractical. Although prevent-
BioNTech and Moderna vaccines are examples of this ing circulation of virus through naturally acquired
technology and are the main vaccines used by the herd immunity would occur eventually, it would also
United States and many countries throughout Europe. result in unnecessary cases and deaths and has possi-
These vaccines were approved by the US Food and bly been achieved only in close situations such as
Drug Administration for Emergency Use Authorization prisons [68].
on 11 December 2020 for Pfizer and on 18 December Current COVID-19 vaccinations have been shown to
2020 for Moderna [60, 63]. The Pfizer vaccine received not only decrease viral load but also decrease risk for
full US Food and Drug Administration approval on 23 asymptomatic transmission [69–71]. However, emerg-
August 2021. ing variants have the potential to escape some of these
The goals of vaccination are grounded on two key benefits of vaccination. Reducing transmission via
concepts: bolstering individual immunity to prevent vaccination carries important implications for reopen-
severe disease and hospitalization and to limit ing and shaping public health guidelines going for-
population-wide spread. “Herd immunity” is an indi- ward, as the CDC and national governments relax
rect form of protection resulting from enough individ- recommended prevention measures for vaccinated
uals obtaining immunity, via vaccination or infection, individuals [72]. This is a monumental finding
to the point where it minimizes further disease circu- because, as mentioned in previous sections, SARS-
lation within a population. This threshold varies from CoV-2 and its variants carry significant mortality and
pathogen to pathogen. Herd immunity to SARS- disproportionately affect the marginalized and the dis-
CoV-2 has been estimated, giving circulating strain advantaged [73]. Given the availability and promising
considerations, to require immunity in approximately results of this technology, immunity via natural circu-
70–80% of the population. However, this number will lation of the virus would be not only medically irre-
increase as newer variants arise with higher R0 and sponsible but also potentially morally unacceptable.
increased transmissibility [64].
For many viruses, the more it circulates in a popula-
Personal Protective Equipment:
tion, the more opportunities it has to replicate and/or
Respirators and Masks
mutate; SARS-CoV-2 has demonstrated this abil-
ity [65]. These mutations have the potential to produce In the United States, hospitals are required to provide
more transmissible and more virulent strains of SARS- personal protective equipment for staff working with
CoV-2. For example, the 501Y mutation (present in the patients with suspected or confirmed COVID-19,
B.1.1.7 or alpha variant) and the L452R mutation (pre- which includes the use of a gown, gloves, a respirator
sent in the B.1.617.2 or delta variant) are both associ- or medical mask, and eye or face protection for pre-
ated with higher levels of transmissibility [66]. venting transmission. N95 masks confer the greatest
Fortunately, preliminary reports of current vaccine protection, especially in conditions of greater patient
effectiveness have demonstrated protection, albeit aerosolization, such as during aerosol-generating pro-
reduced, to such variants and emphasize their need cedures and certain types of environmental cleaning.
against more virulent strains [67]. However, in the event that N95 masks are not available
COVID-19: Epidemiology 13
or are in limited supply, surgical masks are acceptable individual, which, as previously mentioned, is thought
in many hospital settings [72, 74, 75]. to be the principal risk factor for transmission of
In the community, mask wearing with social dis- SARS-CoV-2. This method was taken from previous
tancing as an alternative to widespread lockdown was data preventing SARS and MERS infections. In a meta-
officially endorsed by the CDC in March 2020. The analysis of observational studies evaluating the rela-
CDC subsequently issued a mandate requiring masks tionship between physical distance and transmission
on public transportation and areas or times of gather- of SARS-CoV-2, SARS-CoV, and MERS-CoV, proxim-
ings (including taxis and rideshares) and at transpor- ity and risk for infection were closely associated, and
tation hubs (e.g. airports, bus or ferry terminals, the infection rate was much higher with contact
railway stations, seaports) [76]. The rationale for within 3 ft (1 m) compared with contact beyond that
community mask wearing is, regardless of symptoms, distance (12.8% versus 2.6%) [77].
preventing transmission while maintaining the day- Optimal distance is uncertain, but physical distanc-
to-day functions for individuals and the country. In ing is likely independently associated with a reduced
the United States, cloth masks or disposable masks risk for SARS-CoV-2 transmission. Current guidance
(e.g. commercially available surgical masks) were rec- suggests at least 6 ft. In the United States, the CDC rec-
ommended for the general public or in public settings ommends a minimum distance of 6 ft (2 m), whereas
with individuals outside the household to reduce the WHO recommends a minimum distance of 1 m. In
transmission of SARS-CoV-2. In addition, guidance locations where there is community transmission of
criteria for approved homemade masks were given to SARS-CoV-2 (including throughout the United States),
the public, stating that masks should be made with individuals are advised to practice social or physical
several layers, fit snugly over the face, and should not distancing in both indoor and outdoor spaces by main-
contain respiratory valves [74, 76]. taining a minimum distance from other people out-
Strategies to improve mask fit include using a mask side their household.
with an adjustable nose bridge, wearing a cloth mask Widescale shelter-in-place orders and lockdowns
over a disposable mask, knotting the ear loops of a dis- were the most aggressive form of these distancing
posable mask to secure it against the face, using masks methods. During peak outbreaks, when daily case rates
with ties rather than ear loops, and using a mask brace. and deaths were the highest, governments strongly
Some individuals may opt to wear commercially avail- encouraged or required individuals to quarantine
able KN95 respirators, but many do not meet the inside their homes, only leaving for necessities such as
advertised filtration standards. Furthermore, due to food and other items. Although one of the most contro-
necessity in the healthcare setting, N95 respirators are versial forms enacted by prevention taskforces, given
not indicated or necessary for the general public and societal and mental health considerations, studies can
should generally be reserved for healthcare workers speak to the impact of distancing on viral transmission.
who work in higher-risk environments [74, 75]. One such study involving multiple countries showed a
significant decrease in viral transmission when indi-
viduals were distanced 1 m or more from each other.
Physical Distancing
Moreover, protection was increased as the distance was
In the effort against COVID-19 spread, countries across lengthened [77]. Other studies have shown that, after
the globe used various physical distancing measures cases began to emerge, longer time periods for which
to keep clustering of individuals to a minimum. This countries waited to implement quarantine measures
included, but was not limited to, limiting the number of were associated with greater CFRs [78].
individuals in closed spaces, temporarily shutting down
schools and universities, and limiting the number of
Hand and Surface Sanitation
people during indoor shopping, gymnasium use, per-
sonal services (e.g. hair cutting, manicures), and dining. Inanimate surfaces may be potential sites for the trans-
Distancing guidelines were implemented to mini- mission of COVID-19 infection. Depending on the
mize prolonged close-range contact with an infected nature of the surface and conditions of the surrounding
14 Coronavirus Disease 2019 (COVID-19)
environment (temperature, pH, humidity, etc.), the ventilation flow rates can lead to lower viral air con-
virus can remain viable for several hours [78]. Concern centrations and a decreased risk for exposure and
mainly stems from potential contaminated surfaces transmission of virus [83]. Although conclusions of
contacting hands, which then pass the virus to upper ventilation effects on SARS-CoV-2 transmission are
respiratory tract mucous membranes (conjunctivae, largely drawn from historical and theoretical models,
nose, mouth, etc.) through touch. Although surface they nonetheless highlight the need for improved air
contact spread is only theoretical and has not been circulation to lower airborne viral concentrations and
definitively documented, studies have shown that decrease the risk for transmission.
SARS-CoV-2 has extended longevity on certain surfaces
and through skin-to-skin contact [79, 80]. The US
Use of Outdoor Spaces
Environmental Protection Agency recommends disin-
fectants that contain quaternary ammonium com- Where possible, use of outdoor spaces can further
pounds, hydrogen peroxide, alcohol (ethanol, isopropyl reduce aerosol transmission [84]. Outdoor spaces typi-
alcohol, phenol), aldehyde, hypochlorous acid, octanoic cally offer greater physical distancing and airflow than
acid, citric acid conjugate with silver ions, sodium indoor spaces. Relatively few SARS-CoV-2 transmis-
hypochlorite, sodium bicarbonate, etc., all of which sions have been linked to outdoor setting [85].
contain key virucidal activity. Specifically, alcohols eth- Although outdoor transmission can occur, and the
anol (78–95%) and isopropanol (70–100%) have been precise settings in which this can be minimized are
used as reliable and relatively safe disinfectant options still being investigated, the odds of indoor transmis-
because they show potent virucidal activity with a neg- sion have been shown to be significantly greater [86].
ligible toxic effect on human skin [81]. In autopsy stud- Limiting the duration and frequency of personal
ies, SARS-CoV-2 remained viable on the skin for about contact, using personal protective equipment, and
nine hours but was completely inactivated within avoiding any indoor contacts may increase the safety
15 seconds of exposure to 80% alcohol [81]. of outdoor gatherings [84].
were they successful? Conversely, what was common emergencies. Such a pandemic playbook has previ-
among those who were not? There is a public health ously been proposed by the CDC to help coordinate
consensus that limiting the number of contacts pandemic influenza response [92]. This includes, but
between persons can slow COVID-19 transmission in is not limited to, concepts such as swiftly tightening
a community and give time for healthcare systems to international borders to travel and trade, supervised
respond and vaccines to be developed. Factors such as traveler isolation and well-coordinated quarantines,
population density, leadership, national wealth, infra- early implementation of physical distancing require-
structure, and equitable healthcare resources influ- ments, encouraging good hand hygiene (frequent
ence a nation’s capacity to do so [87]. handwashing, use of alcohol hand sanitizers as an
Before vaccination, the most meaningful approaches alternative, cough etiquette), and having the infra-
governments took to stop community spread were stay- structure for quick and widespread testing and contact
at-home-orders. These guidelines requested or required tracing [91, 93]. In addition to these policies, nations
people to quarantine in their homes, to leave only for must also possess the capacity to provide social sup-
absolute necessities, such as food and healthcare ports in the future, to provide mental health services,
needs [88]. Although there are multiple theoretical and adequate resources, and economic assistance to those
practical models about how stay-at-home orders and in need. This is obviously a more attainable goal for
travel restrictions slowed COVID-19 transmission, it is wealthier countries, but nevertheless, it is imperative
clear that consistency in communication and early that nations and their leaders come together and offer
implementation were key [89]. Retrospective data mutual aid in times of crisis. Sharing of wealth, infor-
show that a longer amount of time before implementa- mation, resources, intellectual property, and financial
tion of physical distancing measures was associated support are all necessary to maximize the safety and
with worse CFRs [77]. Widespread testing efforts were well-being of citizens.
valuable in the identification of cluster outbreaks.
South Korea is a good example of the impact of early
and effective measures, in which large-scale testing Conclusions
efforts in combination with contact tracing and social
distancing measures led to one of the most successful This novel SARS-CoV-2 virus was unique in many
pandemic responses in the world [90, 91]. Countries ways. An insidious, yet defining, characteristic of this
such as New Zealand succeeded by enacting strict bor- disease was its ability for asymptomatic spread.
der control. Of course, having the wealth and resources Without efficient widespread testing measures, we
to accommodate such a large and rapid disease saw a virus, seemingly isolated to a limited region of
response is crucial to improving individual and popula- China, stretch to every corner of the globe in a matter
tion outcomes. Countries with an adequate physician of months. In coordination with international leaders,
workforce and technological capacity to accommodate our global health institutions developed guidelines to
pandemic-level crises were able to detect disease ear- help contain spread, including isolation, mask wear-
lier and fared better in terms of overall mortality [77]. ing, hand hygiene practices, and nationwide shut-
downs of business and mass gatherings. However, the
aftermath of the outbreak cannot be ignored; short-
Future Outbreaks
comings must be addressed. Hospitals quickly filled to
Global trade, travel, climate change, urbanization, and capacity, and we saw our healthcare infrastructure
national wealth all play a part in global infrastructure woefully ill-equipped to handle the volume of indi-
and the ability to address worldwide pandemics. viduals affected by this disease.
Lessons learned over the course of the COVID-19 pan- Indeed, the pandemic has revealed shortcomings in
demic, compiled from multiple national responses, our health systems, notably highlighting, in the United
have created a type of framework, or a “pandemic States, the systemic racial and economic inequities that
playbook,” in which governments and public health plague them. Moreover, this virus has profoundly
agencies can model policy to stave off future pandemic reshaped how we must think about global public health
16 Coronavirus Disease 2019 (COVID-19)
and emphasizes the magnitude of work needed to be e ngineering allowed us to address the novel challenges
done. This pandemic illness has forced us to reevaluate of the pandemic. It is essential for us to build on this
our approach to disease epidemiology, outbreaks, and progress, for the sake of the most affected dense and
how further progress can be made under these new poor populations around the world. Our institutions,
norms. Conversely, we have also seen the capacity for physicians, and healthcare leaders must take the lessons
global coordination in an unprecedented time frame. from this unprecedented event to facilitate change with
Massive mobilization of manufacturing, testing decisive action and prevent any future catastrophes like
resources, healthcare workforce, and biomedical the COVID-19 pandemic from occurring again.
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www.wsj.com/articles/which-countries-have- et al. (2020). Response to COVID-19 in South Korea
responded-best-to-covid-19-11609516800. and implications for lifting stringent interventions.
92 US Department of Health and Human Services BMC Med. 18 (1): 321. https://doi.org/10.1186/
(2017). Pandemic influenza plan: 2017 update: US s12916-020-01791-8.
22
COVID-19: Virology
Saeideh Najafi1, Salar Tofighi1, and Juliana Sobczyk2,3
1
Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
2
Department of Pathology, Memorial Satilla Hospital, HCA Healthcare, Waycross, GA, USA
3
Laboratory Director, St. Augustine Foot & Ankle, Inc., St. Augustine, FL, USA
Coronavirus Disease 2019 (COVID-19): A Clinical Guide, First Edition. Edited by Ali Gholamrezanezhad and Michael P. Dube.
© 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd.
COVID-19: Virology 23
emerged in Saudi Arabia. Similarly, MERS-CoV also rap- initiated the spread of the virus to other continents.
idly crossed species from bats as reservoirs and camels as On 31 January 2020, the World Health Organization
intermediate hosts to humans and caused severe respira- (WHO) declared a public health emergency of inter-
tory symptoms and high mortality [4]. Nevertheless, prior national concern. The International Committee on
to 2019, the majority of CoV types known to infect Taxonomy of Viruses renamed the new virus SARS-
humans (four of six types) primarily caused mild respira- CoV-2 and termed the illness sequelae coronavirus
tory symptoms. disease 2019 (COVID-19) [8]. Rapid worldwide trans-
In early December 2019, an unknown infectious mission led to the pandemic declaration on 11 March
agent caused an outbreak of unusual viral pneumonia 2020. The number of people infected and the geo-
in Wuhan in the Hubei province of China. The first graphical radius of SARS-CoV-2 surpassed those of
cases were linked to a seafood market, but soon wide- both MERS and SARS-CoV and caused unprece-
spread person-to-person transmission was observed [6, dented global public health and economic crises.
7]. Clusters of disease were discovered in families and
their close contacts. Many patients presented with
fever, cough, and chest discomfort. Some of the
Coronaviruses
infected individuals experienced severe dyspnea and
hypoxia with bilateral lung infiltration seen on radio-
Taxonomy
logic imaging. In January 2020, the disease’s causative
agent was determined to be the seventh CoV to infect The Coronavirus family is placed under the order
humans, SARS-CoV-2, and its genome was sequenced. Nidovirales and is also known as Coronaviridae.
In the beginning, the new CoV was known as the Coronavirinea is a subfamily under the family
2019-novel coronavirus (2019-nCoV). The disease Coronaviridae. The Coronavirinae subfamily is fur-
spread reached epidemic levels in China by February ther divided into four genera: Alphacoronavirus,
2020. Although officials worldwide executed rigorous Betacoronavirus, Gammacoronavirus, and
lockdowns as one mean to control the virus spread in Deltacoronavirus (Figure 2.2). The second subfamily
and from China, international travelers had already under Coronaviridae is Torovirinea. Torovirus and
24 Coronavirus Disease 2019 (COVID-19)
Coronaviridae
Coronavirinea Torovirinae
Bafinivirus are two genera under the Torovirinae found in horseshoe bats and pangolins (RmYN02 and
subfamily. Alphacoronaviruses and Betacoronaviruses RaTG13) [2, 5, 6].
replicate in mammal hosts, Gammacoronaviruses
and Deltacoronaviruses in bird hosts, Toroviruses in
Morphology
mammal hosts, and Bafiniviruses in fish hosts [2].
The four human CoVs that have been known to cause Coronaviridae are enveloped viruses with spherical
mild symptoms are two Alphacoronaviruses (229E and (Coronaviruses), bacillar (Bafinivirus), or crescentic
NL63) and two Betacoronaviruses (OC43 and HKU1). (Toroviruses) shapes (Figure 2.3). Virions are deco-
SARS-CoV-2, SARS-CoV, and MERS-CoV belong to the rated with petal-shaped projections of homotrimeric
Betacoronaviruses. Most known Coronavirinea mem- proteins on their surfaces [2, 5]. These projections,
bers have been isolated from bat reservoirs. Bats are known as protein S, spikes, or peplomers, establish
believed to be an optimal host among mammals for the host range and facilitate the initial steps of infec-
viral evolution because they live in large colonies with tion by binding to host cell receptors and genetic
close proximity. SARS-CoV and SARS-related CoVs material injection. Another structural protein, pro-
have been isolated from bats and civets. The closest tein M, is the most abundant protein in the viral par-
genetically related species to SARS-CoV-2 have been ticle. Protein M is a dimeric protein and integrated
Figure 2.4 Schematic of SARS-CoV-2 genome. ORF, open reading frame. Source: Created with http://BioRender.com.
into virion membranes of the Coronaviridae family. It translation to produce 15 or 16 nonstructural proteins
plays an essential role in the assembly and morpho- (nsps), depending on the virus genera. These proteins
genesis of virions. The endodomain of protein M are named from nsp1 to nsp16 in order of their posi-
forms a matrix-like lattice that supports the thick tion from 5′ to 3′. nsps function in viral replication,
membrane of CoVs [5]. The envelope in CoVs virus–host interaction, and evasion from the immune
(7–7.8 nm) is two times thicker than the average thick- system. Distal to the nsp segment, segments for struc-
ness of biologic membranes (4 nm) [2]. tural proteins S, E, M, and N are positioned. In the
The nucleocapsid (protein N) houses the viral Coronavirinea subgroup, various numbers of acces-
genomic RNA. The nucleocapsid forms a helix via sory genes, such as HE, are interspersed among struc-
attachments to basic phosphoproteins, protein N, and tural proteins [2, 4, 5].
is susceptible to treatment with detergents. In addition Viral-positive ssRNA acts as both a messenger RNA
to encapsulation, protein N participates in RNA syn- for protein transcription and a template for the synthe-
thesis, translation, and interferon antagonism [2, 5]. sis of negative ssRNA. CoVs are RNA viruses and use
Some Betacoronaviruses and Toroviruses possess RNA-dependent RNA polymerase (RdRp) to replicate
hemagglutinin esterase (HE) protein on their surface, their genome. Viral RdRp read the genome in a non-
which functions in viral attachment. Coronavirinea contiguous manner, jumping from one region to
also produce protein E, a small protein on its surface, another to synthesize RNA. A distinguishing feature
which acts in virion assembly and morphogenesis. of CoVs is they synthesize segmented subgenomic
messenger RNAs from negative-strand RNA to repli-
cate viral RNA. The nucleocapsid is assembled in the
Nucleic Acid
cytoplasm of the host cell and enters the endoplasmic
The family of Coronaviridae possesses the largest reticulum (ER), whereas the structural proteins are
genetic material among viruses (26–32 kb) that is com- assembled in the ER and Golgi apparatus. Preformed
posed of an unsegmented positive single-stranded nucleocapsids bud from the ER and Golgi systems and
RNA (ssRNA) [2]. The RNA molecule is 5′-capped and exit the host cell through exocytosis [4].
3′-polyadenylated, containing multiple open reading
frames (ORFs) (Figure 2.4). After the 5′ untranslated
Antigenicity
region, two thirds of the genome encode replicase pro-
teins (two overlapping ORF1a and ORF1b segments). The strongest antibody response against CoVs is pro-
As a result of ribosomal frameshifting, these segments voked by exposure to proteins S and N. Production of
yield two polyproteins, pp1a and pp1ab. Proteinases neutralizing antibodies by the immune system is
further process these polyproteins during and after mainly induced by protein S. These antibodies have
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"How do you come on, my dear?" she asked. "I'll hear you
now."
"It does truly, ma; I began right earnest, Aunt Sarah will tell
you, but—"
"Well, you may go to your room now, and lie down, while I
carry the yarn to Nancy."
"Of course not. Take off your clothes and go to bed till I
return."
CHAPTER IV.
FRANKIE'S NEW LESSON.
Tony was on the bed, too, and the boy was amusing himself
with hiding his pocket-handkerchief under the sheets and
telling her to find it.
"I was very sorry that you could not enjoy your favorite
pudding, my dear. Cook said she made it on purpose for
Master Frank."
"I saw him once. Sam had a stick and he threw it away and
told Fox to get it; but the lazy thing never stirred. He just
whisked his tail and stood still. I wouldn't have such a dog.
Now see, ma, how quick Tony minds me."
"I see, Frankie; and I think I know a little boy who could
learn a good lesson from his dog."
"I'm sorry, ma, I didn't obey you better. I acted just like
Sam Lambert's Fox. I didn't think of that before."
Mrs. Colvin leaned over the bed, and kissed her boy.
"Why, ma," the boy went on, "if Tony had acted that way,
when I told her to do something,—I mean if she had fooled
away her time,—I should have got a stick and whipped her.
Why didn't you whip me, ma?"
"But now I want to talk with you about your music. You can
remember how very anxious you were to learn, and how
many promises you made to practise regularly. Your father
is very fond of music, and cheerfully paid the twenty-five
dollars, which Mr. Lenox asks for teaching you."
"But, ma," urged the boy, "I didn't know how it would make
my fingers ache. If I could play nice marches like Etty
Bowles, I'd like it first-rate."
"Etty began when you did, Frankie; and I dare say her
fingers ached till they became accustomed to the motion. If
you persevere, you will soon be able to play marches. Every
lesson you learn thoroughly is a good step in advance. You
know how easy your first lessons have become."
"Oh, yes, ma! I can diddle 'em off tip-top." He laughed
merrily, as he began to practise with his finger on Tony's
back. Presently, he said,—
"Ma, if you'll let me get up, I'll play steady at it. I'll try to
obey you just as nice as Tony does me. Wont I, doggy?"
"And my fingers don't ache at all. They only feel stiff a little.
Now, ma, I feel as if I could dance, I'm so very glad. But
wont Mr. Lenox be surprised, though? He'll say, 'Frankie
Colvin, take your place on the stool;' and he'll frown and be
all ready to scold when he finds I haven't practised the last
lesson. Oh, it will be fun to see him!"
"Why, Frank," said his father; "you dance and hop about for
all the world like Tony."
"I'm so happy, pa. This dear little doggy has given me one
good lesson, and I love her better than ever," he added,
hugging the faithful creature.
CHAPTER V.
THE STOLEN DOG.
ONE day, Frankie was going an errand for his mother; and
Tony, of course, was following closely at his heels, when he
heard the sound of a hand-organ down a lane, and he ran
to find it.
Then he looked behind him for Tony; but she, too, was
missing. He called, loudly, "Tony! Tony!" But there was no
answer back.
"I saw a dog running off that way," said a boy, pointing in
the direction of Frankie's home. "I guess that was your
dog."
Mrs. Colvin was soon convinced that Tony had been stolen.
She told Frankie to sit down and cool himself; and then she
sent Edward to a neighbor, who was a constable, to ask him
what they should do.
Poor Frank cried until his head ached, and could not eat a
mouthful of dinner. He kept saying, "Oh, I wish I hadn't
gone down the lane! I'm afraid they'll kill Tony, or starve
him to death."
"I know she's dead," said poor Frankie, who now looked
really ill. "I know I shall never see her again."
A fresh burst of grief prevented him from saying more. He
laid his arm on the table and cried as if his heart would
break.
Frankie heard it, too, and ran quickly across the room to
open time door. There stood poor Tony, with the lost
handkerchief between her teeth. She had grown so thin that
she could hardly stand, but tried to crawl forward to her
young master's feet.
Mrs. Colvin rang the bell, and sent nurse for some food for
the poor, starved creature.
"We must feed her very cautiously at first," she said, as her
boy began to cut the meat from the bones. "Let her eat but
a little now, and give her more at the end of an hour."
"I wish Tony could tell where she has been. I'd get the
constable to put the people in prison, for treating her so.
Look, ma! Here is the rope they tied her with. I do believe
the good creature gnawed it off, and ran away!"
Toward the close of the day, cook came into the parlor and
told her mistress that there were two boys at the end of the
garden, and she had overheard them talking about the dog.
Mrs. Colvin at once sent the hired man to bring them to the
house. But the boys saw him coming and ran away,
laughing, and shouting loudly, "Catch me if you can."
The man said he knew the boys, and that they were none
too good to steal a dog.
CHAPTER VI.
TONY'S LOVE FOR HER MASTER.
I AM sure the little boys and girls who read this, will be glad
to know that good care, nourishing food, and Frankie's
caresses, at last restored Tony; though it was a long time
before she could run and jump as she had before. It was
quite affecting to see her try to spring after Frankie's ball
when he bid her bring it to him. She would seem to forget
for a moment how feeble she was, and then, quite
exhausted, she would lie down puffing and panting for
breath, but keeping her eyes on her master as if to say, "I
would obey you, if I could."
Then Frank would blame himself for telling her to do it; and
he would ask her pardon, and kiss her over and over again.
Oh, they were very good friends, indeed!
Tony was sure, now, that something was the matter. She
sprang up, licked his hand, and tried, in every way that a
dog could try, to show her sympathy.
Frankie was a proud boy; that is, he would not like anybody
to know that he had been punished, and was crying for it;
but he didn't mind telling his troubles to Tony.
"It was real mean of the master," he began, "to ferule me
for just saying one word. Sam Lambert asked me to lend
him my new ball; and I said it was at home. Master
punished me; but Sam got nothing but praise."
Tony had the poor, swollen hand now, and was kissing it
with all her might.
"Well," Frankie went on, "after all, I had rather have a good
whipping every day, than to lie as Sam does. The master
will find him out some time; and if he don't, God sees him.
I'd be afraid ever to go to sleep, if I was such a liar."
Tony stood by, looking very wishful; and then they went in
together. During all the intermission, Tony did not leave her
master a minute; but watched him closely, every now and
then standing on her hind feet to lick his hand.
"He said, 'Will you let me take your new ball at recess?' and
I told him that I had left it at home."
"Yes, those were the words. I can believe you, Frank, for I
have never known you to tell a lie. You may take your seat."
It was very hard for the good boy to study his lesson, while
his seat-mate was muttering so angrily behind the cover;
but, remembering his victory over himself with his music
lesson, he bent his whole mind to the task, and soon
learned all the map questions in his geography lesson.
You can easily imagine how glad Frankie was that he had
learned his lesson so perfectly. He stood very erect, his eyes
sparkling, his cheeks rosy-red, and was ready with every
answer, the moment the question was asked.
CHAPTER VII.
CONCLUSION.
WHEN the classes had all recited, the visitors took their
leave, Mrs. Colvin asking permission for Frankie to
accompany them home, as their friend would remain only
one night.
I need not tell you that our little friend felt very happy.
Instead of walking along steadily with his mother and the
colonel, he and Tony had a chase, here and there, every
minute or two returning to the side of their friends.
"And that is not the worst of it, my dear son," said the lady;
"the exposure before the school was mortifying, to be sure;
but that is nothing compared to the displeasure of our
heavenly Father. There is no sin which appears to good
people more mean and despicable than lying, and there is
none which God abhors more."
Tony, at this, sprang into Frankie's arms, and laid her head
on his breast.
"No, sir."
"Oh! Oh!" screamed the boy. "I'm so glad. May I go, ma?"
"I can't get all my things in, ma," said the boy, in a
desponding tone.
"Would you carry Tony's new suit, ma? I wish I could; she
does look so funny in it."
"How kind you are, ma!" Frankie jumped up and gave his
mother a warm kiss.
It was still two hours before the train would leave the city;
and Mrs. Colvin tried to persuade him to return to bed; but
his father laughed and said,—
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