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Journal of Autoimmunity xxx (xxxx) xxxx
Journal of Autoimmunity
journal homepage: www.elsevier.com/locate/jautimm
Review article
A R T I C LE I N FO A B S T R A C T
Keywords: Coronavirus disease (COVID-19) is caused by SARS-COV2 and represents the causative agent of a potentially
Coronavirus fatal disease that is of great global public health concern. Based on the large number of infected people that were
COVID-19 exposed to the wet animal market in Wuhan City, China, it is suggested that this is likely the zoonotic origin of
Wuhan city COVID-19. Person-to-person transmission of COVID-19 infection led to the isolation of patients that were sub-
Pneumonia
sequently administered a variety of treatments. Extensive measures to reduce person-to-person transmission of
Pathogenesis
COVID-19 have been implemented to control the current outbreak. Special attention and efforts to protect or
reduce transmission should be applied in susceptible populations including children, health care providers, and
elderly people. In this review, we highlights the symptoms, epidemiology, transmission, pathogenesis, phylo-
genetic analysis and future directions to control the spread of this fatal disease.
∗
Corresponding author. Department of Pharmacology and Experimental Neuroscience Durham Research Center, 8047 985880 Nebraska Medical Center Omaha,
NE, 68198-5880, USA
E-mail addresses: hrothan@gsu.edu (H.A. Rothan), sid.byrareddy@unmc.edu (S.N. Byrareddy).
https://doi.org/10.1016/j.jaut.2020.102433
Received 10 February 2020; Received in revised form 17 February 2020; Accepted 18 February 2020
0896-8411/ © 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: Hussin A. Rothan and Siddappa N. Byrareddy, Journal of Autoimmunity,
https://doi.org/10.1016/j.jaut.2020.102433
H.A. Rothan and S.N. Byrareddy Journal of Autoimmunity xxx (xxxx) xxxx
Figure 1. The chronological incidence of COVID-19 infections and death cases in China. Infections with COVID-19 appears in December 2019. At the time of
preparing this manuscript, February 16, 2020 there have been 51,174 people who have contracted the infection in China, and more than 1666 people have died.
2
H.A. Rothan and S.N. Byrareddy Journal of Autoimmunity xxx (xxxx) xxxx
cases increased to 56 deaths [8]. The percentage of death among the 5. Phylogenetic analysis
reported 2684 cases of COVID-19 was approximately 2.84% as of Jan
25, 2020 and the median age of the deaths was 75 (range 48–89) years World Health Organisation (WHO) has classified COVID-19 as a β
[8]. CoV of group 2B [23]. Ten genome sequences of COVID-19 obtained
Patients infected with COVID-19 showed higher leukocyte numbers, from a total of nine patients exhibited 99.98% sequence identity [19].
abnormal respiratory findings, and increased levels of plasma pro-in- Another study showed there was 99.8–99.9% nucleotide identity in
flammatory cytokines. One of the COVID-19 case reports showed a isolates from five patients and the sequence results revealed the pre-
patient at 5 days of fever presented with a cough, coarse breathing sence of a new beta-CoV strain [5]. The genetic sequence of the COVID-
sounds of both lungs, and a body temperature of 39.0 °C. The patient's 19 showed more than 80% identity to SARS-CoV and 50% to the MERS-
sputum showed positive real-time polymerase chain reaction results CoV [5,19], and both SARS-CoV and MERS-CoV originate in bats [24].
that confirmed COVID-19 infection [14]. The laboratory studies showed Thus, the evidence from the phylogenetic analysis indicates that the
leucopenia with leukocyte counts of 2.91 × 10^9 cells/L of which COVID-19 belongs to the genus betacoronavirus, which includes SARS-
70.0% were neutrophils. Additionally, a value of 16.16 mg/L of blood CoV, that infects humans, bats, and wild animals [25].
C-reactive protein was noted which is above the normal range COVID-19 represents the seventh member of the coronavirus family
(0–10 mg/L). High erythrocyte sedimentation rate and D-dimer were that infects humans and has been classified under the orthocoronavir-
also observed [14]. The main pathogenesis of COVID-19 infection as a inae subfamily. The COVID-19 forms a clade within the subgenus sar-
respiratory system targeting virus was severe pneumonia, RNAaemia, becovirus [25]. Based on the genetic sequence identity and the phylo-
combined with the incidence of ground-glass opacities, and acute car- genetic reports, COVID-19 is sufficiently different from SARS-CoV and it
diac injury [6]. Significantly high blood levels of cytokines and che- can thus be considered as a new betacoronavirus that infects humans.
mokines were noted in patients with COVID-19 infection that included The COVID-19 most likely developed from bat origin coronaviruses.
IL1-β, IL1RA, IL7, IL8, IL9, IL10, basic FGF2, GCSF, GMCSF, IFNγ, IP10, Another piece of evidence that supports the COVID-19 is of bat origin is
MCP1, MIP1α, MIP1β, PDGFB, TNFα, and VEGFA. Some of the severe the existence of a high degree of homology of the ACE2 receptor from a
cases that were admitted to the intensive care unit showed high levels diversity of animal species, thus implicating these animal species as
of pro-inflammatory cytokines including IL2, IL7, IL10, GCSF, IP10, possible intermediate hosts or animal models for COVID-19 infections
MCP1, MIP1α, and TNFα that are reasoned to promote disease severity [20]. Moreover, these viruses have a single intact open reading frame
[6]. on gene 8, which is a further indicator of bat-origin CoVs. However, the
amino acid sequence of the tentative receptor-binding domain re-
sembles that of SARS-CoV, indicating that these viruses might use the
4. Transmission same receptor [5].
Based on the large number of infected people that were exposed to 6. Therapeutics/treatment options
the wet animal market in Wuhan City where live animals are routinely
sold, it is suggested that this is the likely zoonotic origin of the COVID- The person-to-person transmission of COVID-19 infection led to the
19. Efforts have been made to search for a reservoir host or inter- isolation of patients that were administered a variety of treatments. At
mediate carriers from which the infection may have spread to humans. present, there are no specific antiviral drugs or vaccine against COVID-
Initial reports identified two species of snakes that could be a possible 19 infection for potential therapy of humans. The only option available
reservoir of the COVID-19. However, to date, there has been no con- is using broad-spectrum antiviral drugs like Nucleoside analogues and
sistent evidence of coronavirus reservoirs other than mammals and also HIV-protease inhibitors that could attenuate virus infection until
birds [10,18]. Genomic sequence analysis of COVID-19 showed 88% the specific antiviral becomes available [7]. The treatment that have so
identity with two bat-derived severe acute respiratory syndrome far been attempted showed that 75 patients were administrated existing
(SARS)-like coronaviruses [19,20], indicating that mammals are the antiviral drugs. The course of treatment included twice a day oral ad-
most likely link between COVID-19 and humans. Several reports have ministration of 75 mg oseltamivir, 500 mg lopinavir, 500 mg ritonavir
suggested that person-to-person transmission is a likely route for and the intravenous administration of 0·25 g ganciclovir for 3–14 days
spreading COVID-19 infection. This is supported by cases that occurred [26]. Another report showed that the broad-spectrum antiviral re-
within families and among people who did not visit the wet animal mdesivir and chloroquine are highly effective in the control of 2019-
market in Wuhan [13,21]. Person-to-person transmission occurs pri- nCoV infection in vitro. These antiviral compounds have been used in
marily via direct contact or through droplets spread by coughing or human patients with a safety track record. Thus, these therapeutic
sneezing from an infected individual. In a small study conducted on agents can be considered to treat COVID-19 infection [27]. Further-
women in their third trimester who were confirmed to be infected with more, there are a number of other compounds that are in development.
the coronavirus, there was no evidence that there is transmission from These include the clinical candidate EIDD-2801 compound that has
mother to child. However, all pregnant mothers underwent cesarean shown high therapeutic potential aganist seasonal and pandemic in-
sections, so it remains unclear whether transmission can occur during fluenza virus infections and this represents another potential drug to be
vaginal birth. This is important because pregnant mothers are relatively considered for the treatment of COVID-19 infection [28]. Along those
more susceptible to infection by respiratory pathogens and severe lines, until more specific therapeutics become available, it is reasonable
pneumonia (https://www.thelancet.com, DOI:https://doi.org/10. to consider more broad-spectrum antivirals that provide drug treatment
1016/S0140-6736(20)30360-3). options for COVID-19 infection include Lopinavir/Ritonavir, Neur-
The binding of a receptor expressed by host cells is the first step of aminidase inhibitors, peptide (EK1), RNA synthesis inhibitors. It is clear
viral infection followed by fusion with the cell membrane. It is reasoned however, that more research is urgently needed to identify novel che-
that the lung epithelial cells are the primary target of the virus. Thus, it motherapeutic drugs for treating COVID-19 infections. In order to de-
has been reported that human-to-human transmissions of SARS-CoV velop pre-and post-exposure prophylaxis against COVID-19, there is an
occurs by the binding between the receptor-binding domain of virus urgent need to establish an animal model to replicate the severe disease
spikes and the cellular receptor which has been identified as angio- currently observed in humans. Several groups of scientists are currently
tensin-converting enzyme 2 (ACE2) receptor [20,22]. Importantly, the working hard to develop a nonhuman primate model to study COVID-
sequence of the receptor-binding domain of COVID-19 spikes is similar 19 infection to establish fast track novel therapeutics and for the testing
to that of SARS-CoV. This data strongly suggests that entry into the host of potential vaccines in addition to providing a better understanding of
cells is most likely via the ACE2 receptor [20]. virus-host interactions.
3
H.A. Rothan and S.N. Byrareddy Journal of Autoimmunity xxx (xxxx) xxxx
7. Future directions to control the spread of the disease novel coronavirus causing severe pneumonia in human: a descriptive study, Chinese
Med J (2020), https://doi.org/10.1097/CM9.0000000000000722.
[6] C. Huang, Y. Wang, X. Li, L. Ren, J. Zhao, Y. Hu, et al., Clinical features of patients
Extensive measures to reduce person-to-person transmission of infected with 2019 novel coronavirus in Wuhan, China, Lancet 395 (10223) (2020)
COVID-19 are required to control the current outbreak. Special atten- 497–506, https://doi.org/10.1016/S0140-6736(20)30183-5.
tion and efforts to protect or reduce transmission should be applied in [7] H. Lu, Drug treatment options for the 2019-new coronavirus (2019-nCoV), Biosci.
Trends (2020), https://doi.org/10.5582/bst.2020.01020.
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[9] H. Nishiura, S.M. Jung, N.M. Linton, R. Kinoshita, Y. Yang, K. Hayashi, et al., The
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to a weak immune system that permits faster progression of viral in- [10] M. Bassetti, A. Vena, D. Roberto Giacobbe, The Novel Chinese Coronavirus (2019-
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possible intermediate animals and reservoirs. There remains a con- Barrak, et al., Epidemiological, demographic, and clinical characteristics of 47 cases
siderable number of questions that need to be addressed. These include, of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a de-
scriptive study, Lancet Infect. Dis. 13 (2013) 752–761.
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Declaration of competing interest 6736(20)30251-8.
[20] Y. Wan, J. Shang, R. Graham, R.S. Baric, F. Li, Receptor recognition by novel cor-
The authors declare no conflicts of interest. onavirus from Wuhan: an analysis based on decade-long structural studies of SARS,
J. Virol. (2020), https://doi.org/10.1128/JVI.00127-20.
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4
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the dark waters of some deep lake.
“Did she ever tell you so?”
“Y-e-e-e-es,” replied she, doubtfully.
“Mr. Whacker, I assure you,” began Lucy, choking with mortification,
“I—”
“I forgive, though I can never forget—”
“But—”
“St!” whispered Alice; “it is as good as a play!”
“But, Alice, it’s a most outrageous—”
“Never mind,—listen!”
Meantime, we had lost a few sentences of the colloquy, which
seemed to be affording intense amusement to the Stranger.
“But what did she say?” were the first words we caught.
“She said,” began the little thing, gesticulating with her hands and
rolling her eyes,—speaking, in fact, with her whole body,—“sister
Lucy, she said—”
“Well.”
“Sister Lucy, she said Mr. Whacker was mighty fat, but he was right
pretty.”
Imagine the scene behind the curtains! The trouble was that Lucy,
who was as truthful as Epaminondas, could not deny having paid
me, in substance, this two-edged compliment. So she could only
bury her face in her hands. As for the Stranger, he actually laughed
aloud.
“But do ladies always love pretty men?”
“Why, yes; I love my sweetheart, and he is pretty.”
“Your sweetheart! Have you a sweetheart?”
“Yes,” replied she, with decision and complacency.
“What’s his name?”
“I can’t tell you!”
“Do, now.”
“Oh, I can’t!” And she dropped her cheek on her off shoulder and
shut her eyes.
“Say, do you like candy?”
“Yes,” said she, eagerly wheeling round; “where is it?”
“Never mind. If you will tell me, I will bring you some to-morrow.”
“What’s in that paper? I ’spec’ it’s candy, right now!”
“No,” said he, smiling; “but I will bring you some to-morrow if you
will tell me.”
She stuck a finger into her mouth and hung her head.
“Red candy,” began he, “and blue candy,” he continued, nodding his
head up and down, between the varieties, with a sort of pantomimic
punctuation, “and green candy—”
Wide-eyed delight and a half-smile of eager expectation illumined
the face of the little tempted one.
“And yellow candy, and—let me see—and striped candy, and
speckled candy—and—and—and—ALL SORTS OF CANDY!”
She clasped her hands and drew a long breath.
“Will you?”
The infant that hesitates is lost.
“And tied up in most beautiful paper—”
“You won’t tell Mr. Whacker?”
“No, never!!!”
In an instant the little creature had sprung towards him, seized his
head, pulled it down, pressed her lips against his ear, shot the
momentous name therein and bounded back.
“There! Give me the candy!”
“I said I should get it to-morrow. But I didn’t hear a word. Tell me
over again. There,—whisper it in my ear. Willie? Willie what?” said
he, drawing her towards him. “Ah, that is the name, is it?”
We did not hear the name, and I must suppose it was that of some
near neighbor of her father’s.
“Now, don’t tell Mr. Whacker!”
“No,” replied the stranger; but he had heard her with the outward
ear only. He sat, with drawn lids, gazing upon the pavement, and
softly biting his nails, as though solving some problem. His lips
seemed to move; and every now and then he looked, out of the
corners of his eyes, at his little companion. At last he slowly rose,
but stood motionless, with eyes fixed upon the ground.
“Oh, don’t go!” cried she, her fair, upturned face wearing a beautiful
expression of infantile affection.
And here our mysterious friend had another surprise in store for us.
For, when he saw that look, a startled expression came into his face;
and leaning forward, he scrutinized her features with a gaze so
searching that there was a kind of glare in his eyes,—so that the
little girl dropped her eyes and drew back, as though with a feeling
of dread. But the Unknown suddenly sat down beside her, and,
taking one of her hands in both his, patted it softly, and, in a voice
tender as that of a young mother, asked, “But what is your name,
my little cherub?”
“My name is Laura. Let’s make another house—oh, no, let’s make a
boat!”
“Not now. But Laura what? What is your other name?”
“My name is Laura Poythress.”
“Laura Poythress!”
He bowed his broad shoulders till his face was almost on a level with
hers, and scanning her features intently: “Laura Poythress, Laura
Poythress,” repeated he, to himself; “and Lucy, too! and Whacker!”
We looked at each other with wide eyes.
Again the stranger rose; this time with nervous abruptness, and took
a few rapid turns up and down the pavement, close to little Laura;
then walking quickly up to her, and stooping down, he asked her, in
an eager whisper, “Have you any mother?”
“Yeth,” replied she, with a simple little laugh, “of courth; evvybody’th
dot a muvver!”
He seemed to avert his face when she laid down this generalization;
nor could we, from our position, see his expression. “Yes,” said he;
and was silent for a while. “What is your mother’s name?”
“My mother’s name is Mumma.”
“But what is her real sure-enough name?”
“Her name is Mumma,” repeated she, with emphasis. “Oh, my
mother’s got two names. She is named Mumma and she is named
Mrs. Poythress.”
“Ah, yes; but what does your father call her?”
“My papa calls my mumma my dear; oh, and sometimes he calls her
‘honey,’—because she is so sweet.”
“Does he ever call her—let me see—does he ever call her Polly?”
“Oh, me, the idea!” cried she, raising her hands and eyes in infantile
pity of his ignorance. “Why, that’s Aunt Polly’s name!”
“So your Aunt Polly is named Polly, is she?”
“No, she ain’t! Aunt Polly is named Aunt Polly. She is our cook at our
house, she is.”
“She is your cook, is she? And what does she call your mother?”
“Mistiss.”
Just then the mulatto barber, passing by, doffed his hat to the
gentleman; and Dolly, the nurse, left alone, bethought her of her
charge. Coming up, she dropped a courtesy to the Stranger, and told
Laura it was time she were within doors.
“Good-by, Laura,” said the Unknown, taking her plump little hand in
his; “won’t you give me a kiss? Ah, that’s a good little girl! One
more! And another! Ah!” And he patted her cheek. “Good-by!”
“Dood-by!”
CHAPTER III.