COVID- 19

Sumber dan Rujukan Karya

Ilmiah
COVID- 19
Sumber dan Rujukan
Karya Ilmiah

PENYUSUN
SUHARYANTO

PENGURUS PUSAT
IKATAN PUSTAKAWAN INDONESIA
2020
Covid-19 : sumber dan rujukan karya ilmiah
Penyusun : Suharyanto
Diterbitkan oleh : Ikatan Pustakawan Indonesia
Jalan Salemba Raya No. 28 A Jakarta Pusat
 Buku ini didedikasikan untuk

Yang Tercinta

Almarhum Ayahanda Bapak Soemartp Siswomihardjo

Ibunda Soekinah
atas kasih sayang dan do’a – do’a yang telah diberikan.

Yang Terkasih

Isteri Muliati Mallawa, Anak-anak Afif Heryanto, Afifah Nurhayati, Aqilah

Nur Arifah dukungan dan kasih sayangnya,

Buku ini didedikasikan untuk

Kemajuan Kepustakawanan di Indonesia

SUHARYANTO
Pustakawan-Perpusnas
Ketua Komisi Penerbitan
Pengurus Pusat
Ikatan Pstakawan Indonesia
SITUS WEB:
https://ipi.web.id/
EMAIL:
Suharyantomallawa@gmail.com
Prakata
Alhamdulillah, puji dan syukur kehadirat Allah
Swt, atas berkat rahmatnya penyusunan buku “Covid-
19 : sumber dan rujukan karya ilmiah” dapat
diselesaikan. Buku ini merupakan kumpulan artikel
karya ilmiah yang terkait dengan Covid-19 dan berisi
sebanyak 9 judul karya ilmiah.
Penerbitan buku ini merupakan keinginan
penyusun untuk mengumpulkan. mengemas, dan
menyebarluaskan tulisan-tulisan ilmiah yang berkaitan
dengan Coronavirus Disease 2019. Kumpulan tulisan
diambil dari berbagai karya tulis ilmiah yang didapat
dari berbagai sumber dan mengemas dalam satu buku.
Buku berisi 6 judul karya tulis ilmiah, salah satu
judul tulisan yang terdapat dalam buku ini, yaitu “The
Global macroeconomic impact of COVID-19 : seven
scenarios” yang ditulis oleh Warwick McKibbin dan
Roshen Fernando dari University and Centre of
Excellence in Population Ageing Research (CEPAR).
Pada kesempatan ini penyusun mengucapan
terima kasih kepada Bapak M. Syarif Bando, selaku
Pembina PP-IPI dan Bapak T. Syamsul Bahri, selaku
Ketua Umum PP-IPI yang telah memberikan
kesempatan kepada penyusun untuk membuat dan
menerbitkan buku ini. Dan juga kepada seluruh pembina
iv
dan Pengurus Ikatan Pustakawan Indonesia yang telah
mendukung dalam penyusunan dan penerbitan buku
ini. Terima kasih juga buat Pak Upriyadi, selaku Kepala
Pusat Pengembangan Koleksi dan Pengolahan Bahan
Pustaka, Perpustakaan Nasional yang telah
memberikan dukungan dalam penyusunan buku ini,
dan juga buat semua teman-teman di Bidang
Pengolahan Bahan Pustaka.
Semoga buku ini dapat bermanfaat bagi
pembaca dalam mencari rujukan karya tulis ilmiah yang
terkait dengan Covid-19. Namun demikian, penyusun
menyadari akan kekurangan dari buku ini. Oleh karena
itu kritik dan saran sangat diharapkan untuk perbaikan
buku ini di masa mendatang Akhir kata penyusun
berharap semoga buku ini dapat bermanfaat bagi para
pembaca dan menambah khasanah dalam penerbitan
buku di bidang perpustakaan

Jakarta, 09 April 2020

Penyusun

Suharyanto

v
 DAFTAR ISI

Kata Pengantar
Daftar Isi
1 The global macroeconomic impact of COVID- 1-7
10: seven scenarios ……………………………………….
2 The global macroeconomic impact of COVID- 1-43
10: seven scenarios ………………………………………..
3 Impact of non-pharma interventions (NPIS) to 1-20
reduce COVID 19 mortality and healthcare
demand …………………………………………………………
4 Development of novel, genome subtraction- 1-11
derived, SARS-CoV-2-Specific COVID-19-nsp2
real-time RT-PCR Assay and its evaluation using
clinical specimens …………………………………………..
5 Risk assessment of novel coronavirus COVID-19 1-12
outbreaker outside China ……………………………….
6 Corona virus disease (Covid-19) : sebuah 1-6
tinjauan literatur

vi
 1

2019 Novel
Coronavirus (COVID-
19) outbreak : a rivew
of the current
literature
DOI: 10.14744/ejmo.2020.12220
EJMO 2020;4(1):1–7

Review
2019 Novel Coronavirus (COVID-19) Outbreak:
A Review of the Current Literature
Ahmet Riza Sahin,1 Aysegul Erdogan,2 Pelin Mutlu Agaoglu,2 Yeliz Dineri,2 Ahmet Yusuf Cakirci,2

Mahmut Egemen Senel,3 Ramazan Azim Okyay2, Ali Muhittin Tasdogan4
1
Department of Infectious Diseases and Clinical Microbiology, Kahramanmaras Sutcu Imam University Faculty of Medicine,
Kahramanmaras, Turkey
2
Department of Public Health, Kahramanmaras Sutcu Imam University Faculty of Medicine, Kahramanmaras, Turkey
3
Department of Internal Medicine, Kahramanmaras Sutcu Imam University Faculty of Medicine, Kahramanmaras, Turkey
4
Department of Anesthesiology and Reanimation, Hasan Kalyoncu University Health Sciences Faculty, Gaziantep, Turkey

Abstract
Coronaviruses (CoV) belong to the genus Coronavirus with its high mutation rate in the Coronaviridae.
The objective of this review article was to have a preliminary opinion about the disease, the ways of treatment, and
prevention in this early stage of COVID-19 outbreak.
Keywords: COVID-19, Coronaviruses, outbreak

Cite This Article: Sahin AR, Erdogan A, Mutlu Agaoglu P, Dineri Y, Cakirci AY, Senel ME, et al. 2019 Novel Coronavirus (CO-
VID-19) Outbreak: A Review of the Current Literature. EJMO 2020;4(1):1-7.

C oronaviruses (CoV) belong to the genus Coronavirus

in the Coronaviridae. All CoVs are pleomorphic RNA vi-
ruses characteristically containing crown-shape peplomers
with 80-160 nM in size and 27-32 kb positive polarity. Re-
combination rates of CoVs are very high because of con-
stantly developing transcription errors and RNA Depen-
dent RNA Polymerase (RdRP) jumps. With its high mutation
rate, Coronaviruses are zoonotic pathogens that are pres-
ent in humans and various animals with a wide range of
clinical features from asymptomatic course to requirement
of hospitalization in the intensive care unit; causing infec-
tions in respiratory, gastrointestinal, hepatic and neurolog-
ic systems.[1-3] They were not considered as highly patho-
genic for humans until they have been seen with the severe
acute respiratory syndrome (SARS) in the Guangdong state
of China for the first time in 2002 and 2003. Before these
outbreaks, there were the two most known types of CoV
as CoV OC43 and CoV 229E that have mostly caused mild
infections in people with an adequate immune system.[3, 4]
Approximately ten years after SARS this time, another high-
ly pathogenic CoV, Middle East Respiratory Syndrome Coro-
navirus (MERS-CoV) has emerged in the Middle East coun-
tries.[5] In December 2019, 2019 novel Coronavirus (nCoV),
which is another public health problem, has emerged in
the Huanan Seafood Market, where livestock animals are
also traded, in Wuhan State of Hubei Province in China and
has been the focus of global attention due to a pneumo-
nia epidemic of unknown cause.[6] At first, an unknown
pneumonia case was detected on December 12, 2019,
and possible influenza and other coronaviruses were ruled

Address for correspondence: Ahmet Riza Sahin, MD. Kahramanmaras Sutcu Imam Universitesi Tip Fakultesi,
Enfeksiyon Hastaliklari ve Klinik Mikrobiyoloji Anabilim Dali, Kahramanmaras, Turkey
Phone: +90 505 541 37 65 E-mail: drahmet_riza@hotmail.com
Submitted Date: February 11, 2020 Accepted Date: February 12, 2020 Available Online Date: Fabruary 12, 2020
©
Copyright 2020 by Eurasian Journal of Medicine and Oncology - Available online at www.ejmo.org
OPEN ACCESS This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
2 Sahin et al., 2019 Novel Coronavirus (COVID-19) Outbreak / doi: 10.14744/ejmo.2020.12220

out by laboratory testing. Chinese authorities announced hood of an infection transmitted from animals to humans.
on January 7, 2020 that a new type of Coronavirus (novel On January 22, 2020, novel CoV has been declared to
[3, 9]

Coronavirus, nCoV) was isolated.[7] This virus was named be originated from wild bats and belonged to Group 2 of
as COVID-19 by WHO on January 12 and COVID-19 on 11 beta-coronavirus that contains Severe Acute Respiratory
February 2020. As of February 12, 2020, a total of 43.103 Syndrome Associated Coronavirus (SARS-CoV). Although
confirmed cases and 1.018 deaths have been announced. COVID-19 and SARS-CoV belong to the same beta corona-
[8]
When given where the first case originated, the infection virüs subgroup, similarity at genome level is only 70%, and
were transmitted probably as zoonotic agent (from animal the novel group has been found to show genetic differenc-
to human). The increase in the number of cases in Wuhan es from SARS-CoV.[10]
city and internationally after closing the market and evacu- Similar to the SARS epidemic, this outbreak has occurred
ation of the cases in China, has indicated a second trans- during the Spring Festival in China, which is the most fa-
mission from human-to-human. New cases are identified, mous traditional festival in China, during which nearly 3
primarily in other Asian countries and in many countries billion people travel countrywide. These conditions caused
such as the trans-oceanic USA and France (Table 1). favorable conditions for the transmission of this highly con-
The objective of this review article was to have a prelimi- tagious disease and severe difficulties in prevention and
nary opinion about the disease, the ways of treatment, and control of the epidemic. The period of the Spring Festival
prevention in this early stage of this outbreak. of China was between January 17 and February 23 in 2003,
when the SARS epidemic peaked, while the period of the
Epidemiology festival was between January 10 and February 18 in 2020.
In December 2019, many pneumonia cases that were clus- Similarly, there was a rapid increase in COVID-19 cases be-
tered in Wuhan city were reported and searches for the tween January 10-22. Wuhan, the center of the epidemic
source have shown Huanan Seafood Market as the origin. with 10 million population, is also an important center in
The first case of the COVID-19 epidemic was discovered the spring festival transportation network. The estimated
with unexplained pneumonia on December 12, 2019, and number of travelers during the 2020 spring festival has
27 viral pneumonia cases with seven being severe, were of- risen 1.7 folds when compared with the number traveled
ficially announced on December 31, 2019.[7,9] Etiologic in- in 2003 and reached to 3.11 billion from 1.82 billion. This
vestigations have been performed in patients who applied large-scale travel traffic has also created favorable condi-
to the hospital due to similar viral pneumonia findings. The tions for the spread of this difficult-to-control disease.[11]
common history of high-risk animal contact in the medi-
cal histories of these patients has strengthened the likeli-
Virology-Pathogenesis
Coronaviruses are viruses whose genome structure is best
Table 1. The Number of Cases and Death of COVID-19 out- known among all RNA viruses. Two-thirds of RNA they have
break according to World Health Organization (WHO) Situation encodes viral polymerase (RdRp), RNA synthesis materials,
Reports-22 on February 11, 2020[9]
and two large nonstructural polyproteins that are not in-
Country Cases Deaths Region volved in host response modulation (ORF1a-ORF1b). The



other one-third of the genome encodes four structural
China 42.708 1.017 Asia
proteins (spike (S), envelope (E), membrane (M) ve nucleo-



Singapore 45 0 Asia
capsid (N), and the other helper proteins.[12,13] Although



Hong Kong 42 1 Asia
the length of the CoV genome shows high variability for



Thailand 33 0 Asia
ORF1a/ORF1b and four structural proteins, it is mostly as-



South Korea 28 0 Asia
sociated with the number and size of accessory proteins.



Japan 26 0 Asia
[12,13]
The first step in virus infection is the interaction of sen-



Malaysia 18 0 Asia
sitive human cells with Spike Protein. Genome encoding



Germany 16 0 Europe
occurs after entering to the cell and facilitates the expres-



Australia 15 0 Australia
sion of the genes, that encode useful accessory proteins,



Vietnam 15 0 Australia
which advance the adaptation of CoVs to their human host.



United States 13 0 North America
[13]
Genome changes resulting from recombination, gene



France 11 0 Europe
exchange, gene insertion, or deletion are frequent among



Macao 10 0 Asia
CoVs, and this will take place in future outbreaks as in past



United Kingdom 8 0 Europe
epidemics. As a result of the studies, the CoV subfamily is



United Arab Emirates 8 0 Asia
rapidly expanding with new generation sequencing appli-



EJMO
cations that improve the detection and definition of novel
CoV species. In conclusion, CoV classification is continually
changing. According to the most recent classification of The
International Committee on Taxonomy of Viruses (ICTV),
there are four genera of thirty-eight unique species.[14]
SARS-CoV and MERS-CoV that attach to the host cell re-
spectively bind to cellular receptor angiotensin-converting
enzyme 2 (SARS-CoV associated) and cellular receptor of di-
peptidyl peptidase 4 (MERS-CoV associated).[15] After enter-
ing the cell, the viral RNA manifest itself in the cytoplasm.
Genomic RNA is encapsulated and polyadenylated, and
encodes various structural and non-structural polypeptide
genes. These polyproteins are split by proteases that ex-
hibit chymotrypsin-like activity.[13, 15] The resulting complex
drives (-) RNA production through both replication and
transcription. During replication, full-length (-) RNA copies
of the genome are produced and used as a template for
full-length (+) RNA genomes.[12, 13] During transcription, a
subset of 7-9 sub-genomic RNAs, including those encoding
all structural proteins, are produced by discontinuous tran-
scription. Viral nucleocapsids are combined from genomic
RNA and R protein in the cytoplasm and then are budded
into the lumen of the endoplasmic reticulum. Virions are
then released from the infected cell through exocytosis.
The released viruses can infect kidney cells, liver cells, in-
testines, and T lymphocytes, as well as the lower respira-
tory tract, where they form the main symptoms and signs.
[15]
Remarkably, CDT lymphocytes were found to be lower
than 200 cells/mm3 in three patients with SARS-CoV infec-
tion. MERS-CoV is able to affect human dendritic cells and
macrophages in-vitro. T lymphocytes are also a target for
the pathogen due to the characteristic CD26 rosettes. This
virus can make the antiviral T-cell response irregular due to
the stimulation of T-cell apoptosis, thus causing a collapse
of the immune system.[16, 17]
Sources & Modes of Transmission
CoVs have been defined as a novel respiratory tract virus
in the samples collected from the individuals who present
symptoms of respiratory tract infection in 1962.[18] This is
a large family of viruses that are common in many differ-
ent animal species, including camels, cattle, cats, and bats.
Rarely, animal CoVs can infect humans and, as a result, may
spread among humans during epidemics such as MERS,
SARS, and COVID-19.[13-16] At the onset of major outbreaks
caused by CoVs, palm cats have been proposed to be a
natural reservoir of Human CoVs for SARS and dromedary
camels for MERS.[3] However, more advanced virological
and genetic studies have shown that bats are reservoir
hosts of both SARS-CoV and MERS-CoV and before these
viruses spread to humans, they use the other responsible
3
animals as intermediate hosts. Studies have reported that
most of the bat CoVs are the gene source of alpha-CoV and
beta-CoVs, while most of the bird CoVs are the gene source
of gamma-CoVs and delta-CoVs.[3] In recent studies, it has
been observed that the novel virus causing epidemics co-
incides with the CoV isolated in bats. Presence of wild ani-
mal trade in Huanan Seafoods Market where the first cases
appeared, supports this finding.[6, 10]
After the first outbreak, secondary cases began to be re-
ported after approximately ten days. Moreover, while these
new patients had no contact with the marketplace, they
had a history of contact with humans there. Confirmed
recent reports from many infected healthcare workers in
Wuhan show that human-to-human transmission can oc-
cur. As in SARS and MERS epidemics in the past, human-to-
human transmission has accelerated the spread of the out-
break and case reports have also started from other states
of China. The first non-Chinese case of the infection, which
spread to the Chinese provinces, and then to the Asian con-
tinent, was reported from Thailand on January 13, 2020.
The case reported being a Chinese tourist who has traveled
to Thailand and had no epidemiologic connection with the
marketplace.[19] Other cases from oversea countries such as
the USA and France have continued to be reported.[20]
Often, the human-to-human transmission occurs with close
contact. The transmission primarily occurs when an infected
person sneezes and through the respiratory droplets pro-
duced just as the spread of influenza and other respiratory
pathogens. These droplets can settle in the mouth or nasal
mucosa and lungs of people with inhaled air. Currently, it
remains unclear whether a person can be infected by CO-
VID-19 by touching an infected surface or object and then
touching their mouth, nose, or possibly eyes.[21]
Typically, like most respiratory viruses, it is considered to be
the most contagious when people are most symptomatic.
However, cases, who were infected from an asymptomatic
person in the prodrome period of COVID-19, were also re-
ported. Sufficient data are not available on infectiousness
of the disease and research is ongoing.[22]
Clinical Progression-Diagnosis
Before SARS-CoV cases, it was thought that human CoVs
leads to cold-like upper respiratory infection and self-limit-
ing lower respiratory infection. The first death due to coro-
naviruses has reported by the isolation of SARS-CoV from a
patient with pneumonia in China. As in other respiratory-
infected viruses and previous beta-CoV, similarities present
in the clinical aspects of COVID-19 infections, it is known
that clinical picture varies from simple respiratory infection
findings to septic shock. Similar to SARS CoV and MERS CoV
4 Sahin et al., 2019 Novel Coronavirus (COVID-19) Outbreak / doi: 10.14744/ejmo.2020.12220
that caused epidemics in the past years, the first symptoms
are commonly defined as fever, cough, shortness of breath.
[19]
Although diarrhea was presentin about 20-25% of pa-
tients with MERS-CoV or SARS-CoV infection, intestinal
symptoms were rarely reported in patients with COVID-19.
In another study of 99 patients, chest pain, confusion, and
nausea-vomiting were noted in addition to previous find-
ings.[23] On X-rays or thorax CT imaging of the examined pa-
tients, unilateral or bilateral involvement compatible with
viral pneumonia was found, and bilateral multiple lobular
and subsegmental consolidation areas were observed in
patients hospitalized in the intensive care unit.[24, 25]
In a cohort study of 41 hospitalized patients, fever, dry
cough, myalgia and fatigue symptoms were reported in
most patients, and less often, symptoms of expectoration,
headache, hemoptysis and diarrhea were also observed.[24]
According to that study, comorbidities such as underlying
diabetes mellitus, hypertension, and cardiovascular dis-
ease were found in about half of these patients. Besides,
patients developed dyspnea accompanied by abnormal
thorax CT compatible with pneumonia mean eight days af-
ter the admission. Complications include ARDS, acute heart
damage, secondary infections, and pneumothorax. Similar-
ly to the previous data, X-rays or thorax CT images of the
patients revealed unilateral or bilateral lung involvement,
compatible with viral pneumonia. Bilateral multiple lobular
and subsegmental consolidation areas were present in pa-
tients in the intensive care unit.[24] The patients with under-
lying comorbidity exhibited a more severe clinical course,
as expected by the experience gained from the previous
epidemics.[26]
As in SARS and MERS, the diagnosis of 2019 n-CoV infec-
tion is based on a history of detailed contact and travel, and
precise laboratory testing. The diagnostic tools are molecu-
lar methods, serology and viral culture. The most common
diagnostic methods are molecular methods as RT-PCR (re-
verse transcription) or real-time PCR, which are made using
RNA from respiratory samples such as oropharyngeal swabs,
sputum, nasopharyngeal aspirate, deep tracheal aspirate,
or bronchoalveolar lavage. In particular, lower respiratory
tract samples can offer significantly higher viral load and ge-
nome fraction than upper respiratory tract samples. These
techniques are beneficial in terms of evaluating the results
quickly, showing the genome structure and viral load.[25]
The sensitivity of antibody detection is generally lower
than molecular methods and is mostly used in retrospec-
tive diagnosis. Viral culture is a more time consuming
method compared to the other methods. Culture is much
more useful in the first stage of outbreaks before other di-
agnostic methods become clinically available. In addition,
viral cultures can be used in the in-vitro and in-vivo antivi-
ral treatment and vaccine evaluation trials.[3]
Coronavirus from Sars to Mers
SARS-CoV, which originated from China and then was
spread to other parts of the world with hospital-acquired
infectious cases, had a mortality rate of 10%, and was
transmitted to 8000 people during an 8-month outbreak
in 2002-2003.[21] In 2012, MERS-CoV, when it emerged in
Arabian Peninsula MERS-CoV, spread to 27 countries with
35.6% mortality rate in 2220 cases. It is known that both
of them are zoonotic viruses showing hospital-acquired
and human-to-human transmission.[21, 22] Similar dynamics
apply for COVID-19 that was originated from Wuhan and
the current the rate of mortality from this infection is about
2%. CoVs can use different receptors and pathways when
entering the cell. SARS-CoV usually infects young people,
MERS-CoV people aged above 50 years and COVID-19 in-
fects middle age and above. Comparing non-respiratory
complications, MERS-CoV involve the cardiovascular sys-
tem more frequently than SARS-CoV and frequently require
vasopressor treatment.[3, 19, 20] Case series have reported
that COVID-19 affects the cardiovascular system.[23] Acute
kidney failure was more commonly seen in SARS-CoV and
MERS-CoV epidemics compared to COVID-19.[3, 26] Whereas
radiological findings are present in all three pathogens,
airspace opacifications are seen in SARS-CoV and ground-
glass appearance in MERS-CoV and COVID-19.[3, 26] Hospi-
tal-acquired secondary infections have been defined in
all three pathogens.[3, 23] There are no studies that report a
definitely successful drug for their treatment.[24] In terms of
epidemic periods, SARS-CoV ended in less than a year, and
the MERS-CoV epidemic lasted for seven years despite its
spread to more restricted areas and. The question of how
long the novel COVID-19 outbreak will last is a question
that everyone is curious about.
Treatment & Protection
In general, there are few or no treatment options for viral
diseases that occur suddenly.[24] In parallel with this knowl-
edge, today there is no vaccine or effective treatment to
prevent COVID-19 infection. Molecules are being tested
for COVID-19 in in-vitro and human-based SARS-CoV and
MERS-Cov trials. Studies evaluating the antiviral activity
of types I and II interferons have reported, interferon-beta
(IFNb), as the most potent interferon, was reducing in- vi-
tro MERS-CoV replication.[19] According to a human MERS-
CoV case report from South Korea, the use of the combi-
nation of Lopinavir/Ritonavir (LPV/RTV) (Anti-HIV drugs),
pegylated interferon and ribavirin provided a successful
EJMO 5

viral clearance.[23] For this purpose, a randomized control

trial (MIRACLE Trial), that aimed to determine whether
LPV/RTV-IFNb improved clinical results in MERS-CoV pa-
tients, was initiated in 2016 and 76 patients were enrolled.
[27]
Although another antiviral drug, remdesivir was used in
the first case reported from the United States of America,
seemed successful, controlled studies with more cases are
needed.[21] In-vitro studies have shown that viral RNA tran-
scription was terminated with remdesivir in early stage.[28, 29]
There are publications demonstrating that remdesivir has Figure 1. The number of daily new COVID-19 cases through January
22 and February 11, 2020.[35]
a strong antiviral activity in epithelial cell cultures against
SARS-CoV, MERS-CoV and related zoonotic bat CoVs.[30, 31]
Many measures should be taken, such as timely publica-
tion of epidemic information for elimination of the source
of infection, early diagnosis, reporting, isolation, support-
ive treatments and for avoiding unnecessary panic. CDC
reminds basic measures such as hand washing, using dis-
infectant solutions, avoiding contact with patients in order
to prevent the spread of viruses by droplets. Precautionary
actions including the provision of medicines supply chains,
personal protective equipment, and hospital supplies
should be made in a short time for the protection of the
Chinese people and global health, especially in the places
with close travel ports to major Chinese ports.[32] Figure 2. Growth factor of 2019- nCoV out-break between January
23 and February 11, 2020 outbreak.[36]
Based on the 2003 SARS-CoV epidemic experience, the Chi-
nese government takes many effective measures including is expected to reach peak at the beginning of March 2020
closing public transport, reducing migration and promot- (80 days from the onset). The duration between onset of
ing personal protection with masks in Wuhan and other symptoms and isolation is about 6 days, and its expected
provinces. Hence, there are reported cases of infected hos- that each one day reduction in this period will decrease the
pital personnel, healthcare staff should be informed about size of peak population by 72-84% and cumulative infected
taking personal protective measures such as the use of cases and deaths by 68-80%. It is estimated that with the
gloves, eye masks and N95 masks during the examination effects of integrated interventions such as promoting the
of patients with a suspected history of COVID-19 contact or use of face masks and reduced traveling, each 10% reduc-
travel to China.[11, 33] tion in transmission rate, the size of peak population will
decrease by 20-47% and cumulative infected cases and
Future Projections deaths will decrease by 23-49%.[34]
Near future course of COVID-19, which as of 12 Şubat 2020 Owing to the measures by Chinese government, including
has spread to 25 countries in total on 4 continents with passing laws for effective infection management, supports
43.103 confirmed cases and 1.018 deaths, 1.017 being in accelerating the diagnosis and treatment such as distribu-
mainland China and 1 in the Philippines, arouses public in- tion of more than 30.000 PCR- fluorescent probe kits to de-
terest.[9] Since COVID-19 is very similar to SARS-CoV, some termined diagnosis centers in Wuhan, and closing Wuhan
important features of SARS epidemic are guiding the pre- and nearby Huang Guang provinces, the number of casses
dictions on current epidemic. According to the logistical are expected to be below the estimates. Rapid diagnosis
modelling studies performed by combining daily numbers with quarantine and integrated interventions will have a
from COVID-19 cases (Fig. 1) with data obtained in SARS great effect on future trends of the outbreak. Although CO-
epidemics; timely diagnosis is essential for quarantine and VID-19 has a similar spread with SARS and MERS, it exhibits
integrated interventions to control the outbreak. Currently lower mortality rates. However, variables such as traveler
growth factor (New cases of everyday/cases of previous flow due to the Spring Festival and cross-border spread of
day) of COVID-19 started to fall below 1 threshold (Fig. 2). If infection require further research about advanced interven-
the current trend continues, the number of infected people tion strategies in order to make more precise predictions. As
6 Sahin et al., 2019 Novel Coronavirus (COVID-19) Outbreak / doi: 10.14744/ejmo.2020.12220
imposition of globalization, coronaviruses will cause spreads
and outbreaks with different-mutant strains similarly in the
coming years. With increased scientific collaboration, which
is a result of globalization, we may have more powerful
means of fighting against coronaviruses, in which we know
the genome structure very well in the future.[34]
Disclosures
Peer-review: Externally peer-reviewed.
Conflict of Interest: None declared.
Authorship Contributions: Concept – A.R.S., A.E.; Design – A.S.,
P.A.; Supervision – Y.D., A.C.; Materials – A.M.T., A.C., M.S.; Data col-
lection &/or processing – A.S., M.S., A.T.; Analysis and/or interpre-
tation – R.O., A.S.; Literature search – A.S., A.T.; Writing – A.S., P.A.,
Y.D.; Critical review – A.S., A.E.
References
1. Woo PC, Huang Y, Lau SK, Yuen KY. Coronavirus genomics and
bioinformatics analysis. Viruses 2010;2:1804–20.
2. Drexler JF, Gloza-Rausch F, Glende J, Corman VM, Muth
D, Goettsche M, et al. Genomic characterization of severe
acute respiratory syndrome-related coronavirus in Europe-
an bats and classification of coronaviruses based on partial
RNA-dependent RNA polymerase gene sequences. J Virol
2010;84:11336–49.
3. Yin Y, Wunderink RG. MERS, SARS and other coronaviruses as
causes of pneumonia. Respirology 2018;23:130–7.
4. Peiris JSM, Lai ST, Poon L, et al. Coronavirus as a possible
cause of severe acute respiratory syndrome.  The Lancet
2003;361:1319–25.
5. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD,
Fouchier RA. Isolation of a novel coronavirus from a man with
pneumonia in Saudi Arabia. N Engl J Med 2012;367:1814–20.
6. Seven days in medicine: 8-14 Jan 2020. BMJ
2020;368:m132.31948945
7. Imperial College London. Report 2: estimating the potential
total number of novel coronavirus cases in Wuhan City, China.
Jan 2020. https://www.imperial.ac.uk/mrc-globalinfectious-
disease-analysis/news--wuhan-coronavirus.
8. European Centre for Disease Prevention and Control data.
Geographical distribution of 2019- nCov cases. Available on-
line: (https://www.ecdc.europa.eu/en/geographical-distribu-
tion-2019-ncov-cases) (accessed on 05 February 2020)
9. World Helath Organization, 2019- nCoV Situation Report-22
on 12 February, 2020. https://www.who.int/docs/default-
source/coronaviruse/situation-reports/
10. Gralinski L, Menachery V. Return of the Coronavirus: 2019-
nCoV, Viruses 2020;12:135.
11. Chen Z, Zhang W, Lu Y, et al. From SARS-CoV to Wuhan 2019-
nCoV Outbreak: Similarity of Early Epidemic and Prediction of
Future Trends: Cell Press 2020.
12. Luk HK, Li X, Fung J, Lau SK, Woo PC. Molecular epidemiology,
evolution and phylogeny of SARS coronavirus. Infection, Ge-
netics and Evolution 2019;71:21–30.
13. Coronavirinae in ViralZone. Available online: https://viralzone.
expasy.org/785 (accessed on 05 February 2019).
14. Subissi L, Posthuma CC, Collet A, Zevenhoven-Dobbe JC,
Gorbalenya AE, Decroly E, et al. One severe acute respiratory
syndrome coronavirus protein complex integrates processive
RNA polymerase and exonuclease activities. Proc Natl Acad
Sci USA 2014;111:E3900–E3909.
15. Lambeir AM, Durinx C, Scharpe S, De Meester I. Dipeptidyl-
peptidase IV from bench to bedside: An update on structural
properties, functions, and clinical aspects of the enzyme DPP
IV. Crit Rev Clin Lab Sci 2003;40:209–94.
16. Chu H, Zhou J, Wong BH, Li C, Cheng ZS, Lin X, et al. Productive
replication of Middle East respiratory syndrome coronavirus
in monocyte-derived dendritic cells modulates innate im-
mune response. Virology 2014;454–455:197–205.
17. Zhou J, Chu H, Li C, Wong BH, Cheng ZS, Poon VK, et al. Active
replication of Middle East respiratory syndrome coronavirus
and aberrant induction of inflammatory cytokines and che-
mokines in human macrophages: Implications for pathogen-
esis. J Infect Dis 2014;209:1331–42.
18. Hamre D, Procknow JJ. A new virus isolated from the human
respiratory tract. Proceedings of the Society for Experimental
Biology and Medicine 1966;121:190–3.
19. Hui DS, Azhar EI, Madani TA, Ntoumi F, Kock R, Dar O, et al.
The continuing 2019-nCoV epidemic threat of novel corona-
viruses to global health -The latest 2019 novel coronavirus
outbreak in Wuhan, China. Int J Infect Dis 2020;264–6.
20. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce
H, et al. First Case of 2019 Novel Coronavirus in the United
States The New England Journal of Medicine 2020.
21. WHO. Emergencies preparedness, response. Pneumonia of
unknown origin – China. Disease outbreak news. Available
online: https:// HYPERLINK "http://www.who.int/csr/don/12-
january-2020-novel-coronavirus-china/en/" www.who.int/
csr/don/12-january-2020-novel-coronavirus-china/en/ (ac-
cessed on 05 February 2020)
22. Rothe C, Schunk M, Sothmann P, Bretzel G, Froeschl G, Wall-
rauch C, et al. Transmission of 2019-nCoV Infection from an
Asymptomatic Contact in Germany, 30.01.2020.
23. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemio-
logical and clinical characteristics of 99 cases of 2019 novel
coronavirus pneumonia in Wuhan, China: a descriptive study.
Lancet 2020, publish onlined Jan 29, https://doi.org/10.1016/
S0140-6736(20)30211-7.
24. Huang C, Wang Y, Li X, et al. Clinical features of patients in-
fected with 2019 novel coronavirus in Wuhan, China. Lan-
cet 2020; published online Jan 24. HYPERLINK "https://doi.
org/10.1016/S01406736(20)301835" https://doi.org/10.1016/
EJMO
S0140–6736(20)30183–5.
25. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from pa-
tients with pneumonia in China, 2019. N England J Medicine.
Publish onlined Jan 29. DOI: 10.1056/NEJMoa2001017
26. Wang C, Horby PW, Harden FG, Gao GF. A novel coronavirüs
outbreak of global health concern. Lancet 2020, publish on-
lined Jan 24, https://doi.org/10.1016/S0140-6736(20)30185-9.
27. Arabi YM, Alothman A, Balkhy, et al. Treatment of Middle East
respiratory syndrome with a combination of lopinavir-rito-
navir and interferon-β1b (MIRACLE trial): study protocol for a
randomized controlled trial. Trials 2016;19;81.
28. Warren TK, et al. Therapeutic efficacy of the small molecule
GS-5734 against Ebola virus in rhesus monkeys. Nature
2016;531:381–5.
29. Jordan PC, et al. Initiation, extension, and termination of
RNA synthesis by a paramyxovirus polymerase. PLoS Pathog
2018;14:e1006889.
30. Cockrell AS, et al. A mouse model for MERS coronavirus-
induced acute respiratory distress syndrome. Nat. Microbiol
2016;2:16226.
7
31. Brown AJ, et al. Broad spectrum antiviral remdesivir inhib-
its human endemic and zoonotic deltacoronaviruses with a
highly divergent RNA dependent RNA polymerase. Antivir Res
2019;169:104541.
32. 2019 Novel Coronavirus.Prevention and Treatment. Available
online: https://www.cdc.gov/coronavirus/2019-ncov/about/
prevention-treatment.html (accessed on 05 February 2020)
33. What to do if you are sick with 2019 Novel Coronavirus. Avail-
able online:https://www.cdc.gov/coronavirus/2019-ncov/
about/steps-when-sick.html (accessed on 05 February 2020)
34. Shen M.; Peng Z.; Xiao.;Zhang L. Modelling the epidemic trend
of the 2019 novel coronavirus outbreak in China.
35. Daily New 2019-nCoV Cases Chart through January 22 and
February 11, 2020. Available Online: https://www.worldom-
eters.info/coronavirus/coronavirus-cases/ (Accessed on 12
February, 2020)
36. Growth Factor Chart of 2019- nCoV outbreak. Available On-
line: https://www.worldometers.info/coronavirus/coronavi-
rus-cases/ (Accessed on 12 February, 2020).
 2

The global
macroeconomic
impact of COVID-10:
seven scenarios
 The Global Macroeconomic Impacts of COVID-19:
Seven Scenarios*

Warwick McKibbin † and Roshen Fernando ‡

2 March 2020

Abstract
The outbreak of coronavirus named COVID-19 has disrupted the Chinese economy and is
spreading globally. The evolution of the disease and its economic impact is highly uncertain,
which makes it difficult for policymakers to formulate an appropriate macroeconomic policy
response. In order to better understand possible economic outcomes, this paper explores seven
different scenarios of how COVID-19 might evolve in the coming year using a modelling
technique developed by Lee and McKibbin (2003) and extended by McKibbin and Sidorenko
(2006). It examines the impacts of different scenarios on macroeconomic outcomes and
financial markets in a global hybrid DSGE/CGE general equilibrium model.

The scenarios in this paper demonstrate that even a contained outbreak could significantly
impact the global economy in the short run. These scenarios demonstrate the scale of costs that
might be avoided by greater investment in public health systems in all economies but
particularly in less developed economies where health care systems are less developed and
popultion density is high.

Keywords: Pandemics, infectious diseases, risk, macroeconomics, DSGE, CGE, G-Cubed

JEL Codes:

*
We gratefully acknowledge financial support from the Australia Research Council Centre of Excellence in
Population Ageing Research (CE170100005). We thank Renee Fry-McKibbin, Will Martin, Louise Sheiner,
Barry Bosworth and David Wessel for comment and Peter Wilcoxen and Larry Weifeng Liu for their research
collaboration on the G-Cubed model used in this paper. We also acknowledge the contributions to earlier
research on modelling of pandemics undertaken with Jong-Wha Lee and Alexandra Sidorenko.
†
Australian National University; the Brookings Institution; and Centre of Excellence in Population Ageing
Research (CEPAR)
‡
Australian National University and Centre of Excellence in Population Ageing Research (CEPAR)

1
1. Introduction

The COVID-19 outbreak (previously 2019-nCoV) was caused by the SARS-CoV-2 virus. This
outbreak was triggered in December 2019 in Wuhan city in Hubei province of China. COVID-
19 continues to spread across the world. Initially the epicenter of the outbreak was China with
reported cases either in China or being travelers from China. At the time of writing this paper,
at least four further epicenters have been identified: Iran, Italy, Japan and South Korea. Even
though the cases reported from China are expected to have peaked and are now falling (WHO
2020), cases reported from countries previously thought to be resilient to the outbreak, due to
stronger medical standards and practices, have recently increased. While some countries have
been able to effectively treat reported cases, it is uncertain where and when new cases will
emerge. Amidst the significant public health risk COVID-19 poses to the world, the World
Health Organization (WHO) has declared a public health emergency of international concern
to coordinate international responses to the disease. It is, however, currently debated whether
COVID-19 could potentially escalate to a global pandemic.

In a strongly connected and integrated world, the impacts of the disease beyond mortality (those
who die) and morbidity (those who are incapacitated or caring for the incapacitated and unable
to work for a period) has become apparent since the outbreak. Amidst the slowing down of the
Chinese economy with interruptions to production, the functioning of global supply chains has
been disrupted. Companies across the world, irrespective of size, dependent upon inputs from
China have started experiencing contractions in production. Transport being limited and even
restricted among countries has further slowed down global economic activities. Most
importantly, some panic among consumers and firms has distorted usual consumption patterns
and created market anomalies. Global financial markets have also been responsive to the
changes and global stock indices have plunged. Amidst the global turbulence, in an initial
assessment, the International Monetary Fund expects China to slow down by 0.4 percentage
points compared to its initial growth target to 5.6 percent, also slowing down global growth by
0.1 percentage points. This is likely to be revised in coming weeks4.

4
See OECD(2020) for an updated announcement

2
This paper attempts to quantify the potential global economic costs of COVID-19 under
different possible scenarios. The goal is to provide guidance to policy makers to the economic
benefits of globally-coordinated policy responses to tame the virus. The paper builds upon the
experience gained from evaluating the economics of SARS (Lee & McKibbin 2003) and
Pandemic Influenza (McKibbin & Sidorenko 2006). The paper first summarizes the existing
literature on the macroeconomic costs of diseases. Section 3 outlines the global macroeconomic
model (G-Cubed) used for the study, highlighting its strengths to assess the macroeconomics
of diseases. Section 4 describes how epidemiological information is adjusted to formulate a
series of economic shocks that are input into the global economic model. Section 5 discusses
the results of the seven scenarios simulated using the model. Section 6 concludes the paper
summarizing the main findings and discusses some policy implications.

2. Related Literature
Many studies have found that population health, as measured by life expectancy, infant and
child mortality and maternal mortality, is positively related to economic welfare and growth
(Pritchett and Summers, 1996; Bloom and Sachs, 1998; Bhargava and et al., 2001; Cuddington
et al., 1994; Cuddington and Hancock, 1994; Robalino et al., 2002a; Robalino et al., 2002b;
WHO Commission on Macroeconomics and Health, 2001; Haacker, 2004).

There are many channels through which an infectious disease outbreak influences the economy.
Direct and indirect economic costs of illness are often the subject of the health economics
studies on the burden of disease. The conventional approach uses information on deaths
(mortality) and illness that prevents work (morbidity) to estimate the loss of future income due
to death and disability. Losses of time and income by carers and direct expenditure on medical
care and supporting services are added to obtain the estimate of the economic costs associated
with the disease. This conventional approach underestimates the true economic costs of
infectious diseases of epidemic proportions which are highly transmissible and for which there
is no vaccine (e.g. HIV/AIDS, SARS and pandemic influenza). The experience from these
previous disease outbreaks provides valuable information on how to think about the
implications of COVID-19

The HIV/AIDS virus affects households, businesses and governments - through changed labor
supply decisions; efficiency of labor and household incomes; increased business costs and
foregone investment in staff training by firms; and increased public expenditure on health care
and support of disabled and children orphaned by AIDS, by the public sector (Haacker, 2004).

3
The effects of AIDS are long-term but there are clear prevention measures that minimize the
risks of acquiring HIV, and there are documented successes in implementing prevention and
education programs, both in developed and in the developing world. Treatment is also available,
with modern antiretroviral therapies extending the life expectancy and improving the quality
of life of HIV patients by many years if not decades. Studies of the macroeconomic impact of
HIV/AIDS include (Cuddington, 1993a; Cuddington, 1993b; Cuddington et al., 1994;
Cuddington and Hancock, 1994; Haacker, 2002a; Haacker, 2002b; Over, 2002; Freire, 2004;
The World Bank, 2006). Several computable general equilibrium (CGE) macroeconomic
models have been applied to study the impact of AIDS (Arndt and Lewis, 2001; Bell et al.,
2004).

The influenza virus is by far more contagious than HIV, and the onset of an epidemic can be
sudden and unexpected. It appears that the COVID-19 virus is also very contagious. The fear
of 1918-19 Spanish influenza, the “deadliest plague in history,” with its extreme severity and
gravity of clinical symptoms, is still present in the research and general community (Barry,
2004). The fear factor was influential in the world’s response to SARS – a coronavirus not
previously detected in humans (Shannon and Willoughby, 2004; Peiris et al., 2004). It is also
reflected in the response to COVID-19. Entire cities in China have closed and travel restrictions
placed by countries on people entering from infected countries. The fear of an unknown deadly
virus is similar in its psychological effects to the reaction to biological and other terrorism
threats and causes a high level of stress, often with longer-term consequences (Hyams et al.,
2002). A large number of people would feel at risk at the onset of a pandemic, even if their
actual risk of dying from the disease is low.

Individual assessment of the risks of death depends on the probability of death, years of life
lost, and the subjective discounting factor. Viscusi et al. (1997) rank pneumonia and influenza
as the third leading cause of the probability of death (following cardiovascular disease and
cancer). Sunstein (1997) discusses the evidence that an individual’s willingness to pay to avoid
death increases for causes perceived as “bad deaths” – especially dreaded, uncontrollable,
involuntary deaths and deaths associated with high externalities and producing distributional
inequity. Based on this literature, it is not unreasonable to assume that individual perception of
the risks associated with the new influenza pandemic virus similar to Spanish influenza in its
virulence and the severity of clinical symptoms can be very high, especially during the early
stage of the pandemic when no vaccine is available and antivirals are in short supply. This is
exactly the reaction revealed in two surveys conducted in Taiwan during the SARS outbreak

4
in 2003 (Liu et al., 2005), with the novelty, salience and public concern about SARS
contributing to the higher than expected willingness to pay to prevent the risk of infection.

Studies of the macroeconomic effects of the SARS epidemic in 2003 found significant effects
on economies through large reductions in consumption of various goods and services, an
increase in business operating costs, and re-evaluation of country risks reflected in increased
risk premiums. Shocks to other economies were transmitted according to the degree of the
countries’ exposure, or susceptibility, to the disease. Despite a relatively small number of cases
and deaths, the global costs were significant and not limited to the directly affected countries
(Lee and McKibbin, 2003). Other studies of SARS include (Chou et al., 2004) for Taiwan, (Hai
et al., 2004) for China and (Sui and Wong, 2004) for Hong Kong.

There are only a few studies of economic costs of large-scale outbreaks of infectious diseases
to date: Schoenbaum (1987) is an example of an early analysis of the economic impact of
influenza. Meltzer et al. (1999) examine the likely economic effects of the influenza pandemic
in the US and evaluate several vaccine-based interventions. At a gross attack rate (i.e. the
number of people contracting the virus out of the total population) of 15-35%, the number of
influenza deaths is 89 – 207 thousand, and an estimated mean total economic impact for the
US economy is $73.1- $166.5 billion.

Bloom et al. (2005) use the Oxford economic forecasting model to estimate the potential
economic impact of a pandemic resulting from the mutation of avian influenza strain. They
assume a mild pandemic with a 20% attack rate and a 0.5 percent case-fatality rate, and a
consumption shock of 3%. Scenarios include two-quarters of demand contraction only in Asia
(combined effect 2.6% Asian GDP or US$113.2 billion); a longer-term shock with a longer
outbreak and larger shock to consumption and export yields a loss of 6.5% of GDP (US$282.7
billion). Global GDP is reduced by 0.6%, global trade of goods and services contracts by $2.5
trillion (14%). Open economies are more vulnerable to international shocks.

Another study by the US Congressional Budget Office (2005) examined two scenarios of
pandemic influenza for the United States. A mild scenario with an attack rate of 20% and a
case fatality rate (.i.e. the number who die relative to the number infected) of 0.1% and a more
severe scenario with an attack rate of 30% and a case fatality rate of 2.5%. The CBO (2005)
study finds a GDP contraction for the United States of 1.5% for the mild scenario and 5% of
GDP for the severe scenario.

5
McKibbin and Sidorenko (2006) used an earlier vintage of the model used in the current paper
to explore four different pandemic influenza scenarios. They considered a “mild” scenario in
which the pandemic is similar to the 1968-69 Hong Kong Flu; a “moderate” scenario which is
similar to the Asian flu of 1957; a “severe” scenario based on the Spanish flu of 1918-1919
((lower estimate of the case fatality rate), and an “ultra” scenario similar to Spanish flu 1918-
19 but with upper-middle estimates of the case fatality rate. They found costs to the global
economy of between $US300 million and $US4.4trillion dollars for the scenarios considered.

The current paper modifies and extends that earlier papers by Lee and McKibbin (2003) and
McKibbin and Sidorenko (2006) to a larger group of countries, using updated data that captures
the greater interdependence in the world economy and in particular, the rise of China’s
importance in the world economy today.

3. The Hybrid DSGE/CGE Global Model

For this paper, we apply a global intertemporal general equilibrium model with heterogeneous
agents called the G-Cubed Multi-Country Model. This model is a hybrid of Dynamic Stochastic
General Equilibrium (DSGE) Models and Computable General Equilibrium (CGE) Models
developed by McKibbin and Wilcoxen (1999, 2013)

(9) The G-Cubed Model

The version of the G-Cubed (G20) model used in this paper can be found in McKibbin and
Triggs (2018) who extended the original model documented in McKibbin and Wilcoxen (1999,
2013). The model has 6 sectors and 24 countries and regions. Table 1 presents all the regions
and sectors in the model. Some of the data inputs include the I/O tables found in the Global
Trade Analysis Project (GTAP) database (Aguiar et al. 2019), which enables us to differentiate
sectors by country of production within a DSGE framework. Each sector in each country has a
KLEM technology in production which captures the primary factor inputs of capital (K) and
labor (L) as well as the intermediate or production chains of inputs in energy (E) and materials
inputs (M). These linkages are both within a country and across countries.

6
Table 1 – Overview of the G-Cubed (G20) model
Countries (20) Regions (4)
Argentina Rest of the OECD
Australia Rest of Asia
Brazil Other oil-producing countries
Canada Rest of the world
China
Rest of Eurozone Sectors (6)
France Energy
Germany Mining
Indonesia Agriculture (including fishing and hunting)
India Durable manufacturing
Italy Non-durable manufacturing
Japan Services
Korea
Mexico Economic Agents in each Country (3)
Russia A representative household
Saudi Arabia A representative firm (in each of the 6 production sectors)
South Africa Government
Turkey
United Kingdom
United States

The approach embodied in the G-Cubed model is documented in McKibbin and Wilcoxen
(1998, 2013). Several key features of the standard G-Cubed model are worth highlighting here.

First, the model completely accounts for stocks and flows of physical and financial assets. For
example, budget deficits accumulate into government debt, and current account deficits
accumulate into foreign debt. The model imposes an intertemporal budget constraint on all
households, firms, governments, and countries. Thus, a long-run stock equilibrium obtains
through the adjustment of asset prices, such as the interest rate for government fiscal positions
or real exchange rates for the balance of payments. However, the adjustment towards the long-
run equilibrium of each economy can be slow, occurring over much of a century.

Second, firms and households in G-Cubed must use money issued by central banks for all
transactions. Thus, central banks in the model set short term nominal interest rates to target
macroeconomic outcomes (such as inflation, unemployment, exchange rates, etc.) based on
Henderson-McKibbin-Taylor monetary rules. These rules are designed to approximate actual
monetary regimes in each country or region in the model. These monetary rules tie down the
long-run inflation rates in each country as well as allowing short term adjustment of policy to
smooth fluctuations in the real economy.

7
Third, nominal wages are sticky and adjust over time based on country-specific labor
contracting assumptions. Firms hire labor in each sector up to the points that the marginal
product of labor equals the real wage defined in terms of the output price level of that sector.
Any excess labor enters the unemployed pool of workers. Unemployment or the presence of
excess demand for labor causes the nominal wage to adjust to clear the labor market in the long
run. In the short-run, unemployment can arise due to structural supply shocks or changes in
aggregate demand in the economy.

Fourth, rigidities prevent the economy from moving quickly from one equilibrium to another.
These rigidities include nominal stickiness caused by wage rigidities, lack of complete
foresight in the formation of expectations, cost of adjustment in investment by firms with
physical capital being sector-specific in the short run, monetary and fiscal authorities following
particular monetary and fiscal rules. Short term adjustment to economic shocks can be very
different from the long-run equilibrium outcomes. The focus on short-run rigidities is important
for assessing the impact over the initial decades of demographic change.

Fifth, we incorporate heterogeneous households and firms. Firms are modeled separately
within each sector. There is a mixture of two types of consumers and two types of firms within
each sector, within each country: one group which bases its decisions on forward-looking
expectations and the other group which follows simpler rules of thumb which are optimal in
the long run.

4. Modeling epidemiological scenarios in an economic model

We follow the approach in Lee and McKibbin (2003) and McKibbin and Sidorenko (2006) to
convert different assumptions about mortality rates and morbidity rates in the country where
the disease outbreak occurs (the epicenter country). Given the epidemiological assumptions
based on previous experience of pandemics, we create a set of filters that convert the shocks
into economic shocks to reduced labor supply in each country (mortality and morbidity); rising
cost of doing business in each sector including disruption of production networks in each
country; consumption reduction due to shifts in consumer preferences over each good from
each country (in addition to changes generated by the model based on change in income and
prices); rise in equity risk premia on companies in each sector in each country (based on
exposure to the disease); and increases in country risk premium based on exposure to the
disease as well as vulnerabilities to changing macroeconomic conditions.

8
In the remainder of this section, we outline how the various indicators are constructed. The
approach follows McKibbin and Sidorenko (2006) with some improvements. There are, of
course, many assumptions in this exercise and the results are sensitive to these assumptions.
The goal of the paper is to provide policymakers with some idea of the costs of not intervening
and allowing the various scenarios to unfold.

Epidemiological assumptions

The attack rates (proportion of the entire population who become infected) and case-fatality
rates (proportion of those infected who die) and the implied mortality rate (proportion of total
population who die) assumed for China under seven different scenarios are contained in Table
2 below. Each scenario is given a name. S01 is scenario 1.

Table 2 – Epidemiological Assumptions for China

Attack Rate for Case-fatality Rate for Mortality Rate for
Scenario
China China China
S01 1% 2.0% 0.02%
S02 10% 2.5% 0.25%
S03 30% 3.0% 0.90%
S04 10% 2.0% 0.20%
S05 20% 2.5% 0.50%
S06 30% 3.0% 0.90%
S07 10% 2.0% 0.20%

We explore seven scenarios based on the survey of historical pandemics in McKibbin and
Sidorenko (2006) and the most recent data on the COVID-19 virus. Table 3 summarizes the
scenarios for the disease outbreak. The scenarios vary by attack rate, mortality rate and the
countries experiencing the epidemiological shocks.. Scenarios 1-3 assume the epidemiological
events are isolated to China. The economic impact on China and the spillovers to other
countries are through trade, capital flows and the impacts of changes in risk premia in global
financial markets – as determined by the model. Scenarios 4-6 are the pandemic scenarios
where the epidemiological shocks occur in all countries to differing degrees. Scenarios 1-6
assume the shocks are temporary. Scenario 7 is a case where a mild pandemic is expected to
be recurring each year for the indefinite future.

9
Table 3 – Scenario Assumptions

a) Shocks to labor supply

Shocks Shocks
Scen
Countries Seve Attack Rate Case fatality Nature of Activated Activated
ario
Affected rity for China rate China Shocks Other
China
countries
1 China Low 1.0% 2.0% Temporary All Risk
2 China Mid 10.0% 2.5% Temporary All Risk
3 China High 30.0% 3.0% Temporary All Risk
4 Global Low 10.0% 2.0% Temporary All All
5 Global Mid 20.0% 2.5% Temporary All All
6 Global High 30.0% 3.0% Temporary All All
7 Global Low 10.0% 2.0% Permanent All All
The shock to labor supply in each country includes three components: mortality due to infection,
morbidity due to infection and morbidity arising from caregiving for affected family members.
For the mortality component, a mortality rate is initially calculated using different attack rates
and case-fatality rates for China. These attack rates and case-fatality rates are based on
observations during SARS and following McKibbin and Sidorenko (2006) on pandemic
influenza, as well as currently publicly available epidemiological data for COVID-19.

We take the Chinese epidemiological assumptions and scale these for different countries. The
scaling is done by calculating an Index of Vulnerability. This index is then applied to the
Chinese mortality rates to generate country specific mortality rates. Countries that are more
vulnerable than China will have higher rate of mortality and morbidity and countries who are
less vulnerable with lower epidemiological outcomes, The Index of Vulnerability is
constructed by aggregating an Index of Geography and an Index of Health Policy, following
McKibbin and Sidorenko (2006). The Index of Geography is the average of two indexes. The
first is the urban population density of countries divided by the share of urban in total
population. This is expressed relative to China. The second sub index is an index of openness
to tourism relative to China. The Index of Health Policy also consists of two components: the
Global Health Security Index and Health Expenditure per Capita relative to China. The Global
Health Security Index assigns scores to countries according to six criteria, which includes the
ability to prevent, detect and respond to epidemics (see GHSIndex 2020). The Index of
Geography and Index of Health Policy for different countries are presented in Figures 1 and 2,

10
respectively. The lower the value of the Index of Health Policy, the better would be a given
country’s health standards. However, a lower value for the Index of Geography represents a
lower risk to a given country.

When calculating the second component of the labor shock we need to adjust for the problem
that the model is an annual model. Days lost therefore must be annualized. The current
recommended incubation period for COVID-19 is 14 days5, so we assume an average employee
in a country would have to be absent from work for 14 days, if infected. Absence from work
indicates a loss of productive capacity for 14 days out of working days for a year. Hence, we
calculate an effective attack rate for China using the attack rate assumed for a given scenario,
and the proportion of days absent from work and scale them across other countries using the
Index of Vulnerability.

The third component of the labor shock accounts for absenteeism from work due to caregiving
family members who are infected. We assume the same effective attack rate as before and that
around 70 percent of the female workers would be care givers to family members. We adjust
the effective attack rate using the Index of Vulnerability and the proportion of labor force who
have to care for school-aged children (70 percent of female labor force participation). This does
account for school closures.

5
There is evidence that this figure could be close to 21 days. This would increase the scale of the shock.

11
Table 4 contains the labor shocks for countries for different scenarios.

Table 4 – Shocks to labor supply

Region S01 S02 S03 S04 S05 S06 S07
Argentina 0 0 0 - 0.65 - 1.37 - 2.14 - 0.65
Australia 0 0 0 - 0.48 - 1.01 - 1.58 - 0.48
Brazil 0 0 0 - 0.66 - 1.37 - 2.15 - 0.66
Canada 0 0 0 - 0.43 - 0.89 - 1.40 - 0.43
China - 0.10 - 1.10 - 3.44 - 1.05 - 2.19 - 3.44 - 1.05
France 0 0 0 - 0.52 - 1.08 - 1.69 - 0.52
Germany 0 0 0 - 0.51 - 1.06 - 1.66 - 0.51
India 0 0 0 - 1.34 - 2.82 - 4.44 - 1.34
Indonesia 0 0 0 - 1.39 - 2.91 - 4.56 - 1.39
Italy 0 0 0 - 0.48 - 1.02 - 1.60 - 0.48
Japan 0 0 0 - 0.50 - 1.04 - 1.64 - 0.50
Mexico 0 0 0 - 0.78 - 1.64 - 2.57 - 0.78
Republic of Korea 0 0 0 - 0.56 - 1.17 - 1.85 - 0.56
Russia 0 0 0 - 0.71 - 1.48 - 2.31 - 0.71
Saudi Arabia 0 0 0 - 0.41 - 0.87 - 1.37 - 0.41
South Africa 0 0 0 - 0.80 - 1.67 - 2.61 - 0.80
Turkey 0 0 0 - 0.76 - 1.59 - 2.50 - 0.76
United Kingdom 0 0 0 - 0.53 - 1.12 - 1.75 - 0.53
United States of America 0 0 0 - 0.40 - 0.83 - 1.30 - 0.40
Other Asia 0 0 0 - 0.88 - 1.84 - 2.89 - 0.88
Other oil producing countries 0 0 0 - 0.97 - 2.01 - 3.13 - 0.97
Rest of Euro Zone 0 0 0 - 0.46 - 0.97 - 1.52 - 0.46
Rest of OECD 0 0 0 - 0.43 - 0.89 - 1.39 - 0.43
Rest of the World 0 0 0 - 1.29 - 2.67 - 4.16 - 1.29

b) Shocks to the equity risk premium of economic sectors

We assume that the announcement of the virus will cause risk premia through the world to
change. We create risk premia in the United States to approximate the observed initial response
to scenario 1. We then adjust the equity risk shock to all countries across a given scenario by
applying the indexes outlined next. We also scale the shock across scenarios by applying the
different mortality rate assumptions across countries.

The Equity Risk Premium shock is the aggregation of the mortality component of the labor
shock and a Country Risk Index. The Country Risk Index is the average of three indices: Index
of Governance Risk, Index of Financial Risk and Index of Health Policy. In developing these
indices, we use the US as a benchmark due to the prevalence of well-developed financial
markets there (Fisman and Love 2004).

The Index of Governance Risk is based on the International Country Risk Guide, which assigns
countries scores based on performance in 22 variables across three categories: political,
economic, and financial (see PRSGroup 2020). The political variables include government

12
stability, as well as the prevalence of conflicts, corruption and the rule of law. GDP per capita,
real GDP growth and inflation are some of the economic variables considered in the Index.
Financial variables contained in the Index account for exchange rate stability and international
liquidity among others. Figure 3 summarizes the scores for countries for the governance risk
relative to the United States.

One of the most easily available indicators of the expected global economic impacts of
COVID-19 has been movements in financial market indices. Since the commencement of the
outbreak, financial markets continue to respond to daily developments regarding the outbreak
across the world. Particularly, stock markets have been demonstrating investor awareness of
industry-specific (unsystematic) impacts. Hence, when developing the Equity Risk Premium
Shocks for sectors, we include an Index of Financial Risk, even though it is already partially
accounted for within the Index of Governance Risk. This higher weight on financial risk
enables us to reproduce the prevailing turbulence in financial markets. The Index of Financial
Risk uses the current account balance of the countries as a proportion of GDP in 2015. Figure
4 contains the scores for the countries relative to the United States

Even though construction of the Index of Health Policy follows the procedure described for
developing the mortality component of the labor shock, the US has been used as the base-
country instead of China, when developing the shock on equity risk premium since the US is
the center of the global financial system and in the model, all risks are defined relative to the
US. Figure 5 contains the scores for the countries for the Index of Health Policy relative to the
United States.

The Net Risk Index for countries is presented in Figure 6 and Shock on Equity Risk Premia for
Scenario 4-7 are presented in Table 5.

13
Table 5 – Shock to equity risk premium for scenario 4-7
Region S04 S05 S06 S07
Argentina 1.90 2.07 2.30 1.90
Australia 1.23 1.37 1.54 1.23
Brazil 1.59 1.78 2.03 1.59
Canada 1.23 1.36 1.52 1.23
China 1.97 2.27 2.67 1.97
France 1.27 1.40 1.59 1.27
Germany 1.07 1.21 1.41 1.07
India 2.20 2.62 3.18 2.20
Indonesia 2.06 2.43 2.93 2.06
Italy 1.32 1.47 1.66 1.32
Japan 1.18 1.33 1.53 1.18
Mexico 1.76 1.98 2.27 1.76
Republic of Korea 1.25 1.43 1.67 1.25
Russia 1.77 1.96 2.22 1.77
Saudi Arabia 1.38 1.52 1.70 1.38
South Africa 1.85 2.06 2.33 1.85
Turkey 1.98 2.20 2.50 1.98
United Kingdom 1.35 1.50 1.70 1.35
United States of America 1.07 1.18 1.33 1.07
Other Asia 1.51 1.75 2.07 1.51
Other oil-producing countries 2.03 2.25 2.55 2.03
Rest of Euro Zone 1.29 1.42 1.60 1.29
Rest of OECD 1.11 1.22 1.38 1.11
Rest of the World 2.21 2.51 2.91 2.21

c) Shocks to the cost of production in each sector

As well as the shock to labor inputs, we identify that other inputs such as Trade, Land Transport,
Air Transport and Sea Transport have been significantly affected by the outbreak. Thus, we
calculate the share of inputs from these exposed sectors to the six aggregated sectors of the
model and compare the contribution relative to China. We then benchmark the percentage
increase in the cost of production in Chinese production sectors during SARS to the first
scenario and scale the percentage across scenarios to match the changes in the mortality
component of the labor shock. Variable shares of inputs from exposed sectors to aggregated
economic sectors also allow us to vary the shock across sectors in the countries. Table 6
contains the shocks to the cost of production in each sector in each country due to the share of
inputs from exposed sectors.

a) Shocks to consumption demand

14
The G-Cubed model endogenously changes spending patterns in response to changes in income,
wealth, and relative price changes. However, independent of these variables, during an
outbreak, it is likely that preferences for certain activities will change with the outbreak.
Following McKibbin and Sidorenko (2006), we assume that the reduction in spending on those
activities will reduce the overall spending, hence saving money for future expenditure. In
modeling this behavior, we employ a Sector Exposure Index. The Index is calculated as the
share of exposed sectors: Trade, Land, Air & Sea Transport and Recreation, within the GDP
of a country relative to China. The reduction in consumption expenditure during the SARS
outbreak in China is used as the benchmark for the first scenario. The advantage is that this
response was observed. The disadvantage is that other countries could behave differently.
Given we don’t have observations of other epicenters start with this assumption and then adjust
it as follows. This benchmark is then scaled across other scenarios relative to the mortality
component of the labor shock and adjusted across countries through the different sectoral
exposure. Figure 7 contains the Sector Exposure Indices for the countries and the shock to
consumption demand is presented in Table 7. Note that CBO (2005) uses a shock of 3% to US
consumption from an H5N1 influenza pandemic which is between S05 and S06 in Table 7.

15
Table 6 – Shocks to cost of production
Durable Non-durable
Ener Service
Region Mining Agriculture Manufacturi Manufacturi
gy s
ng ng
Argentina 0.37 0.24 0.37 0.35 0.40 0.38
Australia 0.43 0.43 0.42 0.39 0.41 0.45
Brazil 0.44 0.46 0.44 0.42 0.45 0.44
Canada 0.44 0.37 0.42 0.40 0.41 0.44
China 0.50 0.50 0.50 0.50 0.50 0.50
France 0.38 0.31 0.36 0.40 0.42 0.46
Germany 0.43 0.37 0.40 0.45 0.45 0.47
India 0.47 0.33 0.47 0.42 0.45 0.43
Indonesia 0.37 0.33 0.31 0.36 0.40 0.38
Italy 0.36 0.33 0.38 0.42 0.44 0.46
Japan 0.45 0.40 0.45 0.47 0.47 0.49
Mexico 0.41 0.38 0.39 0.42 0.42 0.41
Other Asia 0.44 0.39 0.44 0.45 0.45 0.47
Other oil producing
0.49 0.41 0.47 0.40 0.43 0.45
countries
Republic of Korea 0.39 0.30 0.37 0.43 0.42 0.43
Rest of Euro Zone 0.42 0.41 0.43 0.43 0.46 0.48
Rest of OECD 0.42 0.38 0.41 0.41 0.43 0.46
Rest of the World 0.52 0.46 0.51 0.45 0.49 0.48
Russia 0.54 0.37 0.43 0.41 0.42 0.45
Saudi Arabia 0.32 0.25 0.29 0.29 0.25 0.35
South Africa 0.40 0.35 0.39 0.41 0.43 0.38
Turkey 0.37 0.36 0.39 0.39 0.42 0.42
United Kingdom 0.39 0.37 0.39 0.39 0.42 0.46
United States of
0.53 0.40 0.51 0.50 0.51 0.53
America

16
Table 7 – Shocks to consumption demand

Region S04 S05 S06 S07

Argentina - 0.83 - 2.09 - 3.76 - 0.83
Australia - 0.90 - 2.26 - 4.07 - 0.90
Brazil - 0.92 - 2.31 - 4.16 - 0.92
Canada - 0.90 - 2.26 - 4.07 - 0.90
China - 1.00 - 2.50 - 4.50 - 1.00
France - 0.93 - 2.31 - 4.16 - 0.93
Germany - 0.95 - 2.36 - 4.25 - 0.95
India - 0.91 - 2.29 - 4.11 - 0.91
Indonesia - 0.86 - 2.15 - 3.86 - 0.86
Italy - 0.93 - 2.32 - 4.18 - 0.93
Japan - 1.01 - 2.51 - 4.52 - 1.01
Mexico - 0.89 - 2.22 - 4.00 - 0.89
Other Asia - 0.95 - 2.38 - 4.28 - 0.95
Other oil producing countries - 0.92 - 2.31 - 4.16 - 0.92
Republic of Korea - 0.89 - 2.23 - 4.01 - 0.89
Rest of Euro Zone - 0.98 - 2.45 - 4.40 - 0.98
Rest of OECD - 0.92 - 2.31 - 4.16 - 0.92
Rest of the World - 0.98 - 2.45 - 4.42 - 0.98
Russia - 0.92 - 2.31 - 4.16 - 0.92
Saudi Arabia - 0.74 - 1.86 - 3.35 - 0.74
South Africa - 0.82 - 2.05 - 3.69 - 0.82
Turkey - 0.88 - 2.19 - 3.95 - 0.88
United Kingdom - 0.94 - 2.34 - 4.22 - 0.94
United States of America - 1.06 - 2.66 - 4.78 - 1.06

b) Shocks to government expenditure

With the previous experience of pandemics, governments across the world have exercised a
stronger caution towards the outbreak by taking measures, such as strengthening health
screening at ports and investments in strengthening healthcare infrastructure, to prevent the
outbreak reaching additional countries. They have also responded by increasing health
expenditures to contain the spread. In modeling these interventions by governments, we use
the change in Chinese government expenditure relative to GDP in 2003 during the SARS
outbreak as a benchmark and use the average of Index of Governance and Index of Health
Policy to obtain the potential increase in government expenditure by other countries. We then

17
scale the shock across scenarios using the mortality component of the labor shock. Table 8
demonstrates the magnitude of the government expenditure shocks for countries for Scenario
4 to 7.

Table 8 – Shocks to government expenditure

Region S04 S05 S06 S07

Argentina 0.39 0.98 1.76 0.39
Australia 0.27 0.67 1.21 0.27
Brazil 0.39 0.98 1.76 0.39
Canada 0.26 0.66 1.19 0.26
China 0.50 1.25 2.25 0.50
France 0.30 0.74 1.34 0.30
Germany 0.27 0.68 1.22 0.27
India 0.52 1.30 2.34 0.52
Indonesia 0.47 1.18 2.12 0.47
Italy 0.34 0.84 1.51 0.34
Japan 0.30 0.74 1.33 0.30
Mexico 0.43 1.07 1.93 0.43
Republic of Korea 0.31 0.79 1.41 0.31
Russia 0.49 1.23 2.21 0.49
Saudi Arabia 0.38 0.95 1.71 0.38
South Africa 0.43 1.08 1.94 0.43
Turkey 0.47 1.17 2.11 0.47
United Kingdom 0.27 0.68 1.22 0.27
United States of America 0.22 0.54 0.98 0.22
Other Asia 0.39 0.99 1.77 0.39
Other oil producing countries 0.54 1.35 2.42 0.54
Rest of Euro Zone 0.33 0.81 1.46 0.33
Rest of OECD 0.28 0.70 1.26 0.28
Rest of the World 0.59 1.49 2.67 0.59

5. Simulation Results
(a) Baseline scenario
We first solve the model from 2016 to 2100 with 2015 as the base year. The key inputs into the
baseline are the initial dynamics from 2015 to 2016 and subsequent projections from 2016
forward for labor-augmenting technological progress by sector and by country. The labor-
augmenting technology projections follow the approach of Barro (1991, 2015). Over long
periods, Barro estimates that the average catchup rate of individual countries to the world-wide

18
productivity frontier is 2% per year. We use the Groningen Growth and Development database
(2018) to estimate the initial level of productivity in each sector of each region in the model.
Given this initial productivity, we then take the ratio of this to the equivalent sector in the US,
which we assume is the frontier. Given this initial gap in sectoral productivity, we use the Barro
catchup model to generate long term projections of the productivity growth rate of each sector
within each country. Where we expect that regions will catch up more quickly to the frontier
due to economic reforms (e.g., China) or more slowly to the frontier due to institutional
rigidities (e.g., Russia), we vary the catchup rate over time. The calibration of the catchup rate
attempts to replicate recent growth experiences of each country and region in the model.

The exogenous sectoral productivity growth rate, together with the economy-wide growth in
labor supply, are the exogenous drivers of sector growth for each country. The growth in the
capital stock in each sector in each region is determined endogenously within the model.

In the alternative COVID-19 scenarios, we incorporate the range of shocks discussed above to
model the economic consequences of different epidemiological assumptions. All results below
are the difference between the COVID-19 scenario and the baseline of the model.

19
 (b) Results
Table 9 contains the impact on populations in different regions. These are the core shocks
that are combined with the various indicators above to create the seven scenarios. The
mortality rates for each country under each scenario are contained in Table B-1 in Appendix
B. Note that the mortality rates in Table B-1 are much lower in advanced economies
compared to China.

Table 9 – Impact on populations under each scenario

Population Mortality in First Year (Thousands)

Country/Region
(Thousands) S01 S02 S03 S04 S05 S06 S07
Argentina 43,418 - - - 50 126 226 50
Australia 23,800 - - - 21 53 96 21
Brazil 205,962 - - - 257 641 1,154 257
Canada 35,950 - - - 30 74 133 30
China 1,397,029 279 3,493 12,573 2,794 6,985 12,573 2,794
France 64,457 - - - 60 149 268 60
Germany 81,708 - - - 79 198 357 79
India 1,309,054 - - - 3,693 9,232 16,617 3,693
Indonesia 258,162 - - - 647 1,616 2,909 647
Italy 59,504 - - - 59 147 265 59
Japan 127,975 - - - 127 317 570 127
Mexico 125,891 - - - 184 460 828 184
Republic of Korea 50,594 - - - 61 151 272 61
Russia 143,888 - - - 186 465 837 186
Saudi Arabia 31,557 - - - 29 71 128 29
South Africa 55,291 - - - 75 187 337 75
Turkey 78,271 - - - 116 290 522 116
United Kingdom 65,397 - - - 64 161 290 64
United States of America 319,929 - - - 236 589 1,060 236
Other Asia 330,935 - - - 530 1,324 2,384 530
Other oil producing countries 517,452 - - - 774 1,936 3,485 774
Rest of Euro Zone 117,427 - - - 106 265 478 106
Rest of OECD 33,954 - - - 27 67 121 27
Rest of the World 2,505,604 - - - 4,986 12,464 22,435 4,986
Total 7,983,209 279 3,493 12,573 15,188 37,971 68,347 15,188

Table 9 shows that for even the lowest of the pandemic scenarios (S04), there are estimated
to be around 15 million deaths. In the United States, the estimate is 236,000 deaths. These
20
estimated deaths from COVID-19 can be compared to a regular influenza season in the
United States, where around 55,000 people die each year.

Table 10 - GDP loss in 2020 (% deviation from baseline)

Country/Region S01 S02 S03 S04 S05 S06 S07

AUS -0.3 -0.4 -0.7 -2.1 -4.6 -7.9 -2.0
BRA -0.3 -0.3 -0.5 -2.1 -4.7 -8.0 -1.9
CHI -0.4 -1.9 -6.0 -1.6 -3.6 -6.2 -2.2
IND -0.2 -0.2 -0.4 -1.4 -3.1 -5.3 -1.3
EUZ -0.2 -0.2 -0.4 -2.1 -4.8 -8.4 -1.9
FRA -0.2 -0.3 -0.3 -2.0 -4.6 -8.0 -1.5
DEU -0.2 -0.3 -0.5 -2.2 -5.0 -8.7 -1.7
ZAF -0.2 -0.2 -0.4 -1.8 -4.0 -7.0 -1.5
ITA -0.2 -0.3 -0.4 -2.1 -4.8 -8.3 -2.2
JPN -0.3 -0.4 -0.5 -2.5 -5.7 -9.9 -2.0
GBR -0.2 -0.2 -0.3 -1.5 -3.5 -6.0 -1.2
ROW -0.2 -0.2 -0.3 -1.5 -3.5 -5.9 -1.5
MEX -0.1 -0.1 -0.1 -0.9 -2.2 -3.8 -0.9
CAN -0.2 -0.2 -0.4 -1.8 -4.1 -7.1 -1.6
OEC -0.3 -0.3 -0.5 -2.0 -4.4 -7.7 -1.8
OPC -0.2 -0.2 -0.4 -1.4 -3.2 -5.5 -1.3
ARG -0.2 -0.3 -0.5 -1.6 -3.5 -6.0 -1.2
RUS -0.2 -0.3 -0.5 -2.0 -4.6 -8.0 -1.9
SAU -0.2 -0.2 -0.3 -0.7 -1.4 -2.4 -1.3
TUR -0.1 -0.2 -0.2 -1.4 -3.2 -5.5 -1.2
USA -0.1 -0.1 -0.2 -2.0 -4.8 -8.4 -1.5
OAS -0.1 -0.2 -0.4 -1.6 -3.6 -6.3 -1.5
INO -0.2 -0.2 -0.3 -1.3 -2.8 -4.7 -1.3
KOR -0.1 -0.2 -0.3 -1.4 -3.3 -5.8 -1.3

21
Tables 10 and 11 provide a summary of the overall GDP loss for each country/region under the
seven scenarios. The results in Table 10 are the Change in GDP in 2020 expressed as a
percentage change from the baseline. The results in Table 11 are the results from Table 10
converted into billions of $2020US.

Table 11 - GDP Loss in 2020 ($US billions)

Country/Region S01 S02 S03 S04 S05 S06 S07

AUS (4) (5) (9) (27) (60) (103) (27)
BRA (9) (12) (19) (72) (161) (275) (65)
CHI (95) (488) (1,564) (426) (946) (1,618) (560)
IND (21) (26) (40) (152) (334) (567) (142)
EUZ (11) (13) (19) (111) (256) (446) (101)
FRA (7) (8) (11) (63) (144) (250) (46)
DEU (11) (14) (21) (99) (225) (390) (78)
ZAF (1) (2) (3) (14) (33) (57) (12)
ITA (6) (7) (9) (54) (123) (214) (56)
JPN (17) (20) (28) (140) (318) (549) (113)
GBR (5) (6) (9) (48) (108) (187) (39)
ROW (24) (29) (43) (234) (529) (906) (227)
MEX (2) (2) (3) (24) (57) (98) (24)
CAN (3) (4) (6) (32) (74) (128) (28)
OEC (5) (6) (10) (40) (91) (157) (36)
OPC (10) (12) (18) (73) (164) (282) (69)
ARG (2) (3) (5) (15) (33) (56) (11)
RUS (10) (12) (19) (84) (191) (331) (81)
SAU (3) (3) (5) (12) (24) (40) (22)
TUR (3) (4) (6) (33) (75) (130) (30)
USA (16) (22) (40) (420) (1,004) (1,769) (314)
OAS (6) (10) (19) (80) (186) (324) (77)
INO (6) (7) (11) (45) (99) (167) (46)
KOR (3) (4) (7) (31) (71) (124) (29)
Total Change (USD
(283) (720) (1,922) (2,330) (5,305) (9,170) (2,230)
Billion)

22
Tables 10 and 11 illustrate the scale of the various pandemic scenarios on reducing GDP in
the global economy. Even a low-end pandemic modeled on the Hong Kong Flu is expected to
reduce global GDP by around $SU2.4 trillion and a more serious outbreak similar to the
Spanish flu reduces global GDP by over $US9trillion in 2020.

Figures 9-11 provide the time profile of the results for several countries. The patterns in the
figures represents the nature of the assumed shocks which for the first 6 scenarios are
expected to disappear over time, Figure 9 contains results for China under each scenario. We
present results for Real GDP, private investment, consumption, the trade balance and then the
short real interest rate and the value of the equity market for sector 5 which is durable
manufacturing. Figure 10 contains the results for the United States and Figure 11 for
Australia.

The shocks which make up the pandemic cause a sharp drop in consumption and investment.
The decline in aggregate demand, together with the original risk shocks cause a sharp drop in
equity markets. The funds from equity markets are partly shifted into bonds, partly into cash
and partly overseas depending on which markets are most affected. Central banks respond by
cutting interest rates which drive together with the increased demand for bonds from the
portfolio shift drives down the real interest rate. Equity markets drop sharply both because of
the rise in risk but also because of the expected economic slowdown and the fall in expected
profits. For each scenario, there is a V shape recovery except for scenario 7. Recall that
scenario 7 is the same as scenario 4 in year 1, but with the expectation that the pandemic will
recur each year into the future.

Similar patterns can be seen in the dynamic results for the United States and Australia shown
in Figures 10 an 11. The quantitative magnitudes differ across countries, but the pattern of a
sharp shock followed by a gradual recovery is common across countries. The improvement in
the trade balance of China and deterioration in the US trade balance reflect the global
reallocation of financial capital as a result of the shock. Capital flows out of severely affected
economies like China and other developing and emerging economies and into safer advanced
economies like the United States, Europe and Australia. This movement of capital tends to
appreciate the exchange rate of countries that are receiving capital and depreciate the
exchange rates of countries that are losing capital. The deprecation of the exchange rate
increases exports and reduced imports in the countries losing capital and hence lead to the
current account adjustment that is consistent with the capital account adjustment.

23
These results are very sensitive to the assumptions in the model, to the shocks we feed in and
to the assumed macroeconomic policy responses in each country. Central banks are assumed
to respond according to a Henderson-Mckibbin-Taylor rule which differs across countries
(see Mckibbin and Triggs (2018)). Fiscal authorities are allowing automatic stabilizers to
increase budget deficits but cover addition debt servicing costs with a lump-sum tax levied on
households over time. In addition, there is the fiscal spending increase assumed in the shock
design outlined above.

24
6. Conclusions and Policy Implications
This paper has presented some preliminary estimates of the cost of the COVID-19 outbreak
under seven different scenarios of how the disease might evolve. The goal is not to be definitive
about the virus outbreak, but rather to provide information about a range of possible economic
costs of the disease. At the time of writing this paper, the probability of any of these scenarios
and the range of plausible alternatives are highly uncertain. In the case where COVID-19
develops into a global pandemic, our results suggest that the cost can escalate quickly.

A range of policy responses will be required both in the short term as well as in the coming
years. In the short term, central banks and Treasuries need to make sure that disrupted
economies continue to function while the disease outbreak continues. In the face of real and
financial stress, there is a critical role for governments. While cutting interest rates is a possible
response for central banks, the shock is not only a demand management problem but a multi-
faceted crisis that will require monetary, fiscal and health policy responses. Quarantining
affected people and reducing large scale social interaction is an effective response. Wide
dissemination of good hygiene practices as outlined in Levine and McKibbin (2020) can be a
low cost and highly effective response that can reduce the extent of contagion and therefore
reduce the social and economic cost.

The longer-term responses are even more important. Despite the potential loss of life and the
possible large-scale disruption to a large number of people, many governments have been
reluctant to invest sufficiently in their health care systems, let alone public health systems in
less developed countries where many infectious diseases are likely to originate. Experts have
warned and continue to warn that zoonotic diseases will continue to pose a threat to the lives
of millions of people with potentially major disruption to an integrated world economy. The
idea that any country can be an island in an integrated global economy is proven wrong by the
latest outbreak of COVID-19. Global cooperation, especially in the sphere of public health and
economic development, is essential. All major countries need to participate actively. It is too
late to act once the disease has taken hold in many other countries and attempt to close borders
once a pandemic has started.

Poverty kills poor people, but the outbreak of COVID-19 shows that if diseases are generated
in poor countries due to overcrowding, poor public health and interaction with wild animals,
these diseases can kill people of any socioeconomic group in any society. There needs to be
vastly more investment in public health and development in the richest but also, and especially,

25
in the poorest countries. This study indicates the possible costs that can be avoided through
global cooperative investment in public health in all countries. We have known this critical
policy intervention for decades, yet politicians continue to ignore the scientific evidence on the
role of public health in improving the quality of life and as a driver of economic growth.

26
References

Aguiar, A., Chepeliev, M., Corong, E., McDougall, R., & van der Mensbrugghe, D. (2019).
The GTAP Data Base: Version 10. Journal of Global Economic Analysis, 4(1), 1-27.

Arndt, C. and J. D. Lewis (2001). The HIV/AIDS Pandemic in South Africa: Sectoral
Impacts and Unemployment. Journal of International Development 13(4): 427-49.
Barker, W. H. and J. P. Mullooly (1980). Impact of epidemic type A influenza in a defined
adult population. American Journal of Epidemiology 112(6): 798-811
Barro, R. J. (1991). Economic Growth in a Cross-Section of Countries. The Quarterly Journal
of Economics, Vol. 106, No. 2, pp. 407-443.
Barro, R. J. (2015). Convergence and Modernisation. Economic Journal, Vol. 125, No. 585,
pp. 911-942.
Bell, C., S. Devarajan and H. Hersbach (2004). Thinking about the long-run economic costs
of AIDS, in The Macroeconomics of HIV/AIDS, M. Haacker (eds). Washington DC,
IMF: 96-144.
Beveridge, W. I., 1991. The chronicle of influenza epidemics. History and Philosophy of the
Life Sciences 13(2), 223-34.
Bhargava, A. and et al., 2001. Modeling the Effects of Health on Economic Growth. Journal
of Health Economics 20(3), 423-40.
Bittlingmayer, G., 1998. Output, Stock Volatility, and Political Uncertainty in a Natural
Experiment: Germany, 1880-1940. Journal of Finance 53(6), 2243-57.
Bloom, D. E. and J. D. Sachs, 1998. Geography, Demography, and Economic Growth in
Africa. Brookings Papers on Economic Activity 0(2), 207-73.
Bloom, E., V. d. Wit, et al., 2005. Potential economic impact of an Avian Flu pandemic on
Asia. ERD Policy Brief Series No. 42. Asian Development Bank, Manila.
http://www.adb.org/Documents/EDRC/Policy_Briefs/PB042.pdf.
Chou, J., N.-F. Kuo, et al., 2004. Potential Impacts of the SARS Outbreak on Taiwan's
Economy. Asian Economic Papers 3(1), 84-112.
Congressional Budget Office (2005) A Potential Influenza Pandemic: Possible
Macroeconomic Effects and Policy Issues, CBO Washington DC.
Cox, N. J. and K. Fukuda (1998). Influenza. Infectious Disease Clinics of North America
12(1): 27-38.
Cuddington, J. T., 1993a. Further results on the macroeconomic effects of AIDS: the
dualistic, labour-surplus economy. World Bank Economic Review 7(3), 403-17.
Cuddington, J. T., 1993b. Modeling the macroeconomic effects of AIDS, with an application
to Tanzania. World Bank Economic Review 7(2), 173-89.

27
Cuddington, J. T. and J. D. Hancock, 1994. Assessing the Impact of AIDS on the Growth
Path of the Malawian Economy. Journal of Development Economics 43(2), 363-68.
Cuddington, J. T., J. D. Hancock, et al., 1994. A Dynamic Aggregate Model of the AIDS
Epidemic with Possible Policy Interventions. Journal of Policy Modeling 16(5), 473-
96.
Das, S. R. and R. Uppal, 2004. Systemic Risk and International Portfolio Choice. Journal of
Finance 59(6), 2809-34.
Feldstein, M. and C. Horioka, 1980. Domestic Saving and International Capital Flows.
Economic Journal 90(358), 314-29.
Figura, S. Z. (1998). The forgotten pandemic. The Spanish Flu of 1918 was gravest crisis
American hospitals had ever faced. The Volunteer Leader 39(2): 5.
Fisman, R. and I. Love, 2004. Financial Development and Growth in the Short and Long
Run. The World Bank, Policy Research Working Paper Series 3319.
Freire, S., 2004. Impact of HIV/AIDS on saving behaviour in South Africa. African
development and poverty reduction: the macro-micro linkage, Lord Charles Hotel,
Somerset West, South Africa.
GHSIndex, 2020. Global Health Security Index 2019. Nuclear Threat Initiative, Washington
D.C; Johns Hopkins Center for Health Security, Maryland; and The Economist
Intelligence Unit, London. https://www.ghsindex.org/.
Gordon, R. H. and A. L. Bovenberg, 1996. Why Is Capital So Immobile Internationally?
Possible Explanations and Implications for Capital Income Taxation. American
Economic Review 86(5), 1057-75.
Grais, R. F., J. H. Ellis, et al., 2003. Assessing the impact of airline travel on the geographic
spread of pandemic influenza. European Journal of Epidemiology18(11), 1065-72.
Haacker, M., 2002a. The economic consequences of HIV/AIDS in Southern Africa. IMF
Working Paper W/02/38, 41-95.
Haacker, M., 2002b. Modeling the macroeconomic impact of HIV/AIDS. IMF Working
Paper W/02/195, 41-95.
Haacker, M., Ed. 2004. The Macroeconomics of HIV/AIDS. IMF, Washington DC.
Hai, W., Z. Zhao, et al., 2004. The Short-Term Impact of SARS on the Chinese Economy.
Asian Economic Papers 3(1), 57-61.
Henderson, D. W. and W. McKibbin (1993). A Comparison of Some Basic Monetary Policy
Regimes for Open Economies: Implications of Different Degrees of Instrument
Adjustment and Wage Persistence. Carnegie-Rochester Conference Series on Public
Policy 39(1): 221-317.
Hyams, K. C., F. M. Murphy, et al., 2002. Responding to Chemical, Biological, or Nuclear
Terrorism: The Indirect and Long-Term Health Effects May Present the Greatest
Challenge. Journal of Health Politics, Policy and Law 27(2), 273-91.

28
Kaufmann, D., A. Kraay, et al., 2004. Governance Matters III: Governance Indicators for
1996, 1998, 2000, and 2002. World Bank Economic Review 18(2), 253-87.
Kilbourne, E. D., 2004. Influenza pandemics: can we prepare for the unpredictable? Viral
Immunology 17(3), 350-7.
Kilbourne, E. D., 2006. Influenza immunity: new insights from old studies. The Journal of
Infectious Diseases 193(1), 7-8.
Killingray, D. and H. Phillips, 2003. The Spanish influenza pandemic of 1918-19 : new
perspectives. Routledge, London ; New York.
Lee J-W and W. McKibbin (2004) “Globalization and Disease: The Case of SARS” Asian
Economic Papers Vol . 3 no 1. MIT Press Cambridge USA. pp. 113-131 (ISSN
1535-3516).
Lee J-W and W. McKibbin (2004) “Estimating the Global Economic Costs of SARS” in S.
Knobler, A. Mahmoud, S. Lemon, A. Mack, L. Sivitz, and K. Oberholtzer (Editors),
Learning from SARS: Preparing for the next Outbreak, The National Academies
Press, Washington DC (0-309-09154-3)
Levine D.I. and W. J. McKibbin, W. (2020) “Simple steps to reduce the odds of a global catastrophe”
The Brookings Institution,
https://www.brookings.edu/opinions/simple-steps-to-reduce-the-odds-of-a-global-catastrophe/

Lokuge, B., 2005. Patent monopolies, pandemics and antiviral stockpiles: things that
developing and developed countries can do. Centre for Governance of Knowldege and
Development Working Paper, ANU. mimeo
McKibbin, W. and Sachs, J. (1991). Global Linkages: Macroeconomic Interdependence and
Cooperation in the World Economy. Brookings Institution. Washington D.C. June.
https://www.brookings.edu/book/global-linkages/.

McKibbin, W. and Triggs, A. (2018). Modelling the G20. Centre for Applied
Macroeconomic Analysis. Working paper 17/2018. Australian National University.
April. https://cama.crawford.anu.edu.au/publication/cama-working-paper-
series/12470/modelling-g20.

McKibbin W. and A. Sidorenko (2006) “Global Macroeconomic Consequences of Pandemic

Influenza” Lowy Institute Analysis, February. 100 pages.
McKibbin W. and A. Sidorenko (2009) “What a Flu Pandemic Could Cost the World” ,
Foreign Policy, April.
https://foreignpolicy.com/2009/04/28/what-a-flu-pandemic-could-cost-the-world/
McKibbin W. and P. Wilcoxen (1999) “The Theoretical and Empirical Structure of the G-
Cubed Model” Economic Modelling , 16, 1, pp 123-148 (ISSN 0264-9993)
McKibbin W and Wilcoxen P (2013), A Global Approach to Energy and the Environment:
The G-cubed Model” Handbook of CGE Modeling, Chapter 17, North Holland, pp
995-1068

29
Maddison, A. and Organisation for Economic Co-operation and Development. Development
Centre. (1995). Monitoring the world economy, 1820-1992. Paris, Development
Centre of the Organisation for Economic Co-operation and Development.
Meltzer, M. I., N. J. Cox, et al., 1999. The economic impact of pandemic influenza in the
United States: priorities for intervention. Emerging Infectious Diseases 5(5), 659-71.
Monto, A. S., 2005. The threat of an avian influenza pandemic. New England Journal of
Medicine 352(4), 323-325.
Obstfeld, M. and Rogoff, K. (2000). The six major puzzles in international macroeconomics.
NBER Working Paper 7777, Cambridge, MA. National Bureau of Economic
Research. http://www.nber.org/chapters/c11059.pdf.

OECD (2020) http://www.oecd.org/newsroom/global-economy-faces-gravest-threat-since-

the-crisis-as-coronavirus-spreads.htm

Over, M., 2002. The Macroeconomic Impact on HIV/AIDS in Sub-Saharan Africa. African
Technical Working Paper No. 3 Population Health and Nutrition Division, Africa
Technical Department, World Bank.

Palese, P., 2004. Influenza: old and new threats. Nature Medicine 10(12 Suppl), S82-7.

Patterson, K. D. and G. F. Pyle (1991). The geography and mortality of the 1918 influenza
pandemic. Bulletin of the History of Medicine 65(1): 4-21.

Peiris, J. S., Y. Guan, et al., 2004. Severe acute respiratory syndrome. Nature Medicine 10(12
Suppl), S88-97.

Potter, C. W., 2001. A history of influenza. Journal of Applied Microbiology 91(4), 572-9.

Pritchett, L. and L. H. Summers, 1996. Wealthier Is Healthier. Journal of Human Resources

31(4), 841-868.

PRS Group, 2012. The International Country Risk Guide Methodology (ICRG). PRSGroup.
https://www.prsgroup.com/wp-content/uploads/2012/11/icrgmethodology.pdf.

Reid, A. H. and J. K. Taubenberger (1999). The 1918 flu and other influenza pandemics: "over
there" and back again. Laboratory Investigation: a Journal of Technical Methods and
Pathology 79(2): 95-101

Robalino, D. A., C. Jenkins, et al., 2002a. The Risks and Macroeconomic Impact of HIV/AIDS
in the Middle East and North Africa: Why Waiting to Intervene Can Be Costly. Policy
Research Working Paper Series: 2874, 2002. The World Bank.
[URL:http://econ.worldbank.org/files/16774_wps2874.pdf] URL.

Robalino, D. A., A. Voetberg, et al., 2002b. The Macroeconomic Impacts of AIDS in Kenya
Estimating Optimal Reduction Targets for the HIV/AIDS Incidence Rate. Journal of
Policy Modeling 24(2), 195-218.

Ruef, C., 2004. A new influenza pandemic-unprepared for a big threat? Infection 32(6), 313-
4.

30
Sanford, J. P. (1969). Influenza: consideration of pandemics. Advances in Internal Medicine
15: 419-53.

Schoenbaum, S. C., 1987. Economic impact of influenza. The individual's perspective.

American Journal of Medicine 82(6A), 26-30.

Scholtissek, C., 1994. Source for influenza pandemics. Eur J Epidemiol 10(4), 455-8.

Shannon, G. W. and J. Willoughby, 2004. Severe Acute Respiratory Syndrome (SARS) in

Asia: A Medical Geographic Perspective. Eurasian Geography and Economics 45(5),
359-81.

Shortridge, K. F., J. S. Peiris, et al., 2003. The next influenza pandemic: lessons from Hong
Kong. Journal of Applied Microbiology 94 Suppl, 70S-79S.

Simonsen, L., M. J. Clarke, L. B. Schonberger, N. H. Arden, N. J. Cox and K. Fukuda (1998).

Pandemic versus epidemic influenza mortality: a pattern of changing age distribution.
Journal of Infectious Diseases 178(1): 53-60.

Simonsen, L., D. R. Olsen, et al., 2005. Pandemic influenza and mortality: past evidence and
projections for the future. The threat of pandemic influenza: Are we ready? Workshop
Summary. S. L. Knobler, A. Mack, A. Mahmoud and S. M. Lemon. The National
Academies Press, Washington, D.C., 89-106.

Smith, R. D., M. Yaho, et al., 2005. Assessing the macroeconomic impact of a healthcare
problem: The application of computable general equilibrium analysis to antimicrobial
resistance. Journal of Health Economics 24(5), 1055-75.

Sui, A. and Y. C. R. Wong, 2004. Economic Impact of SARS: The Case of Hong-Kong. Asian
Economic Papers 3(1), 62-83.

Sunstein, C. R., 1997. Bad Deaths. Journal of Risk and Uncertainty 14(3), 259-82.

The World Bank, 2006. Socioeconomic Impact of HIV/AIDS in Ukraine. The World Bank and
The International HIV/AIDS Alliance in Ukraine, Washington D.C. .
http://siteresources.worldbank.org/INTUKRAINE/Resources/328335-
1147812406770/ukr_aids_eng.pdf.

Viscusi, W. K., J. K. Hakes, et al., 1997. Measures of Mortality Risks. Journal of Risk and
Uncertainty 14(3), 213-33.

WHO Commission on Macroeconomics and Health, Ed. 2001. Macroeconomics and Health:
Investing in Health for Economic Development. World Health Organization.

Wilton, P. (1993). "Spanish flu outdid WWI in number of lives claimed." Canadian Medical
Association Journal 148(11): 2036-7

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Figure 1 - Index of Geography

180

160

140

120

100

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40

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Figure 2 - Index of Health Policy

180

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Figure 3 - Index of Governance

180

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Figure 4 - Index of Financial Risk

200

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Figure 5 - Index of Health Policy

450

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Figure 6 - Net Country Risk Index

250

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Figure 7 - Index of Sector Exposure to Exposed Activities

100

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Figure 8: Dynamic Results for China

36
Figure 8 (continued): Dynamic Results for China

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Figure 9: Dynamic Results for the United States

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Figure 9 (continued): Dynamic Results for the United States

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Figure 10: Dynamic Results for Australia

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Figure 10 (continued): Dynamic Results for Australia

41
Appendix A. G-Cubed Regions
Version G20 (6)

United States
Japan
Germany
United Kingdom
France
Italy
Rest of Euro Zone
Canada
Australia
Rest of Advanced Economies
Korea
Turkey
China
India
Indonesia
Other Asia
Mexico
Argentina
Brazil
Russia
Saudi Arabia
South Africa
Oil-exporting and the Middle East
Rest of World

Rest of Euro Zone:

Spain, Netherlands, Belgium, Luxemburg, Ireland, Greece, Portugal, Finland, Cyprus, Malta,
Slovakia, Slovenia, Estonia

Rest of Advanced Economies:

New Zealand, Norway, Sweden, Switzerland, Iceland, Denmark, Iceland, Liechtenstein

Oil-exporting and the Middle East:

Ecuador, Nigeria, Angola, Congo, Iran, Venezuela, Algeria, Libya, Bahrain, Iraq, Israel,
Jordan, Kuwait, Lebanon, Palestinian Territory, Oman, Qatar, Syrian Arab Republic, United
Arab Emirates, Yemen

Other Asia:
Singapore, Taiwan, Hong Kong, Indonesia, Malaysia, Philippines, Thailand, Vietnam

Rest of World:
All countries not included in other groups.

42
Appendix B: Additional results

Table B-112 - Mortality Rates for each Country under each Scenario
Mortality Rate
Country/Region
S01 S02 S03 S04 S05 S06 S07
Argentina - - - 0.12% 0.29% 0.52% 0.12%
Australia - - - 0.09% 0.22% 0.40% 0.09%
Brazil - - - 0.12% 0.31% 0.56% 0.12%
Canada - - - 0.08% 0.21% 0.37% 0.08%
China 0.02% 0.25% 0.90% 0.20% 0.50% 0.90% 0.20%
France - - - 0.09% 0.23% 0.42% 0.09%
Germany - - - 0.10% 0.24% 0.44% 0.10%
India - - - 0.28% 0.71% 1.27% 0.28%
Indonesia - - - 0.25% 0.63% 1.13% 0.25%
Italy - - - 0.10% 0.25% 0.45% 0.10%
Japan - - - 0.10% 0.25% 0.45% 0.10%
Mexico - - - 0.15% 0.37% 0.66% 0.15%
Republic of Korea - - - 0.12% 0.30% 0.54% 0.12%
Russia - - - 0.13% 0.32% 0.58% 0.13%
Saudi Arabia - - - 0.09% 0.23% 0.41% 0.09%
South Africa - - - 0.14% 0.34% 0.61% 0.14%
Turkey - - - 0.15% 0.37% 0.67% 0.15%
United Kingdom - - - 0.10% 0.25% 0.44% 0.10%
United States of America - - - 0.07% 0.18% 0.33% 0.07%
Other Asia - - - 0.16% 0.40% 0.72% 0.16%
Other oil producing
countries - - - 0.15% 0.37% 0.67% 0.15%
Rest of Euro Zone - - - 0.09% 0.23% 0.41% 0.09%
Rest of OECD - - - 0.08% 0.20% 0.36% 0.08%
Rest of the World - - - 0.20% 0.50% 0.90% 0.20%

43
 3

Impact of non-pharma
interventions (NPIS) to
reduce COVID 19
mortality and
healthcare demand
16 March 2020 Imperial College COVID-19 Response Team

Impact of non-pharmaceutical interventions (NPIs) to reduce COVID-

19 mortality and healthcare demand
Neil M Ferguson, Daniel Laydon, Gemma Nedjati-Gilani, Natsuko Imai, Kylie Ainslie, Marc Baguelin,
Sangeeta Bhatia, Adhiratha Boonyasiri, Zulma Cucunubá, Gina Cuomo-Dannenburg, Amy Dighe, Ilaria
Dorigatti, Han Fu, Katy Gaythorpe, Will Green, Arran Hamlet, Wes Hinsley, Lucy C Okell, Sabine van
Elsland, Hayley Thompson, Robert Verity, Erik Volz, Haowei Wang, Yuanrong Wang, Patrick GT Walker,
Caroline Walters, Peter Winskill, Charles Whittaker, Christl A Donnelly, Steven Riley, Azra C Ghani.

On behalf of the Imperial College COVID-19 Response Team

WHO Collaborating Centre for Infectious Disease Modelling

MRC Centre for Global Infectious Disease Analysis
Abdul Latif Jameel Institute for Disease and Emergency Analytics
Imperial College London

Correspondence: neil.ferguson@imperial.ac.uk

Summary
The global impact of COVID-19 has been profound, and the public health threat it represents is the
most serious seen in a respiratory virus since the 1918 H1N1 influenza pandemic. Here we present the
results of epidemiological modelling which has informed policymaking in the UK and other countries
in recent weeks. In the absence of a COVID-19 vaccine, we assess the potential role of a number of
public health measures – so-called non-pharmaceutical interventions (NPIs) – aimed at reducing
contact rates in the population and thereby reducing transmission of the virus. In the results presented
here, we apply a previously published microsimulation model to two countries: the UK (Great Britain
specifically) and the US. We conclude that the effectiveness of any one intervention in isolation is likely
to be limited, requiring multiple interventions to be combined to have a substantial impact on
transmission.

Two fundamental strategies are possible: (a) mitigation, which focuses on slowing but not necessarily
stopping epidemic spread – reducing peak healthcare demand while protecting those most at risk of
severe disease from infection, and (b) suppression, which aims to reverse epidemic growth, reducing
case numbers to low levels and maintaining that situation indefinitely. Each policy has major
challenges. We find that that optimal mitigation policies (combining home isolation of suspect cases,
home quarantine of those living in the same household as suspect cases, and social distancing of the
elderly and others at most risk of severe disease) might reduce peak healthcare demand by 2/3 and
deaths by half. However, the resulting mitigated epidemic would still likely result in hundreds of
thousands of deaths and health systems (most notably intensive care units) being overwhelmed many
times over. For countries able to achieve it, this leaves suppression as the preferred policy option.

We show that in the UK and US context, suppression will minimally require a combination of social
distancing of the entire population, home isolation of cases and household quarantine of their family
members. This may need to be supplemented by school and university closures, though it should be
recognised that such closures may have negative impacts on health systems due to increased

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16 March 2020 Imperial College COVID-19 Response Team

absenteeism. The major challenge of suppression is that this type of intensive intervention package –
or something equivalently effective at reducing transmission – will need to be maintained until a
vaccine becomes available (potentially 18 months or more) – given that we predict that transmission
will quickly rebound if interventions are relaxed. We show that intermittent social distancing –
triggered by trends in disease surveillance – may allow interventions to be relaxed temporarily in
relative short time windows, but measures will need to be reintroduced if or when case numbers
rebound. Last, while experience in China and now South Korea show that suppression is possible in
the short term, it remains to be seen whether it is possible long-term, and whether the social and
economic costs of the interventions adopted thus far can be reduced.

DOI: https://doi.org/10.25561/77482 Page 2 of 20

16 March 2020 Imperial College COVID-19 Response Team

Introduction
The COVID-19 pandemic is now a major global health threat. As of 16th March 2020, there have been
164,837 cases and 6,470 deaths confirmed worldwide. Global spread has been rapid, with 146
countries now having reported at least one case.

The last time the world responded to a global emerging disease epidemic of the scale of the current
COVID-19 pandemic with no access to vaccines was the 1918-19 H1N1 influenza pandemic. In that
pandemic, some communities, notably in the United States (US), responded with a variety of non-
pharmaceutical interventions (NPIs) - measures intended to reduce transmission by reducing contact
rates in the general population1. Examples of the measures adopted during this time included closing
schools, churches, bars and other social venues. Cities in which these interventions were implemented
early in the epidemic were successful at reducing case numbers while the interventions remained in
place and experienced lower mortality overall1. However, transmission rebounded once controls were
lifted.

Whilst our understanding of infectious diseases and their prevention is now very different compared
to in 1918, most of the countries across the world face the same challenge today with COVID-19, a
virus with comparable lethality to H1N1 influenza in 1918. Two fundamental strategies are possible2:

(a) Suppression. Here the aim is to reduce the reproduction number (the average number of
secondary cases each case generates), R, to below 1 and hence to reduce case numbers to low levels
or (as for SARS or Ebola) eliminate human-to-human transmission. The main challenge of this
approach is that NPIs (and drugs, if available) need to be maintained – at least intermittently - for as
long as the virus is circulating in the human population, or until a vaccine becomes available. In the
case of COVID-19, it will be at least a 12-18 months before a vaccine is available3. Furthermore, there
is no guarantee that initial vaccines will have high efficacy.

(b) Mitigation. Here the aim is to use NPIs (and vaccines or drugs, if available) not to interrupt
transmission completely, but to reduce the health impact of an epidemic, akin to the strategy adopted
by some US cities in 1918, and by the world more generally in the 1957, 1968 and 2009 influenza
pandemics. In the 2009 pandemic, for instance, early supplies of vaccine were targeted at individuals
with pre-existing medical conditions which put them at risk of more severe disease4. In this scenario,
population immunity builds up through the epidemic, leading to an eventual rapid decline in case
numbers and transmission dropping to low levels.

The strategies differ in whether they aim to reduce the reproduction number, R, to below 1
(suppression) – and thus cause case numbers to decline – or to merely slow spread by reducing R, but
not to below 1.

In this report, we consider the feasibility and implications of both strategies for COVID-19, looking at
a range of NPI measures. It is important to note at the outset that given SARS-CoV-2 is a newly
emergent virus, much remains to be understood about its transmission. In addition, the impact of
many of the NPIs detailed here depends critically on how people respond to their introduction, which
is highly likely to vary between countries and even communities. Last, it is highly likely that there
would be significant spontaneous changes in population behaviour even in the absence of
government-mandated interventions.

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16 March 2020 Imperial College COVID-19 Response Team

We do not consider the ethical or economic implications of either strategy here, except to note that
there is no easy policy decision to be made. Suppression, while successful to date in China and South
Korea, carries with it enormous social and economic costs which may themselves have significant
impact on health and well-being in the short and longer-term. Mitigation will never be able to
completely protect those at risk from severe disease or death and the resulting mortality may
therefore still be high. Instead we focus on feasibility, with a specific focus on what the likely
healthcare system impact of the two approaches would be. We present results for Great Britain (GB)
and the United States (US), but they are equally applicable to most high-income countries.

Methods
Transmission Model
We modified an individual-based simulation model developed to support pandemic influenza
planning5,6 to explore scenarios for COVID-19 in GB. The basic structure of the model remains as
previously published. In brief, individuals reside in areas defined by high-resolution population density
data. Contacts with other individuals in the population are made within the household, at school, in
the workplace and in the wider community. Census data were used to define the age and household
distribution size. Data on average class sizes and staff-student ratios were used to generate a synthetic
population of schools distributed proportional to local population density. Data on the distribution of
workplace size was used to generate workplaces with commuting distance data used to locate
workplaces appropriately across the population. Individuals are assigned to each of these locations at
the start of the simulation.

Transmission events occur through contacts made between susceptible and infectious individuals in
either the household, workplace, school or randomly in the community, with the latter depending on
spatial distance between contacts. Per-capita contacts within schools were assumed to be double
those elsewhere in order to reproduce the attack rates in children observed in past influenza
pandemics7. With the parameterisation above, approximately one third of transmission occurs in the
household, one third in schools and workplaces and the remaining third in the community. These
contact patterns reproduce those reported in social mixing surveys8.

We assumed an incubation period of 5.1 days9,10. Infectiousness is assumed to occur from 12 hours
prior to the onset of symptoms for those that are symptomatic and from 4.6 days after infection in
those that are asymptomatic with an infectiousness profile over time that results in a 6.5-day mean
generation time. Based on fits to the early growth-rate of the epidemic in Wuhan10,11, we make a
baseline assumption that R0=2.4 but examine values between 2.0 and 2.6. We assume that
symptomatic individuals are 50% more infectious than asymptomatic individuals. Individual
infectiousness is assumed to be variable, described by a gamma distribution with mean 1 and shape
parameter =0.25. On recovery from infection, individuals are assumed to be immune to re-infection
in the short term. Evidence from the Flu Watch cohort study suggests that re-infection with the same
strain of seasonal circulating coronavirus is highly unlikely in the same or following season (Prof
Andrew Hayward, personal communication).

Infection was assumed to be seeded in each country at an exponentially growing rate (with a doubling
time of 5 days) from early January 2020, with the rate of seeding being calibrated to give local
epidemics which reproduced the observed cumulative number of deaths in GB or the US seen by 14th
March 2020.

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16 March 2020 Imperial College COVID-19 Response Team

Disease Progression and Healthcare Demand

Analyses of data from China as well as data from those returning on repatriation flights suggest that
40-50% of infections were not identified as cases12. This may include asymptomatic infections, mild
disease and a level of under-ascertainment. We therefore assume that two-thirds of cases are
sufficiently symptomatic to self-isolate (if required by policy) within 1 day of symptom onset, and a
mean delay from onset of symptoms to hospitalisation of 5 days. The age-stratified proportion of
infections that require hospitalisation and the infection fatality ratio (IFR) were obtained from an
analysis of a subset of cases from China12. These estimates were corrected for non-uniform attack
rates by age and when applied to the GB population result in an IFR of 0.9% with 4.4% of infections
hospitalised (Table 1). We assume that 30% of those that are hospitalised will require critical care
(invasive mechanical ventilation or ECMO) based on early reports from COVID-19 cases in the UK,
China and Italy (Professor Nicholas Hart, personal communication). Based on expert clinical opinion,
we assume that 50% of those in critical care will die and an age-dependent proportion of those that
do not require critical care die (calculated to match the overall IFR). We calculate bed demand
numbers assuming a total duration of stay in hospital of 8 days if critical care is not required and 16
days (with 10 days in ICU) if critical care is required. With 30% of hospitalised cases requiring critical
care, we obtain an overall mean duration of hospitalisation of 10.4 days, slightly shorter than the
duration from hospital admission to discharge observed for COVID-19 cases internationally13 (who will
have remained in hospital longer to ensure negative tests at discharge) but in line with estimates for
general pneumonia admissions14.

Table 1: Current estimates of the severity of cases. The IFR estimates from Verity et al.12 have been adjusted
to account for a non-uniform attack rate giving an overall IFR of 0.9% (95% credible interval 0.4%-1.4%).
Hospitalisation estimates from Verity et al.12 were also adjusted in this way and scaled to match expected
rates in the oldest age-group (80+ years) in a GB/US context. These estimates will be updated as more data
accrue.

Age-group % symptomatic cases % hospitalised cases Infection Fatality Ratio

(years) requiring hospitalisation requiring critical care

0 to 9 0.1% 5.0% 0.002%

10 to 19 0.3% 5.0% 0.006%
20 to 29 1.2% 5.0% 0.03%
30 to 39 3.2% 5.0% 0.08%
40 to 49 4.9% 6.3% 0.15%
50 to 59 10.2% 12.2% 0.60%
60 to 69 16.6% 27.4% 2.2%
70 to 79 24.3% 43.2% 5.1%
80+ 27.3% 70.9% 9.3%

Non-Pharmaceutical Intervention Scenarios

We consider the impact of five different non-pharmaceutical interventions (NPI) implemented
individually and in combination (Table 2). In each case, we represent the intervention mechanistically
within the simulation, using plausible and largely conservative (i.e. pessimistic) assumptions about the
impact of each intervention and compensatory changes in contacts (e.g. in the home) associated with

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16 March 2020 Imperial College COVID-19 Response Team

reducing contact rates in specific settings outside the household. The model reproduces the
intervention effect sizes seen in epidemiological studies and in empirical surveys of contact patterns.
Two of the interventions (case isolation and voluntary home quarantine) are triggered by the onset of
symptoms and are implemented the next day. The other four NPIs (social distancing of those over 70
years, social distancing of the entire population, stopping mass gatherings and closure of schools and
universities) are decisions made at the government level. For these interventions we therefore
consider surveillance triggers based on testing of patients in critical care (intensive care units, ICUs).
We focus on such cases as testing is most complete for the most severely ill patients. When examining
mitigation strategies, we assume policies are in force for 3 months, other than social distancing of
those over the age of 70 which is assumed to remain in place for one month longer. Suppression
strategies are assumed to be in place for 5 months or longer.

Table 2: Summary of NPI interventions considered.

Label Policy Description

CI Case isolation in the home Symptomatic cases stay at home for 7 days, reducing non-
household contacts by 75% for this period. Household
contacts remain unchanged. Assume 70% of household
comply with the policy.
HQ Voluntary home Following identification of a symptomatic case in the
quarantine household, all household members remain at home for 14
days. Household contact rates double during this
quarantine period, contacts in the community reduce by
75%. Assume 50% of household comply with the policy.
SDO Social distancing of those Reduce contacts by 50% in workplaces, increase household
over 70 years of age contacts by 25% and reduce other contacts by 75%.
Assume 75% compliance with policy.
SD Social distancing of entire All households reduce contact outside household, school or
population workplace by 75%. School contact rates unchanged,
workplace contact rates reduced by 25%. Household
contact rates assumed to increase by 25%.
PC Closure of schools and Closure of all schools, 25% of universities remain open.
universities Household contact rates for student families increase by
50% during closure. Contacts in the community increase by
25% during closure.

Results
In the (unlikely) absence of any control measures or spontaneous changes in individual behaviour, we
would expect a peak in mortality (daily deaths) to occur after approximately 3 months (Figure 1A). In
such scenarios, given an estimated R0 of 2.4, we predict 81% of the GB and US populations would be
infected over the course of the epidemic. Epidemic timings are approximate given the limitations of
surveillance data in both countries: The epidemic is predicted to be broader in the US than in GB and
to peak slightly later. This is due to the larger geographic scale of the US, resulting in more distinct
localised epidemics across states (Figure 1B) than seen across GB. The higher peak in mortality in GB

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16 March 2020 Imperial College COVID-19 Response Team

is due to the smaller size of the country and its older population compared with the US. In total, in an
unmitigated epidemic, we would predict approximately 510,000 deaths in GB and 2.2 million in the
US, not accounting for the potential negative effects of health systems being overwhelmed on
mortality.

(A) 25
GB (total=510,000)
US (total=2,200,000)
20
per 100,000 population
Deaths per day

15

10

(B)
Cases per 100,000 populations

Figure 1: Unmitigated epidemic scenarios for GB and the US. (A) Projected deaths per day per 100,000
population in GB and US. (B) Case epidemic trajectories across the US by state.

For an uncontrolled epidemic, we predict critical care bed capacity would be exceeded as early as the
second week in April, with an eventual peak in ICU or critical care bed demand that is over 30 times
greater than the maximum supply in both countries (Figure 2).

The aim of mitigation is to reduce the impact of an epidemic by flattening the curve, reducing peak
incidence and overall deaths (Figure 2). Since the aim of mitigation is to minimise mortality, the
interventions need to remain in place for as much of the epidemic period as possible. Introducing such
interventions too early risks allowing transmission to return once they are lifted (if insufficient herd
immunity has developed); it is therefore necessary to balance the timing of introduction with the scale

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16 March 2020 Imperial College COVID-19 Response Team

of disruption imposed and the likely period over which the interventions can be maintained. In this
scenario, interventions can limit transmission to the extent that little herd immunity is acquired –
leading to the possibility that a second wave of infection is seen once interventions are lifted

300
Surge critical care bed capacity
250
Critical care beds occupied
per 100,000 of population

Do nothing

200
Case isolation

150 Case isolation and household

quarantine
Closing schools and universities
100

Case isolation, home quarantine,

50 social distancing of >70s

Figure 2: Mitigation strategy scenarios for GB showing critical care (ICU) bed requirements. The black line
shows the unmitigated epidemic. The green line shows a mitigation strategy incorporating closure of schools
and universities; orange line shows case isolation; yellow line shows case isolation and household quarantine;
and the blue line shows case isolation, home quarantine and social distancing of those aged over 70. The blue
shading shows the 3-month period in which these interventions are assumed to remain in place.

Table 3 shows the predicted relative impact on both deaths and ICU capacity of a range of single and
combined NPIs interventions applied nationally in GB for a 3-month period based on triggers of
between 100 and 3000 critical care cases. Conditional on that duration, the most effective
combination of interventions is predicted to be a combination of case isolation, home quarantine and
social distancing of those most at risk (the over 70s). Whilst the latter has relatively less impact on
transmission than other age groups, reducing morbidity and mortality in the highest risk groups
reduces both demand on critical care and overall mortality. In combination, this intervention strategy
is predicted to reduce peak critical care demand by two-thirds and halve the number of deaths.
However, this “optimal” mitigation scenario would still result in an 8-fold higher peak demand on
critical care beds over and above the available surge capacity in both GB and the US.

Stopping mass gatherings is predicted to have relatively little impact (results not shown) because the
contact-time at such events is relatively small compared to the time spent at home, in schools or
workplaces and in other community locations such as bars and restaurants.

Overall, we find that the relative effectiveness of different policies is insensitive to the choice of local
trigger (absolute numbers of cases compared to per-capita incidence), R0 (in the range 2.0-2.6), and
varying IFR in the 0.25%-1.0% range.

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Table 3. Mitigation options for GB. Relative impact of NPI combinations applied nationally for 3 months in GB on total deaths and peak hospital ICU bed demand for
different choices of cumulative ICU case count triggers. The cells show the percentage reduction in peak ICU bed demand for a variety of NPI combinations and for triggers
based on the absolute number of ICU cases diagnosed in a county per week. PC=school and university closure, CI=home isolation of cases, HQ=household quarantine,
SD=social distancing of the entire population, SDOL70=social distancing of those over 70 years for 4 months (a month more than other interventions). Tables are colour-
coded (green=higher effectiveness, red=lower). Absolute numbers are shown in Table A1.

Trigger
(cumulative ICU
cases) PC CI CI_HQ CI_HQ_SD CI_SD CI_HQ_SDOL70 PC_CI_HQ_SDOL70
100 14% 33% 53% 33% 53% 67% 69%
R0=2.4 300 14% 33% 53% 34% 57% 67% 71%
Peak beds 1000 14% 33% 53% 39% 64% 67% 77%
3000 12% 33% 53% 51% 75% 67% 81%

100 23% 35% 57% 25% 39% 69% 48%

R0=2.2 300 22% 35% 57% 28% 43% 69% 54%
Peak beds 1000 21% 35% 57% 34% 53% 69% 63%
3000 18% 35% 57% 47% 68% 69% 75%

100 2% 17% 31% 13% 20% 49% 29%

R0=2.4 300 2% 17% 31% 14% 23% 49% 29%
Total deaths 1000 2% 17% 31% 15% 26% 50% 30%
3000 2% 17% 31% 19% 30% 49% 32%

100 3% 21% 34% 9% 15% 49% 19%

R0=2.2 300 3% 21% 34% 9% 17% 49% 20%
Total deaths 1000 4% 21% 34% 11% 21% 49% 22%
3000 4% 21% 34% 15% 27% 49% 24%

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Given that mitigation is unlikely to be a viable option without overwhelming healthcare systems,
suppression is likely necessary in countries able to implement the intensive controls required. Our
projections show that to be able to reduce R to close to 1 or below, a combination of case isolation,
social distancing of the entire population and either household quarantine or school and university
closure are required (Figure 3, Table 4). Measures are assumed to be in place for a 5-month duration.
Not accounting for the potential adverse effect on ICU capacity due to absenteeism, school and
university closure is predicted to be more effective in achieving suppression than household
quarantine. All four interventions combined are predicted to have the largest effect on transmission
(Table 4). Such an intensive policy is predicted to result in a reduction in critical care requirements
from a peak approximately 3 weeks after the interventions are introduced and a decline thereafter
while the intervention policies remain in place. While there are many uncertainties in policy
effectiveness, such a combined strategy is the most likely one to ensure that critical care bed
requirements would remain within surge capacity.

(A) 350
Surge critical care bed capacity
300
Critical care beds occupied
per 100,000 of population

250 Do nothing

200 Case isolation, household quarantine and

general social distancing
150 School and university closure, case
isolation and general social distancing
100

50

(B) 20
18
16
Critical care beds occupied
per 100,000 of population

14
12
10
8
6
4
2
0

Figure 3: Suppression strategy scenarios for GB showing ICU bed requirements. The black line shows the
unmitigated epidemic. Green shows a suppression strategy incorporating closure of schools and universities,
case isolation and population-wide social distancing beginning in late March 2020. The orange line shows a
containment strategy incorporating case isolation, household quarantine and population-wide social
distancing. The red line is the estimated surge ICU bed capacity in GB. The blue shading shows the 5-month
period in which these interventions are assumed to remain in place. (B) shows the same data as in panel (A)
but zoomed in on the lower levels of the graph. An equivalent figure for the US is shown in the Appendix.

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16 March 2020 Imperial College COVID-19 Response Team

Adding household quarantine to case isolation and social distancing is the next best option, although
we predict that there is a risk that surge capacity may be exceeded under this policy option (Figure 3
and Table 4). Combining all four interventions (social distancing of the entire population, case
isolation, household quarantine and school and university closure) is predicted to have the largest
impact, short of a complete lockdown which additionally prevents people going to work.

Once interventions are relaxed (in the example in Figure 3, from September onwards), infections begin
to rise, resulting in a predicted peak epidemic later in the year. The more successful a strategy is at
temporary suppression, the larger the later epidemic is predicted to be in the absence of vaccination,
due to lesser build-up of herd immunity.

Given suppression policies may need to be maintained for many months, we examined the impact of
an adaptive policy in which social distancing (plus school and university closure, if used) is only
initiated after weekly confirmed case incidence in ICU patients (a group of patients highly likely to be
tested) exceeds a certain “on” threshold, and is relaxed when ICU case incidence falls below a certain
“off” threshold (Figure 4). Case-based policies of home isolation of symptomatic cases and household
quarantine (if adopted) are continued throughout.

Such policies are robust to uncertainty in both the reproduction number, R0 (Table 4) and in the
severity of the virus (i.e. the proportion of cases requiring ICU admission, not shown). Table 3
illustrates that suppression policies are best triggered early in the epidemic, with a cumulative total
of 200 ICU cases per week being the latest point at which policies can be triggered and still keep peak
ICU demand below GB surge limits in the case of a relatively high R0 value of 2.6. Expected total deaths
are also reduced for lower triggers, though deaths for all the policies considered are much lower than
for an uncontrolled epidemic. The right panel of Table 4 shows that social distancing (plus school and
university closure, if used) need to be in force for the majority of the 2 years of the simulation, but
that the proportion of time these measures are in force is reduced for more effective interventions
and for lower values of R0. Table 5 shows that total deaths are reduced with lower “off” triggers;
however, this also leads to longer periods during which social distancing is in place. Peak ICU demand
and the proportion of time social distancing is in place are not affected by the choice of “off” trigger.

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16 March 2020 Imperial College COVID-19 Response Team

1400
1200

Weekly ICU cases

1000
800
600
400
200
0

Figure 4: Illustration of adaptive triggering of suppression strategies in GB, for R0=2.2, a policy of all four
interventions considered, an “on” trigger of 100 ICU cases in a week and an “off” trigger of 50 ICU cases. The
policy is in force approximate 2/3 of the time. Only social distancing and school/university closure are
triggered; other policies remain in force throughout. Weekly ICU incidence is shown in orange, policy
triggering in blue.

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Table 4. Suppression strategies for GB. Impact of three different policy option (case isolation + home quarantine + social distancing, school/university closure + case
isolation + social distancing, and all four interventions) on the total number of deaths seen in a 2-year period (left panel) and peak demand for ICU beds (centre panel).
Social distancing and school/university closure are triggered at a national level when weekly numbers of new COVID-19 cases diagnosed in ICUs exceed the thresholds
listed under “On trigger” and are suspended when weekly ICU cases drop to 25% of that trigger value. Other policies are assumed to start in late March and remain in
place. The right panel shows the proportion of time after policy start that social distancing is in place. Peak GB ICU surge capacity is approximately 5000 beds. Results are
qualitatively similar for the US.

Total deaths Peak ICU beds Proportion of time with SD in place

On Do Do
R0 Trigger nothing CI_HQ_SD PC_CI_SD PC_CI_HQ_SD nothing CI_HQ_SD PC_CI_SD PC_CI_HQ_SD CI_HQ_SD PC_CI_SD PC_CI_HQ_SD
60 410,000 47,000 6,400 5,600 130,000 3,300 930 920 96% 69% 58%
100 410,000 47,000 9,900 8,300 130,000 3,500 1,300 1,300 96% 67% 61%
2 200 410,000 46,000 17,000 14,000 130,000 3,500 1,900 1,900 95% 66% 57%
300 410,000 45,000 24,000 21,000 130,000 3,500 2,200 2,200 95% 64% 55%
400 410,000 44,000 30,000 26,000 130,000 3,800 2,900 2,700 94% 63% 55%
60 460,000 62,000 9,700 6,900 160,000 7,600 1,200 1,100 96% 82% 70%
100 460,000 61,000 13,000 10,000 160,000 7,700 1,600 1,600 96% 80% 66%
2.2 200 460,000 64,000 23,000 17,000 160,000 7,700 2,600 2,300 89% 76% 64%
300 460,000 65,000 32,000 26,000 160,000 7,300 3,500 3,000 89% 74% 64%
400 460,000 68,000 39,000 31,000 160,000 7,300 3,700 3,400 82% 72% 62%
60 510,000 85,000 12,000 8,700 180,000 11,000 1,200 1,200 87% 89% 78%
100 510,000 87,000 19,000 13,000 180,000 11,000 2,000 1,800 83% 88% 77%
2.4 200 510,000 90,000 30,000 24,000 180,000 9,700 3,500 3,200 77% 82% 74%
300 510,000 94,000 43,000 34,000 180,000 9,900 4,400 4,000 72% 81% 74%
400 510,000 98,000 53,000 39,000 180,000 10,000 5,700 4,900 68% 81% 71%
60 550,000 110,000 20,000 12,000 230,000 15,000 1,500 1,400 68% 94% 85%
100 550,000 110,000 26,000 16,000 230,000 16,000 1,900 1,800 67% 93% 84%
2.6 200 550,000 120,000 39,000 30,000 230,000 16,000 3,600 3,400 62% 88% 83%
300 550,000 120,000 56,000 40,000 230,000 17,000 5,500 4,700 59% 87% 80%
400 550,000 120,000 71,000 48,000 230,000 17,000 7,100 5,600 56% 82% 76%

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16 March 2020 Imperial College COVID-19 Response Team

Table 5. As Table 4 but showing the effect of varying the ‘off’ trigger for social distancing and school/university
closure on total deaths over 2 years, for R0=2.4.

Total deaths
Off trigger as
On proportion of
trigger on trigger CI_HQ_SD PC_CI_SD PC_CI_HQ_SD
0.25 85,000 12,000 8,700
60 0.5 85,000 15,000 10,000
0.75 85,000 14,000 11,000
0.25 87,000 19,000 13,000
100 0.5 87,000 20,000 15,000
0.75 88,000 21,000 16,000
0.25 90,000 30,000 24,000
200 0.5 92,000 36,000 27,000
0.75 94,000 40,000 30,000
0.25 94,000 43,000 34,000
300 0.5 97,000 48,000 37,000
0.75 99,000 52,000 39,000
0.25 98,000 53,000 39,000
400 0.5 100,000 61,000 46,000
0.75 100,000 65,000 51,000

Discussion
As the COVID-19 pandemic progresses, countries are increasingly implementing a broad range of
responses. Our results demonstrate that it will be necessary to layer multiple interventions, regardless
of whether suppression or mitigation is the overarching policy goal. However, suppression will require
the layering of more intensive and socially disruptive measures than mitigation. The choice of
interventions ultimately depends on the relative feasibility of their implementation and their likely
effectiveness in different social contexts.

Disentangling the relative effectiveness of different interventions from the experience of countries to
date is challenging because many have implemented multiple (or all) of these measures with varying
degrees of success. Through the hospitalisation of all cases (not just those requiring hospital care),
China in effect initiated a form of case isolation, reducing onward transmission from cases in the
household and in other settings. At the same time, by implementing population-wide social distancing,
the opportunity for onward transmission in all locations was rapidly reduced. Several studies have
estimated that these interventions reduced R to below 115. In recent days, these measures have begun
to be relaxed. Close monitoring of the situation in China in the coming weeks will therefore help to
inform strategies in other countries.

Overall, our results suggest that population-wide social distancing applied to the population as a whole
would have the largest impact; and in combination with other interventions – notably home isolation
of cases and school and university closure – has the potential to suppress transmission below the
threshold of R=1 required to rapidly reduce case incidence. A minimum policy for effective suppression

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is therefore population-wide social distancing combined with home isolation of cases and school and
university closure.

To avoid a rebound in transmission, these policies will need to be maintained until large stocks of
vaccine are available to immunise the population – which could be 18 months or more. Adaptive
hospital surveillance-based triggers for switching on and off population-wide social distancing and
school closure offer greater robustness to uncertainty than fixed duration interventions and can be
adapted for regional use (e.g. at the state level in the US). Given local epidemics are not perfectly
synchronised, local policies are also more efficient and can achieve comparable levels of suppression
to national policies while being in force for a slightly smaller proportion of the time. However, we
estimate that for a national GB policy, social distancing would need to be in force for at least 2/3 of
the time (for R0=2.4, see Table 4) until a vaccine was available.

However, there are very large uncertainties around the transmission of this virus, the likely
effectiveness of different policies and the extent to which the population spontaneously adopts risk
reducing behaviours. This means it is difficult to be definitive about the likely initial duration of
measures which will be required, except that it will be several months. Future decisions on when and
for how long to relax policies will need to be informed by ongoing surveillance.

The measures used to achieve suppression might also evolve over time. As case numbers fall, it
becomes more feasible to adopt intensive testing, contact tracing and quarantine measures akin to
the strategies being employed in South Korea today. Technology – such as mobile phone apps that
track an individual’s interactions with other people in society – might allow such a policy to be more
effective and scalable if the associated privacy concerns can be overcome. However, if intensive NPI
packages aimed at suppression are not maintained, our analysis suggests that transmission will rapidly
rebound, potentially producing an epidemic comparable in scale to what would have been seen had
no interventions been adopted.

Long-term suppression may not be a feasible policy option in many countries. Our results show that
the alternative relatively short-term (3-month) mitigation policy option might reduce deaths seen in
the epidemic by up to half, and peak healthcare demand by two-thirds. The combination of case
isolation, household quarantine and social distancing of those at higher risk of severe outcomes (older
individuals and those with other underlying health conditions) are the most effective policy
combination for epidemic mitigation. Both case isolation and household quarantine are core
epidemiological interventions for infectious disease mitigation and act by reducing the potential for
onward transmission through reducing the contact rates of those that are known to be infectious
(cases) or may be harbouring infection (household contacts). The WHO China Joint Mission Report
suggested that 80% of transmission occurred in the household16, although this was in a context where
interpersonal contacts were drastically reduced by the interventions put in place. Social distancing of
high-risk groups is predicted to be particularly effective at reducing severe outcomes given the strong
evidence of an increased risk with age12,16 though we predict it would have less effect in reducing
population transmission.

We predict that school and university closure will have an impact on the epidemic, under the
assumption that children do transmit as much as adults, even if they rarely experience severe
disease12,16. We find that school and university closure is a more effective strategy to support epidemic
suppression than mitigation; when combined with population-wide social distancing, the effect of

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school closure is to further amplify the breaking of social contacts between households, and thus
supress transmission. However, school closure is predicted to be insufficient to mitigate (never mind
supress) an epidemic in isolation; this contrasts with the situation in seasonal influenza epidemics,
where children are the key drivers of transmission due to adults having higher immunity levels17,18.

The optimal timing of interventions differs between suppression and mitigation strategies, as well as
depending on the definition of optimal. However, for mitigation, the majority of the effect of such a
strategy can be achieved by targeting interventions in a three-month window around the peak of the
epidemic. For suppression, early action is important, and interventions need to be in place well before
healthcare capacity is overwhelmed. Given the most systematic surveillance occurs in the hospital
context, the typical delay from infection to hospitalisation means there is a 2- to 3-week lag between
interventions being introduced and the impact being seen in hospitalised case numbers, depending
on whether all hospital admissions are tested or only those entering critical care units. In the GB
context, this means acting before COVID-19 admissions to ICUs exceed 200 per week.

Perhaps our most significant conclusion is that mitigation is unlikely to be feasible without emergency
surge capacity limits of the UK and US healthcare systems being exceeded many times over. In the
most effective mitigation strategy examined, which leads to a single, relatively short epidemic (case
isolation, household quarantine and social distancing of the elderly), the surge limits for both general
ward and ICU beds would be exceeded by at least 8-fold under the more optimistic scenario for critical
care requirements that we examined. In addition, even if all patients were able to be treated, we
predict there would still be in the order of 250,000 deaths in GB, and 1.1-1.2 million in the US.

In the UK, this conclusion has only been reached in the last few days, with the refinement of estimates
of likely ICU demand due to COVID-19 based on experience in Italy and the UK (previous planning
estimates assumed half the demand now estimated) and with the NHS providing increasing certainty
around the limits of hospital surge capacity.

We therefore conclude that epidemic suppression is the only viable strategy at the current time. The
social and economic effects of the measures which are needed to achieve this policy goal will be
profound. Many countries have adopted such measures already, but even those countries at an earlier
stage of their epidemic (such as the UK) will need to do so imminently.

Our analysis informs the evaluation of both the nature of the measures required to suppress COVID-
19 and the likely duration that these measures will need to be in place. Results in this paper have
informed policymaking in the UK and other countries in the last weeks. However, we emphasise that
is not at all certain that suppression will succeed long term; no public health intervention with such
disruptive effects on society has been previously attempted for such a long duration of time. How
populations and societies will respond remains unclear.

Funding
This work was supported by Centre funding from the UK Medical Research Council under a concordat
with the UK Department for International Development, the NIHR Health Protection Research Unit in
Modelling Methodology and Community Jameel.

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16 March 2020 Imperial College COVID-19 Response Team

References
1. Bootsma MCJ, Ferguson NM. The effect of public health measures on the 1918 influenza
pandemic in U.S. cities. Proc Natl Acad Sci U S A 2007;104(18):7588–93.
2. Anderson RM, Heesterbeek H, Klinkenberg D, Hollingsworth TD. Comment How will country-
based mitigation measures influence the course of the COVID-19 epidemic ? 2020;2019(20):1–
4.
3. The Coalition for Epidemic Preparedness Innovations. CEPI welcomes UK Government’s
funding and highlights need for $2 billion to develop a vaccine against COVID-19 [Internet].
2020;Available from: https://cepi.net/news_cepi/2-billion-required-to-develop-a-vaccine-
against-the-covid-19-virus/
4. World Health Organisation. Pandemic influenza A (H1N1) 2009 virus vaccine – conclusions and
recommendations from the october 2009 meeting of the immunization Strategic Advisory
Group of experts. Wkly Epidemiol Rec 2009;84(49):509–16.
5. Ferguson NM, Cummings DAT, Fraser C, Cajka JC, Cooley PC, Burke DS. Strategies for mitigating
an influenza pandemic. Nature 2006;442(7101):448–52.
6. Halloran ME, Ferguson NM, Eubank S, et al. Modeling targeted layered containment of an
influenza pandemic in the United States. Proc Natl Acad Sci U S A 2008;105(12):4639–44.
7. Ferguson NM, Cummings DAT, Cauchemez S, et al. Strategies for containing an emerging
influenza pandemic in Southeast Asia. Nature 2005;437(7056):209–14.
8. Mossong J, Hens N, Jit M, et al. Social contacts and mixing patterns relevant to the spread of
infectious diseases. PLoS Med 2008;5(3):0381–91.
9. Linton NM, Kobayashi T, Yang Y, et al. Epidemiological characteristics of novel coronavirus
infection: A statistical analysis of publicly available case data. medRxiv [Internet] 2020 [cited
2020 Feb 18];2020.01.26.20018754. Available from:
https://www.medrxiv.org/content/medrxiv/early/2020/01/28/2020.01.26.20018754.full.pdf
10. Li Q, Guan X, Wu P, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–
Infected Pneumonia. N Engl J Med 2020;
11. Riou J, Althaus CL. Pattern of early human-to-human transmission of Wuhan 2019 novel
coronavirus (2019-nCoV), December 2019 to January 2020. Euro Surveill 2020;25(4):1–5.
12. Verity R, Okell LC, Dorigatti I, et al. Estimates of the severity of COVID-19 disease. medRxiv
2020; Available from https://www.medrxiv.org/content/10.1101/2020.03.09.20033357v1.
13. Gaythorpe K, Imai N, Cuomo-Dannenburg G, et al. Report 8: Symptom progression of 2019
novel coronavirus [Internet]. 2020. Available from:
https://www.imperial.ac.uk/media/imperial-college/medicine/sph/ide/gida-
fellowships/Imperial-College-COVID19-symptom-progression-11-03-2020.pdf
14. Ostermann H, Blasi F, Medina J, Pascual E, McBride K, Garau J. Resource use in patients
hospitalized with complicated skin and soft tissue infections in Europe and analysis of
vulnerable groups: The REACH study. J Med Econ 2014;17(10):719–29.
15. Kucharski AJ, Russell TW, Diamond C, et al. Early dynamics of transmission and control of
COVID-19: a mathematical modelling study. Lancet Infect Dis [Internet]
2020;3099(20):2020.01.31.20019901. Available from:
http://medrxiv.org/content/early/2020/02/18/2020.01.31.20019901.abstract
16. World Health Organization. Report of the WHO-China Joint Mission on Coronavirus Disease
2019 (COVID-19). 2020.

DOI: https://doi.org/10.25561/77482 Page 17 of 20

16 March 2020 Imperial College COVID-19 Response Team

17. Cauchemez S, Valleron AJ, Boëlle PY, Flahault A, Ferguson NM. Estimating the impact of school
closure on influenza transmission from Sentinel data. Nature 2008;452(7188):750–4.
18. Fumanelli L, Ajelli M, Merler S, Ferguson NM, Cauchemez S. Model-Based Comprehensive
Analysis of School Closure Policies for Mitigating Influenza Epidemics and Pandemics. PLoS
Comput Biol 2016;12(1):1–15.

DOI: https://doi.org/10.25561/77482 Page 18 of 20

16 March 2020 Imperial College COVID-19 Response Team

Appendix
Figure A1: Suppression strategy scenarios for US showing ICU bed requirements. The black line shows the
unmitigated epidemic. Green shows a suppression strategy incorporating closure of schools and universities,
case isolation and population-wide social distancing beginning in late March 2020. The orange line shows a
containment strategy incorporating case isolation, household quarantine and population-wide social
distancing. The red line is the estimated surge ICU bed capacity in US. The blue shading shows the 5-month
period in which these interventions are assumed to remain in place. (B) shows the same data as in panel (A)
but zoomed in on the lower levels of the graph.

250
(A)
Surge critical care bed capacity
200
Critical care beds occupied
per 100,000 of population

Do nothing

150 Case isolation, household quarantine and

general social distancing

100 School and university closure, case

isolation and general social distancing

50

(B) 20
18
16
Critical care beds occupied
per 100,000 of population

14
12
10
8
6
4
2
0

DOI: https://doi.org/10.25561/77482 Page 19 of 20

16 March 2020 Imperial College COVID-19 Response Team

Table A1. Mitigation options for GB. Absolute impact of NPI combinations applied nationally for 3 months in the UK on total deaths and peak hospital ICU bed demand
for different choices of cumulative ICU case count triggers. The cells show peak bed demand and total deaths for a variety of NPI combinations and for triggers based on
the absolute number of ICU cases diagnosed in a county per week. PC=school and university closure, CI=home isolation of cases, HQ=household quarantine, SD=large-
scale general population social distancing, SDOL70=social distancing of those over 70 years for 4 months (a month more than other interventions). Tables are colour-
coded (green= higher effectiveness, red=lower).

Trigger (cumulative ICU

cases) PC CI CI_HQ CI_HQ_SD CI_SD CI_HQ_SDOL70 PC_CI_HQ_SDOL70
100 156 122 85 123 85 61 57
R0=2.4 300 157 122 85 121 78 60 53
Peak beds 1000 158 122 85 111 65 60 42
3000 161 122 85 89 45 60 35

100 125 105 70 120 98 50 83

R0=2.2 300 125 105 70 115 92 50 75
Peak beds 1000 126 105 70 106 76 49 59
3000 132 105 70 86 51 49 40

100 501 421 349 443 406 258 363

R0=2.4 300 499 421 349 440 393 259 360
Total deaths 1000 498 421 349 432 375 257 356
3000 498 421 349 415 354 258 347

100 451 367 308 423 395 238 373

R0=2.2 300 448 367 308 419 384 236 369
Total deaths 1000 445 367 308 412 366 234 360
3000 445 367 308 396 340 234 351

DOI: https://doi.org/10.25561/77482 Page 20 of 20

 4

Development of novel,
genome subtraction-
derived, SARS-CoV-2-
Specific COVID-19-
nsp2 real-time RT-PCR
Assay and its
evaluation using
clinical specimens
 International Journal of
Molecular Sciences

Article
Development of a Novel, Genome
Subtraction-Derived, SARS-CoV-2-Specific
COVID-19-nsp2 Real-Time RT-PCR Assay and Its
Evaluation Using Clinical Specimens
Cyril Chik-Yan Yip 1,† , Chi-Chun Ho 2,† , Jasper Fuk-Woo Chan 3,4,5,6 , Kelvin Kai-Wang To 3,4,5,6 ,
Helen Shuk-Ying Chan 7 , Sally Cheuk-Ying Wong 8 , Kit-Hang Leung 4 , Agnes Yim-Fong Fung 4 ,
Anthony Chin-Ki Ng 4 , Zijiao Zou 4 , Anthony Raymond Tam 9 , Tom Wai-Hin Chung 1 ,
Kwok-Hung Chan 3,4,6 , Ivan Fan-Ngai Hung 10 , Vincent Chi-Chung Cheng 1 ,
Owen Tak-Yin Tsang 11 , Stephen Kwok Wing Tsui 12 and Kwok-Yung Yuen 3,4,5,6, *
1 Department of Microbiology, Queen Mary Hospital, HKSAR, Hong Kong, China;
yipcyril@hku.hk (C.C.-Y.Y.); cwh366@ha.org.hk (T.W.-H.C.); vcccheng@hku.hk (V.C.-C.C.)
2 Genomics and Bioinformatics Programme, The Chinese University of Hong Kong, HKSAR, Hong Kong,
China; hkhcc@link.cuhk.edu.hk
3 State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, HKSAR, Hong Kong,
China; jfwchan@hku.hk (J.F.-W.C.); kelvinto@hku.hk (K.K.-W.T.); chankh2@hku.hk (K.-H.C.)
4 Department of Microbiology, The University of Hong Kong, HKSAR, Hong Kong, China;
khl17@hku.hk (K.-H.L.); agnes_fung@hku.hk (A.Y.-F.F.); anthonyng912@gmail.com (A.C.-K.N.);
jozou0929@gmail.com (Z.Z.)
5 Department of Clinical Microbiology and Infection, The University of Hong Kong-Shenzhen Hospital,
Shenzhen 518053, China
6 Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong,
HKSAR, Hong Kong, China
7 Department of Medicine, Queen Elizabeth Hospital, HKSAR, Hong Kong, China; csy249a@ha.org.hk
8 Department of Pathology, Queen Elizabeth Hospital, HKSAR, Hong Kong, China; wcy288@ha.org.hk
9 Department of Medicine, Queen Mary Hospital, HKSAR, Hong Kong, China; antamwf@connect.hku.hk
10 Department of Medicine, The University of Hong Kong, HKSAR, Hong Kong, China; ivanhung@hku.hk
11 Department of Medicine and Geriatrics, Princess Margaret Hospital, HKSAR, Hong Kong, China;
tsangty@ha.org.hk
12 School of Biomedical Sciences, The Chinese University of Hong Kong, HKSAR, Hong Kong, China;
kwtsui@cuhk.edu.hk
* Correspondence: kyyuen@hku.hk; Tel.: +852-2255-2584; Fax.: +852-2855-1241
† These authors contributed equally to this work.




Received: 27 March 2020; Accepted: 6 April 2020; Published: 8 April 2020


Abstract: The pandemic novel coronavirus infection, Coronavirus Disease 2019 (COVID-19),
has affected at least 190 countries or territories, with 465,915 confirmed cases and 21,031 deaths. In a
containment-based strategy, rapid, sensitive and specific testing is important in epidemiological control
and clinical management. Using 96 SARS-CoV-2 and 104 non-SARS-CoV-2 coronavirus genomes
and our in-house program, GolayMetaMiner, four specific regions longer than 50 nucleotides in the
SARS-CoV-2 genome were identified. Primers were designed to target the longest and previously
untargeted nsp2 region and optimized as a probe-free real-time reverse transcription-polymerase
chain reaction (RT-PCR) assay. The new COVID-19-nsp2 assay had a limit of detection (LOD)
of 1.8 TCID50 /mL and did not amplify other human-pathogenic coronaviruses and respiratory
viruses. Assay reproducibility in terms of cycle threshold (Cp) values was satisfactory, with the
total imprecision (% CV) values well below 5%. Evaluation of the new assay using 59 clinical
specimens from 14 confirmed cases showed 100% concordance with our previously developed

Int. J. Mol. Sci. 2020, 21, 2574; doi:10.3390/ijms21072574 www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2020, 21, 2574 2 of 11

COVID-19-RdRp/Hel reference assay. A rapid, sensitive, SARS-CoV-2-specific real-time RT-PCR

assay, COVID-19-nsp2, was developed.

Keywords: SARS-CoV-2; COVID-19; nsp2; real-time RT-PCR; genome subtraction; GolayMetaMiner;

sensitivity; specificity; clinical evaluation; COVID-19-nsp2 assay

1. Introduction
Coronaviruses are positive sense, single-stranded RNA viruses that cause important diseases in
human and animals [1]. In the past two decades, at least three novel human-pathogenic coronaviruses
have crossed species barriers to cause major epidemics. These included severe acute respiratory
syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV),
and the most recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [2–4].
Emerging in late 2019, the novel Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2 has
disseminated rapidly around the globe and has been declared a pandemic [5,6]. By 27 March 2020,
465,915 confirmed cases have been reported to the World Health Organization (WHO) from 200 countries
or territories, with 21,031 deaths (https://www.who.int/emergencies/diseases/novel-coronavirus-2019).
The case fatality rate estimate ranged from about 1% in resource-rich settings, to up to 12% in
epicentres [6]. Multiple clinical trials evaluating known and novel pharmacological agents have been
in progress [7–10], and innovative epidemiological modelling and mechanistic exploratory studies
have also been made available [11–14]; at the time of writing, there is no effective antiviral therapy of
proven clinical benefit.
While widespread global transmission seemed inevitable, most countries continued to implement
a containment strategy as advised by the WHO [15,16]; to this end, early testing and diagnosing
symptomatic and asymptomatic infectious individuals [4,17], as well as testing of apparently
recovered patients who may continue to shed the virus via various routes [18–20] remains essential
to outbreak control. Various groups have made publicly available broadly-specific assays that target
pan-coronaviruses, various members of the Sarbecovirus subgenus, or modified assays with specific
oligonucleotide probes to achieve SARS-CoV-2 discrimination (https://www.who.int/emergencies/
diseases/novel-coronavirus-2019/technical-guidance/laboratory-guidance). With the identification of
SARS-CoV-2 as the culprit viral species, a highly-specific assay, without cross-reactivity to closely-related
viruses infecting humans such as the severe acute respiratory syndrome coronavirus (SARS-CoV) [21]
and Middle East respiratory syndrome coronavirus (MERS-CoV) [22], is needed.
In this study, using the in-house developed program GolayMetaMiner (https://github.com/hkhcc/
GolayMetaMiner) and our previously obtained SARS-CoV-2 genome data [23], we attempted to deduce
species-specific targets that are conserved among globally detected SARS-CoV-2 isolates. With the
identified targets, primers were designed and optimized for a highly sensitive real-time reverse
transcription-polymerase chain reaction (RT-PCR) assay, eventually without the additional use of
fluorescent reporter probes. The optimized assay was then evaluated on a variety of patient specimens.
Finally, the potential application and significance of the newly-developed assay, as well as the known
limitations, were discussed.

2. Results

2.1. Species-Specific SARS-CoV-2 Genomic Regions Identified by GolayMetaMiner

With default settings on an Intel® Core™ i7-2600 desktop computer equipped with a solid-state
hard disk drive (k-mer size = 12, number of threads = 8), the genome subtraction run completes in about
25 s, after initial genome download from NCBI. As default parameters for bacterial target identification
(uniqueness percentile cutoff = 99.99th centile) failed to report any targets with length > 50 nt,
Int. J. Mol. Sci. 2020, 21, 2574 3 of 11

the uniqueness percentile score cutoff was progressively relaxed to the 98th centile considering
the genome length of HKU-SZ-005b (29,891 bp).
The genome uniqueness/conservedness plot is shown in Figure 1. A total of four SARS-CoV-2
unique targets >50 nt in length (Table 1) were reported while other potential targets were too short and
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 of 11
excluded by the program. The minimum, median and maximum uniqueness scores (U-scores) were
0.106, 0.566 and 0.810 with a 98th percentile cutoff at 0.730. The minimum, median and maximum
maximum conservedness scores (C-scores) were 0.782, 0.999 and 1.031 (> 1 due to overshoot of the
conservedness scores (C-scores) were 0.782, 0.999 and 1.031 (> 1 due to overshoot of the 3rd order
3rd order polynomial in the smoothing function).
polynomial in the smoothing function).

Figure 1. Genome uniqueness/conservedness plot generated by GolayMetaMiner. The orange curve

denotes theGenome
Figure 1. Savitzky–Golay smoothed conservedness
uniqueness/conservedness score (C-score),
plot generated and the blue curve
by GolayMetaMiner. and redcurve
The orange line
denote
denotesthe
thesimilarly smoothed
Savitzky–Golay uniqueness
smoothed score (U-score)
conservedness scorewith the corresponding
(C-score), cutoff and
and the blue curve in the
red98th
line
percentile
denote thecutoff score.smoothed
similarly Areas of the blue curve
uniqueness above
score the cutoff
(U-score) represent
with the severe acute
the corresponding cutoffrespiratory
in the 98th
syndrome
percentile coronavirus 2 (SARS-CoV-2)
cutoff score. Areas of the blue unique targets,
curve above the potentially. Thethe
cutoff represent genomic
severe targets (> 50 nt)
acute respiratory
identified were marked by the numbers 1, 2, 3 and 4 in the figure as part of the program
syndrome coronavirus 2 (SARS-CoV-2) unique targets, potentially. The genomic targets (> 50 nt) output.
identified were marked by the numbers 1, 2, 3 and 4 in the figure as part of the program output.
Table 1. SARS-CoV-2 specific targets (>50 nt) reported by GolayMetaMiner.

Table 1. SARS-CoV-2
Target Nucleotide specific 1
Positiontargets (> 50 nt)
Target reported
Length (nt) by GolayMetaMiner.
Genomic Region

Target 1 1865–2018
Nucleotide Position 1 154 Length (nt)
Target nsp2
Genomic Region
2 21,731–21,788 58 Spike
1 1865–2018 154 nsp2
3 23,536–23,598 63 Spike
2 4 21,731–21,788
27,997–28,909 93 58 ORF8 Spike
3 23,536–23,598
1 With reference to 63
SARS-CoV-2 isolate HKU-SZ-005b_2020, accession MN975262.1.
Spike
4 27,997–28,909 93 ORF8
2.2. Primer Selection for the SARS-CoV-2-Specific Real-Time RT-PCR Assay
1 With reference to SARS-CoV-2 isolate HKU-SZ-005b_2020, accession MN975262.1.
The four reported targets (Table 1) were subjected to analysis using the GenScript real-time PCR
(TaqMan)
2.2. PrimerPrimer and
Selection forProbes Design Tool (https://www.genscript.com/tools/real-time-pcr-taqman-
the SARS-CoV-2-Specific Real-Time RT-PCR Assay
primer-design-tool) with default settings. Only one of the targets fulfilled the primer and probe
design The four (Target
criteria reported1, targets
Table 1).(Table
After1)initially
were subjected to the
optimizing analysis using probe-based
hydrolysis the GenScript real-time
version of
PCR (TaqMan) Primer and Probes
the assay to show that it reached the sensitivity of our previously published COVID-19-RdRp/HelDesign Tool
(https://www.genscript.com/tools/real-time-pcr-taqman-primer-design-tool)
assay (data not shown), we used only the primers (nsp2f: 50 -ATGCATTTGCATCAGAGGCT-3 with default 0settings.
, nsp2r:
Only
0 one of the targets fulfilled 0 the primer and probe design criteria (Target
5 -TTGTTATAGCGGCCTTCTGT-3 ), to develop the subsequent probe-free, COVID-19-nsp2 real-time 1, Table 1). After
initially optimizing
RT-PCR assay. the hydrolysis probe-based version of the assay to show that it reached the
sensitivity of our previously published COVID-19-RdRp/Hel assay (data not shown), we used only
the primers (nsp2f: 5′-ATGCATTTGCATCAGAGGCT-3′, nsp2r:
5′-TTGTTATAGCGGCCTTCTGT-3′), to develop the subsequent probe-free, COVID-19-nsp2
real-time RT-PCR assay.
Int. J. Mol. Sci. 2020, 21, 2574 4 of 11

2.3. Analytical Sensitivity of the Novel COVID-19-nsp2 Real-Time RT-PCR Assay

To determine the analytical sensitivity of the COVID-19-nsp2 assay, the limit of detection (LOD)
was evaluated by using viral genomic RNA extracted from a culture isolate of SARS-CoV-2. Serial
10-fold dilutions of SARS-CoV-2 RNA extracted from the viral isolate were prepared and tested in
triplicate in two independent runs. The LOD of the COVID-19-nsp2 assay was 1.8 TCID50 /mL (Table 2).

Table 2. Evaluation of the limit of detection (LOD) of the COVID-19-nsp2 real-time reverse
transcription-polymerase chain reaction (RT-PCR) assay using SARS-CoV-2 genomic RNA from
cell culture lysate.

Virus Quantity
Cp (Intra-Run) Cp (Inter-Run)
(TCID50 /mL)
Test 1 Test 2 Test 3 Test 1 Test 2 Test 3
1.8 × 102 29.91 30.12 29.90 29.23 29.54 29.28
1.8 × 101 33.55 33.49 33.78 32.41 32.95 32.69
1.8 × 100 37.39 37.31 37.20 36.72 36.25 37.20
1.8 × 10−1 - - - - 38.96 -
Cp: crossing point at which the fluorescence of a sample rises above the background fluorescence.

2.4. Analytical Specificity of the COVID-19-nsp2 Assay

To investigate whether the novel COVID-19-nsp2 assay would non-specifically amplify other
human-pathogenic coronaviruses and respiratory viruses, we tested total nucleic acid (TNA) extracted
from a clinical respiratory specimen with HCoV-HKU1, and TNAs extracted from 17 culture isolates of
SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-229E, HCoV-NL63, respiratory syncytial virus, human
metapneumovirus, influenza A ((H1N1)pdm09 and H3N2) viruses, influenza B virus, influenza C
virus, parainfluenza viruses types 1 to 4, rhinovirus and human adenovirus. This assay did not show
cross reactivity with these viruses.

2.5. Imprecision of the COVID-19-nsp2 Assay

Using TNA extracted from SARS-CoV-2 isolate at different concentrations, the new COVID-19-nsp2
assay was performed in triplicate for each concentration to evaluate the intra- and inter-assay variations.
The total imprecision (% CV) was 1.19% at the lowest concentration tested (Table 3).

Table 3. Imprecision testing of the COVID-19-nsp2 assay using SARS-CoV-2 isolate extracts.

Intra-Assay Inter-Assay
Virus Quantity
Mean Cp ± SD Mean Cp ± SD
(TCID50 /mL) No. of Positive
(% Coefficient of (% Coefficient of
Replicates
Variation) Variation)
1.8 × 102 3 29.98 ± 0.12 (0.41) 29.66 ± 0.37 (1.24)
1.8 × 101 3 33.61 ± 0.15 (0.46) 33.15 ± 0.54 (1.64)
1.8 × 100 3 37.30 ± 0.10 (0.26) 37.01 ± 0.44 (1.19)

2.6. Diagnostic Performance Evaluation of the COVID-19-nsp2 Assay for the Detection of SARS-CoV-2 RNA
in Clinical Specimens
To evaluate the diagnostic performance of the assay, 59 clinical specimens (23 positive and
36 negative) from 14 confirmed cases (defined as at least one respiratory specimen positive for
SARS-CoV-2 by our previously established COVID-19-RdRp/Hel assay) [24] were used. The negative
specimens included extrapulmonary (e.g., urine, rectal swab) and respiratory tract specimens that were
collected during the later phase of illness when the viral load gradually decreased/became negative.
Twenty-three were positive (including 22 respiratory specimens and 1 stool specimen, with Cp values
Int. J. Mol. Sci. 2020, 21, 2574 5 of 11

ranged from 18.69 to 36.21) and 36 were negative (including four respiratory and 32 non-respiratory
specimens) by the COVID-19-nsp2 assay. The melting curve from COVID-19-nsp2-positive specimens
showed a unique peak with the melting temperature of around 80 ◦ C. The results from the two assays
were 100% concordant, and no additional positive result was detected from the specimens previously
tested negative by the COVID-19-RdRp/Hel assay.

3. Discussion
Early in the COVID-19 outbreak, when the virus was reported to be related to the SARS-CoV
and the exact genomic variation of the virus was not adequately known [25], multiple groups
developed and published assays based on conserved regions that could potentially detect additional
coronaviruses [26,27] (see also https://www.who.int/emergencies/diseases/novel-coronavirus-2019/
technical-guidance/laboratory-guidance). The advantage of the traditional approach was two-fold:
first, it was a more certain method to detect a novel member of the clade and avoided missing
cases clinically; second, as SARS-CoV-2 positive control specimens were not globally available at the
beginning of the pandemic, laboratories that did not have a species-specific positive control could use
other existing positive controls such as SARS-CoV to ensure the performance of their assays.
In the present study, we demonstrated that the diagnostic performance of the hydrolysis probe-free
COVID-19-nsp2 assay was comparable to that of our previously developed COVID-19-RdRp/Hel
assay [24]. A major novelty of the current approach was the application of genome subtraction to
deduce a previously untargeted region of the viral genome encoding nsp2 and subsequent adoption
in a diagnostic assay. To our knowledge, no SARS-CoV-2 assay targeting the nsp2 coding region
has been published previously. The current nsp2 assay was highly specific (without cross-reaction
with other common respiratory viruses) and comparable to the COVID-19-RdRp/Hel assay in terms
of analytical sensitivity. The diagnostic sensitivity and specificity of the nsp2 assay was 100% in
comparison with the COVID-19-RdRp/Hel assay in this study. The reproducibility, in terms of Cp
values, was satisfactory with both intra- and inter-assay coefficient of variation values well below the
5% cutoff specified in literature [28,29]. Furthermore, the PCR reaction time of the nsp2 assay was
within an hour, which is shorter than that of the previously developed COVID-19-RdRp/Hel assay [24];
this is a distinct advantage in clinical laboratories, as rapid results can facilitate the timely triage of
suspected COVID-19 cases and guide infection control and patient management. In terms of functional
significance, the nsp2 region highlighted by genome subtraction corroborated with a recent modeling
study which suggested that positively selected regions within the nsp2 protein could contribute to the
pathogenicity of the virus [30].
As COVID-19 unfolded into a pandemic, rapid, robust and sensitive diagnostic testing became a
priority in containment-based control strategies. While antibody-based testing has been developed [31]
and even made commercially available as point-of-care testing kits [32], they lack sensitivity in detecting
early infection before the host has successfully mounted a humoral response [33], cannot be applied
to certain specimen types (such as urine [19], as antibodies cannot be secreted into the glomerular
filtrate unless the patient develops severe renal damage) and cannot be used to determine when the
host ceases to become infectious [34]. As nucleic acid amplification-based testing allows exquisite
sensitivity (1.8 TCID50 /mL in our case) and can be readily adopted in laboratories with basic molecular
facilities, it is an essential tool in the clinical management and triage of patients. The robust design of
the optimized assay, requiring only one pair of SARS-CoV-2-specific primers to diagnose COVID-19
infection in humans, avoids the potential logistics, reagent and manpower constraints in performing
multiple or cascade testing or the use of relatively costly reporter probes. In developed countries
where medical resources have become critically limited [35,36], it is believed that this new assay may
be adopted to allow for the testing of more patients in a shorter time.
While we have validated the primer set against all publicly available SARS-CoV-2 genomes
(Supplementary Materials) and found the proposed nsp2 target to be 100% conserved, it is possible
that with random genetic drift, certain sub-clones of the virus may eventually develop mutations and
Int. J. Mol. Sci. 2020, 21, 2574 6 of 11

escape detection. As SARS-CoV-2 is an RNA virus, which typically has a relatively high mutation
rate (10−4 nucleotide substitutions per site per year for coronaviruses [37]), this is a distinct possibility
that must be considered. However, with the use of less-specific assays, such as pan-coronavirus
primers [38], the diagnostic laboratory can adopt a two-tier approach by first attempting to confirm
infection using the new nsp2 assay, and subsequently use the broadly-specific assays on clinically
suspicious cases to rule out SARS-CoV-2 infection. Finally, GolayMetaMiner is available as a free
and open-source software that can be applied efficiently to newly deduced mutant sequences. Using
the software tool, degenerate bases may be strategically incorporated into the COVID-19-nsp2 assay
primers to broaden the specificity, or additional targets may be iteratively identified from further
coronavirus pan-genome analyses.

4. Materials and Methods

4.1. SARS-CoV-2 Genome Subtraction Using GolayMetaMiner

The GolayMetaMiner software was initially developed with the School of Biomedical Sciences,
The Chinese University of Hong Kong as an in-house software for the design of species- and species-group
specific molecular assays for Mycobacterium species for the Department of Microbiology, Queen
Mary Hospital, and was improved upon the a previously published software, ssGeneFinder [39–41].
The GolayMetaMiner software first downloads the genomes of the target and non-target species
from the NCBI nucleotide database and generates a pool of nucleotide k-mers (k = 12 by default) for
both forward and reverse directions of the non-target genomes. Next, the program steps through
the forward strand of the target genome (–primary_target) and assign a binary uniqueness value of
either 1 (k-mer is unique to the target genome) or 0 (k-mer is found in the non-target pool). As a
pathogen detection assay needs to account for potential genomic variability of the target pathogen,
the GolayMetaMiner software then steps through the target genome to determine if the k-mer is
also present in other intended targets (–secondary_targets or –secondary_target_list), adding a value
of 1 (k-mer is present in a secondary target genome) or 0 (k-mer is absent in a secondary genome).
The conservedness value is normalized to a maximum value of 1 by dividing this absent/present count
by the total number of secondary target genomes. Before plotting the scores, the arrays of uniqueness
and conservedness values are smoothed using an empirically optimized Savitzky–Golay filter (window
size = 501, polynomial order = 3) and transformed to continuous scores (U-score, C-score), and a
U-score cutoff is calculated according to a specified percentile cutoff (defaults to 99.99th).
In this study, GolayMetaMiner was executed under an Anaconda Python 3.7
environment (freely available from https://www.anaconda.com/distribution/) with the command
line as follows: python gmm.py –primary_target MN975262.1 –secondary_target_list
SARS-CoV-2_genomes.txt–non_target_ncbi_table coronaviridae_complete.csv –exclusion_string
“Severe acute respiratory syndrome coronavirus 2” –reporting_centile 98. The longer of the two
SARS-CoV-2 genomes sequenced by our group [23], HKU-SZ-005b, was used as the reference genome
(–primary_target MN975262), and a list of accession numbers of publicly available SARS-CoV-2 genomes
were used as secondary targets (–secondary_target_list SARS-CoV-2_genomes.txt); the accession
number of the reference genome was manually commented out with a “#” to avoid double-counting
the reference genome in estimating conservedness. Non-targets were specified by downloading a
table of complete Coronaviridae genomes from the NCBI genome browser (https://www.ncbi.nlm.nih.
gov/genome/browse#!/viruses/) and passed to the program as a CSV file (–non_target_ncbi_table
coronaviridae_complete.csv). An exclusion string was added to exclude entries marked as SARS-CoV-2
from the genome table (–exclusion_string “Severe acute respiratory syndrome coronavirus 2”). The
genome U-score cutoff was empirically determined: if the default setting of 99.99th percentile could
not yield any potential target, it would be progressively relaxed to 99.9th, 99th, 98th etc. As genome
data could be automatically downloaded when the GolayMetaMiner was executed, no genome data
was included with the software distribution to respect the rights of certain sequence owners. The
Int. J. Mol. Sci. 2020, 21, 2574 7 of 11

lists of accession numbers of the 96 SARS-CoV-2 and 104 non-SARS-CoV-2 coronavirus genomes are
available in Supplementary Materials. The complete Python 3 source code of the GolayMetaMiner
software is freely available from the GitHub repository https://github.com/hkhcc/GolayMetaMiner.

4.2. Viruses and Clinical Specimens

SARS-CoV-2 was isolated from the nasopharyngeal aspirate specimen of a laboratory-confirmed
COVID-19 patient in Hong Kong as previously described [42]. The viral isolate stock (1.8 × 107
50% tissue culture infective doses [TCID50 ]/mL) was prepared using VeroE6 cells as previously
described [20,24,43]. For analytical sensitivity evaluation, TNA extracted from SARS-CoV-2 isolate
was used. For analytical specificity evaluation, a clinical respiratory specimen of HCoV-HKU1
and 17 culture isolates of other human-pathogenic coronaviruses and respiratory viruses were
used [24]. For assay performance evaluation, 59 archived clinical specimens (26 respiratory specimens
including nasopharyngeal aspirate/swab, throat swab, endotracheal aspirate, sputum and saliva,
and 33 non-respiratory specimens including plasma, urine, rectal swab/stool) from 14 patients with
laboratory-confirmed COVID-19 were used [24]. These specimens were evaluated previously using
the established COVID-19-RdRp/Hel assay [24]. The study was approved by Institutional Review
Board of The University of Hong Kong/Hospital Authority (UW 13-372).

4.3. Nucleic Acid Extraction and RT-PCR for SARS-CoV-2

TNA extraction from clinical specimens and viral culture isolates was performed using NucliSENS
easyMAG extraction system (BioMerieux, Marcy-l’Étoile, France) [24,44]. The volume of the specimens
used for extraction and the elution volume depended on the specimen type and the amount of the
specimen available as previously described [28,45,46].
Real-time RT-PCR assay for SARS-CoV-2 RNA detection was performed using QuantiNova SYBR
Green RT-PCR Kit (QIAGEN, Hilden, Germany) and a LightCycler 480 II real-time PCR System (Roche,
Basel, Switzerland) [4,20]. Each 20 µL reaction mixture contained 10 µL of 2× QuantiNova SYBR Green
RT-PCR Master Mix, 0.2 µL of QN SYBR Green RT-Mix, 1 µL of each 10 µM forward and reverse
primer, 2.8 µL of RNase-free water and 5 µL of TNA as the template. The thermal cycling condition
was 10 min at 50 ◦ C and 2 min at 95 ◦ C, followed by 45 cycles of 5 s at 95 ◦ C and 10 s at 60 ◦ C, and then
subjected to melting curve analysis (95 ◦ C for 5 s, 65 ◦ C for 1 min, followed by a gradual increase in
temperature to 97 ◦ C with continuous recording of fluorescence).

5. Conclusions
Using GolayMetaMiner genome subtraction, SARS-CoV-2-specific regions were successfully
identified using 96 SARS-CoV-2 and 104 non-SARS-CoV-2 coronavirus genomes. Identified regions
included a 154-nt conserved sequence in the nsp2 gene, which was absent in other human-pathogenic
coronaviruses and has not previously been targeted in real-time RT-PCR assays of COVID-19. The highly
specific and sensitive nsp2-based assay was validated using multiple viral culture isolates and clinical
specimens. The newly developed assay, COVID-19-nsp2, and the associated genomic findings in this
study will contribute to the control and understanding of the current COVID-19 outbreak.

Supplementary Materials: Supplementary materials can be found at http://www.mdpi.com/1422-0067/21/7/2574/

s1. Supplementary File 1. List of NCBI GenBank accession numbers for target and non-target genome used
for analysis.
Author Contributions: C.C.-Y.Y., C.-C.H., S.K.W.T. and K.-Y.Y. conceived and designed the experiments; C.-C.H.
wrote the GolayMetaMiner software under supervision of S.K.W.T.; C.C.-Y.Y., J.F.-W.C., K.K.-W.T., H.S.-Y.C.,
S.C.-Y.W., K.-H.L., A.Y.-F.F., A.C.-K.N., Z.Z., A.R.T., T.W.-H.C., K.-H.C., I.F.-N.H., V.C.-C.C., O.T.-Y.T. collected the
clinical specimens, performed the experiments, and/or analyzed the data; C.C.-Y.Y. and C.-C.H. verified the data;
C.C.-Y.Y., C.-C.H., J.F.-W.C. and K.-Y.Y. wrote the paper. All authors revised and approved the final version of
the manuscript.
Int. J. Mol. Sci. 2020, 21, 2574 8 of 11

Funding: This study was partly supported by the donations of Richard Yu and Carol Yu, the Shaw Foundation of
Hong Kong, Michael Seak-Kan Tong, May Tam Mak Mei Yin, Respiratory Viral Research Foundation Limited,
Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Chan Yin Chuen Memorial Charitable Foundation,
Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research
Fund, the Jessie & George Ho Charitable Foundation, and Perfect Shape Medical Limited; and funding from
the Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research
Capability on Antimicrobial Resistance for Department of Health of the Hong Kong Special Administrative Region
Government; the Theme-Based Research Scheme (T11/707/15) of the Research Grants Council; Hong Kong Special
Administrative Region; Sanming Project of Medicine in Shenzhen, China (No. SZSM201911014); and the High
Level-Hospital Program, Health Commission of Guangdong Province, China. The funding sources had no role in
the study design, data collection, analysis, interpretation, or writing of the report.
Conflicts of Interest: J.F.-W.C. has received travel grants from Pfizer Corporation Hong Kong and Astellas Pharma
Hong Kong Corporation Limited, and was an invited speaker for Gilead Sciences Hong Kong Limited and
Luminex Corporation. The other authors declare no conflict of interest. The funders had no role in the design of
the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision
to publish the results.

Abbreviations
COVID-19 Novel coronavirus infection
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2
WHO World Health Organization
HCoV Human coronavirus
SARS-CoV Severe acute respiratory syndrome coronavirus
MERS-CoV Middle East respiratory syndrome coronavirus
RT-PCR Reverse transcription-polymerase chain reaction
NCBI National Center for Biotechnology Information, USA
U-score(s) Uniqueness score(s)
C-score(s) Conservedness score(s)
LOD Limit of detection
TNAnt Total nucleic acidnucleotide

References
1. Chan, J.F.-W.; To, K.K.-W.; Tse, H.; Jin, D.-Y.; Yuen, K.-Y. Interspecies transmission and emergence of novel
viruses: Lessons from bats and birds. Trends Microbiol. 2013, 21, 544–555. [CrossRef] [PubMed]
2. Cheng, V.C.C.; Lau, S.K.P.; Woo, P.C.Y.; Yuen, K.Y. Severe acute respiratory syndrome coronavirus as an
agent of emerging and reemerging infection. Clin. Microbiol. Rev. 2007, 20, 660–694. [CrossRef] [PubMed]
3. Chan, J.F.W.; Lau, S.K.P.; To, K.K.W.; Cheng, V.C.C.; Woo, P.C.Y.; Yuen, K.-Y. Middle East respiratory syndrome
coronavirus: Another zoonotic betacoronavirus causing SARS-like disease. Clin. Microbiol. Rev. 2015, 28,
465–522. [CrossRef] [PubMed]
4. Chan, J.F.-W.; Yuan, S.; Kok, K.-H.; To, K.K.-W.; Chu, H.; Yang, J.; Xing, F.; Liu, J.; Yip, C.C.-Y.; Poon, R.W.-S.;
et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person
transmission: A study of a family cluster. Lancet 2020, 395, 514–523. [CrossRef]
5. WHO Announces COVID-19 Outbreak a pandemic. Available online: http://www.euro.who.int/en/health-
topics/health-emergencies/coronavirus-covid-19/news/news/2020/3/who-announces-covid-19-outbreak-a-
pandemic (accessed on 21 March 2020).
6. Mizumoto, K.; Chowell, G. Estimating Risk for Death from 2019 Novel Coronavirus Disease, China,
January-February 2020. Emerging Infect. Dis. 2020, 26, 6. [CrossRef]
7. Cao, B.; Wang, Y.; Wen, D.; Liu, W.; Wang, J.; Fan, G.; Ruan, L.; Song, B.; Cai, Y.; Wei, M.; et al. A Trial of
Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N. Engl. J. Med. 2020. [CrossRef]
8. Li, H.; Wang, Y.M.; Xu, J.Y.; Cao, B. Potential antiviral therapeutics for 2019 Novel Coronavirus. Zhonghua Jie
He He Hu Xi Za Zhi 2020, 43, 170–172.
9. Martinez, M.A. Compounds with therapeutic potential against novel respiratory 2019 coronavirus. Antimicrob.
Agents Chemother. 2020. [CrossRef]
Int. J. Mol. Sci. 2020, 21, 2574 9 of 11

10. Wang, M.; Cao, R.; Zhang, L.; Yang, X.; Liu, J.; Xu, M.; Shi, Z.; Hu, Z.; Zhong, W.; Xiao, G. Remdesivir and
chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020,
30, 269–271. [CrossRef]
11. Roosa, K.; Lee, Y.; Luo, R.; Kirpich, A.; Rothenberg, R.; Hyman, J.M.; Yan, P.; Chowell, G. Real-time forecasts
of the COVID-19 epidemic in China from February 5th to February 24th, 2020. Infect. Dis. Model. 2020, 5,
256–263. [CrossRef]
12. Al-qaness, M.A.A.; Ewees, A.A.; Fan, H.; Abd El Aziz, M. Optimization Method for Forecasting Confirmed
Cases of COVID-19 in China. J. Clin. Med. 2020, 9, 674. [CrossRef] [PubMed]
13. Goh, G.K.-M.; Dunker, A.K.; Foster, J.A.; Uversky, V.N. Rigidity of the Outer Shell Predicted by a Protein
Intrinsic Disorder Model Sheds Light on the COVID-19 (Wuhan-2019-nCoV) Infectivity. Biomolecules 2020,
10, 331. [CrossRef] [PubMed]
14. Pirouz, B.; Shaffiee Haghshenas, S.; Shaffiee Haghshenas, S.; Piro, P. Investigating a Serious Challenge in the
Sustainable Development Process: Analysis of Confirmed cases of COVID-19 (New Type of Coronavirus)
Through a Binary Classification Using Artificial Intelligence and Regression Analysis. Sustainability 2020, 12,
2427. [CrossRef]
15. Salzberger, B.; Glück, T.; Ehrenstein, B. Successful containment of COVID-19: The WHO-Report on the
COVID-19 outbreak in China. Infection 2020, 48, 151–153. [CrossRef]
16. Cheng, V.C.C.; Wong, S.-C.; Chen, J.H.K.; Yip, C.C.Y.; Chuang, V.W.M.; Tsang, O.T.Y.; Sridhar, S.; Chan, J.F.W.;
Ho, P.-L.; Yuen, K.-Y. Escalating infection control response to the rapidly evolving epidemiology of the
Coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 in Hong Kong. Infect. Control. Hosp. Epidemiol.
2020, 1–24. [CrossRef]
17. Rothe, C.; Schunk, M.; Sothmann, P.; Bretzel, G.; Froeschl, G.; Wallrauch, C.; Zimmer, T.; Thiel, V.; Janke, C.;
Guggemos, W.; et al. Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany.
N. Engl. J. Med. 2020, 382, 970–971. [CrossRef]
18. Zhang, W.; Du, R.-H.; Li, B.; Zheng, X.-S.; Yang, X.-L.; Hu, B.; Wang, Y.-Y.; Xiao, G.-F.; Yan, B.; Shi, Z.-L.; et al.
Molecular and serological investigation of 2019-nCoV infected patients: Implication of multiple shedding
routes. Emerg. Microbes Infect. 2020, 9, 386–389. [CrossRef]
19. Ling, Y.; Xu, S.-B.; Lin, Y.-X.; Tian, D.; Zhu, Z.-Q.; Dai, F.-H.; Wu, F.; Song, Z.-G.; Huang, W.; Chen, J.; et al.
Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients. Chin. Med.
J. 2020. [CrossRef]
20. To, K.K.-W.; Tsang, O.T.-Y.; Chik-Yan Yip, C.; Chan, K.-H.; Wu, T.-C.; Chan, J.M.C.; Leung, W.-S.; Chik, T.S.-H.;
Choi, C.Y.-C.; Kandamby, D.H.; et al. Consistent detection of 2019 novel coronavirus in saliva. Clin. Infect.
Dis. 2020. [CrossRef]
21. Woo, P.C.Y.; Lau, S.K.P.; Tsoi, H.; Chan, K.; Wong, B.H.L.; Che, X.; Tam, V.K.P.; Tam, S.C.F.; Cheng, V.C.C.;
Hung, I.F.N.; et al. Relative rates of non-pneumonic SARS coronavirus infection and SARS coronavirus
pneumonia. Lancet 2004, 363, 841–845. [CrossRef]
22. Chan, J.F.-W.; Choi, G.K.-Y.; Tsang, A.K.-L.; Tee, K.-M.; Lam, H.-Y.; Yip, C.C.-Y.; To, K.K.-W.; Cheng, V.C.-C.;
Yeung, M.-L.; Lau, S.K.-P.; et al. Development and Evaluation of Novel Real-Time Reverse Transcription-PCR
Assays with Locked Nucleic Acid Probes Targeting Leader Sequences of Human-Pathogenic Coronaviruses.
J. Clin. Microbiol. 2015, 53, 2722–2726. [CrossRef] [PubMed]
23. Chan, J.F.-W.; Kok, K.-H.; Zhu, Z.; Chu, H.; To, K.K.-W.; Yuan, S.; Yuen, K.-Y. Genomic characterization of the
2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting
Wuhan. Emerg. Microbes Infect. 2020, 9, 221–236. [CrossRef] [PubMed]
24. Chan, J.F.-W.; Yip, C.C.-Y.; To, K.K.-W.; Tang, T.H.-C.; Wong, S.C.-Y.; Leung, K.-H.; Fung, A.Y.-F.; Ng, A.C.-K.;
Zou, Z.; Tsoi, H.-W.; et al. Improved molecular diagnosis of COVID-19 by the novel, highly sensitive and
specific COVID-19-RdRp/Hel real-time reverse transcription-polymerase chain reaction assay validated
in vitro and with clinical specimens. J. Clin. Microbiol. 2020. [CrossRef] [PubMed]
25. Shen, Z.; Xiao, Y.; Kang, L.; Ma, W.; Shi, L.; Zhang, L.; Zhou, Z.; Yang, J.; Zhong, J.; Yang, D.; et al. Genomic
diversity of SARS-CoV-2 in Coronavirus Disease 2019 patients. Clin. Infect. Dis. 2020. [CrossRef] [PubMed]
26. Corman, V.M.; Landt, O.; Kaiser, M.; Molenkamp, R.; Meijer, A.; Chu, D.K.W.; Bleicker, T.; Brünink, S.;
Schneider, J.; Schmidt, M.L.; et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR.
Eurosurveillance 2020, 25, 2000045. [CrossRef]
Int. J. Mol. Sci. 2020, 21, 2574 10 of 11

27. Chu, D.K.W.; Pan, Y.; Cheng, S.M.S.; Hui, K.P.Y.; Krishnan, P.; Liu, Y.; Ng, D.Y.M.; Wan, C.K.C.; Yang, P.;
Wang, Q.; et al. Molecular Diagnosis of a Novel Coronavirus (2019-nCoV) Causing an Outbreak of Pneumonia.
Clin. Chem. 2020, 66, 549–555. [CrossRef]
28. Yip, C.C.Y.; Sridhar, S.; Leung, K.-H.; Cheng, A.K.W.; Chan, K.-H.; Chan, J.F.W.; Cheng, V.C.C.; Yuen, K.-Y.
Evaluation of RealStar® Alpha Herpesvirus PCR Kit for Detection of HSV-1, HSV-2, and VZV in Clinical
Specimens. Biomed. Res. Int. 2019, 2019, 5715180. [CrossRef]
29. Yip, C.C.Y.; Sridhar, S.; Cheng, A.K.W.; Fung, A.M.Y.; Cheng, V.C.C.; Chan, K.-H.; Yuen, K.-Y. Comparative
evaluation of a laboratory developed real-time PCR assay and the RealStar® HHV-6 PCR Kit for quantitative
detection of human herpesvirus 6. J. Virol. Methods 2017, 246, 112–116. [CrossRef]
30. Angeletti, S.; Benvenuto, D.; Bianchi, M.; Giovanetti, M.; Pascarella, S.; Ciccozzi, M. COVID-2019: The role of
the nsp2 and nsp3 in its pathogenesis. J. Med. Virol. 2020. [CrossRef]
31. To, K.K.-W.; Tsang, O.T.-Y.; Leung, W.-S.; Tam, A.R.; Wu, T.-C.; Lung, D.C.; Yip, C.C.-Y.; Cai, J.-P.; Chan, J.M.-C.;
Chik, T.S.-H.; et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum
antibody responses during infection by SARS-CoV-2: An observational cohort study. Lancet Infect. Dis. 2020,
S1473309920301961. [CrossRef]
32. Li, Z.; Yi, Y.; Luo, X.; Xiong, N.; Liu, Y.; Li, S.; Sun, R.; Wang, Y.; Hu, B.; Chen, W.; et al. Development and
Clinical Application of A Rapid IgM-IgG Combined Antibody Test for SARS-CoV-2 Infection Diagnosis.
J. Med. Virol. 2020. [CrossRef] [PubMed]
33. Guo, L.; Ren, L.; Yang, S.; Xiao, M.; Chang, D.; Yang, F.; Dela Cruz, C.S.; Wang, Y.; Wu, C.; Xiao, Y.; et al.
Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19). Clin. Infect. Dis.
2020. [CrossRef] [PubMed]
34. Zhang, J.-F.; Yan, K.; Ye, H.-H.; Lin, J.; Zheng, J.-J.; Cai, T. SARS-CoV-2 turned positive in a discharged
patient with COVID-19 arouses concern regarding the present standard for discharge. Int. J. Infect. Dis. 2020.
[CrossRef] [PubMed]
35. Legido-Quigley, H.; Mateos-García, J.T.; Campos, V.R.; Gea-Sánchez, M.; Muntaner, C.; McKee, M. The
resilience of the Spanish health system against the COVID-19 pandemic. Lancet Public Health 2020. [CrossRef]
36. Remuzzi, A.; Remuzzi, G. COVID-19 and Italy: What next? Lancet 2020. [CrossRef]
37. Lu, R.; Zhao, X.; Li, J.; Niu, P.; Yang, B.; Wu, H.; Wang, W.; Song, H.; Huang, B.; Zhu, N.; et al. Genomic
characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor
binding. Lancet 2020, 395, 565–574. [CrossRef]
38. Yip, C.C.Y.; Lam, C.S.F.; Luk, H.K.H.; Wong, E.Y.M.; Lee, R.A.; So, L.-Y.; Chan, K.-H.; Cheng, V.C.C.;
Yuen, K.-Y.; Woo, P.C.Y.; et al. A six-year descriptive epidemiological study of human coronavirus infections
in hospitalized patients in Hong Kong. Virol. Sin. 2016, 31, 41–48. [CrossRef]
39. Ho, C.-C.; Wu, A.K.L.; Tse, C.W.S.; Yuen, K.-Y.; Lau, S.K.P.; Woo, P.C.Y. Automated pangenomic analysis in
target selection for PCR detection and identification of bacteria by use of ssGeneFinder Webserver and its
application to Salmonella enterica serovar Typhi. J. Clin. Microbiol. 2012, 50, 1905–1911. [CrossRef]
40. Ho, C.-C.; Yuen, K.-Y.; Lau, S.K.P.; Woo, P.C.Y. Rapid identification and validation of specific molecular
targets for detection of Escherichia coli O104:H4 outbreak strain by use of high-throughput sequencing data
from nine genomes. J. Clin. Microbiol. 2011, 49, 3714–3716. [CrossRef]
41. Ho, C.-C.; Lau, C.C.Y.; Martelli, P.; Chan, S.-Y.; Tse, C.W.S.; Wu, A.K.L.; Yuen, K.-Y.; Lau, S.K.P.;
Woo, P.C.Y. Novel pan-genomic analysis approach in target selection for multiplex PCR identification
and detection of Burkholderia pseudomallei, Burkholderia thailandensis, and Burkholderia cepacia complex species:
A proof-of-concept study. J. Clin. Microbiol. 2011, 49, 814–821. [CrossRef]
42. Chu, H.; Chan, J.F.-W.; Yuen, T.T.; Shuai, H.; Yuan, S.; Wang, Y.; Hu, B.; Yip, C.C.-Y.; Tsang, J.O.-L.;
Huang, X.; et al. An observational study on the comparative tropism, replication kinetics, and cell
damage profiling of SARS-CoV-2 and SARS-CoV: Implications for clinical manifestations, transmissibility,
and laboratory studies of COVID-19. Lancet Microbe 2020, in press.
Int. J. Mol. Sci. 2020, 21, 2574 11 of 11

43. Chan, J.F.-W.; Zhang, A.J.; Yuan, S.; Poon, V.K.-M.; Chan, C.C.-S.; Lee, A.C.-Y.; Chan, W.-M.; Fan, Z.;
Tsoi, H.-W.; Wen, L.; et al. Simulation of the clinical and pathological manifestations of Coronavirus Disease
2019 (COVID-19) in golden Syrian hamster model: Implications for disease pathogenesis and transmissibility.
Clin. Infect. Dis. 2020, ciaa325. [CrossRef] [PubMed]
44. Yip, C.C.-Y.; Chan, W.-M.; Ip, J.D.; Seng, C.W.-M.; Leung, K.-H.; Poon, R.W.-S.; Ng, A.C.-K.; Wu, W.-L.;
Zhao, H.; Chan, K.-H.; et al. Nanopore sequencing reveals novel targets for the diagnosis and surveillance of
human and avian influenza A virus. J. Clin. Microbiol. 2020. [CrossRef] [PubMed]
45. Wong, S.S.Y.; Yip, C.C.Y.; Sridhar, S.; Leung, K.-H.; Cheng, A.K.W.; Fung, A.M.Y.; Lam, H.-Y.; Chan, K.-H.;
Chan, J.F.W.; Cheng, V.C.C.; et al. Comparative evaluation of a laboratory-developed real-time PCR assay
and RealStar® Adenovirus PCR Kit for quantitative detection of human adenovirus. Virol. J. 2018, 15, 149.
[CrossRef] [PubMed]
46. Chan, J.F.-W.; Yip, C.C.-Y.; Tee, K.-M.; Zhu, Z.; Tsang, J.O.-L.; Chik, K.K.-H.; Tsang, T.G.-W.; Chan, C.C.-S.;
Poon, V.K.-M.; Sridhar, S.; et al. Improved detection of Zika virus RNA in human and animal specimens by a
novel, highly sensitive and specific real-time RT-PCR assay targeting the 50 -untranslated region of Zika virus.
Trop. Med. Int. Health 2017, 22, 594–603. [CrossRef] [PubMed]

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
 5

Risk assessment of
novel coronavirus
COVID-19 outbreaker
outside China
 Journal of
Clinical Medicine

Article
Risk Assessment of Novel Coronavirus COVID-19
Outbreaks Outside China
Péter Boldog, Tamás Tekeli, Zsolt Vizi, Attila Dénes * , Ferenc A. Bartha and Gergely Röst
Bolyai Institute, University of Szeged, H-6720 Szeged, Hungary; boldogpeter@gmail.com (P.B.);
tekeli.tamas@gmail.com (T.T.); zsvizi@math.u-szeged.hu (Z.V.); barfer@math.u-szeged.hu (F.A.B.);
rost@math.u-szeged.hu (G.R.)
* Correspondence: denesa@math.u-szeged.hu




Received: 5 February 2020; Accepted: 14 February 2020; Published: 19 February 2020


Abstract: We developed a computational tool to assess the risks of novel coronavirus outbreaks
outside of China. We estimate the dependence of the risk of a major outbreak in a country from
imported cases on key parameters such as: (i) the evolution of the cumulative number of cases
in mainland China outside the closed areas; (ii) the connectivity of the destination country with
China, including baseline travel frequencies, the effect of travel restrictions, and the efficacy of
entry screening at destination; and (iii) the efficacy of control measures in the destination country
(expressed by the local reproduction number Rloc ). We found that in countries with low connectivity
to China but with relatively high Rloc , the most beneficial control measure to reduce the risk of
outbreaks is a further reduction in their importation number either by entry screening or travel
restrictions. Countries with high connectivity but low Rloc benefit the most from policies that further
reduce Rloc . Countries in the middle should consider a combination of such policies. Risk assessments
were illustrated for selected groups of countries from America, Asia, and Europe. We investigated
how their risks depend on those parameters, and how the risk is increasing in time as the number of
cases in China is growing.

Keywords: novel coronavirus; transmission; risk assessment; interventions; travel; outbreak;

COVID-19; compartmental model; branching process

1. Introduction
A cluster of pneumonia cases in Wuhan, China, was reported to the World Health Organization
(WHO) on 31 December 2019. The cause of the pneumonia cases was identified as a novel
betacoronavirus, the 2019 novel coronavirus (2019-nCoV, recently renamed as SARS-CoV-2, the cause
of coronavirus disease COVID-19). The first patient showing symptoms was recorded by Chinese
authorities on 8 December 2019 [1]. On 9 January 2020, WHO confirmed that a novel coronavirus
had been isolated from one of the hospitalized persons [2], and the first death case was reported on
the same day. The first case outside China was witnessed on 13 January in Thailand [3], and in the
following days, several other countries also reported 2019-nCoV cases [4]. The first confirmed cases
in China, but outside Hubei province, were reported on 19 January. [4]. As of 1 February, there were
14,628 confirmed cases worldwide (out of which 14,451 happened in China) with 305 total deaths [5].
Since no specific antiviral agent is available for treatment of this infection, and there is no
vaccine [6], the control measures, introduced both in China and other countries, aimed to prevent
the transmission. A metropolitan-wide quarantine of Wuhan and nearby cities was introduced on
23–24 January [7]. Several airports and train stations have started temperature screening measures
to identify people with fevers [8]. All public transportation was suspended in Wuhan from 10 a.m.,
23 January, including all outbound trains and flights, and all bus, metro and ferry lines; additionally,

J. Clin. Med. 2020, 9, 571; doi:10.3390/jcm9020571 www.mdpi.com/journal/jcm

J. Clin. Med. 2020, 9, 571 2 of 12

all outbound trains and flights were halted [9]. Construction of a specialist emergency hospital was
started in Wuhan [10], and nearly 6000 medical workers were sent to Wuhan from across China [11].
Beijing also announced the suspension of all inter-provincial bus and train services; several touristic
attractions, including the Forbidden City and Shanghai Disneyland were closed [9]. Other countries
also introduced control measures, including screening passengers arriving from China and closing
their borders [12]. Several airlines, including British Airways and Lufthansa, canceled all flights to and
from mainland China [9].
The potential dangers of 2019-nCoV have prompted a number of studies on its epidemiological
characteristics. The 2018 travel data from the International Air Transport Association (IATA) were used
to identify the countries and their infectious disease vulnerability indexes (IDVIs) [13], which received
substantial travel inflow from Wuhan Tianhe International Airport [14]. The IDVI has a range of 0–1,
with a higher score implying lower vulnerability. The top destinations, Bangkok, Hong Kong, Tokyo
and Taipei, all have an IDVI above 0.65.
It is essential to estimate the number of infections (including those that have not been diagnosed),
to be able to analyze the spread of the disease. To that end, data on exported infections and
individual-based mobility models were used by several researchers, obtaining comparable numbers.
For 17 January 2020, preliminary estimates were given for various scenarios in the range 350–8400 by
Chinazzi et al. for the total number of infections up to that date [15]. Imai et al. [16] also estimated
the total number of infections in China and warned that the number is likely to substantially exceed
that of the officially confirmed cases (see also [17]). They reported an estimate of 4000 infections
(range: 1000–9700) by 18 January 2020. Nishiura et al. calculated 5502 (range: 3027–9057) infections by
24 January 2020 [18].
To better assess the epidemic risk of 2019-nCoV, among the key parameters to be approximated
are the basic reproduction number R0 and the incubation period. We summarize previous efforts made
toward those ends in Table 1, and present a short summary below.

Table 1. Published estimates of the key epidemiological parameters of 2019-nCoV. Uncertainty range is
given where provided.

R0 Incubation Period Method of Estimation Reference

2.6 (1.5–3.5) - Epidemic Simulations [19]
2.2 (1.4–3.8) - Stochastic Simulations [20]
2.9 (2.3–3.6) 4.8 days Exp. Growth, Max. Likelihood Est. [21]
2.56 (2.49–2.63) - Exp. Growth, Max. Likelihood Est. [17]
3.11 (2.3–4.1) - SEIR [22]
2.5 (2.0–3.1) - Incidence Decay and Exponential Adjustment model [23]
2.2 (1.4–3.9) 5.2 days (4.1–7.0) Renewal Equations [24]
- (1.4–4.0) - SEIR [25]
4.71 (4.5–4.9) 5.0 days (4.9–5.1) Dec. 2019, SEIJR, MCMC [26]
2.08 (1.9–2.2) - Jan. 2020, SEIJR, MCMC [26]
2.68 (2.4–2.9) - SEIR, MCMC [27]
- 5.8 days (4.6–7.9) Weibull [28]
- 4.6 days (3.3–5.8) Weibull incl. Wuhan [29]
- 5.0 days (4.0–5.8) Weibull excl. Wuhan [29]
- 5.1 days (4.4–6.1) LogNormal [30]

The majority of the estimates for R0 range between 2 and 3. Obtaining these was done by modeling
epidemic trajectories and comparing them to the results of [16] as a baseline [19,20], using a negative
binomial distribution to generate secondary infections. Liu et al. utilized the exponential growth and
maximum likelihood estimation methods and found that the 2019-nCoV may have a higher pandemic
risk than SARS-CoV in 2003 [21].
Read et al. based their estimates on data from Wuhan exclusively (available up to 22 January
2020) and a deterministic SEIR model [22]. The choice of this date is motivated by the actions of
 J. Clin. Med. 2020, 9, 571 3 of 12

authorities, that is the substantial travel limitations the next day. Li et al. used solely the patient data
with illness onset between 10 December 2019 and 4 January 2020 [24]. The Centre for the Mathematical
Modelling of Infectious Diseases at the London School of Hygiene and Tropical Medicine have analyzed
2019-nCoV using SEIR and multiple data series [25]. Shen et al. used a SEIJR model (where J denotes
the compartment of diagnosed and isolated individuals) and Markov chain Monte Carlo (MCMC)
simulations [26] similarly to [27]. An alternative approach was presented by Majumder and Mandl [23]
as they obtained their estimate based on the cumulative epidemic curve and the incidence decay and
exponential adjustment (IDEA) model [31].
The incubation period was estimated to be in between 4.6 and 5.8 days by various studies. The first
calculations used data up to 23 January [21]. Weibull distribution was identified as the best-fit model
by several researches when comparing LogNormal, Gamma, and Weibull fits. Backer et al. used newly
available patient data with known travel history and identified the Weibull distribution as the one
with the best LOO (Leave-One-Out) score [28]; Linton et al. gave estimates for with and without
Wuhan residents using their statistical model with, again, the Weibull distribution scoring the best
AIC (Akaike information criterion) [29]. The Johns Hopkins University Infectious Disease Dynamics
Group has been collecting substantial data on exposure and symptom onset for 2019-nCoV cases. They
recommend using their LogNormal estimate [30], which gives a 5.1 day incubation period.
In this study we combine case estimates, epidemiological characteristics of the disease,
international mobility patterns, control efforts, and secondary case distributions to assess the risks of
major outbreaks from imported cases outside China.

2. Materials and Methods

2.1. Model Ingredients

Our method has three main components:

(i) We estimate the cumulative number of cases in China outside Hubei province after 23 January,
using a time-dependent compartmental model of the transmission dynamics.
(ii) We use that number as an input to the global transportation network to generate probability
distributions of the number of infected travellers arriving at destinations outside China.
(iii) In a destination country, we use a Galton–Watson branching process to model the initial spread
of the virus. We calculate the extinction probability of each branch initiated by a single imported
case, obtaining the probability of a major outbreak as the probability that at least one branch
will not go extinct.

2.2. Epidemic Size in China Outside the Closed Areas of Hubei

The starting point of our transmission model is 23 January, when major cities in Hubei province
were closed [7]. From this point forward, we run a time dependent SEn Im R model in China outside
Hubei, which was calibrated to be consistent with the estimated case numbers outside Hubei until
31 January. We impose time dependence in the transmission parameter due to the control measures
progressively implemented by Chinese authorities on and after 23 January. With our baseline
R0 = 2.6, disease control is achieved when more than 61.5% of potential transmissions are prevented.
We introduce a key parameter t∗ to denote the future time when control measures reach their full
potential. For this study we assume it to be in the range of 20–50 days after 23 January. Using our
transmission model, we calculate the total cumulative number of cases (epidemic final size) outside
Hubei, for each t∗ in the given range. This also gives an upper bound for the increasing cumulative
number of cases C = C (t).
J. Clin. Med. 2020, 9, 571 4 of 12

2.3. Connectivity and Case Exportation

The output C of the transmission model is used as the pool of potential travellers to abroad,
and fed into the online platform EpiRisk [32]. This way, we evaluated the probability that a single
infected individual is traveling from the index areas (in our case Chinese provinces other than Hubei)
to a specific destination. Using a ten day interval for potential travel after exposure (just as in [15]),
one can find from EpiRisk that in the January–February periods, assuming usual travel volumes, there
is a 1/554 probability that a single case will travel abroad and cause an exported case outside China.
The dataset for relative importation risks of countries is available as well; thus, one can obtain the
probability of an exported case appearing in a specific country. This probability is denoted by θ0 ,
and we call it the baseline connectivity of that country with China. The baseline connectivity can be
affected by other factors, such as the reduction in travel volume between the index and destination
areas, exit screening in China, and the efficacy of entry screening at the destination country. Hence,
we have a compound parameter, the actual connectivity θ, which expresses the probability that a
case in China outside Hubei will be eventually mixed into the population of the destination country.
For example, the relative risk of Japan is 0.13343, meaning that 13.343% of all exportations are expected
to appear in Japan. Thus, under normal circumstances, the probability that a case from China eventually
ends up in Japan is 0.13343/554 = 2.41 × 10−4 during the January–February period [32]. Assuming
a 20% reduction in travel volume between China and Japan, this baseline connectivity is reduced
to a connectivity 0.8 × 2.41 × 10−4 = 1.928 × 10−4 . Additionally, assuming a 40% efficacy on entry
screening [33], there is a 0.6 probability that an arriving case passes the screening, and the connectivity
parameter is further reduced to 0.6 × 1.928 × 10−4 = 1.16 × 10−4 . If we assume interventions at the
originating area, for example, exit screening with 25% efficacy, then our actual connectivity parameter
is θ = 0.75 × 1.16 × 10−4 = 8.7 × 10−5 , which represents the probability that a case in China will
eventually mix into the population in Japan. Assuming independence, this θ, together with the
cumulative cases C, generates a binomial distribution of importations that enter the population of a
given country.

2.4. Probability of a Major Outbreak in a Country by Imported Cases

Each imported case that passes the entry screening and mixes into the local population can
potentially start an outbreak, which we model by a Galton–Watson branching process with negative
binomial offspring distribution with dispersion parameter k = 0.64 [19,20] and expectation Rloc , where
Rloc is the local reproduction number of the infection in a given country. Each branch has extinction
probability z, which is the unique solution of the equation z = g(z) on the interval (0, 1), where g is
the generating function of the offspring distribution (see [34]). The process dies out if all the branches
die out; thus, we estimate the risk of a major local outbreak from importation as 1 − zi , where i cases
were imported.

2.5. Dependence of the Risk of Major Outbreaks on Key Parameters

The number of imported cases i is given by a random variable X, where X ∼ Binom(C, θ ).
The outbreak risk in a country x is then estimated as Riskx = E[1 − z X ], where E is the expectation
of the outbreak probabilities; thus, we consider a probability distribution of branching processes.
This way Riskx = Risk(C, θ, Rloc ), which means that the risk depends on the efficacy of Chinese
control measures that influence the cumulative case number C, the connectivity between the index and
destination areas θ, and the local reproduction number Rloc . The main question we aim to get insight
into is how this risk depends on these three determining factors.
The technical details of the modeling and calculations can be found in Appendices A, B, and C.
J. Clin. Med. 2020, 9, 571 5 of 12

3. Results

3.1. Epidemic Size in China

After calibration of the SE2 I3 R model, we numerically calculated the final epidemic size
(total cumulative number of cases) in China outside Hubei, using three different basic reproduction
numbers and different control functions. The control functions were parametrized by t∗ , which is the
time after 23 January at which the control reaches its maximal value umax . Smaller t∗ corresponds
to more rapid implementation of the control measures. In Figure 1, we plotted these cumulative
numbers versus t∗ , and we can observe that the epidemic final size is rather sensitive to the speed
of implementation of the control measures. These curves also give upper bounds for the number of
cumulative cases at any given time, assuming that the control efforts will be successful.

Figure 1. Final epidemic sizes in China, outside Hubei, with R0 = 2.1, 2.6, 3.1, as a function of the time
when the control function u(t) reaches its maximum (in days after 23 January). Rapid implementation of
the control generates much smaller case numbers. The inset shows the estimations of the ascertainment
rate for the week 25–31, with average 0.063, based on the ratio of confirmed cases and the maximum
likelihood estimates of the case numbers from exportation.

3.2. Risk of Major Outbreaks

We generated a number of plots to depict Risk(C, θ, Rloc ) for selected groups of countries from
America, Europe, and Asia.
In the left of Figure 2, we can see the risks of American countries as functions of cumulative
number of cases C, assuming each country has Rloc = 1.6 and their connectivity is their baseline θ.
When C exceeds 600,000, with this local reproduction number and without any restriction in
importation, outbreaks in the USA and Canada are very likely, while countries in South America
(including Mexico), which are all in the green shaded region, still have moderate risks. To illustrate the
impacts of control measures for the USA and Canada, we reduced Rloc to 1.4, and plotted the risks for
different levels of reduction in connectivity to China, either due to travel restrictions or entry screening;
see Figure 2 on the right. As the number of cases in China approaches one million, such reductions
have a limited effect on the risk of outbreak. Figure 1 provides us with scenarios when C remains
below certain values.
J. Clin. Med. 2020, 9, 571 6 of 12

Figure 2. (Left) Risk of major outbreaks as a function of cumulative number of cases in selected
countries, assuming Rloc = 1.6 and baseline connectivity to China. Other countries in South America,
including Mexico, are inside the green shaded area. (Right) The effects of reductions of imported case
numbers (either by travel restriction or entry screening) in the USA and Canada, assuming Rloc = 1.4.

We considered the group of countries from Asia which are the most connected to China: Thailand,
Japan, Taiwan, and the Republic of Korea. They have similar baseline connectivity θ, and we focus
on how travel restrictions and entry screenings can potentially reduce their risks, assuming different
values of Rloc in the case C = 150,000 (on the left of Figure 3) and C = 600,000 (on the right of Figure 3).
For illustration purposes, we plotted Thailand (red) and the Republic of Korea (blue), but Taiwan and
Japan are always between those two curves. We can see that, for example, on the right of Figure 3 for
C = 600,000, unless Rloc is very small, considerable reduction of the outbreak risk can be achieved only
by extreme measures that prevent most importations.

Figure 3. Outbreak risks for highly connected countries in Asia. Thailand and the Republic of Korea
are plotted; the curves for Japan and Taiwan are in between them. (Left) We plot the risk vs. the efficacy
of prevented importations when the cumulative number of cases reaches 150,000. (Right) C = 600,000.
Black parts of the curves represent situations when the four countries are indistinguishable.

In Figure 4, we assumed that European countries have very similar Rloc and looked at their risks
as a function of the number of cases. For illustration purposes, we selected countries which have
relatively high (UK, Germany, France, Italy), medium (Belgium, Poland, Hungary), and low (Bulgaria,
Croatia, Lithuania) connectivity to China. On the left, we assumed Rloc = 1.4 and baseline θ, and with
these parameters, outbreaks will likely occur in high risk countries as the case number approaches one
million. By reducing Rloc to 1.1 and by reducing θ to the half of its baseline (meaning that we assume
J. Clin. Med. 2020, 9, 571 7 of 12

that there is a 50% reduction in importations due to decreased travel and entry screenings), then the
risk is significantly reduced, even with one million cases.

3.3. Profile of Countries Benefiting the Most From Interventions

We also plotted the risks on a two-parameter map, as functions of θ and Rloc . Observing the
gradients of the risk map, we can conclude that countries with low connectivity but high Rloc should
focus on further reducing importations by entry screening and travel restrictions, while countries with
high connectivity but smaller Rloc better focus on control measures that potentially further reduce Rloc .
Countries in the middle benefit most from the combination of those two types of measures.

Figure 4. Selected European countries with high, medium, and low connectivity to China. (Left) The
outbreak risk is plotted assuming their baseline connectivity θ, and Rloc = 1.4 for each country, as the
cumulative number of cases is increasing. A significant reduction in the risks can be observed (Right),
where we reduced Rloc to 1.1 and assumed a 50% reduction in importations.

4. Discussion
By combining three different modelling approaches, we created a tool to assess the risk of
2019-nCoV outbreaks in countries outside of China. This risk depends on three key parameters:
the cumulative number of cases in areas of China which are not closed, the connectivity between China
and the destination country, and the local transmission potential of the virus. Quantifications of the
outbreak risks and their dependencies on the key parameters were illustrated for selected groups of
countries from America, Asia, and Europe, representing a variety of country profiles.
There are several limitations of our model, as each ingredient uses assumptions, which are
detailed in the Appendices. There are great uncertainties in the epidemiological parameters as well.
It is difficult to predict the epidemic trajectory in China, as the effects of the control measures are not
clear yet. There were recent disruptions in international travel, suggesting that the EpiRisk parameters
will not be accurate in the future. Nevertheless, when we have new information in the future about the
case numbers in China, travel frequencies, efficacy of entry screenings, and local control measures,
our method will still be useful for assessing outbreak risks.
We found that in countries with low connectivity to China but with relatively high Rloc , the most
beneficial control measure to reduce the risk of outbreaks is a further reduction in their importation
number either by entry screening or travel restrictions (see Figure 5). Countries with high connectivity
but low Rloc benefit the most from policies that further reduce Rloc . Countries in the middle should
consider a combination of such policies.
Different control measures affect different key parameters. Several of these measures have been
readily implemented in China, aiming to prevent transmissions. These are incorporated into our
transmission model influencing the cumulative number of cases C. The connectivity θ may be affected,
for example, by exit screening at Chinese airports, entry screening at the destination airport, and a
J. Clin. Med. 2020, 9, 571 8 of 12

decline in travel volume, all of which decrease the probability that a case from China will enter the
population of the destination country. The parameter Rloc is determined by the characteristics and the
control measures of the destination country. As new measures are implemented, or there is a change in
travel patterns, these parameters may change in time as well.
Cumulative cases and connectivity can be estimated, in general. However, to make a good
assessment of the outbreak risk, it is very important to estimate Rloc in each country. In the absence of
available transmission data, one may rely on the experiences from previous outbreaks, such as the
detailed description in [35] of the reductions in the effective reproduction numbers for SARS due to
various control measures. In this study, we used a range of Rloc values between the critical value 1
and the baseline R0 = 2.6. A further source of uncertainty is in the distribution of the generation time
interval, since a different distribution gives a different outbreak risk even with the same Rloc . For our
calculations, we used the distribution from [19] (see also [20]); a more in-depth discussion of this topic
may be found in [36]. Knowing Rloc and the generation interval are needed not only to have a better
quantitative risk estimation, but also for guidance as to which types of control measures may reduce
the outbreak risk the most effectively.

Figure 5. Heatmap of the outbreak risks as functions of θ and Rloc , when C = 200,000. The arrows
show the directions corresponding to the largest reductions in the risk.

Author Contributions: Conceptualization and methodology, G.R.; codes and computations A.D., T.T., F.A.B., P.B.,
G.R., and Z.V.; data collection and analysis, A.D., F.A.B., and T.T.; writing and editing, A.D., F.A.B., and G.R.;
visualization, F.A.B., T.T., and Z.V. All authors have read and agreed to the published version of the manuscript.
Funding: G.R. was supported by EFOP-3.6.1-16-2016-00008. F.B. was supported by NKFIH KKP 129877. T.T. was
supported by NKFIH FK 124016. A.D. was supported by NKFIH PD 128363 and by the János Bolyai Research
Scholarship of the Hungarian Academy of Sciences. P.B. was supported by 20391-3/2018/FEKUSTRAT.
Conflicts of Interest: The authors declare no conflict of interest.

Appendix A. Transmission Dynamics

The governing system of the transmission dynamics model is

3 3
S0 = −(1 − u) βS ∑ Ik /N, E10 = (1 − u) βS ∑ Ik /N − 2αE1 , E20 = 2αE1 − 2αE2 ,
i =1 i =1
J. Clin. Med. 2020, 9, 571 9 of 12

I10 = 2αE2 − 3γI1 − µI1 , I20 = 3γI1 − 3γI2 − µI2 , I30 = 3γI2 − 3γI3 − µI3 , R0 = 3γI3 .

This is an extension of a standard SEIR model assuming gamma-distributed incubation and

infectious periods, with the Erlang parameters n = 2, m = 3 (following the SARS-study [37]). Note that
the choice of n = 2 is also consistent with the estimates summarized in Table 1. Given that disease
fatalities do not have significant effect on the total population, we ignored them in the transmission
model to ease the calculations (i.e., µ = 0 was used). In this model, the basic reproduction number is
R0 = β/γ, the incubation period is α−1 and the infectious period is γ−1 . The model is used to describe
the disease dynamics in China outside Hubei province after 23 January. We assume that at time t after
23 January, an increasing control function u(t) represents the fraction of the transmissions that are
prevented, thus the effective reproduction number becomes R(t) = (1 − u(t)) R0 S(t)/N.
Based on the previous estimates from the literature (see Table 1), we chose an incubation period
− 1
α = 5.1 days [30], basic reproduction number R0 = 2.6 (2.1–3.1) with the corresponding infectious
period γ−1 = 3.3 (1.7–5.6) days [19]. To predict the final number of cases outside Hubei, we assume
a gradually increasing control u from zero until a saturation point, and define t∗ the time when the
eventual control umax is achieved. The sooner this happens, the more successful the control is. Using
the control term u(t) = min{umax t/t∗ , umax }, disease control is reached at t = t∗ (1 − 1/R0 )/umax .
For the calculations we choose umax = 0.8, noting that such a drop in transmission has been observed
for SARS, where the reproduction number was largely reduced by subsequent interventions [35].
With our baseline R0 = 2.6, disease control R(t) < 1 is achieved when u(t) > 0.615, meaning that
more than 61.5% of potential transmissions are prevented, which occurs at time t = 0.77t∗ .
Since the first case outside Hubei was reported on 19 January [5], for the initialization of the
model we could assume that number of infected individuals on 23 January outside Hubei was equal to
the number of cumulative cases outside Hubei up to that day. To calibrate the model, we estimated
the number of cases from 24 January till 31 January outside Hubei based on case exportations, using
the methodology of [15], assuming that exportations after 24 January were only from outside Hubei.
Based on the maximal likelihood of case numbers that produce the observed number of exportations
using EpiRisk [32], we estimate that the reported confirmed cases represent only 6.3% of the total
cases for the regions outside Hubei (other estimates for ascertainment rate were: 5.1% [22], 10% in [38],
and 9.2% (95% confidence interval: 5.0, 20.0) [39]), see the inset in Figure 1. The initial values for the
exposed compartments in the SEIR model were selected such that the model output was consistent
with the estimated case numbers outside Hubei between 24 January and 31 January. Solving the
compartmental model, we obtained final epidemic sizes for various reproduction numbers and control
efforts (see Figure 1), providing upper bounds for the cumulative number of cases C outside Hubei.

Appendix B. Calculating the Risk of Outbreaks by Importation

We create a probabilistic model to estimate the risk of a major outbreak in a destination country as
a function of the cumulative number of cases C in China outside the closed areas, the local reproduction
number Rloc in the destination country, and the connectivity θ between China and the destination
country. We summarize these in Table A1.

Table A1. Parameters for calculating the risk of major outbreaks.

Parameter Interpretation Depends on . . . Typical Range

Cumulative case number properties of nCoV-2019,
C [100K, 6000K ]
in China, outside the closed areas efficacy of Chinese control
Local reproduction number
Rloc destination country [1, 2.6]
in destination country
Probability of a importation
China and
θ chance that a case from the origin travelling to and [0, 0.00025]
destination country
mixing into the local population of the destination country
J. Clin. Med. 2020, 9, 571 10 of 12

We assume that the number of the imported cases entering the local population of the destination
country follows a binomial distribution, i.e., the probability pi corresponding to i imported cases in the
destination country with connectivity θ to China is given by
 
C i
pi = θ (1 − θ ) C −i .
i

We calculate the extinction probability z of a branching process initiated by a new infection in the
destination country. As in [19,20], we assume the number of secondary infections to follow a negative
binomial distribution with generator function
 k
q
g(z) = ,
1 − (1 − q ) z

with dispersion parameter k and mean µ = Rloc . Then, the probability parameter q of the distribution
is obtained as q = k+kR . The extinction probability of a branch is the solution of the fixed point
loc
equation z = g(z).
Assuming that the destination country has i imported cases from China that are mixed into the
local population, we estimate the probability of a major outbreak as the probability that not all the
branches started by those i individuals die out, which is 1 − zi . Thus, the expectation of the risk of a
major outbreak in country x can be calculated as

C
Riskx = ∑ pi (1 − zi ) = 1 − (θz + 1 − θ )C ,
i =0

where we used the binomial theorem to simplify the sum. Having the input values of the parameters
C, θ, Rloc , with this model we can numerically calculate the risk.

Appendix C.
The codes for the computations were implemented in Mathematica and in Python, and they are
available, including the used data, at [40].

References
1. Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical features
of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395, 497–506. [CrossRef]
2. WHO. Statement Regarding Cluster of Pneumonia Cases in Wuhan, China; World Health Organization: Geneva,
Switzerland, 2020. Available online: https://www.who.int/china/news/detail/09-01-2020-who-statement-
regarding-cluster-of-pneumonia-cases-in-wuhan-china (accessed on 17 February 2020).
3. WHO. Novel Coronavirus—Thailand (ex-China); World Health Organization: Geneva, Switzerland, 2020.
Available online: https://www.who.int/csr/don/14-january-2020-novel-coronavirus-thailand-ex-china/en
(accessed on 17 February 2020).
4. WHO. Novel Coronavirus (2019-nCoV) Situation Report—1; World Health Organization: Geneva, Switzerland,
2020. Available online: https://www.who.int/docs/default-source/coronaviruse/situation-reports/
20200121-sitrep-1-2019-ncov.pdf (accessed on 17 February 2020).
5. JHU IDD Team. 2019-nCoV Global Cases by Center for Systems Science and Engineering. 2020.
Available online: https://docs.google.com/spreadsheets/d/1wQVypefm946ch4XDp37uZ-wartW4V7ILdg-
qYiDXUHM/edit?usp=sharing (accessed on 17 February 2020).
6. CDC. 2019 Novel Coronavirus. Prevention & Treatment. Cent. Disease Control Prev. 2020. Available online: https:
//www.cdc.gov/coronavirus/2019-ncov/about/prevention-treatment.html (accessed on 17 February 2020).
7. NPR. Chinese Authorities Begin Quarantine Of Wuhan City As Coronavirus Cases Multiply. 2020.
Available online: https://www.npr.org/2020/01/23/798789671/chinese-authorities-begin-quarantine-of-
wuhan-city-as-coronavirus-cases-multiply (accessed on 17 February 2020).
J. Clin. Med. 2020, 9, 571 11 of 12

8. Cheng, W.C.C.; Wong, S.-C.; To, K.K.W.; Ho, P.L.; Yuen, K.-Y. Preparedness and proactive infection control
measures against the emerging Wuhan coronavirus pneumonia in China. J. Hosp. Infect. 2020. [CrossRef]
9. Arnot, M.; Mzezewa, T. The Coronavirus: What Travelers Need to Know; The New York Times: New York,
NY, USA, 2020. Available online: https://www.nytimes.com/2020/01/26/travel/Coronavirus-travel.html
(accessed on 17 February 2020).
10. National Health Commission of the People’s Republic of China. Work begins on mobile hospital in Wuhan.
2020. Available online: http://en.nhc.gov.cn/2020-01/29/c_76034.htm (accessed on 17 February 2020).
11. National Health Commission of the People’s Republic of China. Medics flood to Hubei to fight disease. 2020.
Available online: http://en.nhc.gov.cn/2020-01/29/c_76031.htm (accessed on 17 February 2020).
12. Parry, J. Pneumonia in China: lack of information raises concerns among Hong Kong health workers.
BMJ 2020. [CrossRef]
13. Moore, M.; Gelfeld, B.; Okunogbe, A.T.; Christopher, P. Identifying Future Disease Hot Spots: Infectious
Disease Vulnerability Index; RAND Corporation: Santa Monica, CA, USA, 2016. Available online: https:
//www.rand.org/pubs/research_reports/RR1605.html (accessed on 17 February 2020).
14. Bogoch, I.I.; Watts, A.; Thomas-Bachli, A.; Huber, C.; Kraemer, M.U.G.; Khan, K. Pneumonia of Unknown
Etiology in Wuhan, China: Potential for International Spread Via Commercial Air Travel. J. Travel Med. 2020.
[CrossRef]
15. Chinazzi, M.; Davis, J.T.; Gioannini, C.; Litvinova, M.; Pastore y Piontti, A.; Rossi, L.; Xiong, X.;
Halloran, M.E.; Longini, I.M.; Vespignani, A. Preliminary assessment of the International Spreading Risk
Associated with the 2019 novel Coronavirus (2019-nCoV) outbreak in Wuhan City. Lab. Model. Biol.
Soc.–Techn. Syst. 2020. Available online: https://www.mobs-lab.org/uploads/6/7/8/7/6787877/wuhan_
novel_coronavirus__6_.pdf (accessed on 17 February 2020).
16. Imai, N.; Dorigatti, I.; Cori, A.; Donnelly, C.; Riley, S.; Ferguson, N.M. Report 2: Estimating the potential
total number of novel Coronavirus cases in Wuhan City, China. Imper. Coll. London 2020. Available
online: https://www.imperial.ac.uk/media/imperial-college/medicine/sph/ide/gida-fellowships/2019-
nCoV-outbreak-report-22-01-2020.pdf (accessed on 17 February 2020).
17. Zhao, S.; Musa, S.S.; Lin, Q.; Ran, J.; Yang, G.; Wang, W.; Lou, Y.; Yang, L.; Gao, D.; He, D.; et al. Estimating
the Unreported Number of Novel Coronavirus (2019-nCoV) Cases in China in the First Half of January 2020:
A Data-Driven Modelling Analysis of the Early Outbreak. J. Clin. Med. 2020, 9, 388. [CrossRef] [PubMed]
18. Nishiura, H.; Jung, S.-M.; Linton, N.M.; Kinoshita, R.; Yang, Y.; Hayashi, K.; Kobayashi, T.; Yuan, B.;
Akhmetzhanov, A.R. The Extent of Transmission of Novel Coronavirus in Wuhan, China, 2020. J. Clin. Med.
2020, 9, 330. [CrossRef] [PubMed]
19. Imai, N.; Cori, A.; Dorigatti, I.; Baguelin, M.; Donnelly C.A.; Riley, S.; Ferguson, N.M. Report 3:
Transmissibility of 2019-nCoV. Imper. Coll. London 2020. Available online: https://www.imperial.ac.uk/
media/imperial-college/medicine/sph/ide/gida-fellowships/Imperial-2019-nCoV-transmissibility.pdf
(accessed on 17 February 2020).
20. Riou, J.; Althaus, C.L. Pattern of early human-to-human transmission of Wuhan 2019-nCoV. bioRχiv 2020.
[CrossRef]
21. Liu, T.; Hu, J.; Kang, M.; Lin, L.; Zhong, H.; Xiao, J.; He, G.; Song, T.; Huang, Q.; Rong, Z.; et al. Transmission
dynamics of 2019 novel coronavirus (2019-nCoV). bioRχiv 2020. [CrossRef]
22. Read, J.M.; Bridgen, J.R.E.; Cummings, D.A.T.; Ho, A.; Jewell, C.P. Novel coronavirus 2019-nCoV: early
estimation of epidemiological parameters and epidemic predictions. medRχiv 2020. [CrossRef]
23. Majumder, M.; Mandl, K.D. Early Transmissibility Assessment of a Novel Coronavirus in Wuhan, China.
SSRN 2020. [CrossRef]
24. Li, Q.; Guan, X.; Wu, P.; Wang, X.; Zhou, L.; Tong, Y.; Ren, R.; Leung, K.S.M.; Lau, E.H.Y.; Wong, J.Y.; et al.
Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia. N. Engl. J. Med.
2020. [CrossRef] [PubMed]
25. Kucharski, A.; Russell, T.; Diamond, C.; CMMID nCoV Working Group; Funk, S.; Eggo, R.M. Analysis of
early transmission dynamics of nCoV in Wuhan. 2020. Available online: https://cmmid.github.io/ncov/
wuhan_early_dynamics (accessed on 17 February 2020).
26. Shen, M.; Peng, Z.; Xiao, Y.; Zhang, L. Modelling the epidemic trend of the 2019 novel coronavirus outbreak
in China. bioRχiv 2020. Available online: https://www.biorxiv.org/content/10.1101/2020.01.23.916726v1
(accessed on 17 February 2020).
J. Clin. Med. 2020, 9, 571 12 of 12

27. Leung, K.; Wu, J.T.; Leung, G.M. Nowcasting and forecasting the potential domestic and international
spread of the 2019-nCoV outbreak originating in Wuhan, China: A modelling study. Lancet 2020. to appear.
[CrossRef]
28. Backer, J.A.; Klinkenberg, D.; Wallinga, J. The incubation period of 2019-nCoV infections among travellers
from Wuhan, China. medRχiv 2020. [CrossRef]
29. Linton, N.M.; Kobayashi, T.; Yang, Y.; Hayashi, K.; Akhmetzhanov, A.R.; Jung, S.-M.; Yuan, B.; Kinoshita, R.;
Nishiura, H. Epidemiological characteristics of novel coronavirus infection: A statistical analysis of publicly
available case data. medRχiv 2020. [CrossRef]
30. Zheng, Q.; Meredith, H.; Grantz, K.; Bi, Q.; Jones, F.; Lauer S.; JHU IDD Team. Real-time estimation of
the novel coronavirus incubation time. 2020. Available online: https://github.com/HopkinsIDD/ncov_
incubation (accessed on 17 February 2020).
31. Fisman, D.N.; Hauck, T.S.; Tuite, A.R.; Greer, A.L. An IDEA for Short Term Outbreak Projection: Nearcasting
Using the Basic Reproduction Number. PLoS ONE 2013, 8, 12. [CrossRef] [PubMed]
32. EpiRisk. Available online: http://epirisk.net (accessed on 17 February 2020).
33. Quilty, B.; Clifford, S.; CMMID nCoV Working Group; Flasche, S.; Eggo, R.M. Effectiveness of airport
screening at detecting travellers infected with 2019-nCoV. 2020. Available online: https://cmmid.github.io/
ncov/airport_screening_report/airport_screening_preprint_2020_01_28.pdf (accessed on 17 February 2020).
34. Britton, T. Stochastic epidemic models: A survey. Math. Biosci. 2020, 225, 24–35. [CrossRef] [PubMed]
35. Riley, S.; Fraser, C.; Donnelly, C.A.; Ghani, A.C.; Abu-Raddad, L.J.; Hedley, A.J.; Leung, G.M.; Ho, L-M.;
Lam, T-H.; Thach, T.Q.; et al. Transmission Dynamics of the Etiological Agent of SARS in Hong Kong:
Impact of Public Health Interventions. Science 2003, 300, 1961–1966. [CrossRef] [PubMed]
36. Park, S.W.; Champredon, D.; Earn, D.J.; Li, M.; Weitz, J.S.; Grenfell, B.T.; Dushoff, J. Reconciling
early-outbreak estimates of the basic reproductive number and its uncertainty: A new framework and
applications to the novel coronavirus (2019-nCoV) outbreak. medRχiv 2020. [CrossRef]
37. Wearing, H.J.; Rohani, P.; Keeling, M.J. Appropriate Models for the Management of Infectious Diseases.
PLoS Med. 2005, 2. [CrossRef] [PubMed]
38. Lauer S.; Zlojutro, A.; Rey, D.; Dong, E.; JHU IDD Team; UNSW Sydney rCITI Team. Update January 31:
Modeling the Spreading Risk of 2019-nCoV. 2020. Available online: https://systems.jhu.edu/research/
public-health/ncov-model-2 (accessed on 17 February 2020).
39. Nishiura, H.; Kobayashi, T.; Yang, Y.; Hayashi, K.; Miyama, T.; Kinoshita, R.; Linton, N.M.; Jung S-M.;
Yuan, B.; Suzuki, A.; et al. The Rate of Underascertainment of Novel Coronavirus (2019-nCoV) Infection:
Estimation Using Japanese Passengers Data on Evacuation Flights. J. Clin. Med. 2020, 9, 419. [CrossRef]
[PubMed]
40. Bolyai Institute, University of Szeged. Risk assessment of novel coronavirus 2019-nCoV outbreaks
outside China. Github 2020. Available online: https://github.com/zsvizi/corona-virus-2020 (accessed on
17 February 2020).

c 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
 6

Corona virus disease

(Covid-19) : sebuah
tinjauan literatur
WELLNESS AND HEALTHY MAGAZINE
Volume 2, Nomor 1, February 2020, p. 187
87 – 192
ISSN 2655-9951 (print), ISSN 2656-0062
0062 (online)

Corona virus diseases (Covid

Covid-19); Sebuah tinjauan literatur
Yuliana*)

Fakultas Kedokteran Universitas Lampung

Email: ylianaa98@gmail.com

ARTICLE INFO ABSTRACT

Coronavirus Disease (Covid-19).19). In 2020, a new type of coronavirus

(SARS-CoV-2) 2) was spread, called a disease called Coronavirus disease
Keyword: 2019 (COVID-19).19). This virus was discovered in Wuhan, China for the
Coronavirus first time and has infected 90,308 ppeople
eople as of March 2, 2020. The
Covid-19 number of deaths reached 3,087 people or 6%, the number of patients
Pneumonia recovering 45,726 people. This type of single positive RNA strain
Wuhan
infects the human respiratory tract and is sensitive to heat and can
effectively be activated by chlorine-containing
containing disinfectants. The source
of the host is thought to come from animals, especially bats, and other
*) corresponding author vectors such as bamboo rats, camels and ferrets. Common symptoms
include fever, cough and difficulty breathing. Clinical syndrome is
Mahasiswa, Fakultas Kedokteran, divided into uncomplicated, mild pneumonia and severe pneumonia.
Universitas Lampung Specimen examination is taken from the throat swab (nasopharynx and
Jl.Prof. Dr. Ir. Sumantri Brojonegoro No. 1,
Gedong Meneng, Kec. Rajabasa, Kota
oropharynx) and lower airway (sputum, bronchial rinse, endotracheal
Bandarlampung, 35145 Indonesia aspirate). Isolation was carried out on patients proven
prove to be infected
with Covid-19 to prevent wider spread.

This is an open access article under the CC–

–BY-SA license.

PENDAHULUAN
Diawal tahun 2020, dunia digemparkan dengan merebaknya virus baru yaitu coronavirus jenis baru
(SARS-CoV-2) 2) dan penyakitnya disebut Coronavirus disease 2019 (COVID
(COVID-19).
19). Diketahui, asal
mula virus ini berasal dari Wuhan, Tiongkok. Ditemukan pa
pada
da akhir Desember tahun 2019. Sampai
saat ini sudah dipastikan terdapat 65 negara yang telah terjangkit virus satu ini. (Data WHO, 1
Maret 2020) (PDPI, 2020).
Pada awalnya data epidemiologi
menunjukkan 66% pasien berkaitan atau terpajan dengan satu pasar seafood atau live market di
Wuhan, Provinsi Hubei Tiongkok (Huang, et.al., 2020). Sampel isolat dari pasien diteliti dengan

https://wellness.journalpress.id/wellness
lness.journalpress.id/wellness
Email: wellness.buletin@gmail.com
 Wellness and Healthy Magazine, 2(1), February 2020, – 188
Yuliana

hasil menunjukkan adanya infeksi coronavirus, jenis betacoronavirus tipe baru, diberi nama 2019
novel Coronavirus (2019-nCoV). Pada tanggal 11 Februari 2020,
World Health Organization memberi nama virus baru tersebut Severe acute respiratory syndrome
coronavirus-2 (SARS-CoV-2) dan nama penyakitnya sebagai Coronavirus disease 2019 (COVID-
19) (WHO, 2020). Pada mulanya transmisi virus ini belum dapat ditentukan apakah dapat melalui
antara manusia-manusia. Jumlah kasus terus bertambah seiring dengan waktu. Selain itu, terdapat
kasus 15 petugas medis terinfeksi oleh salah satu pasien. Salah satu pasien tersebut dicurigai kasus
“super spreader”. (Channel News Asia, 2020). Akhirnya dikonfirmasi bahwa transmisi pneumonia
ini dapat menular dari manusia ke manusia (Relman, 2020). Sampai saat ini virus ini dengan cepat
menyebar masih misterius dan penelitian masih terus berlanjut.
Saat ini ada sebanyak 65 negara terinfeksi virus corona. Menurut data WHO per tanggal 2 Maret
2020 jumlah penderita 90.308 terinfeksi Covid-19. Di Indonesia pun sampai saat ini terinfeksi 2
orang. Angka kematian mencapai 3.087 atau 2.3% dengan angka kesembuhan 45.726 orang.
Terbukti pasien konfrimasi Covid-19 di Indonesia berawal dari suatu acara di Jakarta dimana
penderita kontak dengan seorang warga negara asing (WNA) asal jepang yang tinggal di malaysia.
Setelah pertemuan tersebut penderita mengeluhkan demam, batuk dan sesak napas (WHO, 2020).
Berdasarkan data sampai dengan 2 Maret 2020, angka mortalitas di seluruh dunia 2,3% sedangkan
khusus di kota Wuhan adalah 4,9%, dan di provinsi Hubei 3,1%. Angka ini diprovinsi lain di
Tiongkok adalah 0,16%.8,9 Berdasarkan penelitian terhadap 41 pasien pertama di Wuhan terdapat 6
orang meninggal (5 orang pasien di ICU dan 1 orang pasien non-ICU) (Huang, et.al., 2020). Kasus
kematian banyak pada orang tua dan dengan penyakit penyerta. Kasus kematian pertama pasien
lelaki usia 61 tahun dengan penyakit penyerta tumor intraabdomen dan kelainan di liver (The Straits
Time, 2020).
Kejadian luar biasa oleh Coronavirus bukanlah merupakan kejadian yang pertama kali. Tahun 2002
severe acute respiratory syndrome (SARS) disebakan oleh SARS-coronavirus (SARS-CoV) dan
penyakit Middle East respiratory syndrome (MERS) tahun 2012
disebabkan oleh MERS-Coronavirus (MERS-CoV) dengan total akumulatif kasus sekitar 10.000
(1000-an kasus MERS dan 8000-an kasus SARS). Mortalitas akibat SARS sekitar 10% sedangkan
MERS lebih tinggi yaitu sekitar 40%. (PDPI, 2020).

METODE
Jurnal laporan kasus diambil dari kasus yang ada di puskesmas dan referensi dari berbagai sumber
dari (Medscape, emedicine, data WHO dan lain-lain) kemudian diambil ringkasan dari sumber
tersebut yang dijadikan satu menjadi bahan bacaan.

HASIL DAN PEMBAHASAN

Coronavirus merupakan virus RNA strain tunggal positif, berkapsul dan tidak bersegmen.
Coronavirus tergolong ordo Nidovirales, keluarga Coronaviridae. Struktur coronavirus membentuk
struktur seperti kubus dengan protein S berlokasi di
permukaan virus. Protein S atau spike protein merupakan salah satu protein antigen utama virus dan
merupakan struktur utama untuk penulisan gen. Protein S ini berperan dalam penempelan dan
masuknya virus kedalam sel host (interaksi protein S dengan reseptornya di sel inang) (Wang,
2020). Coronavirus bersifat sensitif terhadap panas dan secara efektif dapat diinaktifkan oleh
desinfektan mengandung klorin, pelarut lipid dengan suhu 56℃ selama 30 menit, eter, alkohol,

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 Wellness and Healthy Magazine, 2(1), February 2020, – 189
Yuliana

asam perioksiasetat, detergen non-ionik, formalin, oxidizing agent dan kloroform. Klorheksidin
tidak efektif dalam menonaktifkan virus (Wang, 2020; Korsman, 2012).
Patogenesis dan Patofisiologi
Kebanyakan Coronavirus menginfeksi hewan dan bersirkulasi di hewan. Coronavirus menyebabkan
sejumlah besar penyakit pada hewan dan kemampuannya menyebabkan penyakit berat pada hewan
seperti babi, sapi, kuda, kucing dan ayam. Coronavirus disebut dengan virus zoonotik yaitu virus
yang ditransmisikan dari hewan ke manusia. Banyak hewan liar yang dapat membawa patogen dan
bertindak sebagai vektor untuk penyakit menular tertentu. Kelelawar, tikus bambu, unta dan
musang merupakan host yang biasa ditemukan untuk Coronavirus. Coronavirus pada kelelawar
merupakan sumber utama untuk kejadian severe acute respiratorysyndrome (SARS) dan Middle
East respiratory syndrome (MERS) (PDPI, 2020).
Coronavirus hanya bisa memperbanyak diri melalui sel host-nya. Virus tidak bisa hidup tanpa sel
host. Berikut siklus dari Coronavirus setelah menemukan sel host sesuai tropismenya. Pertama,
penempelan dan masuk virus ke sel host diperantarai oleh Protein S yang ada dipermukaan virus.5
Protein S penentu utama dalam menginfeksi spesies host-nya serta penentu tropisnya (Wang, 2020).
Pada studi SARS-CoV protein S berikatan dengan reseptor di sel host yaitu enzim ACE-2
(angiotensin-converting enzyme 2). ACE-2 dapat ditemukan pada mukosa oral dan nasal,
nasofaring, paru, lambung, usus halus, usus besar, kulit, timus, sumsum tulang, limpa, hati, ginjal,
otak, sel epitel alveolar paru, sel enterosit usus halus, sel endotel arteri vena, dan sel otot polos.20
Setelah berhasil masuk selanjutnya translasi replikasi gen dari RNA genom virus. Selanjutnya
replikasi dan transkripsi dimana sintesis virus RNA melalui translasi dan perakitan dari kompleks
replikasi virus. Tahap selanjutnya adalah perakitan dan rilis virus (Fehr, 2015).Berikut gambar
siklus hidup virus (gambar 1).
Setelah terjadi transmisi, virus masuk ke saluran napas atas kemudian bereplikasi di sel epitel
saluran napas atas (melakukan siklus hidupnya). Setelah itu menyebar ke saluran napas bawah.
Pada infeksi akut terjadi peluruhan virus dari saluran napas dan virus dapat berlanjut meluruh
beberapa waktu di sel gastrointestinal setelah penyembuhan. Masa inkubasi virus sampai muncul
penyakit sekitar 3-7 hari (PDPI, 2020).
Manifestasi Klinis
Infeksi COVID-19 dapat menimbulkan gejala ringan, sedang atau berat. Gejala klinis utama yang
muncul yaitu demam (suhu >380C), batuk dan kesulitan bernapas. Selain itu dapat disertai dengan
sesak memberat, fatigue, mialgia, gejala gastrointestinal seperti diare dan gejala saluran napas lain.
Setengah dari pasien timbul sesak dalam satu minggu. Pada kasus berat perburukan secara cepat
dan progresif, seperti ARDS, syok septik, asidosis metabolik yang sulit dikoreksi dan
perdarahan atau disfungsi sistem koagulasi dalam beberapa hari. Pada beberapa pasien, gejala yang
muncul ringan, bahkan tidak disertai dengan demam. Kebanyakan pasien memiliki prognosis baik,
dengan sebagian kecil dalam kondisi kritis bahkan meninggal. Berikut sindrom klinis yang dapat
muncul jika terinfeksi. (PDPI, 2020). Berikut sindrom klinis yang dapat muncul jika terinfeksi.
(PDPI, 2020)
a. Tidak berkomplikasi
Kondisi ini merupakan kondisi teringan. Gejala yang muncul berupa gejala yang tidak spesifik.
Gejala utama tetap muncul seperti demam, batuk, dapat disertai dengan nyeri tenggorok,
kongesti hidung, malaise, sakit kepala, dan nyeri otot. Perlu diperhatikan bahwa pada pasien
dengan lanjut usia dan pasien immunocompromises presentasi gejala menjadi tidak khas atau
atipikal. Selain itu, pada beberapa kasus ditemui tidak disertai dengan demam dan gejala relatif

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 Wellness and Healthy Magazine, 2(1), February 2020, – 190
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ringan. Pada kondisi ini pasien tidak memiliki gejala komplikasi diantaranya dehidrasi, sepsis
atau napas pendek.
b. Pneumonia ringan
Gejala utama dapat muncul seperti demam, batuk, dan sesak. Namun tidak ada tanda
pneumonia berat. Pada anak-anak dengan pneumonia tidak berat ditandai dengan batuk atau
susah bernapas
c. Pneumonia berat. Pada pasien dewasa:
· Gejala yang muncul diantaranya demam atau curiga infeksi saluran napas
· Tanda yang muncul yaitu takipnea (frekuensi napas: > 30x/menit), distress pernapasan berat
atau saturasi oksigen pasien <90% udara luar. 26
Penegakkan Diagnosis
Pada anamnesis gejala yang dapat ditemukan yaitu, tiga gejala utama: demam, batuk kering
(sebagian kecil berdahak) dan sulit bernapas atau sesak.
a. Pasien dalam pengawasan atau kasus suspek / possible
1. Seseorang yang mengalami:
a. Demam (≥380C) atau riwayat demam
b. Batuk atau pilek atau nyeri tenggorokan
c. Pneumonia ringan sampai berat berdasarkan klinis dan/atau gambaran radiologis. (pada
pasien immunocompromised presentasi kemungkinan atipikal) DAN disertai minimal satu
kondisi sebagai berikut :
· Memiliki riwayat perjalanan ke Tiongkok atau wilayah/ negara yang terjangkit*
dalam 14 hari sebelum timbul gejala
· Petugas kesehatan yang sakit dengan gejala sama setelah merawat pasien infeksi
saluran pernapasan akut (ISPA) berat yang tidak diketahui penyebab / etiologi
penyakitnya, tanpa memperhatikan riwayat bepergian atau tempat tinggal.29
2. Pasien infeksi pernapasan akut dengan tingkat keparahan ringan sampai berat dan salah satu
berikut dalam 14 hari sebelum onset gejala:
a. Kontak erat dengan pasien kasus terkonfirmasi atau probable COVID-19, ATAU
b. Riwayat kontak dengan hewan penular (jika hewan sudah teridentifikasi), ATAU
c. bekerja atau mengunjungi fasilitas layanan kesehatan dengan kasus terkonfirmasi atau
probable infeksi COVID-19 di Tiongkok atau wilayah/negara yang terjangkit.*
d. Memiliki riwayat perjalanan ke Wuhan dan memiliki demam (suhu ≥380C) atau riwayat
demam.29
b. Orang dalam Pemantauan
Seseorang yang mengalami gejala demam atau riwayat demam tanpa pneumonia yang memiliki
riwayat perjalanan ke Tiongkok atau wilayah/negara yang terjangkit, dan tidak memiliki satu
atau lebih riwayat paparan diantaranya:
· Riwayat kontak erat dengan kasus konfirmasi COVID-19
· Bekerja atau mengunjungi fasilitas kesehatan yang berhubungan dengan pasien konfirmasi
COVID-19 di Tiongkok atau wilayah/negara yang terjangkit (sesuai dengan perkembangan
penyakit),
· Memiliki riwayat kontak dengan hewan penular (jika hewan penular sudah teridentifikasi) di
Tiongkok atau wilayah/negara yang terjangkit (sesuai dengan perkembangan penyakit

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 Wellness and Healthy Magazine, 2(1), February 2020, – 191
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c. Kasus Probable
Pasien dalam pengawasan yang diperiksakan untuk COVID-19 tetapi inkonklusif atau tidak
dapat disimpulkan atau seseorang dengan hasil konfirmasi positif pan-coronavirus atau beta
coronavirus.29,30
d. Kasus terkonfirmasi
Seseorang yang secara laboratorium terkonfirmasi COVID-19.

Pemeriksaan Penunjang (PDPI, 2020)

1. Pemeriksaan radiologi: foto toraks, CT-scan toraks, USG toraks. Pada pencitraan dapat
menunjukkan: opasitas bilateral, konsolidasi subsegmental, lobar atau kolaps paru atau nodul,
tampilan groundglass.
2. Pemeriksaan spesimen saluran napas atas dan bawah
· Saluran napas atas dengan swab tenggorok(nasofaring dan orofaring)
· Saluran napas bawah (sputum, bilasan bronkus, BAL, bila menggunakan endotrakeal tube
dapat berupa aspirat endotrakeal
3. Bronkoskopi
4. Pungsi pleura sesuai kondisi
5. Pemeriksaan kimia darah
6. Biakan mikroorganisme dan uji kepekaan dari bahan saluran napas (sputum, bilasan bronkus,
cairan pleura) dan darah26,27 Kultur darah untuk bakteri dilakukan, idealnya sebelum terapi
antibiotik. Namun, jangan menunda terapi antibiotik dengan menunggu hasil kultur darah)26
7. Pemeriksaan feses dan urin (untuk investasigasi kemungkinan penularan).
Tatalaksana Umum
1. Isolasi pada semua kasus
Sesuai dengan gejala klinis yang muncul, baik ringan maupun sedang.
2. Implementasi pencegahan dan pengendalian infeksi (PPI)26
3. Serial foto toraks untuk menilai perkembangan penyakit27
4. Suplementasi oksigen
Pemberian terapi oksigen segera kepada pasien dengan, distress napas, hipoksemia atau syok.
Terapi oksigen pertama sekitar 5L/menit dengan target SpO2 ≥90% pada pasien tidak hamil
dan ≥ 92-95% pada pasien hamil
5. Kenali kegagalan napas hipoksemia berat
6. Terapi cairan
Terapi cairan konservatif diberikan jika tidak ada bukti syok Pasien dengan SARI harus
diperhatikan dalam terapi cairannya, karena jika pemberian cairan terlalu agresif dapat
memperberat kondisi distress napas atau oksigenasi. Monitoring keseimbangan cairan dan
elektrolit
7. Pemberian antibiotik empiris
8. Terapi simptomatik
Terapi simptomatik diberikan seperti antipiretik, obat batuk dan lainnya jika memang
diperlukan.
9. Pemberian kortikosteroid sistemik tidak rutin diberikan pada tatalaksana pneumonia viral atau
ARDS selain ada indikasi lain.
10. Observasi ketat
11. Pahami komorbid pasien
Saat ini belum ada penelitian atau bukti talaksana spesifik pada COVID-19. Belum ada tatalaksana
antiviral untuk infeksi Coronavirus yang terbukti efektif. Pada studi terhadap SARSCoV, kombinasi

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 Wellness and Healthy Magazine, 2(1), February 2020, – 192
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lopinavir dan ritonavir dikaitkan dengan memberi manfaat klinis. Saat ini penggunaan lopinavir dan
ritonavir masih diteliti terkait efektivitas dan keamanan pada infeksi COVID-19. Tatalaksana yang
belum teruji / terlisensi hanya boleh diberikan dalam situasi uji klinis yang disetujui oleh komite
etik atau melalui Monitored Emergency Use of Unregistered Interventions Framework (MEURI),
dengan pemantauan ketat. Selain itu, saat ini belum ada vaksin untuk mencegah pneumonia
COVID-19 ini (PDPI, 2020).

SIMPULAN DAN SARAN

Covid-19 merupakan infeksi virus baru yang mengakibatkan terinfeksinya 90.308 orang per tanggal
2 Maret 2020. Virus ini bermula di Wuhan, China pada 31 Desember 2019. Virus yang merupakan
virus RNA strain tunggal positif ini menginfeksi saluran pernapasan. Penegakan diagnosis dimulai
dari gejala umum berupa demam, batuk dan sulit bernapas hingga adanya kontak erat dengan
negara-negara yang sudah terifinfeksi. Pengambilan swab tenggorokan dan saluran napas menjadi
dasar penegakan diagnosis coronavirus disease. Penatalaksanaan berupa isolasi harus dilakukan
untuk mencegah penyebaran lebih lanjut.

DAFTAR PUSTAKA
Channel News Asia. (2020). Wuhan virus outbreak: 15 medical workers infected, 1 in critical
condition. [Homepage on The Internet]. Cited Jan 28th 2020. Available
on:https://www.channelnewsasia.com/news/asia/wuhanpneumonia-outbreak-health-workers-
coronavirus-12294212
Fehr, A.R., Perlman, S. (2015). Coronavirus: An Overview of Their Replication and Pathogenesis.
Methods Mol Biol. 2015 ; 1282: 1–5
Huang, C., Wang, Y., Li, X., Ren, L., Zhao ,J., Zan,g Li., Fan, G., etc. (2020). Clinical features of
patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet. 24 jan 2020.
Korsman, S.N.J., van Zyl, G.U., Nutt, L., Andersson, M.I, Presier, W. (2012). Viroloy. Chins:
Churchill Livingston Elsevier
Perhimpunan Dokter Paru Indonesia. (2020). Panduan Praktik Klinis: Pneumonia 2019-nCoV.
PDPI: Jakarta
Relman, E. (2020). Business insider Singapore. Cited Jan 28th 2020. Available
on:https://www.businessinsider.sg/deadly-china-wuhan-virusspreading- human-to-human-
officials-confirm-2020- 1/?r=US&IR=T.
WHO. (2020). WHO Director-General’s remarks at the media briefing on 2019-nCov on 11
February 2020. Cited Feb 13rd 2020. Available on:
https://www.who.int/dg/speeches/detail/who-director-generals- remarks-at-the-media-
briefing-on-2019-ncov-on-11-february- 2020. (Feb 12th 2020)
Wang, Z., Qiang, W., Ke, H. (2020). A Handbook of 2019-nCoV Pneumonia Control and
Prevention. Hubei Science and Technologi Press. China

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