1) The letter discusses the possibility that the Covid-19 virus originated from zoonotic spillover in Southeast Asia rather than Wuhan, China based on cases detected in pangolins in that region. 2) Surveillance of coronaviruses in pangolins is needed to address the possibility of novel coronavirus spillover from animals to humans in Southeast Asia. 3) The authors respond that genomic sequencing, observational studies, and modeling are needed to distinguish repeated zoonotic spillover events from human-to-human transmission.

1. C or r e sp ondence
The new engl and jour nal of medicine
n engl j med nejm.org 1
Epidemiology of Covid-19
To the Editor: With regard to the Perspective
article by Lipsitch et al. (published Feb. 19 at
NEJM.org),1
cases of Covid-19 (the illness caused
by SARS-CoV-2 infection) with no epidemiologic
link to travel to China or known cases outside
China have caused international concern about
undetected introduction of the virus from sub-
clinical infection. It is also possible that local
zoonotic spillover of this coronavirus from an
intermediate animal reservoir or reservoirs into
human populations might have occurred, par-
ticularly in Southeast Asia.
For example, coronaviruses that are phyloge-
netically close to SARS-CoV-2 have been detected
in pangolins (scaly anteaters),2
especially in
Malayan pangolins (also known as Sunda pan-
golins) that are obtained in antismuggling op-
erations in Guangdong Province and the Guangxi
Zhuang Autonomous Region in China.3
This spe-
cies, which is located throughout Southeast Asia,
is thus currently considered to be a potential in-
termediate host of SARS-CoV-2. In addition, a
recent phyloepidemiologic analysis suggested that
the Covid-19 outbreak did not arise from a “Big
Bang”–like event at Huanan Seafood Wholesale
Market in Wuhan, China, but rather it may have
originated elsewhere and probably involved more
than one zoonotic spillover.4
Finally, a person with
a confirmed case of Covid-19 in Shanghai was
probably infected by consuming bush meat
(i.e., wild animals hunted for food) while travel-
ing in Guangdong Province in China.5
Taken together, the possibility of novel coro-
navirus spillover to humans in Southeast Asia
cannot be ruled out. Surveillance to detect coro-
naviruses in pangolins is needed to address this
concern.
Xiaodong Zhang, Ph.D.
Jilin University
Changchun, China
zhang_xd@​­jlu​.­edu​.­cn
No potential conflict of interest relevant to this letter was
reported.
This letter was published on March 27, 2020, at NEJM.org.
1. Lipsitch M, Swerdlow DL, Finelli L. Defining the epidemi-
ology of Covid-19 — studies needed. N Engl J Med 2020;382:
1194-6.
2. Cyranoski D. Did pangolins spread the China coronavirus to
people? Nature 2020:​February 20 (Epub ahead of print).
3. Lam TT-Y, Shum MH-H, Zhu H-C, et al. Identification of
2019-nCoV related coronaviruses in Malayan pangolins in south-
ern China. bioRxiv. February 18, 2020 (https://www​.biorxiv​.org/​
content/​10​.1101/​2020​.02​.13​.945485v1).
4. Yu W-B, Tang G-D, Zhang L, Corlett RT. Decoding evolution
and transmissions of novel pneumonia coronavirus using the
whole genomic data. ChinaXiv. February 21, 2020 (http://
chinaxiv​.org/​abs/​202002​.00033).
5. Newly 14 increased cases infected with novel coronavirus in
Shanghai (in Chinese). January 29, 2020 (https://news​.163​.com/​
20/​0129/​09/​F424CO6A0001899O​.html).
DOI: 10.1056/NEJMc2005157
The authors reply: Zhang hypothesizes that
Covid-19 cases continue to occur from repeated
zoonotic spillover events from pangolins to hu-
mans. There are several ways to distinguish repeat-
ed spillover events from human-to-human trans-
mission. Genomic sequencing of animal and
human isolates as well as observational studies,1
case–control studies,2
and modeling can distin-
guish the number of independent introductions
from animals to humans.3
Zhang’s citations nei-
ther support nor refute the spillover hypothesis,
whereas sequencing data provide support for
worldwide human-to-human transmission.4
Nev-
ertheless, we agree that surveillance to detect
spillover events is important.
Since our Perspective article about Covid-19
was published, much has been learned about case
fatality rates, transmission, asymptomatic cases,
and risk factors for severe disease and death. We
have seen marked declines in transmission in
some areas. Now is the time to conduct com-
munity household serosurveys to answer two im-
portant outstanding questions: How many infec-
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2. The new engl and jour nal of medicine
n engl j med nejm.org2
tions are out there, going undetected? And what
level of population-wide immunity is being at-
tained? The answers to those questions have
worldwide implications.
David L. Swerdlow, M.D.
Pfizer Vaccines
Collegeville, PA
Lyn Finelli, Dr.P.H.
Merck
Kenilworth, NJ
Marc Lipsitch, D.Phil.
Harvard T.H. Chan School of Public Health
Boston, MA
mlipsitc@​­hsph​.­harvard​.­edu
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
This letter was published on March 27, 2020, at NEJM.org.
1. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coro-
navirus disease 2019 in China. N Engl J Med. DOI:​10.1056/
NEJMoa2002032.
2. Alraddadi BM, Watson JT, Almarashi A, et al. Risk factors for
primary Middle East respiratory syndrome coronavirus illness in
humans, Saudi Arabia, 2014. Emerg Infect Dis 2016;​22:​49-55.
3. Cauchemez S, Epperson S, Biggerstaff M, Swerdlow D, Fi-
nelli L, Ferguson NM. Using routine surveillance data to esti-
mate the epidemic potential of emerging zoonoses: application
to the emergence of US swine origin influenza A H3N2v virus.
PLoS Med 2013;​10:​e1001399.
4. The COVID-19 Investigation Team. First 12 patients with
coronavirus disease 2019 (COVID-19) in the United States.
medRxiv preprint. DOI:​​10.1101/2020.03.09.20032896.
DOI: 10.1056/NEJMc2005157
Correspondence Copyright © 2020 Massachusetts Medical Society.
The New England Journal of Medicine
Downloaded from nejm.org by ROD STER on March 28, 2020. For personal use only. No other uses without permission.
Copyright © 2020 Massachusetts Medical Society. All rights reserved.