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January 23, 2020

Coronavirus Infections—More Than Just the Common Cold

Author Affiliations
  • 1Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania
  • 2National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
JAMA. 2020;323(8):707-708. doi:10.1001/jama.2020.0757

Human coronaviruses (HCoVs) have long been considered inconsequential pathogens, causing the “common cold” in otherwise healthy people. However, in the 21st century, 2 highly pathogenic HCoVs—severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV)—emerged from animal reservoirs to cause global epidemics with alarming morbidity and mortality. In December 2019, yet another pathogenic HCoV, 2019 novel coronavirus (2019-nCoV), was recognized in Wuhan, China, and has caused serious illness and death. The ultimate scope and effect of this outbreak is unclear at present as the situation is rapidly evolving.

Coronaviruses are large, enveloped, positive-strand RNA viruses that can be divided into 4 genera: alpha, beta, delta, and gamma, of which alpha and beta CoVs are known to infect humans.1 Four HCoVs (HCoV 229E, NL63, OC43, and HKU1) are endemic globally and account for 10% to 30% of upper respiratory tract infections in adults. Coronaviruses are ecologically diverse with the greatest variety seen in bats, suggesting that they are the reservoirs for many of these viruses.2 Peridomestic mammals may serve as intermediate hosts, facilitating recombination and mutation events with expansion of genetic diversity. The surface spike (S) glycoprotein is critical for binding of host cell receptors and is believed to represent a key determinant of host range restriction.1

Until recently, HCoVs received relatively little attention due to their mild phenotypes in humans. This changed in 2002, when cases of severe atypical pneumonia were described in Guangdong Province, China, causing worldwide concern as disease spread via international travel to more than 2 dozen countries.2 The new disease became known as severe acute respiratory syndrome (SARS), and a beta-HCoV, named SARS-CoV, was identified as the causative agent. Because early cases shared a history of human-animal contact at live game markets, zoonotic transmission of the virus was strongly suspected.3 Palm civets and raccoon dogs were initially thought to be the animal reservoir(s); however, as more viral sequence data became available, consensus emerged that bats were the natural hosts.

Common symptoms of SARS included fever, cough, dyspnea, and occasionally watery diarrhea.2 Of infected patients, 20% to 30% required mechanical ventilation and 10% died, with higher fatality rates in older patients and those with medical comorbidities. Human-to-human transmission was documented, mostly in health care settings. This nosocomial spread may be explained by basic virology: the predominant human receptor for the SARS S glycoprotein, human angiotensin-converting enzyme 2 (ACE2), is found primarily in the lower respiratory tract, rather than in the upper airway. Receptor distribution may account for both the dearth of upper respiratory tract symptoms and the finding that peak viral shedding occurred late (≈10 days) in illness when individuals were already hospitalized. SARS care often necessitated aerosol-generating procedures such as intubation, which also may have contributed to the prominent nosocomial spread.

Several important transmission events did occur in the community, such as the well-characterized mini-outbreak in the Hotel Metropole in Hong Kong from where infected patrons traveled and spread SARS internationally. Another outbreak occurred at the Amoy Gardens housing complex where more than 300 residents were infected, providing evidence that airborne transmission of SARS-CoV can sometimes occur.4 Nearly 20 years later, the factors associated with transmission of SARS-CoV, ranging from self-limited animal-to-human transmission to human superspreader events, remain poorly understood.

Ultimately, classic public health measures brought the SARS pandemic to an end, but not before 8098 individuals were infected and 774 died.2 The pandemic cost the global economy an estimated $30 billion to $100 billion.1 SARS-CoV demonstrated that animal CoVs could jump the species barrier, thereby expanding perception of pandemic threats.

In 2012, another highly pathogenic beta-CoV made the species jump when Middle East respiratory syndrome (MERS) was recognized and MERS-CoV was identified in the sputum of a Saudi man who died from respiratory failure.3 Unlike SARS-CoV, which rapidly spread across the globe and was contained and eliminated in relatively short order, MERS has smoldered, characterized by sporadic zoonotic transmission and limited chains of human spread. MERS-CoV has not yet sustained community spread; instead, it has caused explosive nosocomial transmission events, in some cases linked to a single superspreader, which are devastating for health care systems. According to the World Health Organization (WHO), as of November 2019, MERS-CoV has caused a total of 2494 cases and 858 deaths, the majority in Saudi Arabia. The natural reservoir of MERS-CoV is presumed to be bats, yet human transmission events have primarily been attributed to an intermediate host, the dromedary camel.

MERS shares many clinical features with SARS such as severe atypical pneumonia, yet key differences are evident. Patients with MERS have prominent gastrointestinal symptoms and often acute kidney failure, likely explained by the binding of the MERS-CoV S glycoprotein to dipeptidyl peptidase 4 (DPP4), which is present in the lower airway as well as the gastrointestinal tract and kidney.3 MERS necessitates mechanical ventilation in 50% to 89% of patients and has a case fatality rate of 36%.2

While MERS has not caused the international panic seen with SARS, the emergence of this second, highly pathogenic zoonotic HCoV illustrates the threat posed by this viral family. In 2017, the WHO placed SARS-CoV and MERS-CoV on its Priority Pathogen list, hoping to galvanize research and the development of countermeasures against CoVs.

The action of the WHO proved prescient. On December 31, 2019, Chinese authorities reported a cluster of pneumonia cases in Wuhan, China, most of which included patients who reported exposure to a large seafood market selling many species of live animals. Emergence of another pathogenic zoonotic HCoV was suspected, and by January 10, 2020, researchers from the Shanghai Public Health Clinical Center & School of Public Health and their collaborators released a full genomic sequence of 2019-nCoV to public databases, exemplifying prompt data sharing in outbreak response. Preliminary analyses indicate that 2019-nCoV has some amino acid homology to SARS-CoV and may be able to use ACE2 as a receptor. This has important implications for predicting pandemic potential moving forward. The situation with 2019-nCoV is evolving rapidly, with the case count currently growing into the hundreds. Human-to-human transmission of 2019-nCoV occurs, as evidenced by the infection of 15 health care practitioners in a Wuhan hospital. The extent, if any, to which such transmission might lead to a sustained epidemic remains an open and critical question. So far, it appears that the fatality rate of 2019-nCoV is lower than that of SARS-CoV and MERS-CoV; however, the ultimate scope and effects of the outbreak remain to be seen.

Drawing on experience from prior zoonotic CoV outbreaks, public health authorities have initiated preparedness and response activities. Wuhan leaders closed and disinfected the first identified market. The United States and several other countries have initiated entry screening of passengers from Wuhan at major ports of entry. Health practitioners in other Chinese cities, Thailand, Japan, and South Korea promptly identified travel-related cases, isolating individuals for further care. The first travel-related case in the United States occurred on January 21 in a young Chinese man who had visited Wuhan.

Additionally, biomedical researchers are initiating countermeasure development for 2019-nCoV using SARS-CoV and MERS-CoV as prototypes. For example, platform diagnostic modalities are being rapidly adapted to include 2019-nCoV, allowing early recognition and isolation of cases. Broad-spectrum antivirals, such as remdesivir, an RNA polymerase inhibitor, as well as lopinavir/ritonavir and interferon beta have shown promise against MERS-CoV in animal models and are being assessed for activity against 2019-nCoV.5 Vaccines, which have adapted approaches used for SARS-CoV or MERS-CoV, are also being pursued. For example, scientists at the National Institute of Allergy and Infectious Diseases Vaccine Research Center have used nucleic acid vaccine platform approaches.6 During SARS, researchers moved from obtaining the genomic sequence of SARS-CoV to a phase 1 clinical trial of a DNA vaccine in 20 months and have since compressed that timeline to 3.25 months for other viral diseases. For 2019-nCoV, they hope to move even faster, using messenger RNA (mRNA) vaccine technology. Other researchers are similarly poised to construct viral vectors and subunit vaccines.

While the trajectory of this outbreak is impossible to predict, effective response requires prompt action from the standpoint of classic public health strategies to the timely development and implementation of effective countermeasures. The emergence of yet another outbreak of human disease caused by a pathogen from a viral family formerly thought to be relatively benign underscores the perpetual challenge of emerging infectious diseases and the importance of sustained preparedness.

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Article Information

Corresponding Author: Anthony S. Fauci, MD, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, 31 Center Dr, MSC 2520, Bldg 31, Room 7A-03, Bethesda, MD 20892-2520 (afauci@niaid.nih.gov).

Published Online: January 23, 2020. doi:10.1001/jama.2020.0757

Conflict of Interest Disclosures: None reported.

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3 Comments for this article
Lets step back a bit and take a breath
Maurice Stutzman, Ohio State University, MD | Family Medicine, Private Practice
Is anyone wondering, like me, about Washington State's nursing home coronavirus cases? Thus far, there is no known connection to the “novel” COVID-19 virus originating from China. So, this coronavirus’ source seems to be local. Primary care physicians who do geriatric care and take care of patients in nursing homes often have had “clusters” of patients who died from respiratory disease despite testing negative for the usual culprits. Our final diagnosis would then be recorded as “Pneumonia - unspecified.”

Due to the availability of new diagnostic tools and treatments, we have new diseases, or have seen an increase in
diagnosis of certain diseases almost unheard of 40 or 50 years ago. Chronic diseases such as sleep apnea are now tested for and treated. Due to aggressive screening and the benefits of early autism treatment, by necessity, its diagnosis has increased. (No it is not due to immunizations.) We now have an over-diagnosis of Vitamin D deficiency due to the use of arbitrarily defined “normal” levels.

The ability to test for a disease increases the likeliness of its diagnosis. Today, the diagnosis of coronavirus is directly proportional to the amount of testing being done. Hence, S. Korea (besides China - whose testing numbers are unknown) has the most diagnoses. As of March 2, South Korea performed 106,591 with Italy next at 23,345. It is no surprise that these two countries (outside of China) have the highest incidence of COVID-19 infections. As testing becomes prevalent in the US, we are going to see similar increases in its diagnosis due to the “novel” discovery that coronavirus rather than being pandemic is a virus that has natural endemic and seasonal characteristics.

As with all endemic viruses, its spread is directly proportional to population density, crowded living conditions, and time of the year. Hence, its spread in China, cruise ships, and nursing homes this winter with the majority of deaths seen among our most vulnerable.

Whether this coronavirus strain is more virulent (see swine flu), may act synergistically with other viruses (see Hepatitis A with Hepatitis C), or is just affecting highly vulnerable populations (elderly frail, immuno-compromised) is not yet fully known.

What is known is that South Korea’s (one of the most thoroughly tested populations thus far) fatality rate for COVID-19 after testing nearly 140,000 people is 0.6%. For comparison, during the 2018/2019 US influenza endemic, the 65 and older population had a death rate of 0.83%.

So what can we do? Promote prevention. Get immunizations up to date. Constantly use infection precautions. Be diligent, and we should be fine. A vaccine should help.
Comment for Maurice Stuzman:"Lets step back and take a breath"
Mike Mage, Scientist Emeritus | NIH
The genomic sequences of the SARS-CoV-2 isolates seem to fit the pattern of originating from the first cases in Wuhan in December 2019.


If the same data support these sequences being compatible with a "natural endemic", please point us to the analysis.
Prescient Caution about COVID-19 and the Common Cold
Michael McAleer, PhD (Econometrics), Queen's | Asia University, Taiwan
Although published on 23 January 2020, and before the World Health Authority (WHO) named the disease COVID-19 on 11 February 2020 and declared it a pandemic on 11 Match 2020, much of the contents of this Viewpoint are strikingly prescient.

A cautionary tale was: “The ultimate scope and effect of this outbreak is unclear at present as the situation is rapidly evolving” and “the ultimate scope and effects of the outbreak remain to be seen.”

The world has changed rapidly since the initial critical analysis.

Like SARS, where the transmission process does not yet seem to be
fully understood, higher fatality rates from COVID-19 have occurred in older patients and those experiencing medical comorbidities, among other factors.

Despite the WHO having placed SARS-CoV and MERS-CoV on its Priority Pathogen list in 2017, safe and effective vaccines have not yet been discovered.

The paper ends with the warning:

“Effective response requires prompt action from the standpoint of classic public health strategies to the timely development and implementation of effective countermeasures … and sustained preparedness.”

Almost 8 weeks after publication, the prescient caution that was highlighted stands in stark contrast to what has transpired from a public health perspective.