How Is the New Coronavirus (SARS-CoV-2) Transmitted and How Does It Cause Disease? The Latest Scientific Developments

This comprehensive review was prepared by a physician-scientist working in the Division of Infection and Global Health at Saint Andrews University School of Medicine in England, Müge Çevik and her team and published on 23 October in The BMJ (British Medical Journal) (Müge Çevik's biography can be found at the end of this article).

A Brief Summary of SARS-CoV-2 — What You Need to Know:

• The Covid-19 pandemic is caused by the novel coronavirus SARS-CoV-2, which is genetically similar to SARS-CoV-1. However, SARS-CoV-2's characteristics, such as structural differences in its surface protein and viral-load kinetics, may help explain why it has caused a more serious outbreak.
• The highest SARS-CoV-2 load in the respiratory tract is observed at symptom onset or during the first week of illness. The highest potential for transmission is during or immediately before the first five days of symptom onset and subsequently declines.
• RT-PCR (Reverse Transcriptase – Polymerase Chain Reaction) tests can detect viral SARS-CoV-2 RNA in the upper respiratory tract for an average of 17 days. However, detecting viral RNA does not necessarily mean infectiousness, and viral culture is rarely positive after 9 days of illness.
• In the spread of SARS-CoV-2, symptomatic (showing symptoms) and presymptomatic (1-2 days before symptoms begin) transmission probably play a greater role than asymptomatic transmission (from people who show no symptoms throughout the illness).
• A wide range of virus-neutralizing antibodies has been reported. Emerging evidence suggests that these may be associated with disease severity but decline over time.

Covid-19 as a 2-Stage Disease

Since SARS-CoV-2 emerged in December 2019, a worldwide effort has been made to characterize the virus and the clinical course of the disease it causes.

Coronavirus disease 2019 (Covid-19), caused by SARS-CoV-2, most likely follows a two-stage model combining an early viral-response phase and an inflammatory second phase in its development.

Most patients experience mild Covid-19. Rather than directly presenting as severe pneumonia, Covid-19 begins with fever, cough, fatigue, muscle pain, headache and loss of taste and smell. In this respect it shares some symptoms with seasonal influenza (see Covid-19 Symptoms and Differences from Influenza).

This review provides a broad update on SARS-CoV-2 pathophysiology, including virology, transmission dynamics and immune responses to the virus. The article will be updated as new information emerges.

What Is the Structure of the New Coronavirus?

SARS-CoV-2, which closely resembles SARS-CoV-1 and the bat coronavirus RaTG13, is an enveloped β-coronavirus in classification.

The viral envelope is coated with spike (S) glycoprotein, envelope (E) and membrane (M) proteins.

Attachment and entry of the virus into human cells are mediated by the S protein. The first step in infection is attachment to a host cell through the virus's target receptor. S1, a subunit of the S protein, contains a receptor-binding domain that binds to the peptidase domain of angiotensin-converting enzyme 2 (ACE2). The S2 subunit in SARS-CoV-2 is highly conserved and considered a potential antiviral drug target. Viral structure and the replication cycle are described in Figure 1.

Figure 1: (1) The virus binds to ACE2 as its host target-cell receptor, in synergy with the host's transmembrane serine protease (a cell-surface protein), expressed mainly in airway epithelial lining cells and vascular endothelial cells. This leads to membrane fusion and releases the viral genome into the host cytoplasm (2). Stages 3 and 7 show the remaining steps of viral replication, leading to viral assembly, maturation and release.

Coronaviruses have proofreading (a kind of genetic-code repair mechanism) during replication, so their mutation rates are lower than those of other RNA viruses.

As SARS-CoV-2 has spread worldwide, it has accumulated some mutations containing geographical signatures in its genome, like other viruses. Researchers study these mutations to characterize the virus and understand its epidemiology and pattern of spread. In general, mutations have caused changes affecting viral transmissibility or pathogenicity.

The G614 variant in the S protein has been proposed to increase viral transmissibility and infectivity. Higher viral loads have been reported in samples containing G614 than in variant D614, although no association with disease severity measured by hospitalization outcomes has been established. These findings have not yet been confirmed in natural infection.

Why Is SARS-CoV-2 More Transmissible than SARS-CoV-1?

SARS-CoV-2, compared with SARS-CoV-1, has a higher reproduction number (R0) indicating much more efficient spread. Many features of SARS-CoV-2 may help explain this increased transmissibility. While both SARS-CoV-1 and SARS-CoV-2 preferentially interact with angiotensin-converting enzyme 2 (ACE2), structural differences in SARS-CoV-2 surface proteins allow stronger binding to the ACE2 receptor and greater efficiency in invaded host cells. SARS-CoV-2 also has greater affinity for the upper respiratory tract and conjunctiva (the membrane lining the eyelids and covering the whites of the eyes), enabling upper respiratory infection and easier use of the airways.

How Is SARS-CoV-2 Transmitted? Viral-Load Dynamics and Duration of Infectiousness

Viral-load kinetics may also explain some differences between SARS-CoV-2 and SARS-CoV-1. The highest SARS-CoV-2 load in the respiratory tract is observed at symptom onset or in the first week of illness. The greatest transmission potential is during or immediately before the first 5 days of symptom onset and then declines (Figure 2).

In contrast, peak SARS-CoV-1 viral loads were detected in the upper respiratory tract during the second week of illness, explaining its minimal infectiousness in the first week after symptoms begin and allowing early case detection in the community.

Figure 2: After initial exposure, patients typically develop symptoms within 5–6 days (the incubation period). SARS-CoV-2 produces a wide range of clinical manifestations, from mild infection to severe disease with high mortality. In patients with mild infection, the initial host immune response can control the infection. In severe disease, an excessive immune response causes organ damage, intensive care admission or death. Viral load peaks during the first week of infection and then gradually declines, while the antibody (IgG) response gradually increases and is often detectable on day 14.

qRT-PCR (Quantitative Reverse Transcriptase – Polymerase Chain Reaction) technology can detect viral SARS-CoV-2 RNA in the upper respiratory tract for an average of 17 days (a maximum of 83 days) after symptom onset. Detecting viral RNA by qRT-PCR does not necessarily mean infectiousness, however, and viral culture from the PCR-positive upper respiratory tract is rarely positive after 9 days of illness. This corresponds to what is known about transmission from contact-tracing studies: transmission capacity is greatest in the first week of illness and transmission has not been documented after that period. Severely ill or immunocompromised patients may shed virus for relatively long periods, and some patients may shed RNA intermittently; however, low-level results near the detection limit may not represent infectious viral particles. Although asymptomatic individuals can spread infection, their relative degree of infectiousness appears limited. People with mild symptoms (paucisymptomatic) and those whose symptoms have not yet appeared still carry large amounts of virus in the upper respiratory tract, which may contribute to the easy, rapid spread of SARS-CoV-2. Symptomatic and presymptomatic transmission (when the person carrying the virus has symptoms and 1–2 days before symptom onset) may play a greater role in the spread of SARS-CoV-2.

A combination of preventive measures such as social distancing, testing, tracing and individual isolation is the foundation of the fight against Covid-19.

SARS-CoV-2 Transmission Routes and Dynamics

Like other coronaviruses, SARS-CoV-2 is transmitted primarily by viral infection through direct or indirect contact with nasal, eye or mouth mucosa (moist surfaces), via infected respiratory droplets. Target host receptors are mainly found in human respiratory epithelial lining cells, including the oropharynx and upper respiratory tract. The eyes and gastrointestinal system are also susceptible to infection and may serve as entry routes (to better understand droplet transmission, see our related video).

As described elsewhere, transmission risk depends on factors such as contact type, environment, host susceptibility and socioeconomic factors. Most Spread Occurs through Close-Range Contact (face to face within 2 meters for 15 minutes), particularly at family and friend gatherings and within households. Household secondary attack rates (the proportion of susceptible individuals infected among contacts of a primary case) range from 4% to 35%. Sleeping in the same room as an infected person or being their spouse increases infection risk, while keeping the infected person away from the family is associated with reduced risk. Other high-risk activities include eating close to an infected person, sharing food and joining group activities. Infection risk rises substantially indoors compared with sitting outdoors. Prolonged time in crowded, poorly ventilated indoor spaces may enable airborne spread (meaning spread over distances greater than 2 meters).

In the spread of SARS-CoV-2, fecal and fomite (inanimate surface) transmission still needs clearer understanding. Both SARS-CoV-2 and SARS-CoV-1 can remain viable for several days (1-4 days) on smooth surfaces (stainless steel, plastic and glass) and at lower temperature and humidity, such as in air-conditioned environments. Transfer from contaminated surfaces via unwashed hands to the eye, nose and mouth mucosa is therefore a possible transmission route. This may occur particularly in facilities with shared areas and an increased likelihood of environmental contamination. However, both SARS-CoV-1 and SARS-CoV-2 are easily inactivated by commonly used disinfectants, highlighting the potential value of surface cleaning and handwashing.

 SARS-CoV-2 RNA has been found in stool, and RNA shedding generally continues longer than in respiratory samples; however, isolating virus from stool has rarely succeeded. No published report has documented fecal-oral transmission. Fecal-oral spread was not considered to occur in most SARS-CoV-1 situations, but an uncontrolled outbreak was attributed to virus spreading and becoming airborne through a faulty sewage system in an apartment building. Whether similar spread can occur with SARS-CoV-2 will become clear over time.

How Does SARS-Cov-2 Cause Disease? Pathogenesis (the Disease Development Process)

Viral Entry and Interaction with Target Cells

SARS-CoV-2 binds to its target host-cell receptor ACE2. Active viral replication in lung cells and dissemination through the body cause nonspecific symptoms such as fever, muscle pain, headache and respiratory symptoms.

In an experimental hamster model, the virus temporarily damaged olfactory receptor cells in the olfactory epithelium and caused olfactory dysfunction, which may explain the temporary loss of taste and smell common in COVID-19 (see Why Do Covid-19 Patients Lose Smell and Taste? When Do They Return?).

The distribution of ACE2 receptors across tissues may explain infection sites and symptoms. For example, ACE2 receptors are abundant in other organs such as the intestine, endothelial cells in the kidney and blood vessels, which may explain gastrointestinal symptoms and cardiovascular problems. Pathological examination of the lungs, heart, kidneys and liver at autopsy in patients who died from COVID-19 found inflammation, from lymphocyte accumulation in endothelial cells, liver-cell necrosis and myocardial infarction (heart attack). These findings suggest that the virus directly affects many organs, as seen in SARS-CoV-1 and influenza.

Much remains unknown. Are pathological respiratory changes or endothelial dysfunction consequences of direct viral infection, cytokine dysregulation or coagulopathy, or are they multifactorial? Does direct viral invasion or coagulopathy directly contribute to ischemic complications such as ischemic infarction? More studies are needed to clarify these and other questions.

Immune Response to SARS-CoV-2 and the Disease Spectrum (Figure 2)

After viral entry, the initial immune system response is to attract virus-specific T cells to the infection site. If the virus is eliminated in this way, the patient recovers without the infection spreading. This is the most common scenario for most people who contract Covid-19.

In patients with severe disease, SARS-CoV-2 elicits an abnormal host immune response. For example, postmortem examination of lung tissue from people who died of Covid-19 reflects the inflammatory nature of the damage: findings of acute respiratory distress syndrome (ARDS) characterized by alveolar damage, hyaline deposition and interstitial mononuclear inflammatory infiltrates. This resembles the lung pathology in severe Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). A distinctive COVID-19 feature is mucus plugging with fibrinous exudate in the respiratory tract, potentially explaining COVID-19 severity even in young adults. This may result from excessive production of proinflammatory cytokines accumulating in the lungs and eventually damaging lung tissue.

Some patients also experience septic shock, multiple-organ dysfunction and sepsis. For example, the cardiovascular system is affected mainly early in COVID-19, evident through release of highly sensitive troponin and natriuretic peptides. Platelet-fibrin clots in small pulmonary vessels are also seen, reflecting clinical coagulopathy. Cytokines normally mediate and regulate immunity, inflammation and hematopoiesis (blood-cell formation). In some patients, however, an intensified immune reaction and cytokine accumulation in other organs may cause extensive tissue damage or cytokine-release syndrome (cytokine storm), leading to capillary leakage, clot formation and organ dysfunction.

What Mechanisms Underlie the Problems Caused by Covid-19?

Clinical outcomes are influenced by personal factors such as older age, male sex and comorbidities, as well as viral factors such as viral-load kinetics, the host immune response and potential cross-reactive immune memory from previous seasonal coronavirus exposure.

Risk Factors Associated with Severe Disease, Intensive Care Admission and Mortality

Underlying Conditions

• Older age
• Hypertension
• Cardiovascular diseases
• Chronic obstructive pulmonary disease
• Diabetes
• Obesity
• Cancer

Clinical Manifestations

• Higher fever (39 °C or above)
• Shortness of breath above the accepted level
• Higher qSOFA score (a scoring system measuring low blood pressure, impaired consciousness and rapid breathing)

Laboratory Markers

• Neutrophilia / lymphopenia
• High kactate and lactate dehydrogenase
• High C-reactive protein (CRP)
• High ferritin
• High ACE2
• D-dimer> 1 μg / m2

Sex-related differences in immune responses have been reported, showing higher blood-plasma levels of innate immune cytokines and chemokines in men than women. Women, in contrast, have clearly stronger T-cell activation, and T-cell activation declines more with age in men than women. Because older age and male sex are associated with increased comorbidity and mortality risk, these findings suggest that the adaptive (acquired) immune response may be important in determining clinical outcomes.

Elevated proinflammatory cytokine levels are associated with severe pneumonia in the lungs and increased ground-glass opacities on examination. Comparing severe with nonsevere disease, increased plasma concentrations of inflammatory cytokines and biomarkers were observed.

Emerging evidence suggests a relationship between viral dynamics, disease severity and outcomes. Comprehensive immune-response features show associations between severity, viral load and IFN-a, IFN-y and TNF-a responses. In the same study, many interferons, cytokines and chemokines were elevated early in patients with severe disease and higher viral loads. This is consistent with influenza, SARS and MERS pathogenesis, in which prolonged viral shedding is also associated with severity.

Given the immune response's important role in clinical outcomes, several immunosuppressive treatments intended to limit immune-mediated damage are currently at different development stages. (Table 1)

Which Treatments Are Currently Being Investigated for Covid-19?

The Immune Response to the Virus and Its Role in Protection

COVID-19 produces an antibody response against several viral proteins, but spike (S) protein and nucleocapsid are most often used for serological diagnosis. Small amounts of antibodies can be detected in the first four days, but patients continue developing them and most have a clearly detectable response after four weeks. A wide range of virus-neutralizing antibodies has been reported, and emerging evidence suggests association with disease severity but decline over time. The duration and protective nature of antibody and T-cell responses await definition through longer follow-up studies. CD-4 T-cell responses to other human coronaviruses appear to show cross-reactivity with SARS-CoV-2, but their protective role remains unclear.

Unanswered Questions

Better understanding SARS-CoV-2's disease-causing properties will be vital for developing COVID-19 treatments, vaccines and supportive approaches. More data are needed to understand immune-response differences between mild and severe Covid-19. Neutralizing antibodies are potential keys to protection, but other protective antibody mechanisms may exist. The protective role of T-cell immunity, the duration of antibody and T-cell responses and their correlates of protection likewise need defining. Optimal testing systems and technology are also needed to inform and support early diagnosis and clinical management. Long-term outcomes following acute illness and multisystem inflammatory disease require further understanding, particularly in children.

Questions for Future Studies

• What is the role of cytokine storm, and how does it affect development of treatments, vaccines and supportive approaches?
• What is the window when patients are most infectious?
• Why do some patients develop severe disease while others, particularly children, have mild or no symptoms?
• What biomarkers identify healthy, dysfunctional or nonfunctioning immune responses for effective patient triage (screening to prioritize treatment), and define immune correlates of protection and severity?
• What is the protective role of T-cell immunity, how long do antibody and T-cell responses last, and how do we define correlates of protection?

Who Is Müge Çevik? A Short Biography

Müge Çevik works as a physician-scientist in the Division of Infection and Global Health at St Andrews University School of Medicine. Her research addresses HIV, viral hepatitis, emerging infections and tropical infections in developing countries. A recognized academic, Asst. Prof. Dr. Müge Çevik worked on the front line during the Covid-19 pandemic and advised Scotland's Chief Medical Officer and the World Health Organization.

Early Life and Medical Education

Müge Çevik studied medicine at Ege University Faculty of Medicine. As a medical student, she participated in sexual-health projects and youth organizations. She served on the executive committee of the reproductive-health committee of the International Federation of Medical Students' Associations. In this role, she worked with international organizations including the United Nations Population Fund (UNFPA), UNAIDS and MTV. Working with UNFPA, she ran an international peer-education program on sexual and reproductive health and rights. She received funding from the United States Embassy's Youth Empowerment Grants to examine HIV-related stigma in healthcare settings.

Dr. Çevik has led international peer-education programs throughout her medical training.

She moved to London for postgraduate education and completed a master's in public health at the London School of Hygiene & Tropical Medicine and University College London. Her research addressed HIV and other sexually transmitted infections. Her work was supported by Rotary International's international postgraduate scholarship, awarded annually to outstanding leaders worldwide. She was appointed a clinical researcher at Chelsea and Westminster Hospitals, where she completed internal medicine specialist training. She completed her doctorate at St Andrews University.

Research Interests and Career

Dr. Çevik moved to Scotland in 2016, joining NHS Lothian as a senior specialist physician in infectious diseases. Her research addresses HIV and tuberculosis. She studied their epidemiology in South Africa, Uganda, Zimbabwe and Tanzania. She leads a phase 3 clinical trial aiming to shorten treatment for drug-resistant tuberculosis. In 2020, she received a Clinical Academic Training Fellowship supported by Scotland's Chief Scientist Office to establish the biological mechanisms underlying poor tuberculosis treatment response in patients in Kampala.

Leadership during the COVID-19 Outbreak

During the COVID-19 outbreak, Çevik advised Scotland's Chief Medical Officer and the World Health Organization. As part of this work, she works on managing misinformation about coronavirus disease. Throughout the pandemic, she provided public expert commentary on the disease.

Çevik used Twitter to keep the public updated on coronavirus research (see her Twitter profile). As of May 2020, she demonstrated that transmission often follows close contact and occurs indoors, in interconnected enclosed settings such as homes, family gatherings, restaurants and offices. She called for more comprehensive contact-tracing data to understand SARS-CoV-2 transmission dynamics better. Working with Colin McCowan, she investigated household SARS-CoV-2 transmission in Scotland.

Working with the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), Çevik sought to transfer coronavirus clinical studies to developing countries. She developed guidelines for doctors outlining how to respond to SARS-CoV-2. As part of her ISARIC work, she identified patient risk factors for severe disease. She works with ISARIC on rapid scientific reviews that can inform government policy.

Academic Service

Çevik is an associate editor of Clinical Microbiology and Infection. She serves on the steering committee of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and leads an Erasmus Programme project to implement infectious-disease teaching in medical education. She serves on the executive committees of the Scottish Microbiology & Virology Network and the British HIV Association.

Beyond academic research, Çevik is interested in science communication and how doctors can best use social media to disseminate research. She used social-network analysis to understand how scientists and doctors use Twitter. Her interest in science communication led her to develop BHIVA's social-media strategy.

We congratulate Dr. Müge Çevik, a source of scientific pride for Turkey whose work we follow closely.

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Further Reading

Here we wanted to summarize findings from 2 recent studies because they are closely related to the topic:

• Published in September, an Italian study found that, for unknown reasons, among people hospitalized and discharged because of COVID-19, approximately one in every 6 people had a positive PCR test at least 2 weeks later. Sore throat and rhinitis (nasal inflammation) were the only symptoms associated with testing positive again. Lead author Dr. Francesco Landi said, "Patients who continued to have respiratory symptoms were particularly more likely to have a new positive test result".

• A Common SARS-CoV-2 Mutation May Have Made COVID-19 More Transmissible. On 30 October, mBio published an article presenting new evidence that most SARS-CoV-2 strains have a specific mutation making them more transmissible. In contrast to the wide variety of strains early in the pandemic, 99.9% of currently circulating SARS-CoV-2 strains contain the spike-protein D614G mutation. People infected with a D614G strain also have higher nasal and nasopharyngeal viral loads at diagnosis. This is not entirely bad news. This single-point mutation is not associated with more severe COVID-19. It is also not expected to interfere with the effectiveness of antibody cocktails, small-molecule therapeutics or vaccines being developed.

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