Questions and Answers on CoViD19

Last update: 15 June 2020

Senior citizens, pregnant women and those with a weaker immune system (e.g. patients undergoing chemotherapy or with any other illness) must strictly follow measures of physical distancing, go out only when absolutely necessary, wear masks while outside, and practice hand hygiene.

A. Pregnant women

So far, there is no conclusive evidence for transmission of COVID-19 from an infected woman to the fetus in the uterus (see this analysis, and a review). However, the immune response to COVID-19 could potentially affect the developing fetus (Liu et al., 2020). At the time of delivery, the mother may transmit the infection to the newborn due to close physical contact or through care-givers. As we are just beginning to understand the novel coronavirus, it is difficult to predict long-term effects on the newborn. Hence, pregnant women need to be extra cautious to reduce their risk of contracting COVID-19. 

In addition to the standard measures above and taking all the recommended vaccines as per schedule, the Centres for Disease Control and Indian Council of Medical Research (ICMR) recommend reducing the number of hospital visits during pregnancy, in consultation with the maternal care provider. Hospital travel should be limited to either private vehicles or hospital ambulances.

B. Senior citizens or people with compromised immune systems 

Senior citizens and people with compromised immunity such as cancer patients are at a higher risk from COVID-19 as shown by several studies, e.g. reported by Leung 2020 and Dai et al., 2020 . Considering the severity of the disease and  higher mortality rate among senior citizens and those with underlying comorbid conditions, transmission can be reduced by following strict precautionary measures as follows.

1. Stay at home unless absolutely essential, and avoid visitors at home. Keep physical distance from others. 
2. Take medications for any underlying health conditions exactly as prescribed.
3. Postpone surgeries such as cataract or other interventions that are not urgent. 

More information can be found in the advisory issued by MoHFW and guidance by CDC. 

References

1. An Analysis of 38 Pregnant Women with COVID-19, Their Newborn Infants, and Maternal-Fetal Transmission of SARS-CoV-2: Maternal Coronavirus Infections and Pregnancy Outcomes
2. Vertical Transmission of Severe Acute Respiratory Syndrome Coronavirus 2: A Systematic Review
3. Why are pregnant women susceptible to COVID-19? An immunological viewpoint
4. If You Are Pregnant, Breastfeeding, or Caring for Young Children
5. Guidance for management of pregnant women in COVID-19 pandemic 
6. Risk factors for predicting mortality in elderly patients with COVID-19: A review of clinical data in China
7. Patients with Cancer Appear More Vulnerable to SARS-CoV-2: A Multicenter Study during the COVID-19 Outbreak
8. Health advisory for elderly population of India during COVID-19
9. COVID-19 guidance for older adults

Last update: 15 June 2020

Once the novel coronavirus infects a person, it takes about 5 days to develop symptoms (but this period can vary from 2 to 15 days). This phase is called the ‘incubation period’; if tested positive during this period, the patient is classified as “presymptomatic”. A subset of infected people can carry the virus in their body, but never develop any symptoms of the disease. They appear healthy but can still spread the virus to other people. These are termed as “asymptomatic carriers”. In case of COVID-19, 5-80% of the infections are asymptomatic (Melissa M. et al 2020, Michael 2020, Michael 2020, Oran et al 2020, Xi He et al 2020). The amount of virus in both asymptomatic and presymptomatic cases can be as high as that in symptomatic patients. Both asymptomatic and presymptomatic people can transmit the virus to others. This is thought to explain the rapid spread of COVID-19, and seems to be one of the major differences between COVID-19 and the previous coronavirus infections (SARS and MERS) that could be controlled relatively easily.

If there are no symptoms like coughing or sneezing, how can someone transmit the disease?

The novel coronavirus is transmitted primarily through droplets released while sneezing or coughing. However, small droplets are also generated when we talk or exhale air, and these may also carry virus particles. A recent study found out that even loud speech generates more than 1000 droplets per minute, which can remain air-borne for about 8 min. Although most large droplets eventually settle down within 1 m, smaller droplets or even larger droplets in some cases can travel 7-8 m. The distance travelled by droplets and their role in transmitting the virus is being investigated. Article in Lancet has supported the role of physical distancing of 1 m or more in reducing the risk of transmission. Another mode of transfer is through direct contact such as handshakes, or through shared objects (‘fomites’ like utensils and towels). A recent study showed that undocumented infections may account for as high as 55% of total transmission.

Why are some people asymptomatic but others show symptoms?

The symptoms and severity of an infectious disease is a complex outcome of many factors, such as features of both the pathogen and the host (e.g. their respective genetic makeup, the host’s overall health and immune function), and the interaction between the host and pathogen. In the case of COVID-19, we do not have a clear understanding of why some people develop COVID-19 symptoms while others do not.

How can we stay safe from asymptomatic carriers?

Follow physical distancing, and personal and public hygiene. The best way is to assume that you yourself or other people are already infected with the novel coronavirus. Accordingly, avoid close contact with others, even if you/they seem healthy.

References and more information: 

1. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application
2. Evidence Supporting Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 While Presymptomatic or Asymptomatic
3. Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility
4. Covid-19: four fifths of cases are asymptomatic, China figures indicate
5. Prevalence of Asymptomatic SARS-CoV-2 Infection: A Narrative Review: Annals of Internal Medicine 
6. Evidence Supporting Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 While Presymptomatic or Asymptomatic
7. Temporal dynamics in viral shedding and transmissibility of COVID-19
8. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients
9. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19
10. Violent expiratory events: on coughing and sneezing
11. Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2)
12. The coronavirus pandemic and aerosols: Does COVID-19 transmit via expiratory particles?
13. Reducing transmission of SARS-CoV-2
14. Turbulent Gas Clouds and Respiratory Pathogen Emissions
15. Infectious virus in exhaled breath of symptomatic seasonal influenza cases from a college community
16. The airborne lifetime of small speech droplets and their potential importance in SARS-CoV-2 transmission
17. WHO: Coronavirus disease (COVID-19) advice for the public

Last update: 15 June 2020

COVID-19 positive cases span a range of outcomes, from about 80% being asymptomatic to about 5% becoming critically ill and exhibiting Acute Respiratory Distress Syndrome (ARDS), according to data from China. Some patients also exhibit non-respiratory symptoms such as acute liver and heart injury, kidney failure, or diarrhoea (as referenced here, here, and here). 

Upon gaining entry through the ear, nose, or mouth, the novel coronavirus binds to the angiotensin converting enzyme-2 (ACE-2) receptor (a protein) on human cells in the nose, bronchi (corridors through which air passes), lungs, heart, esophagus, kidney, stomach, bladder, and ileum. Initially, the novel coronavirus reproduces in the cells lining the inside of the upper respiratory tract (nasal cavity and pharynx), with further multiplication in the lower respiratory tract and cells lining the gastrointestinal system (stomach and intestines), as reported here.

During the COVID-19 epidemic, the severe deterioration of some patients has been closely related to the cytokine storm in their bodies. Cytokines are very small proteins that are produced by many types of cells, including immune cells. They help cells to communicate with each other. In the immune system, cytokines regulate the balance between antibody based immune response and cellular immune responses. In a cytokine storm, levels of some cytokines soar far beyond what is needed, causing immune cells to attack healthy tissues. As a result, in some patients blood vessels leak and blood pressure drops. To compensate, blood clots form; but they can lead to severe organ failure, as discussed in this review. Strokes are often caused by blood clots that break free and travel to blood vessels in the brain. Thus, doctors link COVID-19 to potentially deadly blood clots (as shown here) and strokes (discussed in strokes and blood clots in COVID-19 patients).

During COVID-19 related cytokine storms inflammatory cytokines such as IL-1beta, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) that activate the T-helper type 1 (Th1) cell response against intracellular parasites such as viruses (see this report) are elevated. According to another review, the severity of COVID-19 is related to levels of two specific cytokines (IL-2R and IL-6) in the blood of patients.  

The  pathogenesis of COVID-19, and disorders associated with infection by the novel coronavirus, is depicted here, here and here.

References:

1. Viruses | Free Full-Text | Virology, Epidemiology, Pathogenesis, and Control of COVID-19  
2. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China 
3. Kidney impairment is associated with in-hospital death of COVID-19 patients 
4. Clinical Characteristics of Patients With 2019 Novel Coronavirus (2019-nCoV)–Infected Pneumonia in Wuhan, China 
5. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection
6. Evidence for Gastrointestinal Infection of SARS-CoV-2. 
7. Definition of cytokine storm – NCI Dictionary of Cancer Terms
8. How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes 
9. The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19 
10. https://www.ncbi.nlm.nih.gov/pubmed/31986264
11. COVID-19 cytokine storm: the interplay between inflammation and coagulation 
12. Strokes And Blood Clots Seen In COVID-19 Patients : Shots – Health News 
13. Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young | NEJM 
14. Viruses | Free Full-Text | Virology, Epidemiology, Pathogenesis, and Control of COVID-19 | HTML
15. PubMed Central, Fig. 2: J Autoimmun. 2020 May; 109: 102433. Published online 2020 Feb 26. doi: 10.1016/j.jaut.2020.102433 
16. Appreciating potential complications of COVID-19

Last update: 15 June 2020

Viral Load: Also known as ‘viral burden’, it is defined as the number of viral particles in a fixed amount of body fluid. Since COVID-19 is a respiratory disease (caused by the novel coronavirus), its viral load is measured in nasal/oral droplets or fluids. The viral load gives an indication of the extent of infection (severity). Depending on the diagnostic method used, the viral load can be calculated from the nucleic acid (RNA) copy number or from the viral antigens present in a patient. For COVID-19, the primary diagnostic test uses a technique called RT-PCR to detect and estimate viral loads in nose and throat swabs. The viral load decreases as a person enters the recovery stage of COVID-19.

Viral Shedding: Viral shedding is a measure of the transmissibility of the infection. Once a virus gets inside a cell, it hijacks that cell and uses it to make more viruses. These are released into the body and infect new cells, leading to an increase in the viral load in the host. The new virus particles are also released outside the body, through respiratory droplets and aerosols. Such “shedding” of the novel coronavirus is known to occur even before an infected person begins to show symptoms. Therefore, everyone is advised to wear a face mask to prevent transmission in case of a pre-symptomatic or asymptomatic infection.

References and more information:

1. Detection of SARS-CoV-2 in Different Types of Clinical Specimens 
2. Viral dynamics in mild and severe cases of COVID-19 
3. Diagnosing COVID-19: The Disease and Tools for Detection
4. FDA Statement: Coronavirus (COVID-19) Update: FDA Authorizes First Antigen Test to Help in the Rapid Detection of the Virus that Causes COVID-19 in Patients
5. Quantitative Detection and Viral Load Analysis of SARS-CoV-2 in Infected Patients
6. Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens for COVID-19
7. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor 
8. Respiratory virus shedding in exhaled breath and efficacy of face masks 
9. Temporal dynamics in viral shedding and transmissibility of COVID-19

Last update: 15 June 2020

All organisms acquire mutations (changes in the genetic code) while replicating. Viruses have a high mutation rate, especially those with RNA as their genetic material. However, coronaviruses (including SARS-CoV-2) are an exception, partly due to their proofreading mechanism that corrects most mutations.

A mutation does not always lead to a new virus strain. A ‘new strain’ differs from its ancestor in significant ways. It might vary in how easily it spreads, its ability to cause disease, whether it is recognized differently by the immune system, or how differently it responds to medications. Most mutations do not affect these properties and are silent. Hence, without information on the effects of specific mutations, there is insufficient information to classify the virus as a new ‘strain’. Currently, claims regarding diversification of SARS-CoV-2 into various strains due to mutations are not supported by conclusive evidence. 

Will the different sequences of the circulating novel coronavirus affect the efficacy of vaccines which are currently under development? Antibodies, which the body produces in response to a vaccine (or the virus), work by binding to specific regions of a virus, called antigens. If viral mutations alter the antigen, they can make a vaccine less effective against the virus. However, currently we do not know whether the observed mutations in the virus affect its antigenic properties. Hence, it is too early to speculate about the possible effects on vaccines. But scientists think that the efficacy of the vaccines towards the mutating virus may not be a problem in the immediate future, owing to the slow mutation rate of the novel coronavirus.

More research is required to know if different strains of the novel coronavirus exist and if a vaccine will work properly against all of them.

References:

1. Mutations in SARS-C0V-2
2. Different strains of SARS-CoV-2 and Vaccines 
3. Vaccine Development and Mutations in Coronavirus
4. COVID19: Mutations and Vaccines
5. Coronavirus Proofreading Protein
6. Strains of SARS-CoV-2
7. Mutation rate in RNA viruses
8. Slow Mutation rate of SARS-CoV-2
9. ncov diversification dashboard

Last update: 15 June 2020

A contact-tracing app is a smartphone app that helps locate other smartphones with the same app that have been physically close to each other. Such apps are being used in some countries, including India, to help contain the spread of COVID-19 [BBC]. These apps have been largely inspired by the success of the Trace Together app used in South Korea [BBVA]. However, the success story in Korea is based not only on the smartphone app, but also on implementing other strategies such as large scale testing, observing physical distancing norms, wearing masks, and extensive contact tracing [National Geographic].

The apps require users to give information about their home address, gender, and age; and in some cases, past ailments. Users are also given a unique user id attached to their smartphone. Users sign an agreement that if they test positive for COVID-19, the government can request data on their contacts and movements from their service provider (e.g. Jio, Airtel, BSNL). Whenever they go out of their home, users need to turn on their phone’s bluetooth, so that information about their movements can be collected.

Suppose X has this app and is diagnosed with COVID-19 today. Everyone who has been in contact with X in the past two weeks (the incubation period of the virus) is contacted. They are asked to self-quarantine because there is a chance that X may have transmitted the infection, and they may also unknowingly give it to others.

How do these apps trace people who have been in contact with X?

When two people (X and Y) who have both downloaded these apps are within 2-3 metres of each other, their cell phones exchange messages using bluetooth. The user id of X is encrypted using a secret key unique to Y, and is stored on Y’s phone. Similarly, the user id of Y is encrypted using a key unique to X, and is stored on X’s phone. Encryption means a user id is transformed using a secret key, in such a way that it is computationally difficult to recover the user id from the transformed version, unless you have the key. The encrypted user ids are stored for about two weeks. If X develops COVID-19, all encrypted user ids stored on X’s phone from the previous two weeks are collected by government agencies. They decrypt (unscramble) the user ids stored on X’s phone (using X’s secret key, which they have access to), so that all users whose phones were in close proximity to X’s phone can be traced, contacted and warned that they may have picked up an infection. The unscrambling of encrypted ids on X’s phone can only be done by government agencies. Alternately, the app stores the messages exchanged between the two phones, on both the phones, for two weeks. If X falls ill with COVID-19, all messages stored on X’s phone are downloaded onto a central server. Every day the app on Y’s phone contacts this server to see if there is a message on Y’s phone that is also there on the server. If such a message is found, Y gets alerted about having been physically close to someone who has the disease. See the article by Nicky Case where this is explained using cartoons.

If these apps are useful, why are people concerned about using them?

An issue with such apps is privacy. Is the collected data stored on the phone, or on a centralized server? Most people would be happy if it is stored on their phone, since their data is safe with them. If it is stored on a centralized server, is the data safe? Who has access to it? Is the data encrypted before storing, so that anonymity of users is ensured? How does one know that the data will only be used for COVID-19 tracking? Shouldn’t the use of such an app be voluntary? These articles in Nature and National Herald discuss these issues at length.

What steps are being taken to address these issues? 

Software leaders such as Google and Apple, and several researchers in Europe and in the US, are working on developing an app which meets stringent requirements for anonymity, privacy and security, and also scales to a large number of users. Using ideas from cryptography, researchers have proposed solutions which do not require a central server to store the data. See this MIT article for details on the issues involved, and the solutions being proposed.

References and more information:

1. Nature: COVID-19 digital apps need due diligence.
2. BBVA:  How do COVID-19 tracing apps work and what data do they use?
3. BBC: Source code behind contact tracing apps.
4. National Herald: Is privacy a myth?
5. Nicky Case, Protecting Lives & Liberty.
6. MIT: A flood of coronavirus apps are tracking us.
7. National Geographic, How South Korea prevented a coronavirus disaster, May 2020.

Last update: 15 June 2020

Advisories from the office of the Principal Scientific Advisor to the GoI and from the CDC recommend wearing homemade masks for controlling the spread of Covid-19. Transmission of the novel coronavirus is thought to happen primarily through droplets emitted when an infected person coughs, sneezes or speaks. Large droplets, typically larger than 10 microns in size, settle quickly to the ground due to gravity, typically within a distance of 1-2 m of the person. Smaller droplets (less than 5 microns) form “aerosols” that can stay suspended in the air for several minutes and propagate as far as 7-8 m. Currently, transmission of Covid-19 is believed to happen via large droplets rather than smaller aerosols. However, this is debated, and recent reports have suggested the possibility of aerosol transmission of the novel coronavirus (see recent publications in JAMA and Nature).

Health workers and caregivers who are directly in contact with infected patients are advised to use fitted N95 respirators that are highly effective in filtering out small particles. However, due to increased demand during the pandemic, N95 respirators and surgical masks are in short supply. Therefore, the general public is advised to use homemade face masks or face covers. Some people infected with the novel coronavirus do not show any symptoms but are capable of transmitting the disease. Therefore, it is suggested that the use of face masks can play an important role in controlling Covid-19. Wearing a facemask changes the nature of the turbulent expulsion of air during sneezing or coughing. Also, simple fabric face masks filter out and absorb a majority of the emitted large drops, preventing release of the virus into the environment. Recent research has suggested that face masks from a combination of fabrics (such as cotton, silk, synthetic materials) can provide improved filtration. However a standard homemade 2-layer cotton cloth mask with strings to tie at the back of the head will provide protection, especially when used in addition to physical distancing. ISRC has videos on making masks at home and how to use masks correctly.

It must be emphasized that wearing masks alone is insufficient to control virus transmission, and needs to be supplemented by rigorous physical distancing and hand wash hygiene to prevent the spread of Covid-19. In addition, when you wear a mask try to ensure that it fits well with no gaps. When you take it off, do not touch its outside surface; disinfect the mask right away (by boiling or washing with soap and water), and wash your hands with soap and water.

References and more information: 

1. PSA manual on facemasks
2. CDC advisory on facemasks
3. WHO note on transmission of Covid-19 through large droplets
4. JAMA paper highlighting possible importance of aerosols
5. Nature paper highlighting possible importance of aerosols
6. Imaging the propagation of cough through a facemask
7. Combinations of fabrics for improved filtration by facemasks

Last update: 15 June 2020

A country (or location) may go through four different levels of COVID-19 transmission, as classified by WHO: 

i.  No cases reported

ii. Sporadic cases

iii. Cluster of cases

iv. Community Transmission

1. No cases reported: In India, the first case of COVID-19 was reported on 30th January, 2020. So, until 30/01/2020, India was at this level. 

2. Sporadic cases: At this level, everyone detected with COVID-19 must have a travel history from an affected country, within the incubation period of the virus (upto 14 days for COVID-19). 

3. Clusters of cases (also known as Local Transmission stage): At this stage, the transmission of the infection can be traced. People who test positive either travelled themselves to an affected region, or someone in their close contact group (such as family members) have travel history within the incubation period of the virus. 

4. Community transmission: A country is said to enter the Community Transmission stage if at least one of these criteria is fulfilled: (a) a large number of confirmed cases cannot be traced through chains of transmission, or (b) a very high number of positive cases are found in random samples collected from patients with respiratory illness  (known as sentinel samples). Countries like Italy, Spain, and the USA are at this stage. 

Strategies to be followed at different stages, as suggested by WHO:

Clusters of cases: At this stage, the goal is to prevent from going to the community transmission stage. To achieve this, it is suggested that all cases should be rapidly found, isolated and treated; and all their contacts should be traced, quarantined, and supported (track-test-treat).

In addition, physical distancing and restrictions on domestic and international travel help in preventing the pandemic from progressing to the next stage.

Community Transmission: At this stage, it is difficult to stop the spread of the disease because of difficulty in isolating probable carriers. All public health measures including awareness campaigns about hand washing, physical distancing, and prevention should continue. In addition, testing laboratories should be prepared to handle a large number of samples. If testing capacity is limited, priority should be given to vulnerable populations and high-risk groups including healthcare workers. More details can be found here and here. 

Note that the measures mentioned here at varying times in the local evolution of the COVID-19 pandemic are not set in stone. Countries are reviewing the situation regularly and taking a range of public health and social measures in different combinations. 

References and more information:

1. COVID-19 Situation Report prepared by WHO
2. COVID-19 Strategy Update prepared by WHO
3. Preparation for large scale community transmission: Guideline by WHO
4. Laboratory testing strategy recommendations for COVID-19: Guideline by WHO 
5. Responding to Community Spreading: Guideline by WHO 
6. Operational considerations for case management of COVID-19 in health facility and community Interim guidance

Last update: 15 June 2020

The virus from respiratory droplets or surfaces enters our respiratory tract through the mouth, nose, or eyes. The genetic material of the novel coronavirus (RNA) is surrounded by a layer of protein, forming the nucleocapsid. This, in turn, is enveloped by a layer of modified fats called phospholipids. The outer envelope has proteins called S (for spike) glycoproteins studded in it. The first step of viral entry is the binding of the S protein to its receptor on the human cell. A part of the S protein called the fusion peptide is normally buried inside the S protein. Once bound to its receptor on the host cell (ACE 2),  the S protein undergoes subtle changes in shape. This causes the fusion peptide to be brought to the surface, where it can get embedded into the host cell’s membrane. Another part of the S protein called the transmembrane domain is also brought near the fusion peptide,  allowing the viral membrane to fuse with the host cell’s membrane. Modifications (mutations) to the S protein enable different coronaviruses to infect different host animals via different receptors. 

Note that the virus cannot enter through intact skin, because skin cells lack the ACE 2 receptor. However, the novel coronavirus can enter any human cell that has the ACE2 receptor protein in the membrane (primary targets being nasal and lung tissue because the virus spreads primarily through droplets). Different tissues have different amounts of the ACE2 receptor in their cells. Although the virus primarily spreads by droplets and infects the lung and respiratory tract, in severe cases it can potentially infect many other tissues, such as the heart vessels, liver and kidney. It is now widely accepted that the virus spreads from person to person by reproducing and producing viral particles from cells in the oral cavity, which show high expression of the ACE2 receptor. However, lung tissues of diseased vs. healthy patients do not have significantly different amounts of the ACE2 receptor.  
Although no direct information is available for the novel coronavirus, studies in a closely related coronavirus show that the virus can also enter cells in a completely different manner. Upon infection, our immune system generates antibodies against viral proteins, including the S protein. Sometimes, binding to the antibody can also change the shape of the S protein and activate it (as described above with the ACE2 protein). Meanwhile, cells that have receptors for the antibody can bind to this antibody-virus complex, allowing the virus to piggyback with the antibody and enter those cells.

References and more information

1. Mechanisms of Coronavirus Cell Entry Mediated by the Viral Spike Protein
2. COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses
3. Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry
4. Structures and Mechanisms of Viral Membrane Fusion Proteins
5. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues
6. Assessing ACE2 expression patterns in lung tissues in the pathogenesis of COVID-19
7. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa
8. A pathological report of three COVID-19 cases by minimally invasive autopsies].pathological report of three COVID-19 cases by minimally invasive autopsies

Last update: 15 June 2020

A second wave of infection refers to the phenomenon of re-emergence of infections in the population after they seem to have subsided. Currently, we do not have sufficient information to predict whether, and when, a second wave may occur. However, there are several possible reasons to expect a second wave:

1.Emergence of a new strain.

A new strain is a variant of the virus that differs in its biological properties, e.g. the ease of transmission, the way it is recognized by the immune system, or how it responds to medicines. A new strain could, therefore, manage to evade the immune system of even those who have recovered from the older virus strain, and cause re-infections. Although the COVID-19 virus is mutating slowly as compared to other coronaviruses, it has accumulated a few mutations. But the absence of experimental evidence for any biological differences between these isolates suggests that they most likely are the same strain. Hence, more studies are required to conclude if this could contribute to a second wave of infection.

2. Re-infection in a recovered population. 

Recently, some cases of relapses of COVID-19 have been reported. Although a study in Rhesus macaques ruled out the possibility of re-infection in recovered animals exposed to the same strain, more studies are needed to confirm this effect in humans. Besides, the time taken to develop immunity and the duration for which it lasts remains to be determined. It is important to note that faulty testing could give a false impression of a relapse. False negatives or low viral load (that escapes detection with test kits) could lead to false conclusions of recovery, even though the infection may still be active. Such false negative cases could also contribute to a second wave of infection.

3.Community transmission after lockdown restrictions are lifted. 

Lockdown can only slow down the spread of the virus, and should not be considered as a cure for COVID-19. Mathematical modelling already predicts a second wave of infection on relaxing interventions.  Based on evidence for pre-symptomatic and asymptomatic transmission, a second wave is very likely to occur if people stop following preventive measures recommended by WHO, like physical distancing, wearing masks and washing hands regularly, after the lockdown is phased out.

References:

1. Second wave
2. WHO’s advice for public during COVID-19 pandemic
3. Pre-symptomatic transmission
4. Can someone be re-infected after they have recovered from Covid-19? 
5. Nurse in Chennai hospital succumbs to COVID-19, suspected case of relapse
6. Reinfection could not occur in SARS-CoV-2 infected rhesus macaques. 
7. SARS-CoV2 mutation rate is much lower than other SARS-CoV 2002
8. The Nextstrain
9. Eight-strains-of-coronavirus-afflicting-the-world
10. Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant
11. First-wave COVID-19 transmissibility and severity in China outside Hubei after control measures, and second-wave scenario planning: a modelling impact assessment
12. WHO ‘s advice for phased process of lifting lockdowns
13. Video of flattening the curve

Last update: 15 June 2020

What do COVID19 serological tests detect?

Once a person starts showing COVID19 symptoms, over about one to two weeks, virus-specific antibodies begin to appear in their blood (Huang, Carreras et al., 2020). These are proteins produced by the immune system, that specifically bind to and neutralise viruses and help recovery. COVID19 serological tests (video: Serological tests 101) are designed to detect such neutralising or any other virus-specific antibodies in a blood sample (Vashist, 2020). As with pregnancy tests, serological tests are cheap and easy to do; and the results can be read out in minutes. 

What do the test results mean?

A negative test result means that the blood sample does not have antibodies specific to the novel coronavirus. This could mean that the person has not been infected, or has been infected too recently for antibodies to be produced (Huang, Carreras et al., 2020, Vabret, Britton et al., 2020). A positive test result would mean that the person’s blood contains antibodies against the novel coronavirus. This could be because the person is currently infected and their immune system is fighting the virus; or because they have recovered and their immune system is still producing protective antibodies against the virus. For SARS-CoV1, a closely related virus, recovered patients continued to have detectable antibodies upto about a year after infection (Huang, Carreras et al., 2020, Vabret, Britton et al., 2020).

The immune system produces different kinds of antibodies at different times during and after infection. Tests may be designed to detect one or more of these antibody types. After an infection, the first antibodies to appear are IgM antibodies (within 1-2 weeks from infection for COVID19), followed by IgG antibodies (2-4 weeks, lasting upto a year after infection) (Huang, Carreras et al., 2020, Vabret, Britton et al., 2020). Tests that detect IgMs would detect infection earlier. IgG tests would indicate if a person has had the infection in the past, and would show a person’s long-term ability to fight COVID19. 

 Are serological tests reliable?

Antibodies against the novel coronavirus recognise and bind to specific molecules on the virus’ surface. Serological tests mimic these viral molecules to bind and detect antibodies in a blood sample. But different test products use different target molecules, and so they have different sensitivity (i.e. ability to detect small amounts of antibody) (Infectious Diseases Society of America guidelines). When a person is infected by other coronaviruses, e.g. those that cause common colds, they produce antibodies against them. But these antibodies might cross-react with the novel coronavirus target molecules in a serological test. If this happens, the test would give an incorrect positive result, without infection by the novel coronavirus (Infectious Diseases Society of America guidelines). All serological tests do not work in the same way (i.e. they are not standardised). The gold standard in COVID19 diagnosis remains PCR-based testing that detects viral genetic material (Esbin, Whitney et al., 2020). But these tests take about a day to run, require expensive laboratory equipment and supplies, and qualified technicians.

References:

1. Huang, Carreras et al., 2020 
2. Vashist, 2020
3. Infectious Diseases Society of America guidelines on COVID19 serological tests
4. Video: Serological tests 101 by Beckman Coulter
5. Immunology of COVID-19: current state of the science

Last update: 15 June 2020

Herd immunity is the situation when a sufficiently high proportion of the population is immune to an infectious disease, slowing its spread in the population. The term ‘herd immunity’ is generally used in the context of immunity acquired via vaccines (see this animation). Sometimes, even if a vaccine is available and administered widely, some individuals remain unvaccinated. These could be infants, children, the elderly or people with certain medical conditions, depending on the disease/vaccine. They are not immune, yet have a much lower chance of getting infected, because the people they come in frequent contact with are immunized. They are thus protected by being part of a herd or a group. Herd immunity relies on immunized people to help break the chain of spread of infection. 

Herd immunity is also possible if many people in a population become infected and then recover, so that they no longer transmit infection for the period during which they have active immunity. However, for a new infectious disease with adverse outcomes, it could be dangerous to depend on herd immunity for disease control before a vaccine is available. 

More details about herd immunity

Herd immunity for an infectious disease is mainly decided by the reproductive number (R₀) – the number of susceptible people that one infected person can directly infect in a population. R₀ reflects ‘infectiousness’ of the disease (this video explains reproductive number). It decides the proportion (P_crit) of the population that needs to be immune to make the entire population safe. The more infectious the disease, the higher the values of R₀ and P_crit. For example, measles is a highly infectious disease, with an R₀ of about 12-18. As a result, 95% of the population has to be immunized (P_crit = about 95) to provide herd immunity to the remaining 5%. On the other hand, seasonal influenza or ‘flu’ is less infectious (R₀ is about 1-3) and herd immunity can be achieved by around 65% of the population being immune. 

The exact conditions required for herd immunity are not easy to predict, because the reproductive number depends upon the population density and social structure. The protective effect of a herd can also get diluted if some people have weaker immunity against the pathogen, or if immunity decreases with time. Finally, If new strains of the virus/bacterium emerge, a large fraction of the population may become susceptible again.

COVID-19 and herd immunity 

For the novel coronavirus, R₀ is currently estimated to be about 3 (even higher in some countries). Thus, at least 70% of the population will have to be immune to the novel coronavirus, to ensure the safety of the remaining people. With no vaccine or cure available yet and a mortality rate of upto 3%, it would mean that a very large number of people will become severely sick with and/or die from COVID-19 before herd immunity is viable. Presently, following physical distancing and other precautions, and isolating patients and their close contacts, seems to be the only safe way to control the pandemic.

References:

1. CDC glossary of terms for definition of herd immunity
2. A video explaining herd immunity
3. Paper on reproductive number and herd immunity for COVID-19 
4.  A summary on herd immunity in some infectious diseases
5. A summary of data on reproductive numbers for some infectious diseases.
6. A popular science article on herd immunity basics and COVID-19  
7. A video explaining the reproductive number (R₀)
8. Another video on R₀ and spread of an epidemic