COVID19 TESTS & VACCINES

The estimated reproduction number (R0) for SARS-CoV-2 ranges from 2.2 to 5.5, meaning one person can potentially transmit the disease to 5–6 people, making it highly transmissible.

Three main routes of transmission have been proposed:

The 'fomite' path, through touching a surface that contains the SARS-CoV-2 virus. That can transfer the virus onto your hand, and then you can infect yourself by touching your mouth, nostrils, or eyes.
The ‘large droplet’ or ‘ballistic droplet’ path. Droplets are particles of saliva or respiratory fluid (larger than about 100 μm, with 1 μm = a millionth of a meter) that are expelled from infected individuals when coughing, sneezing, and to a lesser extent, talking. They infect by impacting on the mouth, nostrils, or eyes. If they don’t hit someone, they fall to the ground in 1-2 m (3-6 ft).
The ‘aerosol’ path. Aerosols are smaller (less about 100 μm) particles of saliva or respiratory fluid. They can linger more in the air, from tens of seconds to hours, and can travel longer distances. They infect by being inhaled through the nose or mouth, or (less likely) by deposition on the eyes.
The relative importance of these modes of transmission is uncertain and open to debate

It is likely that some individuals are more contagious than others. This may be due to a higher viral load at the onset of symptoms, to higher emissions of respiratory particles, or (likely) to both. Viral RNA shedding is higher at the time of symptom onset and declines after days or weeks. The RNA of the virus has been identified in respiratory tract specimens 1-2 days before the onset of symptoms and it can persist for up to eight days in mild cases and for longer periods in more severe cases, peaking in the second week after infection.

Prolonged viral RNA shedding has been reported from nasopharyngeal swabs (up to 67 days among adult patients) and in faeces (more than one month after infection in paediatric patients). Infectious virus has been detected up to day eight post disease onset using cell culture based systems.

Late viral RNA clearance (≥15 days after illness onset), is associated with male sex, old age, hypertension, delayed admission to hospital, severe illness at admission, invasive mechanical ventilation, and corticosteroid treatment.

Seasonality
Human coronavirus infection rates show peaks in the winter months, similar to influenza and human respiratory syncytial viruses (RSV) and are therefore, according to their seasonality, classified as winter viruses. Low temperature and dry air impair and disrupt the integrity of the epithelial layer of the lungs, which might explain the winter seasonality of respiratory viruses.

Other factors that might contribute to transmission are increased indoor activities during the winter months, which increases susceptible host proximity. Such behavioural factors have been implicated in other winter viruses such as influenza. Whether SARS-CoV-2 will show similar seasonality remains to be seen.


References
European Centre for Disease Prevention and Control. Coronaviruses: General background.

He, X., Lau, E.H.Y., Wu, P. et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med 26, 672–675 (2020). [Abstract]

Marr L, et al. FAQs on Protecting Yourself from Aerosol Transmission. Version: 1.78, 1-Oct-2020.

Ma J, et al. COVID-19 patients in earlier stages exhaled millions of SARS-CoV-2 per hour, Clinical Infectious Diseases, , ciaa1283.

CDC. Coronavirus Disease 2019 (COVID-19). People with Certain Medical Conditions. Accessed 5 October 2020.

Current estimates suggest a median incubation period from five to six days for COVID-19, with a range from two to up to 14 days. Modelling studies suggest that the incubation period can be from 2.3 days (95% CI, 0.8–3.0 days) before symptom onset and up to 14 days, although incubation periods beyond 10 days are thought to be rare.

In terms of viral load profile, SARS-CoV-2 is similar to that of influenza, which peaks at around the time of symptom onset, but contrasts with that of SARS-CoV, which peaks at around 10 days after symptom onset, and that of MERS-CoV which peaks at the second week after symptom onset. Older age has also been associated with higher viral loads. The high viral load close to symptom onset suggests that SARS-CoV-2 can be easily transmissible at an early stage of infection.

A study from China that clearly and appropriately defined asymptomatic infections suggests that the proportion of infected people who never developed symptoms was 23%.

Presenting signs and symptoms of COVID-19 vary. Most people experience:

fever (83–99%),
cough (59–82%),
fatigue (44–70%),
anorexia (40–84%),
shortness of breath (31–40%),
myalgias (11–35%).
Other non-specific symptoms, such as sore throat, nasal congestion, headache, diarrhoea, nausea and vomiting, have also been reported. Loss of smell (anosmia) or loss of taste (ageusia) preceding the onset of respiratory symptoms has also been reported.

Older people and immunosuppressed patients in particular may present with atypical
symptoms such as fatigue, reduced alertness, reduced mobility, diarrhoea, loss of appetite,
delirium, and absence of fever.

Symptoms such as dyspnoea, fever, gastrointestinal symptoms or fatigue due to
physiologic adaptations in pregnant women, adverse pregnancy events, or other diseases
such as malaria, may overlap with symptoms of COVID-19.


Children
COVID-19, like SARS and MERS, is observed less frequently in children, who tend to present with milder symptoms and have a better overall outcome than adults. The most commonly reported symptoms in children are fever and cough. Other symptoms include gastrointestinal symptoms, sore throat/pharyngitis, shortness of breath, myalgia, rhinorrhoea/nasal congestion and headache, with varying prevalence among different studies. Asymptomatic infections in children have been reported.

Severe or critical illness has been reported among 2.5% to 5% of paediatric cases from China. Pre-existing medical conditions have been suggested as a risk factor for severe disease and ICU admission in children and adolescents


Pregnant women and neonates
Clinical manifestations in pregnant women are predominantly mild, with few reports of severe disease and fatal outcomes.

Underlying health conditions among severe cases
Underlying health conditions reported among patients with COVID-19 and admitted to ICU include hypertension, diabetes, cardiovascular disease, chronic respiratory disease, immune compromised status, cancer and obesity.

Elderly residents of long-term care facilities and nursing homes
A high proportion of long-term care facilities (LTCF) and nursing homes across Europe and the world have been severely affected by COVID-19. High morbidity and mortality in residents as well as high rates of staff absence due to SARS-CoV-2 infections have been observed.

Healthcare workers
Healthcare workers (HCW) are at high risk of COVID-19 infection because of more frequent exposure to COVID-19 cases and may contribute to the spread of COVID-19 in healthcare institutions. A recent study in the United Kingdom and the US estimated that frontline healthcare workers had a 3.4-fold higher risk than people living in the general community for reporting a positive test, adjusting for the likelihood of receiving a test. In addition, exposure to higher virus concentrations, especially from severely ill patients, may influence disease severity.


References
European Centre for Disease Prevention and Control. Coronavirus: Epidemiology of COVID-19.

European Centre for Disease Prevention and Control. Coronavirus: Infection. Accessed 6 October 2020.

Wang Y, Tong J, Qin Y, Xie T, Li J, Li J, et al. Characterization of an asymptomatic cohort of SARS-COV-2 infected individuals outside of Wuhan, China. Clin Infect Dis. 2020;ciaa629.

World Health Organisation. Clinical management of COVID-19. May 2020. https://www.who.int/publications/i/item/clinical-management-of-covid-19

Nguyen LH, Drew DA, Joshi AD, Guo C-G, Ma W, Mehta RS, et al. Risk of COVID-19 among frontline healthcare workers and the general community: a prospective cohort study. medRxiv. 2020:2020.04.29.20084111.

The immune response to SARS-CoV-2 involves both cell-mediated immunity and antibody production.


Cell-mediated immune response
T-cell responses against the SARS-CoV-2 spike protein have been characterised and correlate well with IgG and IgA antibody titres in COVID-19 patients. It is currently unknown whether antibody responses or T-cell responses in infected people confer protective immunity, and if so, how strong a response is needed for this to occur.

CD8+ T cells are the main inflammatory cells and play a vital role in virus clearance. Total lymphocytes, CD4+ T cells, CD8+ T cells, B cells, and natural killer cells show a significant association with inflammatory status in COVID-19, especially CD8+ T cells and CD4+/CD8+ ratio. Decreased absolute numbers of T lymphocytes, CD4+ T cells, and CD8+ T cells were observed in both mild cases and severe cases, but accentuated in the severe cases. In multivariate analysis, post-treatment decrease in CD8+ T cells and B cells and increase in CD4+/CD8+ ratio were indicated as independent predictors of poor treatment outcome. The expression of IFN-γ by CD4+ T cells also tends to be lower in severe cases than in moderate cases.


Antibody-mediated immune response and protective immunity
The detection of antibodies to SARS-CoV-2 does not indicate directly protective immunity and correlates of protection for COVID-19 have not yet been established.

Most people infected with SARS-CoV-2 display an antibody response between day 10 and day 21 after infection. Detection in mild cases can take longer (four weeks or more) and, in a small number of cases, antibodies (IgM, IgG) are not detected at all (at least during the studies’ time scale).

Based on the currently available data, the IgM and IgG antibodies to SARS-CoV-2 develop between 6–15 days post disease onset. A study in China showed a median seroconversion time for total antibodies, IgM and then IgG of day-11, day-12 and day-14 post symptom onset, respectively. The presence of antibodies was detected in <40% among patients within 1 week from onset, and rapidly increased to 100% (total antibodies), 94.3% (IgM) and 79.8% (IgG) from day-15 after onset.

The longevity of the antibody response is still unknown.


References
European Centre for Disease Prevention and Control. Coronavirus: Immune responses and immunity to SARS-CoV-2. Accessed 6 October 2020.
Zhao J, et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin Infect Dis. 2020 Mar 28:ciaa344. doi: 10.1093/cid/ciaa344. Epub ahead of print. PMID: 32221519; PMCID: PMC7184337.
Wang F, Nie J, Wang H, Zhao Q, Xiong Y, Deng L, et al. Characteristics of Peripheral Lymphocyte Subset Alteration in COVID-19 Pneumonia. The Journal of Infectious Diseases. 2020.
Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. The Journal of Clinical Investigation. 2020 04/13/;130(5).

Standard confirmation of acute SARS-CoV-2 infections is based on the detection of unique viral sequences by nucleic acid amplification tests (NAATs), such as real-time reverse-transcription polymerase chain reaction (RT-PCR). The assays’ targets include regions of the E, RdRP, N and S genes. PCR is the current “Gold Standard” test for the detection of SARS-Cov-2.

Using nasal/throat swabs, samples are collected from symptomatic patients between days 1-5 from onset of symptoms. Respiratory secretions may be quite variable in composition, however, and the adequacy of sampling efforts may also vary. This can occasionally result in negative PCR results. In patients for whom SARS-CoV-2 infection is strongly suspected and upper respiratory tract swabs are negative, viral RNA may be detected in lower respiratory tract secretions, such as sputum or bronchoalveolar lavage.

Detection of viral RNA by PCR may not equate with infectivity. Infectious virus particles have been detected using cell culture systems but the relationship between the infectivity of a sample and the contagiousness of the patient is unclear. Viral load can, however, be a potentially useful marker for assessing disease severity and prognosis: a study indicated that viral loads in severe cases were up to 60 times higher than in mild cases.

Lateral flow devices for the detection of SARS-CoV-2 antigen in respiratory samples have been developed and are being used for large scale testing. These have limited value due to their ease of use, but they have significantly reduced sensitivity compared to PCR and the quality control is deficient with a high test failure rate.


References
European Centre for Disease Prevention and Control. Coronavirus: Infection. Accessed 6 October 2020.

Grant P, et al. Extraction-free COVID-19 (SARS-CoV-2) diagnosis by RT-PCR to increase capacity for national testing programmes during a pandemic. BioXriv 8 April 2020.

Wölfel R, et al. Virological assessment of hospitalized patients with COVID-2019. Nature. 2020 May;581(7809):465-469. doi: 10.1038/s41586-020-2196-x. Epub 2020 Apr 1. PMID: 32235945.

Preliminary report from the Joint PHE Porton Down & University of Oxford. SARS-CoV-2 test development and validation cell: Rapid evaluation of Lateral Flow Viral Antigen detection devices (LFDs) for mass community testing. [PDF]

The long-term sequelae of COVID-19 are unknown. However, a range of complaints have been observed in COVID-19 convalescents – not only those recovering from the severe form of the acute disease (ie, post intensive care syndrome), but also those who had mild and moderate disease.

These long-term complaints include:

Extreme fatigue
Muscle weakness
Low grade fever
Inability to concentrate
Memory lapses
Changes in mood
Sleep difficulties
Headaches
Needle pains in arms and legs
Diarrhea and bouts of vomiting
Loss of taste and smell
Sore throat and difficulties to swallow
New onset of diabetes and hypertension
Skin rash
Shortness of breath
Chest pains
Palpitations
The term ‘Long COVID’ has recently emerged as a description of the clinical ‘syndrome’ associated with chronic, but not yet describable as long-term, sequelae of COVID-19. The nature and causation, as well as remediable options and social implications, of Long Covid are yet to be established.

Long-term impacts on pulmonary function, exercise capacity and health status, as well as psychiatric morbidities and chronic fatigue, have been observed in survivors of severe acute respiratory syndrome (SARS). However, it is not known whether lessons from SARS are applicable to COVID-19.


References
Yelin D, et al. Long-term consequences of COVID-19: research needs. Lancet Infect Dis. 2020 Oct;20(10):1115-1117. [Full text]

Ngai JC, et al. The long-term impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status. Respirology. 2010 Apr;15(3):543-50. doi: 10.1111/j.1440-1843.2010.01720.x. Epub 2010 Mar 19. [Full text]

Lam MH, et al. Mental morbidities and chronic fatigue in severe acute respiratory syndrome survivors: long-term follow-up. Arch Intern Med. 2009 Dec 14;169(22):2142-7. [Abstract]