Authors: Julian W Tang (Respiratory Sciences, University of Leicester, Leicester, UK)
In the last 5 months since the previous article, the virus has spread globally to include Australasia and the Western Pacific, South Asia, Africa, Europe and North and South America, with over 13 million cases and over 570,000 deaths worldwide (as of 13 July 2020) . This is very likely still an underestimate, but we just don’t know by how much. However, now a huge amount of progress has been made on understanding SARS-CoV-2 (the virus) and COVID-19 (the disease that it causes).
Whilst the true origins of the virus are still being debated and investigated (with many conspiracy theories on all sides being suggested) , we now have a more complete awareness and understanding of: 1) the clinical spectrum of the disease, including some unusual presentations in children; 2) an unusual bias towards higher morbidity and mortality in certain ethnic minority groups in some countries; 3) human host immune responses to the virus; 4) the final recognition that masks are useful to control the spread of the virus, together with the ongoing debate around whether the virus is transmitted via aerosols; 5) new COVID-19 treatments; 6) the appearance of a specific viral mutation (D614G in the viral S protein) that seems to be enhancing the transmissibility of the virus.
Clinical spectrum of disease
Whilst it is still true that the most common presenting symptoms are respiratory in nature, there is a large variation in this, including just mild fever, or just lethargy, or just fever and myalgia, or just loss of smell and/or taste – without sore throat, coughing, shortness of breath. Symptoms can last for weeks and recovery can take weeks to months, especially if there are complications .
Although COVID-19 is usually benign in most children , one of the most striking recent developments is the recognition of a Kawasaki-like presentation in children aged 1–18 years . This hyperinflammatory syndrome has been associated with a SARS-CoV-2 infection sometime in the previous 4 weeks, which can usually be confirmed by a positive SARS-CoV-2 PCR result and/or a positive SARS-CoV-2 IgG serology result. There is also a higher proportion of children from Black, Asian and other Minority Ethnic (BAME) backgrounds being affected .
This illness can present with fever, rash, septic shock, or cardiac complications and usually follows acute COVID-19 days 2–4 weeks later. Some may be still SARS-CoV-2 PCR positive when they present with this syndrome. The initial COVID-19 illness can present in a variety of ways and is not obviously correlated to the risk of developing this hyperinflammatory syndrome, which makes it difficult to predict or recognize which individual child may be at risk .
Management protocols are still under development, but are likely to involve some form of anti-inflammatory and immunosuppressive approach to reduce the damage caused by the host immune system – similar to that for Kawasaki disease . However, note that this is still a rare presentation and the vast majority of children will recover uneventfully from COVID-19.
Vulnerability of ethnic minorities to COVID-19
Recent studies from the USA, UK and some other European countries have revealed that patients from BAME groups appear to have both a higher incidence of infection and also a higher mortality when infected .
These are mainly in immigrant BAME populations in these countries where the incidence and mortality is compared to the local white Caucasian populations. Such immigrant populations often live in multi-generation families in more crowded, deprived environments with lower income and socioeconomic status. These settings predispose to more easy and rapid spread of SARS-CoV-2 and will lead to higher mortality in the older members of these populations who often have comorbidities linked to higher mortality with COVID-19, such as diabetes, obesity and chronic heart, kidney and lung diseases .
However, even controlling for all these factors, there is still a residual higher risk of BAME patients dying from COVID-19. Apart from the factors mentioned above, other possible contributors include vitamin D deficiency (as darker skin requires more prolonged sunlight exposure), possible ethnic differences in ACE2 distribution (the receptor for SARS-CoV-2) and potential genetic susceptibilities and differences in host immune responses to COVID-19, all of which are under investigation .
Interestingly, in Singapore, where there have been large outbreaks amongst dormitories housing immigrant workers from India, Bangladesh and other South Asian nationalities, very few have required hospitalization. This may be due to their younger age, but there appears to be something about being a BAME immigrant into these Western societies that poses a higher risk of more severe SARS-CoV-2 infection and resulting COVID-19 mortality .
Human immune responses to COVID-19
Widespread serological testing has only begun relatively recently at national population levels in affected countries. Although the sensitivities and specificities of various commercially available serological assays vary widely, it is clear that SARS-CoV-2 antibody levels continue to rise for 15 days post-illness onset . Hence most serological assays reach their peak sensitivity at around 15–20 days post-onset of symptoms, during convalescence, which is not unusual in viral serology.
However, it is becoming apparent that some COVID-19 recovered patients do not produce detectable antibodies, and even those that do may lose them quite quickly. In addition, although more symptomatic patients may produce more antibodies that may last longer than milder or asymptomatic infections, where SARS-CoV-2 IgG may still remain detectable for some months, it is still unclear how protective these will be upon re-exposure to SARS-CoV-2 . The level of protection is thought to depend on the levels of ‘neutralizing’ antibodies induced.
Some studies have shown that a subset of IgG antibodies directed towards the viral surface S (spike) glycoproteins are ‘neutralizing’ (i.e. protective). The virus uses this S protein to bind to the human host cell ACE2 enzyme molecule, which is the receptor for SARS-CoV-2, to enter the human cell to start replication. So, antibodies (induced by natural infection or vaccine) or antiviral drugs that can bind to this S protein can stop the virus from entering human host cells. This would prevent infection and COVID-19 .
These SARS-CoV-2 antibody (humoral) responses are due to B lymphocytes, but more recently, studies on T lymphocyte (cell-mediated) immune responses been shown to possibly induce even longer lasting protective immunity – even in the absence of detectable antibodies . However, unlike antibody (serology) testing, these T lymphocyte responses are currently only detectable by research assays, not currently available in routine diagnostic laboratories. So it will be difficult to assess such T-cell responses in patients recovering from COVID-19.
Widespread recommendations for face coverings or mask use
Despite earlier guidelines from multiple Western countries stating that masking was not useful and not to do this, this has now been reversed globally and most countries are recommending the use of some form of face covering in public places where there are crowds, as well as in healthcare premises and other indoor crowded environments with little or no ventilation [17, 18].
Although there are ongoing debates in the media about the lack of evidence for the effectiveness of masks, there is in fact a lot of published evidence already. Studies have demonstrated that surgical masks can contain and therefore reduce the dissemination of droplets and aerosols produced by a sick wearer by up to 3–4-fold (i.e. ~67–75%) [19, 20], to protect others. Surgical masks can also protect the wearer to some degree by reducing the exposure to incoming droplets and aerosols by up to 6-fold (i.e. ~83%), from others who are ill [21, 22]. Homemade cloth masks (made out of tea cloths in this study) can reduce the exposure from incoming aerosols by up to 2–4-fold (i.e. ~50–75%) , though this will depend to some extent on how the mask is made, what it is made from, and the nature of the aerosols to which it is exposed.
Finally, a comprehensive review of face shields (or visors) suggest a protection efficacy slightly higher than surgical masks initially, from immediate exposures, but that decreases over time as the finer aerosols produced start to be inhaled underneath the visor . Note that to optimize protection the face shield has to curve round the sides of the face to the ears and to extend down long enough in front of the face, to reduce aerosol entry from the sides and underneath the shield as much as possible. Face shields/visors have the added advantage that they include eye protection, as well as being washable and reusable, being less claustrophobic and generally allowing mostly normal communication if worn instead of a face mask, though both can be worn in combination for added protection (Figure 1) .
Figure 1. Example of face shield/visor, worn together with a face mask
From US CDC Public Image Library (PHIL): https://phil.cdc.gov/Details.aspx?pid=16422
This image is in the public domain and thus free of any copyright restrictions.
One intuitive way to understand these various mask protection factors more clearly is to consider the impact of wearing the mask if 1000 viruses are coming towards you in droplet and/or aerosol form. So a 6-fold reduction indicates that you will only be exposed to one-sixth of these viruses (i.e. 1000/6 = 167 viruses); a 2–4-fold reduction would indicate that only half (i.e. 500 viruses) to one-quarter (i.e. 250 viruses) of these viruses would reach you. Similarly, if wearing a mask contains and reduces the amount of virus that you are spreading to others by 3–4fold, this effectively reduces this 1000 viruses to just 333 or 250 viruses.
The US CDC (Centers for Disease Control and Prevention) and UK PHE (Public Health England) and now the WHO (World Health Organization) guidance have been recently updated [25–27], to recognize the role of droplets and aerosols, outside of AGPs (aerosol-generating procedures), in the transmission of SARS-CoV-2 – particularly in crowded, poorly ventilated indoor spaces [28, 29].
Further studies have demonstrated the production of aerosols (containing a mixture of droplet sizes in differing numbers) from human volunteers talking loudly  and possibly singing . An earlier review article summarized the available evidence on how various COVID-19 outbreaks in public transport and other crowded, poorly ventilated public settings could most easily be explained by aerosol transmission and offered recommendations to reduce this route of spread including improved ventilation without recirculation, the use of air-cleansing technologies and reducing crowding in poorly-ventilated indoor spaces, which ties in with maintaining adequate social distancing (e.g. 1–2m, depending on local guidelines) [32, 33].
New COVID-19 treatments
Recently two drugs have been approved for COVID-19 treatment, but showing clinical benefits only in relatively severe, hospitalized patients who were oxygen-dependent: the viral polymerase inhibitor remdesivir (originally a drug design to inhibit Ebola replication) and dexamethasone, a commonly used steroid for immunosuppressive therapy.
A 10 day course of remdesivir (loading dose 200 mg followed by 9 days of 100 mg daily, intravenously) given to 538 patients compared to 521 patients given a placebo, all of whom showed evidence of lower respiratory tract disease, showed a 4 day median reduction of hospital stay from 15–11 days . A further report on the outcomes of compassionate use of remdesivir with the same dosing regimen as above, in patients with oxygen saturations of 94% or less, or who were on supplemental oxygen, showed clinical improvement in 36 out of 53 (68%) .
A dose of 6 mg once daily for 10 days of dexamethasone reduced overall mortality at 28 days by one-third when used in ventilated COVID-19 patient, and by one-fifth when used on COVID-19 patients who were only on oxygen therapy. It showed no benefit for COVID-19 patients who were not oxygen-dependent .
Both of these treatment options are now available to clinical teams managing more severely ill COVID-19 patients.
Viral mutations and implications
Perhaps one of the most interesting findings recently is the rapid emergence of the D614G mutation in the SARS-CoV-2 S (spike) gene that codes for this protein, which binds to ACE2 to allow viral entry into host cells [37,38]. Other studies have proposed that this mutation also increases the transmissibility of the virus in humans, which may accelerate the spread of COVID-19 in susceptible populations [39, 40].
Such changes in the viral S protein may reduce the neutralizing efficiency of SARS-CoV-2 antibodies collected in earlier convalescent plasma, as well as that of any vaccines designed to elicit such antibodies based on an earlier version of the S protein and its related gene sequence. Further work needs to confirm these findings, but this is important as it may also impact on any earlier antiviral drug targeting this protein. If the SARS-CoV-2 S protein and gene continue mutating, it may eventually invalidate any such antiviral drugs and vaccines in development, which will need to be modified. This will delay the start of clinical trials and ultimately the licensing and availability of any of these interventions against COVID-19.
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