Professor Robin Wood, one of South Africa’s eminent medical scientists, says that while Western medicine tends to focus on the sickest patients, to make a public health impact efforts need to concentrate on stopping people getting COVID-19and on providing good, early treatment to prevent disease progression. In the first of five PPS webinars drawing on global research to inform local prevention and treatment, Wood also said he was no longer sure what South Africa’s overall strategy was in responding to the pandemic.
Wood believes governments and the World Health Organization may be playing down the importance of small breath particles in the transmission of the coronavirus, writes Karen MacGregor for MedicalBrief. This is a matter of great importance to COVID-19 prevention.
And he finds current mortality data “compelling”. Worldwide the number of cases of COVID-19 is growing but the numbers of deaths per day are staying stable. “This is an interesting phenomenon. It is good if your strategy is to limit mortality; not good if your strategy is to limit infections.”
In the webinar series, Wood will unpack fast-moving research and developments around the COVID-19 pandemic. The webinars are a partnership between the Medical Protection Society (MPS) MedicalBrief and the Desmond Tutu HIV Foundation (DTHF). MedicalBrief Managing Editor William Saunderson-Meyer is the series moderator.
Wood is director of the Desmond Tutu HIV Centre in the Institute of Infectious Diseases and Molecular Medicine at the University of Cape Town, and of the DTHF. He has been a National Research Foundation A-Rated scientist, a visiting fellow at Harvard Medical School, and honorary professor at the London School of Hygiene and Tropical Medicine.
What should South African medical practitioners be thinking about?
Wood said he was no longer sure what South Africa’s precise overall strategy is in responding to the pandemic. “The strategy has changed from temporally flattening the curve in order to prevent the medical infrastructure being overwhelmed. It could be to try and decrease mortality by protecting the elderly and other vulnerable groups but now the focus seems to be to decrease the incidence numbers even in groups at low risk of any morbidity. We need to be clear which of those is our strategic aim and then focus on achieving it.”
There have been major concerns about hospital systems being overwhelmed. It is interesting, Wood said, that South Africa has 300,000 TB cases a year and 63,000 TB deaths a year. “Yet that doesn’t stress our hospital system to the same degree as 1,500 COVID deaths.
“The interactions with TB are of interest. TB is a disease that affects poor populations. It is a disease which gets propagated in crowded, poorly ventilated areas and similar to COVID. We have an added problem that the symptoms with which patients present look very similar.”
Mortality rates are particularly important, and comparing South Africa with other countries, “it looks as though we don’t have a hidden mortality as reflected by an excess mortality over and above what we would expect”.
Wood gave the example of Ecuador, “where it looked almost medieval, with people dying in the streets etc”. According to official figures, mortality rates were relatively low. But hidden mortality was high, indicating they weren’t picking up all of the COVID deaths.
“The evidence is that we’ve got a reasonable handle on our epidemic,” Wood said.
In South Africa as elsewhere, COVID-19 mortality is largely determined by the presence of co-morbidities – especially diabetes and hypertension – and age. “The risks to the elderly and those with co-morbidities are hundreds fold higher than for young people.”
Still, Wood believes that there are individuals whose innate immune system may make them less vulnerable to respiratory diseases. “I suspect that there are some people that have met diseases that cross-react with this. A recent Science article demonstrated that blood taken several years ago contained t-cells that were able to immunologically respond to the COVID-19 virus.”
People’s innate immunity is different, their Vitamin D status varies, their blood groups are different. “There is a lot of heterogeneity within the human population,” Wood said.
The conundrum of the Western Cape being hardest hit by COVID-19 illustrates that many factors play into susceptibility to the virus and the course of infection. “The numbers are different in different places and we don’t understand all of them.”
There has been criticism of government’s approach to testing. Your thoughts?
Despite widespread criticism, Wood believes government has done quite a good job of testing. “There has been a steady increase in numbers of tests, performed which has been associated with a steady increase in the test yield that has increased from about 2% to almost 15%.
“It is an achievement to get up to 1.2 million tests in a country of 58 million people. It does gives us a good idea of the progress of the epidemic,” he told the webinar.
Wood believes the tests for COVID involving RNA assays are pretty good, though there can be difficulties with sample collection and with the site of infection.
“It seems as though there is increasing sensitivity of the assay as testing moves from the tissues of the upper respiratory to the lower respiratory tract. Bronchoalveolar lavage has a much higher positivity rate than sputum or a nasal swab which in turn has greater sensitivity than a throat swab. So it is graded but the sensitivity is still reasonable.”
The sensitivity from a nasal swab is above 60%. This doesn’t sound great but, Wood pointed out: “You have to remember that in TB we find a sputum positive diagnosis in about 50% of cases. In this disease we have a good diagnostic.”
Currently, antibody tests are not available. In March SAHPRA, the South African Health Products Regulatory Agency, ruled that rapid serology test kits (serological test kits) currently available for COVID-19 diagnosis were not suitable for that purpose.
Wood said antibody tests would probably not be used for diagnosis but could be a “very useful adjunct” for identifying if significant numbers of people have been asymptomatic and unaware that they have had the Covid-19 infection.
“Knowing that a large proportion of the population is relatively immune to a new infection is, from an epidemiological point of view, really important,” he said.
Much excitement has greeted the Oxford University dexamethasone study. What is the research telling us? Can we all go home now?
There has indeed been excitement about the potential role in treating COVID-19 of dexamethasone, a steroid that helps to reduce inflammation and damp down over-exuberant immune systems. The Oxford study found it reduced deaths among very sick patients.
“It’s a step forward,” said Wood. “However, I don’t think it’s going to be panacea.”
The large study used about 6,000 patients, so even though it has not yet been peer reviewed, the results appear robust. “The death rate amongst people on ventilators was decreased from 41% to 27%. With these large numbers, that’s very statistically significant,” Wood said.
Quite low doses of dexamethasone were used, six milligrams a day. When it was given to patients a bit earlier in the disease, those who were oxygen dependent, “the decrease went from 25% mortality to 20% mortality, which is an effect size of about 20%. Again, because of the large numbers, this reaches statistical significance”.
Dexamethasone has been around for a long time. Normally it is recommended for patients with acute respiratory disease syndrome or ARDS, but has been used at much higher doses. It will not solve all COVID-19 treatment problems because among people at an earlier stage of the disease, who did not require oxygen, it provided no benefit.
But the drug will be important in improving the health of a quite large group of COVID patients who are oxygen-dependent, to reduce them going on to ventilators; and it will help a relatively smaller group of patients on ventilators who have a poor prognosis.
What are the implications of research into hydroxychloroquine and related drugs?
Hydroxychloroquine, the malaria prevention and treatment medicine that United States President Donald Trump promoted as a possible treatment for COVID-19, also sparked interest as a potential weapon in the anti-COVID-19 drug arsenal.
Hydroxychloroquine started off being attractive because it is cheap, has been given to millions of people over decades, and has been shown to switch off viral activity in test tube studies.
Some studies in China reported beneficial results, as did one small study in France. “But subsequently we’ve got equivocal results for prophylaxis,” Wood pointed out. Deaths were reported in a Brazilian study that used a 12 gram dose, four or five times higher than normal.
“Higher doses do appear to be cardio-toxic. Additionally a lot of the patients with COVID-19 do have cardiac co-morbidity, so therefore the high dose is really problematic.”
At the weekend the US National Institutes of Health halted its study of hydroxychloroquine, stating that the drug was very unlikely to be beneficial.
What about other treatments under current discussion?
Regarding other treatments, much has been written about the ability of Remdesivir – the broad-spectrum antiviral medication – to decrease the length of hospitalisation among COVID-19 patients who are oxygen-dependent or on a ventilator.
“The rationale for steroids such as dexamethasone is to damp down an over-exuberant immune response,” Wood explained. “I don’t think there’s a rationale for giving it very early in the disease. When it may increase viral replication”
Convalescent serum – blood drawn from a person who has recovered from Covid-19 and whose blood is considered high in antibodies – “is interesting and has a rationale behind it, because it was used in the earlier SARS and MERS epidemics and was shown to be beneficial,” Wood said. It was also useful in treating Ebola.
But there are practical limitations. An appropriate donor must be found, with matching blood, and one donor can normally produce enough treatment for only two or three patients. So it has limited availability. There have been around 6,000 units given to close to 5,000 patients in the US.
There are medications, such as tocilizumab, which seem to have an effect on the cytokine storm but are very expensive. But again, these treatments focus on the end stage of COVID.
“I think we should be looking at the earlier stages and make sure that individuals that have a COVID-19 diagnosis have reasonable nutrition and are properly screened for progression.
How do you see the picture for prevention at the moment?
In a webinar in April, Wood was emphatic that (homemade) masks for the public were essential as were N95 masks for medical personnel, and that there should be effective testing. He has since been proved correct on both fronts.
Last week he outlined the three methods of transmission of COVID-19, “although the South African guidelines report is only two methods”.
The first method is fomites, surfaces that can be contaminated; that is reduced by hand and surface cleaning. A second method of transmission is via large particles, produced mainly during speech as a shower of particles that accompanies the articulation of vowels and consonants. “That can be relatively easily stopped by a cloth mask and by a reasonable distancing.”
A third method is via small particles. These are less than five microns in diameter and can remain airborne for prolonged periods of time. “This is the same method of dissemination as proposed for tuberculosis.
“It has been ignored and has been played down by the World Health Organization and by our own national guidelines. That’s probably a mistake,” warned Wood. The way to control small particle transmission is by old fashioned ventilation. “You can substitute ventilation with UV light and individual protection is with the N95 masks.”
Policy in many parts of the world has been that a surgical mask suffices against transmission. “The evidence from Europe is that there have been high infection rates amongst doctors, and shows that’s probably wrong. I don’t see why transmission shouldn’t be by small particles. We know that most individuals produce small aerosol particles when they take deep breaths or when they shout or perform any forceful respiratory manoeuvre.”
A problem, explained Wood, is that it is not known which transmission method is most important in each and every scenario. In a creche, fomite transmission would clearly be important. In hospitals, small particle transmission may become more crucial. Wood feels strongly about the need for good indoor ventilation, as most transmission of respiratory diseases is indoors and not outdoors.
There’s a lot of interest in transmission by asymptomatic patients. Your thoughts?
Transmission of COVID-19 by people who display no symptoms is “very significant”, said Wood, but very little is known about the scale of this problem. There is a lot of evidence of transmission by asymptomatics, but the key question is the population attributable risk.
Some studies have attempted to measure the risk; one found it was around 15% and another suggested asymptomatic transmission was responsible for up to 60% of infections. The absolute magnitude of asymptomatic transmission is not known, and Wood believes this will vary tremendously depending on the environment.
The small country of Iceland, where there has been a lot of testing, reported that as many as 40% of people were not aware of symptoms. There is also the problem of people having symptoms but not thinking of them as particularly unusual.
“Definitely, asymptomatic disease transmission is a challenge. But there’s no doubt that it does occur and many of the asymptomatic cases occur due to the variability of the immune response to the virus and don’t necessarily reflect testing failure.”
Are there people who are more susceptible or less susceptible to getting the disease?
It is thought that people who have had COVID-19 and produced antibodies are likely to be somewhat protected, said Wood. “Certainly that was the case with MERS and SARS. But what about vitamin D status?”
There is a problem in temperate zones where people with darker skin colour are being infected and dying of COVID-19 much more frequently than pale skinned individuals, he explained. One proposed cause could be Vitamin D deficiency, as melanin lowers the skin’s ability to produce Vitamin D in response to sunlight exposure.
Looking at countries that have been particularly severely affected by COVID-19, “a lot of that effect could be explained by Vitamin D status”, said Wood. Data from Philippines and Indonesia found a connection between level of COVID-19 sickness and lower Vitamin D levels. A couple of studies in Europe have linked infection rates of different countries with background Vitamin D deficiency rates.
“It’s circumstantial evidence but there’s an awful lot of it,” said Wood. Fortunately, Vitamin D is cheap and easily available. Some countries in Europe use vitamin fortification of food substances to a high degree.
“Finland is very aggressive on that, and Finland had very low case rates and case fatalities compared to other nearby countries. Interesting, in northern Italy elderly females have an high deficiency rate of Vitamin D,” he continued.
“Vitamin D status may explain some of the strange anomalies between nations. It has a rationale at an individual level, group level and at a country level, and it is a relatively cheap intervention.”
Wood said studies had put the population level deficiency of Vitamin D deficiency in South Africa at around 10%. “In northern Italy, among the elderly it was 80% and Belgium, which was particularly hard hit, was about 44% deficient. So we are relatively better off.”
What if nothing had been done?
There is no doubt, Wood said, that “all respiratory illnesses that have plagued us historically have eventually been controlled by a lack of susceptible people, and that’s why we’re talking about whether or not people can get re-infected.”
While there have been reports of re-infection, Wood believes those results could be due to inaccurate testing. Also, some people take a long time to clear the virus, so it can be difficult to determine whether such people have not truly recovered or have been re-infected.
Generally, there is some immunity linked to diseases such as COVID, where antibodies are produced. The level of antibodies produced by individuals varies tremendously, Wood said: “But generally the feeling is that individuals aren’t getting infected more than once.”
He has been wondering what would have happened if nothing had been done about COVID.
Marion Correctional Institution in Ohio in the US is an interesting case study. Little was done to prevent coronavirus transmission – no hand washing, beds spaced within a metre of each other with no social distancing at all.
Marion had 2,500 prisoners, of whom 80% became infected with COVID-19. There were 88 deaths, which was a death rate around 3%. Now the epidemic has been labelled as burnt out. The reason being because the virus has run out of susceptible people. “There is no doubt that in a closed setting with high transmission the resultant population immunity did reduce the epidemic,” Wood remarked.
Extrapolating the Marion experience to other populations is tricky, because it is not known if all people are equally susceptible to COVID-19. “But certainly the disease will not prosper when it runs out of appropriate susceptible individuals. For whatever reason they became less susceptible, it will have a big impact on the epidemic curves.”
Ends
[link url="https://youtu.be/ndMR6QlO6Lg"]To view Prof Wood's webinar[/link]
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