Be prepared
"COVID-19 is not a seasonal flu"
Natalia Leskova, "Scientific Russia"
Does the lifting of quarantine measures mean that we have defeated the coronavirus? Should we wait for the next wave and, if so, when? Will it be less heavy than the first one? What should I do if I don't want to get sick? When to expect a safe and effective vaccine? This is our conversation with N.A. Kryuchkov, public health expert, General director of the contract research company Clinical Excellence Group, immunologist, candidate of Medical Sciences.
– Nikolai Alexandrovich, almost all quarantine measures have been canceled in Moscow, domestic tourism is opening soon and recreation centers are starting to work. Don't you think it's too early?
– In my opinion, it's early. Now, not only in Russia, but also in a number of other countries, successes in the fight against the pandemic are being actively discussed, which, of course, there are. But victory is still far away. Let's look at such an important indicator as the increase in new cases of COVID-19. If we compare with the beginning of June, we do not see a slowdown in the spread of infection, but on the contrary, we see an acceleration from 1.7 to 1.9 percent. The acceleration is small, but still noticeable. The rate of infection remains quite high. In the last few days, the number of newly detected cases of COVID-19 in the world has exceeded 140 thousand per day – this is the maximum value for the entire time of the pandemic. As for Russia, we are at about the global level in terms of the spread of infection. In Russia, the daily increase in new cases is 1.8 percent, in Moscow – about 1 percent. Yes, the situation in our country is far from the worst. Moreover, if we compare with Brazil or the USA, then things are noticeably better here. But this does not mean that the infection is completely defeated. Moreover, the situation can get worse at any moment. We must remember: it is not difficult to make it worse. It is difficult to achieve real success and maintain the positive result achieved.
– Why do we hear the words about "our common victory" from the high stands?
– In any phenomenon important to society, including an epidemic, there are real and virtual components. The real component is the laws of the spread of infection that actually exist, their implementation, the readiness of the healthcare system and the economy, and the virtual, media component is how this situation is presented to us. We see that in the last month the vector of coverage of these issues has changed dramatically and, accordingly, the perception of the epidemic in society. Of course, "self-isolation fatigue" and socio-economic problems played a role. Many people have formed the opinion that the pandemic is already ending, just a little more - and everything will be fine. In fact, this is absolutely not the case. And this, in particular, is indicated by the growth rate of "covid" mortality. In Russia, they currently amount to about 2.8 percent. We also see that the focus of the epidemic is shifting from Moscow to the regions. We have leading regions - such as Moscow, Sverdlovsk, Nizhny Novgorod, Voronezh regions, St. Petersburg – where there are many detected cases and the rate of spread of coronavirus infection remains high.
– How much can we trust the mortality statistics from COVID-19?
– There are many important nuances here. For example, in May, 5,800 more people died in Moscow than usual for the same month on average in the previous three years – this reflects the so-called "excess mortality". In April, about 1,850 excess deaths were officially confirmed in Moscow. Of the approximately six thousand additional deaths in May, according to the Moscow Department of Health, 92 percent are related to COVID-19, that is, in these cases, this disease appears as the main or concomitant cause of death. And I agree with this assessment. If we look at the official data published on the website "Stopkoronavirus.the Russian Federation", then there is a much smaller total (cumulative) number of deaths from covid in Moscow – 3,200 for the entire period from the beginning of the pandemic to the current moment. Apparently, in this case, only deaths were included in federal statistics, the main cause of which was considered COVID-19. This approach very noticeably underestimates the mortality and lethality directly related to the new coronavirus infection (in Moscow – by 2-2.5 times, in the regions as a whole – by 4 or more times, and for example, in St. Petersburg, the degree of underestimation can be 10 times). So, we see that the number of deaths and the number of new cases are accounted for differently in practice. Hence, we get a noticeable variation in the estimates of the key characteristics of the epidemic. Anyway, it's too early to talk about sufficient control over the situation. Especially in the regions. Therefore, if we want to save the greatest number of lives in the end and get the least number of negative consequences, I would not relax in this situation.
– What does that mean?
– It is necessary to listen to the recommendations of specialists and continue to apply effective anti-epidemic measures: "social distancing", wearing masks in closed public spaces, using alcohol–containing sanitizers for hand treatment, avoiding large crowds of people and traveling in public transport (and not only urban, but also intercity - in buses, trains, commuter trains, planes). All these recommendations were valid in March and now remain fully in force. Now in most regions there are no such legislative restrictions, but this does not mean at all that effective measures should be neglected. The risk of infection is still high. Of course, it is impossible to completely exclude social contacts. For example, will it be possible not to go to stores in regions where there are no working goods delivery services? But it is quite possible to reduce the number of exits to shops and shopping centers. For example, visit them not three times a week, but once or even less often. Of course, "panicking" is the other extreme. But you should not underestimate the seriousness of the situation.
– Why doesn't the state introduce all these measures?
– That's what's important to understand here. Ultimately, the health and life of each person is especially important for himself and his loved ones. If you want to preserve your health, reduce the number of visits to public places and try not to go to resorts this summer season, where there will be a lot of people. Now is not the best time for this. Experts cannot prohibit this, but conscious people should understand how important it is. Yes, we have reached the notorious plateau, but the daily number of new COVID-19 cases in Russia has remained at a consistently high level since mid–May - 8-9 thousand per day. Despite the fact that many cases remain undetected. This is not a little.
– At the same time, we know that there are even more undetected, asymptomatic cases. Are such people contagious or not?
– This issue is being discussed. Experts have not yet come to an unambiguous opinion. Although WHO recently made a statement on this. One thing is clear – there are many such people, and if you look at the entire population, their contribution to the development of the epidemic can be significant. After all, you may not know that there is an infected person next to you. In addition, it is known that even with an asymptomatic course of COVID-19, the lungs can be affected, fibrosis can form. It is also impossible to neglect this fact. Therefore, walking in the fresh air while observing "social distancing", jogging in the park is good. But it is better to exclude trips to shops and places of mass gathering of people. If you can't do this, put on a mask, use sanitizers and keep your distance. Many people think: I am less than 65 years old and there is no diabetes and other chronic diseases, so I will get over it in a mild form. However, in fact, there are no guarantees. There are cases of serious illnesses and deaths among young people without obvious comorbidities.
– The official mortality rate in Russia is one of the lowest in the world. Some even talk about the "Russian coronavirus miracle". Your figures are several times higher. Why?
– Lethality is the number of deaths in the group of detected cases (CFR), or in the group of all infected (IFR). This is not one parameter, but several, and its value depends on which numerator and denominator we take into account. The easiest way to calculate it is by dividing the total number of deaths by the total number of detected cases "day to day". Simpler, but incorrect, since this approach systematically underestimates the actual mortality of CFR in the population. The fact is that some time passes from the moment of infection to death. Usually it is 2-3 weeks. And when we count such people in this way, it means that none of those who have recently (in the last week or two) become infected will die. There are two more correct methods for assessing the mortality of CFR. The first is to determine the percentage of deaths among all completed cases. In some countries, we can do this – where the epidemic (its "wave") is coming to an end and the outcome of the majority (say, 90 percent or more) is more or less clear to us identified cases. The most adequate method of assessing the mortality of CFR during the epidemic is when we divide the total (cumulative) number of deaths on the current date by the total number of cases detected 10-14-18 days ago. With this calculation, the mortality rate of CFR in Russia, according to official data, will not be 0.9, but about 2 percent.
– But in this way it is impossible to calculate the true lethality – that is, the number of dead to the number of all infected.
– In fact, both of these indicators – CFR and IFR – are important, and neither of them can be given priority. The problem with the second indicator is that it is very difficult to estimate it. We don't know how many people have actually been infected by now. A good way to calculate is to determine the level of population immunity. For example, for anti-SARS-COV-2 antibodies of class G (IgG). Greatly simplifying, we can say this: when the body first encounters a virus, a specific immunity is usually formed, which can be "measured" by detecting a sufficient concentration of immunoglobulins in the blood – specific antibodies against SARS-COV-2. Accordingly, people in whom these antibodies are detected can be considered immune – protected from COVID-19.
– Is this the logic of examining a huge number of Muscovites for antibodies to COVID-19?
– Yes, this was the logic of testing. And according to its preliminary results, a figure was recently announced – 17.4 percent of Muscovites have antibodies to the new coronavirus. From this, it was concluded that exactly so many Muscovites were sick with coronavirus. Based on these figures, it turns out that the coronavirus is not much more dangerous than seasonal influenza – IFR-the mortality rate of SARS-COV-2 is about 0.15%. Therefore, they say, there is nothing alarming about the current pandemic. However, this is a hasty conclusion, and here's why. The fact is that we received these 17.4 percent in Moscow not from a representative sample, but from a biased sample: a large number of people who received an invitation to participate in this study, but at the same time confident that they were not ill with anything similar to covid, simply refused to be "tested". At the same time, people who suspect they have COVID-19 at the time of testing or in the previous months were more likely to get into the sample.
– Now there is even a meme: "I think I got over the coronavirus in January."
– Yes, such people are more likely to be "tested". And in this subgroup, the percentage of people who have actually encountered SARS-COV-2 is much higher. It is very likely that the figures obtained are overstated, and the sample does not fully reflect the population of Moscow residents. Most likely, the collective immunity of Muscovites is lower than this figure. We don't know what the degree of overestimation is, but the fact itself is obvious. Many epidemiologists now disagree with these biased figures. I think the real figures are much lower – maybe 5-6 percent. And if we use such values in the denominator in the calculation, then the lethality of IFR in the population will be higher. And here it is necessary to repeat once again that the number of "covid" deaths can also be greatly underestimated (and this is the numerator in the formula for calculating mortality). In a study published in the journal "Health Affairs" in May, the IFR estimate for early statistical data for the United States was 1.2%. Imperial College London also made a similar estimate in May based on their UK data – 0.9%. However, in May, the works of French, Japanese and American specialists were also published with significantly lower assumptions about the lethality of IFR – from 0.02 to 0.4%. More recently, a meta-analysis has been published summarizing the results of dozens of studies conducted in different countries and allowing to evaluate IFR. So – according to its authors, the true IFR level is in the range of 0.5-0.78%. At the same time, even if this is the case (I am inclined to the figure of about 1%), then it is necessary to compare the lethality of IFR not with CFR for seasonal influenza (according to the estimates of the US Centers for Disease Control, it is 0.12% for most seasons), namely with IFR. Therefore, even according to conservative estimates, the mortality rate from coronavirus infection is at least 8 times higher than from seasonal flu. I think the real ratio will be greater. Therefore, I emphasize: coronavirus is not a seasonal flu, but a much more serious disease, more contagious, and there is no vaccine to control it yet. It is enough to look at the figures of the number of newly identified cases and deaths in the world at the beginning of April, the beginning of May and now – mid-June. The mortality rate of CFR for completed cases and "with a time lag" in dynamics are also indicative – I made such calculations and graphs for all countries with COVID-19 cases. By the way, the cases of "covid" in the numerator CFR include both asymptomatic and mild. And in the case of seasonal flu, these are only episodes with clinical manifestations.
– Many people say that mortality has increased due to self-isolation and physical inactivity.
– There is such a point of view, but it does not have sufficient scientific evidence. If we turn to the experience of countries such as Norway, Denmark, Austria (which were little affected by the coronavirus, but universal quarantines were introduced there), it will be clear that the overall mortality rate there increased slightly. This indicates that quarantine and "self-isolation" for one to two months does not lead to a significant increase in mortality. There is no evidence to the contrary, although such an opinion is often presented in the media as confirmed. Although a small part of the excess mortality may be due to problems with receiving medical care for indications unrelated to the new coronavirus infection. There are a lot of various speculations now. Then they say that the virus does not mutate and therefore is not dangerous, then, on the contrary, that it quickly mutates, "weakens", and therefore we are about to adapt to it (it has already "filtered through the population"). Then they write that we need to rely on universal vaccination against polio and BCG. Now they expect that warm weather has come, and the virus will "go away" by itself. Indeed, it is believed that the activity of the coronavirus decreases with an increase in temperature in the region of its positive values. But is this enough to make the effective reproductive number less than 1? There is no evidence of this. In Brazil and Ecuador, where the weather is warm, we do not see low virus activity, rather the opposite. Therefore, you can hope for a miracle, but it is best to rely on yourself and on the effective measures that we apply in our country. If we underestimate the real danger, it will inevitably lead to a deterioration of the epidemiological situation.
– They write a lot about the situation in Sweden, where, as you know, quarantine has not been introduced. Allegedly, thanks to this, they managed to get out of the pandemic. What can you say about this?
– The situation in Sweden and Brazil is very revealing. Indeed, no harsh measures were taken there, and today we see high morbidity and mortality rates. So, in Sweden, the "covid" mortality rate is now about 500 people per million, while in neighboring Scandinavian countries – Denmark, Finland and Norway, where effective measures have been introduced, it is several times lower (from 45 to 103 people per million). At the same time, the population size and density, approaches to statistical accounting in healthcare, socio-economic and cultural characteristics of these countries are similar. What is the reason for such a big difference? Maybe because the Swedes have some special genotype that is more susceptible to this virus? Or is there some other, more "evil" version of the virus circulating in this country? All these assumptions look extremely unconvincing. Yes, we cannot exclude all this completely, but it is more logical to assume that in fact the explanation is simpler – the absence of strict universal anti-epidemic measures and, in the case of lethality, the unpreparedness of the healthcare system for the resulting overload. I would also really like this whole situation to be resolved as soon as possible. Probably, there are no people who would not like this. But for this you will have to work hard.
– Nikolai Alexandrovich, many are now hoping for a vaccine, which, as its manufacturers say, will begin to be used en masse in the fall. Can we be sure of her safety?
– Vaccines are immunobiological drugs, and their development and registration include several stages. The first stage is pharmaceutical development, when candidate drugs are being prepared. This is followed by a stage of preclinical studies, which can be carried out in vitro, that is, in cell and tissue cultures, and in vivo, that is, on animals. After that, clinical trials are conducted in several stages. During Phase I, the safety, reactogenicity and immunogenicity of vaccines are evaluated. In Phase II clinical trials, the same is true, plus the pharmacodynamics is analyzed in more detail, and the optimal dose and administration regimen are selected. Phase III is a large study, during which safety, immunogenicity, and sometimes effectiveness are evaluated by true endpoints, that is, how the tested vaccine reduces morbidity is checked. And only after all these procedures, the drug can be registered. Accelerated scenarios are possible in case of emergencies, when these deadlines are forcibly reduced. But now they have to shrink too much. In the allotted time, it is impossible to conduct full-fledged preclinical and clinical studies. At the same time, we are talking about drugs that are supposed to be administered to hundreds of millions of healthy people. Vaccines are being developed that will have to be used for preventive use by many people, and the price of error here is very high.
– They undertook to produce our vaccine in six months. And what terms do you consider reasonable?
– Several approaches are possible. For example, China plans to complete early clinical trials of its vaccines in December 2020, February 2021, and later. And this is already a very tight deadline. The vaccines currently being developed in the United States will be in Phase I-II clinical trials until the middle or end of next year. Why is this happening? If the use of an under-researched drug begins in the United States, and it turns out that even a small percentage of people have severe side effects, then the manufacturer, insurance companies and the state will incur significant financial costs. Therefore, everyone understands the price of a mistake there. In Europe, there is a kind of intermediate option between China and the United States. Although in the last couple of days there has been new information about the joint efforts of several European countries and a large pharmaceutical company, and the expected completion of the accelerated registration of one of the vaccines by December this year.
– And what about Russia?
– Different developers have different plans here. But we are really seeing one vaccine (and possibly two already), which is going to be massively used in September this year. This could become a world record for the speed of bringing vaccines to market, which, in addition to pride, causes considerable concern. It is very dangerous to use an under-researched drug widely. It's not that you just need to go through some formal procedures. These procedures allow you to evaluate the safety and efficacy profiles of the drug. It is impossible to estimate these parameters reliably enough until the research is completed. It happens that the developers are initially confident in the high safety of their drug and that it "works well", but subsequent studies and post–registration observations show that the initial assumptions are incorrect - serious adverse events and deaths are recorded. The history of medicine is replete with such examples. All this suggests that we cannot know everything in advance, and preclinical and clinical studies are needed so that we can find out the properties of the drug before its widespread use. This is a very serious story that cannot be underestimated. It's one thing if a person got infected and, unfortunately, died. And quite another thing – if the state approves and promotes the introduction of a drug to a person, from which he will die or receive persistent pronounced negative consequences. The authorities' desire to speed up the vaccination process is absolutely understandable, because the pandemic may escalate in the fall. Accordingly, I really want to have a drug in September that can be used to start mass immunization of the population, thus preventing the "second wave". But still, it's not worth taking risks in this way. And we should not expect that with the vaccine we will prevent the autumn-winter exacerbation of the epidsituation. It will be necessary to deal with it in a different way.
– How?
– About the same as now – anti-epidemic measures, setting up the health system, careful monitoring. We need to prepare for autumn now. Effective and safe vaccines should appear. But it is worth waiting for this not earlier than February-March next year. And scaling up production and mass immunization will also take time.
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