US, WASHINGTON (ORDO NEWS) — In the third week of February, when the Sovid-19 epidemic was still raging in China, I arrived in the Indian city of Calcutta. Waking up in a sultry morning, I saw from a hotel window how black kites soared upward, lifted by currents of heating air. I went to the temple of the goddess Shitala. Her name translates as “cold.” According to the myth, she rose from the cold ashes of the sacrificial fire. It cools not only the summer heat that prevails in the city in mid-June, but also internal inflammation.
This goddess must protect children from smallpox, alleviate the pain of those who have contracted it, and weaken the onslaught of the smallpox epidemic if it occurs.File CC0
The temple was small, with a small sanctuary. It was located a few blocks from Calcutta College of Medicine. Inside was a figurine of a goddess sitting on a donkey and holding a jug of coolant in her hands. So Shitalu has been depicted for a thousand years.
The minister told me that the sanctuary is 250 years old. Around this time, the first stories appeared about the mysterious sect of the Brahmins, who wandered up and down the Ganges and applied a “teak” pattern, which was one of the first vaccinations in the world. To do this, it was necessary to take the contents of the abscess of the patient with smallpox and attach it to the punctured skin of a healthy person, after which this point was covered with a tissue flap.
The tiku practitioners of the Brahmins must have learned this from Arab healers who learned about the ancient Chinese vaccine. As far back as 1100, Chinese healers realized that they who had contracted smallpox and survived would not get it for the second time. It was the survivors who were instructed to take care of smallpox patients. The Chinese suggested that if a person was specifically infected, this would protect him from the disease in the future. Doctors grinded the smallpox crust into powder and injected it into the nostrils of the children with a long silver tube.
Inoculating with a live virus was dangerous. If there was too much viral inoculum in the powder, the child was really sick with smallpox. This happened, probably, once out of a hundred. If everything went well, the child experienced a slight discomfort, the disease passed in a weak form, and he gained immunity for life. By the eighteenth century, this practice was widespread throughout the Arab world. In the 60s of the 18th century, women in Sudan were engaged in “buying smallpox”. One mother bargained with another to get the contents of the ripened abscesses of a sick child for their own children. It was a real art, requiring great accuracy. The most discerning folk healers looked for lesions that would produce enough viral material, but not too much.
Smallpox has a European name – variola. From Latin, this word is translated as “spotted” or “pimple.” The smallpox vaccination process was called “variation”.
The wife of the British ambassador to Constantinople, Lady Mary Wortley Montagu, herself fell ill with this disease in 1715, after which smallpox remained on her perfect skin. Later she saw how in one Turkish village they were vaccinated against smallpox – variolation, and wrote about this to her friends in an admiring letter, telling how one specialist worked. “An elderly woman comes with a nut shell filled with the best smallpox material and asks which vein to open for the vaccine. After that, she injects as much substance into the vein as is placed on the tip of the needle.
” The vaccinated patients had a fever for several days, and they lay in bed, but eventually recovered and remained safe and sound, Lady Montague noted. “They very rarely have smallpox on their faces, and after eight days these people feel as good as before the illness. ” According to her, every year thousands of people underwent such a procedure, and they managed to contain the disease in the region. “Believe me, I am quite satisfied with the safety of such an experiment,” Lady Montague wrote, “since I intend to test it on my dear little son.” Her son was never sick with smallpox.File CC0
Over the many years and centuries since Lady Montague admired the effectiveness of vaccination, we have made unimaginable discoveries in the biology and epidemiology of infectious diseases. However, the COVID-19 pandemic has many puzzles. Why did it spread, like a steppe fire, in Italy, which is located thousands of kilometers from the original epicenter of Wuhan, while India is still sparing? What animals transmitted the infection to humans?
But there are three questions that deserve special attention, since the answers to them can change all our actions in isolation, treatment and patient care. First, what does the “curve” of the initial infection teach us? Can we quantify the increased risk of infection due to people getting a large dose of the virus? Secondly, is there a connection between the initial dose of the virus and the severity of the disease? And thirdly, are there quantitative indicators of how the virus behaves in the body of an infected person? When does the viral load peak? How does it grow and decrease? This would help to predict the severity of the disease and the degree of contagion of the sick to others.
This is the initial stage of the pandemic, and we are measuring the spread of the virus among people. But when the pace of the pandemic increases, we will also have to study the virus inside the human body.
Since there is not enough data, most epidemiologists are forced to model the spread of the new coronavirus as if it were a two-component phenomenon: a person is either at risk of infection or is not exposed, he is either infected or not, we have patients with symptoms or carriers without symptoms. Recently, the Washington Post published a striking online simulation, depicting people in the city as points that move freely in space. The uninfected were depicted in gray, the infected in red (then it changed to pink when they gained immunity). Whenever the red dot was in contact with the gray dot, transmission of infection occurred. Without intervention, the entire field of dots gradually turned from gray to red.
This was the picture of the spread of the virus among the population – a sort of bird’s-eye view. This can be considered as a two-position phenomenon. As a doctor and researcher (I studied viral immunology at a university), I wanted to know what was going on inside the dots, how many viruses were in this or that red dot. How fast do they play at this point? What is the relationship between contact time and chance of infection? How long does the red dot remain red, that is, how does the human contagion change over time? And what is the severity of the disease in each case?
What we know about other viruses, including those that cause AIDS, SARS, and smallpox, indicates a more complex picture of the disease, its pace of development, and its containment strategy. In the 1990s, when scientists learned how to measure the amount of HIV in a patient’s blood, a clear pattern emerged. After a person is infected, the number of viruses in his body increases to a level known as the “peak of viremia”. Patients with the highest peak viremia are most severely ill and least able to resist viral infection.
Even more indicative than the peak viral load was the so-called breakpoint. This is the level at which the number of viruses in the infected person after the initial growth is stabilized. This point represents a dynamic balance between the virus and its carrier. People with high breakpoints usually get AIDS faster; people with low exact stops quite often get sick much more slowly. Viral load, being a continuous process, and not a binary value, helps to predict the nature, course and contagiousness of the disease. Of course, each virus has its own characteristics, and HIV has such features that make the viral load especially indicative: this virus causes a chronic infection, and it targets specifically the cells of the immune system. But similar patterns are observed in other viruses.
From the point of view of immunology, this is not surprising. If our system is capable of combating the reproduction of viruses with some efficiency – due to age, genetics, and other indicators of the strength of immunity – then we have a low breakpoint. Or maybe a slight initial contact with the source of infection, as in the case when the children do “tiku”, will also lead to the fact that the breakpoint will be low? When a blow to the immune system is inflicted weak, it is probably more likely to control the pathogen. But if you have a large number of contacts and a large dose, a rapidly multiplying invader can firmly gain a foothold in your body, and it will be more difficult for the immune system to cope with it.
A very original study of the relationship between the intensity of contact with a viral source and the susceptibility of the human body to infection was conducted by a team from the Research Center for Oncology. Fred Hutchinson and the University of Washington in Seattle. In 2018, an epidemiologist and statistician named Bryan Mayer joined a group of doctors and biologists who were researching a problem that seemed almost impossible to solve at that time.
Meyer is about thirty-five years old or so, a man with soft manners, accurately articulating his thoughts. He selects the words carefully, speaks slowly, in long sentences. “Back in my student years, I was interested in the question of the dose of the virus or pathogen,” he told me. “But the problem is that the initial dose is often impossible to fix, because we learn that a person became infected only after he was infected.” Most infectious diseases can only be seen in the rearview mirror: by the time the patient becomes a patient, this critical moment of infection has already been passed.
However, the researchers found an unusual source of material for study. It was a group of young mothers and their children from the capital of Uganda, Kampala. A few years earlier, a pediatrician Soren Gantt with a group of doctors examined these women and asked them to do smears from the oral mucosa for a year.
Doctors examined the swabs obtained by determining the amount of HHV-6 virus contained in them, which is usually transmitted through the secrets of the oral cavity from mother to baby after birth, causing fever and a red rash throughout the body. Now they could understand how the amount of transmitted virus, or contact “dose,” affects the likelihood of infection in a newborn baby. Gant, Meyer and their colleagues invented a way to spy on the dynamics of transmission of viral infection from person to person from the very beginning. “Our data confirmed the association of HHV-6 virus transmission between dose and response,” Meyer said.
“The more virus you get, the more likely you are to infect others.” He managed to deploy a rearview mirror in epidemiology in the opposite direction.
But there is another aspect of the transmission of the virus and disease: the response of the host immune system. Viral attack and defense of the immune system are two opposing forces that constantly confront each other. Russian immunologist Ilya Mechnikov, who worked at the beginning of the 20th century, in the German editions of his works called this phenomenon a struggle (Kampf).
Mechnikov imagined a constant battle between germs and immunity. During this struggle, the parties seized and lost territory. What is the total “number” of microbial presence? What carrier features (genetics, earlier contacts, immunity) limit microbial invasion? And one more thing: in which direction does the initial balance lean toward the virus or its carrier?
In this regard, the second question arises: when the “dose” of viruses is greater, does the disease become more severe? It is impossible to erase from memory the image of 33-year-old Chinese ophthalmologist Li Wenliang, who was the first to sound the alarm about Sovid-19 in the last days of his life. In the photo we see a person with a reddened face, sweating profusely, breathing with difficulty through a mask. And there was the unexpected death of 29-year-old doctor Xia Sisi from Wuhan Hospital, the father of a two-year-old child. According to The Times, the doctor loved the Sichuan hogo (this dish is also called the Chinese samovar). One 29-year-old nurse from Wuhan fell ill so badly that she started hallucinating. She later said that she had “walked the edge of death.”
Is the severity of the disease of these rather young people, who, in theory, should have taken Sovid-19 in a mild form – like a cold – not related to the amount of virus that they received at the very beginning? In the United States, at least two doctors who were at the forefront of the pandemic struggle became very ill. One of them, from Washington, is a little over forty.
Based on the available data from Wuhan and Italy, we can say that the mortality rate among doctors is not higher than that of others. But why is the number of health workers suffering the most severe form of the disease so disproportionate? “We know about high mortality among older people,” said CNN infection and vaccine specialist Peter Hotez, who works at Baylor College of Medicine. “But for reasons that we don’t understand, health workers who work directly with patients are at serious risk of the disease, despite their young age.”
Studies on other viruses are suggestive. In animal influenza models, the intensity of infection can be accurately quantified. Mice given large doses of certain influenza viruses were more severely ill than others. However, in different strains of influenza, the dependence of the severity of the disease on the dose varies greatly. In connection with this, one study is interesting. With a high initial viral load of the syncytial respiratory virus, which can cause pneumonia, especially in infants, the severity of the disease was not very great. Although another study says that this relationship is evident in toddlers, who are most susceptible to this disease.
The few data on coronavirus that we have indicate that this disease develops according to the same patterns as the flu. In 2004, a team of scientists from Hong Kong investigated the coronavirus that causes SARS and is related to the coronavirus that causes Sovid-19. They found that with a higher initial viral load (it was measured by the content of the virus in the nasopharynx), respiratory disease is more severe. Almost all SARS patients who received low or undetectable virus concentration in the nasopharynx were still alive after two months. Among those whose content was highest, mortality was 20–40%. This pattern is maintained regardless of the age of the patient, other diseases, and so on.File CC0
Studies of Congo-Crimean hemorrhagic fever, which is an acute viral infection, led to similar conclusions: the more the patient has the virus at the onset of the disease, the more likely it is to die.
Perhaps the strongest connection between the intensity of contacts and the severity of a subsequent illness can be seen in measles studies. “I want to emphasize that measles and Sovid-19 are different diseases caused by different types of viruses with different characteristics,” Rik de Swart, a virologist at Rotterdam University of Erasmus, told me. “But measles has a number of clear indications that the severity of the disease is related to the dose of viral exposure.” From the point of view of immunology, this is logical, because the interaction between the virus and the immune system is a race against time, a race between a virus that finds enough cells for self-reproduction, and an antiviral reaction aimed at destroying the virus. If you give odds to the virus with a large dose, the peak of viremia will be higher, the virus will spread more, the infection will be higher and the disease will be more severe. ”
Rick de Swart talked about one study in 1994 when scientists gave monkeys different doses of measles virus and found that a higher infectious dose leads to an earlier peak in viremia. For man, added de Swart, the most convincing evidence is provided by studies conducted in central Africa. “If you become infected with measles by contacting your family — and at home the density and dose are the highest because you can sleep in the same bed as an infected child — then you’re more likely to get seriously ill,” he said. “If a child gets infected on the playground or through accidental contact, the disease usually does not go so badly.”
I discussed this infection with a Harvard virologist and immunologist Dan Barouch, whose laboratory is developing a vaccine against the coronavirus that causes Sovid-19. He told me that in experiments on macaques, the relationship between the initial infectious dose of the viral inoculum and the amount of virus in the secretions from the lungs is studied at a later stage. He believes that such a relationship exists. “If we transfer this logic to a person, then we should expect a similar connection,” Baruch said. And it is logical that a large dose of the virus should increase the severity of the disease, causing faster inflammatory processes. But for now, these are only assumptions. The relationship between the initial viral dose and the severity of the disease has not yet been identified. ”
To answer the third question – is it possible to trace the concentration of coronavirus in a patient in such a way as to predict the course of the disease – here we will need to conduct more quantitative studies and sars-CoV-2 counts in patients. In one study in Germany, scientists measured viral load from a swab from the mouth that they took from people with and without symptoms. At first, in patients without symptoms, the concentration of the virus was slightly higher than in those who became ill. It was a curious result. But at that time, the study was conducted on only seven patients. Sandra Ciesek, director of the Frankfurt Medical Virology Institute, who led it, told me that when samples were taken from more patients, the difference between the two groups began to smooth out. “We don’t know the ratio of strokes,”
The problem of measuring the viral load by smears is that factors affecting the preanalytical stage, say, how the smear was taken, she said, influence it. Such analyzes are significantly affected even by small differences in sampling methods. “However, the relationship between the concentration of the virus and the severity of the disease may well exist,” concludes Ciesek.
Virologist Joshua Schiffer of the Fred Hutchinson Center, co-author of the HHV-6 study, reports that more stringent smear tests for a variety of respiratory viruses provide consistent and reliable quantitative results and that, in this case, the concentration is consistent with symptoms and development illnesses. Researchers from the universities of Hong Kong and Nanchang published in March on the website of The Lancet Infectious Diseases a report stating that the virus concentration in nasopharyngeal swabs taken from the group of seriously ill Sovid-19 was 60 times higher on average than in patients with a mild form of the disease.
As the virus continues to swirl around the planet, we will find new answers to questions about how the intensity of infection and the subsequent concentration of the virus correlate with the course of Covid-19 disease. A bird’s-eye view, we complement the view from the inside. How will this knowledge change our methods of treating patients, the operation of hospitals and population behavior?
Let’s start with the connection between infection rate and infection. Think for a minute about how we observe those who work with radiation. Using dosimetry, we measure the total radiation dose and set threshold values. We already know how important it is for doctors and nurses to limit contact with coronavirus using protective equipment (masks, gloves, bathrobes). But as for the health workers who are at the forefront of the fight against the Сovid-19 pandemic, especially where the protective equipment is not enough, we can monitor the total dose of the virus they receive, create methods of viral dosimetry so that a person avoids repeated contacts with extremely infectious patients.
If we establish a relationship between the dose and severity of the disease, this in turn will affect patient care practices. If we learn how to identify those who have received a large dose of the virus due to living together or communicating with several sick family members (remember the Fusco family from New Jersey in which four people died) or due to the communication of a health worker with several seriously ill patients by doing this before they develop symptoms, we will be able to predict the severity of the disease and treat such people as a matter of priority in the event of a shortage of medical supplies and medicines so that they recover faster and do not get seriously ill.File Reuters
Finally, co-care with Sovid-19 may change if we begin to monitor the amount of virus. These parameters can be measured by very inexpensive and affordable laboratory methods. Imagine a two-step process. First, we identify the infected, and then determine the concentration of the virus (viral load) in the secretion of the nasal cavity and respiratory organs, especially in patients who may require the most intensive treatment. By correlating the concentration data and treatment measures with the results, we will eventually develop different treatment, care, or isolation strategies.
This quantitative approach is also applicable in clinical trials. Clinical trials of drugs are usually more informative when they are performed on patients who are not yet in critical condition. When the subject reaches this point, it may turn out that it is too late to treat him. And if such a patient monitors not only the symptoms, but also the viral load, the effectiveness of a particular drug during different tests will be easier to compare and these comparisons will be more accurate.
We will also need to identify recovered people who have developed immunity to sars-CoV-2 and who are no longer contagious. Such people must meet two requirements: they must be guaranteed to be free from contagiousness and they should have signs of stable immunity in their blood (this can easily be determined by an antibody test). As the Chinese who fought with smallpox in the 12th century found, such people, especially among the medical workers, are especially valuable for medicine: if their immunity does not disappear, they can take care of the most severe patients without fear of infection.
My clinical practice relates to the field of oncology. In my area, measuring and quantifying is critical. It is necessary to determine the size of the tumor, the number of metastases, the exact amount of reduction in malignant mass after chemotherapy. We are talking about “risk stratification” (dividing patients into categories depending on health status) and about “stratification of reaction” (dividing patients into categories depending on their response to treatment) I can spend half an hour or more with each patient, telling him about risks, explaining how remission is measured and carefully developing a clinical plan.
But a pandemic goes hand in hand with panic. The world is in chaos. Italian doctors give droppers on makeshift racks to patients lying on makeshift beds in hastily organized wards. In such circumstances, measuring viral load seems unbelievable and impossible. But the crisis requires us to stratify and assess risk, as well as the most efficient use of few and rapidly disappearing resources.
The term “epidemiology” comes from the words “epi” and “demos” – “above people”. This is the science of generalization, the science of sets. But it works most efficiently when it keeps up with medicine, the science of one.
That morning, when I visited the Shitala temple in Calcutta, this goddess of past epidemics, destroying entire nations, rendered personal services to a mother who brought a child who had not had a fever for a week. In order to prevail in the fight against Sovid-19, it is very important to track the path of the virus movement among the population. But it is equally important to study the development of the disease in each individual patient. The unit becomes the multitude. It is necessary to consider both that and another, for both that and another matters.
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The article is written and prepared by our foreign editors from different countries around the world – material edited and published by Ordo News staff in our US newsroom press.