An Indian physician, in a long article for the New Yorker, recalls what we know about viruses and epidemics, and poses three questions that we must answer in order to start taking really effective measures to isolate, treat and prevent the current coronavirus.
In the third week of February, when the COVID-19 epidemic was still raging in China, I arrived in the Indian city of Calcutta. When I woke up on a sultry morning, I saw from the hotel window how black kites soar upward, lifted by currents of heating air. I went to the temple of the goddess Shitala. Her name is translated as "cold". As the myth says, she rose from the cold ashes of the sacrificial fire. It cools not only the summer heat that reigns in the city in mid-June, but also the internal inflammation. This goddess must protect children from smallpox, relieve the pain of those infected with it, and also ease the onslaught of a smallpox epidemic if it occurs.
The temple was small, with a small sanctuary. It was located a few blocks from the Calcutta Medical College. Inside was a figurine of a goddess sitting on a donkey and holding a jug of cooling liquid in her hands. This is how Shitala has been portrayed for a thousand years.
The minister told me that the sanctuary is 250 years old. Around this time, the first stories appeared of a mysterious sect of Brahmins who roamed up and down the Ganges and inscribed the teak pattern, which was one of the world's first grafts. To do this, it was necessary to take the contents of an abscess from a smallpox patient and apply it to the punctured skin of a healthy person, after which this point was closed with a tissue flap.
The brahmanas who practiced tiku probably learned this from the Arab healers, who learned about the ancient inoculation from the Chinese. Back in 1100, Chinese healers realized that a person who had been ill with smallpox and the survivor would not get sick with it a second time. It was the survivors who were assigned to care for the smallpox patients. The Chinese suggested that if you specifically infect a person, it would protect him from illness in the future. Doctors would grind smallpox into powder and blow it into the children's nostrils using a long silver tube.
It was dangerous to vaccinate with a live virus. If there was too much viral inoculum in the powder, the child really fell ill with smallpox. This happened, probably, once in a hundred. If everything went well, the child would feel mildly unwell, the disease was mild, and he gained immunity for life. By the 18th century, this practice had spread throughout the Arab world. In the 1860s, women in Sudan were engaged in "buying smallpox." One mother bargained with another to get the contents of the sick child's mature abscesses for her own children. It was a real art that required great precision. The most astute traditional healers were looking for lesions that would yield enough viral material, but not too much.
Smallpox has a European name - variola. From Latin this word is translated as "spotted" or "pimply". The smallpox vaccination process was called "variolation".
The wife of the British ambassador to Constantinople, Lady Mary Wortley Montagu, contracted the disease herself in 1715, leaving pock marks on her perfect skin. Later, she saw how in one Turkish village they were vaccinating 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 walnut shell filled with the finest smallpox material and asks which vein to open for the vaccinated. After that, she injects as much substance into the vein as is placed on the tip of the needle. " The vaccinated patients had fever for several days and lay in bed, but eventually recovered and remained safe and sound, Lady Montagu noted. “They very rarely have pockmarks on their faces,and after eight days these people feel as good as before the illness. " According to her, thousands of people underwent such a procedure every year, and the disease in the region was contained. "Believe me, I am quite satisfied with the safety of such an experiment," wrote Lady Montague, "as I intend to test it on my dear son." Her son has never had smallpox.
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Over the years and centuries since Lady Montague marveled at the effectiveness of vaccination, we have made unimaginable discoveries in the biology and epidemiology of infectious diseases. However, the COVID-19 pandemic has many mysteries for us. Why did it spread, like a steppe fire, in Italy, which is thousands of kilometers from the original epicenter of Wuhan, while India is still sparing? Which animals transmitted the infection to humans?
But there are three questions that deserve special attention, as the answers to them can change all of our isolation, treatment, and nursing actions. First, what does the initial infection “curve” teach us? Can we quantify the increased risk of infection due to people receiving high doses of the virus? Second, is there a relationship 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 viral load peak? How does it grow and decrease? This would help to predict the severity of the disease and the degree of infectiousness of the disease to others.
We are now in the early stages of a pandemic and we are measuring the spread of the virus among humans. But as the rate of the pandemic increases, we will also have to study the virus inside the human body.
Since data are scarce, most epidemiologists are forced to simulate the spread of the new coronavirus as if it were a two-component phenomenon: a person is either at risk of infection or not, he is either infected or not, we have symptomatic patients or carriers without symptoms. The Washington Post recently published a striking online simulation of people in a city as dots moving 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 touched the gray dot, infection was transmitted. Without interference, the entire field of dots gradually turned from gray to red. Social distancing and isolation kept the dots from touching and slowed down the reddening of the screen.
Such was the picture of the spread of the virus among the population - a kind of bird's-eye view. This can be seen as a two-position phenomenon. As a doctor and researcher (at the university I studied viral immunology), I wanted to know what happens inside the dots, how many viruses are in one or another red dot. How quickly do they reproduce at this point? What is the relationship between contact time and chance of infection? How long does a red dot stay red, that is, how does a person's infectivity 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, suggests a more complex picture of the disease, its pace of development and containment strategies. In the 1990s, when scientists learned to measure the amount of HIV in a patient's blood, a clear pattern emerged. Once a person is infected, the number of viruses in their 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 telling than the peak viral load was the so-called stopping point. This is the level at which the number of viruses in the infected person after initial growth stabilizes. This point represents a dynamic balance between the virus and its carrier. People with a high stopping point tend to get AIDS faster; people with a low precision stop often get sick much more slowly. The viral load, being a continuous process, not a binary value, helps to predict the nature, course and contagiousness of the disease. Of course, every virus has its own characteristics, and HIV has features that make the viral load especially revealing: this virus causes 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 fighting the reproduction of viruses with a certain efficiency - due to age, genetics and other indicators of the strength of immunity - then we have a low stopping point. Or maybe the slight initial contact with the source of infection, such as when children are given a tic, will also cause the stopping point to be low? When the immune system is hit weakly, it is likely to have a better chance of controlling the pathogen. But if you have a large number of contacts and a high dose, a rapidly multiplying invader can become firmly entrenched in your body and make it 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 carried out by a team from the V. I. Fred Hutchinson and Washington University Seattle. In 2018, an epidemiologist and statistician named Bryan Mayer joined a team of doctors and biologists who were investigating a problem that then seemed almost impossible to solve.
Meyer, thirty-five or so, is a gentle man who articulates his thoughts with precision. He chooses his words carefully, speaks slowly, in long sentences. “Back in my student years, I was interested in the question of the dose of a virus or pathogen,” he told me. "But the problem is that the initial dose is often impossible to fix, because we only know that a person has become infected after he has been infected." Most infectious diseases can only be viewed in the rearview mirror: by the time the sick person becomes the patient, this critical moment of infection has already passed.
However, the researchers found an unusual source of material to study. It was a group of young mothers and their children from the capital of Uganda, Kampala. Several years earlier, pediatrician Soren Gantt and a team of doctors examined these women and asked them to take oral swabs for a year. The swabs were examined by doctors to determine the amount of HHV-6 virus they contained, which is usually transmitted through mouth secretions from mother to baby after birth, causing fever and a red rash all over the body. They could now understand how the amount of virus transmitted, or the contact "dose", affects the likelihood of infection in a newborn baby. Gant, Meyer and their colleagues have devised a way to peep the dynamics of viral transmission from person to person from the very beginning.“Our data has confirmed that there is a link between dose and response in HHV-6 transmission,” Meyer said. "The more virus you get, the more likely you are to infect others." He managed to turn the rear-view mirror in the opposite direction in epidemiology.
But there is another aspect of the transmission of the virus and disease: the response of the host's immune system. The virus attack and the defense of the immune system are two opposing forces that constantly confront each other. The Russian immunologist Ilya Mechnikov, who worked at the beginning of the 20th century, called this phenomenon a struggle (Kampf) in German editions of his works. Mechnikov envisioned a constant battle between germs and immunity. In the course of this struggle, the sides captured and lost territories. What is the total "abundance" of microbial presence? What features of the host (genetics, earlier contacts, state of immunity) limit the invasion of microbes? And one more thing: in which direction does the initial balance lean - towards the virus or towards its carrier?
In this regard, a 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 the 33-year-old Chinese ophthalmologist Li Wenliang, who first sounded the alarm about COVID-19, in the last days of his life. In the photo, we see a man with a flushed face, sweating profusely, breathing through the mask with difficulty. And then there was the unexpected death of 29-year-old doctor Xia Sisi from a Wuhan hospital, the father of a two-year-old. According to The Times, the doctor loved Sichuan hogo (also called a Chinese samovar). One 29-year-old nurse from Wuhan became so severely ill that she began hallucinations. She later said that she "walked along the edge of death."
Isn't the severity of the illness of these rather young people, who, in theory, had to suffer mild Covid-19 - like a cold - with the amount of the virus they received at the very beginning? In the United States, at least two doctors who were on the front lines of the fight against the pandemic fell very seriously ill. One of them, from Washington State, is in his early forties.
Based on the available data from Wuhan and Italy, it can be said that the death rate among doctors is not higher than among others. But why is there a disproportionately large number of health workers suffering from the most severe form of the disease? “We are aware of high mortality rates among the elderly,” infectious disease and vaccinologist Peter Hotez of Baylor College of Medicine told CNN. “But for reasons we do not understand, health workers who work directly with patients are at serious risk of severe illness, despite their young age.”
Research on other viruses is suggestive. In animal models of influenza, infection rates can be accurately quantified. Mice that were given high doses of certain influenza viruses got sicker than others. However, in different strains of influenza, the dependence of the severity of the disease on the dose varies greatly. In this regard, one study is interesting. With a high initial viral load of syncytial respiratory virus, which can cause pneumonia, especially in infants, the severity of the disease was not very high. Although another study says this link is evident in toddlers, who are most at risk for the condition.
The few data we have on coronavirus 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, which causes atypical pneumonia and is related to the coronavirus that causes Covid-19. They found that with a higher initial viral load (measured by the amount of virus in the nasopharynx), the respiratory disease is more severe. Almost all SARS patients who were admitted with low or undetectable concentrations of the virus in the nasopharynx were still alive two months later. Among those with the highest content, the mortality rate was 20-40%. This pattern persists regardless of the patient's age, other diseases, and so on.
Studies of Crimean-Congo hemorrhagic fever, which is an acute viral infection, have led to similar conclusions: the more virus a patient has at the onset of the disease, the more likely they are to die.
Perhaps the strongest link between the intensity of contact and the severity of subsequent illness is found in measles studies. “I want to emphasize that measles and COVID-19 are different diseases caused by different types of viruses with different characteristics,” Rik de Swart, a virologist at Erasmus University, Rotterdam, 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 an immunological point of view, 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 to reproduce itself, and an antiviral response aimed at destroying the virus. If you give the virus a head start with a large dose, the peak of viremia will be higher, the virus will spread more strongly, the degree of infection will be higher and the disease will be more severe.
Rick de Swart talked about a 1994 study in which scientists gave monkeys different doses of the measles virus and found that a higher infectious dose led to an earlier peak in viremia. By man, de Swart added, the most compelling evidence comes from studies in central Africa. “If you contract measles through contact with your family - and at home the density and dose is highest because you can sleep in the same bed with an infected child - then you are more likely to get severely ill,” he said. “If a child becomes infected on the playground or through accidental contact, the disease is usually less severe.”
I discussed this feature of the infection with Harvard virologist and immunologist Dan Barouch, whose lab is developing a vaccine against the coronavirus that causes COVID-19. He told me that experiments on macaques are studying the relationship between the initial infectious dose of a viral inoculum and the amount of virus in lung secretions at a later stage. He believes that such a connection exists. “If we transfer this logic to a person, then we should expect a similar connection,” said Baruch. And it is quite logical that a large dose of the virus should increase the severity of the disease, causing more rapid inflammatory processes. But so far 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 track the concentration of coronavirus in a patient in such a way as to predict the course of the disease - here we need to conduct more quantitative studies and calculations of sars-CoV-2 in patients. In one study in Germany, scientists measured viral load from mouth swabs they took from people with and without symptoms. At first, asymptomatic patients had a slightly higher concentration of the virus than those who fell ill. This was an interesting result. But at the time, the study was conducted on only seven patients. Sandra Ciesek, director of the Institute for Medical Virology in Frankfurt, told me that as samples were taken from more patients, the difference between the two groups began to smooth out. "We do not know the ratio by smears",she said.
The problem with measuring viral load from smears is that pre-analysis factors such as how the smear were taken, she added. Even small differences in sampling methods can significantly affect such analyzes. “However, there may well be a link between the concentration of the virus and the severity of the disease,” concludes Cizek.
Virologist Joshua Schiffer of the Fred Hutchinson Center, who co-authored the HHV-6 virus study, reports that stricter swab techniques for a range of respiratory viruses produce consistent and reliable quantitative results, and that the concentration is consistent with symptoms and development. disease. Researchers from both the universities of Hong Kong and Nanchang published a paper on the website of The Lancet Infectious Diseases in March, which reported that the concentration of the virus in swabs from the nasopharynx taken from a group of seriously ill Covid-19 was, on average, 60 times higher than that of patients. with a mild form of the disease.
As the virus continues to sweep across the planet like a whirlwind, 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 the COVID-19 disease. We will supplement the bird's-eye view with an inside look. How will this knowledge change the way we treat patients, how hospitals operate, and how people behave?
Let's start with the relationship between infection rate and infection. Think for a moment about how we observe those who work with radiation. With the help of 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 the coronavirus using protective equipment (masks, gloves, gowns). But as for the medical workers who are on the front line of the fight against the COVID-19 pandemic, especially where there are not enough protective equipment, we can monitor the total dose of the virus that they receive, create viral dosimetry methods so that a person avoids multiple contacts with extremely contagious patients.
If we establish a relationship between dose and disease severity, this in turn affects the way we care for patients. If we learn how to identify those infected who 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 show symptoms, we will be able to predict the severity of the disease and treat such people as a priority in the event of a shortage of medical supplies and drugs, so that they recover faster and do not get seriously ill.
Finally, caring for COVID-19 patients could change if we start monitoring the amount of the virus. These parameters can be measured by very inexpensive and accessible laboratory methods. Imagine a two-step process. We first identify the infected person and then determine the concentration of the virus (viral load) in the secretions of the nasal cavity and respiratory organs, especially in patients who may require the most intensive treatment. By correlating concentration data and treatment measures with outcomes, we end up with different treatment, withdrawal, or isolation strategies.
This quantitative approach is also applicable in clinical trials. Clinical trials of drugs are usually more informative when performed on patients who are not yet critically ill. When the subject comes to this, it may be 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 in different trials will be easier to compare and these comparisons will be more accurate.
We will also need to identify people who have recovered who have developed immunity to sars-CoV-2 and who are no longer infectious. Such people must meet two requirements: they must be guaranteed to be free from contagiousness and they must have signs of stable immunity in their blood (this can be easily determined by an antibody test). As the Chinese who fought against smallpox in the 12th century discovered, such people, especially among medical workers, are especially valuable for medicine: if their immunity does not disappear, they can take care of the most serious patients without fear of infection.
My clinical practice is in the field of oncology. In my field, measurement and quantification are essential. It is necessary to determine the size of the tumor, the number of metastases, the exact amount of reduction of the malignant mass after chemotherapy. We are talking about “risk stratification” (dividing patients into categories depending on their health status) and “response stratification” (dividing patients into categories based 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 the pandemic goes hand in hand with panic. The world is in chaos. Italian doctors give IVs on makeshift racks to patients lying on makeshift beds in hastily organized wards. Under these circumstances, measuring viral load seems incredible and impossible. But the crisis requires us to stratify and assess risk, as well as make the most efficient use of scarce and rapidly disappearing resources.
The term "epidemiology" comes from the words "epi" and "demos" - "over people." This is the science of generalization, the science of sets. But it works most effectively when it keeps pace with medicine, the science of the unit.
On the morning when I visited the Shitala temple in Calcutta, this goddess of past epidemics that destroyed entire nations, provided personal services to a mother who brought a child whose temperature had not subsided for a week. To gain the upper hand in the fight against COVID-19, it is very important to track the path of the virus through the population. But it is equally important to study the development of the disease in each individual patient. One becomes many. Both must be counted, for both are important.
Siddhartha Mukherjee