In the early 20th century, every self-respecting city had a tuberculosis sanatorium. By the beginning of the 21st century, most had become tourist attractions. In Israel, there was one left: the Tuberculosis Department at Be'er Ya'akov's Shmuel Harofe Geriatric Medical Center still housed several dozen TB patients until 2019, when the ward closed, apparently because one of the patients attacked a staff member.
This event was one factor that led to the department head's retirement. No replacement was found, and the patients who had inhabited the isolated tuberculosis ward were dispersed among the lung disease wards at regular hospitals. It may be that learning how to isolate these patients within regular respiratory wards proved a good thing the following year. But it was also a reminder that this disease, which once would kill over 10% of the populations of Europe's largest cities every year -- taking the lives of young luminaries like Rabbi Nachman of Breslov, Franz Kafka, Henry David Thoreau, and of course the poet Rachel -- still kills about a million people a year. TB is still with us, albeit on a small scale.
A few months ago, "Globes" reported on how the Covid-19 pandemic had affected the ability to treat tuberculosis patients in developing and underdeveloped countries, noting that TB is still present in Western countries, and in Israel. Several hundred Israeli patients still have the disease, with most cases latent and inactive. However, as Dr. Natalia Freund from the Sackler Faculty of Medicine at Tel Aviv University explains, we should not be complacent.
Tuberculosis is treated with antibiotics. When the disease gets out of control, it develops a resistance to antibiotics, after which there is actually no effective therapy. "Tuberculosis is a third-world disease, but drug-resistant tuberculosis is a disease of the modern world, with its wide exposure to antibiotics in recent decades. In the countries of the former Soviet Union, for example, about half of tuberculosis strains are resistant to at least one type of antibiotic. The combination of an infectious, latent bacterium and its resistance to existing treatments, is very dangerous."
Freund and her team are working on a new method of attacking tuberculosis using antibodies, similar to the antibody treatments developed over the past year to fight coronavirus by companies like Regeneron, Eli Lilly - even Israel's Kamada Ltd. (TASE: KMDA). This treatment is relevant not only to tuberculosis but holds the possibility of being effective for both AIDS and other viral diseases.
In Israel, there are about 200-250 new tuberculosis cases a year. "These patients come from two populations. One is the legal and illegal immigrants from Africa, and the other is among immigrants from the former Soviet Union." Although the main immigration from the USSR happened a long time ago, latent TB carriers fall ill when their immune systems weaken, allowing the disease to break out. "In non-immigrant Israeli society there is very little tuberculosis. But, because Israel is a country of immigrants, variants constantly enter from different places, and can include drug-resistant types.
"We have to be vigilant about the tuberculosis variants that come to Israel. The problem is that illegal immigration doesn't go through border control, so there's no way to monitor. Along with monitoring, we must find new forms of treatment, discover mechanisms in the bacterium that can hold TB back."
Should I be walking around afraid of catching drug-resistant tuberculosis?
"No, no. Heaven forbid. Fortunately, it isn't a common disease in Israel. If a person is diagnosed with tuberculosis, they must be given a 6-month course of antibiotics at a hospital. A half-year is necessary to eradicate the disease, because stopping the course of antibiotics before treatment is complete increases the chances of developing a resistant strain. So, treatment is very, very strict and tuberculosis patients are kept in isolation. After they're discharged, they're not contagious, but must still be monitored by our Tuberculosis Department."
Nobody really talks about tuberculosis in Israel
"Tuberculosis has the reputation of being a disease of the past, and we'll do what it takes to keep in the past."
"No treatment for drug-resistant TB"
The issue of drug-resistant bacteria is, of course, not relevant just for tuberculosis. "The bacteria live within the human cell, and replicate through their own mechanism," Freund explains. "By contrast, viruses use the cell mechanism to multiply, then kill the cell and leave to find a new cell in which to replicate. So, we can 'trap' viruses more easily by means of antibodies in the bloodstream, while we can inhibit bacteria by damaging their reproductive mechanism, which is different from ours. "
Various antibiotics are able to interfere with the pathogenic reproductive mechanism with almost no harm to humans. It is hard to imagine that this drug has been in widespread use for only about 100 years. "Antibiotics are a great medicine," says Freund. "Inexpensive and easy to transport. It's true that they have a certain level of toxicity and also damage important intestinal bacteria, but overall they are effective. The only problem is that when used incorrectly, if the treatment is incomplete or if overused, we may strengthen drug-resistant bacteria. And indeed tuberculosis, which used to kill millions, now kills about a million a year, thanks to today's treatments. On the other hand, it becomes resistant, and presently, there is no treatment for drug-resistant tuberculosis."
Tuberculosis is a bacterium, not a virus. Once treated, the patient is not contagious. In the case of latent tuberculosis, a person with a normal immune system will be able to suppress the bacterium without antibiotic treatment. If the same person suffers from a temporary or permanent immune failure, the disease may break out. This is why tuberculosis is the leading cause of death in AIDS patients.
In the case of active tuberculosis, if it is not treated properly, there is about a 50% chance that the patient will die. Moreover, coughing transmits tuberculosis via droplets. "TB bacteria are protected by a thick membrane, so not only are they carried by aerosols, they also are far more protected when they land, meaning they can survive a long time on surfaces," says Freund. One recommendation for preventing disease in tuberculosis-affected areas is frequent floor cleaning, which is almost irrelevant, for example, for coronavirus.
Is there a vaccine for tuberculosis?
"The existing vaccine, the BCG vaccine, is based on a weakened strain of tuberculosis that infects cattle. It's only 50% effective and only in children, so they stopped giving it in the US, and in Israel it's given only to high-risk groups. There are attempts to develop a new vaccine, a study largely funded by the Bill and Melinda Gates Foundation, but currently there is no good vaccine."
If it was so easy to develop a vaccine for Covid-19, why is it hard to develop a vaccine for tuberculosis?
"A coronavirus is much simpler than a bacterium. It has only three protein sheaths, one of which is responsible for binding to cell receptors. Inhibiting this protein is enough to neutralize the virus. However, a bacterium is an independent creature. It has thousands of protein sheaths that it produces itself, not by attaching to our cells. The proteins it produces to bind to cells are different from the proteins our body knows how to produce. The human body can't be instructed to produce this protein, as it can in the case of an RNA vaccine, or in the case of a virus that reproduces from the start through our own mechanism."
The hope is that antibodies can also prevent the onset of drug-resistant tuberculosis. "Biological medicines, like antibodies, have an advantage. They are non-toxic, they are specific to the bacterium they were made to fight against, and they don't kill 'good' bacteria," says Freund. "They're more expensive and more complex to make than antibiotics, but gradually, they're becoming cheaper and are used widely in treating other diseases, such as cancer and immune deficiencies. There's no reason not to use them in drug-resistant cases."
It is also hoped that as well as killing bacteria, the antibodies will save infected cells. "In many cases, after a person has contracted tuberculosis, the body continues to harbor bacteria hiding within cells. We think we may be able to use our drugs to clean the cells of TB, and eradicate it from the body, or at least significantly reduce the amount of tuberculosis in the body."
An even greater hope is the possibility of dealing with AIDS the same way. "Today, AIDS is treated with antiviral drugs that suppress replication. However, the body still retains the virus. If you miss a few days of treatment, the virus builds up. With antibody therapy, we see a decrease in the number of infected cells, meaning a decrease in the level of virus present in the body."
Even if it isn't a cure, could you actually help HIV-positive people so that missing a day of medication wouldn't be so fateful?
"Yes, the antibodies remain in the bloodstream longer, so they can be administered every few months, instead of daily. It gives us more confidence that both the disease and infection can be controlled. For the first time in a long time, we can dare hope - cautiously - that there is a cure."
People who have had Covid-19 should have at least one dose of the vaccine"
When it comes to Covid-19, Freund says, the virus actually exits the body quickly, even in severe cases. The long-term side effects stem from the damage caused by the virus during its stay. Covid-19, therefore, is less likely to have very long-term effects, unlike HIV, measles or chickenpox/shingles, which can erupt later in life as a more serious disease, years after the initial infection.
"Coronavirus is different from viruses like AIDS and herpes. It doesn't enter our DNA, doesn't penetrate genetic material, and doesn't lay dormant within the cell. I should qualify that there has been evidence of nonviable virus in people who have recovered, in places like the gut, so, there's no real way to know what will happen over time. But in terms of the viral mechanism, it does not persist within the cell, and I think the chances of long-term effects are small."
The antibodies Freund uses are designed for their specific target virus, but can protect against a number of its variants. "In the future we'll probably use a cocktail of antibodies, not because each one alone is ineffective, but because the virus mutates, and by doing so it can 'evade' the antibody. If another antibody is present, there's significantly less chance it can mutate to escape both antibodies simultaneously. From the human point of view, the coronavirus is good at stimulating antibody production. Most people produce a lot of antibodies."
Freund believes in the predictive power of serological tests. "The more antibodies there are against the spike protein, the more protection there is, and it is absolutely linear. In our study published last month, we examined amounts of antibodies in critically ill patients and in asymptomatic patients. Severely ill people produced high levels of antibodies of various types. In contrast, people with mild cases of the disease produced fewer antibodies and fewer types. So, it seems worthwhile to vaccinate recovered people with at least one dose, certainly in cases of asymptomatic infection. The level of antibodies roughly reflects the level of protection There are methods to check the quality of the antibodies as well but these are complex, lengthy and expensive. There are still open questions, such as how long the antibodies remain in the body. "
Freund emphasizes that knowing how to cure a disease with medication, doesn't necessarily mean the end of worrying about it. "We're in an never-ending arms race against diseases. We can't be complacent, because pathogens are constantly evolving."
Over the last few decades we made a mistake and got too comfortable, right?
"Yes, the field of infectious diseases was underfunded and perceived as not 'sexy.' It was considered something for the Third World, for poor and developing countries. Meanwhile, in the West, they were studying diseases resulting from longevity, like Alzheimer’s, diabetes and cancer. But now, we see the world is inter-connected, and diseases can pass from one end of the world to the other.
"I did my doctorate on SARS, the 'cousin' of the coronavirus that broke out in China about 18 years ago. When I defended my thesis, one of my examiners said, 'Who cares about SARS today?' Of course, we now understand why it's of interest. We have to investigate uncommon events too, to truly understand the world in which we live. "
There is also good news. "In light of the precautions taken over the past year - masks, social distancing, crowd limitations, and border closures - we've seen a decrease in all respiratory diseases, including influenza and tuberculosis as well."
Published by Globes, Israel business news - en.globes.co.il - on February 24, 2021
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