In May 2019, the A Coruña health area announced that the tuberculosis outbreak in the Galician town of Camariñas was under control , after having located twelve minors who were developing the disease in very early stages and to whom treatment began to be applied.
Pulmonary tuberculosis is, today, preventable and curable, but it is far from being eradicated, not in Europe, much less in the world. “It is a disease that hits the most disadvantaged social strata: it is more frequent in situations of poverty, overcrowding, malnutrition and low economic status. In addition, the increase in the movement of people around the planet makes this and other conditions spread more easily ”, explains Javier García Pérez, pulmonologist at Hospital La Princesa (Madrid).
However, while the global incidence of tuberculosis is 130 cases per 100,000 inhabitants, in Europe the average is 30 cases per 100,000 inhabitants. As for what is happening in Spain, the specialist tells us that “tuberculosis is in recession but we continue to have figures slightly higher than the rest of the countries in our economic, geographical, cultural and social environment. Even so, we are already bordering on the figures in which we can consider ourselves a low-incidence country, which is when there are less than 10 cases per 100,000 inhabitants ”.
How is a case of tuberculosis approached in our country? In Spain, tuberculosis is a notifiable disease. This means that the public health authorities of the autonomous communities have to report cases to the National Epidemiology Center through the National Epidemiological Surveillance Network. “In our hospital in particular we have a Tuberculosis Unit, and when a patient comes that we suspect may be infected, we analyze the case to see if he needs hospital admission, because most of the time it can be treated on an outpatient basis”, explains García to Muy Interesting. “The first thing of all is to make a rapid diagnosis of confirmation of the disease, and especially a pattern of resistance to see with which antibiotics it should be treated. An early diagnosis and adequate treatment are the best way to interrupt the chain of transmission: patients are cured and, therefore, the number of cases in society decreases ”.
Contact study
Precisely to prevent the spread of the disease, another step in the protocol consists of a case study: about 90% of those infected with Mycobacterium tuberculosis , the bacterium that causes the disease, do not develop it. This distinction is important: “A sick person is one who has lesions in an organ, which is usually the lung. There is tuberculosis that affects the colon, bones, and lymph nodes, but the most frequent and the one that is of interest from a public health point of view because it is easily contagious is pulmonary tuberculosis ”, García clarifies. Sick people present numerous symptoms and, in addition, the bacillus has been isolated in some of the sample cultures. These individuals need specific treatment.
On the other hand, there are infected people, that is, those who have contacted a person with tuberculosis and obtain positive results in the detection tests for the bacteria, but do not present symptoms and their chest X-ray is normal. “These people are considered to have latent tuberculosis infection, but they are not sick. And only 10 or 12% of these patients evolve to disease “, explains the doctor.
To detect those people who are likely to be infected, doctors carry out an exhaustive study among those who maintain intimate contact with the patient: the cohabitants in the same family nucleus (partner, parents, children …) or those who spend more than five or six hours in a fairly direct contact in the workplace.
“It is necessary to identify those people who, being infected, are more likely to develop disease to be able to offer them preventive treatment,” Garcia says. “We are talking about young children, immunosuppressed people, patients receiving corticosteroid treatments, HIV patients … in general people with low levels of defenses.
A disease that hits the most disadvantaged
In developed countries like ours, the mortality figures from tuberculosis are very low, almost anecdotal. “People who die, die with tuberculosis, but not because of it, but because of another serious disease, such as lung cancer,” García clarifies. But other regions of the world are not so lucky.
According to the World Health Organization (WHO), tuberculosis is the infectious disease that causes the highest mortality in the world and it is estimated that in 2017 it caused 1.6 million deaths. Due to this, the institution has launched the END-TB strategy, and its objectives are clear: by the year 2035 a reduction in mortality of 95% must be achieved compared to 2015 and a reduction in the rate incidence by 90%. By that time, in addition, it is desirable that there are no families who have to face catastrophic expenses due to tuberculosis. To achieve this, WHO emphasizes the need to improve the prevention, diagnosis and treatment of the disease.
What can be contributed from the scientific field to help achieve the objectives of END-TB? In Muy Interesante we have made a tour of some of the Spanish laboratories that work in tuberculosis, discovering some of the many and promising lines of research in progress.
In search of new vaccines
Currently, the only vaccine available against tuberculosis is the one using the Bacillus Calmette-Guérin. It is a live, attenuated vaccine derived from Mycobacterium bovis, the bacterium that causes disease in cattle. The World Health Organization recommends its application in regions of the world with a high incidence of the disease, but this vaccine is not the definitive solution, since “it protects above all against severe forms of tuberculosis and partially in children, but it does not cope with the most frequent form of the disease – and the one that is contagious – which is the pulmonary form. That is why it is necessary to develop new vaccines that can protect against infection by M. tuberculosis , and right now there are several in various clinical phases “, the researchers from the Africa González-Fernández team, professor of Immunology and Director of the Center for Biomedical Research at the University of Vigo.
In this Galician group, work is being done on the development of a vaccine that enhances the immune response in the region of entry of the pathogen. Since the tuberculosis bacillus enters the body through the respiratory tract, the idea is to attack at that level, in the mucous membranes of the respiratory system , and develop a vaccine that can reinforce the action of the one currently used.
Along these lines, González-Fernández’s team has participated in an international project financed by the European Union in its Horizon2020 program that has just concluded, and one of its contributions was the use of nanomaterials for the development of a nanovaccine with recombinant proteins from the bacterium that enhances the current vaccine and that is currently pending infection trials by the project coordinator. In addition, the team from the University of Vigo has analyzed the protection of two other vaccine prototypes developed by English researchers, at short and long times, in order to evaluate how long the protection induced by these vaccines lasts.
These are not the only vaccines that are being worked on in our country. At the Center for Biomedical Research in Respiratory Diseases (CIBERES) of the Miguel Servet University Hospital of the University of Zaragoza, the team led by Carlos Martín Montañés has been working since 1998 on the development of a new vaccine consisting of a live attenuated bacterium derived from M. tuberculosis , that is, the bacillus that causes disease in humans, and which is already in the clinical trial phase.
The first human trial was conducted in 2013 with healthy Swiss adults and the results were published in 2015 in The Lancet Respiratory Medicine . “Currently there are two other studies underway: one funded by the European Union in newborn babies in South Africa, and another funded by the US Government carried out in adults to find the optimal dose,” explains Martín.
Antibiotic resistance, a growing problem
But developing a more effective vaccine than the current one is not the only great challenge facing science in its fight against tuberculosis. According to the WHO, antibiotic resistance is today one of the greatest threats to global health, food security and development. Treatment of many infections, including tuberculosis, is becoming increasingly difficult due to the loss of efficacy of antibiotics.
“There are strains of M. tuberculosis resistant to first-line anti-tuberculosis drugs, some of them are even multi-resistant, which means that they are resistant to the two most effective drugs; or extremely resistant, which implies that, in addition, they have resistance to some flouroquinolone and to at least one of the three existing second-line injectable drugs ”, the researchers from the University of Vigo team explain. According to the annual report of the WHO for the year 2018, about 3.5% of the M. tuberculosis strains of never-treated patients and 18% of those previously treated were cases of multidrug-resistant strains.
“We are finding more and more cases, especially in South Africa and in prisons in Eastern Europe, that cannot be treated. The percentage of multi-resistant strains in these regions is very high ”, agrees Martín. Within his group of Mycobacterial Genetics at CIBERES there is also a line of research, directed by José Antonio Aínsa, which studies precisely the molecular bases of resistance in this group of bacteria in order to identify compounds that serve to create new drugs to defeat antibiotic resistant strains.
A change of focus
To face the challenges in the fight against tuberculosis, it is often necessary to seek creative solutions and move away from the more classical methods. We have talked about vaccines and antibiotics, but there are scientists like Pere-Joan Cardona, head of the Experimental Tuberculosis Unit at the Germans Trias i Pujol Institute (Badalona), who are working on other strategies. Cardona’s team is developing a dietary supplement that appears to be effective in both preventing and treating tuberculosis.
The new product consists of the use of the inactivated bacillus Mycobacterium manresensis , and will begin to be distributed in Kenya, Vietnam, Myanmar and the Philippines once the last tests and final procedures are completed. “The bacterium we use is of natural origin, since it is present in drinking water, therefore it is part of a food, and the peculiarity it has is that it belongs to the M. tuberculosis family”, Cardona explains in an interview with Very Interesting. ” This allows, through oral administration, to generate an immune response of the balancing type to a present or future infection by M. tuberculosis .”
Although it sounds simple, the new food supplement against tuberculosis is the product of a long process of research and trials that has taken years. “We realized that all the strategies were aimed, until recently, at destroying the bacteria, that is, generating a very strong immunity, capable of ending it,” says the researcher. “We were struck by the discovery, in a mouse model, that the bacteria are actually interested in having a very powerful inflammatory response .” To understand this, it is necessary to know how the immune response works: the bacillus enters the pulmonary alveolus and then the alveolar macrophage – a type of cell of the immune system – phagocytes it, but it does not manage to eliminate it as it happens with other pathogens, and the bacillus begins to grow inside. “When neutrophils enter, not only do they not eliminate the bacillus, but it also begins to grow on top of it, extracellularly. That is, until now the bacillus grew intracellularly within the macrophage, but suddenly a fantastic space is found in which it can grow extracellularly, and faster, with which the lesion expands ” , explains the expert.
This was a process that had been known for years, but the Catalan team rescued it and in 2013 published a revolutionary work in The Journal of Infectious Diseases that showed that, in animal models, the administration of an anti-inflammatory prevented the progression of the disease. “It was the moment when we decided to change our approach,” recalls Cardona. “We are going to fight against the tuberculosis bacillus, not trying to destroy it, but by balancing the host’s response against the bacterium, because if it is too important, in the end the bacterium wins.”
How to moderate that immune response? “We cannot recommend taking anti-inflammatory drugs to people for life, because it has other negative effects. So it occurred to us to look in classical immunology for the effect of tolerance: there are methods to achieve tolerance to autoimmune diseases, which consist of orally introducing this bacterium. The intestinal system is the most important immune organ we have: the entire intestine is lined with dendritic cells, macrophages … even the epithelial cells themselves are dedicated to identifying these antigens that enter, which are food, so as not to generate an immune response against them. Because it is understood that, if something enters the intestine, you have eaten it, and then it is good. That is the key point ”, relates the scientist.
Although the same tuberculosis bacillus could be given orally, due to the complexity of developing a new drug, Cardona’s team decided to explore another alternative. “We know that there are environmental mycobacteria in water due to their presence in rivers. That is, we have a regular contact with them, what happens is that this contact is not enough to generate the response of tolerance that we seek. What we did was isolate one of these bacteria from a river in Manresa and test its effectiveness, obtaining positive results. For this reason we launched ourselves to develop this food supplement, we believe that it can be beneficial for health. It is not the first to be used against tuberculosis, supplements with vitamin D are already prescribed many times as an adjunct to the WHO standard treatment ”, clarifies the researcher.
Faster diagnosis and shorter treatments
As we have already seen, the study of tuberculosis and the search for new tools to combat it can be approached from many different approaches, and the lines of research open in this regard are promising. However, as CIBERES researcher Carlos Martín reminds us, “ tuberculosis is a very complex disease because it is a bacterium that has adapted perfectly to humans , and being infected does not always have disadvantages. If you are infected but do not develop the disease, an immune response is produced that can protect you, for example, against asthma. In fact, the current vaccine is also used as an immunotherapy treatment against bladder cancer. There is a perfect adaptation of the bacillus to man ”, says the expert.
For this researcher, one of the main challenges also lies in the improvement of the diagnosis: “Right now it is very slow, although we have some molecular methods, they do not reach Africa”. In tuberculosis, the diagnosis is slow and the treatments are very long , so many infected people who have not developed the disease and receive preventive treatment end up abandoning it.
The team from the University of Vigo that Africa González-Fernández directs has an open line of research that seeks biomarkers that allow the easy recognition of infected people with a higher risk of developing active tuberculosis. “Because only 5-15% of infected people will end up having the disease, preventive treatment requires treating a large number of people to prevent a single case of tuberculosis, unnecessarily exposing many patients to possible drug toxicities , in addition of suffering the discomforts of a treatment and increased economic costs ”, explain the researchers, who have carried out a study to identify biomarkers in saliva, blood and sputum. “Biomarkers allow us to differentiate infected contacts from those who are not. Using artificial intelligence we have been able to identify those latent contacts with a transcriptomic profile that resembles patients with tuberculosis, and possibly with a higher risk of developing the disease, and that would be the ones that would benefit the most from anti-tuberculosis treatment ”, they affirm.
A challenge that escapes the medical and scientific field
However, and although scientific advances will greatly facilitate the objective of reducing tuberculosis cases in the world, if the majority of researchers interviewed agree on one thing, it is that the greatest effort in this fight must have a socioeconomic perspective.
“To achieve effective control of tuberculosis, a global approach is necessary that integrates lines of development and political-social commitment, greater investment in new drugs, (the standard treatment guidelines for tuberculosis have not changed in the last four decades ) and in the development of more effective vaccines ”, indicated the researchers of the Galician group.
Scientists also lament the slowness of the processes and procedures that lead to the development of new drugs and vaccines. ” Clinical trials are very slow, each year they are delayed there are thousands of deaths that we can no longer avoid, ” said Carlos Martín, from CIBERES. “In our case, in two years we will already know the dose of the vaccine that we are testing and we will need an enormous effort and support from society to carry it out. Clinical trials cost a lot of money and pharmaceutical companies are not interested because we are talking about a vaccine for people with few resources, which is not going to generate income ”.
Tuberculosis is a disease that may not resonate as much as HIV or malaria but, as we have said, it causes more than a million deaths a year. ” Many people in Africa are infected with HIV, but what they die of is tuberculosis, ” Martin reminded us. “It is a shame that there are so many cases of a treatable disease all over the world.”
Frédéric Chopin died in Paris in the 19th century from a complication derived from his chronic tuberculosis. However, it is very likely that the great composer would not have died for that reason in 21st century France. The unfortunate thing is that the same cannot be said for other regions of the world. ” The great drama of tuberculosis is that it is a preventable and curable disease , I wish I could say the same about many other ailments that my patients have!” Said pulmonologist Javier García, from Hospital La Princesa. “It will not be an easy disease to eradicate in the medium term, because as long as there are countries with public health problems, there will continue to be cases of tuberculosis.”
Advisors:
Javier García Pérez , pulmonologist at Hospital La Princesa (Madrid).
The team from the Center for Biomedical Research (CINBIO) of the University of Vigo, led by Professor Africa González-Fernández, has participated in a project financed by the European Union in its Horizon2020 program (Eliciting Mucosal Immunity to Tuberculosis ”. EMI-TB 643558) , which has just ended.
Carlos Martín Montañés , is Professor of Microbiology at the Miguel Servet University Hospital of the University of Zaragoza and directs the Mycobacteria Research Group at the Center for Biomedical Research in Respiratory Diseases (CIBERES) of said hospital. The University of Zaragoza, together with a Spanish biotechnology company, is developing the candidate for a new vaccine.
Pere-Joan Cardona , head of the Experimental Tuberculosis Unit at the Germans Trias i Pujol Institute (Badalona), has created a spin-off to develop and market a dietary supplement against tuberculosis.
