Tuberculosis is one of humanity’s oldest infectious diseases and the one that has caused the most deaths throughout history. In the last 200 years alone, it has claimed the lives of more than a billion people and is still the most lethal infectious disease today.

To address this major global health challenge, more and more progress is being made in prevention, diagnosis and treatment. The only vaccine available for the disease was developed in 1921 but there are currently 14 new vaccine candidates under clinical development, getting closer to being tested on humans.

There are social, economic and scientific challenges to eradicating tuberculosis but also promising advances that offer hope for the future. On 26 March, in a new CaixaResearch Debate, we examined the situation of tuberculosis with three experts: Pere-Joan Cardona (Germans Trias i Pujol Hospital), Iñaki Comas (Institute of Biomedicine of Valencia, IBV-CSIC) and Alberto García-Basteiro (Barcelona Institute for Global Health and Manhiça Health Research Centre).

Below we review the main ideas that were addressed during the debate, chaired by Jessica Mouzo, a health journalist for El País newspaper.

Knowing about tuberculosis

What is tuberculosis?

“Tuberculosis is an infectious disease caused by the bacterium Mycobacterium tuberculosis, which is transmitted through the air and reaches people’s lungs, where different scenarios can occur. Some people are able to get rid of the infection; however, what usually happens is that the immune system is able to contain the infection in a structure called a granuloma. A granuloma is a kind of “Chernobyl sarcophagus” that contains the infection. If the bacterium escapes, it can produce the disease” – Iñaki Comas

About 25% of the world’s population are infected but don’t develop the disease. Why?

“ Once a person is infected, whether they actually develop TB or not depends on a number of factors and has a lot to do with interactions with the immune system. All those determinants that affect our immune system can increase the risk of the infection progressing to disease. We know that about 5-10% of those infected will develop the disease in their lifetime, mainly in the first two years post-infection. Some of the known risk factors are human immunodeficiency virus (HIV), diabetes, alcoholism, smoking and immunosuppressive drugs, which may be given, for example, to cancer patients or transplant recipients. All these factors affect the immune system. However, in some cases the disease develops without any apparent immune disorder“ – Alberto García-Basteiro

To develop the disease per se, the bacteria also have to move to the upper lung, which is a slightly more vulnerable area. In about half the cases we don’t know precise understanding of the exact factors that cause the disease to develop. What we do know is that malnutrition is the most important immunosuppressive factor” – Pere-Joan Cardona.

Is tuberculosis easily transmitted, and what factors influence its spread?

“Classically it was said that to keep TB circulating you’d need each sick person to infect about 10 people because, of these 10 people, one would develop a new case of TB. But the reality is more complex. It has been observed, for example, that some people emit aerosols (small droplets suspended in the air that contain the bacteria) with a higher infectious capacity. The ability of a sick person to spread socially, to move around in different settings and infect more or fewer people, also plays a role” – Pere-Joan Cardona

“It also depends quite a lot on the context and the country where it’s measured. There are studies in the Netherlands that say each infected person generates less than one new case, whilst, other studies concerning countries in Sub-Saharan Africa or Southeast Asia say that it could result in three or four new cases. It depends on a large number of factors and is very complex to estimate” – Alberto Garcia-Basteiro

Tuberculosis in the world

How is tuberculosis distributed globally?

“Eighty-five percent of cases globally are found in 20 countries. Most are in India, Indonesia, the Philippines, South Africa and Mozambique. However, globalisation and social inequalities help the disease to spread to other regions” – Pere-Joan Cardona

“TB is a disease very much associated with poverty, so those regions with lower socio-economic development, poorer regions, have higher TB indicators. India has a large number of cases in absolute terms because it has a large population, but, in terms of cases per inhabitant, the ranking is headed by Southeast Asia and Sub-Saharan Africa” – Alberto García-Basteiro

“The factors that determine the distribution of TB vary according to the context of each country. In Mozambique, for example, HIV plays a crucial role in its spread, while in other places it may be multi-resistance, in others diabetes…. But there’s always a common theme, namely socio-economic status, the capacity of the social health system. In all countries, even the most developed, the disease emerges when the health and social support systems fail” – Iñaki Comas

Are there differences according to gender or age?

“The numbers tell us that it affects more men than women (65% men / 35% women). However, it’s not clear whether this is due to a biological factor. We don’t know if there’s a higher proportion in men because they’re more exposed to the infection or because they have an intrinsic weakness, or if there’s a diagnostic delay in women. What we do know is that children have a much higher risk of developing TB. In children between the ages of 2 and 5, the probability of developing TB after infection is 40% whereas the risk falls after the age of 14. This seems to be due to factors related to children’s lung development” – Pere-Joan Cardona

How does this combination of poverty and lack of resources interact with the disease?

“People living in poverty are much more likely to be infected. They live in overcrowded conditions, many people in the same room, so if there’s one person with the disease it’s much easier for them to pass it on. Once infected, a person living in poverty is much more exposed to risk factors that favour the progression of TB. In the case of Sub-Saharan Africa, malnutrition is the most important factor. Infected people living in low socio-economic contexts are therefore much more likely to develop the disease. They also have more difficulty accessing early diagnosis and adhering to treatment, which increases the risk of mortality. This whole cluster of factors means that, in countries with fewer resources, we have more infected people; more cases of TB and more mortality” – Alberto García-Basteiro

“In Brazil, a recent ISGlobal study found a 40% reduction in the incidence of TB in families receiving a small cash allowance called “bolsa familia”, highlighting the effectiveness of social interventions” – Alberto García-Basteiro.

“Something very similar was published about giving food supplements to prevent malnutrition. This reduced cases by 50%. Just by giving a food supplement or monetary aid, we save a large number of lives” – Iñaki Comas

What’s the situation in countries like Spain, where there are about 4,000 new cases a year?

“In developed countries, TB tends to affect large cities in particular, where there are ghettos and areas where people live under difficult socio-economic conditions. In addition, there are cases associated with people on immunosuppressive treatments. Finally, there may be specific outbreaks, such as the one recently detected in Barcelona. Currently, genomic epidemiology tools are helping us to identify the chains of transmission in great detail, so we can take action to reduce the incidence of the disease” – Pere-Joan Cardona

Treatments and vaccines for tuberculosis

What therapeutic tools are currently available and do they have any side effects?

“Treatment for TB is effective in more than 95% of the cases (consisting of four antibiotic drugs for at least six months), but the treatment’s duration can make it difficult to stick to, especially in poor socio-economic contexts or with limited access to education. When the current treatment emerged in the 1980s, it was a major advance over previous therapies which had lasted up to three years. It was thought that the disease would be eradicated by 2000 but this hasn’t been the case” – Pere-Joan Cardona

“There are very few side effects. The biggest problem is antibiotic drug resistance in some strains of the bacterium, caused by the treatment being misused. This is especially complicated when the bacteria are resistant to rifampicin, one of the most effective drugs. Fortunately, other solutions are starting to become available, other new treatments, but the problem of resistance will always be there, as the bacterium has an extraordinary ability to mutate” – Pere-Joan Cardona

“Bedaquiline, one of these new drugs developed after more than 30 years of research, is already encountering resistant strains after only two years of use. It’s a clear example of a race we’re still losing” – Iñaki Comas

Tuberculosis is one of the oldest diseases and has been studied extensively, so why hasn’t it been eradicated?

“As we’ve already said, multi-resistance to treatment is an important issue. This should be of great concern because it prevents us from using the cheapest antibiotic drugs and therefore reduces our therapeutic arsenal, but we have to put it into context.  Only 4% of TB cases in the world are resistant to rifampicin and one piece of good news is that the proportion of cases that are resistant to rifampicin hasn’t increased over the past few years. So, although it’s a considerable problem (in some regions, such as Eastern Europe and Central Africa, 30-40% of the cases are resistant to rifampicin), more complex factors lie behind the current lack of progress in containing the disease” – Alberto Garcia-Basteiro

“Another important factor is that one in four TB cases is not properly diagnosed or reported. Each undiagnosed case means that the spread of the disease expands;  the infection continues being passed on, unchecked. Asymptomatic TB should also be considered. These are people who show lesions in their lung tissue that may have been caused by a tuberculous disease. They feel well and so don’t go to the doctor but they can still pass on the disease. There are studies based on modelling (not empirical data) that suggest asymptomatic TB may be responsible for a significant proportion of global transmission. In many parts of the world there are already problems in identifying and treating symptomatic cases, and the situation is even more complex with asymptomatic cases” – Alberto Garcia-Basteiro

“On a positive note, we’ve improved a lot in diagnostic capacity and treatment. Although the incidence is still high, the number of deaths has come down a lot since the 1990s. If you stay on the treatment for 6 months, the chances of being cured is very high (and resistance doesn’t develop). Since diagnosis and treatment programmes were implemented worldwide in the 1990s, an estimated 10 million lives have been saved” – Iñaki Comas

What’s the situation with vaccines and what can we expect in the future?

“Most of the vaccines administered produce antibodies in the body that kill the pathogens. The problem with TB is that the bacterium infects an area of the lung where there are virtually no antibodies and where the action of antibodies is very limited, so it’s difficult to develop an effective vaccine. There’s a vaccine, BCG, which was developed 20 years ago and is still in use. It’s administered in a lot of countries with a high incidence of tuberculosis disease to prevent it from developing on a massive scale” – Pere-Joan Cardona

“We’ve been working on therapeutic vaccines, such as the Ruti vaccine, which will be given to people who are already infected in an attempt to reduce treatment time and give more effective prophylaxis to people who are only infected so that they don’t actually develop the disease. There’s a vaccine, DGSK, which is also being developed by the Bill Gates Foundation, which provides 40% protection, similar to or slightly less than offering a nutritional supplement to the contacts of a case” – Pere-Joan Cardona

“With the development of new vaccines we’re at an encouraging moment but factors such as improved nutrition are still very important in reducing the incidence of the disease” – Pere-Joan Cardona

“We’ve made a lot of progress with TB vaccines and I think we’re on the right track, but the social aspect of the disease and the cracks in the system at an economic and health level are still there” – Iñaki Comas

What remains to be done?

“We must realise that our approach to TB cannot be exclusively medical; it has to be multi-sectoral. We need countries to improve their socio-economic status. Eliminating inequality gaps in housing, in food and many other sectors could go a long way to helping to control the disease” – Alberto Garcia-Basteiro