Tuberculosis is treatable. Despite this, over one million people die from this disease every year. This can be mitigated by new diagnostic tests and active substances. The danger is close at hand. The proportion of multidrug-resistant pathogens is especially high in Ukraine, among other countries.
Norbert Heinrich’s decision to go into research came 17 years ago. The place: in a bush hospital in Malawi. The pediatrician had to watch helplessly as his little patients became thinner and weaker. They were wasting away because of consumption, as tuberculosis used to be known. The extreme deterioration of muscle and fatty tissue is characteristic of the disease. In the 19th century, roughly a seventh of the population in Germany died from the “White Plague”, which is spread by droplet transmission. The disease became rare in Germany due to improved living conditions, the establishment of tuberculosis care centers and, from the mid-1940s, antibiotics. However, it is one of the most common causes of death in some regions of Africa and Southeast Asia. Tuberculosis is the infectious disease that claims the most lives worldwide. The toll was 1.25 million in 2023 alone.
Heinrich returned from Malawi with the will to fight this disease. He knows that early diagnosis and rapid, effective treatment are crucial. Heinrich and his colleagues at the Fraunhofer Institute for Translational Medicine and Pharmacology ITMP and the LMU Klinikum München (University Hospital of the Ludwig Maximilian University of Munich) are working on both. They have just filed a patent application for one of the results of their research.
The diagnosis of tuberculosis has hardly changed since the time of Robert Koch. In 1882, Koch, who went on to become a Nobel laureate, discovered Mycobacterium tuberculosis in the sputum of patients. The viscous secretion collects in the deep regions of the lungs and is expelled by coughing. Even today, tuberculosis is still detected by a sputum specimen.
“But try getting sputum from small children,” Heinrich points out. The younger the children, the higher the probability of so-called extrapulmonary tuberculosis, in which the bacterium migrates to other organs. The lungs then often remain asymptomatic. “More than 200,000 children worldwide die every year because the disease is not recognized,” says Heinrich.
Heinrich’s colleague, pediatrician Laura Olbrich, explains how difficult it is to process the highly infectious sputum specimen. The pathogen can only be detected by microscopy at a very high bacterial load of roughly 10,000 pathogens per milliliter of sputum. That quantity is only present in cases of severe disease. The gold standard for diagnosis is therefore a bacterial culture, which can also be used to identify potential antibiotic resistance. The laboratories must comply with stringent safety requirements, and the procedures and machines must be specially controlled for successful culturing. “But the necessary medical infrastructure, also including the appropriate specialist staff, is lacking precisely in many of the poorer countries with high numbers of tuberculosis cases,” says Olbrich. Furthermore, the culture only grows slowly; it can be two to eight weeks before the final proof is available.
Only one in ten becomes ill
In the DisTB project, Olbrich is therefore developing new diagnostic tests together with an interdisciplinary team and with the participation of pharmaceutical company Roche. They want to facilitate a quick, simple and early diagnosis of tuberculosis. This is crucial to ensure that infected people do not spread the disease and are spared serious harm to their health as well as complications. The researchers are looking for highly sensitive specific biomarkers in blood, urine and saliva, such as specific immune signaling molecules or antigens.
There is an IGRA test, a blood test that can prove that the patient’s immune system has been in contact with the tuberculosis bacterium. “But the IGRA test does not tell us whether a person has tuberculosis,” explains immunologist Kathrin Held, who is conducting research alongside Olbrich in DisTB. This is because the disease only manifests in roughly one out of ten infected individuals, especially in those with compromised immune systems. Olbrich: “A healthy body is normally able to encapsulate the bacterium and render it harmless.” Doctors speak of latent tuberculosis, which is not infectious. However, if the immune system is severely stressed by another pathogen such as HIV or is artificially compromised, such as due to chemotherapy or rheumatological treatment, the tuberculosis bacterium can gain the upper hand and the person can fall ill, even years after infection.
The researchers have now succeeded in finding biomarkers in the blood that are not only highly specific for tuberculosis, but are also easy to detect. They have even identified a specific combination of biomarkers that can be used to diagnose an active disease and measure the success of treatment. A patent application has since been filed for this so-called signature.
The research scientists want to implement their findings in a test that is as simple as possible and does not require complex laboratory diagnostics or specialists. “The ideal solution would be a type of finger prick test,” says Olbrich, “such as those used by diabetes patients to measure their blood sugar levels.” All that would be required is a drop of blood, a test strip and a small reading device. Held adds: “With sufficiently sensitive tests that show us how active the tuberculosis is in the body, we could provide more targeted preventative treatment than has been possible to date and prevent the disease from manifesting.” With this, the two researchers hope to shorten treatment times and reduce the number of new infections.
Severe side effects
Tuberculosis is currently treated with a combination of four antibiotics. This combination therapy is necessary because the bacterium very quickly develops mutations that confer resistance to individual drugs. “In this way,” says Heinrich, “we reduce the risk of some bacteria surviving the therapy and continuing to multiply.” The therapy lasts at least four months, but usually six or more. The side effects are severe, with patients often suffering from nausea, vomiting and diarrhea, and occasionally also from skin rashes, dizziness and liver dysfunction. The side effects are even more serious in the treatment of multidrug-resistant tuberculosis, when the so-called first-line antibiotics no longer help because the bacteria have become resistant to these agents, necessitating the use of reserve antibiotics. Multidrug-resistant pathogens are especially widespread in the WHO’s European region, which also includes Russia, Belarus and Ukraine. They account for roughly 24 percent of all newly diagnosed cases. During treatment, a quarter of patients with multidrug-resistant tuberculosis suffer neuropathy, i.e. nerve damage, as well as bone marrow suppression. This results in anemia, which weakens the immune system and makes the patient susceptible to serious infections and bleeding. The harm to health can be permanent. Sometimes the therapy has to be discontinued, which promotes the development of further resistance.
An especially problematic agent in the mix of antibiotics is the highly toxic but also highly effective linezolid. Heinrich and his colleagues hope to replace it soon with two new substances: Sutezolid and Delpazolid. These antibiotics belong to the same class, but are significantly less toxic. In two Phase IIb trials, the researchers and their African partners have now tested these drugs for the first time in combination with the other three tuberculosis antibiotics. The drugs were studied in patients with multidrug-resistant tuberculosis in South Africa and Tanzania. The results indicate significantly better tolerability and, in the case of Delpazolid, also very good efficacy. These results were published in high-impact journal “The Lancet Infectious Diseases” and attracted significant attention among experts, as they could enable significant progress in therapy.
New beacons of hope
The research team hopes to build on its success in a Phase III trial, coming one step closer to approval of the innovative active ingredients. BTZ-043, a new antibiotic developed at the Institute of Infectious Diseases and Tropical Medicine at the LMU Klinikum München and the Hans Knöll Institute in Jena, is to join Delpazolid here, replacing another problematic agent in the quadruple combination therapy: Bedaquiline. The bacterium is becoming increasingly resistant to that former beacon of hope, which revolutionized the treatment of multidrug-resistant tuberculosis roughly 20 years ago by making the therapy significantly more tolerable and reducing the treatment time by two thirds. This development is especially threatening in many countries in southern Africa.
Heinrich is also very concerned about the USA’s withdrawal from global prevention and treatment efforts. Until now, the US government has been the heaviest funder of tuberculosis research. “I must say, our American colleagues are quite desperate.” The funding cuts also mean that many aid programs can no longer be continued and supplies are at risk in numerous countries. Heinrich fears a significant increase in tuberculosis cases and deaths. As antibiotic treatments have to be discontinued prematurely due to a lack of medication, new, even more resistant pathogens could emerge, posing a serious threat to global health. “We urgently need new tools to get this disease under control,” says Heinrich. And that before the white plague conquers Europe and other regions around the world because none of our drugs help any more.
Fraunhofer-Gesellschaft