Immunizations

New Tool Makes It Easier To Diagnose Tuberculosis In Children

An international research consortium led by Ludwig Maximilian University of Munich (LMU) has tested a rapid new analytical tool which needs just a blood sample from the fingertip.

About 240,000 children worldwide die of tuberculosis every year. The disease is among the top 10 causes of death in children under the age of 5. One of the main reasons for this mortality is that tuberculosis is often misdiagnosed or not diagnosed in time, particularly in regions with limited resources.

A new diagnostic tool, which an international research consortium led by LMU medical scientists Laura Olbrich and Norbert Heinrich from the Division of Infectious Diseases and Tropical Medicine at LMU University Hospital Munich has tested as part of a large-scale study in five countries, offers significant progress in this area. The authors report on their findings in The Lancet Infectious Diseases.

Before now, the most commonly used tuberculosis tests have been based on microbiological analysis of sputum—that is, mucus taken from the lower airways. These samples are difficult to obtain in children. Moreover, child tuberculosis is often characterized by a low bacterial load and unspecific symptoms. "Therefore, new tests are urgently needed," says Olbrich.

The new tool, which the researchers have now tested, is based on the activity of three specific genes, which can be measured in capillary blood. An innovative, semi-automatic system allows health care workers to identify a so-called transcriptomic signature for these genes. This transcriptomic signature can help to diagnose tuberculosis.

The test has the advantage that the blood sample can be conveniently taken from the fingertip and the results are available very quickly: "We have the results in just over an hour. For most other tests, the samples have to be sent to other laboratories for analysis," says Olbrich.

The researchers have tested the new tool as part of the comprehensive RaPaed-TB tuberculosis study, which is led by Heinrich and carried out in collaboration with partners in South Africa, Mozambique, Tanzania, Malawi, and India. In total, the study included 975 children younger than 15 years suspected of having tuberculosis. To determine the accuracy of the test, the researchers additionally investigated the tuberculosis status of the children using a standardized reference test, which is based on the analysis of sputum and bacterial cultures.

"The results were encouraging," says Olbrich. "Compared to detection in culture, the test identified almost 60% of children with tuberculosis, with 90% specificity. This makes the test comparable with or better than all other tests that work with biomarkers. The bacterial culture is always the reference because it yields the most stable results. But it takes up to eight weeks and is often not available where children with tuberculosis present."

As the reference signature of the new tool was largely identified from adult samples, the researchers expect that the test accuracy can be further improved after adjusting the calculation of the signature for children.

More information: Laura Olbrich et al, Diagnostic accuracy of a three-gene Mycobacterium tuberculosis host response cartridge using fingerstick blood for childhood tuberculosis: a multicentre prospective study in low-income and middle-income countries, The Lancet Infectious Diseases (2023). DOI: 10.1016/S1473-3099(23)00491-7

Citation: New tool makes it easier to diagnose tuberculosis in children (2023, October 31) retrieved 31 October 2023 from https://medicalxpress.Com/news/2023-10-tool-easier-tuberculosis-children.Html

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How Cord-like Aggregates Of Bacteria Lead To Tuberculosis Infections

The ability of Mycobacterium tuberculosis (MTB), a serious respiratory infection, to form snake-like cords was first noted nearly 80 years ago. In a study published October 20 in the journal Cell, investigators report the biophysical mechanisms by which these cords form and demonstrate how several generations of dividing bacteria hang together to create these structures that enable resistance to antibiotics.

"Our work clearly showed that cord formation is important for infection and why this highly ordered architecture might be important for pathogenesis," says senior author Vivek Thacker, who led the work at the Global Health Institute at École Polytechnique Fédérale de Lausannen (EPFL) in Switzerland and is now based at the Department of Infectious Diseases at Heidelberg University in Germany.

The study used a unique combination of technologies to address the role of MTB cord formation. One was a lung-on-chip model, which allowed the researchers to get a direct look at "first contact" between MTB and host cells at the air-liquid interface in the lungs. This revealed that cord formation is prominent in early infection.

The researchers also used a mouse model that develops pathologies mimicking human tuberculosis, allowing them to obtain tissue that could be studied using confocal imaging and confirming that cording also occurs early in infection in vivo.

The work yielded several new findings about how these cords interact with and compress the cell nucleus, how this compression affects the immune system and connections between host cells and epithelial cells, and how cord formation affects the alveoli in the lungs. The study also revealed how these cords retain their structural integrity and how they increase tolerance to antibiotic therapy.

"There is an increasing understanding that these mechanical forces influence cellular behavior and responses, but this aspect has been overlooked since traditional cell culture models do not recapitulate the mechanical environment of a tissue," says Melanie Hannebelle, formerly at EPFL's Global Health Institute and now at Stanford University.

"Understanding how forces at the cellular and tissue level or crowding at the molecular level affects cell and tissue function is therefore important to develop a complete picture of how biosystems work."

"By thinking of MTB in infection as aggregates and not single bacteria, we can imagine new interactions with host proteins for known effectors of MTB pathogenesis and a new paradigm in pathogenesis where forces from bacterial architectures affect host function," says Thacker.

Future research will focus on understanding whether cord formation enables new functionality to known effectors of MTB pathogenesis, many of which are located on the MTB cell wall. In addition, it will look at the consequence of tight-packing on the bacteria within the clump and how this may lead to a protective effect against antibiotics.

"Antibiotic therapy is the mainstay of treatment for tuberculosis infections, but therapeutic regimens are long and complicated, with an increasing threat of drug resistance," says Richa Mishra, the other first author who is currently at EPFL's Global Health Institute. "There is a recognized need for host-directed therapies or therapies that inhibit specific virulence mechanisms that can shorten and improve antibiotic therapy."

More information: Mechanopathology of biofilm-like Mycobacterium tuberculosis cords, Cell (2023). DOI: 10.1016/j.Cell.2023.09.016. Www.Cell.Com/cell/fulltext/S0092-8674(23)01037-1

Journal information: Cell

Citation: How cord-like aggregates of bacteria lead to tuberculosis infections (2023, October 20) retrieved 31 October 2023 from https://phys.Org/news/2023-10-cord-like-aggregates-bacteria-tuberculosis-infections.Html

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TB Vaccine: WHO Expert Explains Why It's Taken 100 Years For A Scientific Breakthrough, And Why It's Such A Big Deal

The BCG vaccine for TB has been used for 100 years. It is largely effective for children under five, but less so in older people and can't be used on patients who have certain medical conditions. Today we're the closest we've ever been to discovering a vaccine that might replace or complement it. Charles Shey Wiysonge, the World Health Organization's Regional Adviser for Immunisation, discusses the latest developments in the fight against one of the world's deadliest diseases.

Why has it taken so long?

We do not yet have a new vaccine for TB. But, for the first time, there are several vaccine candidates that are at advanced stages of clinical development.

Vaccine development usually takes decades and unfolds step by step. Experimental vaccine candidates are created in the laboratory and tested in animals before moving into progressively larger human clinical trials.

Clinical trials are research studies that test an intervention such as a vaccine in human beings and occur in phases, from phase 1 to phase 3. We say vaccines are in clinical development when they reach the clinical trial stage.

A phase 1 trial is a first-in-human study which recruits a small number of healthy people (usually fewer than 100), to assess whether a candidate vaccine is safe.

Phase 2 trials are typically conducted among several hundred participants, to assess whether the candidate vaccine produces an immune response.

For phase 3 trials, thousands of people are enrolled to assess whether the vaccine is efficacious and safe. Phase 3 TB vaccine trials are currently going on in Gabon, Kenya, Russia, South Africa, Tanzania and Uganda.

Even though we are still, at best, three years away from broad regulatory approval of a new TB vaccine, the scientific community can do a lot now to prepare for its use, and to inform the public so that the vaccine may be accepted when it becomes available.

TB vaccines are very challenging to develop. The bacterium that causes the disease is complex, and is proficient at evading the human immune system. We don't yet have a full understanding of how to appropriately target the bacterium or what kind of immune responses are needed to induce immunity. But there are some interesting approaches in the pipeline and there have been some encouraging data from clinical trials that are providing clues.

Why do we need a new TB vaccine?

TB is a global health emergency. About 2 billion people are currently infected with Mycobacterium tuberculosis, and of those, 5% to 10% may become ill with TB and will potentially transmit the bacterium.

In 2021, nearly 10.6 million people developed TB disease and 1.6 million died. We urgently need new tools to fight TB, including new and improved vaccines.

The Bacille Calmette-Guérin (BCG) vaccine has saved tens of millions of lives and is effective in children under the age of five in preventing TB deaths and severe forms of the disease.

The vaccine has variable efficacy for protection against pulmonary TB (TB affecting the lungs) in adolescents and adults – and it is pulmonary TB that's responsible for the majority of TB transmission. So new and improved vaccines that are effective in preventing pulmonary TB in adolescents and adults are essential to control TB, and to reduce transmission to all, including newborn babies.

TB is the leading cause of death among people living with HIV. People living with HIV have up to 20 times higher risk of developing TB disease compared to those without HIV infection. The current BCG vaccine is not recommended for use in people living with HIV, for safety reasons. Although BCG is a safe vaccine in immunocompetent infants (those whose immune systems are working properly), severe adverse events can occur in HIV-infected infants following vaccination with BCG.

These adverse events include a rare but life threatening condition known as disseminated BCG disease. However, new TB vaccine candidates are being developed and evaluated to offer clinical benefit in people living with HIV.

How effective has the BCG vaccine been?

BCG vaccines are given to more than 100 million children every year worldwide, at birth or soon after. The effectiveness of BCG can vary depending on several factors, including the prevalence of TB in a given area, the strain of the BCG vaccine used, and the age at which BCG was administered.

Several studies have shown that the effect of the BCG wanes as children approach adolescence. People may become infected with TB but not be aware of it.

What will happen to the BCG vaccine?

The BCG vaccine will not be replaced by another TB vaccine until and unless there is compelling data on the safety and efficacy of an alternative. Most of the current vaccines in advanced stages of clinical trials are tested in adolescents and adults. Their safety and efficacy would need to be proven in newborn infants to be able to replace BCG.

In addition, BCG vaccination has nonspecific beneficial effects on overall mortality and leads to more reductions in child mortality than would be expected by just protecting against tuberculosis. There is thus a great possibility that BCG would remain in use.

What will a new vaccine mean for the fight against TB?

This depends on what the clinical trial data for the new vaccine candidates show. Most importantly, any new vaccine will need to be safe, and it will need to offer clear clinical benefit to populations at risk. We hope that the TB vaccine candidates that are in the pipeline will be effective at reducing TB infection, TB disease and TB transmission and can become part of a combination of tools in the fight against TB.

This article is part of a media partnership between The Conversation Africa and the 2023 Conference on Public Health in Africa.

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