Personal Stories from TB Survivors - My Journey fighting TB

Superbugs Could Kill 39 Million People By 2050. Here's What Canadian Survivors, Doctors Say Should Change

Melissa Murray says the pain of her serious infection was 'thousands' times worse than what she'd experienced in childbirth. (Submitted by Melissa Murray)

This story is part of CBC Health's Second Opinion, a weekly analysis of health and medical science news emailed to subscribers on Saturday mornings. If you haven't subscribed yet, you can do that by clicking here.

Melissa Murray regularly ran 10 kilometres a day — until a serious bacterial infection caused her to nearly lose a leg. 

Last summer, the Toronto woman who'd worked 60-hour weeks as an account manager suddenly needed round-the-clock care to recover from sepsis. The life-threatening condition results from the immune system's overreaction to fighting an infection.

Septic shock deprived Murray's heart and kidneys of vital blood and oxygen, and her blood pressure plunged dangerously low. To save her life, surgeons urgently had to cut out half a calf muscle and tendons plus the inner side of her right upper thigh.

"I kept saying it feels like there's like a campfire in my leg," Murray, 46, recalled of the "excruciating" ordeal in July 2023.

"The pain was so bad I wanted to get out of my body."

Murray had an invasive Group A strep (iGAS) bacterial infection that could not be treated with standard antibiotics.  Doctors don't know how Murray got the infection, saying it could've been from something as small as a nick in the skin from shaving. 

Antibiotic-resistant microbes, sometimes called superbugs, are major contributors to sepsis — and may well be the biggest international public health threat of our time. World leaders called antibiotic resistance "an urgent global health threat." Here's what patients and doctors say should change.

An urgent global threat

Bacteria live in or on us, often beneficially or harmlessly. But antimicrobial resistance occurs when the germs that can cause infections develop the ability to evade medicines like antibiotics.

At this week's United Nations General Assembly in New York, world leaders called antimicrobial resistance or AMR "an urgent global health threat," and aimed to reduce the estimated 4.95 million human deaths associated with it per year by 10 per cent by 2030.

Murray's leg when she was in intensive care for septic shock caused by a bacterial infection. (Submitted by Melissa Murray)

As bacteria evolve over time, they can stop responding to the antibiotics that once killed them. Infections are then harder to treat — and sometimes even impossible.

Sepsis is one of the devastating consequences of antimicrobial resistance. The resistance can also render a minor skin wound incurable or turn a routine surgery into an opportunity for dangerous microbes to invade.

Antimicrobial resistance "is one of the major causes of death in [all] our countries as we speak, but the worst part of the news is that it will be the No. 1 cause of death by 2050," Barbadian Prime Minister Mia Mottley, the chair of the Global Leaders Group on AMR, told reporters from the UN on Thursday.

Antibiotics are a precious resource. Bacteria acquire resistance genes from each other. If someone doesn't take all of the antibiotic pills they've been prescribed, a single bacterium remaining in the person's system can evolve resistance and quickly pass on the advantage.

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Dr. Alison Fox-Robichaud, scientific director of Sepsis Canada, witnesses the links between antimicrobial resistance and sepsis in the intensive care unit where she works.

"We can often cure the infection," said Fox-Robichaud, a professor of medicine at McMaster University. "It takes longer to cure the sepsis, the results from that infection. But it means we may have less antibiotics to use for those serious bacteria that have acquired all of those resistance genes."

It takes longer to cure sepsis that results from infection than the infection itself, says Dr. Alison Fox-Robichaud. (Submitted by Alison Fox-Robichaud)

Fox-Robichaud said in Canada, 80 per cent of people with serious infections are identified in the emergency department, meaning they picked up microbes in the community where they live. And many infections acquired in intensive care units are resistant to antibiotics, because of overuse of the drugs, the long stays of patients who are highly susceptible due to co-occurring illnesses, as well as invasive procedures like placing urinary catheters.

"It's frustrating because I know we've got vaccine-preventable infections," Fox-Robichaud said, listing flu and pneumonia as well as RSV in older adults as examples. "If people took them, I wouldn't be seeing as many people in my ICU."

A sample that tested positive for tuberculosis (TB) is seen from a microscope in Buenos Aires, Argentina. Drug-resistant forms of TB sicken people worldwide. (Magali Druscovich/Reuters) 'Like 3 tennis balls underneath my skin'

For Murray, the iGAS infection initially weakened her from vomiting, followed a day later by diarrhea that kept her up overnight. Her temperature hit 40 C and persisted all day, despite her taking fever-reducing pills.

When the sun rose, Murray said her legs felt weirdly hot: "It just looked like three tennis balls underneath my skin," she said.

Murray called her boyfriend into the room and they headed to the emergency department.

She learned the hot, balled skin was from cellulitis, a common but potentially serious bacterial skin infection. She said the pain of the infection was "thousands" times worse than what she'd experienced in childbirth.

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After 13 days in hospital, Murray went home with a cocktail of IV antibiotics that doctors nicknamed the "Melissa blend."

Antibiotics prescribed too blindly, surgeon says

Ara Darzi of Imperial College London is a surgeon who attended the UN meeting. He said he'd like the world to adopt a new goal by 2030: Diagnose the type of bacteria that's causing the infection before prescribing any antibiotic.

"The supply of new antibiotics is not keeping up with demand," Darzi said in an email to CBC News. But for this approach to work, new therapeutics and vaccines, as well as new diagnostic kits need to be developed and made widely available.

"We wouldn't dream of giving chemotherapy without knowing the type of cancer — why do we tolerate this with infections?"

WATCHOttawa woman resorts to experimental phage therapy for joint infection:  Ottawa woman says phage therapy for joint infection saved her 6 months ago

Duration 2:40

Thea Turcotte says her life was likely saved by an experimental treatment developed in Winnipeg for her periprosthetic joint infection.

Mathieu Poirier, an assistant professor of social epidemiology at Toronto's York University, notes antimicrobial resistance in bacteria directly caused over a million deaths in 2021 globally, ranging from common infections like pneumonia to untreatable sepsis or tuberculosis.

Preventing infections through access to safe water and sanitation as well as improving vaccination rates are important steps to curbing antimicrobial resistance, he said.

Poirier said that in North America and Europe, people have been using antibiotics and other antimicrobials at far higher rates than elsewhere in the world: "In many ways we are contributing more to the problem, while not even dealing with the worst of the consequences."

For Murray, the ongoing consequences of her infection, which occurred a year ago, include splotches of sore skin on her shoulder, and a leg she must often keep elevated because of swelling. But she can walk now, with a cane, and can now drive short distances.

"I like to think I'm thriving because I'm alive."

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New Findings On Tuberculosis Could Change How We Treat Inflammatory Disorders

Tuberculosis (TB) is a confounding scourge. It's the leading cause of death from infectious disease in the world, and yet it's estimated that those deaths represent perhaps 5% of infections with Mycobacterium tuberculosis (Mtb). Antibiotics can take credit for saving the lives of some of those with Mtb, but a chasm nevertheless persists between the prevalence of infection and the targeted severity of its impact. A growing body of evidence suggests genetic vulnerabilities to TB account for that gap.

Now researchers from The Rockefeller University have found another rare mutation that leaves its carriers much more likely to become ill with TB—but, curiously, not with other infectious diseases. This finding, recently published in Nature, may upend long held assumptions about the immune system.

It's long been known that an acquired deficiency of a pro-inflammatory cytokine called TNF is linked to an increased risk of developing TB. The current study, led by Rockefeller's Stéphanie Boisson-Dupuis and Jean-Laurent Casanova, revealed a genetic cause of TNF deficiency, as well as the underlying mechanism: a lack of TNF incapacitates a specific immune process in the lungs, leading to severe—but surprisingly targeted—illness.

The findings suggest that TNF, long considered a key galvanizer of the immune response, might actually play a much narrower role—a discovery with far-reaching clinical implications.

"The past 40 years of scientific literature have attributed a wide variety of pro-inflammatory functions to TNF," says Casanova, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases. "But beyond protecting the lungs against TB, it may have a limited role in inflammation and immunity."

Rare risk

Casanova's lab has been studying the genetic causes of TB for more than two decades through field work in several countries and a wide network of collaborating physicians across the world. They maintain an ever-growing database of whole-exome sequences from a global pool of patients—more than 25,000 people to date. Of those, some 2,000 have had TB.

Over the years they've identified several rare genetic mutations that render some people vulnerable to TB. For example, mutations in a gene called CYBB can disable an immune mechanism called the respiratory burst, which produces chemicals called reactive oxygen species (ROS). Despite its pulmonary-sounding name, the respiratory burst takes place in immune cells throughout the body.

ROS help pathogen-consuming white blood cells called phagocytes (from the Greek for "eating") to destroy the invaders they've devoured. If ROS aren't produced, those pathogens can thrive unchecked, leading to debilitating complications. As a result, carriers of this CYBB mutation become vulnerable to not just TB but to a wide variety of infectious diseases.

For the current study, the team suspected that a similar inborn error of immunity may lay behind the severe, recurring TB infections experienced by two people in Colombia—a 28-year-old woman and her 32-year-old cousin—who had been repeatedly hospitalized with significant lung conditions. In each cycle, they initially responded well to anti-TB antibiotics, but within a year, they were sick again.

Puzzlingly, however, their long-term health records showed that their immune systems functioned normally, and that they were otherwise healthy.

A telling deficiency

To find out why they were particularly prone to getting TB, the researchers performed whole-exome sequencing on the two, as well as a genetic analysis of their respective parents and relatives.

The two were the only members of their extended family with a mutation in the TNF gene, which encodes for proteins linked to the regulation of a variety of biological processes. Short for "tumor necrosis factor," increased TNF production is also associated with a variety of conditions, including septic shock, cancer, rheumatoid arthritis, and cachexia, which causes dangerous weight loss.

The protein is largely secreted by a type of phagocyte called a macrophage, which relies on the ROS molecules generated by the respiratory burst to finish off pathogens they've consumed.

In these two patients, the TNF gene failed to function, preventing the respiratory burst from occurring, and thus the creation of ROS molecules. As a result, the patients' alveolar macrophages, located in their lungs, were overrun with Mtb.

"We knew that the respiratory burst was important for protecting people against various types of mycobacteria, but now we know that TNF is actually regulating the process," says Boisson-Dupuis. "And when it's missing in alveolar macrophages, people will be susceptible to airborne TB."

She adds, "It's very surprising that the people we studied are adults who have never been sick with other infectious diseases, despite being repeatedly exposed to their microbes. They are apparently selectively at risk for TB."

Treatment potential

The discovery also solves a long-standing mystery about why TNF inhibitors, which are used to treat autoimmune and inflammatory diseases, raise the chances of contracting TB. Without TNF, a key part of the defense against it is defunct.

The findings may lead to a radical reassessment of TNF's role in immune function—and new treatment possibilities.

"TNF is required for immunity against Mtb, but it seems to be redundant for immunity against many other pathogens," Casanova says. "So the question is, what other pro-inflammatory cytokines are doing the jobs we thought TNF was doing? If we can discover that, we may be able to block these cytokines rather than TNF to treat diseases where inflammation plays a role."

More information: Jean-Laurent Casanova, Tuberculosis in otherwise healthy adults with inherited TNF deficiency, Nature (2024). DOI: 10.1038/s41586-024-07866-3. Www.Nature.Com/articles/s41586-024-07866-3

Citation: New findings on tuberculosis could change how we treat inflammatory disorders (2024, August 28) retrieved 29 September 2024 from https://medicalxpress.Com/news/2024-08-tuberculosis-inflammatory-disorders.Html

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