Category: Respiratory Diseases

Slow Progress after Decision to Make TB Prevention Pills More Widely Available

Tuberculosis bacteria. Credit: CDC

By Tiyese Jeranji

Besides preventing illness and death, tuberculosis prevention therapy is estimated to be highly cost effective. Yet, uptake of the medication is not what it could be in South Africa. Tiyese Jeranji asks how much has changed since the Department of Health last year decided to make TB prevention therapy much more widely available.

Many people who have the TB bug in their lungs are not ill with TB disease. Having the bug in your body, does mean however that you are at risk of falling ill, should the TB bacteria get the overhand in its battle with your immune system.

Fortunately, we have medications that can kill TB bacteria before one falls ill. A recent World Health Organization (WHO) investment case, suggests such TB prevention therapy, commonly called TPT, reduces the risk of falling ill with TB in those exposed to the bug by 60% to 90% compared to people who do not get the treatment.

In South Africa, TPT has been available in the public sector for years, but until the publication of new government guidelines last year, only kids aged five or younger and people living with HIV could get the medication. Under the new guidelines, everyone who has had close contact with someone with TB should be offered a TB test and if they test negative be offered TPT – if they test positive they should be offered TB treatment. These changes dramatically expanded the number of people in South Africa who are eligible for TPT.

The antibiotics used for TPT has also changed in recent years. For many years, the only option was a medication called isoniazid taken for six or more months. We now also have two three-month options – isoniazid and rifapentine given once weekly and rifampicin and isoniazid given daily. These shorter duration treatment courses should help more people complete the treatment.

Down and up?

Dr Norbert Ndjeka, Chief Director of TB Control and Management at the National Department of Health, tells Spotlight that in recent years, South Africa has seen a steady decline in the number of people initiated on TPT.

The decline has been substantial. In people living with HIV, initiation on TPT dropped from 454 000 in 2018 to around 241 000 in 2023. In children aged five and younger who have had contact with someone with TB, it fell from 25 357 in 2018 to 15 775 in 2023.

TPT enrolments per province for 2023

ProvincePeople living with HIVContacts < 5 YearsContacts > 5 Years
Eastern Cape34 6232 5514 771
Free State14 5355621 027
Gauteng67 3331 3684 241
KwaZulu-Natal62 3623 1688 519
Limpopo15 871391452
Mpumalanga25 6186692 006
Northern Cape3 1788551 595
North West9 4335961 425
Western Cape8 5325 6151 278
South Africa241 48515 77525 314
*Typically, provinces with higher numbers of people diagnosed with TB or those with high numbers of people living with HIV will report higher TPT initiations.

There are two significant reasons for this decline, according to Ndjeka. Firstly, declining TB incidence, and secondly, declining HIV incidence.

“With fewer people diagnosed with TB disease, fewer contacts will need TPT, and with fewer people being diagnosed with HIV, fewer people will initiate TPT regardless of TB exposure,” he says.

WHO figures have shown a significant downward trend in the estimated TB cases per year in South Africa and according to Thembisa, the leading mathematical model of HIV in South Africa, the number of people newly starting HIV treatment has dropped from a peak of over 700 000 in 2011, to well under 300 000 in 2023.

But the recent downward trend in people taking TPT may be coming to an end. “We believe that the implementation of the new guidelines within the current strategic framework will lead to increases in TPT enrolment,” says Ndjeka.

In line with the new guidelines, there are also changes to what TPT data is being collected. “For example, we never used to report on TPT provision to contacts 5 years and older, but now we do and in 2023 at least 25 314 TB contacts 5 years and older were initiated on TPT,” he says.

20% increase expected in 2024

Based on the data reported for January and February of this year, Ndjeka expects that overall TPT initiations will increase by at least 20% in 2024 compared to 2023. Moreover, as documented in the National Strategic Plan for HIV, TB and STIs 2023-2028, there is a plan to have a steady annual increase in TPT enrolments leading up to 2028.

Ndjeka says based on the NSP TPT targets, South Africa is exceeding TPT targets for people living with HIV, but reaching less than 25% of targets for TB contacts. He points out that performance varies by province, but that all provinces have a long way to go in terms of reaching TB contacts.

‘Cost saving over time’

“The aim of offering TPT is to reduce the TB incidence,” Ndjeka says. “So, if everyone eligible is offered TPT there will obviously be increased costs initially but cost saving over time. This looks at cost of treating people with TB, lives saved/ deaths prevented as well as costs to patients.”

For South Africa, he says, it is estimated that we can reduce the number of people with TB by 138 000 by 2050 at an estimated cost of R23 226.90 per TB episode prevented.

Ndjeka says it costs the health department an estimated at R1 498.51 to treat one person with drug-susceptible TB for 6 months and R16 612.82 to treat one person with the standard drug-resistant TB treatment for 6 months. “These costs are for medications alone, which can also go beyond R70 000 depending on the patient and the type of resistant TB. Moreover, when factoring in clinical consultations, hospitalisations, and costs to patients the costs go up considerably,” he says.

The cost of providing TPT also depends on the regimen. One person on TPT can cost as little as R608.77 for a course of three months of isoniazid and rifapentine given once weekly, and up to R1 358.02 for 12 months of isoniazid. “TPT also has much lower associated costs for example there is no hospitalisation, fewer clinic visits and consultations,” Ndjeka says.

“By preventing TB, the cost of TB treatment is avoided along with the costs of treating some of the acute and chronic conditions that someone with TB may experience even after being cured of TB. These include chronic obstructive pulmonary disease, bronchiectasis and pneumonia,” says Alison Best, communication manager at Cape Town-based NGO TB HIV Care.

“For children under five in particular, who are at increased risk of disseminated TB like TB meningitis, the cost of not preventing TB could be death or severe lifelong disability,” she says, adding that preventing TB in a single individual also prevents the costs associated with any onwards transmission of TB from that individual to others.

Questions over implementation

Expanded TPT eligibility has been widely welcomed, but questions have been raised over how well the new guidelines are being implemented.

Best says government austerity measures have made implementing new initiatives in the healthcare setting challenging.

“There is not much political will to implement the guidelines (to expand eligibility for TPT) at provincial and district levels and this has translated into the slow release of circulars, delays in training health workers, poor knowledge of the policy and its low prioritisation,” she says.

Ingrid Schoeman, Director of Advocacy and Strategy at TB Proof (a local advocacy group), says often when a national policy is released, there are delays at provincial-level in releasing circulars to enable health worker training.

“This results in these services not being available at district-level. In the Western Cape, civil society organisations, the [provincial] Department of Health, City of Cape Town and implementing partners are now all working together to support health worker training, and implementing community-led awareness campaigns so that all close TB contacts know they are eligible for TPT,” she says.

Best adds that tracking the data to show how many people are starting and completing TPT tends to be difficult. She notes there are many gaps in capturing the information. This includes, at times, the limited recording of information in patient folders by clinicians and suboptimal inputting of data by data capturers.

Ndjeka says the national department of health has been conducting training on the new guidelines with provincial and district TB and HIV programme managers, district support partners and other trainers.

“They are then responsible for training health care workers. The antiretroviral therapy guideline training also includes TPT. Webinars on the knowledge hub (an online training platform) have also conducted,” he says.

However, Ndjeka conceded that there is a lack of awareness about the value of TPT. “Additionally,” he says, “there is reluctance from clinicians to provide TPT. This result in poor demand for TPT. Treatment adherence is another problem especially for people on the long regimen (12 months)”.

Plans to address these challenges, among other things, include marketing TPT as treatment for TB infection rather than prevention, targeted communication strategies, community mobilisation, and ongoing training and mentoring of healthcare workers, says Ndjeka.

Republished from Spotlight under a Creative Commons licence.

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Extreme Heat Linked to Children’s Asthma Hospital Visits

Credit: Pixabay CC0

For children seeking care at a California urban paediatric health centre, extreme heat events were associated with increased asthma hospital visits, according to research published at the ATS 2024 International Conference.

“We found that both daily high heat events and extreme temperatures that lasted several days increased the risk of asthma hospital visits,” said corresponding author Morgan Ye, MPH, research data analyst, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco School of Medicine. “Understanding the impacts of climate-sensitive events such as extreme heat on a vulnerable population is the key to reducing the burden of disease due to climate change.”

Ms Ye and colleagues looked at 2017-2020 electronic health records from the UCSF Benioff Children’s Hospital Oakland, which included data on asthma hospital visits by patients of the hospital, some of whom are from Benioff Oakland’s Federally Qualified Health Center, and demographics including patients’ zip codes. They used data from the PRISM Climate Group of Oregon State University to determine the timing of daily maximum (daytime heat waves) and minimum (nighttime heat waves) for each zip code. The researchers restricted their analyses to the region’s warm season (June to September). To evaluate the potential range of effects of different heat wave measurements, they used 18 different heat wave definitions, including the 99th, 97.5th and 95th percentile of the total distribution of the study period for one, two or three days.

They designed the study in a way that allowed them to determine the association between each heat wave definition and a hospital visit. They repeated the analysis for Bay Area and Central California zip codes.

The team discovered that daytime heat waves were significantly associated with 19% higher odds of children’s asthma hospital visits, and longer duration of heat waves doubled the odds of hospital visits. They did not observe any associations for night-time heat waves.

According to Ye, “We continue to see global temperatures rise due to human-generated climate change, and we can expect a rise in health-related issues as we observe longer, more frequent and severe heat waves. Our research suggests that higher temperatures and increased duration of these high heat days are associated with increased risk of hospital visits due to asthma. Children and families with lower adaptation capacity will experience most of the burden. Therefore, it is important to obtain a better understanding of these heat-associated health risks and susceptible populations for future surveillance and targeted interventions.”

The authors note that past research has suggested positive associations between extreme heat and asthma, but findings regarding hospitalisations and emergency room visits have been conflicting. Additionally, many other studies have focused on respiratory hospitalizations and not hospitalizations for asthma, specifically, and have not included or had a focus on children. This study is also unique because it investigated the effect of daily high temperatures but also the effects of persistent extreme temperatures.

The San Francisco Bay Area and California overall are unique areas of interest because the state is considered a coastal region with less prevalence of cooling units, such as air conditioners. While temperatures may not reach the extremes experienced in other parts of the country, this study demonstrates that even milder extreme heat temperatures may significantly impact health. These effects are more pronounced in climate-susceptible populations, including children and those who are medically vulnerable, such as those served by the urban paediatric health centre in this study. The authors hope these study results will lead to more equitable health outcomes and reduce racial/ethnic disparities observed in climate-sensitive events.

“These results can be used to inform targeted actions and resources for vulnerable children and alleviate health-related stress during heat waves,” they conclude.

Source: American Thoracic Society

SA’s Flu Rates Anticipated to Return to Pre-COVID-19 Levels

Creative artwork featuring colourised 3D prints of influenza virus (surface glycoprotein hemagglutinin is blue and neuraminidase is orange; the viral membrane is a darker orange). Note: Not to scale. Credit: NIAID

By Elri Voigt for Spotlight

COVID-19-related factors resulted in several years of lower-than-normal rates of the flu, but experts say that is now something of the past. As this year’s flu season gets under way, Elri Voigt asks several local experts what their expectations are, which flu vaccines are available this year, and whether we should be concerned about new strains of bird flu.

While most people who get the flu experience only mild to moderate symptoms, some can get severe symptoms and even die, especially the very young and the old. As Spotlight previously reported, the influenza virus causes around 11 000 deaths per year in South Africa, with around 40 000 people hospitalised.

Dr Sibongile Walaza, a medical epidemiologist and the Head of Epidemiology at the Centre for Respiratory Disease and Meningitis at the National Institute for Communicable Diseases (NICD), says that it is difficult to predict what a flu season will look like beforehand.

Nicole Jennings, spokesperson for the South African Pharmaceutical company Pharma Dynamics, agrees. “Influenza is a global disease and the spread of the virus in other parts of the world can influence the trajectory of flu seasons in different regions. For now, it’s too early to make any predictions,” she says.

It is difficult to predict the trajectory of flu seasons ahead of time, Jennings says, because of a “complex interplay” of factors, including the fact that influenza viruses are constantly mutating. This makes it difficult to accurately predict which strains of the influenza virus will dominate and how they will behave.

“The level of immunity in the population can also vary from year to year due to factors, such as vaccination rates, previous exposure to similar strains and so forth,” she adds. “However, surveillance efforts, modelling and ongoing research conducted by the NICD can help the public to prepare for the cold and flu season as best possible.”

NICD guidelines published in April 2023 already stated that since the COVID-19 pandemic, there have been some changes in the timing of flu transmission.

The transmission reduction strategies – like masking and social distancing – during the pandemic had an impact on the rates of flu transmission and the duration of the flu season between 2020 to 2022, according to Dr Jocelyn Moyes, a medical epidemiologist at the Centre for Respiratory Disease and Meningitis at the NICD.

Back to normal?

Although the numbers were still much lower, it appears that the winter flu season’s peak had started to return to levels seen pre-COVID-19 in 2022 and 2023, Walaza confirms.

“In 2023, the flu season was a little bit longer than we’d seen before [COVID-19], but it started on time. So, in terms of the timing, it was similar to what we would see before COVID-19,” she says.

When exactly the winter flu season starts each year varies, Walaza says, but on average it can start anytime from the third week of April and can circulate until August. It has been known to go on longer though.

At the time of the interview, the NICD had only detected sporadic cases of flu but had not yet seen the sustained uptick in transmission which usually signals the start of the flu season. The latest surveillance data published by the NICD indicate that 108 cases of influenza had been detected so far this year. The real number of flu cases will be much higher since most cases of flu are not diagnosed.

This year’s vaccines

Walaza explains that the flu vaccine is updated each year based on the World Health Organization’s (WHO) recommendations. This is to ensure it provides protection against evolving influenza viruses seen in global surveillance programmes.

Photo by National Cancer Institute

Flu shots used in South Africa are inactivated influenza vaccines. This means they do not contain live virus and cannot cause flu.

In the public healthcare sector, the government this year procured the trivalent vaccine which protects against three strains of the influenza virus – two influenza A strains (H1N1pdm 2009 and H3N2) and one influenza B strain (known as the B/Victoria), Walaza says. These jabs should be in public health clinics by the first week of May.

In the private healthcare sector, she says a trivalent and a quadrivalent vaccine are available. The quadrivalent shot includes protection against a second influenza B strain (B/Yamagata), but that strain has not been seen circulating in a few years. These flu shots are already available in the private healthcare sector.

The level of protection provided by the flu shot varies and generally it ranges in effectiveness against infection from about 30% to 60%, according to Walaza, but importantly it protects against severe illness.

How effective this year’s flu shot will be depends on which influenza strain or strains circulate in the country. “The hope is that if an individual gets infected by any of those strains [in the vaccine], then that individual is protected or has some level of protection [against these strains] and will have some protection against severe illness” she says.

However, she adds, it’s difficult to predict how effective this year’s flu shot will be against preventing someone from getting the flu or experiencing symptoms of the flu. This is because there is always the chance that the strains which do circulate this season are different from the ones in the vaccine or have mutated so the shot becomes less effective.

Should we worry about bird flu?

At the start of April, the WHO reported that one case of avian influenza A (H5N1), one of the avian/bird flu viruses, had been detected in a person in the United States after they had come into contact with a cow who was presumed to be infected. This was the second human case of influenza A (H5N1) detected in that country, and the first case of a person being infected with this strain after coming into contact with a non-avian species.

So far, the risk to the general public is low, according to the WHO.

“Since the virus [avian influenza A (H5N1)] has not acquired mutations that facilitate transmission among humans and based on available information the WHO assesses the public health risk to the general population posed by this virus to be low and for occupationally exposed persons, the risk of infection is considered low-to-moderate,” the WHO statement said.

There are many subtypes of influenza A viruses, Moyes tells Spotlight, and avian influenzas are similar to human influenza A viruses. And so, she explains, there is always a possibility that these viruses mutate, enabling them to infect humans, or more importantly develop the ability to transmit effectively from one person to another. This could potentially cause a pandemic.

She tells Spotlight that over the last decade sporadic cases of human avian influenza have been described related to global outbreaks in birds. These cases have all been in people who have had very close contact – usually during the culling process – with sick birds. She advises that people involved in the management of avian influenza outbreaks take precautions, such as using appropriate personal protective equipment to prevent infection.

When asked whether people in South Africa need to be concerned about a potential bird flu outbreak, Walaza says so far, no cases of bird flu infection in humans – even during the recent widespread outbreaks in birds – have been identified in the country. But it is something that the NICD is aware of and surveillance for human cases during outbreaks of bird flu in the country is being conducted.

“What’s important though to note is that even when cases have been detected [in other countries] the risk of person-to-person transmission is extremely low,” she adds.

Launch of Cough Watch SA

Walaza tells Spotlight that most of the data gathered by the NICD on influenza is from surveillance in healthcare facilities, which means that not all cases of influenza are necessarily identified.

To gather additional data, the NICD is in the process of rolling out an additional digital surveillance system to detect influenza cases, called Cough Watch SA. This online web application allows the public to report influenza symptoms.

People who sign up are asked to provide basic demographic data like age and postal code. Participants will then be sent a weekly prompt asking if they’ve had any flu symptoms. If they have had symptoms, according to Walaza, then they will be asked to provide more information. This data will then be linked to the NICD database where it will be compared to other surveillance data to see if the platform could serve as an early warning system for a flu outbreak.

Cough Watch SA will be launched in the week of 7 May, says Moyes, who urged the public to help keep an eye on flu by signing up.

Republished from Spotlight under a Creative Commons licence.

Source: Spotlight

To Beat Lung Fibrosis, Researchers Turn to Body’s own Healing Powers

Photo by Robina Weermeijer on Unsplash

The most common type of lung fibrosis is idiopathic – of unknown cause. Researchers are urgently trying to find ways to prevent or slow idiopathic pulmonary fibrosis (IPF) and related lung conditions, which can cause worsening shortness of breath, dry cough, and extreme fatigue. Average survival following diagnosis of IPF is just three to five years, and the disease has no cure.

A recent U-M study from a team led by Sean Fortier, MD and Marc Peters-Golden, MD at University of Michigan Medical School uncovers a pathway used during normal wound healing that has the potential to reverse IPF. They published their research in the Journal of Clinical Investigation.

Using a mouse model, they simulated IPF by administering bleomycin, a chemotherapy agent that causes cell injury and confirmed that the resulting lung scarring resolved itself over the span of about six weeks.

Because of this, “studying fibrosis is kind of tough,” said Fortier. “If we’re going to give experimental drugs to try and resolve fibrosis, we have to do it before it resolves on its own.

Otherwise, we will not be able to tell if the resolution was the action of the drug or natural repair mechanisms of the body.”

However, he said, “there’s actually a lot to learn about how the mouse gets better on its own. If we can learn the molecular mechanisms by which this occurs, we may uncover new targets for IPF.”

The process by which lung injury either leads to healing or fibrosis relies in part on what happens to fibroblasts – cells which forms connective tissue.

During injury or illness, fibroblasts are activated, becoming myofibroblasts that form scar tissue by secreting collagen. When the job is done, these fibroblasts must be deactivated, or de-differentiated, to go back to their quiet state or undergo programmed cell death and be cleared.

“This is the major distinction between normal wound healing and fibrosis – the persistence of activated myofibroblasts,” explained Fortier. That deactivation is controlled by molecular brakes. The study examined one of these brakes, called MKP1 – which the team found was expressed at lower levels in fibroblasts from patients with IPF.

By genetically eliminating MKP1 in fibroblasts of mice after establishing lung injury, the team saw that fibrosis continued uncontrolled.

“Instead of at day 63, seeing that nice resolution, you still see fibrosis,” said Fortier.

“We argued by contradiction: when you knock out this brake, fibrosis that would otherwise naturally disappear, persists and therefore MKP1 is necessary for spontaneous resolution of fibrosis.”

They performed several additional studies using CRISPR techniques to demonstrate how MKP1 applies the brakes, mainly by deactivating the enzyme p38α, which is implicated in a cell’s reaction to stress.

Furthermore, they demonstrated that neither of the two current FDA approved drugs for lung fibrosis, pirfenidone and nintedanib, are able to turn off myofibroblasts.

“That’s totally in keeping with the fact that they do slow the progression, but they don’t halt or reverse disease,” said Fortier.

Fortier hopes the discovery that this pathway reverses fibrosis leads to exploration of additional brakes on fibrosis.

“So much work on fibrosis has focused on how we can prevent it, but when a patient presents to my clinic with a dry cough, shortness of breath, and low oxygen as a result of underlying IPF, the scarring is already present. Of course, we’d love a way to prevent the scarring from getting worse, but the Holy Grail is to reverse it.”

Source: Michigan Medicine – University of Michigan

Large Study Finds Antibiotics are Ineffective for Most Lower Respiratory Tract Infections

Photo by Robina Weermeijer on Unsplash

Use of antibiotics provided no measurable impact on the severity or duration of coughs, even if a bacterial infection was present, finds a large prospective study of people seeking care for lower-respiratory tract infections. The study by researchers at Georgetown University Medical Center and colleagues appeared in the Journal of General Internal Medicine.

“Upper-respiratory tract infections usually include the common cold, sore throat, sinus infections and ear infections and have well established ways to determine if antibiotics should be given,” says the study’s lead author, Dan Merenstein, MD, professor of family medicine. “Lower-respiratory tract infections tend to have the potential to be more dangerous, since about 3% to 5% of these patients have pneumonia. But not everyone has easy access at an initial visit to an X-ray, which may be the reason clinicians still give antibiotics without any other evidence of a bacterial infection. Plus, patients have come to expect antibiotics for a cough, even if it doesn’t help. Basic symptom-relieving medications plus time brings a resolution to most people’s infections.”

The antibiotics prescribed in this study for lower-tract infections were all appropriate, commonly used antibiotics to treat bacterial infections. But the researchers’ analysis showed that of the 29% of people given an antibiotic during their initial medical visit, there was no effect on the duration or overall severity of cough compared to those who didn’t receive an antibiotic.

“Physicians know, but probably overestimate, the percentage of lower-tract infections that are bacterial; they also likely overestimate their ability to distinguish viral from bacterial infections,” says Mark H. Ebell, MD, MS, a study author and professor in the College of Public Health at the University of Georgia. “In our analysis, 29% of people were prescribed an antibiotic, while only 7% were given an antiviral. But most patients do not need antivirals, as there exist only two respiratory viruses where we have medications to treat them: influenza and SARS-CoV-2. There are none for all of the other viruses.”

To determine if there was an actual bacterial or viral infection present, beyond the self-reported symptoms of a cough, the investigators confirmed the presence of pathogens with advanced lab tests to look for microbiologic results classified as only bacteria, only viruses, both virus and bacteria, or no organism detected. Very importantly, for those with a confirmed bacterial infection, the length of time until illness resolution was the same for those receiving an antibiotic versus those not receiving one –about 17 days.

Overuse of antibiotics can result in dizziness, nausea, diarrhoea and rash, along with about a 4% chance of serious adverse effects including anaphylaxis, which is a severe, life-threatening allergic reaction; Stevens-Johnson syndrome, a rare, serious disorder of the skin and mucous membranes; and Clostridioides difficile-associated diarrhoea. The World Health Organization considers antibiotic resistance to be a major an emerging threat.

“We know that cough can be an indicator of a serious problem. It is the most common illness-related reason for an ambulatory care visit, accounting for nearly 3 million outpatient visits and more than 4 million emergency department visits annually,” says Merenstein. “Serious cough symptoms and how to treat them properly needs to be studied more, perhaps in a randomized clinical trial, as this study was observational and there haven’t been any randomized trials looking at this issue since about 2012.”

Source: Georgetown University School of Medicine

Landmark Study Supports Use of Cystic Fibrosis Drug in Infants from Four Weeks of Age

Photo by William Fortunato on Pexels

A cystic fibrosis drug targeting the basic defect that causes the condition has been shown to be safe and effective in newborns aged four weeks and above, new research involving RCSI University of Medicine and Health Sciences and Children’s Health Ireland has found.

The finding is described as a “huge moment” for cystic fibrosis by one of the lead researchers. The study included the first baby in the world with cystic fibrosis to be diagnosed from birth and enrolled directly onto a trial of this sort.

The drug, ivacaftor (Kalydeko), is the first drug designed to treat the basic defect in cystic fibrosis. It was originally approved for adults, then sequentially over several years for older and younger children. Currently, it is approved for babies aged four months and older, however, this new research suggests that it is safe and effective for babies as young as four weeks of age.

Cystic fibrosis experts predict that the earlier treatments can begin, the more likely that progression of the condition can be slowed down or halted in children, and this is the focus of several international research studies led by RCSI and Children’s Health Ireland. The findings of this study could pave the way for eligible newborns to start treatment on the medicine at the time of diagnosis (typically at newborn screening) rather than having to wait until they are four months old.

“This is a huge moment in cystic fibrosis,” said Paul McNally, Associate Professor of Paediatrics at RCSI and Consultant in Respiratory Medicine at CHI. McNally is one of the authors of the new study which was published in the Journal of Cystic Fibrosis.

“Over the years ivacaftor, or Kalydeko, has been put through clinical trials in younger and younger children. Now, through this study, it has been shown to be safe and effective all the way down to four weeks of age,” he said.

“This is an important development because almost all children are diagnosed through newborn screening at around this time. The availability of a treatment that targets the underlying cause of the disease in newborns and can be started immediately at diagnosis will provide a huge sense of reassurance and hope for families.”

Cystic fibrosis is an inherited disease that mainly affects the lungs and digestive system. Ireland has the highest incidence of the condition in the world: approximately 1400 children and adults in Ireland live with the condition and more than 30 new cases of cystic fibrosis are diagnosed here each year, typically around four weeks of age through the newborn screening programme.

In recent years, new medicines have emerged that target the basic defect that causes cystic fibrosis. Ivacaftor (Kalydeko) is one such treatment. It targets a genetic change seen in around 4% of people with cystic fibrosis worldwide, and around 10% in Ireland.

Siblings Kara (aged 5) and Isaac Moss (aged 2) both participated in the study through Children’s Health Ireland. Kara was part of an earlier phase of the study that paved the approval of the drug in older infants and led to the latest trial that Isaac took part in.

Isaac was the first baby with cystic fibrosis in the world to be diagnosed from birth and enrolled directly onto a trial of these ground-breaking treatments.

“Both Kara and Isaac are doing really well and remarkably are not experiencing any of the typical symptoms of cystic fibrosis at the moment,” said their mother Debbie.

“Research studies like this one are so important to ensuring that children get access to the right treatments as early as possible. With the right medications, they can enjoy a healthy childhood and look forward to a brighter future”

Ivacaftor is manufactured by pharmaceutical company Vertex Pharmaceuticals, who are currently applying to the European Medicines Agency for an extension to the marketing authorization for Ivacaftor down to one month of age.

The study involved researchers from RCSI, Children’s Health Ireland, the U.S. and the UK.

Source: RCSI

Limiting the Damage from an Asthma Attack could Halt the Disease

Credit: Pixabay CC0

Scientists at King’s College London have discovered that the features of asthma attacks, a disease usually treated as being inflammatory, in fact stem from constriction of airways, making breathing difficult. The new study, published in Science, shows for the first time that many features of an asthma attack – inflammation, mucus secretion, and damage to the airway barrier that prevents infections – result from this mechanical constriction in a mouse model.

The findings suggest that blocking a process that normally causes epithelial cell death could prevent the damage, inflammation, and mucus that result from an asthma attack.

Professor Jody Rosenblatt from King’s College London said: “Our discovery is the culmination of more than ten years work. As cell biologists who watch processes, we could see that the physical constriction of an asthma attack causes widespread destruction of the airway barrier. Without this barrier, asthma sufferers are far more likely to get long-term inflammation, wound healing, and infections that cause more attacks. By understanding this fundamental mechanism, we are now in a better position to prevent all these events.”

Asthma symptoms include wheezing, coughing, feeling breathlessness and a tight chest. Triggers such as pollen or dust can make asthma symptoms worse and can lead to a life-threatening asthma attack.

Despite the disease commonality, the causes of asthma are still not understood. Current medications treat the consequences of an asthma attack by opening the airways, calming inflammation, and breaking up the sticky mucus which clogs the airway, which help control asthma, but do not prevent it.

The answer to stopping asthma symptoms may lie in cell extrusion, a process the researchers discovered that drives most epithelial cell death. Scientists used mouse lung models and human airway tissue to discover that when the airways contract, known as bronchoconstriction, the epithelial cells that line the airway get squeezed out to later die.

Because bronchoconstriction causes so many cell extrusions, it damages the airway barrier which causes inflammation and excess mucus.

In previous studies, the scientists found that the chemical compound gadolinium can block extrusion. In this study, they found it could work in mice to prevent the excess extrusion that causes damage and inflammation after an asthma attack. The authors note that gadolinium has not been tested in humans and has not been deemed to be safe or efficacious.

Professor Rosenblatt said: “This constriction and destruction of the airways causes the post-attack inflammation and excess mucus secretion that makes it difficult for people with asthma to breathe.

“Current therapies do not prevent this destruction – an inhaler such as Albuterol opens the airways, which is critical to breathing but, dishearteningly, we found it does not prevent the damage and the symptoms that follow an attack. Fortunately, we found that we can use an inexpensive compound, gadolinium which is frequently used for MRI imaging, to stop the airway damage in mice models as well as the ensuing inflammation and mucus secretion. Preventing this damage could then prevent the build-up of musculature that cause future attacks.”

Professor Chris Brightling from the University of Leicester and one of the co-authors of the study said: “In the last decade there has been tremendous progress in therapies for asthma particularly directed towards airway inflammation. However, there remains ongoing symptoms and attacks in many people with asthma. This study identifies a new process known as epithelial extrusion whereby damage to the lining of the airway occurs as a consequence of mechanical constriction and can drive many of the key features of asthma. Better understanding of this process is likely to lead to new therapies for asthma.”

The discovery of the mechanics behind cell extrusion could underlie other inflammatory diseases that also feature constriction such as cramping of the gut and inflammatory bowel disease.

Source: King’s College London

What we can Learn about TB at the Autopsy Table

Credit: Scientific Animations CC4.0

By Tiyese Jeranji for Spotlight

In addition to shedding light on what people actually die of, autopsies can also play an important role in helping us to better understand disease. Tiyese Jeranji unpacks tuberculosis-related autopsy research in the Western Cape and delves into some of the fascinating complexities of this branch of TB research.

Figuring out how many people in South Africa die every year of tuberculosis (TB) is not straight-forward. On the one hand, Stats SA’s frequent mortality reports put the number at under 30 000, on the other hand, the World Health Organization (WHO) estimates that it is over 50 000.

While this may at first glance seem like a large discrepancy, there is a simple explanation. The Stats SA figures are based on what is written on death notifications, and these notifications very often do not tell the full story of what a person died of. The WHO estimate, is derived using mathematical modelling that triangulates estimates based on several data sources.

Looking at the numbers from studies that determine the cause of death (or what people actually died of) is one of the ways we know that relying on death notifications result in an undercount of TB deaths. Such autopsy studies have consistently found that many people had undiagnosed TB at the time of death and that the undiagnosed TB was often the actual cause of death.

One review study published in the journal AIDS concluded that “in resource-limited settings, TB accounts for approximately 40% of facility-based HIV/AIDS-related adult deaths” and that “almost half of this disease remains undiagnosed at the time of death”. According to WHO figures, of the estimated 280 000 people who fell ill with TB in South Africa in 2022, over 65 000 were not diagnosed.

Importance of autopsy research

Dr Muhammad Osman, Academic Portfolio Lead and Senior Lecturer: Public Health at the University of Greenwich, tells Spotlight that it is important to do TB autopsy studies because it enables us to identify TB that was not diagnosed during life – and this helps us understand the true burden of the disease.

Osman says identifying TB at autopsies has significant benefits. He says by overlaying health seeking behaviour (how people visit clinics), we can identify missed opportunities for TB screening and design interventions to improve screening for TB. “We could trace family contacts of the deceased and offer TB screening and prevention. This is not taking place at present,” he says.

Osman and his colleagues published a paper in the International Journal of Infectious diseases in 2021  looking at TB in people with sudden unexpected death (SUD) in Cape Town. They found that active TB was identified at post-mortems in 6.2% of the 770 cases they studied. More strikingly, in around 92% of those cases the TB had not been diagnosed while the person was alive.

Osman says that these days there is an increasing awareness of undiagnosed and untreated TB. He points out that new interventions to improve TB testing and diagnosis have been implemented such as targeted universal testing — an approach by which people who do not have any TB symptoms, but who are considered to be at high risk of TB, are routinely offered TB tests.

He says these days healthcare worker risk is considered more carefully and he stresses the importance of protecting forensic and pathology teams. (Forensics focuses on determining the cause and manner of death while  pathology  is the study and diagnosis of disease through examination of tissue, cells, autopsies, and so on.)

Closing the gaps

Osman says their study also identified a gap between the pathology services and access to routine health service records. “We thought that this is an essential gap to close – the forensic/pathology services need access to routine health service. For a limited number of these deaths we were able to match their records to the public health clinic and hospital records – and many of them had contact with the health services in the six months before death,” he says.

“If forensic pathologists are given full access to the health records, they would know the timing of previous TB and the treatment outcomes of those episodes. The lung changes seen with TB are different in the case of active TB and healed/recovered TB. There are well documented macroscopic (what’s is seen by the examination) and microscopic (seen through histology and microbiology) findings,” says Osman.

A complex disease

The study of TB is complicated by the fact that TB can occur at several stages on a continuum and can impact several different parts of the body.

Professor Threnesan Naidoo, research pathologist at the African Health Research Institute (AHRI), tells Spotlight that when people think of TB, they usually think of the person who’s been coughing for a few months, loss of weight, loss of appetite, having night sweats, and maybe coughing up some blood. “But there’s a journey to that point and then generally beyond that point, and clinically, there’s a continuum of the disease. We refer to it as latent disease, subclinical, active and then healed TB,” he says. It is an area in which things are changing fast – a paper published in the Lancet medical journal last week proposed dividing TB into five stages.

Naidoo says autopsies provide an opportunity to study TB at different stages (latent, subclinical, active, healed) especially when someone with TB dies of another cause. He says they  can encounter people at any stage along the TB continuum because at any point someone could be shot, stabbed, or involved in a motor vehicle accident. “You (pathologist) have a unique opportunity to study the effect of TB on cells and tissue physically under a microscope and not through imaging (x-ray),” Naidoo says.

Autopsies also presents the opportunity to look at TB disease not only in the lung, but also the brain, thyroid gland, kidney or urinary system since TB has the capacity to spread everywhere, explains Naidoo.

“Autopsy gives you the opportunity to study TB everywhere,” he says. “Clinically (when someone is alive), you don’t  go about investigating the entire body. Neither is it practical nor feasible or safe. But [with an] autopsy you’re examining the entire body anyway. We study TB in totality,” he says.

How it is done

The standard manner of doing an autopsy involves a thorough examination of the body. Naidoo explains that the process starts with an external examination to document injuries, marks, and other physical characteristics that are visible. The internal examination involves dissecting organs, tissues, and body cavities to identify any abnormalities or signs of disease. Samples may be taken for further analysis, such as toxicology tests, histological examination, or TB research.

Any findings from the samples, Naidoo notes, must be interpreted taking into account changes that occur in a dead body. “[In] the living, you know, it’s a living person and they’re able to do things and you’re able to see things on imaging (X-Ray), but in the dead you have to account for the fact that the person has now demised and certain changes occur after death.”

Autopsy study at UCT

An ongoing study at the University of Cape Town is exploring the role of lymph nodes in the spread or containment of TB disease by looking at tissue of the deceased.

Much TB research so far have been done on animals and not on humans, points out Dr Virginie Rozot, research officer at the South African TB Vaccine Initiative (SATVI) and co-principal investigator of the UCT study. “We have great non-human primate and great mice studies that try to underline the mechanism of the  disease progression. However, animal models are not a true reflection of what happens in humans.

“For the longest time in these human studies, most studies have been done in the blood and what is happening in the blood has been taken to correlate with what is happening in the lung.”

In short, autopsies allow researchers to look directly at lung, brain and other tissue in a way that simply isn’t feasible in living people.

“So the only way you can actually access tissues is to do post mortem studies. Post mortem studies have been happening since the beginning of last century. And they were like fantastic studies, but the tools were not the same as we have today.  I think that should come back to the front of the scene of research because then you can ask all the questions we’ve been trying to answer on what is happening in the tissue by looking into the blood,” she says. “Autopsy allows us to study the exact part we want to study not just the blood.”

Collecting samples

In collaboration with the Western Cape Forensic Pathology Service, UCT has created  a postmortem sample collection platform to help with TB research. By leveraging the Inquest Act of 1959, which states that people that die of unnatural causes  must undergo a medico-legal investigation to determine the cause of death, Rozot and her team come in to conduct a post-mortem to get their samples. They aim to do the post-mortem in less than 24 hours after death.

Since starting this study about eight months ago, they have done 125 autopsies , with a consent rate of 64%. “I think our consent rate is incredible. We are still putting together our findings to determine how many cases of TB we have found so far by looking at autopsies,” says Rozot.

Representative samples

Dr Laura Taylor, forensic pathologist at the Western Cape Forensic Pathology Services, says the bodies that they look at, in line with the Inquest Act relating to unnatural deaths, are representative of people in South Africa. “However, they are not exactly representative of the entire South African population because there are certain socio economic groups that are more likely to die of unnatural deaths due to increased prevalence of trauma and violence in their communities,” she says.

Because there is no central database, Taylor couldn’t say how many cases of TB they find among the deceased. “[T]here are autopsy records or reports which are written for each case, but there is no central database for TB specifically detected [through] autopsy,” she says.

Forensic autopsy and other diseases

Rozot and Naidoo share the view that, if done well, TB autopsy studies can help shed light on other diseases.

The value of this information is that people dying with or from TB will also have any of  the other conditions such as hypertension, HIV, and diabetes, Naidoo says.

“You can work out all those variables… [people] don’t just come with diabetes, the diabetes changes the face of TB, HIV changes the face of TB and TB changes the face of those diseases as well. So, the complexity of it becomes something that we need to pay attention to, and look at all the common variables, like the association of TB and HIV is a big one. So studies might look at HIV infection and how it may affect TB and vice versa. Same with diabetes, hypertension, any of the other non-communicable diseases as well,” he concludes.

Republished from Spotlight under a Creative Commons licence.

Source: Spotlight

New Enzymatic Cocktail can Kill Tuberculosis-causing Mycobacteria

Mycobacterium tuberculosis drug susceptibility test. Photo by CDC on Unsplash

With resistance to chemical antibiotics on the rise, the world needs entirely new forms of antibiotics. A new study published in Microbiology Spectrum, a journal of the American Society for Microbiology, shows that an enzymatic cocktail can kill a variety of mycobacterial species of bacteria, including those that cause tuberculosis. The research was carried out by scientists at Colorado State University and Endolytix Technologies.

“We have a mycobacterial drug that works for Nontuberculous Mycobacteria and M. tuberculosis that is biological, not phage therapy, and not small molecule antibiotics,” said Jason Holder, Ph.D., a study coauthor and Founder and Chief Science Officer at Endolytix Technology.

“Mycobacterial infections are particularly hard to treat due to poor efficacy with standard of care drugs that are used in multidrug regimens resulting in significant toxicities and treatments lasting 6 months to years. This is often followed up by reemergence of the bacterial infection after a year of testing negative.”

In the new proof of principle study, the researchers took a biological approach instead of a chemical one to develop a cocktail of enzymes that attack the cell envelope of mycobacteria.

The cocktail of enzymes contains highly specific biochemical catalysts that target and degrade the mycobacteria cell envelope that is essential for mycobacterial viability.

To increase efficacy, the researchers delivered the enzymatic drug inside of host macrophages where mycobacteria grow. In laboratory experiments, the drug was effective against M. tuberculosis and Nontuberculous Mycobacteria (NTMs), both lethal pulmonary lung diseases (PD). TB kills roughly 1.5 million people per year.

“We characterised the mechanism of bactericide as through shredding of the bacterial cells into fragments,” Holder said.

“We’ve shown we can design and develop biological antibiotics and deliver them to the sites of infection through liposomal encapsulation. By combining drug delivery science with enzymes that lyse bacteria, we hope to open up treatment options in diseases such as NTM pulmonary disease, tuberculosis pulmonary disease and others.”

According to study coauthor Richard Slayden, PhD, a professor in the Department of Microbiology, Immunology and Pathology at Colorado State University, the new therapy complements current standard-of-care drugs and does not have many of the drug-drug interactions that are problematic with many anti-mycobacterial drugs in use. “Endolytix enzymes work powerfully with standard-of-care antibiotics to kill bacteria with lower drug concentrations,” Holder said. “This has the potential to reduce the significant toxicities associated with multi-drug regimens that are the standard for mycobacterial infections and hopefully lead to more rapid cures.”

Source: American Society for Microbiology

Massive TB Vaccine Trial Kicks off in SA – it could be the First TB Vaccine in over a Century

A massive and long-awaited study of an experimental tuberculosis vaccine has kicked off in South Africa. Marcus Low reports.

Photo by National Cancer Institute

By Marcus Low for Spotlight

The first jabs in a much-anticipated clinical trial of an experimental tuberculosis (TB) vaccine have been administered at a clinical trial site at the University of the Witwatersrand in Johannesburg. Up to 20 000 people are anticipated to take part in the study, according to study sponsor, the Bill and Melinda Gates Medical Research Institute (Gates MRI).

The study will be conducted at 60 different sites in South Africa, Zambia, Malawi, Mozambique, Kenya, Indonesia, and Vietnam. The researchers estimate that between 50% and 60% of the study participants will be in South Africa.

The experimental vaccine called M72/AS01E (M72 for short) made waves in 2018 and 2019  when it was found to be around 50% effective at preventing people with latent TB infection from falling ill with TB over a three-year period in a phase 2b clinical trial. In June 2023, it was announced that, after some delays, $550 million in funding had been secured for a phase 3 study of the vaccine. Medicines or vaccines are typically only registered and brought to market after being shown to be safe and effective in large, phase 3 clinical trials.

While most cases of TB can be cured using a combination of four antibiotics for four or six months, TB rates are declining relatively slowly and it is widely thought that an effective vaccine would help bring TB rates down much more quickly. The World Health Organization estimates that at the level of protection seen in the phase 2b trial, the vaccine could potentially save 8.5 million lives and prevent 76 million people from falling ill with TB over a 25-year period. The one TB vaccine we already have, called bacille Calmette-Guerin (BCG), is over a century old and only provides limited protection against severe illness for children and no protection for adolescents or adults.

“Reaching Phase 3 with an urgently needed TB vaccine candidate is an important moment for South Africans because it demonstrates that there is a strong local and global commitment to fight a disease that remains distressingly common in our communities,” said Dr Lee Fairlie,  national principal investigator for the trial in South Africa, in a media statement released by Gates MRI.

“South Africa also has considerable experience with TB- and vaccine-related clinical trials and a strong track record for protecting patient safety and generating high quality data essential for regulatory approvals.”

Fairlie is also the Director of Maternal and Child Health at the Wits Reproductive Health and HIV Institute at Wits University.

The initial response from TB activists was positive.

“TB Proof (a South African TB advocacy group) is delighted that the M72 phase 3 trial has been launched,” the organisation’s Ruvandhi Nathavitharana and Ingrid Schoeman told Spotlight.  “Having an effective TB vaccine is critical for TB elimination efforts.”

While he said it is good to finally see the phase 3 trial of M72 get underway, Mike Frick, TB co-director at Treatment Action Group, a New York-based TB advocacy organisation, went on to say:

“The fact that we had to wait so long between phase II and phase III says everything one needs to know about the headwinds – financial, political, commercial – that TB research is up against.”

How the study will work

Half of the up to 20 000 study participants will receive the M72 jab and the other half a placebo. The vaccine is administered as two intramuscular injections given a month apart. After being jabbed, study participants, all aged 15 to 44, will be followed for four years from the date of the first study participant being enrolled to see if they fall ill with TB.

“The plan is to complete enrolment in 2 years,” Fairlie and Alemnew Dagnew, clinical lead for the trial, told Spotlight in response to written questions. They explained that the actual duration of the trial will depend on how long it takes for 110 people in the study to fall ill with TB. According to the Gates MRI statement, the study is expected to take around five years to complete.

According to Fairlie and Dagnew, the majority of study participants (around 18 000 people) will be people who are HIV negative and who have latent TB infection – that is to say people who have TB bacteria in their lungs, but who are not ill with TB. Latent TB infection is thought to be very common in South Africa and only around 10% of people with latent infection ever fall ill with TB. In the study, latent infection will be tested for using a type of test called an IGRA (Interferon-Gamma Release Assay).

Around 1000 HIV negative people with no TB infection will also be recruited to the study. This is being done to make sure the vaccine is safe and effective in this group of people – while latent infection will be tested for in the study, in the real world such testing may not always be feasible prior to vaccination.

It is anticipated that 1000 of the 20 000 study participants will be people living with HIV. Establishing how well the vaccine works in people living with HIV is important since around 13% of people in South Africa are living with HIV and HIV substantially increases the risk of falling ill with TB. The main phase 2b study of M72 did not include people living with HIV although another phase 2 study looked specifically at the safety and immunogenicity of M72 in people living with HIV – according to Fairlie and Dagnew, “that trial “was completed and supported the inclusion of such participants in a phase 3 trial”.

Smaller than previously thought

When funding for the phase 3 trial was announced last year, it was estimated that 26 000 people would participate in the study. That number has now been revised down to 20 000.

“As a result of ongoing discussions between the institute and our funders, the decision was taken to review the study protocol with the intent of simplifying the study given its size and complexity.  This will not affect the safety of the trial. It is common to continue to refine a protocol. We found a way to expedite the study that would potentially allow us to offer the public health impact of this vaccine to those in need sooner. All partners, including the trial funders, are fully aligned to the protocol refinements,” Fairlie and Dagnew explained to Spotlight.

“Some assumptions used to inform the design of the first protocol were deemed overly conservative, so the clinical team used slightly less conservative assumptions on vaccine efficacy and TB incidence rate, thus allowing for a reduction in the number of participants in the trial, while still retaining the primary goal of confirming the safety and efficacy of the M72/AS01-E-4 vaccine for prevention of TB, guided by the final results of the phase 2b study completed several years ago.”

Planning for access

The development of M72 has taken a somewhat unusual path – with the pharmaceutical company GSK leading development up to the end of phase 2b and then largely passing the baton to Gates MRI with the conclusion of a licensing deal in 2020. GSK has come in for some criticism for not moving more quickly after the initial publication of the phase 2b results in 2018. A ProPublica article published last year suggested that the development of M72 slowed because GSK were focussing on more profitable vaccines.

According to the Gates MRI statement, GSK continues to provide technical assistance to the Gates MRI, supplies the adjuvant component of the vaccine for the phase 3 trial, and will provide the adjuvant post licensure should the trial be successful. An adjuvant is an agent included in the vaccine that improves the immune response elicited by the vaccine – in the case of M72/AS01E the AS01E refers to the adjuvant made by GSK.

This ongoing dependence on a single company for the adjuvant has some activists worried. “We are concerned about reports that scaling this vaccine may be difficult due to limited availability of the vaccine adjuvant. Access for everyone who needs it should be part of the early phases of the research process – not an afterthought,” said Nathavitharana and Schoeman.

“The press release announcing the study’s start in several places refers to the ‘complexity’ of ‘developing and ensuring access’ to a new vaccine. Part of the unspoken complexity here is the opaque licensing deal GSK and Gates MRI signed in 2020 in which GSK gave rights to develop and commercialise M72 to Gates MRI while retaining control over the AS01E adjuvant,” Frick told Spotlight. “There are legitimate concerns that the fine print of this arrangement could work against equitable access, but terms of the licence remain unknown to the public.”

When asked about supply concerns, Gates MRI told Spotlight:  “Gates MRI collaboration with GSK includes provisions to ensure there is sufficient supply of adjuvant for the clinical development and first adoption in low-income countries with high TB burden, at an affordable price, should the vaccine candidate be successful in phase 3 trials and approved for use. For broader implementation, GSK has committed to working with its partners to ensure there is sufficient supply.”

Disclosure: The Gates MRI is a non-profit subsidiary of the Bill and Melinda Gates Foundation. Spotlight receives funding from the Bill and Melinda Gates Foundation. Spotlight is editorially independent and a member of the South African Press Council.

Republished from Spotlight under a Creative Commons licence.

Source: Spotlight