A surprising fact is that bitter taste receptors are found not just in the mouth, but elsewhere including the airways. Activating those receptors dilates up lung passageways, making them a potential target for treating asthma or chronic obstructive pulmonary disease (COPD). Now, researchers report in the Journal of Medicinal Chemistry that they have designed a potent and selective compound that could lead the way to such therapies.
Among the 25 different types of bitter taste receptors, the TAS2R14 subtype is one of the most widely distributed in tissues outside the mouth. Scientists are uncertain about the structure of the receptor, and they haven’t identified the particular compound or “ligand” in the body that activates it. However, a few synthetic compounds, such as the nonsteroidal anti-inflammatory drug (NSAID) flufenamic acid, are known to bind to and activate TAS2R14s. But these compounds aren’t very potent, and they don’t have similar structural features. These difficulties make it challenging to create a better ligand. Nevertheless, Masha Niv, Peter Gmeiner and colleagues used flufenamic acid as a starting point to design and synthesise analogues with improved properties. Next, the team wanted to extend that work to develop a set of even better TAS2R14 ligands.
Building on these earlier findings, the researchers made several new variations. They tested these compounds in a cell-based assay that measures receptor activation. This approach revealed that replacing a phenyl ring with a 2-aminopyrimidine and substituting a tetrazole for a carboxylic acid group was a promising strategy. One of the new ligands was six times more potent than flufenamic acid, meaning less of the compound was needed to produce a similar response as the NSAID. This ligand was also highly selective for TAS2R14 compared to non-bitter taste receptors, which could potentially minimise side effects. The researchers speculate that new compounds will help shed light on the structure, mechanism and physiological function of bitter taste receptors and guide development of drug candidates to target them.
Chronic obstructive pulmonary disease (COPD) affects one in 10 adults, reducing quality of life and making physical activity challenging as they struggle to get enough air. Research around a new breathing device developed by pulmonologists at the University of Cincinnati offers promise for improving their lives. The research was published in the journal Respiratory Care.
The device, called PEP Buddy, was created by Muhammad Ahsan Zafar, MD, and Ralph Panos, MD. “Dr Panos and I both see patients with COPD, and it’s a huge population,” says Zafar. “Their life really changes when they have COPD. They were active individuals but now they’re debilitated and limited, so we wanted to come up with something easy that helps improve their life.”
For people with COPD, it takes longer to get inhaled air out of their lungs with each breath due to tighter air tubes. Therefore, when they breathe fast, like during physical activities, air is retained in the lungs. This air stacking or “dynamic hyperinflation” is the main reason for breathlessness and also leads to lower oxygen levels. As the breathing gets difficult during physical activity, people become less and less active and more isolated.
Panos and Zafar developed a hands-free device that is the size of a whistle. Zafar said he looked at positive-expiratory pressure (PEP) breathing devices on the market and they were handheld, big and bulky, so they tried to come up with something that is very simple, lightweight and easy to use. The device is designed to be worn around the neck with a lanyard for day-to-day use and inserted into the mouth when needed, during or after exertion.
In the study, they examined people with COPD who were short of breath and gave them two tasks. “We conducted a six-minute walk test with and without the device,” says Zafar. “They were given the device to take home and use in their daily routines. In two weeks, there was a follow-up to see how PEP Buddy use impacted their shortness of breath and quality-of-life scores.”
The study found 72% of the participants had a significant impact in reducing their shortness of breath and improving their quality of life. Among those who would drop their oxygen levels during walking, 36% of them did not drop oxygen levels when using PEP Buddy. This is the first mechanical device to show such an impact on oxygen levels in people with COPD.
Maja Flannery, a PEP Buddy user with chronic lung disease and airflow obstruction, says the device has changed her day-to-day living.
“I am so happy that I was lucky enough to be part of the study and able to use this great little device to breathe better,” Flannery says. “I use it when I get up in the morning. It helps with the air requirement when changing position from laying down to standing and exercises my lungs to get them more prepared for the day. I find it helpful in getting the trapped air out as I am active, so I can play longer points during tennis, and also recover between points more quickly. My friends at tennis laugh that it is my ‘magic whistle.'”
UC’s Zafar says the next step in this research is to conduct a long-term study to see the impact on the use of rescue inhalers, emergency department visits and long-term symptoms and functional capacity in people with COPD. PEP Buddy may also be a promising addition to pulmonary rehabilitation programs for faster improvement and sustaining better outcomes. They are also exploring other uses of PEP Buddy in health care.
“As a physician I feel gratified that we are providing something new that can actually improve people’s lives,” says Zafar. “That’s where my passion is. These people are really debilitated with not many tools in their hand to improve their symptoms right now. PEP Buddy will be one such tool.”
Cystic fibrosis (CF), which is caused by a faulty gene inherited from one’s parents, is a debilitating disease requiring difficult and time-consuming treatment and resulting in premature death. CF causes mucus in the body to thicken, with often disastrous consequences in organs such as the lungs and pancreas, and triggers a range of symptoms in people living with the condition, including chronic coughing, wheezing, and malnutrition. Ongoing treatment of symptoms often requires children with CF to miss school and can make it difficult for adults with CF to hold steady employment.
Yet, a new class of medicines introduced over the past decade called CFTR modulator therapies offers new hope to people living with CF – dramatically reducing CF’s symptoms and allowing people with CF to live longer healthier, and more productive lives.
These new treatments, whose research and development benefited from significant public and philanthropic financing, have been hailed as a “miracle” for people with CF. As antiretrovirals did for HIV, the introduction of CFTR modulator therapies is transforming cystic fibrosis from a progressive, life-threatening illness into a chronic, manageable condition. CFTR modulator therapies are so effective because they address the underlying cause of cystic fibrosis symptoms – a malfunctioning protein made by the CFTR gene.
But, more than a decade after the introduction of the first CFTR modulator therapy to treat CF in the United States, no CFTR modulator therapies are yet registered in South Africa and only a fraction of patients who need this therapy have access to it, and that is only after jumping through some extraordinary hoops. As a result, the only way for the vast majority of people to manage CF in South Africa is to aggressively prevent and treat its symptoms using older therapies. This is no small task for patients and their families, as it can require time-consuming, daily physical therapy to loosen mucus in the lungs and weeks-long hospital stays to treat infections. In severe cases, treating cystic fibrosis can even require a lung transplant.
Without access to CFTR modulator therapies, people with CF in South Africa continue to die prematurely. The average age of death of people with CF in South Africa was 27.5 in 2020. People in the global North live almost twice as long. The life expectancy of people living with cystic fibrosis in the United States is now 50 and is expected to lengthen as a result of newly introduced treatments.
Why can’t people in South Africa access CFTR modulator therapies?
As a person living with cystic fibrosis, or the parent of a child with cystic fibrosis, it can be unbearable to know there is a medicine that could allow you to breathe easier, keep you or your child out of hospital, and even prevent the need for a lung-transplant or premature death, but that you can’t have it, largely due to decisions taken by one company.
As recently detailed in the New York Times, one company holds a monopoly on the manufacture and sale of CFTR modulator therapies and is choosing not to make new CF treatments available to people in the developing world through the normal channels. Vertex, the company that holds monopoly patents on all available CFTR modulator therapies, is – for the most part – not registering or marketing its CFTR modulator therapies in developing countries. Registration is typically required before a drug can be marketed in a country.
While Vertex does offer some compassionate use and donation access programmes in select developing countries, Vertex Save Us, a global coalitional of advocates seeking affordable and universal access to CFTR modulator therapies, says these efforts reach only a small minority of patients that could benefit from the treatments and are restricted to countries with which Vertex believes it can secure a reimbursement deal.
Some activists suggest that the neglect of patients in developing countries is part of a strategy to squeeze the highest possible prices for CFTR modulator therapies from health systems in wealthy countries, with which Vertex has been locked in extended negotiations. Offering lower prices to developing countries for its CF medicines could provide ammunition to wealthy countries in demanding lower prices.
“This is a really fundamental and really simple example of how unfettered profit-driven business practices basically sacrifice the lives of people, particularly those of people who happen to live in low- and middle-income countries,” says Diarmaid McDonald, medicine access advocate and Director of the UK-based advocacy group, Just Treatment.
Vertex charges over R5 million ($322 000) annually for its most effective CFTR therapy, Trikafta (which must be taken as a life-long treatment) in the United States. But researchers in the United Kingdom have shown that the medicine can be manufactured and profitably marketed at a fraction of that cost.
Does Vertex plan to register its products in South Africa?
In response to queries from Spotlight regarding whether Vertex plans to register its drugs in South Africa and what the timeline for doing this is, the company indicated that they did not plan to register their medicines but would supply them via Section 21 authorisations – a mechanism allowing for importation of unregistered medicines into the country.
“As seen in other rare disease areas, bringing medicines to patients in South Africa is challenging as the reimbursement system and willingness to invest do not support a viable path to sustainable access. Analyses show that most novel, high-value medicines targeting disease areas comparable to and including CF are not on the Prescribed Minimum Benefits (PBM) list. There is therefore no obligation for funders to reimburse the costs of these medicines even after a lengthy regulatory registration process,” said Vertex’s Director of International Communications Daria Munsel.
“Given this, we believe that sustainable access could be achieved through ‘Section 21’ (on a named patient basis), which provides the fastest and most efficient route to access for rare disease medicines in South Africa,” Munsel added. “As part of this effort, we are currently in discussions with relevant stakeholders in the private insurance system to ensure sustainable access is available to eligible CF patients in South Africa.”
However, Munsel declined to identify the local company with which Vertex has signed an agreement for distributing its medicines, saying, “We can confirm that we have recently signed a distribution contract with a local distribution partner for our CF medicine in South Africa. Given that reimbursement conversations are still ongoing, it is inappropriate for us to name other parties for the moment.”
For now, the lack of transparency about the local distributor effectively blocks the use of Section 21 authorisations for importing Vertex’s medicines into South Africa, as patients and clinicians must supply details of local distributors in their applications to the South African Health Products Regulatory Authority (SAHPRA) for authorisation to import unregistered drugs.
Vertex did not respond to a question from Spotlight regarding what price it would charge patients in South Africa able to secure Section 21 authorisations to import their medicines.
Landmark court case seeks to challenge Vertex’s monopoly in South Africa
Vertex has secured a global monopoly over CFTR modulator therapies by aggressively pursuing patents related to the class of drugs around the world. These patents prevent other companies from manufacturing and marketing CFTR modulator therapies and give Vertex wide latitude in setting prices.
Between 2007 and 2016, Vertex filed six patents in South Africa related to the CFTR modulator therapies, Kalydeco and Trikafta. While Vertex received marketing approval to sell Kalydeco and Trikafta to treat CF in the United States in 2012 and 2019, respectively – it has still not applied for registration of either product in South Africa.
What this means is that despite Vertex’s failure to take steps to register or market its medicines in South Africa years after doing so in the US, patents granted to Vertex in South Africa block any other companies from supplying the medicines to CF patients in the country.
“The bottom line is that people are dying, they need to be able to access affordable treatments,” says Kelly du Plessis, founder of Rare Diseases South Africa. “If Vertex isn’t going to be able to come to the party in South Africa, then fine. We respect their choice, but then move out the way and allow someone else to do it. You can’t maintain the market and hold it ransom, but also not do anything from your perspective to help.”
According to Fatima Hassan, director of the Health Justice Initiative, “You can’t have a system where you file your patents, [but then] you refuse to bring a product to market or you have it at such an excessive price in the country with the highest inequality in the world, but then you don’t allow any generic manufacturers to come in at a lower price.”
Cheri Nel, a woman living with cystic fibrosis in South Africa, and the Cystic Fibrosis Association have now gone to court to challenge Vertex’s monopoly. On 7 February 2023, Nel’s lawyers submitted a Notice of Motion to the Court of the Commissioner of Patents (within the High Court) requesting that the court grants a compulsory license to override Vertex’s patents on Kalydeco and Trikafta.
Nel and the Cystic Fibrosis Association are seeking a compulsory license on the grounds that the patents held by Vertex are being abused. Nel’s lawyers argue that by failing to register or supply their CF medicines in South Africa, make them available in South Africa at reasonable prices, or license other companies to supply the medicines, Vertex is abusing its patents. They further argue that Vertex’s actions are violating the Constitutional rights of people with cystic fibrosis in South Africa, including the right to health care.
If granted, a compulsory license in South Africa would effectively override Vertex’s monopoly and allow the importation of generic cystic fibrosis medicines into South Africa, as well as their manufacturing in the country.
The legal action taken in South Africa is being pursued simultaneously with broader global efforts, led by Vertex Save Us, to overcome Vertex’s monopoly on CFTR modulator therapies and ensure universal access for all people who can benefit from these treatments.
“South Africa is the only country where papers have been launched with courts to start a legal process to try and secure a compulsory license, although the process is playing out in other countries following the most logical, legal routes set out in their national law,” explains McDonald.
“Requests of the government to issue compulsory licenses [have been made] in both Ukraine and in Brazil. And in India, it’s a petition of the government requesting that they revoke the patent under the terms of the Indian patent law,” says McDonald.
Any precedent for granting compulsory license on a medicine in South Africa?
If Nel and the Cystic Fibrosis Association’s pursuit of a compulsory license on the cystic fibrosis medicines is ultimately successful, then the issuing of a compulsory license order will be the first time this type of license is granted in the country on a pharmaceutical product. While South Africa has not issued a compulsory license on a medicine, the Treatment Action Campaign (TAC) has previously used competition law to overcome patents impeding access to affordable antiretroviral medicines in South Africa.
TAC cases at the Competition Commission and the threat of ‘compulsory licensing’ resulting from these cases led several multinational companies to grant voluntary licenses that enabled manufacturing and marketing of generic ARVs in the country. Generic competition resulted in massive price decreases for ARVs and has been critical to South Africa’s success in building the world’s largest public sector HIV treatment programme.
While South Africa’s courts have not issued a compulsory license on a medicine, its own challenges in securing access to affordable HIV medicines contributed to the affirmation and strengthening of the rights of countries to issue compulsory licenses to address health challenges within international trade law in the early 2000s. Both developing and developed countries have subsequently used compulsory licensing to improve access to critical health tools under patent including for HIV, cancer, and more recently, COVID-19.
The Fix the Patent Laws coalition, a coalition of over forty patient groups in South Africa, has long called on government to amend South Africa’s patent laws to improve the usability of compulsory licensing provisions to address health challenges in the country. The landmark court case of Nel vs Vertex will provide important insight into the ongoing need for these reforms in the country.
Who can benefit from Kalydeco and Trikafta
While cystic fibrosis is caused by a defect of the CFTR gene, over a thousand different types of mutations can occur in the gene that causes CF. People with CF must inherit a mutated gene from each parent in order to develop CF illness. The type of gene mutations that each person with cystic fibrosis inherits from their parents determines their eligibility for different CFTR modulator therapies.
Vertex, which has a monopoly over the entire class of CFTR modulator therapies available for CF, currently markets six medicines made up of different combinations of active ingredients that seek to correct the faulty CFTR protein (produced by the CFTR gene).
Kalydeco, made with the active ingredient ivacaftor, was the first CFTR modulator therapy approved to treat CF, yet it is only effective in treating five percent of people living with CF. Trikafta, which was approved in the U.S. in 2019 and combines three active ingredients – elexacaftor, tezacaftor and ivacaftor – is effective in treating 90 percent of people living with cystic fibrosis.
How many people in South Africa could benefit from Trikafta?
The recently established South African Cystic Fibrosis Registry has compiled health and demographic data for 525 people diagnosed with cystic fibrosis in the country. According to 2020 registry data, 450 patients (85.7%) would benefit from currently available CFTR modulator treatments. Dr Marco Zampoli, paediatric pulmonologist at the University of Cape Town, estimates that around 35 patients are currently sourcing generic CFTR modulators in their personal capacity from overseas (see more below on how a small group of patients in the country are accessing treatment from Argentina).
While the registry counts 525 patients diagnosed with CF in South Africa, the true number of people born with CF in the country is likely far higher. Zampoli estimates (using population and genetic data) that between two and three thousand babies could have been born with cystic fibrosis in South Africa since 1999.
“We think a lot of them are probably dying from a very young age without being diagnosed with cystic fibrosis as it looks similar to other common things like malnutrition, TB, and HIV,” says Zampoli.
While improving CF detection and diagnosis can save lives and will also increase the number of known patients in the country that could benefit from currently available CFTR modulator therapies, many of the new patients identified from better detection efforts would be unable to benefit from existing treatments. This is because black Africans are less likely than people of Caucasian descent to have the mutations that are responsive to currently available treatment.
Zampoli, however, notes that research is underway that will likely deliver new treatments that benefit patients who are ineligible for currently available drugs and adds “we’re going to be facing the same issues [of unaffordability] down the line… when we do eventually license a drug that will target their specific genes.”
How do a few people in South Africa get access to CFTR modulators?
While the South African government is not currently in negotiations with Vertex, price negotiations with health systems in wealthy countries have often dragged on for years, as price remained a sticking point.
People living with severe cystic fibrosis, however, do not have years to wait as their disease advances, placing them at risk of severe complications and death. Some have joined together to start a CF Buyers Club. The Buyer’s Club supports CF patients from around the world in buying generic versions of CFTR modulators from Argentina.
Argentina has taken steps to set strict criteria for granting patents and limit the granting of patents on certain types of claims related to pharmaceutical products. As a result, Vertex has not been granted patents on its CFTR modulator treatments in Argentina, and two Argentinian pharmaceutical companies, Gador and Tuteur, are legally manufacturing generic versions of these medicines.
While the Argentinian companies producing these medicines are unwilling to export them to South Africa for fear of facing patent infringement challenges from Vertex, Argentinian pharmacies will supply medicines to CF patients from South Africa visiting Argentina.
“You need to have a doctor’s script and you need to have a Section 21 authorisation,” explains Belinda Nell, a South African advocate working to facilitate access to CF medicines in South Africa. “You’ve got to fly to Argentina in your personal capacity or have a family representative go there and collect [the medicines] and then fly back.”
South Africans holding Section 21 authorisations from SAHPRA can legally travel with up to six months’ medicine supply on them.
While the CF Buyers Club provides an important access pathway enabling some people in South Africa to access life-saving CFTR modulator therapies, this pathway is not a feasible mechanism to ensure access to the CF medicines for all patients that could benefit from them.
The cost of generic CF medicines from Argentina is a fraction of the prices charged by Vertex. They are, however, still prohibitively high for most people living in South Africa. The annual cost of generic Trikafta from Argentina is almost R1 million ($60 000) [other CFTR modulator therapies (tezacaftor/ivacaftor and lumacaftor/ivacaftor) can be bought from Argentina for around R245 000 ($15 000) annually]. The medicine costs, combined with the costs of biannual travel to Argentina, are simply unaffordable for most.
How can a CL further reduce prices?
As seen with other classes of drugs, such as antiretroviral medicines for HIV, and antiviral medicines for Hepatitis C, the introduction of generic competition is expected to substantially reduce the cost of CF medicines.
If compulsory licenses are granted in the countries that they are being sought by Vertex Save Us, or if Vertex buckles under the pressure for expanded and affordable access to CF medicines and grants voluntary licenses allowing other companies to produce generics, then prices are expected to fall.
An analysis of the costs of production of CF medicines produced by health economists shows that generic Trikafta can be manufactured and sold with a 10 percent profit margin for around R93 000 ($5700) per patient per year – 2% of what is charged for the medicine by Vertex in the United States. While supplying medicines at this price would remain a stretch for South Africa’s public health sector, the introduction of new CF medicines must be considered within the context of potential cost savings arising from reduced hospitalisation periods and fewer transplants.
“The ripple effects of an effective CL campaign and petition in South Africa would be felt globally,” says McDonald. “First of all, I think we would see increased interest from generic suppliers… that could help to… drive down prices… this would [also] show the rest of the world that… accepting the unquestioned, monopoly power of Vertex is not necessary – you can put the lives of your citizens over the profits of that drug company.”
Note:The Fix the Patent Laws coalition and the TAC are mentioned in this article. Tomlinson worked at the TAC until 2012 and was a member of the Fix the Patent Laws steering committee until 2019. SECTION27 has also applied to be admitted as amici curiae to the case. Spotlight is published by SECTION27 and the TAC, but is editorially independent – an independence that the editors guard jealously. Spotlight is a member of the South African Press Council.
An international Task Force has recommended a method to help diagnose preschool age children with Primary Ciliary Dyskinesia (PCD), a rare, inherited condition that leads to chronic lung, ear and sinus infections. The Task Force’s findings were published in the European Respiratory Journal.
Children with PCD have a problem with mucus build-up, which leads to inflammation in the airways and infections in the lungs, nose, sinuses and ears. Most people with PCD have symptoms from birth or early childhood. But some children with PCD may not be diagnosed until much later.
Currently, a commonly used diagnostic test for PCD is measuring the nitric oxide (nNO) in the nose using a chemiluminescent analyser. This involves holding a sampling tube at the nostril, whilst the patient either holds their breath, or breathes out through their mouth against a resistance – but for young children such controlled breathing isn’t always practical. Furthermore, chemiluminescence analysers are extremely expensive, not portable, and not available in most countries.
Jane Lucas, Professor of Paediatric Respiratory Medicine at University of South Hampton, led an international Task Force to review existing studies and literature to establish whether there were more effective and accessible methods of diagnosis for PCD in younger children.
The task force concluded that although holding the breath or breathing against a resistor whilst using a chemiluminescence analyser was more reliable in older children and adults, adequate measurements could be achieved by measuring nasal nitric oxide whilst a pre-school child breathes normally and should be the standard way when diagnosing PCD in children under the age of five.
The Task Force also suggested that although chemiluminescence analysers are more reliable, the relatively inexpensive electrochemical devices have a role in healthcare systems with limited resources. They also recognised that the portability of electrochemical devices may be useful in countries where patients live long distances from a specialist centre, enabling the specialist to travel to the patient.
“We know that the earlier we can diagnose a condition, the better the chances are of implementing the best treatment plan for the patient,” Professor Lucas said. “But current guidelines and technical standards focus on nNO measurements in older, cooperative children using technology that is not widely available.
“Pre-schoolers often need different methods to be employed when measuring nNO, methods that are less invasive and adaptable. Without guidelines for younger children, and electrochemical analysers there is huge variability in how people take the measurements and interpret them.
“This paper is the first step towards standardising sampling, analysis, and reporting of nNO measured as part of the diagnostic testing for PCD in all age groups including preschool-age children. We hope this will promote earlier diagnosis of PCD, and a standardised approach to interpreting and reporting results.”
The task force also recommends that future research is needed to ensure the technical standard is kept up to date.
Despite being one of the most common non-communicable diseases globally and there being highly effective treatments for it, asthma is often not well controlled in many low-resource settings, according to a cross-sectional study recently published in the Lancet medical journal.
Closer to home, the Global Asthma Report from 2022 showed that there has been an increase in severe asthma symptoms among adolescents in Cape Town over the last few years. There is little data available for the rest of the country, which makes comparisons with other South African cities very tricky.
‘Disproportionate number of children have severe asthma’
Dr Ahmed Ismail Manjra, a paediatrician and allergologist at the Allergy and Asthma Centre in Durban, tells Spotlight that globally more children than adults have asthma. The centre is in the Life Westville Hospital and provides specialist services to adults and children with asthma or allergic disorders.
“Asthma is quite common in children. It is estimated [globally] that one in ten children have asthma, and in adults, the prevalence is less than in children,” he says. “But the problem is that in South Africa we see a disproportionate number of children with severe asthma. And what has been shown is that over the years the prevalence of asthma is rising, and the severity is rising.” (For more on what asthma is and how it is treated in South Africa’s public sector, see this Spotlight article from December 2022.)
Impact of undiagnosed uncontrolled asthma
The impact of undiagnosed or uncontrolled asthma on children is huge. First, according to Professor Refiloe Masekela, Paediatric Pulmonologist and the Head of Department of Paediatrics and Child Health at the University of KwaZulu-Natal, the symptoms are very noticeable, which can affect children socially. Secondly, a child with undiagnosed asthma will miss school because of their symptoms and be unable to participate in school activities like sport. They will also become less active because exercise may trigger symptoms, which have further effects on their health.
Another implication of uncontrolled asthma, according to Manjra, is poor sleep quality, which can impact a child’s academic performance.
“And in severe asthma without proper treatment, it can lead to recurrent admissions to hospital. This places a burden on the healthcare system, which can be easily prevented by proper management of asthma. And of course, in a small percentage of cases where the asthma is not well controlled, it can also lead to fatality,” he says.
Manjra urges parents to take their children to be checked for asthma if they have recurrent respiratory symptoms.
“The asthma treatment is extremely effective, very safe as well, [and] they have very few side effects. Parents should not be afraid to use asthma treatments to control their children’s asthma,” he says. “Although we don’t have a cure for asthma, we do have medicines that can control it and give better quality of life.”
Asthma trends in children: what the data says
Masekela explains that the data published in the Global Asthma Report is published by the Global Asthma Network (GAN), which consists of a network of centres across the world – including three in South Africa – that contribute data on asthma in their regions every few years.
This data collection effort started with the ISAAC one and ISAAC three studies (International Studies of Asthma and Allergens in Children). The GAN centre in Cape Town contributed data to ISAAC I in 1995 and for ISAAC III data was collected in Cape Town in 2002 and Polokwane in 2004-2005 where adolescents were also included.
According to Masekela, the latest study collecting data on asthma was the Global Asthma Network (GAN) Phase one study, to which the Cape Town centre contributed. Masekela says the data from the ISAAC studies – ISAAC 1 and ISAAC 3 as well as GAN is available in South Africa only for Cape Town.
This means that it is possible to compare trends in childhood asthma in Cape Town over a longer time period, and data from ISAAC 3 can be used to compare Polokwane and Cape Town. But there isn’t current data collected by the GAN to give a clear picture of childhood asthma in the other cities and provinces.
In the 2022 Global Asthma report changes among the prevalence of asthma symptoms – measured as a 12-month prevalence rate of wheezing among adolescents aged 13 to14 – showed that in ISAAC 1, 16% of the around 5 000 adolescents surveyed in Cape Town had symptoms, which increased to 20.3% of just over 5 000 surveys in ISAAC 3 and finally 21.7% of the just under 4 000 adolescents surveyed for the 2022 study.
Masekela says in Cape Town if we look at the period between ISAAC Phase 1 and phase three, there was an increase in the prevalence [of asthma in children], but from the ISAAC 3 to the GAN Phase 1, there has been a stabilisation in the asthma prevalence [among children. “So, it’s very high, it’s over 20%, but it’s stable so it hasn’t been increasing, which it was doing before.”
When comparing data from Polokwane and Cape Town in ISAAC 3, at the time of the study, more children and adolescents in Cape Town had severe asthma than in Polokwane. The prevalence of asthma in children and adolescents was also higher in Cape Town.
Situation is ‘interesting and worrying’
Masekela explains that in many low-and-middle-income countries, those living with asthma don’t have access to the right asthma medications, namely inhalers. What also happens is that when those individuals have access to asthma medications, they are only able to get the reliever inhaler, not the controller inhaler.
People living with asthma need two types of inhalers, a reliever inhaler which brings relief and opens up the chest during an asthma attack and a control medication which is used every day to reduce inflammation in the long run. In order to control asthma adequately, both inhalers need to be used and used correctly.
In South Africa, both types of inhalers are on the Essential Medicines List.
“The story of South Africa is interesting and worrying. We have in our essential medicine list inhalers [both relievers and controllers],” she says. “It should be available. It’s on the essential medicine list for the primary care level. So any person who has asthma in South Africa should have access to that first step of treatments.”
Yet the data from South Africa suggests there is a problem. When looking at the symptoms of asthma among schoolchildren from the GAN phase one study, Masekela says it is worrying because they found that many children in South Africa with asthma symptoms don’t have an asthma diagnosis and of those that do have the diagnosis most only have the reliever inhaler and very few are using both the reliever and the controller inhaler.
“We know that asthma is under-diagnosed and actually the data from Cape Town, as well as Durban, is very similar. You see that 50% of adolescents have severe symptoms, half of them have never got the label – they’ve never been diagnosed as having asthma,” she says.
Under-diagnosed
A possible reason for the under-diagnosis, according to Masekela, is that when a child presents to a clinic with wheezing, the child is treated for something else that might be causing the symptoms and sent home. Then when the child goes back a few weeks or months later with the same symptoms, they are seen by a different doctor or nurse and there isn’t continuity, so the fact that the symptoms are recurrent isn’t picked up on.
Manjra tells Spotlight that asthma can sometimes be difficult to diagnose in small children because its symptoms – wheezing, shortness of breath, tight chest, and coughing – can be caused by a number of other diseases. Wheezing, in particular, can be caused by a number of conditions that can affect children.
“The most common being viral upper respiratory tract infection, particularly with RSV [respiratory syncytial virus] and rhinovirus. And sometimes in young children, it can be extremely difficult to make a correct diagnosis of asthma because there’s overlap between viral-induced wheezing and asthma,” he says.
“However, if the child has an underlying – what we call atopic predisposition – that means if the child has eczema or has allergic rhinitis or food allergy or has [an] inhalant allergy, then the possibility of that child having asthma is very high,” he says.
Other childhood conditions that can cause wheezing in children are TB and inhaling foreign bodies into the lungs.
“So, the diagnosis of asthma in young children is basically made by an exclusion of other causes of wheezing,” he says. “Asthma diagnosis is made over a period of time because, as I’ve mentioned, it’s recurrent wheezing.”
Another problem, according to Masekela, is that those people who do receive a diagnosis of asthma are often not getting the right treatment.
“People who have a label at least should have access to the treatments, but we do see that even in those that have the diagnosis, a lot of them are not using their medicine because they’re getting repeated attacks, they have severe symptoms,” she says. “So, something is not right. Either they are not getting the label, we know that’s happening, or they’re not getting the right treatment.”
This is a bi-directional problem, Masekela says, in that either healthcare workers are not adequately teaching patients how to use both inhalers or patients are relying on the reliever medications despite being taught how to use both.
Manjra says that while inhalers are on the EML, this doesn’t necessarily translate to healthcare facilities having stock. Meaning that there can be stock-out of the medication, but also of the spacers that children need to use with the inhalers.
According to Manjra, children are unable to use inhalers properly with spacers, because the inhaler releases the plume of medication too quickly for the child to be able to breathe it into their lungs. The spacer allows the medication to go into a holding chamber where the child is able to breathe the medication into their lungs in a controlled way, through a special valve.
Better education needed
The solution to the problems of the under-diagnosis of asthma and incorrect inhaler use is better education on all fronts, says Masekela. There needs to be better training among healthcare workers on how to recognise asthma, how to manage it and how to teach patients how to manage it properly.
“We know that there is a system problem about them [children] getting the correct medication, using the correct medication and that all boils down to education of the patient, education of the health workers. And really, overall education in the community about how to handle asthma,” she says.
She adds that patients and the wider community also need to be educated on what asthma is and how to manage it properly and destigmatise it. A good starting place is in schools so that children who are living with asthma and their peers are able to better understand the condition and be more accepting of the use of inhalers.
“It’s important that we then find strategies to get people to understand the need for using these medicines, even when they’re feeling well,” she says.
A study of 104 children wearing pedometers to monitor daily activity showed that higher levels of physical activity are associated with reduced susceptibility to upper respiratory tract infections such as the common cold. Reporting the findings in Pediatric Research, the researchers suggest reduced inflammatory cytokines and improved immune responses as a possible mechanism.
Wojciech Feleszko, Katarzyna Ostrzyżek-Przeździecka and colleagues measured the physical activity levels and symptoms of upper respiratory tract infections of children aged between four and seven years in the Warsaw city region between 2018 and 2019. Participants wore a pedometer armband 24 hours a day for 40 days to measure their activity levels and sleep duration. For 60 days, parents used daily questionnaires to report their children’s symptoms of upper respiratory tract infections, such as coughing or sneezing. On a second questionnaire, parents reported their children’s vaccinations, participation in sport, whether they had siblings, and their exposure to smoking and pet hair.
The authors found that as the average daily number of steps taken by children throughout the study period increased by 1000, the number of days that they experienced symptoms of upper respiratory tract infections decreased by an average of 4.1 days. Additionally, children participating in three or more hours of sport per week tended to experience fewer days with respiratory tract infection symptoms than those not regularly participating in sports.
Higher activity levels at the beginning of the study were associated with fewer days with respiratory tract infection symptoms during the following six weeks. Among 47 children, with 5668 average daily steps during the first two weeks of the study period, the combined number of days during the following six weeks that these children experienced upper respiratory tract infection symptoms was 947. However, among 47 children whose initial average daily steps numbered 9368, the combined number of days during the following six weeks that these children experienced respiratory symptoms for was 724. Upper respiratory tract infection symptoms were not associated with sleep duration, siblings, vaccinations, or exposure to pet hair or smoking.
The authors speculate that higher physical activity levels could help reduce infection risk in children by reducing levels of inflammatory cytokines and by promoting immune responses involving T-helper cells. They also suggest that skeletal muscles could release small extracellular vesicles that modulate immune responses following exercise. However, they caution that future research is needed to investigate these potential mechanisms in children. In addition, since this was an observational study, causality could not be established.
Airway inflammation and emphysema are more common in marijuana smokers than cigarette smokers, according to a study published in Radiology. Researchers said the difference may be due to the way that marijuana is smoked, which is usually inhaled more deeply and without a filter.
Marijuana is one of the most widely used psychoactive substances in the world and the most-commonly smoked substance after tobacco. Its use has increased in recent years amid legalisation of recreational marijuana in many countries. The growing use has created an urgent need for information on marijuana’s effects on the lungs, something that is currently lacking.
“We know what cigarettes do to the lungs,” said study author Giselle Revah, MD, a cardiothoracic radiologist and assistant professor at the University of Ottawa. “There are well researched and established findings of cigarette smoking on the lungs. Marijuana we know very little about.”
To find out more, Dr Revah and colleagues compared chest CT results from 56 marijuana smokers with those of 57 non-smoking controls and 33 tobacco-only smokers.
Pulmonary emphysema in (A, B) marijuana and (C, D) tobacco smokers. (A) Axial and (B) coronal CT images in a 44-year-old male marijuana smoker show paraseptal emphysema (arrowheads) in bilateral upper lobes. (C) Axial and (D) coronal CT images in a 66-year-old female tobacco smoker with centrilobular emphysema represented by areas of centrilobular lucency (arrowheads). (Murtha, et al.)
Lack of filtering partly to blame
Three-quarters of the marijuana smokers had emphysema, a lung disease that causes difficulty with breathing, compared with 67% of the tobacco-only smokers. Only 5% of the non-smokers had emphysema. Paraseptal emphysema, which damages the tiny ducts that connect to the air sacs in the lungs, was the predominant emphysema subtype in marijuana smokers compared to the tobacco-only group.
Airway inflammation was also more common in marijuana smokers than non-smokers and tobacco-only smokers, as was gynecomastia, enlarged male breast tissue due to a hormone imbalance. Gynecomastia was found in 38% of the marijuana smokers, compared with 11% of the tobacco-only smokers and 16% of the controls.
The researchers found similar results among age-matched subgroups, where the rates of emphysema and airway inflammation were again higher in the marijuana smokers than the tobacco-only smokers.
There was no difference in coronary artery calcification between age-matched marijuana and tobacco-only groups.
Dr. Revah said the results were surprising, especially considering that the patients in the tobacco-only group had an extensive smoking history.
“The fact that our marijuana smokers – some of whom also smoked tobacco – had additional findings of airway inflammation/chronic bronchitis suggests that marijuana has additional synergistic effects on the lungs above tobacco,” she said. “In addition, our results were still significant when we compared the non-age-matched groups, including younger patients who smoked marijuana and who presumably had less lifetime exposure to cigarette smoke.”
The reasons for the differences between the two groups is likely due to several factors. Marijuana is smoked unfiltered, Dr Revah noted, while tobacco cigarettes are usually filtered. This results in more particulates reaching the airways from smoking marijuana.
In addition, marijuana is inhaled with a longer breath hold and puff volume than tobacco smoke.
“It has been suggested that smoking a marijuana joint deposits four times more particulates in the lung than an average tobacco cigarette,” Dr Revah said. “These particulates are likely airway irritants.”
The higher incidence of emphysema may also be due to the way that marijuana is smoked. Full inhalation with a sustained Valsalva manoeuvre, an attempt at exhalation against a closed airway, may lead to trauma and peripheral airspace changes.
More research is needed, Dr Revah said, with larger groups of people and more data on how much and how often people are smoking. Future research could also look at the impact of different inhalation techniques, such as through a bong, a joint or a pipe.
“It would be interesting to see if the inhalation method makes a difference,” Dr Revah said.
In pulmonary medicine, it has long been debated as to whether ventilator overstretches lung tissue, and now new research published in the American Journal of Respiratory and Critical Care Medicine has proven that they do in fact cause overstretching.
The University of California Riverside researchers showed that there were major differences between natural breathing versus the forced breathing from ventilators. These results are critical, particularly in context of the COVID pandemic and the rush to build ventilators.
“Using novel techniques, we observed that ventilators can overextend certain regions of the lungs,” said Mona Eskandari, assistant professor of mechanical engineering, who led the research. These results may explain why lung health declines for patients the longer they spend on the machines, especially in the case of disease.
Eskandari’s bMECH lab pioneered a technique to study lungs as they are made to breathe. On a custom-built ventilator designed in their lab, the researchers imitated both natural and artificial breathing. Then, they observed isolated lungs involved in both types of breathing using multiple cameras collecting fast, high-resolution images, a method called digital image correlation.
“Our setup allows us to imitate both physiological and artificial breathing on the same lung with the switch of a button,” Eskandari said. “The unique combination of our ventilator with digital image correlation gives us unprecedented insights into the way specific regions of the lungs work in concert with the whole.”
Using their innovative method to interface these two systems, UCR researchers collected evidence demonstrating that natural breathing stretches certain parts of the lung as little as 25% while those same regions stretch to as much as 60% when on a ventilator.
Scholars traditionally model the lungs like balloons, or what they refer to as thin-walled pressure vessels, where pushing air in and pulling air out are understood to be mechanically equivalent.
To explain what they observed in this study, the researchers propose moving away from thin-walled pressure vessel models and instead towards thick-walled models. Unlike thin-walled pressure vessels theory, a thick-walled model accounts for the differing levels of stress in airways resulting from ventilators pushing air in versus natural breathing, which pulls air in. This helps to explain how airways are more engaged and air is more evenly distributed in the lung during physiological breathing.
Iron lungs, the gigantic ventilators used during the late 1940s polio outbreak, acted more like a human chest cavity, expanding the lung as it naturally would. This creates a vacuum effect that pulls air into the lungs. Though this action is gentler for the lungs, these bulky systems prevented easy access to monitoring other organs in hospital care.
By contrast, modern ventilators are more portable and easier for caretakers to work with. However, they push air into the lungs that is not evenly distributed, overstretching some parts and causing a decline in lung health over time.
While it is unlikely that hospitals will return to the iron lung models, it is possible that modern machines can be altered to reduce injury.
“Now that we know about excessive strain when air is delivered to the lungs, the question for us becomes about how we can improve ventilation strategies by emulating natural breathing,” Eskandari said.
In a world first, scientists have witnessed the fusion two viruses, influenza A virus (IAV) and respiratory syncytial virus (RSV), forming a single, hybrid virus particle (HVP). The discovery was published in Nature Microbiology.
Viruses often share tropism for the same system, such as respiratory viruses preferentially infecting the respiratory system. Coinfections by more than one virus represent between ~10–30% of all respiratory viral infections and are common among children. The clinical impact of viral coinfections is unclear: while some studies indicate that coinfections do not alter the outcome of disease, others report increased incidence of viral pneumonia.
Though evidence suggests virus–virus interactions play an important role in virus dynamics and transmission, viruses are typically studied in isolation. Recent work showed that interactions among respiratory viruses occur and have impacts at multiple levels, from populations, to individuals and tissues. However, studies characterising direct virus–virus interactions within cells are scarce. Here we report previously unknown interactions between IAV and RSV, two clinically important respiratory viruses that belong to different taxonomical families.
To investigate virus–virus interactions, the researchers infected human lung cells with both influenza A virus (IAV) and respiratory syncytial virus (RSV). Using super-resolution microscopy, live-cell imaging, scanning electron microscopy and cryo-electron tomography, the researchers found extracellular and membrane-associated filamentous structures consistent with hybrid viral particles (HVPs).
The researchers found that HVPs harbour surface glycoproteins and ribonucleoproteins of IAV and RSV. HVPs use the RSV fusion glycoprotein to evade anti-IAV neutralising antibodies and infect and spread among cells lacking IAV receptors. Finally, we show that IAV and RSV coinfection in primary cells of the bronchial epithelium results in viral proteins from both viruses latching on together at the apical cell surface.
“Our observations define a previously unknown interaction between respiratory viruses that might affect virus pathogenesis by expanding virus tropism and enabling immune evasion,” the researchers wrote.
“This kind of hybrid virus has never been described before,” virologist and senior author Pablo Murcia toldThe Guardian. “We are talking about viruses from two completely different families combining together with the genomes and the external proteins of both viruses. It is a new type of virus pathogen.”
When IAV and RSV coinfect, IAV becomes more infectious, infecting a wider array of human cells. Carrying the RSV surface proteins, IAV was able to better evade the immune system. The HVP also spread into cells lacking influenza receptors, letting it progress further down the respiratory tract.
The relationship is not mutually beneficial for the viruses as RSV loses potency. Overall though, pilfering another virus’s tools could play a role in viral pneumonia.
“RSV tends to go lower down into the lung than the seasonal flu virus, and you’re more likely to get more severe disease the further down the infection goes,” said Dr Stephen Griffin, a virologist at the University of Leeds who was not involved in the study.
“It is another reason to avoid getting infected with multiple viruses, because this [hybridisation] is likely to happen all the more if we don’t take precautions to protect our health,” he added.
The researchers also found that the combination of viruses was important; IAV did not form an effective hybrid with rhinovirus.
People with fibrotic interstitial lung disease that has no obvious cause are more likely to die if they live in areas with higher levels of air pollution composed of chemicals associated with industrial sources and vehicular traffic, according to new published today in JAMA Internal Medicine.
The University of Pittsburgh study is the first to link the chemical composition of fine particulate air pollution to worsened fibrotic interstitial lung disease (fILD) outcomes. It is also the largest study ever done to evaluate the impact of air pollution on these patients.
“Some people with these lung diseases have an expected lifespan from diagnosis to death of only a few years, and yet it’s a mystery as to why they developed the disease, why their lungs become so scarred,” said lead author Gillian Goobie, MD, doctoral candidate. “Our study points to air pollution – specifically pollutants from factories and vehicles – as potentially driving faster disease progression and premature death in these patients.”
Goobie and her team obtained data from 6,683 patients with fILDs in the U.S. and Canada and linked their home addresses with satellite and ground-monitoring air pollution data to determine air pollutant composition to an accuracy of less than half a mile.
The team specifically looked at a pollutant known as PM2.5, which refers to particulate matter that measures less than 2.5 microns across, a size invisible to the naked eye. This type of pollution is so small that it can infiltrate deep into the lungs and even cross into the blood stream, where it can contribute to other diseases outside of the lungs, such as heart disease.
“In the past, most environmental health research has focused on the simple definition of PM2.5 as anything of that size,” said co-author James Fabisiak, Ph.D., associate professor in Pitt Public Health’s Department of Environmental and Occupational Health. “But PM2.5 is chemically diverse, with a different composition depending on whether it came from a forest fire or a tailpipe. Research has lacked in determining if the type of PM2.5 matters when it comes to health effects. Our new research is a big step toward filling in that knowledge gap.”
The team found that increasing levels of PM2.5 were linked to more severe disease at diagnosis, faster disease progression as measured by lung function decline and higher likelihood of dying sooner. Pollution high in sulfate (typically produced by factories, such as the coal and steel industries), nitrate (primarily from fossil fuel combustion) and ammonium (usually produced by industry or agriculture) were associated with worse outcomes, whereas chemical signatures from more naturally occurring particulate matter such as sea salt or soil dust didn’t carry as high of an association.
After pollution leaves a smokestack or tailpipe, Goobie noted that sulfate- and nitrate-containing aerosols can be formed in the atmosphere from those and other gaseous pollutants and can be acidic, which can be very damaging to the tiny air sacs of the lungs.
The team is now doing laboratory studies looking at the impact of these pollutants on lung cells at the molecular level to better understand why they are particularly damaging to the lungs of certain people and whether exposure to the pollutants triggers changes to how certain genes work that could cause runaway scarring.
According to the team’s calculations, if exposure to industrial pollutants hadn’t occurred, most premature deaths among participants living in areas of North America with a heavier burden of industry could have been avoided. Participants of colour were disproportionately exposed to higher levels of human-made air pollutants: 13% of the high-exposure group were non-white, but only 8% of the low-exposure group, highlighting the impact of environmental injustice in these findings as well.
Co-senior author S. Mehdi Nouraie, MD, PhD, associate professor of pulmonary, allergy and critical care medicine at Pitt’s School of Medicine, said that the findings further emphasise the need for people with lung conditions that make them more vulnerable to pollution to pay attention to the air quality index and consider minimising time outdoors or in rooms without good air filtration during poor air quality days.
“Ultimately, we want to encourage a data-driven awareness,” A/Prof Nouraie said. “We want people to think about the quality of the air we breathe. Patients, health care providers and policymakers can all use the new information we’re providing to try to improve health outcomes. When you make the air safe for the most vulnerable to breathe, you’re making it safe for all of us.”
