This article was originally published here

Stud Health Technol Inform. 2022 May 16;293:260-261. doi: 10.3233/SHTI220378.


BACKGROUND: Chronic low back pain is a global health problem having a tremendous effect on the quality of life of patients.

OBJECTIVES: An online therapy management system (TMS) is developed for comprehensive management of chronic low back pain patients.

METHODS: A smartphone and a web app are built based on the Keep-In-Touch Telehealth Platform. The smartphone app allows entering patient reported outcomes and connection to third party devices to monitor physiological data and parameters of therapy.

RESULTS: The TMS has been realized and a wearable auricular vagus nerve stimulation device has been integrated. The TMS is currently evaluated in a randomized clinical trial.

PMID:35592991 | DOI:10.3233/SHTI220378

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As I lie in bed spooning my wee robot, one hand on its gently undulating belly as it slows my breathing, I’m struck by the memory of co-sleeping with my kids when they were babies. It can be soothing to share your bed. Research suggests we report better sleep when bed-sharing, even when objective measures reveal sleep quality has worsened. (It helps that my current sleep partner plays soothing rain sounds and does not need a bottle at 3 am.)

Somnox 2 is a limbless bean-shaped torso designed to gradually slow your breathing, as you unconsciously match its rhythm. It can adjust to your breathing rate to calm you and help you drop off. Boosting its soporific power is a speaker that plays dreamy soundscapes or nature sounds. You can tweak everything via an app on your phone.

The original Somnox was born of a Kickstarter campaign in 2017, and this improved model has been in the works for four years. Smaller and lighter, the new version boasts a larger breathing area, longer battery life, and an improved speaker. But other major upgrades, such as Bluetooth audio streaming and sleep tracking, are still “coming soon,” making the $600 price tag much harder to swallow than a sleeping pill.

Sleep Well

Somnox 2 is just over 12 inches long and weighs less than 4 pounds. It is covered in a soft fabric with memory foam underneath and has a simple control panel to turn it on or off and adjust the volume. A pneumatic system inside fills and empties an air bladder in an impressive simulation of natural breathing. It is eminently easy to cuddle, spoon, or rest a hand on. 

The Somnox app offers a variety of breathing exercises. You can use the bot to help you calm down or even boost alertness during the day, but it is mainly for helping you get off to sleep at night. If you toggle on “Somnox Sense” and hold it against your body, it will adjust to your breathing rate and help you to take longer and deeper breaths, gradually slowing your heart rate and making it easier to sleep. It combines a six-axis accelerator and three-axis gyroscope with a proprietary algorithm to achieve this.

The default settings worked well for me, and I relaxed and fell asleep faster with Somnox 2 than without. Somnox starts at a breathing pace of 12 breaths per minute and steadily decreases to six. It uses a standard ratio of 1:2, so the exhale is twice as long as the inhale. If you feel the need, you can set a specific breathing rate, tweak the ratio, and change the breathing intensity of your sleep bot (how loudly and deeply it breathes).

The science behind Somnox is sound, and the latest version had input from sleep experts and scientists. A clinical trial is underway that will be published later this year. But the impact of controlled breathing on our ability to relax is not in doubt. The thing is, you don’t need a $600 robot to do it. There are countless apps, like Calm or Breathwrk, that can help. Somnox’s array of soundscapes and natural sounds is also similar to what many apps and other sleep gadgets offer.

It is nice to cuddle up to someone or something when you’re in bed, but the physical presence is all that makes Somnox unique. Whether that’s enough to justify the high price is debatable, especially when you consider the other downsides.

Dreaming of Dystopia

While Somnox 2 helped me drop off, it did not help me stay asleep. My sleep tracker, Withings Sleep Tracking Pad ($99), showed no change in the average duration or quality of my slumber. I found waking with a dead weight next to me slightly unpleasant. Sometimes turning in my sleep would knock it out of bed to thump on the floor.

We had connection issues with the original Somnox, and I was disappointed to find that its successor, though more reliable, still sometimes fails to connect to the app for no apparent reason. The need to tap through a connection process every time I open the app is annoying.

Once set, you can trigger your sleep program with the power button on the Somnox 2, but it only plays one program at a time. To change it or tweak the settings or sounds, you must make selections in the app and upload them to your Somnox. The process is clunky and takes longer than it should.

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Having a rebound of Covid-19 after taking Paxlovid is not exactly the same as having a rebound relationship. Although both could make you sick in different ways. A post-Paxlovid rebound may come after you feel better from taking Paxlovid for a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The rebound is when at some point after the five-day course of the medication is completed, you experience a relapse of Covid-19 symptoms. And it seems like more and more people have been reporting such relapses.

For example, there’s that pre-print case report uploaded to Research Square on April 26, 2022, of a 71-year-old man who had been fully vaccinated and boosted against Covid-19. He began taking Paxlovid as soon as he tested positive for Covid-19, two days after he had gotten exposed to the virus. His Covid-19 symptoms essentially disappeared after two days of Paxlovid. Yet, nine days after he had first tested positive and four days after he had completed the five-day course of Paxlovid, his runny nose, sore throat, and difficulty breathing returned, along with his SARS-CoV-2 levels going up again. Viral genome sequencing showed that during his initial symptoms and his return of symptoms, he was infected with the BA.1 Omicron subvariant of the SARS-CoV-2. Of course, a pre-print is not the same as a peer-reviewed article, and anyone with opposable thumbs, a laptop, and Internet access could in theory upload a pre-print. But the authors of the case report (Kalpana Gupta, Judith Strymish, Gary Stack, and Michael Charness) are legitimate doctors from legitimate healthcare systems, the VA Connecticut and Boston Healthcare Systems.

Plus this certainly hasn’t been the only report of such a rebound. For example, here’s what Tatiana Prowell, MD, an Associate Professor of Oncology at the Johns Hopkins School of Medicine tweeted:

And Peter Hotez, MD, PhD, Dean of the National School of Tropical Medicine at Baylor Medical College, tweeted about his case of post-Paxlovid relapse:

As a reminder, Paxlovid received emergency use authorization (EUA) back on December 22, 2021, from the U.S. Food and Drug Administration (FDA) as a treatment for those 12 years and older with mild-to-moderate Covid-19. These antivirals are supposed to keep the SARS-CoV-2 from doing the nasty in your body, which is a non-technical way of saying reproducing in your cells. While Paxlovid doesn’t put tiny condoms of the viruses’ spikes, it is actually the combination of two different antiviral tablet, nirmatrelvir and ritonavir, packaged together. The recommended dose of these antivirals is two 150 mg tablets of nirmatrelvir along with one 100 mg tablet of ritonavir twice a day for five days, assuming that you have normal kidney function.

Like Hall & Oates, these two medications work together. Nirmatrelvir can block the action of an enzyme called MPRO, not to be confused with GoPro. MPRO cleaves two different viral polyproteins, which may not sound very sexy but is an important step when the SARS-CoV-2 wants to reproduce. Meanwhile, ritonavir inhibits cytochrome P450 (CYP) 3A4 enzymes in the liver that can break down nirmatrelvir and thus allows nirmatrelvir to hang out in your body longer.

And just like condoms, Paxlovid doesn’t work after reproduction has already occurred. That’s why it’s important to take Paxlovid as soon as you’ve learned that you are positive for Covid-19. Waiting beyond five days after symptoms first appeared may allow the virus to reproduce too much for Paxlovid to make much of a difference. So there is a finite window, less than half a Scaramucci, during which taking Paxlovid will help.

As this NBC News segment shows, the FDA is currently investigating the reports of Covid-19 rebound cases:

Do these rebound cases then mean that Paxlovid is not doing its job? No, not necessarily. Just because symptoms return doesn’t mean that things wouldn’t have been even worse without the medication. Plus, it’s not yet clear what percentage of people have been experiencing such relapses. Again stories on Twitter and a pre-print case report ain’t the same as peer-reviewed studies. While Pfizer’s clinical trial did show possible rebound Covid-19 occurring in about 2% of those who had received Paxlovid, around 1.5% of those who had received only placebo also suffered similar relapses. With these two percentages not being statistically significantly different from each other, the conclusion from the clinical trial was that these rebounds weren’t specific to Paxlovid. Of course, what happens or doesn’t happen in a clinical trial doesn’t necessarily mean the same will apply exactly in the real world.

So what’s going on, in the words of Marvin Gaye? One possibility is that the five-day course of the medication is turning out to be not long enough for everyone. The medication is supposed to suppress viral replication long enough for your immune system to clear the virus from your body. It’s kind of like smearing deodorant on yourself until you’ve had a chance to take a real shower. Remember Paxlovid doesn’t clear the virus from your body. It just keeps it from replicating. The amount of time needed for your immune system to accomplish this virus clearing task may vary depending on how much virus happens to be in your body and the status of your immune system. It could be that your immune system hasn’t geared up enough before the five-day course of the medication has been completed. So one question is whether the course of Paxlovid should be longer than five days.

Another possibility is that the Omicron variant may be different enough from previous versions of the virus that the medication may not be quite as effective. Remember Pfizer’s clinical trial occurred last year while the Delta variant was dominant. So all results may be more Delta-specific.

A third possibility is that the virus has been developing resistance to the antiviral medication. While resistance may not be futile, it can reduce the effectiveness of the medication. Resistance is why flu antivirals such as Tamiflu may not be as effective against certain strains of the flu. And with the Covid-19 coronavirus replicating so much, resistance could very well develop. Each time the SARS-CoV-2 replicates, it can be like a drunk person making photocopies of his or her butt. Mistakes can result when the virus tries to copy its genetic code leaving resulting progeny with mutations and thus different genetic sequences. Some of these mutations may alter virus proteins enough to allow the virus to better evade the antiviral.

Many people using the antiviral medication could then end up selecting for viruses with such resistance mutations, because they are better able to survive. These resistant versions could then eventually become the dominant version of the virus. That’s why antiviral medications shouldn’t be overused.

While there was no clear evidence of resistance developing during the Pfizer Paxlovid clinical trial, the trial may not have gone on long enough to see this possibility. It will be important for public health officials to track the possible emergence of resistant virus strains and potentially limit the use of Paxlovid if such resistance is found.

A fourth possibility is re-infection. Could some of the supposed relapse cases actually be people getting infected and then re-infected in a short period of time? I did cover for Forbes a case of someone getting infected with the Omicron variant within 20 days of getting infected with the Delta variant. But it’s not clear how common such getting two separate infections within such a short time period may be.

So if you do have a rebound case of Covid-19 after taking Paxlovid, what should you do? Should you take more of this antiviral medication? Well, currently, things are about as clear as Nutella soup. There is not enough evidence about what to do. And the EUA only covers taking the medication for five days.

Ultimately, more studies, more data, and more drug surveillance are needed. All of this is a reminder that while Paxlovid may be a very useful part of dealing with the pandemic, it is not a magical pill. Nothing in life is a magical solution with the possible exception of avocados or chocolate. Relying solely on a medication to “rescue you” if you were to get Covid-19 could be like relying on finding a soul mate to rescue you from your current life. Don’t think that the existence of Covid-19 treatments can allow you forego other Covid-19 precautions such as face mask wearing and vaccination against Covid-19. Remember Covid-19 interventions are like Swiss cheese, not that you should start putting them on your ham sandwich. Rather, this means that each individual precaution or treatment has its specific set of holes. And the hole thing means that you should always be layering at least several Covid-19 precautions on top of each other as long as the pandemic is still going on and the virus is circulating widely around you. If you don’t maintain other Covid-19 precautions and rely solely on getting Paxlovid when needed, the Covid-19 coronavirus could very well catch you on the rebound.

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A first-in-human clinical trial testing the safety and tolerability of EP395, EpiEndo Pharmaceuticals’ experimental treatment for chronic obstructive pulmonary disease (COPD), is now finished.

EpiEndo is planning to launch a Phase 2a trial testing EP395 in people with COPD later this year.

“The successful completion of this study brings us a step closer to addressing the global burden of COPD and other airway diseases by restoring and preserving epithelial integrity and reducing inflammation without the issue of potential anti-microbial resistance,” Ginny Norris, chief medical officer of EpiEndo, said in a press release.

Recommended Reading

ISM1 | COPD News Today | illustration of animal study

EP395 is a macrolide — a class of molecules that contain a characteristic structural feature, called a macrocyclic lactone ring. Most macrolides are antibiotics that are designed to kill bacteria. EP395 is part of a novel class of nonantibiotic macrolides being developed by EpiEndo, which the company has dubbed “Barriolides.”

According to EpiEndo, EP395 has anti-inflammatory properties and may help promote the integrity of the epithelial layer that lines the surface of the lung airways. This layer helps protect the lungs from damage. Reduced epithelial integrity has been implicated in COPD and other inflammatory diseases.

The Phase 1 trial (NCT04819854), sponsored by EpiEndo, enrolled 78 healthy volunteers, who were given a single dose of EP395, or multiple doses taken daily for up to 28 days.

According to EpiEndo, results showed the experimental treatment was generally well tolerated, and its pharmacological profile was consistent with once-daily dosing.

“This First Time in Human study provides key clinical insights which highlight the potential for this new class of therapeutic — an encouraging step towards a new treatment for COPD,” said principal trial investigator Dave Singh, MD, who is also a professor at the University of Manchester.

EpiEndo is now planning to launch a Phase 1b clinical trial to further test the pharmacological properties of EP395 in healthy volunteers. The company also plans to start a Phase 2a study that will assess the safety and tolerability of EP395 in people with COPD. The Phase 2a study will also evaluate the treatment’s effect on inflammation biomarkers.

Both trials are expected to start this year, with top-line results anticipated in 2023.

“We are now planning the next stage of clinical development for EP395 and look forward to initiating 2 clinical studies later this year including the first study with EP395 in COPD patients,” Norris said.

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By Dr. Mukesh Batra

The COVID-19 pandemic has tested our medical system in more ways than any of us could’ve imagined. In the past two years, every individual, thanks to the Indian Government, has got a shield against the Novel Coronavirus. Just recently, the Drug Controller General of India (DCGI) approved vaccination for the age group of children between 5 to 12 years. It’s a great initiative to protect children vulnerable to the virus. While some children have suffered short-term health issues, healthy youngsters have shown long-term health hazards driven by Omicron and its new variant BA.2. 

After recovering from the virus, many children have faced health problems for months, one of the side effects of long-COVID or post-COVID. Children have encountered multiple health complications related to weakness, stomach issues, depression, and lungs (like breathing problems, Asthma, pneumonia, lung cancer, chronic mucus, etc.). According to the NCBI, between 0.39–12.3% of children in India were exposed to pandemic-infused respiratory diseases last year, making the virus dangerous for the lungs. Let’s take a brief look at how Long COVID affects kids’ respiratory systems.

Some of the symptoms of long covid can last for 3 months or longer. Children 6 years or older with lasting symptoms may need lung function tests.

How does Long COVID affect the respiratory system?

Although COVID-19 starts with mild flu-like symptoms, it gradually attacks a person’s body and leads to severe symptoms. The virus badly infects the upper or lower portion of the respiratory tract. It travels through the airways, causing the lining to become inflamed and irritated. Some instances show that the infection can even reach the alveoli (tiny air sacs) that transfer oxygen to the blood cells. Such conditions cause symptoms like dry cough, sore throat, heavy breathing, breathing difficulties, increased heart rate, and pneumonia, followed by lung infections where the alveoli get inflamed. As COVID-19 directly correlates with Acute Respiratory Distress Syndrome (ARDS), its adverse effects continue to trouble every individual’s (including kids) respiratory system even after recovering from it. 

With the prevailing health hazards among children, parents desperately opted for various medical systems such as Allopathy, Ayurveda, and Homeopathy, for their kids’ treatment. Fortunately, Homeopathy has garnered significant traction amid the pandemic between the two medical systems, as it is known for treating the root cause of any illness, including respiratory problems. Here’s how homeopathy helps treat respiratory issues in children.

Homeopathy for kids’ immunity

Owing to the safety of the Homeopathic medicines, many mothers prefer them since it ensures great results and proves to be 100% safe for kids. Homeopathy is considered an ideal treatment method for toddlers, infants and young adults. Homeopathic medicines help strengthen a kid’s immunity system and thus, help them fight against flu naturally It has therefore become the preferred medicine system that a lot of countries are starting to adopt.

Homeopathy remedies for respiratory problems

Homeopathic remedies are exceptionally effective in treating respiratory infections without any side effects. Even the National Library of Medicine (NIH) stated the use of homeopathy in fighting respiratory infections and offering symptomatic relief in its clinical trial. Homeopathic medicines provide a practical approach to reducing the symptoms, intensity, and recurrence. Some of the prescribed medicines for respiratory problems include Aconitum Napellas, Hepar Sulphur, Belladonna, Antimonium Tartaricum, and Bryonia alba. But before taking such medications/treatments, consulting your nearest homeopath is always advisable.

Home remedies for respiratory ailments

For respiratory diseases like shortness of breath, deep breathing is exceptionally beneficial for managing breathlessness. Other valuable tips like pursed-lip breathing, steam inhalation, salt water gargling, and consuming fresh ginger & fresh fruits also come to the rescue of kids. In case of severe health conditions, parents must visit the nearest homeopathic medical facility for guidance. 

Apart from respiratory ailments, there are many other side effects of Post COVID-19:

Post-COVID Chronic Cough and Breathlessness: Homeopathy has proven efficacy against respiratory illnesses and provides symptomatic relief. A clinical study published by the National Library of Medicine (NIH) shows its efficacy in combating respiratory infections.

Post-COVID depression: A clinical trial supported the efficacy and safety of homeopathic treatments for depression. The trial concluded that patients who received homeopathic treatments reported lower rates of depression.

Post-COVID gastrointestinal issues: Homeopathy is used to provide relief from a range of gastrointestinal issues. According to, a study conducted on 25 cases of acute diarrhoea observed that 97% of cases were cured, which indicates that homeopathic remedieshave the power to cure the acute diarrhoeal condition.

Post COVID weakness: In 2004, the journal of Psychosomatic Research conducted an extensive triple-blind trial on the effectiveness of individualized homeopathic treatment for chronic fatigue syndrome. This trial was carried out over six months, and results showed that homeopathy treatment had a significant improvement over placebo.

(The author is the Founder, Dr. Batra’s Group of Companies. The article is for informational purposes only. Please consult medical experts and health professionals before starting any therapy, medication and/or remedy. Views expressed are personal and do not reflect the official position or policy of the

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Withings has been doing wearables for several years now. Last year we reviewed the ScanWatch; the company has announced the ScanWatch Horizon. This is the latest version modeled off of a deep-sea diver watch and looks fantastic.

Estimated reading time: 3 minutes

ScanWatch Horizon combines iconic diver watch design with breakthrough health tech. Nested in a high-end watch, state-of-the-art medical technology has been carefully selected to create the most health-oriented watch ever offered to the public. Developed with cardiologists, and clinically validated, this is our first hybrid smartwatch that can take a clinically validated ECG and SpO2 measurement and track breathing disturbances. ScanWatch also offers in-depth activity and sleep tracking, water resistance to 100m, and an exceptional battery life of up to 30 days before it needs to be charged.


  • Up to 30 days of battery life
  • Exclusive multi-wavelength PPG: heart rate/SpO2 sensor
  • Stainless steel electrodes
  • PMOLED display
  • Flat sapphire glass
  • Water-resistant 10ATM
  • Altimeter
  • Smart notifications
  • Bluetooth® Low Energy
  • Health Mate app
  • Electrocardiogram / AFib detection*
  • Respiratory wellness scan via PPG sensor & accelerometer
  • Heart rate
  • Activity (steps, calories, distance)
  • Sleep cycles (light and deep)
  • Connected GPS / multi-sport tracking
  • Elevation
Withings announces the ScanWatch Horizon

The health and wellness features of this ground-breaking device are encased in a luxurious design
that features sapphire-glass casing with anti-reflection coating and a stunning finish. It boasts a
stainless-steel rotating bezel with laser engraved markings that incorporate the standard codes of
diving practice, alongside Luminova hollow watch hands, indicators, and thick indices that allow it to
be used in low light, all of which add to its high-end design.

For the classic diver watch look, ScanWatch Horizon comes with a stainless-steel band as well as a
more elasticated, rubberised wristband for sports usage. In addition, it has an impressive 30-day
battery life and 10 ATM water resistance, making it the perfect accessory for swimming, snorkelling,
and water sports. All of which can be monitored using its sport tech features and the connected
Health Mate app. You can even take an ECG while under water!

Horizon is the latest hybrid smartwatch in the Withings ScanWatch range, which also includes the
original and Rose Gold versions. Each version has health, wellness, and fitness capabilities, that
were developed by experts and validated in multiple clinical trials.

“The luxury design and robust health features of ScanWatch Horizon are a great compliment to the
existing ScanWatch line and we are delighted to bring it to the U.S.,” said Mathieu Letombe, CEO of
Withings. “Sophisticated health devices that monitor advanced vitals do not have to look like hospital
equipment. With the original ScanWatch, the elegant Rose Gold version, and now ScanWatch Horizon,
we have a style option to meet every fashion preference, social occasion, and budget.”

Withings ScanWatch Horizon is available online at, Amazon, and Best Buy stores from May 17
priced at $499.95. Customers can choose from a 43mm screen in either Blue or Green. ScanWatch
horizon has a 5-year guarantee and comes with both stainless steel wristband and an FKM strap

What do you think of the Withings ScanWatch Horizon? Please share your thoughts on any of the social media pages listed below. You can also comment on our MeWe page by joining the MeWe social network.

Last Updated on May 17, 2022.

Withings Scanwatch-min

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Withings' most medically advanced wearable gets diver style design with rotating bezel, luminescent indexes, and upgraded water resistance to 10 ATM

ISSY-LES-MOULINEAUX, France, May 17, 2022 /PRNewswire/ -- Today, Withings, pioneers of the connected health revolution, has announced the US availability of its highly anticipated ScanWatch Horizon. Available from, Amazon, and Best Buy stores, it is the first hybrid smartwatch inspired by the luxury diver watch tradition to deliver state-of-the-art health technology. Priced $499, it can take an ECG and monitor heart rate, breathing disturbances, blood oxygen levels, sleep, and physical activity, even underwater!

Withings ScanWatch Horizon - the connected health hybrid smartwatch inspired by the luxury diver watch tradition

Withings ScanWatch Horizon - the connected health hybrid smartwatch inspired by the luxury diver watch tradition

The health and wellness features of this ground-breaking device are encased in a luxurious design that features sapphire-glass casing with anti-reflection coating and a stunning finish. It boasts a stainless-steel rotating bezel with laser engraved markings that incorporate the standard codes of diving practice, alongside Luminova hollow watch hands, indicators, and thick indices that allow it to be used in low light, all of which add to its high-end design.

For the classic diver watch look, ScanWatch Horizon comes with a stainless-steel band as well as a more elasticated, rubberised wristband for sports usage. In addition, it has an impressive 30-day battery life and 10 ATM water resistance, making it the perfect accessory for swimming, snorkelling, and water sports. All of which can be monitored using its sport tech features and the connected Health Mate app. You can even take an ECG while under water!

Horizon is the latest hybrid smartwatch in the Withings ScanWatch range, which also includes the original and Rose Gold versions. Each version has health, wellness, and fitness capabilities, that were developed by experts and validated in multiple clinical trials. Features of the ScanWatch Horizon include:

  • Clinically validated detection of atrial fibrillation by ECG

  • Heart Rate scan every 10 minutes using a PPG sensor

  • Clinically validated SpO2

  • Automatic activity tracking (walking, running, swimming, distance, and calories burned)

  • Training mode with up to 30 activities (measurement of distance, pace, and altitude)

  • Fitness level assessment with VO2 Max

  • Sleep monitoring (length, quality, sleep phases)

  • Smart smartphone notifications

  • Altimeter records floors travelled

  • Water resistant up to 10 ATM

  • Up to 30 days battery life

"The luxury design and robust health features of ScanWatch Horizon are a great compliment to the existing ScanWatch line and we are delighted to bring it to the U.S.," said Mathieu Letombe, CEO of Withings. "Sophisticated health devices that monitor advanced vitals do not have to look like hospital equipment. With the original ScanWatch, the elegant Rose Gold version, and now ScanWatch Horizon, we have a style option to meet every fashion preference, social occasion, and budget."


ScanWatch Horizon is available online at, Amazon and Best Buy stores from May 17 priced at $499.95. Customers can choose from a 43mm screen in either Blue or Green. ScanWatch horizon has a 5-year guarantee and comes with both stainless steel wristband and FKM strap.

For further information please visit the ScanWatch Horizon page at

About Withings
Established in 2008, Withings, is a world leader in connected health technology. Its team of engineers, data scientists, and healthcare professionals have enthused every day, elegant lifestyle objects with medical and wellness capabilities to efficiently track health vitals. Its range of in-home devices can monitor more than 20 health and wellness parameters and are used daily by millions of people worldwide. Its portfolio of devices that includes connected scales, hybrid watches, smart thermometers, blood pressure monitors, and sleep trackers empower individuals to take back control of their health and track medical and wellness data.

Contact is: Ian Twinn, [email protected].

Withings Logo (PRNewsfoto/Withings)

Withings Logo (PRNewsfoto/Withings)



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SOUTHAMPTON, England--(BUSINESS WIRE)-- Synairgen plc (LSE: SNG), the respiratory company developing SNG001, an investigational formulation for inhalation containing the broad-spectrum antiviral protein interferon beta, today announces the first presentation of the full data analysis from its Phase 3 SPRINTER trial evaluating the efficacy and safety of SNG001 in patients hospitalised with COVID-19.

SPRINTER (SG018; NCT04732949) was a global, randomised, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of inhaled SNG001 for the treatment of adults hospitalised due to COVID-19 who required treatment with supplemental oxygen. The trial recruited a total of 623 patients who were randomised to receive SNG001 (n=309) or placebo (n=314) on top of standard of care (SOC).

The data from this pivotal trial will be presented today at the Clinical Trials Symposium of the American Thoracic Society 2022 (ATS 2022) International Conference, being held in San Francisco, California from 13-18 May 2022. A separate poster presentation is scheduled for 17 May 2022.

Synairgen announced in February 2022 that the Phase 3 SPRINTER trial did not meet the primary endpoints of discharge from hospital and recovery. There was, however, an encouraging signal in reduction in the relative risk (RRR) of progression to severe disease or death within 35 days (25.7%1 reduction in the Intention-to-Treat population and 36.3% reduction in the Per Protocol population).2

To assess the strength of this signal and identify specific patient populations that might benefit most from treatment, post hoc analyses were performed on groups of patients recognised to be at greater risk of developing severe disease in hospital. These analyses included patients ≥65 years old, those with co-morbidities associated with worse COVID-19 outcomes, and those who, at baseline, despite receiving low flow oxygen, had clinical signs of compromised respiratory function (defined as oxygen saturation of ≤ 92% or respiratory rate ≥ 21 breaths/min).

These analyses showed stronger treatment effects with SNG001 in these high-risk patient sub-groups, with the strongest effect observed in those who had clinical signs of compromised respiratory function. In these patients, who represented approximately one-third of the SPRINTER trial population, SNG001 significantly reduced the risk of progression to severe disease and death compared to placebo by 70% in the Per Protocol population (Odds Ratio (95% Confidence Interval) 0.23 (0.06, 0.98); p=0.046).

SNG001 was well tolerated in the SPRINTER trial with a favourable safety profile consistent with previous studies:

  • The proportion of patients with any treatment-emergent adverse events (TEAE) related to study treatment was 22.6% for SNG001 vs. 25.4% for placebo.
  • The proportion of patients with any serious TEAE was 12.6% for SNG001 vs. 18.2% for placebo.
  • The proportion of patients with a serious respiratory3 TEAE was 4.7% for SNG001 vs. 9.9% for placebo.

Phillip Monk, Ph.D., Chief Scientific Officer of Synairgen, said: “The post hoc analyses presented at the ATS conference today suggest that SNG001 may be having a beneficial effect with respect to prevention of severe disease or death. These results provide a strong clinical rationale to continue to investigate SNG001 in a trial evaluating progression and/or mortality in hospitalised patients with COVID-19 and more widely in patients with severe viral lung infections.”

Tom Wilkinson, Chief Investigator of the SPRINTER trial and Professor of Respiratory Medicine, University of Southampton, said: “The improvement in standard of care for COVID-19 means that most patients are currently discharged fairly rapidly from hospital; however, this further analysis shows that some patients struggle in their battle with the virus and show signs of respiratory compromise, with faster breathing rates and lower oxygen saturations, despite being on oxygen. For these higher-risk patients, there remains an urgent need for new treatment options, and this analysis suggests that SNG001 could be a potentially efficacious treatment option for them.”

The full analysis of the Phase 3 SPRINTER trial data will be submitted for publication in a peer-reviewed journal. A company recording of the ATS presentation will be available on the Synairgen website by 12:00 Pacific Daylight Time/20:00 British Summer Time today, and for ATS members, the symposium recording will be available on the ATS website.

SNG001 is not approved for use anywhere in the world.

For further information on the ATS International Conference visit:

This announcement contains inside information for the purposes of Article 7 of Regulation (EU) No. 596/2014 ('MAR').

Notes for Editors

About SPRINTER (SG018) trial

The SPRINTER trial (SG018; NCT04732949) was a global Phase 3, randomised, placebo-controlled, double-blind, clinical trial assessing the efficacy and safety of inhaled SNG001 on top of standard of care (SOC) for the treatment of adults hospitalised due to COVID-19 requiring treatment with supplemental oxygen by mask or nasal prongs. Patients requiring high-flow nasal oxygen therapy, non-invasive ventilation, or endotracheal intubation (invasive ventilation) at randomisation were excluded. COVID-19 was confirmed using a validated molecular test for the presence of the SARS-CoV-2 virus.

About SNG001

SNG001 is a pH-neutral formulation of interferon-beta (IFN-beta) for inhalation that is delivered directly into the lungs using a mesh nebuliser, currently being investigated as a potential host-directed antiviral treatment for patients hospitalised with COVID-19. SNG001 has broad potential applicability for patients hospitalised with respiratory symptoms due to viral infections such as influenza, Respiratory Syncytial Virus (RSV) and para-influenza.

The SARS-CoV-2 virus has been shown to suppress the production of IFN-beta, a naturally-occurring protein that orchestrates the body's antiviral defences, with the aim of evading host immune responses. By administering IFN-beta into the lungs, the aim is to correct this deficiency, potentially switching back on the lungs' antiviral pathways to clear the virus. SNG001 has been shown to demonstrate potent in vitro antiviral activity against a broad range of viruses including SARS-CoV-2 and Alpha, Beta, Gamma, Delta and Omicron variants.

About Synairgen

Synairgen is a UK-based respiratory company focused on drug discovery, development and commercialisation. The Company’s primary focus is developing SNG001 (inhaled interferon beta) for the treatment of severe viral lung infections, including COVID-19, as potentially the first host-targeted, broad-spectrum antiviral treatment delivered directly into the lungs. SNG001 has been granted Fast Track status from the US Food and Drug Administration (FDA). Founded by University of Southampton Professors Sir Stephen Holgate, Donna Davies and Ratko Djukanovic in 2003, Synairgen is quoted on AIM (LSE: SNG). For more information about Synairgen, please see



This was reported as 27.1% in the topline analysis in February 2022 but changed between 35- and 90-day database lock.



The main reason patients were excluded from the Per Protocol population was failure to receive two full doses in the first three days of treatment.



Respiratory, thoracic and mediastinal system organ class


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This article was originally published here

Am J Case Rep. 2022 May 14;23:e936734. doi: 10.12659/AJCR.936734.


BACKGROUND Despite unprecedented speed in the execution of the COVID-19 vaccine and therapeutic clinical trials, pregnant patients have been largely excluded from initial studies. In addition, pregnant patients who are unvaccinated against SARS-CoV-2 have greater morbidity risk with severe COVID-19 disease as compared to patients of similar age and comorbidity status. Intravenous immunoglobulin (IVIG) has been deemed safe in pregnancy in other diseases. Prior data demonstrate the possible benefit of utilizing IVIG for the treatment in hospitalized patients with severe respiratory symptoms associated with COVID-19 active infections when administered within 14 days of COVID symptom onset. CASE REPORT We administered IVIG (Privigen®, CSL Behring) 0.5 g/kg daily for 3 consecutive days to 4 pregnant patients (ages 24-34 years of age) who were hospitalized with moderate-to-severe COVID-19 and not vaccinated against SARS-CoV-2. All patients received concomitant glucocorticoid therapy. Gestational ages were 26, 17, 35, and 35 weeks. All patients were discharged home breathing room air after a mean hospital stay of 15 days. Two patients had uncomplicated cesarean section at 35 weeks during the hospitalization. The pre-term pregnancies at 17 and 26 weeks were intact at hospital discharge and resulted in normal vaginal deliveries at term. All 4 patients consented to participate in this case series report. CONCLUSIONS IVIG may be a safe treatment consideration in pregnant women with severe COVID-19 to avoid pregnancy complications. Its use warrants further study in pregnancy acute respiratory distress syndrome (ARDS) due to SARS-CoV-2, influenza, and other respiratory viruses to which pregnant patients are vulnerable.

PMID:35567293 | DOI:10.12659/AJCR.936734

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NEW YORK AND MAINZ, GERMANY, May 13, 2022Pfizer Inc. (NYSE: PFE, “Pfizer”) and BioNTech SE (Nasdaq: BNTX, “BioNTech”) today announced they have reached an agreement with the European Commission (EC) to amend their originally agreed contractual delivery schedules for the Pfizer-BioNTech COVID-19 Vaccine. This amendment rephases planned deliveries to help support the European Commission and Member States' ongoing immunization programs, and is aligned to the companies’ commitment to working collaboratively to identify pragmatic solutions to address the evolving pandemic needs. Doses scheduled for delivery in June through August 2022, will now be delivered in September through fourth quarter 2022. This change of delivery schedule does not impact the companies’ full-year 2022 revenue guidance or the full-year commitment of doses to be delivered to EC Member States in 2022.

Pfizer and BioNTech continue to evaluate potential adapted vaccines, including variant-based vaccines, and expect to share these data in the coming months.

U.S. Indication & Authorized Use

Pfizer-BioNTech COVID-19 Vaccine is FDA authorized under Emergency Use Authorization (EUA) for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 5 years of age and older.  
Pfizer-BioNTech COVID-19 Vaccine is FDA authorized to provide:

Primary Series

  • a 2-dose primary series to individuals 5 years of age and older
  • a third primary series dose to individuals 5 years of age and older with certain kinds of immunocompromise

Booster Series

  • a first booster dose to individuals 12 years of age and older who have completed a primary series with Pfizer-BioNTech COVID-19 Vaccine or COMIRNATY® (COVID-19 Vaccine, mRNA)
  • a first booster dose to individuals 18 years of age and older who have completed primary vaccination with a different authorized or approved COVID-19 vaccine. The booster schedule is based on the labeling information of the vaccine used for the primary series
  • a second booster dose to individuals 50 years of age and older who have received a first booster dose of any authorized or approved COVID-19 vaccine
  • a second booster dose to individuals 12 years of age and older with certain kinds of immunocompromise and who have received a first booster dose of any authorized or approved COVID-19 vaccine

COMIRNATY® (COVID-19 Vaccine, mRNA) is a vaccine approved for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 16 years of age and older. 

  • COMIRNATY® is administered as a 2-dose primary series 

COMIRNATY® (COVID-19 Vaccine, mRNA) is FDA authorized under Emergency Use Authorization (EUA) to provide:

Primary Series

  • a 2-dose primary series to individuals 12 through 15 years of age
  • a third primary series dose to individuals 12 years of age and older with certain kinds of immunocompromise

Booster Dose 

  • a first booster dose to individuals 12 years of age and older who have completed a primary series with Pfizer-BioNTech COVID-19 Vaccine or COMIRNATY® 
  • a first booster dose to individuals 18 years of age and older who have completed primary vaccination with another authorized or approved COVID-19 vaccine. The booster schedule is based on the labeling information of the vaccine used for the primary series
  • a second booster dose to individuals 50 years of age and older who have received a first booster dose of any authorized or approved COVID-19 vaccine
  • a second booster dose to individuals 12 years of age and older with certain kinds of immunocompromise and who have received a first booster dose of any authorized or approved COVID-19 vaccine

Emergency Use Authorization 
Emergency uses of the vaccine have not been approved or licensed by FDA, but have been authorized by FDA, under an Emergency Use Authorization (EUA) to prevent Coronavirus Disease 2019 (COVID 19) in either individuals 12 years of age and older, or in individuals 5 through 11 years of age, as appropriate. The emergency uses are only authorized for the duration of the declaration that circumstances exist justifying the authorization of emergency use of the medical product under Section 564(b)(1) of the FD&C Act unless the declaration is terminated or authorization revoked sooner. 

FDA-approved COMIRNATY® (COVID-19 Vaccine, mRNA) and the Pfizer-BioNTech COVID-19 Vaccine FDA-authorized for Emergency Use Authorization (EUA) for individuals 12 years of age and older can be used interchangeably by a vaccination provider when prepared according to their respective instructions for use. 

The formulation of the Pfizer-BioNTech COVID-19 Vaccine authorized for use in children 5 through 11 years of age differs from the formulations authorized for individuals 12 years of age and older and should therefore not be used interchangeably. The Pfizer-BioNTech COVID-19 Vaccine authorized for use in children 5 through 11 years of age should not be used interchangeably with COMIRNATY® (COVID-19 Vaccine, mRNA).


Tell your vaccination provider about all of your medical conditions, including if you:

  • have any allergies
  • have had myocarditis (inflammation of the heart muscle) or pericarditis (inflammation of the lining outside the heart)
  • have a fever
  • have a bleeding disorder or are on a blood thinner
  • are immunocompromised or are on a medicine that affects the immune system
  • are pregnant, plan to become pregnant, or are breastfeeding
  • have received another COVID-19 vaccine
  • have ever fainted in association with an injection

•    Pfizer-BioNTech COVID-19 Vaccine or COMIRNATY® (COVID-19 Vaccine, mRNA) may not protect all vaccine recipients

•    You should not receive Pfizer-BioNTech COVID-19 Vaccine or COMIRNATY® (COVID-19 Vaccine, mRNA) if you have had a severe allergic reaction to any of its ingredients or had a severe allergic reaction to a previous dose of Pfizer-BioNTech COVID-19 Vaccine or COMIRNATY® 

•    There is a remote chance that Pfizer-BioNTech COVID-19 Vaccine or COMIRNATY® (COVID-19 Vaccine, mRNA) could cause a severe allergic reaction. A severe allergic reaction would usually occur within a few minutes to 1 hour after getting a dose of the vaccine. For this reason, your vaccination provider may ask you to stay at the place where you received the vaccine for monitoring after vaccination. If you experience a severe allergic reaction, call 9-1-1 or go to the nearest hospital

Seek medical attention right away if you have any of the following symptoms:

  • difficulty breathing, swelling of the face and throat, a fast heartbeat, a bad rash all over the body, dizziness, and weakness

•    Myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the lining outside the heart) have occurred in some people who have received the vaccine, more commonly in males under 40 years of age than among females and older males. In most of these people, symptoms began within a few days following receipt of the second dose of the vaccine. The chance of having this occur is very low 

Seek medical attention right away if you have any of the following symptoms after receiving the vaccine:

  • chest pain
  • shortness of breath
  • feelings of having a fast-beating, fluttering, or pounding heart

•    Fainting can happen after getting injectable vaccines, including Pfizer-BioNTech COVID-19 Vaccine or COMIRNATY® (COVID-19 Vaccine, mRNA). Sometimes people who faint can fall and hurt themselves. For this reason, your vaccination provider may ask you to sit or lie down for 15 minutes after receiving the vaccine

•    Some people with weakened immune systems may have reduced immune responses to Pfizer-BioNTech COVID-19 Vaccine or COMIRNATY® (COVID-19 Vaccine, mRNA)

•    Additional side effects include injection site pain; tiredness; headache; muscle pain; chills; joint pain; fever; injection site swelling; injection site redness; nausea; feeling unwell; swollen lymph nodes (lymphadenopathy); decreased appetite; diarrhea; vomiting; arm pain; and fainting in association with injection of the vaccine

These may not be all the possible side effects of the vaccine. Call the vaccination provider or healthcare provider about bothersome side effects or side effects that do not go away.

•    You should always ask your healthcare providers for medical advice about adverse events. Report vaccine side effects to the US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) Vaccine Adverse Event Reporting System (VAERS). The VAERS toll-free number is 1‐800‐822‐7967 or report online to You can also report side effects to Pfizer Inc. at or by calling 1-800-438-1985

Click for Fact Sheets and Prescribing Information for individuals 5 years of age and older:

Recipients and Caregivers Fact Sheet (5 through 11 years of age)
Recipients and Caregivers Fact Sheet (12 years of age and older)
COMIRNATY® Full Prescribing Information (16 years of age and older), DILUTE BEFORE USE, Purple Cap
COMIRNATY® Full Prescribing Information (16 years of age and older), DO NOT DILUTE, Gray Cap
EUA Fact Sheet for Vaccination Providers (5 through 11 years of age), DILUTE BEFORE USE, Orange Cap
EUA Fact Sheet for Vaccination Providers (12 years of age and older), DILUTE BEFORE USE, Purple Cap
EUA Fact Sheet for Vaccination Providers (12 years of age and older), DO NOT DILUTE, Gray Cap

About Pfizer: Breakthroughs That Change Patients’ Lives
At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 170 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at In addition, to learn more, please visit us on and follow us on Twitter at @Pfizer and @Pfizer News, LinkedIn, YouTube and like us on Facebook at

Pfizer Disclosure Notice
The information contained in this release is as of May 13, 2022. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.
This release contains forward-looking information about Pfizer’s efforts to combat COVID-19, the collaboration between BioNTech and Pfizer to develop a COVID-19 vaccine, the BNT162b2 mRNA vaccine program, and the Pfizer-BioNTech COVID-19 Vaccine, also known as COMIRNATY (COVID-19 Vaccine, mRNA) (BNT162b2) (including an agreement with the European Commission to amend their originally agreed contractual delivery schedules, revenue guidance, potential adapted vaccines, including variant-based vaccines, qualitative assessments of available data, potential benefits, expectations for clinical trials, potential regulatory submissions, the anticipated timing of data readouts, regulatory submissions, regulatory approvals or authorizations and anticipated manufacturing, distribution and supply) involving substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as risks associated with preclinical and clinical data (including Phase 1/2/3 or Phase 4 data) for BNT162b2 or any other vaccine candidate in the BNT162 program in any of our studies in pediatrics, adolescents or adults or real world evidence, including the possibility of unfavorable new preclinical, clinical or safety data and further analyses of existing preclinical, clinical or safety data; the ability to produce comparable clinical or other results, including the rate of vaccine effectiveness and safety and tolerability profile observed to date, in additional analyses of the Phase 3 trial and additional studies, in real world data studies or in larger, more diverse populations following commercialization; the ability of BNT162b2 or any future vaccine to prevent COVID-19 caused by emerging virus variants; the risk that more widespread use of the vaccine will lead to new information about efficacy, safety, or other developments, including the risk of additional adverse reactions, some of which may be serious; the risk that preclinical and clinical trial data are subject to differing interpretations and assessments, including during the peer review/publication process, in the scientific community generally, and by regulatory authorities; whether and when additional data from the BNT162 mRNA vaccine program will be published in scientific journal publications and, if so, when and with what modifications and interpretations; whether regulatory authorities will be satisfied with the design of and results from these and any future preclinical and clinical studies; whether and when submissions to request emergency use or conditional marketing authorizations for BNT162b2 in additional populations, for a potential booster dose for BNT162b2 or any potential future vaccines (including potential future annual boosters or re-vaccinations) and/or other biologics license and/or emergency use authorization applications or amendments to any such applications may be filed in particular jurisdictions for BNT162b2 or any other potential vaccines that may arise from the BNT162 program, including a potential adapted, variant based, higher dose, or bivalent vaccine, and if obtained, whether or when such emergency use authorizations or licenses will expire or terminate; whether and when any applications that may be pending or filed for BNT162b2 (including any requested amendments to the emergency use or conditional marketing authorizations) or other vaccines that may result from the BNT162 program may be approved by particular regulatory authorities, which will depend on myriad factors, including making a determination as to whether the vaccine’s benefits outweigh its known risks and determination of the vaccine’s efficacy and, if approved, whether it will be commercially successful; decisions by regulatory authorities impacting labeling or marketing, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of a vaccine, including development of products or therapies by other companies; disruptions in the relationships between us and our collaboration partners, clinical trial sites or third-party suppliers; the risk that demand for any products may be reduced or no longer exist; risks related to the availability of raw materials to manufacture a vaccine; challenges related to our vaccine’s formulation, dosing schedule and attendant storage, distribution and administration requirements, including risks related to storage and handling after delivery by Pfizer; the risk that we may not be able to successfully develop other vaccine formulations, booster doses or potential future annual boosters or re-vaccinations or new adapted vaccines, including variant based vaccines; the risk that we may not be able to maintain or scale up manufacturing capacity on a timely basis or maintain access to logistics or supply channels commensurate with global demand for our vaccine, which would negatively impact our ability to supply the estimated numbers of doses of our vaccine within the projected time periods as previously indicated; whether and when additional supply agreements will be reached; uncertainties regarding the ability to obtain recommendations from vaccine advisory or technical committees and other public health authorities and uncertainties regarding the commercial impact of any such recommendations; challenges related to public vaccine confidence or awareness; uncertainties regarding the impact of COVID-19 on Pfizer’s business, operations and financial results; and competitive developments.

A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2021 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “Forward-Looking Information and Factors That May Affect Future Results”, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at and

About BioNTech
Biopharmaceutical New Technologies is a next generation immunotherapy company pioneering novel therapies for cancer and other serious diseases. The Company exploits a wide array of computational discovery and therapeutic drug platforms for the rapid development of novel biopharmaceuticals. Its broad portfolio of oncology product candidates includes individualized and off-the-shelf mRNA-based therapies, innovative chimeric antigen receptor T cells, bi-specific checkpoint immuno-modulators, targeted cancer antibodies and small molecules. Based on its deep expertise in mRNA vaccine development and in-house manufacturing capabilities, BioNTech and its collaborators are developing multiple mRNA vaccine candidates for a range of infectious diseases alongside its diverse oncology pipeline. BioNTech has established a broad set of relationships with multiple global pharmaceutical collaborators, including Genmab, Sanofi, Bayer Animal Health, Genentech, a member of the Roche Group, Regeneron, Genevant, Fosun Pharma, and Pfizer. For more information, please visit

BioNTech Forward-looking Statements
This press release contains “forward-looking statements” of BioNTech within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements may include, but may not be limited to, statements concerning: BioNTech’s efforts to combat COVID-19; the collaboration between BioNTech and Pfizer including the program to develop a COVID-19 vaccine and COMIRNATY (COVID-19 vaccine, mRNA) (BNT162b2) (including an application submission to the FDA for EUA of a potential booster  dose of the Pfizer-BioNTech COVID-19 Vaccine for children 5 through 11 years of age, who have previously received a two-dose primary series of the Pfizer-BioNTech COVID-19 vaccine, and planned submissions to other regulatory agencies, qualitative assessments of available data, potential benefits, expectations for clinical trials, the anticipated timing of regulatory submissions, regulatory approvals or authorizations and anticipated manufacturing, distribution and supply); our expectations regarding the potential characteristics of BNT162b2 in our clinical trials, real world data studies, and/or in commercial use based on data observations to date; the ability of BNT162b2 or a future vaccine to prevent COVID-19 caused by emerging virus variants; the expected time point for additional readouts on efficacy data of BNT162b2 in our clinical trials; the nature of the clinical data, which is subject to ongoing peer review, regulatory review and market interpretation; the timing for submission of data for BNT162, or any future vaccine, in additional populations, or receipt of, any marketing approval or emergency use authorization or equivalent, including or amendments or variations to such authorizations; the development of other vaccine formulations, booster doses or potential future annual boosters or re-vaccinations or new variant based vaccines; our contemplated shipping and storage plan, including our estimated product shelf life at various temperatures; the ability of BioNTech to supply the quantities of BNT162 to support clinical development and market demand, including our production estimates for 2022; challenges related to public vaccine confidence or awareness; decisions by regulatory authorities impacting labeling or marketing, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of a vaccine, including development of products or therapies by other companies; disruptions in the relationships between us and our collaboration partners, clinical trial sites or third-party suppliers; the risk that demand for any products may be reduced or no longer exist; the availability of raw material to manufacture BNT162 or other vaccine formulation; challenges related to our vaccine’s formulation, dosing schedule and attendant storage, distribution and administration requirements, including risks related to storage and handling after delivery; and uncertainties regarding the impact of COVID-19 on BioNTech’s trials, business and general operations. Any forward-looking statements in this press release are based on BioNTech current expectations and beliefs of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: the ability to meet the pre-defined endpoints in clinical trials; competition to create a vaccine for COVID-19; the ability to produce comparable clinical or other results, including our stated rate of vaccine effectiveness and safety and tolerability profile observed to date, in the remainder of the trial or in larger, more diverse populations upon commercialization; the ability to effectively scale our productions capabilities; and other potential difficulties.

For a discussion of these and other risks and uncertainties, see BioNTech’s Annual Report as Form 20-F for the Year Ended December 31, 2021, filed with the SEC on March 30, 2022, which is available on the SEC’s website at All information in this press release is as of the date of the release, and BioNTech undertakes no duty to update this information unless required by law.

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Cystic fibrosis pulmonary exacerbations (CFPExs) are generally defined as a sudden decrease in lung function accompanied by a change in symptoms. Pulmonary exacerbations (PExs) are linked to worsening lung function, low quality of life, increased hospitalizations, and shorter life expectancy in people with cystic fibrosis (CF). Symptoms include coughing, mucus production, and shortness of breath. Lung infections are believed to be the most common cause.

Even though declining lung function accurately describes PExs, there is no universal definition of the condition. This means that there is no standardized treatment for PExs. Therefore, if you develop a PEx, your healthcare provider will create a unique treatment plan based on your symptoms and medical history.

In this article, you learn what CF is, what causes PExs in people with CF, treatment options, and current research on the condition.

Nikodash / Getty Images

What Is Cystic Fibrosis?

Cystic fibrosis is a condition that causes the mucus in your body to become too thick. The organs most heavily impacted by this are the lungs, intestines, sinuses, pancreas, liver, and sex organs. Repeated lung infections and breathing problems are common because the thicker mucus clogs up the lungs. Eventually, this results in lung damage.

People with CF are also at higher risk for developing diabetes, liver disease, arthritis, and osteoporosis (weak and brittle bones).

Chronic Nature of CF

CF is an inherited condition with no cure, so it is considered a chronic disease and must be managed for life with a treatment plan. Symptoms can be mild to severe and either present at birth or appearing later in life. Screening for this disease is done at birth in the United States.

Treatments have greatly improved over the years, so people with CF live well into their 40s, 50s, and beyond. However, living longer means they will be faced with managing multiple chronic conditions, such as PEx.

Facts About Pulmonary Exacerbation (PEx)

There are no standardized treatments for PExs because there is no agreed-upon definition of what it is. Generally, if lung exacerbations increase, a healthcare provider will change the CF patient’s treatment plan. But these changes will be different for every individual.

CF Exacerbations Symptoms

Signs of PEx in CF patients may include some or all of the following symptoms:

  • Decrease in lung function
  • Increase in coughing
  • Increase in mucus and/or change in its color
  • Shortness of breath
  • Decrease in appetite or weight loss
  • Fatigue

These symptoms may come on suddenly or be an increase in severity.

Varying Definitions Can Guide PEx Treatment

Despite there not being a universal definition for the condition, a few widely recognized signs and symptoms of PEx can help guide a diagnosis, including:

  • Having at least four symptoms from a predefined list: Decreased lung function, increased mucus, increased coughing or coughing up blood, increased shortness of breath, fatigue, fever of 100.4 degrees Fahrenheit.
  • When additional antibiotics are needed due to a change in at least two symptoms: Increase in mucus and/or change in color, increased cough, fatigue, weight loss, increased shortness of breath, decrease in lung function, lung changes seen through an x-ray.
  • Three or more symptoms in patients older than 6 years: Decline in FEV1 (forced expiratory volume, the amount of air exhaled in a forced breath in one second), increased cough, new crackles, coughing up blood.
  • Point system to diagnose PEx: Decreased exercise tolerance, increased cough, increased mucus, changes in the lungs on examination, decreased appetite, change in FEV1.
  • One to two symptoms of the following: Fever of 100.4 degrees or more, 50% increase in cough and/or mucus, weight loss, work or school absence (three of previous seven days), upper lung infection, decrease in FEV1 of at least 10%, an increased breathing rate, elevated white blood cell count (from list two).

"Lung Attack" Responsible for CF Mortality

PEx, COPD (chronic obstructive pulmonary disease) exacerbations, and asthma are all considered “lung attacks.” Patients with CF that have regular PExs experience a rapid decline in lung function and have an increased risk of needing a lung transplant or death.

Even though CF treatments have greatly improved and contributed to longer life expectancy, PEx rates have not decreased in the same manner. Early detection of PEx is critical because of its link to a decline in lung function, poor quality of life, and premature death.

PEx Treatment Options

Treatment options for PEx include antibiotics, corticosteroids, and pulmonary rehabilitation. There are also special considerations for treating PEx in children. Early diagnosis and treatment help increase quality of life and survival.


CF patients with PEx may be treated with oral, inhaled, or intravenous (IV, within a vein) antibiotics. It is estimated that 25%–35% of adults with CF have chronic airway infections with bacteria that are resistant to multiple antibiotics. A combination of antibiotics will be prescribed to prevent drug resistance. Your healthcare provider will decide which is best based on the PEx severity.


A short course of corticosteroids may be beneficial for a PEx, but research does not support this being a standard for treatment. Studies show that corticosteroids are not always effective at reducing inflammation from a PEx, especially if it is severe. Currently, there is an ongoing large clinical trial to determine the role of steroids in CF pulmonary exacerbations.

Pulmonary Rehabilitation

Pulmonary rehabilitation (PR) is an exercise program that helps improve lung function for people with chronic breathing problems. PR acts as a supplement to your treatment plan and may include the following:

  • Exercise training: This will help improve endurance and muscle strength.
  • Nutritional counseling: Being overweight or underweight can cause breathing difficulties.
  • Disease management education: You will learn how to avoid situations that can cause PEx (such as infections) and how to best take your medications.
  • Techniques to help save energy for daily tasks: You will learn how to move in specific ways that are easier on your lungs and stress management to help you stay calm.

PEx In Children

Children who have PEx can also be treated with antibiotics. However, signs, symptoms, and diagnosis look different compared to adults. For instance, the type of intervention to ease symptoms (such as antibiotics) is sometimes used to diagnose PEx in adults. But it is recommended that healthcare providers rely on symptoms alone to diagnose PEx in children.

In addition, PEx in children is typically triggered by a viral infection, but symptoms tend to be mild. Blood oxygen may still be normal. The most common symptoms include:

  • Cough
  • Wheeze
  • Fever
  • Runny nose

Co-Occuring Conditions

While chronic lung disease is the main complication of CF, other parts of the body can be impacted as well. This means CF patients will have a higher risk of other conditions such as diabetes, arthritis, liver disease, infertility, and intestinal issues.

Nutritional Considerations

CF can cause digestive problems such as constipation, gas, nausea, weight loss, pale stools, and malnutrition. Treatments for these issues can include:

  • A diet high in protein and calories
  • Pancreatic enzymes to help your body absorb fats and protein
  • Supplements like vitamin K, D, E, and A
  • Treatment for constipation

Lung Health and PEx Recovery

Preventing chronic PEx can be challenging, especially for CF patients. However, doing everything you can to avoid PEx will protect your lungs from long-term damage and a decline in lung function.

Good nutrition, controlling blood sugar (if you have diabetes), and getting treatment as soon as you think you may have PEx will provide an excellent foundation to safeguard lung function. Because there is no universal standard for PEx treatments, your healthcare provider will decide what treatments are right for you. With treatment, most people recover from PEx within a few weeks.


Cystic fibrosis (CF) is a condition that makes the mucus inside your body thick and sticky. Symptoms include coughing, wheezing or shortness of breath, increased mucus, and fatigue. This causes chronic lung disease and puts you at risk for pulmonary exacerbations (PEx).

Because there is no standard for diagnosis or treatment, your healthcare provider will use their professional judgment to determine if you have PEx and what treatments will help you. Antibiotics are prescribed for most PEx episodes. PEx in children can be challenging because their symptoms are usually mild, and their oxygen levels may be normal during an episode of PEx.

Other treatments for PEx may include corticosteroids or pulmonary rehabilitation (PR). PR will help you learn how to do daily tasks that will not negatively impact your breathing and trigger PEx. However, research does not support the use of corticosteroids for PEx, especially if symptoms are severe.

Chronic PEx will cause long-term damage to your lungs and cause poor lung function. Eating a CF-friendly diet (high calorie, high protein), following your treatment plan, and checking in with your doctor when you believe you may have PEx is the best prevention.

A Word From Verywell

Cystic fibrosis can cause multiple chronic illnesses at the same time. While there is no cure for CF, treatments have greatly improved over the years.

It can be extremely challenging to prevent lung infections and chronic pulmonary exacerbations. However, preventing PEx is the only way to protect your lung health and preserve lung function. Get familiar with your baseline lung function so that if anything changes, you can see your healthcare provider right away to get treatment. Eat well, exercise, and take all prescribed medicines as directed.

If you find that you are having more PExs than usual or having a new onset of PEx, consider talking to your healthcare provider about the possibility of changing your treatment plan.

Frequently Asked Questions

  • How long do CF pulmonary exacerbations last?

    PEx can last for just a few days or a few weeks, depending on its severity and how quickly treatment clears up symptoms.

  • Do patients with mild cystic fibrosis have PEx symptoms?

    Because people with atypical CF may have mild dysfunction in at least one organ system, such as the lungs. Therefore, it is possible for them to have PEx symptoms.

  • How effective are antibiotics for CF?

    Oral antibiotics are the most common treatment for PEx in patients with cystic fibrosis. It can take a few days to a few weeks for symptoms to subside.

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With the demands of busy modern life, it can sometimes feel like fitting exercise and muscle recovery into your everyday routine is impossible. Our muscles decline with age, running the risk of conditions like sarcopenia and frailty. Prioritising exercise and recovery is therefore a long-term investment into your health, longevity, and enjoyment of life. There are several strategies you can use to take control of muscle recovery.

What is muscle recovery?

Exercise affects our body’s natural equilibrium, known as homeostasis, in several ways. We can feel some of these changes immediately, for example our breathing and heart rate accelerate during exercise in order to provide the body with enough oxygen. Exercise also requires a lot of energy, which the body provides through adenosine triphosphate (ATP), used to power our muscles. ATP is produced by the mitochondria, known from biology class as the powerhouse of the cell. If there’s not enough oxygen available, ATP is instead produced using a different process, the by-product of which is lactic acid.

Changes also happen in our muscles. During exercise, especially strength-based training, muscle fibres are forced to contract and stretch repeatedly. This causes tiny tears in the muscle fabric. While this process is necessary to building muscle, these tears, as well as lactic acid, can cause muscle soreness after exercise. While this may be uncomfortable in the short term, the stress exercise exposes your muscles to actually leads to larger gains in the long term.

This is where muscle recovery comes in. As exercise stops and we enter the cool down period, your body will return to normal homeostasis. This gives your body a chance to repair muscle damage and clear any residual lactic acid from exercise. So-called satellite cells swarm to the site of the microscopic muscle tears. Here, they form a new muscle protein strand to help prepare the muscle for future exercise. The rest period is therefore as important as exercise itself, as this is when muscles are rebuilt bigger and stronger.

We all know the distinct feeling of muscle fatigue the day after a workout. Taking a rest day to recover your muscles is integral to building and strengthening our muscles. But what if there was a way to accelerate this process?

How long does it take for your muscles to recover?

How long it takes for your muscles to recover depends on the intensity, type and duration of exercise as well as your individual fitness level.  In general though, muscle repair after particularly intense exercise can take between 24 and 48 hours. There is much debate around which type of muscle recovery is more effective, active or passive. Active recovery involves doing low-impact exercise to recover from a more intense work out, for example by walking or cycling. While passive recovery requires no movement at all. Active recovery appears to clear lactic acid from your muscles more quickly than passive recovery as it keeps your heart rate up [1].

How to improve muscle recovery

While the pain we go through during exercise makes us stronger, many people seek to speed up the recovery process. There are several different methods to do this, but how effective are they?

Foods that improve muscle recovery

Eating a healthy, balanced diet is always beneficial to health and longevity. In fact, nutrition is thought to be the easiest and more effective lifestyle change we can make to lose weight, protect health and improve longevity. Building muscle is as much to do with diet as it is with exercise, so can the benefits of a balanced diet be extended to improving muscle recovery?

Eating a healthy, balanced diet is always beneficial to health and longevity.
  • Our muscles are made of protein, so it makes sense that eating more protein before and after workouts would boost muscle recovery. Indeed, one study showed that eating 20-40 grams of high-quality protein pre- and post-workout can boost muscle protein synthesis after exercise [2]. In practice, this could look like one serving of grilled chicken, Greek yogurt or a tin of tuna.
  • Carbohydrates are stored as glycogen and used as fuel for ATP during exercise. Therefore, eating more carbohydrates before exercise will give us more energy, see the pre-marathon tradition of eating carb-high meals like pasta. This can also be done post-workout to restore the glycogen used up during exercise.
  • Eating a balanced diet. As well as boosting health and longevity, getting enough nutrients through a balanced diet full of colourful fruit and vegetables can help your muscles’ ability to recover.

Read more about the ‘longevity diet’ for improving health and lifespan HERE.

Drinks for faster muscle recovery

What we drink can also have an impact on how well our muscles recover after exercise. We need water to survive, especially during exercise when we lose water through sweat and respiration in a hot and sweaty gym hall. Replenishing water during and after exercise is integral to making you as well as your muscles feel better, as dehydration can impair muscle recovery.

Less conventional libations include tart cherry juice, which consumed before and after exercise can reduce inflammation, muscle damage and soreness after exercise [3]. This makes a natural alternative to so-called sports drinks laced with glucose designed to replenish energy after exercise. However, considering their high concentrations of sugar, additives, and citric acid, they are more suited to marathon runners than casual gym-goers.

Less conventional libations include tart cherry juice, which consumed before and after exercise can reduce inflammation, muscle damage and soreness after exercise

The best supplements for muscle recovery

Many people are supplementing their diet with protein powders to top up their protein intake and build and improve muscles. A variety of options are available on the market using protein from plants, eggs or milk. However, some protein powders contain other ingredients like added sugars, flavourings and thickeners. While considerably safer than using anabolic steroids, it may be healthier to get your protein from high-quality sources in your diet than in powdered form.

A more effective way of improving muscle strength and recovery is by using urolithin A, the powerful postbiotic that is produced in the gut after eating certain foods like pomegranate. A simpler way to get enough urolithin A is by taking Timeline supplements that contain 500mg of Mitopure’s purified urolithin A. Our muscles are powered by the ATP produced by mitochondria, which are most concentrated in muscle cells. With age, our mitochondria can wear out, hastening muscle fatigue. Luckily, urolithin A can trigger mitophagy, the process by which old and dysfunctional mitochondria and cleared. It has also been shown to maximise muscle endurance in human clinical trials. Regularly taking Mitopure supplements could therefore help maintain mitochondria and muscle health as we age.

Many people are supplementing their diet with protein powders to top up their protein intake and build and improve muscles.

Healthy habits to help muscle recovery

Our general health is determined by a complex interplay of our genetics, lifestyle choices, and a combination of both known as epigenetics. Therefore, there are other lifestyle habits that can impact muscle recovery along with what we consume.

  • Tailor your exercise routine. The type, duration and intensity of your chosen exercise greatly impacts muscle recovery. For example, a marathon runner stresses very different muscles than a weightlifter does. It is therefore important to tailor your recovery to your workout. Endurance training like cycling or running works out multiple groups of muscles and has holistic health benefits. It therefore also requires full-body recovery. Whereas strength training, working out specific muscle groups through repetitive reps using weights, resistance bands or your own bodyweight requires more localised recovery. Some exercise, like swimming, combines these two types of exercise and require their own type of recovery.

Varying your workouts so you’re exercising different muscle groups can help hasten muscle recovery. Follow a day of running with weightlifting so you’re resting one part of your body while training another. As you build your fitness, your recovery time should also improve. It is a good idea to scale up your training, to push your fitness as well as your recovery capacity.

  • Take rest days. As well as alternating muscle groups, it is important to leave gaps for rest days in your weekly exercise schedule. While it may be tempting to do as much exercise as possible to maximise your gains, you’re actually doing your muscles a disservice – as well as increasing the chance of muscle strain and injuries. As well as active and passive recovery periods during exercise, it is important to leave days blank for full recovery. If you’re not allowing your muscles the chance to recover fully, you could accumulate minute muscle tears that could lead to muscle strains. As well as being painful, these can also impair your athletic performance.
  • Get more sleep. There’s nothing like a good night’s sleep following exercise. Working out tires out your body, so you may need extra sleep to compensate. Sleep allows your heart to recover, promotes cellular growth and muscle repair. Research into sleep agrees that seven hours a night is the optimal amount of sleep for better health and longevity. If you’ve been working out, your body may require even more. However, it is important not to indulge in too many long lies, as chronic oversleeping as well as under-sleeping has been implicated in the development of chronic diseases. Sleep should therefore be as big a priority in your fitness routine as nutrition and exercise itself.
As well as alternating muscle groups, it is important to leave gaps for rest days in your weekly exercise schedule.

Things to avoid for better muscle recovery

We all need to occasionally indulge in things branded as ‘bad’ for us to fully enjoy our lives. However, we all know that vices such as smoking, unhealthy foods and excessive alcohol consumption are bad to health and longevity and should be kept to a minimum. They can also impair exercise performance and muscle recovery.

A glass of red wine may be a staple of longevity-boosting Mediterranean diets, excessive alcohol consumption is unfortunately perilous to health and lifespan. Many team sports promote the culture of hard drinking after training sessions. One study investigated the effect of this on athletes’ muscle recovery and found that alcohol consumption impairs protein synthesis after exercise [4]. Try to keep alcohol consumption to a minimum for holistic health benefits, and especially after training to avoid impairing muscle recovery.

The negative health impacts of smoking tobacco have been in public knowledge since the 1960s. As well as severely impacting your fitness and lung capacity, smoking can also affect your musculoskeletal system, hindering muscle recovery [5]. Studies have linked smoking with increased risk of muscle injury, joint disease and broken bones. It therefore should be avoided to boost your general fitness as well as your muscle recovery.



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Chronic obstructive pulmonary disease (COPD) is a major public health problem and is the third leading cause of death in China.1 According to Global Strategy for the Diagnosis, Management, and Prevention of COPD (GOLD) 2022,2 pulmonary rehabilitation (PR) as one of the effective non-pharmacological therapies was recommended in COPD patients, to improve their symptoms, activities of daily living, muscle and emotional function as well as quality of life. Although the improvements of PR were well documented, these benefits could decrease gradually over time.3,4 Therefore, researches explored long-term maintenance strategies to extend PR benefits. Based on the results of recent studies,5,6 GOLD 2022 stated that a maintenance program should be provided to patients to increase and maintain activities of daily living.2

Despite the benefits, different PR maintenance programs were also challenged by many difficulties, such as distance to obstacle,7 lower frequency8 and unsupervised maintenance exercise.9 Recently, the American Thoracic Society (ATS)/European Respiratory Society (ERS) statement recommended that tele-rehabilitation was regarded as an alternative approach to increase the long-term degree of participation for PR maintenance,10 making it more efficient and feasible. Tele-rehabilitation involves the delivery of medical rehabilitation services to patients remotely via electronic information and social media.11 For example, one study of 10 patients with COPD investigated the effectiveness of telerehabilitation maintenance indicating that the strategy can decrease the frequency of acute exacerbation of COPD, improve health status and QoL.12 Recently, an intervention of PR maintenance strategy via tele-contact provided relevant clinical benefits on reduction in risk of exacerbation of COPD, hospitalization at the end of one-year follow-up.13 Moreover, Twitter and Facebook can provide convenient visual guidance and supervision to participants, results in improving the maintenance efficiency.14 To date, accumulating evidence indicates improvement from telerehabilitation. Although the results are promising, a system review showed that QoL, and exercise capacity could be possibly improved via supervised PR maintenance (telephone or web platform) but with low strength evidence due to high risk of bias.15 Likewise, other limitations such as high dropout rate, short PR maintenance duration, small sample size or poor adherence,16,17 made the value of telerehabilitation maintenance limited.

WeChat has rapidly developed into a comprehensive information platform integrating communication, entertainment, search, office collaboration, corporate customer service and medicine in China.18 The recent study indicated that WeChat app-based education and rehabilitation could reduce the emotional dysfunction such as anxiety, depression and improve QoL in non-small lung cancer patients undergoing surgery.19 It is reasonable to apply new technology in PR maintenance management in patients with COPD. Thus, we established a new system for PR maintenance under the WeChat platform. To our knowledge, our study is the first prospective clinical trial to explore a new WeChat PR maintenance strategy to maintain the clinical improvements of an initial PR program in Tianjin, North China.


Study Design and Participants

A one-year single-center random clinical trial was conducted by Tianjin Chest Hospital to investigate the effect of home-based maintenance strategy via WeChat and hospital-based maintenance compared with usual care (ChiCTR1900021320) from January 2019 to March 2021. Patients were enrolled by respiratory department in Tianjin Chest Hospital, which is a tertiary hospital offering specialized medical care in pulmonary and cardiovascular diseases. We included patients who were 1) having a diagnosis of stable COPD in the first 4 weeks according to guideline,2 2) able to complete the PR program and questionnaire survey successfully and independently, and 3) able to use WeChat proficiently. The exclusion criteria included the following: 1) having asthma; obstructive sleep apnea syndrome; underdiagnosis of cancer; diagnosed with Alzheimer’s disease or depression and anxious disorder, 2) having severe dysfunction of the heart, liver, or kidney, 3) unavailable for exercise, 4) suffering emotional trauma in the previous 6 months such as relative death and divorce, 5) life expectancy less than 1 year, and 6) history of PR exercise for a long time (≥3 times/week, ≥20 minutes/time, persisting for more than 12 months). All of the patients were requested to perform an 8-week primary PR program. Then, eligible participants were randomized after baseline post-PR measure on a 1:1:1 basis using a computer-generated randomized sequence to two interventional groups and one control group of the following. After the generation of this sequence, the envelopes were created, numbered in the appropriate order, and contained the result of the allocation. The order of the envelopes’ number was defined based on the order of participants’ enrollment. Randomization was independent of the control of the principal investigator, thereby maintaining a minimization randomization process. Based on intervention during follow-up, patients were allocated into Group A: PR maintenance via WeChat at home, Group B: PR maintenance at hospital, or Group C: Usual care throughout 12-month observation without maintenance. All patients provided written and verbal informed consent. This study was approved by the Ethics Committees of Tianjin Chest Hospital (No. 2019KY-004-01), and was conducted in accordance with the Declaration of Helsinki.

PR Intervention

The initial 8-week PR includes; (A) upper resistance training, (B) aerobic training, (C) balance and flexibility training, (D) respiratory training, and (E) health education and self-management. The details of PR physical sessions are well documented in our previous study.6 The session of health education and self-management help COPD patients to acquire the skills they need to carry out disease-specific medical regimens, guide changes in health behavior and provide emotional support to enable them to control their disease.20

Maintenance Strategy

After the initial 8-week PR, the patients of Group A performed the maintenance exercises at home via WeChat supervision. We established a PR maintenance group-chat platform team, which consisted of respiratory specialists, physiotherapists, pharmacists, nutritionists, and nurses. The respiratory specialists and head nurse served as the team leaders and were responsible for the operation and guidance of the project. The PR guideline video was uploaded once a week by physiotherapists. The home-based PR maintenance program was requested twice a week and completion of exercise had to be uploaded in time by participants. Patients could also upload their training pictures or speeches. Other patients and PR teammates can interact with them by commenting or giving thumbs up, thus promoting not only peer support between patients but also communication between doctors and patients. Moreover, the physiotherapists were also responsible for making tailored prescriptions and sending it to the patients via private message. Patients could get the electronic PR prescription and contact a nurse online if the training program needed to be adjusted. The pharmacists were in charge of pharmacological therapy including the correct use of any prescribed respiratory medicine. Recognition of exacerbations of COPD, information for the family and social support were also provided by nurses via the WeChat platform. The PR teammates will answer the questions raised by patients in the platform by different message forms, such as text, voice, picture and video from 8am to 8pm every day. The information of health education and skill of self-management were also announced in this WeChat group regularly.

As for patients of Group B, they continued to perform the same maintenance training sessions twice a week at the out-patients department in hospital when they accomplished the primary 8-week PR. The consultant for pharmacology and nutrition was also offered by our PR team.

After the initial PR, the patients in Group C were only offered the health consultant including cigarettes cessation, long-term oxygen therapy, correct use skill of respiratory medicine, symptoms management, and nutrition without any exercise.


The assessments below were performed before and after the integrated PR program as well as every three months in the outpatient department with the same physiotherapist during follow-up, aiming to supervise and evaluate the change of health status in COPD patients.

Primary Outcomes Measure

The numbers of acute exacerbation of COPD, hospitalizations due to acute exacerbation of COPD and ED visits, were compared among the three groups over one year following completion of the initial PR program. Acute exacerbation of COPD is defined as an acute worsening of respiratory symptoms that result in additional therapy according to GOLD.2 Hospitalizations (severe exacerbations) and Emergency Department visits (ED visits) because of acute exacerbation of COPD were also assessed.

Secondary Outcomes Measure

1) Spirometry, such as forced expiratory volume in 1 s (FEV1), FEV1% pred, forced vital capacity (FVC), FEV1/FVC%. Spirometry was measured at the baseline and post inhaling bronchodilator respectively.2

2) Physical capacity assessment: Six-minutes walking test (6MWT) will be recommended. According to protocol of American Thoracic Society,21 patients walk as long as they can in a 30-meter straight corridor in six minutes without any interruption. The valid distances they completed were recorded when they finished the test.

3) Chronic Obstructive Pulmonary Disease Assessment Test (CAT),22 CAT was used to evaluate the Health-Related Quality of Life (HRQoL) for follow-up.

4) Modified Medical Research Council scale (mMRC)23 was applied to assess the severity of breathless. The mMRC is an effective and convenient evaluation of clinical methods for rating apnea, which can be performed under different conditions for COPD patients.

5) Beck Depression Inventory (BDI) and State-trait Anxiety Inventory (STAI).24 The content of BDI includes 21 items including evaluation of nervousness, dizziness, inability to relax. STAI is aimed at measuring severity of current anxiety and tendency to be anxious.

6) Instrumental Activities of Daily Living (IADL). Measuring IADL is one of the best ways to evaluate the level of health,25 assess the progress of the disease, and evaluate the efficacy of rehabilitation or other treatments in patients with COPD.

Once any accident events of tachycardia (higher than 85% of target HR), hypoxia (pulse oxygen saturation (SaO2) is lower than 10% of baseline), hypertension (blood pressure is higher than 200/100 mmHg), and syncope were observed during exercise, patients are forbidden to continue training and given therapy immediately.

Study Procedures

The outcomes of all subjects were evaluated at baseline before primary 8-week PR, and immediately after completion of the PR program in all three groups. Then, the patients of Group A performed the maintenance exercise described above at home with WeChat supervision during 12-month follow-up, while Group B did the maintenance training at the out-patient department in hospital for one year. For Group C, only health suggestions were provided without any form of rehabilitation exercise following completion of the initial PR. The regular reviews were applied every three months during the one-year follow-up by the same physiotherapists.

Sample Size

The sample size requirements for this study were intended to provide adequate power for the analysis of the primary outcome. In the current study, the calculation of sample size was based on ANOVA repeated measurements between the three groups. From the previous study with patients with similar characteristics,26 we estimated the power calculation by using the minimum detectable difference in the number of acute exacerbations of COPD. This previous study assessed the effect of PR program on frequency of acute exacerbation of COPD before and after PR. The mean number of acute exacerbations of COPD was reduced from 4.56 in the year preceding PR to 3.18 (a mean difference (1.37) and SD (3.26), an effect of size 0.4) in the year following PR. We calculated that a sample size of 114 patients would achieve a power of 0.90, with a type-I error (α) of 0.05 (two-sided). To compensate for a potential dropout rate of 20%, 136 patients (46 patients in each group) will be enrolled.

Statistical Analysis

The Shapiro–Wilk test revealed that all data were normally distributed. Descriptive data for the three groups are presented as mean and SD for continuous variables and frequency for categorical variables. One-way analysis of variance (ANOVA) was used to compare differences among the three groups at baseline for all variables. Pair-wise Tukey’s post-hoc analysis was used to compare all pairs of variables in each group of pre- and post-initial PR. We applied repeated-measure ANOVA and multivariate ANOVA to test the differences over time in 6WMD, CAT, mMRC, BDI, SAI, TAI and between-group differences. Time to first AECOPD for each group were analyzed by Kaplan–Meier survival curves and Log rank tests. We analyzed data via SPSS, version 22.0 software (SPSS Inc., Chicago, IL, USA). A probability P-value of <0.05 was considered statistically significant.


150 eligible patients with COPD who met the inclusion criteria and accomplished the baseline assessments (Table 1) undertook the primary pulmonary rehabilitation program at the out-patient department in Tianjin Chest Hospital for 2 months. At the end of the PR, 148 participants were randomized and evaluated again with the exception of two subjects who were excluded due to transportation. During the one-year observation, 3 patients were excluded due to lack of motivation in Group A, while 5 quit the maintenance PR because of transportation problems, lower exercise self-efficacy and an adverse event in Group B (Figure 1).

Table 1 Demographic and Clinical Characteristics of Patients at Baseline (N = 150)

Figure 1 Flow chart of the study population.

Effect of PR

Compared to pre-PR, the patients in all groups had statistically significant improvements in the 6MWD, mMRC, CAT and emotional evaluation at the end of primary PR (post-hoc paired t-tests), particularly the difference for change in 6MWD in Group A and Group C that exceeded 26 m which is considered a minimal clinically important difference (MICD) in patients with COPD.27 The between-group differences in each outcome measures after initial PR showed no statistical significance analyzed by one-way ANOVA (Table 2).

Table 2 The Differences of Clinical Improvements Between Pre- and Post-PR in All Three Groups

The Frequencies of Acute Exacerbation, Hospitalization, and ED Visits

In comparison with the baseline, the frequencies of acute exacerbation of COPD, hospitalization, and ED visits all showed a significant decline at the end of one-year follow-up both in Group A (3.4 ± 1.5 vs 2.6 ± 1.2, p = 0.011; 1.4 ± 0.9 vs 0.9 ± 1.2, p = 0.027; 3.1 ± 1.7 vs 1.5 ± 1.8, p < 0.001) and Group B (3.2 ± 1.3 vs 2.5 ± 1.6, p = 0.004; 1.5 ± 1.2 vs 1.0 ± 1.4, p = 0.018; 3.3 ± 1.4 vs 2.6 ± 1.2, p < 0.001), analyzed by post hoc paired t-tests. Moreover, the frequencies of AECOPD after one-year PR maintenance in Group A and Group B were both lower than Group C (2.6 ± 1.2, 2.5 ± 1.6 vs 3.5 ± 1.3, p < 0.05, respectively). Similarly, the numbers of hospitalization for AECOPD in Group A and Group B were lower than Group C (0.9 ± 1.2, 1.0 ± 1.4 vs 1.4 ± 0.9, p < 0.05, respectively). Finally, the ED visits after one-year observation in Group A were lower than Group B and Group C (1.5 ± 1.8 vs 2.6 ± 1.2, 3.1 ± 1.9, p < 0.05, respectively).

The Kaplan–Meier curves evaluating the time to first acute exacerbation of COPD during our follow-up are shown in Figure 2. In the univariate regression analysis, significant predictors of AECOPD were smoking status, exacerbation numbers in the prior year and PR (either home-based maintenance via social media or hospital-based maintenance) (Table 3). In multivariate analysis, PR is an independent predictor of lower risk for acute exacerbation of COPD in the one-year follow-up for home-based maintenance via social media (incidence rate ratio (IRR) 0.712, 95% CI 0.595–0.841; p < 0.001) and hospital-based maintenance (incidence rate ratio (IRR) 0.799, 95% CI 0.683–0.927; p = 0.002), respectively (Table 3).

Table 3 Predictors of Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Figure 2 Kaplan–Meier estimates of the time to next COPD exacerbation. Group A: PR Maintenance at home via WeChat. Group B: PR Maintenance at hospital. Group C: Usual care. The COPD exacerbation refers to all types of acute exacerbation of COPD, including mild, moderate and severe.

One-Year Follow-Up Maintenance

During one-year follow-up, the 6MWD in Group A and Group B increased over time from month 3 to month 12, compared to month 0 (p < 0.001). In contrast, the result of 6MWD in Group C showed a decreased trend from month 6, and it declined below the level of month 0 at the end of observation (p < 0.001). The between-group differences (F(2, 136)= 5.834, p = 0.025), the time effect (F(4, 544)= 178.872, p < 0.001) and the time*group interact effect of 6MWD (F(8, 544)= 88.957, p < 0.01) showed significance when analyzed by repeat-measure ANOVA (Figure 3A).

Figure 3 Patterns of change of 6MWD, mMRC, CAT (AC), BDI, SAI, TAI (DF) over study of 12-month follow-up between groups. Data shown are mean values with error bars representing SE. Circles are values for the home-based PR maintenance via WeChat group (Group A), squares are values for hospital-based PR maintenance group (Group B), triangles are values for usual care group (Group C). Month 0 is the time point when patients completed the initial 8-week PR. *Significant differences of between-group over time (p < 0.05).

Compared to month 0, the mMRC scores in Group A showed significant decrease in month 3, and then increased gradually from month 6 to month 12, but was still lower than the level of month 0 (p < 0.05). Similarly, the trend of mMRC scores in Group B showed a decline from month 3 to the end without any increase (p < 0.05). To the contrary, in Group C, the mMRC scores decreased initially and increased over time to the end (p < 0.001). The between-group differences (F(2, 136)= 23.433, p < 0.001), the time effect (F(4, 544)= 57.976, p < 0.001) and the time*group interact effect (F(8, 544)= 52.25, p < 0.001) showed significance when analyzed by repeat-measure ANOVA (Figure 3B).

The scores of CAT in Group A and Group B showed a similar trend which decreased from month 3 to month 12 (p < 0.001), while after the initial smooth decrease by month 3, the scores of CAT in Group C increased from month 6 to the end of observation. The between-group differences, the time effect and the interact effect of CAT showed significance analyzed by repeat-measure ANOVA (F(2, 136)= 12.489, p = 0.014; F(4, 544)= 150.404, p < 0.001; F(8, 544)= 20.764, p < 0.001, respectively) (Figure 3C).

During maintenance observation, BDI (Figure 3D), SAI (Figure 3E) and TAI (Figure 3F) did not show significant between-group differences over time (p > 0.05). Similarly, neither time effect (p > 0.05) nor interact effect (p > 0.05) of BDI, SAI, or TAI showed significant difference when analyzed by repeat-measure ANOVA.


The main finding of the present study was that the PR maintenance strategy (both home-based WeChat-supervised maintenance and hospital-based maintenance) could preserve, even extend the effect of initial PR benefits on the performance of exercise tolerance, HRQL. After one-year follow-up, the frequency of AECOPD, hospitalization due to AECOPD and ED visits all showed significant decline in patients with COPD applying PR maintenance in Groups A and B, compared to the non-maintenance group. Moreover, home-based PR maintenance was as effective as the hospital-based PR maintenance and superior to non-maintenance in reducing the acute exacerbation of COPD during long-term follow-up. Finally, PR maintenance was an independent predictor of decreased risk for acute exacerbation of COPD.

In a previous study, the improvements pulmonary rehabilitation provided to COPD patients was preserved for a short term, most of the PR gains diminished over time without any maintenance.28 In the present study, we reached a similar conclusion that the effect of the initial 8-week PR provided to the patients in Group C faded gradually during the one-year follow-up. By contrast, the PR maintenance which was provided in Group A and Group B preserved, even extended, part of the benefits of initial PR at the end of follow-up. Therefore, PR maintenance strategy was recommended in GOLD 2022 recently.2 With respect to the reduction of risk for acute exacerbation of COPD in our study, the patients in PR maintenance groups were at a lower risk of deterioration than the non-PR maintenance group. This result was consistent with previous randomized controlled trials (RCT) which applied the similar long-term PR maintenance strategy.29,30 Indeed, program components including the suitable intensity of exercise, integrated skill for recognition of exacerbation, encouragement and support from family or physicians, even the nutrition and medicine information were provided to patients regularly during the maintenance follow-up. As a result, these patients taking part in and completing the structured maintenance program will have more chance to alleviate symptoms as well as decrease the risk for deterioration of COPD, hospitalization and ED visits, compared to the usual care strategy. Therefore, these findings implied that the PR maintenance strategy should be continued to be offered to patients who have a higher risk of exacerbation and more symptom burden in daily lives following an initial PR program, and as an extension of pulmonary rehabilitation. Moreover, maintenance could not only provide potential sustaining clinical improvements but also reduce the substantial healthcare cost to society.

In the last decade, studies have demonstrated the efficacy and safety of the technology-based interventions in promoting the physical activity, improving HRQL, monitoring physiological signs and reducing acute exacerbation in COPD.31–33 With the rapid development of internet technology, smart devices, and social media, information communication via network is convenient and accurate. WeChat is the most popular social network platform in China.34 In recent years, the “Internet Medical” model covers the shortage of unbalanced distribution of medical resources around the world, such as Twitter and Facebook, have been steadily applied in medical education.35,36 Likewise, WeChat has been gradually used in medical education and the follow-up of patients in China, and it has reported benefits in clinic. The recent study indicated that WeChat app-based education and rehabilitation could reduce emotional dysfunction such as anxiety, depression and improve HRQLin non-small lung cancer patients undergoing surgery.19 Another recent clinical trial demonstrated that WeChat PR strategy provided a greater improvement in HRQL, lung function, and showed better adherence.37 In the current study, we applied WeChat PR maintenance strategy in Group A. The patient-physician communications in this remote model were accomplished via smartphone applications which provided all PR maintenance components to patients and gave feedback or suggestions by clinicians according to uploaded patients’ vital signs during exercise. As a consequence, the novel remote PR maintenance model has a similar effect on clinical improvements and reduction of risk for AECOPD to the hospital-based PR maintenance group. This conclusion may be useful to inform the decision-making on resource allocation.38

Despite the clear evidence of benefit of hospital-based PR on physical activity and HRQL, the insufficient funding, imbalance resource allocation, and distance obstacle made value of traditional PR limited.39 Recently, many more studies have focused on implementing behavior-targeted interventions to improve physical activity via technology and the internet,40–42 and demonstrated the positive effect on reducing on risk for AECOPD. A systematic review from Cochrane database also illustrated that social media intervention may be effective at improving physical activity and well-being, which included 88 studies (871378 participants).14 Therefore, this novel remote maintenance model might be used to deliver alternatives to conventional PR across wide geographical areas, especially during the COVID-19 pandemic.

Although the PR is recommended2 and well documented in high-income countries’ COPD guidelines,3,43 the PR services are not widely available in low-income and middle-income countries (LIMICs) where the prevalence of COPD is higher and evidence of benefit of PR is very small.44 Whether the PR as implemented in high-income countries is the suitable model for LIMICs is also a critical question. The present study, to our knowledge, is the first clinical trial in regard to the PR maintenance via social media supervision in north China. The positive result of this research provided more evidence of PR and maintenance strategy benefits and verified the feasibility of this model in the local region. So, there was an important implication that it is necessary to explore the different forms and culturally appropriate PR program in LIMICs.


There are several limitations to this work. First, this study is not a blinded design. The patients were given general information about the allocation and related intervention even different medical resources. Second, although the convenient and clear, the CAT and emotional function assessments could not evaluate the patients’ HRQL comprehensively, compared to St George’s Respiratory Questionnaire (SGRQ). Third, the technology applications were not familiar to elder COPD patients with likely recognition dysfunction. This led to uploaded vital sign being incorrect and made communication ineffective between patients and clinicians. Future studies need to explore more convenient and effective methods with comprehensive evaluation for PR maintenance delivery.


The remote PR maintenance via WeChat is effective at reducing the risk for AECOPD and keeping the improvements in 6MWD, mMRC, and CAT from decline. The remote PR maintenance via WeChat might be used to deliver alternatives to conventional PR.

Data Sharing Statement

Individual participant data that underlie the results reported in this article (tables and figures) are available after deidentification for 36 months after publication from the corresponding author Yi Li on reasonable request, and researchers should provide a methodologically sound proposal.


The authors thank Dr. Jerry Liu for improving the use of English in the manuscript.


This study was supported by the grants from China Soong Ching Ling Foundation (No. 2018MZFZY-009) and Tianjin Key Medical Discipline (Specialty) Construction Project.


All authors declare no competing interests.


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2. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease Report: 2022. Available from: Accessed May 4, 2022.

3. Spruit MA, Singh SJ, Garvey C, et al. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med. 2013;188(8):e13–e64. doi:10.1164/rccm.201309-1634ST

4. Spruit MA, Singh SJ. Maintenance programs after pulmonary rehabilitation: how may we advance this field? Chest. 2013;144(4):1091–1093. doi:10.1378/chest.13-0775

5. Güell MR, Cejudo P, Ortega F, et al. Benefits of long-term pulmonary rehabilitation maintenance program in patients with severe chronic obstructive pulmonary disease. Three-year follow-up. Am J Respir Crit Care Med. 2017;195(5):622–629. doi:10.1164/rccm.201603-0602OC

6. Li Y, Feng J, Li Y, et al. A new pulmonary rehabilitation maintenance strategy through home-visiting and phone contact in COPD. Patient Prefer Adherence. 2018;12:97–104. doi:10.2147/PPA.S150679

7. Sabit R, Griffiths TL, Watkins AJ, et al. Predictors of poor attendance at an outpatient pulmonary rehabilitation programme. Respir Med. 2008;102:819–824. doi:10.1016/j.rmed.2008.01.019

8. Wilson AM, Browne P, Olive S, et al. The effects of maintenance schedules following pulmonary rehabilitation in patients with chronic obstructive pulmonary disease: a randomised controlled trial. BMJ Open. 2015;5:e005921. doi:10.1136/bmjopen-2014-005921

9. Maltais F, Bourbeau J, Shapira S, et al. Effects of home-based pulmonary rehabilitation in patients with chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2008;149:869–878. doi:10.7326/0003-4819-149-12-200812160-00006

10. Rochester CL, Vogiatzis I, Holland AE, et al. An official American Thoracic Society/European Respiratory Society policy statement: enhancing implementation, use, and delivery of pulmonary rehabilitation. Am J Respir Crit Care Med. 2015;192(11):1373–1386. doi:10.1164/rccm.201510-1966ST

11. Brennan D, Tindall L, Theodoros D, et al. A blueprint for telerehabilitation guidelines. Int J Telerehabil. 2010;2(2):31–34. doi:10.5195/ijt.2010.6063

12. Zanaboni P, Hoaas H, Aaroen Lien L, et al. Long-term exercise maintenance in COPD via telerehabilitation: batwo-year pilot study. J Telemed Telecare. 2017;23(1):74–82. doi:10.1177/1357633X15625545

13. Vasilopoulou M, Papaioannou AI, Kaltsakas G, et al. Home-based maintenance tele-rehabilitation reduces the risk for acute exacerbations of COPD, hospitalisations and emergency department visits. Eur Respir J. 2017;49(5):1602129. doi:10.1183/13993003.02129-2016

14. Petkovic J, Duench S, Trawin J, et al. Behavioural interventions delivered through interactive social media for health behaviour change, health outcomes, and health equity in the adult population. Cochrane Database Syst Rev. 2021;5(5):CD012932. doi:10.1002/14651858.CD012932.pub2

15. Malaguti C, Dal Corso S, Janjua S, et al. Supervised maintenance programmes following pulmonary rehabilitation compared to usual care for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2021;8(8):CD013569. doi:10.1002/14651858.CD013569.pub2

16. Hoaas H, Andreassen HK, Lien LA, et al. Adherence and factors affecting satisfaction in long-term telerehabilitation for patients with chronic obstructive pulmonary disease: a mixed methods study. BMC Med Inform Decis Mak. 2016;16:26. doi:10.1186/s12911-016-0264-9

17. Lundell S, Holmner A, Rehn B, et al. Telehealthcare in COPD: a systematic review and meta-analysis on physical outcomes and dyspnea. Respir Med. 2015;109(1):11–26. doi:10.1016/j.rmed.2014.10.008

18. Chen J, Ho E, Jiang Y, et al. Mobile social network-based smoking cessation intervention for Chinese male smokers: pilot randomized controlled trial. JMIR MhealthUhealth. 2020;8(10):e17522. doi:10.2196/17522

19. Sui Y, Wang T, Wang X. The impact of WeChat app-based education and rehabilitation program on anxiety, depression, quality of life, loss of follow-up and survival in non-small cell lung cancer patients who underwent surgical resection. Eur J Oncol Nurs. 2020;45:101707. doi:10.1016/j.ejon.2019.101707

20. Schrijver J, Lenferink A, Brusse-Keizer M, et al. Self-management interventions for people with chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2022;1(1):CD002990. doi:10.1002/14651858.CD002990.pub4

21. Qaseem A, Wilt TJ, Weinberger SE, et al.; American College of Physicians; American College of Chest Physicians; American Thoracic Society; European Respiratory Society. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155(3):179–191. doi:10.7326/0003-4819-155-3-201108020-00008

22. Gupta N, Pinto LM, Morogan A, et al. The COPD assessment test: a systematic review. Eur Respir J. 2014;44(4):873–884. doi:10.1183/09031936.00025214

23. Mahler DA, Wells CK. Evaluation of clinical methods for rating dyspnea. Chest. 1988;93(3):580–586. doi:10.1378/chest.93.3.580

24. Julian LJ. Measures of anxiety: State-Trait Anxiety Inventory (STAI), Beck Anxiety Inventory (BAI), and Hospital Anxiety and Depression Scale-Anxiety (HADS-A). Arthritis Care Res. 2011;63(011):S467- S472. doi:10.1002/acr.20561

25. Monjazebi F, Dalvandi A, Ebadi A, et al. Functional status assessment of COPD based on ability to perform daily living activities: a systematic review of paper and pencil instruments. Glob J Health Sci. 2015;8(3):210–223. doi:10.5539/gjhs.v8n3p210

26. van Ranst D, Stoop WA, Meijer JW, et al. Reduction of exacerbation frequency in patients with COPD after participation in a comprehensive pulmonary rehabilitation program. Int J Chron Obstruct Pulmon Dis. 2014;9:1059–1067. doi:10.2147/COPD.S69574

27. Holland AE, Spruit MA, Troosters T, et al. An official European respiratory society/American thoracic society technical standard: field walking tests in chronic respiratory disease. Eur Respir J. 2014;44(6):1428–1446. doi:10.1183/09031936.00150314

28. Ko FW, Dai DL, Ngai J, et al. Effect of early pulmonary rehabilitation on health care utilization and health status in patients hospitalized with acute exacerbations of COPD. Respirology. 2011;16(4):617–624. doi:10.1111/j.1440-1843.2010.01921.x

29. Guell R, Casan P, Belda J, et al. Long-term effects of outpatient rehabilitation of COPD: a randomized trial. Chest. 2000;117(4):976–983. doi:10.1378/chest.117.4.976

30. Rubi M, Renom F, Ramis F, et al. Effectiveness of pulmonary rehabilitation in reducing health resources use in chronic obstructive pulmonary disease. Arch Phys Med Rehabil. 2010;91(3):364–368. doi:10.1016/j.apmr.2009.09.025

31. Voncken-Brewster V, Tange H, de Vries H, et al. A randomized controlled trial evaluating the effectiveness of a web-based, computer-tailored self-management intervention for people with or at risk for COPD. Int J Chronic Obstr Pulm Dis. 2015;1061–1073. doi:10.2147/COPD.S81295

32. Demeyer H, Louvaris Z, Frei A, et al. Physical activity is increased by a 12-week semiautomated telecoaching programme in patients with COPD: a multicentre randomised controlled trial. Thorax. 2017;72(5):415–423. doi:10.1136/thoraxjnl-2016-209026

33. Moy ML, Collins RJ, Martinez CH, et al. An internet-mediated pedometer-based program improves health-related quality-of-life domains and daily step counts in COPD: a randomized controlled trial. Chest. 2015;148(1):128–137. doi:10.1378/chest.14-1466

34. TechWeb. WeChat Chinese and International versions combined monthly active users over 1.2 billion, mini-programme daily users over 400 million; 2020. Available from: Accessed May 4, 2022.

35. Admon AJ, Kaul V, Cribbs SK, et al. Twelve tips for developing and implementing a medical education Twitter chat. Med Teach. 2020;42(5):500–506. doi:10.1080/0142159X.2019.1598553

36. Junhasavasdikul D, Srisangkaew S, Sukhato K, et al. Cartoons on Facebook: a novel medical education tool. Med Educ. 2017;51(5):539–540. doi:10.1111/medu.13312

37. Bi J, Yang W, Hao P, et al. WeChat as a platform for baduanjin intervention in patients with stable chronic obstructive pulmonary disease in China: retrospective randomized controlled trial. JMIR MhealthUhealth. 2021;9(2):e23548. doi:10.2196/23548

38. Dakin H, Wordsworth S. Cost-minimisation analysis versus cost effectiveness analysis, revisited. Health Econ. 2013;22(1):22–34. doi:10.1002/hec.1812

39. Vogiatzis I, Rochester CL, Spruit MA, et al.; American Thoracic Society/European Respiratory Society Task Force on Policy in Pulmonary Rehabilitation. Increasing implementation and delivery of pulmonary rehabilitation: key messages from the new ATS/ERS policy statement. Eur Respir J. 2016;47(5):1336–1341. doi:10.1183/13993003.02151-2015

40. Mantoani LC, Rubio N, McKinstry B, et al. Interventions to modify physical activity in patients with COPD: a systematic review. Eur Respir J. 2016;48(1):69–81. doi:10.1183/13993003.01744-2015

41. Robinson SA, Shimada SL, Quigley KS, et al. A web-based physical activity intervention benefits persons with low self-efficacy in COPD: results from a randomized controlled trial. J Behav Med. 2019;42(6):1082–1090. doi:10.1007/s10865-019-00042-3

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Eosinophils are proinflammatory granulocytes associated with symptom severity and exacerbation frequency in asthma and chronic obstructive pulmonary disease (COPD).1–3 The degree of eosinophilia (raised eosinophils) in these obstructive lung diseases varies: while eosinophil inflammation due to allergic sensitisation has been considered characteristic of asthma, not all patients with asthma have eosinophilia.1 4 Moreover, while airway inflammation in COPD is typically mediated by neutrophils, some individuals with COPD have raised eosinophils.1 5

The production and survival of eosinophils is partly regulated by interleukin-5 (IL-5), and anti-IL5 therapies (eg, mepolizumab, reslizumab, and the anti-IL5Rα agent, benralizumab) are now licensed in many countries for the treatment of severe eosinophilic asthma.6–12 The decision to treat asthma with these drugs is currently based on blood eosinophil count, among other factors,1 since post-hoc analyses of clinical trials stratified by eosinophil levels have shown increased efficacy of mepolizumab for treating severe asthma in those with higher baseline eosinophils.2 Results from Mendelian randomisation (MR) analyses have also provided evidence for a role of eosinophils in asthma (estimated OR 1.70 (95% CI 1.53 to 1.91).13 MR analyses use genetic variants as instrumental variables (IVs) to investigate causality between exposure and outcome, and under certain assumptions may obviate problems with traditional observational epidemiology (eg, reverse causation, confounding), permitting causal inference.

In addition to asthma, blood eosinophils are associated with quantitative lung function in general populations (ie, including individuals without asthma).14 However, causality has yet to be established: an inverse relationship between eosinophils and lung health has been suggested, yet a previous MR of lung function (plus another including asthma and COPD) were of small sample size, with imprecise estimates precluding confident inference.15 16 Moreover, causality of eosinophils on other respiratory phenotypes, for example, asthma-COPD overlap (ACO), and respiratory infections are yet to be investigated. COPD is diagnosed by spirometry if the ratio of the forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC), FEV1/FVC, is <0.7, with airflow obstruction graded by predicted FEV1. Therefore, studying eosinophils as determinants of quantitative lung function is a powerful way of understanding their role in the development of fixed airflow obstruction such as in COPD.17 18 Investigating causality between eosinophils and fixed airflow obstruction is pertinent given interest in the potential use of mepolizumab in COPD9–12; evidence for causality of eosinophils in a wider range of respiratory phenotypes could suggest that anti-IL5 agents (designed to lower eosinophils) might be helpful in conditions beyond asthma.

We undertook two-sample MR analyses using summary-level genome-wide association study (GWAS) data to assess causality between eosinophils and conditions encompassing fixed and reversible airflow obstruction, using genetic variants associated with blood eosinophils as IVs.13 We investigated causality of eosinophils on three quantitative lung function spirometry traits, and four clinical phenotypes (moderate-to-severe asthma, acute exacerbations of COPD (AECOPD), ACO and respiratory infections). We used MR approaches relying on different assumptions for validity, and followed up traits showing evidence of possible causality to assess evidence that the IVs affected lung function via eosinophil counts and not via other blood cell types. Overall, our aim was to provide a comprehensive assessment of the causal role of blood eosinophil counts in relation to respiratory health and disease.


We assessed causality between eosinophils and other blood cell counts in relation to respiratory outcomes using MR.19 20 MR involves using genetic variants (here single-nucleotide polymorphisms, SNPs), as IVs for an exposure of interest, in this case eosinophil counts, by comparing the magnitude of the effect of the SNPs on the outcome to the effect of the SNPs on the exposure.19 20 All analyses reported are two-sample MR analyses, since SNP–exposure and SNP–outcome associations were extracted from different (yet overlapping21) samples. Core MR assumptions for inferring causality between are that: (1) the genetic variants are associated with the exposure of interest; (2) there are no unmeasured confounders of the associations between genetic variants and outcome; and (3) the genetic variants affect the outcome only via the exposure of interest (figure 1).19 Additional assumptions for accurate point estimation of effect sizes are discussed in online supplemental file 1, and elsewhere.22

Figure 1
Figure 1

Mendelian randomisation (MR): core assumptions Mendelian randomisation may be used to test for causality between an exposure (eg, eosinophils) and outcome (eg, a respiratory outcome such as FEV1/FVC), if the following core assumptions hold (see 1–3 on the figure): (1) the genetic variation (single nucleotide polymorphisms in this work) used as instrumental variables are associated with the exposure of interest; the genetic variants are not associated with unobserved confounders of the exposure-outcome association (straight dashed arrow). Genetic variants are allocated randomly at conception (Mendel’s law of independent assortment) and so typically should not be associated with these confounding variables; association between the genetic variants and the outcome is via the exposure, and not via an alternate pathway (ie, there is no ‘horizontal pleiotropy’, see curved dashed arrow). While difficult to verify, reassurance that this assumption holds can be provided using biological knowledge of how the SNP functions, and by checking whether multiple MR methods, each relying on different assumptions for validity, give consistent results (known as triangulation).20 FEV1, forced expiratory volume in 1 s, FVC, forced vital capacity; SNP, single-nucleotide polymorphisms.

All GWAS datasets analysed included UK Biobank, a prospective cohort study including spirometry, biological assays, questionnaire data, and linked healthcare records, and 450 000 participants with genotype data.23 Other studies were incorporated where available, and all GWAS data were from individuals of European ancestry. Datasets are summarised below, and descriptions of covariate adjustments, and exposure-outcome GWAS overlap are given in the extended methods (online supplemental file 1).

Exposure GWAS data sets (blood cell parameters)

We used summary-level data from eight published GWASs of blood cell counts13 in the initial release of UK Biobank genetic data (N up to 132,959, that is, around 30% of participants with genotype data), plus the INTERVAL study (N up to 40 521)).13 GWASs were of blood eosinophils, basophils, neutrophils, monocytes, lymphocytes, platelets, red blood cells and reticulocytes, with adjustments for technical and seasonal covariates, plus age, menopausal status, height, weight, smoking and alcohol (online supplemental file 1).

Outcome GWAS data sets (respiratory outcomes)

See also online supplemental file 1.

Quantitative lung function GWASs

We used published summary-level data from three GWAS of FEV1, FVC and FEV1/FVC, in UK Biobank (n=3 21 047) and the SpiroMeta consortium (n=79 055).18 Prior to GWAS, traits were preadjusted for age, age2, sex, height, smoking status and other covariates as appropriate, for example, ancestry principal components. Residuals were inverse-normal rank transformed.

Clinical outcome GWAS

Moderate-to-severe asthma

We used a published GWAS of moderate-to-severe asthma within the Genetics of Asthma Severity and Phenotypes initiative, the U-BIOPRED asthma cohort, and UK Biobank.24 Cases (n=5135) were taking asthma medication, and met criteria for moderate-to-severe asthma (British Thoracic Society 2014 guidelines). Controls (n=25 675) excluded those with a doctor diagnosis of asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis, or missing medication data. Analyses were adjusted for 10 ancestry principal components.

Acute exacerbations of COPD

We defined AECOPD in UK Biobank; the eligible sample was restricted to individuals with FEV1/FVC<0.7. Exacerbation cases (n=2771) had an ICD-10 code for AECOPD or a lower respiratory tract infection in Hospital Episode Statistics data (online supplemental table 1). Controls (n=42 052) had FEV1/FVC<0.7, without an AECOPD code. Associations were adjusted for age (at recruitment), age2, sex, smoking status (ever/never), genotyping array and 10 principal components.

Asthma-COPD overlap

We defined ACO in UK Biobank (N=8068) as individuals self-reporting a doctor diagnosis of asthma, with FEV1/FVC<0.7 and FEV1 <80% predicted at any study visit. Controls (N=40 360) were selected in approximately a 5:1 ratio, from participants reporting no asthma or COPD, (FEV1 >80% predicted, FEV1/FVC>0.7). Associations were adjusted for age (at recruitment), sex, smoking status and 10 principal components.25

Respiratory infections

We defined respiratory tract infections requiring hospital admission in UK Biobank, using the ICD-10 codes in online supplemental table 2. Cases had ≥1 admission for respiratory infections (N=19 459). Controls had no admissions for respiratory infections and were selected in approximately a 5:1 ratio (N=101 438). Associations were adjusted for age (at recruitment), age2, sex, smoking status, genotyping array, and 10 principal components.26

Statistical methods

Univariable MR of eosinophils and respiratory traits and diseases

We performed separate MR analyses of eosinophils on three quantitative lung function traits (FEV1, FVC, FEV1/FVC); and four clinical phenotypes (asthma, AECOPD, ACO, respiratory infections) using genetic IVs from the work of Astle and colleagues.13 Selection of 151 eosinophil IVs and harmonisation of SNP-exposure and SNP-outcome datasets is detailed in the online supplemental file 1. The primary MR analysis used the inverse-variance weighted (IVW) method and a random-effects model, which will return a valid causal estimate provided that the average pleiotropic effect is zero. We investigated the ‘no pleiotropy’ assumption using MR-Egger regression,27 the weighted median estimator28 and MR-PRESSO29 (see online supplemental file 1 for details on assumptions relied on for validity by each method). Further sensitivity analyses: (1) investigated robustness of findings to heterogeneity using MR-PRESSO (for traits with some evidence of causation by eosinophils), (2) restricted to non-UKB FEV1/FVC GWAS data, to assess sensitivity to sample overlap and (3) restricted to FEV1/FVC GWAS data in UKB, stratifying by asthma status.

Multivariable MR analyses of multiple blood cell types and respiratory outcomes

Since SNPs affecting eosinophils also affect other blood cell types,13 we used multivariable MR to estimate the influence of multiple cell types on respiratory outcomes, after conditioning on the effects of the SNPs on other cell types. Multivariable MR analyses were performed for respiratory outcomes with evidence of eosinophil causation in the IVW MR analyses above, and with broadly consistent effect estimates in the weighted median and MR-Egger analyses. We also performed an analysis of FEV1/FVC in UKB (stratifying by asthma status).

There were 1166 SNPs associated with at least one of eight blood traits reported by Astle and colleagues13 at a genome-wide threshold. These SNPs were LD clumped, and effect sizes extracted from each blood cell GWAS, and each outcome GWAS. Effects for 318 clumped SNPs were harmonised, that is, so effect sizes for SNP-exposure and SNP-outcome effects corresponded to the same allele (online supplemental table 3, online supplemental file 1). Conditional F-statistics were estimated using the strength_mvmr() function of the ‘MVMR’ R package.30

For IVW multivariable MR analyses, we used the mv_multiple() function of the ‘TwoSampleMR’ R package.31–33 This analysis aimed to further investigate the possibility of horizontal pleiotropy affecting the results of the univariable eosinophil MR; and to establish whether other blood cell types besides eosinophils could affect the respiratory outcomes studied.

Sensitivity MVMR methods (online supplemental file 1) included: (1) use of an MVMR method more robust to pleiotropy in the presence of weak instruments (using the qhet_mvmr() function of the ‘MVMR’ R package,30—standard errors calculated by a jack-knife approach) and (2) recalculation of IVW MVMR estimates after removal of SNPs contributing most to heterogeneity (SNPs identified using the pleiotropy_mvmr() function).


Univariable MR analyses of eosinophils and respiratory outcomes

There were 151 SNPs available for the univariable MR analyses of three quantitative traits (FEV1, FVC and FEV1/FVC), and four respiratory disease phenotypes (moderate-to-severe asthma, AECOPD, ACO and respiratory infections). Details of SNP selection are described in figure 2.

Figure 2
Figure 2

Selection of SNPs for univariable MR analyses of eosinophils and respiratory outcomes flow chart describing the analysis workflow for initial MR analyses of eosinophils. Of 209 SNPs associated with eosinophil count, 167 were available in lung function GWASs (missingness is due to some SpiroMeta studies not being imputed to the HRC panel).18 LD proxies at R2 >0.8 were retrieved for 24/42 missing variants. Of the resulting 191 SNPs, 188 were successfully harmonised between the SNP-eosinophil and SNP-lung function data sets, and 151* remained after LD clumping at an R2 threshold of 0.01. These 151 SNPs were used in analyses. *One SNP, rs9974367, was missing in the moderate-severe asthma GWAS. AECOPD, acute exacerbation of COPD; ACO, asthma COPD overlap; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s, FVC, forced vital capacity; GWAS, genome-wide association study; MR, Mendelian randomisation; SNPs, single-nucleotide polymorphisms.

Results are presented in figure 2. Among the quantitative traits, there was evidence for an effect of eosinophils on FEV1/FVC (SD change in FEV1/FVC per SD eosinophils, IVW estimate=−0.049 (95% CI −0.079 to–0.020)), with a smaller effect on FEV1 (IVW estimate=−0.028 (95% CI −0.054 to –0.003)). However, there was substantial heterogeneity of SNP-specific causal estimates, as evidenced by the large values of Cochran’s Q statistic, suggesting that core MR assumptions were violated for at least some SNPs. Scatterplots of SNP-outcome against SNP-exposure effects are given in online supplemental figure 1).

Among the respiratory disease phenotypes (figure 3), there was evidence for an effect of eosinophils on asthma (OR per SD eosinophil count, IVW method=2.46 (95% CI 1.98 to 3.06)), and ACO (IVW OR=1.86 (95% CI 1.52 to 2.27)). There was substantial heterogeneity of SNP-specific causal estimates for these two traits, and weighted median estimates were of smaller magnitude than IVW estimates (weighted median OR: 1.50 (95% CI 1.23 to 1.83) for asthma, and 1.44 (95% CI 1.19 to 1.74) for ACO). While confidence intervals for the MR Egger estimates were still broad, estimates were generally similar to weighted median estimates. The asthma estimates in particular may have been inflated by overlap between the SNP-exposure and SNP-outcome datasets (see online supplemental file 1). Scatterplots of SNP-outcome against SNP-exposure effects for these outcomes are given in online supplemental figure 2.

Figure 3
Figure 3

MR analyses of eosinophils (exposure) on three quantitative lung function traits (top) and four respiratory disease phenotypes (bottom), using 151 eosinophil-associated SNPs top: results of MR analyses of eosinophil counts (exposure) on three quantitative lung function traits (outcome), FEV1, FVC and FEV1/FVC. A forest plot of three estimates for each traits is shown (IVW, MR Egger, weighted median), along with the maximum sample size in the outcome GWAS (N), the effect size in SD change in outcome trait per SD increase eosinophil count, and 95% CI, values for Cochran’s Q statistic (Q) and the associated df (Q_df), and the p value for the MR Egger intercept (Intercept_P). Boxes of the forest plot represent effect sizes, whiskers are 95% CIs. Bottom: results of MR analyses of eosinophil counts (exposure) on four respiratory disease phenotypes (outcome), moderate-to-severe asthma, acute exacerbations of COPD (AECOPD), asthma-COPD overlap (ACO), and respiratory infection (Resp. IX). A forest plot of three estimates for each traits is shown (IVW, MR Egger, weighted median), along with sample size in the outcome GWAS for cases and controls, respectively (N), the effect size as OR per SD eosinophil count, and 95% CI, values for Cochran’s Q statistic (Q) and the associated df (Q_df), and the p value for the Mr Egger intercept (Intercept_P). Boxes of the forest plot represent ORs, whiskers are 95% CIs. Nb only 150/151 of the eosinophil SNPs were available in the moderate-to-severe asthma GWAS. COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s, FVC, forced vital capacity; GWAS, genome-wide association study; IVW, inverse-variance weighted; MR, Mendelian randomisation; SNPs, single-nucleotide polymorphisms.

There was no evidence of association of eosinophils with AECOPD or respiratory infections. CIs for all three MR methods included the null, and point estimates approached the null. See online supplemental table 4 for results for all models and all traits.

Sensitivity analysis to assess further the robustness of findings to heterogeneity, using MR-PRESSO

For FEV1, FEV1/FVC, ACO and asthma (traits showing strongest evidence of causation), we used MR-PRESSO to identify possible pleiotropic outliers (online supplemental table 5). Results were qualitatively similar to IVW estimates (higher eosinophils consistent with respiratory morbidity), but ACO and asthma effect estimates attenuated after MR-PRESSO outlier correction; MR-PRESSO estimates were most similar to weighted median causal estimates.

Sensitivity analysis to assess the effects of sample overlap for quantitative lung function traits

UK Biobank featured in all GWAS datasets used, although the blood cell count GWAS and asthma GWAS included only approximately one third of the UK Biobank genotype data.13 We conducted sensitivity analyses to assess for the effect of sample overlap, since we had access to quantitative lung function GWAS data without UK Biobank participants (see online supplemental file 1). Results were generally consistent (SD change in FEV1/FVC per SD eosinophil count, IVW estimate=−0.041 (95% CI −0.072 to –0.009); SD change FEV1 per SD eosinophil count=−0.043 (95% CI −0.077 to –0.010)) (online supplemental table 6).

Sensitivity analysis to assess the effect on FEV1/FVC in individuals with and without asthma

The causal effect of eosinophils on FEV1/FVC was recalculated using data from UK Biobank, stratifying by asthma status (37 868 cases, 283 179 controls). The effect size was larger in individuals with asthma (IVW −0.083 (95% CI −0.139 to –0.028)) than in those without asthma, in whom there was no effect (IVW −0.013 (95% CI −0.041 to 0.015)). However, confidence intervals for both subgroups overlapped one another (see online supplemental table 7).

Multivariable MR analyses of blood cell counts and respiratory outcomes

To further explore causality between blood cell parameters and FEV1, FEV1/FVC, moderate-to-severe asthma and ACO, and to see if other exposures could have accounted for the heterogeneity observed in the previous analyses, we carried out multivariable MR analyses, using eight cell type exposures (eosinophils, basophils, neutrophils, monocytes, lymphocytes, platelets, red blood cells and reticulocytes).

Selection of 318 SNP IVs for multivariable MR is described in online supplemental file 1, online supplemental table 3. SNPs used in the univariable and multivariable MR are listed in online supplemental tables 8 and 9. Briefly, 1166 unique SNPs were associated with at least one of the eight cell types at a genome-wide level in the cell type GWAS, and were available in outcome GWAS. After LD-clumping, 329 SNPs remained, and after harmonising SNP-exposure and SNP-outcome effects, 318 remained (see online supplemental table 3) for conditional F statistics, which were all F>10, except for basophils (Fconditional=8).

Multivariable MR results for FEV1 and FEV1/FVC are presented in figure 4. Even after conditioning on the effects of the SNPs on other cell types, the average effect of the eosinophil-lowering IVs was to reduce lung function as measured by FEV1/FVC (multivariable estimate, SD change in FEV1/FVC per SD eosinophils adjusted for other cell types: −0.065 (95% CI −0.104 to –0.026)). The eosinophil point estimate for FEV1 (−0.032 (95% CI −0.068 to 0.005)) was consistent with the univariable estimate (figure 3), but CIs for all cell types were consistent with the null. When asthma cases were excluded from SNP-FEV1/FVC results, the eosinophil estimate attenuated, and confidence intervals overlapped the null (−0.028 (95% CI −0.069 to 0.013)), consistent with the causal effect of eosinophils on lung function being of greater magnitude in people with a history of asthma (online supplemental figure 3).

Figure 4
Figure 4

Multivariable MR analyses of eight cell types and forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) forest plot showing multivariable MR estimating the causal effect of multiple cell types on quantitative lung function outcomes, after conditioning on the effects of the SNPs on other cell types. Models were run for each of FEV1 and the ratio of FEV1 to FVC separately, but effect sizes are shown next to one another for comparison. Effect sizes (beta, 95% CI) are in SD change in lung function outcome per SD cell count (adjusted for the effects of other cell types). Points of the forest plot represent effect size estimate; whiskers are 95% CIs. MR, Mendelian randomisation.

Results of the multivariable MR analysis for ACO and asthma are presented in figure 5. There was an association of eosinophil count with both ACO (OR 1.95 (95% CI 1.57 to 2.42)) and asthma (OR 2.90 (95% CI 2.31 to 3.65)), after adjusting for the effects of the SNPs on other cell types. Confidence intervals for other cell type estimates were consistent with the null, with the exception of neutrophils for ACO. None of the additional seven cell types showed strong evidence of causality.

Figure 5
Figure 5

Multivariable MR analyses of eight cell types and two respiratory disease outcomes, ACO and asthma forest plot showing multivariable MR estimating the causal effect of multiple cell types on respiratory disease outcomes, after conditioning on the effects of the SNPs on other cell types. Models were run for each of ACO and asthma separately, but effect sizes are shown next to one another for comparison. ORs (95% CI) are per SD cell count (adjusted for the effects of other cell types). Points of the forest plot represent ORs; whiskers are 95% CIs. ACO, asthma-COPD overlap; MR, Mendelian randomisation; SNP, single-nucleotide polymorphisms.

Sensitivity multivariable MR analyses

Sensitivity MVMR analyses (1) used an estimation technique more robust to balanced pleiotropy and (2) repeated IVW MVMR, omitting SNP IVs with the most evidence of heterogeneity. Effect directions of sensitivity analyses and the main MVMR analyses were concordant for FEV1, FEV1/FVC, ACO, and asthma. However, CIs for FEV1 and FEV1/FVC were broad, and overlapped the null. For ACO and asthma estimates, there was still evidence of an effect, although attenuated in both analyses (estimates from analysis more robust to pleiotropy; ACO OR 1.57 (95% CI 1.07 to 2.30); asthma OR 2.66 (95% CI 1.65 to 4.33); estimates after omitting the most heterogeneous SNPs: ACO OR 1.51 (95% CI 1.23 to 1.85); asthma OR 2.29 (95% CI 1.84 to 2.86)).


In MR analyses, we found that the average effect of raising eosinophils was to decrease FEV1/FVC and FEV1, and to increase ACO and asthma risk, and there was broad consistency across MR methods. However, causal estimates of individual variants were highly heterogeneous, suggesting that caution is needed in concluding causal inference: some IVs may have violated MR assumptions, and other important genetically correlated mechanisms could be responsible for the effect on lung health and disease by the eosinophil-raising variants studied.

To our knowledge, this is the largest MR of eosinophils and lung function, and the first to investigate eosinophils and AECOPD, ACO and respiratory infections. Terminology of ACO has changed over time, yet recognition that asthma and COPD coexist in some patients has not changed,34 and this is what our analysis aimed to capture.

A previous two-sample MR of eosinophils and asthma was undertaken by the authors of the GWAS that discovered the eosinophil IVs used; this MR analysis used asthma GWAS data from the GABRIEL study.13 We are aware of one other small MR of eosinophils and asthma, COPD, FEV1 and FEV1/FVC, conducted in the LifeLines cohort (N=13 301, 5 SNPs IVs).15 In that study, CIs for causal estimates of eosinophils overlapped the null, although point estimates were consistent with a harmful effect for FEV1/FVC, asthma and COPD. We used a larger eosinophil GWAS (N=172 275)13 to derive IVs, and found that the average effect of eosinophil-raising IVs was to reduce FEV1/FVC, the trait used in COPD diagnosis and FEV1, used to grade COPD airflow limitation. However, sensitivity analyses highlighted a larger causal estimate of eosinophils on FEV1/FVC among those with asthma, with effect estimates attenuating when excluding this group. These findings may highlight the importance of eosinophils as a marker of impaired lung function and airflow obstruction in people with a history of asthma.

We highlight a need for caution in inferring simple causation between eosinophils and these phenotypes, since high degrees of heterogeneity in our results may arise from pleiotropy. To investigate, we compared MR methods relying on differing assumptions for validity (Methods section). Attenuation of some results when using the MR-Egger, weighted median, and MR-PRESSO approaches suggests that some SNP IVs are associated with asthma and ACO via pathways other than eosinophils, which is a known challenge in MR studies (see also Methods section).

Since many of the eosinophil SNP IVs are also associated with other cell counts,13 we performed multivariable MR to estimate the influence of multiple cell types simultaneously, after conditioning on the effects of the SNPs on other cell types. While we did not find substantial evidence for a harmful effect of neutrophils on asthma, nor a protective effect of monocytes and lymphocytes, as reported previously,13 effect directions in our IVW multivariable MR were consistent with the previous study for neutrophils, monocytes and lymphocytes. We observed a larger effect of eosinophils on asthma than reported previously: this could be because our SNP-outcome dataset was of moderate-to-severe asthma (which has a higher point estimate of genetic correlation with eosinophils), but also, around half of the cases and the majority of controls were also included in the exposure GWAS, which may make this analysis closer to a one-sample MR, and inflate causal effect estimates. Notably, effect sizes partly attenuated in sensitivity analyses which may be more robust to heterogeneity. The MR estimates from multivariable analyses, and the MR-Egger regression and weighted median univariable analyses were consistent with the previous estimate reported for asthma in multivariable analysis by Astle et al.13 Nevertheless, these limitations may preclude precise estimation of effect sizes, and our results may be more useful in terms of assessing whether there is causality between eosinophils and the phenotypes studied, as opposed to providing estimates of the magnitude of any causal effect between phenotypes.

While we did not find strong evidence for causality of eosinophils on AECOPD and respiratory infections, point estimates were consistent with a harmful effect on AECOPD, and may have been limited by power. The effects of anti-IL5 drugs that have been attributed to the reduction of eosinophils have been noted to be smaller in AECOPD compared with asthma.2 35

Key strengths are that we used MR methods with differing sensitivities to underlying assumptions. We a large GWAS of eosinophil counts, to provide a comprehensive assessment of the role of blood eosinophils in relation to multiple respiratory health and disease outcomes. Another strength is that we undertook multivariable MR to investigate causality between multiple cell types and the outcomes studied, while controlling for the effects of IVs that may have had pleiotropic effects via other cell types.

We acknowledge several limitations. We did not have post-bronchodilator measures of spirometry. We used GOLD Stage 2–4 COPD (prebronchodilator FEV1 <80% predicted) when defining ACO; using the same prebronchodilator spirometry definition of COPD, a positive predictive value of 98% for diagnosis of postbronchodilation-defined COPD has been shown.36 Sample overlap between the SNP-eosinophil and SNP-outcome datasets (all included participants from UK Biobank) could bias estimates towards the observational eosinophil-outcome association21; we repeated the univariable MR analysis of eosinophils using SNP-lung function results excluding UK Biobank participants, and observed a consistent IVW estimate. Nevertheless, our other analyses (particularly the asthma analysis) could be vulnerable to some non-conservative bias.19 21 GWAS analyses of cell counts have, since analysis, been extended to a larger sample across UKB, and future work deriving IVs from this study would be valuable.37 UK BiLEVE participants (a subset of UK Biobank selected for extremes of respiratory traits), were overrepresented in Astle et al, which used the interim release of UKB data. While correlation between effect sizes from the two GWAS for the 151 IVs used in this analyses were high, the possibility of selection effects remains. Our MR analyses also use genome-wide results adjusted for covariates, and therefore may be susceptible to collider bias.19 38 There is also potential bias in the causal estimates for binary outcomes due to non-collapsibility of the OR,22 and we did not consider the possibility of non-linear effects. The multivariable analyses may still be vulnerable to pleiotropy via pathways other than the eight cell types studied, so while we cannot strongly assert causality of eosinophils on lung function, neither do we rule it out, as our results are consistent with a causal effect.

At present, treatment with anti-IL5/anti-IL5Rα agents in asthma is initiated according to eosinophil counts and other factors,8 yet it is possible that a more proximal factor may be an even better predictor of drug response. Future work could seek therefore to identify whether particular pathways upstream of eosinophil counts might help design better methods for deciding on treatment initiation. In addition, use of suitable IVs for IL5 levels would permit two-step MR analyses, assessing for a mediating effect of eosinophils on the action of anti-IL5 agents in reducing respiratory morbidity.

To conclude, using MR, we found that the average effect of raising eosinophils was to increase risk of ACO and asthma, and to reduce FEV1/FVC (the latter association was only prominent in individuals with asthma). Broad consistency across MR methods is suggestive of a causal effect of eosinophils on asthma overall, and in individuals with features of both asthma and fixed airflow obstruction, although of uncertain magnitude. However, given heterogeneity in results derived from individual IVs, which may indicate violation of MR assumptions, we highlight a need for caution, since alternative mechanisms may be responsible for the impairment of respiratory health by these eosinophil-raising variants. These results could suggest that anti-IL5 agents (designed to lower eosinophils) may be of value in a wider range of respiratory traits, including people with features of both asthma and COPD. Future work should seek to explore other potential mechanisms besides eosinophils by which anti-IL5 agents may improve respiratory health.

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Adults without respiratory symptoms such as a chronic phlegmy cough or wheezing and shortness of breath don’t need routine screening for chronic obstructive pulmonary disorder (COPD), according to new guidelines from an influential U.S. medical group.

The new recommendations, issued by the U.S. Preventive Services Task Force (USPSTF), are in line with 2016 guidelines that discouraged widespread screening of people without any symptoms of COPD, a chronic progressive respiratory disease that is most often caused by smoking. People with respiratory symptoms or who are at higher risk of COPD due to genetics or workplace exposure to certain chemicals that can damage the lungs should be still get tested for the condition, the USPSTF notes in its latest recommendations, published in JAMA.

“There is no evidence that detecting and treating COPD in individuals without respiratory symptoms improves health-related quality of life or reduces mortality,” wrote Jill Jin, MD, MPH, associate editor of JAMA, in a patient page accompanying the recommendations.

“For people with mild to moderate COPD who have symptoms, treatment decreases COPD exacerbations and hospitalizations, but the effect of COPD treatment on risk of death is uncertain,” Dr. Jin notes.

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Asthma is a heterogeneous chronic inflammatory disease of the airways characterized by airway hyper-responsiveness, bronchoconstriction, and airway remodeling. Asthma affects over 260 million people worldwide and was responsible for over 21 million Disability-adjusted Life Years (DALYs) in 2019,1 representing significant morbidity and economic burden. The prevalence of asthma is highest in countries with the highest socio-demographic index (SDI); however, death rates are highest in countries with low–middle SDI.1

Table 1 Overview of Integrins Involved in Asthmatic Airway Remodeling

The symptoms of asthma include wheezing, shortness of breath, chest tightness, and cough that fluctuate in frequency and intensity, as well as variable expiratory airflow restriction.2 Treatment includes targeting bronchoconstriction through the use of β2 adrenergic agonists, or some cases muscarinic receptor antagonists, and reducing airway inflammation via inhaled or oral corticosteroids. Such an approach is sufficient to control symptoms in most patients, however, some patients suffer from difficult-to-treat asthma, with uncontrolled symptoms despite good adherence to treatment. Severe asthma, defined as uncontrolled symptoms despite treatment with highest doses of inhaled corticosteroids in combination with an additional controller medication (eg, long-acting β2 agonist), affects approximately 5–10% of patients and is associated with frequent and uncontrolled exacerbations, and a long-term decrease in lung function.3–5

Remodeling of the airways contributes to airway wall thickening and has a detrimental effect on asthma. It is associated with accelerated decline in lung function, an increased rate of exacerbation in asthmatic patients, and irreversible airflow obstruction.6–8 Thickening of the airways is not limited to patients suffering from the severest forms of the disease and can be evident even in mild forms of asthma; however, the degree of thickening is associated with increased disease severity and degree of airflow obstruction.9,10 Airway remodeling is thought to play a vital role in the uncontrolled symptoms and disease burden observed in severe asthmatics. Over recent years many studies have implicated a family of cell surface receptors known as integrins in the development and progression of airway remodeling. This review aims to bring together our current knowledge of how integrins may either drive or inhibit airway remodeling in asthma, and discuss the potential utility of targeting integrins as a therapeutic strategy in severe asthma.

Airway Remodeling in Asthma

Airway remodeling is the collective term given to the structural changes that occur within the asthmatic airway. These changes include sub-epithelial fibrosis, thickening of the airway smooth muscle (ASM) layer, mucous gland hyperplasia, angiogenesis, and loss of epithelial layer integrity, all of which contribute to a thickened and stiffened airway wall. The development of airway remodeling begins early in the disease course, with structural changes being evident in preschool children with clinically confirmed wheeze, even prior to an asthma diagnosis.11–13

The underlying mechanisms driving the development of airway remodeling are largely unclear and likely to be extremely complex and multifaceted. While for many years airway remodeling was thought to result from the presence of chronic inflammation within the asthmatic airway, this has more recently been questioned. Structural changes in the airways of preschool wheezers do not correlate with inflammatory cell counts in bronchoalveolar lavage fluid.11 It is possible that different features of airway remodeling differ in the underlying mechanisms driving them. The following section will discuss the potential mechanisms responsible for the development and progression of airway remodeling in asthma.

Potential Mechanisms Driving Airway Remodeling

Airway inflammation has long been thought to drive the development of asthmatic airway remodeling. Asthma is largely driven by TH2 inflammation associated with interleukin-4 (IL4), interleukin-5 (IL5), and interleukin-13 (IL13), and TH2 inflammation remains a crucial target in asthma therapy development. However, a cluster analysis of asthmatic patients has suggested that patients with fixed airflow obstruction and evident airway remodeling have predominantly TH17 rather than TH2 driven inflammation.14

Further evidence of a link between inflammation and airway remodeling comes from in vivo and in silico models of asthma. A theoretical model of airway remodeling demonstrates that inflammation is sufficient to promote thickening of the airway wall towards the lumen, although increased thickening occurs when biomechanical contractile forces and inflammation are modeled simultaneously,15 suggesting interplay of multiple pathways. Additionally, numerous mouse models have highlighted a potential link between inflammation and remodeling. For example, Interleukin-33 (IL33) can exacerbate allergen-induced inflammation and remodeling in a mouse model,16 and M2 macrophages, which IL33 promotes polarization towards,17,18 has been associated with allergen-induced remodeling in mice.19

From the studies described above it is clear that the mechanistic link between airway inflammation and airway remodeling is still ambiguous. The fact that remodeling occurs very early in the disease course, including in young children with wheeze prior to a diagnosis of asthma,11–13 suggests that chronic inflammation may not be the sole driver of airway remodeling.

An alternative possibility is that the mechanical environment of the asthmatic airway drives remodeling changes. This was initially suggested in 2011 when Grainge et al20 demonstrated remodeling changes in response to bronchoconstriction in the absence of additional inflammation. Mechanistically, contraction of ASM cells and airways causes activation of the pro-remodeling cytokine TGFβ and downstream remodeling changes.21–23 Moreover, pharmacological inhibition of transient receptor potential vanilloid-1 (TRPV1), which can modulate ASM tone, reduces airway remodeling in vivo.24,25 Mathematical modeling has also suggested that airway contraction contributes to remodeling.15

In addition to contractile mechanical forces promoting airway remodeling it is also possible that non-contractile biomechanical forces contribute.26 ECM proteins within the asthmatic airway wall can promote proliferation of ASM cells27 and drive remodeling changes in vivo.28 Additionally, altered mechanics due to a stiffer airway wall may drive remodeling changes. Increased matrix stiffness promotes epithelial–mesenchymal transition,29 collagen production by fibroblasts,30 and ASM cell proliferation,31 all of which may contribute to airway remodelling. Recently, a link between matrix crosslinking, which stiffens ECM, and the development of asthmatic airway remodeling has been described whereby the matrix crosslinking enzyme lysyl oxidase-like-2 (LOXL2) has been implicated.32 Crucially, LOXL2 levels were increased in asthmatic ASM cells and pharmacological inhibition of LOXL2 in vivo reduced allergen-induced airway remodeling.32


Integrins are heterodimeric transmembrane receptors that facilitate cell–cell and cell–matrix interactions. They provide a direct link between the environment outside of the cell and the cytoskeleton within the cell, and involved in the transmission of biomechanical signals. The family is composed of 24 mammalian members, made up by a variety of combinations of alpha (α) and a beta (β) subunit; there are eight distinct β subunits and 18 distinct α subunits.33 The α subunit is responsible for the ligand binding properties of integrins, while the downstream intracellular signaling events are co-ordinated by the β subunit. Some integrins can bind to only one type of ligand, while other integrins are able to recognize several ECM proteins.

Integrins can mediate bi-directional signals through the cell membrane; inside-out signalling regulates extracellular binding activity of integrins and thereby switching into active conformation. On the other hand, binding of ECM proteins on integrins activate signals that are transmitted into the cells known as outside-in signaling.33 These signaling events modulate roles in cell attachment, survival, proliferation, leukocyte trafficking, cell differentiation, cytoskeleton organization, cell migration, gene expression, tumorigenicity, and intracellular pH.

Integrins combine with multiple proteins to form integrin adhesion complexes (IAC), also known as the integrin adhesome, to activate downstream signaling pathways. To date the literature suggests such complexes involve at least 232 distinct integrin-associated proteins (IAP),34 including talin, paxillin, kindlins, filamin, vinculin, integrin-linked kinase (ILK), focal adhesion kinase (FAK), Src family protein tyrosine kinases (SFK), and GTPases of the Rho family. Such complexes can be split into four compartments: the ECM, the integrin, IAPs, and the actin cytoskeleton.34 The wide-ranging and diverse functions of just 24 distinct integrins are largely dependent on the complexity and diversity of IACs.

Several integrins are expressed within the lung and have roles in lung development, including branching morphogenesis, epithelial cell polarization, and differentiation.35,36 Expression of integrins varies across lung cell types and at varying times of development. Within the airway epithelium eight integrins are expressed, namely α2β1, α3β1, α5β1, α6β4, α9β1, αvβ5, αvβ6, and αvβ8.36–38 In some cases, integrin subunit expression in the epithelium is dramatically increased during inflammation or repair, most notably for the epithelially-restricted integrin αvβ6.37,39–41 Within the lung mesenchymal cells expression of α5β1, αvβ3, α2β1, α4β1, α5β1, αvβ5, and α7β5 have all been reported.22,42,43 Lung inflammatory cells also express integrin receptors; macrophages express β2 integrins, α4β1 and α5β1,44,45 and T lymphocytes are known to express α4β1, α5β1, αEβ7 and β2 integrins.42 Eosinophils, which have an important role in the pathophysiology of asthma, have a distinctive combination of eight integrins, α4β1, α6β1, αLβ2, αDβ2, αMβ2, αXβ2, and α4β7.46,47

The known function of integrins and integrin adhesomes make them attractive candidates for understanding how mechanical cues, including contractile forces and matrix stiffening, might influence airway remodeling processes. Furthermore, integrins are well-known for regulating leukocyte and inflammatory cell trafficking, which could also have important implications for asthma development and progression and for airway remodeling. The following section will discuss the role of integrin superfamily members in mediating specific airway remodeling processes in a variety of lung cells important to asthma pathogenesis. We have summarised how specific integrin heterodimers might be involved in asthmatic airway remodeling process in Table 1 and Figure 1.

Epithelial Changes in Airway Remodeling

The epithelial layer serves as a physical barrier to the exterior environment. As a result, it is the lungs’ first line of defence against foreign bodies inhaled during breathing. In addition, the healthy airway epithelium modulates immune responses and promotes the expulsion of inhaled particles through mucous production and cilia movement. The asthmatic airway epithelium undergoes dramatic phenotypic changes resulting in loss of epithelial integrity through epithelial shedding and increased mucous production via mucous gland hyperplasia.

Loss of airway epithelium is a well-documented phenomenon in asthma48–51 and is linked with airway hyper-reactivity.48,50 Loss of epithelial integrity occurs early in the disease course,49 and is thought to result from cellular apoptosis, senescence, and ineffective repair mechanisms.52,53 The asthmatic airway epithelium expresses markers of cellular injury/repair including increased epidermal growth factor receptor (EGFR),54,55 transforming growth factor β (TGFβ),56,57 and decreased E-cadherin.58 Furthermore, apoptosis and proliferative pathways are altered.59

Senescence of the epithelium occurs in asthma53 and may promote asthma development by compromising epithelial integrity and barrier function. Moreover, epithelial cell senescence drives thymic stromal lymphopoietin (TSLP)-induced airway remodeling.53 Crucially, airway epithelial senescence can be driven by a deficiency in integrin β4 expression in a P53 dependent manner,60 and the asthmatic human bronchial airway epithelium has reduced integrin β4 expression.61 In the ovalbumin mouse model of asthma, integrin β4 expression is reduced on the airway epithelium and is associated with structural disruption of the epithelial layer.62 Together, these studies in human asthmatic patients and animal models of asthma suggest a crucial role for β4 integrins in maintaining epithelial integrity in the airway.

In addition to loss of epithelial integrity, the asthmatic airway produces excessive quantities of mucous. MUC5AC and MUC5B are polymeric mucins that are significantly increased in the asthmatic airway and MUC5AC levels correlate with clinical measures of asthma including fractional exhaled nitric oxide (FeNO), sputum eosinophils, and airway hyper-responsiveness.63 A key driver of increased mucous production is goblet cell hyperplasia, which is evident in mild through to severe asthma.64,65 Additionally, mucous over-production can be driven by paracrine interactions with underlying airway smooth muscle cells.66 Overall, mucous gland hyperplasia and excessive mucus production can lead to mucous plugging of the airway, reduced airway lumen area, and airflow obstruction.67 Integrins have been implicated in mucous overproduction and goblet cell hyperplasia. β1 integrins have recently been shown to regulate cellular and secreted MUC5AC and MUC5B production in lung epithelial cells.68,69 Conversely, interactions between Mfge8 and integrin β3 subunits protect against allergen induced airway remodeling changes, including goblet cell hyperplasia.70

Increased Airway Smooth Muscle Mass (ASM)

Thickening of the airway smooth muscle (ASM) layer is a common and prominent feature of asthmatic airway remodeling. In the healthy airway, ASM cells are thought to play an important role in modulating respiratory airway tone. During disease processes, however, they have an important role in inflammatory and remodeling processes, releasing chemokines, pro-inflammatory and/or pro-fibrotic cytokines, and ECM proteins,22,26,71–73 which contributes to asthma pathogenesis.

In the asthmatic airway increased ASM mass appears to be driven by both increased myocyte size (hypertrophy) and increased myocyte number (hyperplasia), which are in turn associated with disease duration and severity.74 Some studies have suggested that the increase is due to hyperplasia rather than hypertrophy75 and others have suggested that hyperplasia only occurs in cases of fatal asthma.76 The causes of increased ASM mass in asthma are likely to be multifaceted. Interactions between ASM cells and airway epithelial cells can promote increased ASM cell proliferation and production of inflammatory cytokines and chemokines,77 suggesting a role for paracrine signaling between the two cell types. Furthermore, interactions between ASM cells and CD4+ T lymphocytes, known to be crucial to the pathogenesis of asthma, can increase ASM cell proliferation.78 Numerous ASM cell mitogens have been implicated in asthma, including Platelet derived growth factor (PDGF),79 TGFβ80 epidermal growth factor (EGF),78 heparin-binding EGF,81 and vascular endothelial growth factor (VEGF).82 In certain cases, such as PDGF,83 these mitogens can also promote ASM cell migration, which may contribute to the thickening of the ASM layer and expansion of the airway wall. Regardless of the underlying mechanism, during an asthma exacerbation, the thickened ASM bundle contributes to the airway-constricting capacity of the muscle84 and is thought to contribute to fixed airflow obstruction in severe asthma.

Several integrins have been linked with the contractile function of ASM cells. The fibronectin binding α5β1 integrins are involved in ASM cell contraction; functional blockade of α5β1 interrupts the function of focal adhesions, reduces interleukin-13 (IL13)-induced contraction of tracheal rings and inhibits airway hyper-responsiveness in vivo.85 Crucially, pharmacological inhibition of α5β1 had no effect on baseline tone of the smooth muscle rings and only reduced contraction in response to asthma-relevant contractile agonists, making it a potentially attractive approach for therapeutic targeting in asthma as the homeostatic functions of ASM could be preserved.85 A similar role has recently been identified for α2β1 integrins in regulating IL13-induced contraction, in this case through interrupting ASM cell tethering to collagen I and laminin-111.86

Contraction of ASM cells occurs via force transmission through polymerization and reorganization of the actin cytoskeleton. The cytoplasmic tail of β integrins binds to actin filaments through “linker” proteins such as vinculin, talin, and α-actinin, whereas the extracellular component of integrins interacts with the extracellular matrix to tether the cell.87 Force transmission between the cell and the extracellular matrix is therefore delivered by the actin–integrin–matrix complex. Actin filament polymerization and myosin activation are two concurrent biochemical mechanisms that are critical for smooth muscle contraction homeostasis, however, inhibiting actin polymerization limits smooth muscle force generation with minimal impact on myosin light chain phosphorylation.88–90 Crucially, actin-regulatory proteins are involved in regulating proliferation of smooth muscle cells,91 demonstrating how force transmission through integrins may influence cell proliferation and remodeling. Finally, TGFβ, which can be activated by ASM cells via integrins in response to reorganization of the actin cytoskeleton,22 augments ASM cell contraction in a RhoA-independent manner.92 This suggests a perpetual feedback loop whereby bronchoconstriction causes integrin-mediated TGFβ activation to promote airway remodeling, which in turn increases the contractility of the ASM cells and contributes to fixed airflow obstruction by increasing the baseline tone of the ASM layer.

In addition to promoting cell contractility through interactions with actin, integrin superfamily members are also involved in negative regulation of ASM contraction. Ligation of α8β1 integrins on ASM cells by milk fat globule-EGF factor-8 (Mfge8) proteins prevents IL13-induced ASM contraction.93 α9β1 integrins are also capable of negatively regulating ASM contraction. Loss of, or inhibition of, α9β1 integrins in mice increases airway contraction.94 These studies all highlight the importance of ASM cell interactions with matrix proteins through cell surface integrins to regulate ASM contraction and airway narrowing. As discussed previously, uncontrolled bronchoconstriction can promote airway remodeling via integrin-mediated activation of the pro-remodeling cytokine TGFβ.21–23 Taken together, it is clear that integrins have a potentially crucial role in regulating both pathological ASM contraction and downstream pro-remodeling effects, representing a direct link between uncontrolled asthma symptoms and the development of airway remodeling through a mechanobiological mechanism.

In addition to effects on ASM contraction, integrins expressed by ASM cells may also promote migration and proliferation of ASM cells, which is thought to contribute to thickening of the ASM layer and airway lumen narrowing in airway remodeling.95 Global blockade of RGD-binding integrins with a synthetic RGDS peptide attenuates allergen-induced ASM hyperplasia and hypercontractility, suggesting a crucial role for this subset of integrins in ASM remodeling.96 β1 integrins are highly expressed in ASM cells plus other mesenchymal cells in the lung, including myofibroblasts, and have recently been shown to localize key adaptor proteins at the leading edge of migrating ASM cells.97 Additionally, β1 integrins have been implicated in pro-proliferative responses of ASM cells to increasing matrix stiffness.31 α2β1, α4β1, and α5β1 have all been shown to regulate ASM cell proliferation.98 The matrix protein fibulin-5 has been implicated in this process through binding to β1 integrins to promote ASM cell proliferation via the mechanosensing YAP/TAZ pathway.99 Furthermore, laminin binding to α7β1 integrins promotes ASM cell survival and differentiation to a contractile phenotype.100 All together these studies support an important role of β1 integrins in regulating increased ASM mass in asthmatic airway remodeling.

Subepithelial Fibrosis

Subepithelial fibrosis in the asthmatic airway occurs in the lamina reticularis, just below the basement membrane, where ECM proteins such as interstitial collagens, fibronectin, tenascin, and proteoglycan accumulate.101 Subepithelial fibrosis is linked to asthma severity; collagen expression in the airway wall is higher in patients with moderate or severe asthma compared with those with mild disease,57 and the degree of subepithelial fibrosis is inversely correlated with FEV1.102 Increased deposition and decreased degradation of extracellular matrix (ECM) proteins is one of the major hallmarks of fibrosis regardless of organ or tissue type, and is primarily controlled by fibroblasts and myofibroblasts. Within the asthmatic airway, the number of myofibroblasts present correlates with the amount of collagens and tenascin detected in the subepithelial region.102 Furthermore, fibrocytes, which can differentiate into myofibroblasts, are increased in asthma and may contribute to subepithelial fibrosis.103

Information relating to a direct role for integrins in regulating matrix deposition in asthma is limited. In vitro studies have shown that treatment of ASM cells with the pro-remodeling cytokine TGFβ leads to increased fibronectin deposition via an α5β1 mediated mechanism involving ERK signaling.104 Additionally, in murine models it has been reported that interleukin-32 (IL32) reduces allergen-induced fibrosis via suppression of the integrin-FAK-paxillin signaling axis.105

Transforming growth factor-β (TGFβ) is thought to be a key driver of subepithelial fibrosis in asthma. TGFB1 mRNA is increased in bronchial biopsies from asthmatic individuals and levels correlate with the degree of subepithelial fibrosis.106 Furthermore, all three isoforms of TGFβ are increased in the asthmatic airway.56,57,107–109 TGFβ causes transdifferentiation of airway fibroblasts into highly synthetic, matrix producing myofibroblasts110,111 and increases production of matrix proteins by fibroblasts/myofibroblasts.112,113 Crucial evidence from murine animal models shows that inhibition of both TGFβ1 and 2 with isoform-specific function blocking antibodies reduced allergen-induced subepithelial collagen deposition,114 and intra-tracheal instillation of TGFβ1 is sufficient to cause subepithelial fibrosis.115 Finally, there is recent evidence suggesting that human bronchial fibroblast responses to TGFβ are altered in asthma, with pro-fibrotic responses being increased while anti-fibrotic responses are decreased.116 Together, these studies highlight a crucial role for TGFβ in regulating subepithelial fibrosis in asthma.

αvβ8 integrins are capable of activating TGFβ via recruitment of matrix metalloproteinases, which proteolytically cleave the latent TGFβ complex on the cell surface.117 Proteolytic cleavage of TGFβ has been previously reported,71,118 however, αvβ8 is the only integrin described thus far that mediates TGFβ activation via proteolysis. Importantly, expression of αvβ8 integrins is increased in asthma119 and expression of MMP-9 and MMP-8 in the airway inversely correlate with FEV1.120,121 Other cell types are capable of activating TGFβ via integrins including myofibroblasts, lung epithelial cells, and ASM cells.22,122–124 This raises the possibility that integrin-mediated TGFβ contributes to matrix deposition in the asthmatic airway, although this remains to be definitively proved.

Integrins have been implicated in inflammatory cell-mediated mechanisms of airway remodeling. Inhibiting RGD-binding integrins peptide on eosinophils using an RGDS blocks their ability to bind to ASM cells and interrupts the eosinophil-induced increased in ECM gene expression.125,126 Despite these studies it has been shown that a blockade of RGD-binding integrins, again using a synthetic RGDS peptide, reduces markers of ASM remodeling in vivo but has no effect on airway fibrosis, suggesting that this subset of integrins does not mediate subepithelial fibrosis.96 Finally a limited study has shown that collagen deposition in the asthmatic airway is inversely correlated with expression of α2 subunits on blood and CD4+ cells.


Angiogenesis refers to the process of forming new blood vessels. Increased vascularity of the asthmatic airway is a common observation and is evident in newly diagnosed asthma patients.127–129 The implications of increased vascularity on the pathogenesis of asthma and airway remodeling are still somewhat unclear. Correlations between increased vascularity and decreased lung function in asthma are inconsistent, with some reports finding a correlation128 and others reporting no link.127 Furthermore, animal models have shown that reducing angiogenesis experimentally using the inhibitor of angiogenesis, tumstatin, does not improve lung function.130 Although a link between increased vascularity and decreased lung function in asthma is still unclear, angiogenesis within the asthmatic airway wall enhances inflammatory cell recruitment and can cause edema, which may contribute to asthma pathogenesis.129

VEGF is one of the most potent activators of endothelial cell growth and promotes vascular permeability. VEGF levels in bronchial biopsies, serum, and bronchoalveolar lavage fluid are increased in asthma,131–133 and VEGF expression within airway cells correlates with the number of vessels.134 ASM cells isolated from asthmatics can drive angiogenesis via increased VEGF secretion.135 Crucially, pharmacological inhibition of VEGF signaling has shown promise in experimental models of asthma by reducing expression of growth factors, improving epithelial barrier function,136,137 and reducing markers of airway remodeling.138

Integrins have long been implicated in angiogenic processes, with the earliest descriptions demonstrating links between αvβ3 and αvβ5 and angiogenesis.139,140 Single nucleotide polymorphisms (SNPs) within the ITGB3 gene are associated with asthma pathogenesis.141 Additionally, pharmacological inhibition of αvβ3 prevents blood vessel maturation.142 However, genetic knockout of either β3 or β5 subunits does not alter vascular development.143,144

Genetic knockdown of integrin subunits has highlighted some potentially important roles in angiogenesis during development, which may also be important in disease. For example, genetic loss of integrin α5, which binds to fibronectin, leads to vascular defects and mice that are embryonic lethal, similar to the fibronectin knockout animals.145 This suggests a crucial role of α5 integrins and fibronectin in early angiogenesis. However a separate study found that inhibiting α5β1 with a small molecule inhibitor alpha5beta1 Integrin blockade inhibits lymphangiogenesis in airway inflammation and interrupts lymphatic vessel development without affecting blood vessel development.146 Finally, an important role for endothelial cell α2β1 integrin in promoting lumen formation in new capillaries has been described.147

Integrins in Airway Remodeling: Inflammation

Chronic airway inflammation is a hallmark of asthma and, as has been discussed previously in this article, has the potential to influence pro-remodeling pathways. Several integrins including α2β1, α5β1, αvβ3, and αvβ1 have been linked with increased cytokine release when ASM cells are cultured on collagen and fibronectin, suggesting that an altered mechanical environment may influence the inflammatory environment within the airway wall.148

Eosinophils are thought to be important to the pathogenesis of asthma and they express numerous integrins. Integrins have a key role in mediating migration of eosinophils from the blood into the lung, where they accumulate in asthma.149 Integrins, particularly β2 integrins such as αmβ2 and α4 integrins, have been implicated in eosinophil degranulation and inflammatory mediator release.150–152 In addition, α4 integrin binding to its ligand fibronectin via Fas antigen signaling increases the eosinophil survival, which may contribute to airway eosinophilia in asthma.153

Airway neutrophilia is associated with increased asthma severity and asthma that is refractory to corticosteroids, the backbone of asthma treatment.154 There is a paucity of research focused directly upon a potential role for integrins in driving airway neutrophilia in asthma; however, integrins, particularly β2 integrins, are well known to regulate neutrophil recruitment to sites of inflammation.155,156 Furthermore, neutrophils and their products have been implicated in lung fibrogenesis in other chronic lung diseases such as interstitial lung disease (ILD). For example αMβ2 integrins can regulate neutrophil extracellular trap (NET) formation in ILD,157 and secretory leukocyte protease inhibitor (SLPI), which inhibits neutrophil elastase, has differential effects on collagen expression in mouse lung tissue.158 Previous work has shown that integrin expression by sputum neutrophils in asthmatic patients is aberrant compared with healthy controls,159 however, whether such changes in integrin expression affect the overall activity of neutrophils in asthma and the impact this has on airway remodeling is yet to be elucidated.

Exposure to allergens causes an increase in TH2 cell infiltration and TH2 cytokine expression in asthmatic patients. TH2 cells co-ordinate allergy-induced asthmatic inflammatory responses through Th2 cytokines (IL-4 and IL-5), causing eosinophil infiltration and hyper-responsiveness of the airways.160 Airway epithelial cells, by acting as antigen presentation cells (APCs), can cause T-cell activation and proliferation, and silencing β4 integrins in asthmatic airway epithelial cells impairs their antigen presentation capacity and decreases T-cell proliferation.161 This is one possible integrin-dependent mechanism that may contribute to TH2 inflammation bias in asthmatic airways.

Therapeutic Targeting of Integrins to Impact Airway Remodeling

To date no drug has been developed that specifically targets the development and progression of airway remodeling. Corticosteroids, which are the mainstay of asthma treatment and primarily target airway inflammation, can reduce several markers of airway remodeling, including ASM proliferation,162 TGFβ expression in fibroblasts,163 and VEGF expression by epithelial cells,164 and can reconstitute epithelial structure.165 Despite these effects, airway remodeling persists in asthmatic patients despite long-term treatment with inhaled or oral corticosteroids, suggesting there is no overwhelming impact of corticosteroids on airway remodeling in asthmatic patients.

In recent years several new biological therapies have been developed and approved, particularly for the treatment of severe asthma, some of which have shown some effects on airway remodeling. Mepolizumab, a clinically approved anti-IL5 monoclonal antibody, has been shown to reduce airway wall thickness in CT scans166 and reduce matrix protein deposition in bronchial biopsies.167 Benralizumab is another monoclonal antibody that targets IL5 signaling, which computational modeling has suggested reduces ASM mass and the number of tissue myofibroblasts present in the airway wall.168 Omalizumab targets IgE for the treatment of allergic asthma and has been shown to reduce airway wall thickness when measured by computed tomography.169 Research into the effects of other new monoclonal antibody therapies such as dupilumab (anti-Il4 receptor) and reslizumab (anti-Il5) are yet to be published, however, the former studies suggest that inhibiting TH2 inflammation may reduce asthmatic airway remodeling in severe asthma patients. Whether such treatments can sufficiently reduce airway remodeling to lead to long-term positive effects on fixed airflow obstruction or slow the decline in lung function seen in asthmatics, which is thought to be driven by airway remodeling, is likely to be the focus of ongoing studies into the utility of biological therapies. Another key question that remains to be answered is whether therapeutic treatment of airway remodeling will be sufficient or whether prophylactic treatment much earlier in the disease course will be required for the biggest clinical benefit.

Research Dilemmas in Airway Remodeling

As discussed above, airway remodeling is a complex and diverse collection of structural changes involving many tissues and cell types. Despite the introduction of various new therapies for asthma in recent years including various biological treatments targeting airway inflammation, there has yet to be an effective treatment for airway remodeling. This is potentially a result of the many specific challenges associated with researching the underlying mechanisms driving airway remodeling, which were highlighted in detail in an American Thoracic Society statement in 2017,170 and which will be discussed briefly here.

Lack of Appropriate Animal Models

A major hindrance to research investigating airway remodeling and asthma pathogenesis more widely is the lack of an appropriate animal model. Mice are the most commonly used species for in vivo models of asthma and airway remodeling, however, rats, guinea pigs, and larger species including pigs, sheep, and horses are also used.171

A significant drawback to animal models of asthma is that asthma is a human disease that does not spontaneously occur within the animal kingdom, with the exception of eosinophilic bronchitis in cats and heaves in horses, both of which are obstructive airway diseases with some similarities to asthma. Animal models are therefore largely dependent upon sensitizing animals experimentally to an allergen and then delivering that allergen to the airways to elicit an allergic inflammatory response.171 Such models are advantageous when studying how allergy and/or inflammation drive features of asthma; however, as discussed above, the relative roles of these processes in driving airway remodeling is still largely unclear and so using such models to drive airway remodeling in animals may not accurately reflect the pathogenesis driving remodeling in man.

Size and anatomical differences between human lungs and the species used for models of asthma and airway remodeling also have the potential to negatively impact the utility of findings from such models. For example the human lung has a vastly greater number of branching airways compared with mouse lungs, the effect of which on the development of remodeling is unclear with our insufficient understanding of the mechanisms driving remodeling.170 Recent methodological advances in assessing airway remodeling in airways of various sizes in murine models of asthma172 may aid our understanding of the heterogeneic nature of remodeling, albeit within the confines of a rodent disease model discussed above.

Lack of Uniformity in Core Experimental and Technological Design

Aside from species differences, the ability to compare results across studies is further complicated by methodologies used to assess airway remodeling. Airway remodeling is often quantified across large- and medium-sized airways by measuring airway wall thickness; however, bronchioles and other smaller bronchi, because of their diverse components and structures, may have different impacts on the evolution of airway remodeling. Even at the cellular level, distinct morphological, synthetic, and epigenetic differences between lung compartments exist, as has been described for fibroblasts isolated from airways compared with distal lung regions.173,174 Existing whole-organ/whole-body imaging modalities do not have enough resolution to distinguish particular cell types and can only assess various degrees of wall thickness.170

Quantifying airway remodeling in human airways largely depends upon measuring indices within airway biopsy samples, or imaging modalities such as high-resolution computed tomography (HR-CT), both of which can predict fixed airflow obstruction in asthmatic patients.7,175 These techniques present challenges when attempting to study the longitudinal development and slow progression of airway remodeling in asthma patients due to either their invasive nature (biopsy) or high radiation exposure and cost (HR-CT). Several studies have suggested potential biomarkers of airway remodeling including TGFβ and periostin,176 galectin-3,177 hyaluronan,178 however, they have yet to be widely validated, which restricts their utility in clinical research. It is clear that both mechanistic studies of airway remodeling and clinical trials testing potential interventions that target airway remodeling remain incredibly difficult due to a lack of consensus on which AR index to use, cost effectiveness, safety, ability to make repeated measurements, plus sensitivity and specificity of measurement.

Concluding Remarks

As our understanding of the underlying mechanisms driving airway remodeling in asthma improves, so does our knowledge of how cell surface integrins play a critical role in the development and progression of airway remodeling. There is still much that we do not fully understand including the relative importance of mechanical and inflammatory cues to the development of airway remodeling. However, what is clear from research in recent years is that integrins may be involved in multiple aspects of airway remodeling across all lung cells types (see Figure 1). In the years to come, therapeutic targeting of airway remodeling may improve morbidity and lung function in patients with severe, uncontrolled asthma. With the advent of biological therapies in recent years we have begun to observe some positive effects on features of airway remodeling in the most severe asthmatics. Questions remain, however, about whether these effects are sufficient to produce long-term and long lasting impacts on airway remodeling that would improve fixed airflow obstruction and slow the decline in lung function that is observed in asthma. While the effects of some biologics on airway remodeling are encouraging we believe targeting airway remodeling specifically, rather than as a bi-product of targeting inflammatory pathways, will lead to the biggest clinical improvement in airway remodeling in the years to come. Such targeting could include approaches to target integrin mediated pathways since we have hopefully demonstrated in this review that integrins are integral to many pathways involved in airway remodeling pathogenesis. Targeting integrins directly to impact airway remodeling could be a useful adjunct to existing therapies that target airway inflammation to enable both fundamental features of asthma to be treated simultaneously.

Figure 1 Schematic diagram giving an overview of how different integrin heterodimers expressed by a variety of lung cell types may contribute to the development and/or progression of airway remodeling in asthma. Both environmental and cellular stimuli converge upon integrin signaling pathways in a variety of cell types to contribute to airway hyper-responsiveness and ASM thickening, mucous over-production, subepithelial fibrosis, new blood vessel formation, and airway inflammation.


Amanda Tatler reports grants from Medical research foundation, Asthma UK, and Biogen during the conduct of the study and personal fees from Pliant therapeutics outside the submitted work. The authors report no other potential conflicts of interest for this work.


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Bhatt reports serving on an advisory board for Boehringer Ingelheim and receiving consultant fees from Sanofi/Regeneron. O’Connor reports receiving research grants from the NIH and consultant fees from Grupo Menarini and Dicema Pharmaceuticals. Webber reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

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The U.S. Preventive Services Task Force finalized its recommendation against screening for COPD in asymptomatic adults, which is consistent with its 2016 recommendation.

“In 2008, and again in 2016, the U.S. Preventive Services Task Force issued a D recommendation against screening for COPD in asymptomatic adults (defined as individuals who do not recognize or report respiratory symptoms),” Elizabeth M. Webber, MS, research associate at the Kaiser Permanente Evidence-based Practice Center at the Center for Health Research in Portland, Oregon, and colleagues wrote in JAMA. “Although prior evidence demonstrated that screening could identify adults with COPD, there was no direct evidence that screening for COPD improved patient outcomes and limited treatment evidence to suggest a clinically meaningful benefit in persons considered to be most applicable to a screen-detected population.”


Source: Adobe Stock.

The final recommendation comes after a draft recommendation statement evidence review were published in November 2021 for public comment.

Recommendation against screening

The USPSTF task force evaluated MEDLINE, the Cochrane Central Register of Controlled Trials and CINAHL to identify relevant studies that screened individuals who did not recognize or report respiratory symptoms and studies of treatment in adults with mild to moderate or symptomatic COPD. All studies were published from January 2015 to January 2021.

The evidence report included three trials or analyses of pharmacologic treatment (n = 20,058), 13 trials on nonpharmacologic interventions (n = 2,657) and two large observational studies addressing pharmacologic treatment harm (n = 243,517).

Results of clinical trials of pharmacologic therapy were consistent with the 2016 USPSTF review supporting the recommendation that bronchodilators with or without inhaled corticosteroids reduce COPD exacerbations and tiotropium (Spiriva, Boehringer Ingelheim) improves health-related quality of life in adults with moderate COPD, according to the evidence review. The task force reported no consistent benefit for any nonpharmacologic intervention for COPD and no significant harms among treatment trials that reported adverse events, according to the review.

The two large observational studies demonstrated associations between initiation of long-acting muscarinic antagonists or long-acting beta agonists and risk for serious cardiovascular events among treatment-naive patients as well as an association between inhaled corticosteroid use and risk for diabetes development, according to the task force.

This finalized recommendation applies to asymptomatic adults who do not recognize or report respiratory symptoms, not to those who present with symptoms such as chronic cough, sputum production, breathing difficulties or wheezing.

“This recommendation is a reaffirmation of the USPSTF 2016 recommendation statement. In 2016, the USPSTF reviewed the evidence for COPD and found that screening for COPD in asymptomatic adults has no net benefit. The USPSTF found no new substantial evidence that could change its recommendation and, therefore, reaffirms its recommendation against screening for COPD in asymptomatic adults,” the task force wrote.

In 2011, a joint guideline from the American College of Physicians, American College of Chest Physicians, American Thoracic Society and European Respiratory Society recommended against screening for COPD with spirometry in asymptomatic adults.

Research needs, gaps

The task force highlighted several research needs and gaps, including more information on the effectiveness of asymptomatic COPD screening to reduce morbidity or mortality or improve health-related quality of life; the effectiveness of early treatment in asymptomatic, minimally symptomatic or screen-detected adults; harms of screening and treatment in this population; and drivers of COPD health disparities and effective prevention strategies.

In an accompanying editorial, Surya P. Bhatt, MD, MSPH, associate professor of medicine in the division of pulmonary, allergy and critical care medicine at the University of Alabama, Birmingham, and George T. O’Connor, MD, MS, professor of medicine in the Pulmonary Center at Boston University School of Medicine and associate editor for JAMA, wrote, “[w]hile the recommendation of the USPSTF is reasonable, based on currently available data, so is its call for further research to fill the gaps in knowledge regarding potential COPD screening or case-finding.

“Even though available data may not support screening asymptomatic adults for COPD, there is substantial rationale for further investigation of strategies to enhance earlier detection of this condition,” Bhatt and O’Connor wrote.


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Nebulizer Market Is Expected To Reach USD 1.77 Billion By 2030, Due To Increased Patient Acceptance, Quick Treatment, Portability, And Convenience | Grand View Research, Inc.

“Grand View Research, Inc. – Market Research And Consulting”

According to a new report published by Grand View Research, the rising incidence rate of chronic respiratory diseases, increasing demand for home healthcare devices, and rising geriatric population worldwide are the major factors leading to the market growth.

Nebulizer Industry Overview

The global nebulizer market size was valued at USD 1.04 billion in 2021 and is expected to reach USD 1.77 billion by 2030, registering a CAGR of 6.2% over the forecast period. The high growth is attributed to the rising incidence rate of chronic respiratory diseases, increasing demand for home healthcare devices, and the rising geriatric population. As per the Centers for Disease Control and Prevention, Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death in the U.S.

Moreover, the rising consumption of alcohol, tobacco, and ultra-processed products, including sugar-sweetened beverages, is a major cause behind the increasing prevalence of respiratory diseases in North America. According to the Centers for Disease Control and Prevention (CDC) data, about 14% of deaths in adults aged 30 to 70 years in North America are caused due to tobacco consumption. Thus, an increase in the number of smokers and environmental pollution are anticipated to increase the demand for nebulizers. In addition, as per the WHO, in 2019, there were around 3.23 million deaths worldwide due to COPD. However, initiatives such as the “Global Alliance against Chronic Respiratory Diseases” are likely to improve diagnosis and treatment rates of respiratory disorders, which may, in turn, drive the market for nebulizers.

Gather more insights about the market drivers, restrains and growth of the Global Nebulizer market

The COVID-19 outbreak has affected millions of people around the world. The pandemic has compelled the healthcare industry to take emergency actions, with a race to develop both therapeutic and preventive interventions. Asthma or COPD patients, who were aware of the risk of airborne transmission of COVID-19, were hesitant with regard to the use of inhaled medications, which are considered a potential source of viral transmission and immunosuppression. However, medical practitioners advised all such patients to continue using their prescribed inhaled medications, including nebulizers. Nebulized albuterol was recommended in some parts of the U.S. as an alternative to albuterol rescue inhalers when pharmacies faced a shortage of albuterol inhalers.

In addition, many pharmaceutical corporations are focusing on developing effective treatments to treat the COVID-19 viruses, which will be primarily administered via a nebulizer. For instance, in May 2021, Inspira Pharmaceuticals and Vectura declared a collaboration to develop a potential inhalation-based COVID-19 therapy. Under this contract, Vectura will test IPX formulation delivery to lungs through its FOX vibrating mesh nebulizer.

The market for nebulizers and respiratory devices is quite mature with the jet segment dominating the market due to the low cost. Hence, other nebulization devices are expected to experience high competition. Furthermore, it is a challenge for new technology or device to gain momentum in mature markets, particularly with the intricacies of different reimbursement and national regulatory systems that need to be followed for both drugs as well as devices.

North America nebulizer market size, by type, 2020 - 2030 (USD Million)

Furthermore, it is a challenge for new technology or device to gain momentum in mature markets, particularly with the intricacies of different reimbursement and national regulatory systems that need to be followed for both drugs as well as devices. Mesh nebulizers are more expensive than jet nebulizers because of the increased number of tolerances, components, critical parts, and assembly related to both mesh and electronic control circuits. Besides, increasing applications of mesh nebulizers in clinical trials since 2006 by major companies such as Philips, Vectura, and Pari Gmbh are expected to boost the market growth in the near future.

Medicare Part B covers the cost of nebulizers and the cost of a few nebulizer medicines that are considered necessary. Under Part C, coverage is provided for medically-necessary nebulizers. Medicare reimburses 75% of the manufacturer’s suggested retail price for durable medical equipment. Nebulizers are classified as durable medical equipment by Medicare. Initiatives are being undertaken by government and non-government organizations to streamline the diagnosis and treatment of respiratory disorders, thus further supporting the market growth. For instance, the GARD is a voluntary alliance of national and international organizations to cure respiratory disorders.

Nebulizer Market Segmentation

Based on the Type Insights, the market is segmented into Jet, Mesh, and Ultrasonic.

  • Jet nebulizers accounted for the largest revenue share of over 65.0% in 2021 owing to the low cost of the devices. Besides, ease of handling nebulizers and efficient design for drug delivery have made jet nebulizers the prime segment over the years.
  • The mesh nebulizers segment is expected to witness lucrative growth over the forecast period due to the technologically advanced compact size devices and minimized drug loss.

Based on the End-use Insights, the market is segmented into Hospitals & Clinics, Emergency Centers, and Home Healthcare.

  • The hospitals and clinics segment accounted for the largest revenue share of over 65.0% in 2021 owing to the favorable reimbursement policies and larger patient footfall.
  • Home healthcare is a cost-effective alternative to expensive hospital stays, which is expected to boost the market growth.

Based on the
Nebulizer Regional Insights, the market is segmented into North America, Europe, Asia Pacific, Latin America, and Middle East & Africa.

  • North America captured the largest revenue share of over 30.0% in 2021 owing to growing respiratory disorders and efforts by the government such as favorable reimbursement scenario, rise in customer awareness, and well-established healthcare infrastructure.
  • Asia Pacific is expected to be the fastest-growing regional market over the forecast period owing to a large geriatric population, increasing focus on preventive care, and government initiatives promoting technological innovations.

Browse through Grand View Research’s Medical Devices Industry Research Reports.

  • Home Healthcare Market – The global home healthcare market size was valued at USD 320.6 billion in 2021 and is expected to expand at a compound annual growth rate (CAGR) of 7.9% from 2022 to 2030. The growing geriatric population and rising incidence of target diseases such as dementia and Alzheimer’s as well as orthopedic diseases are factors expected to fuel market growth.


  • Clinical Trials Market – The global clinical trials market size was valued at USD 47.0 billion in 2021 and is expected to expand at a compound annual growth rate (CAGR) of 5.8% from 2022 to 2030. However, the market growth was hindered in 2020 due to the COVID-19 pandemic.

Market Share Insights:

  • October 2020: HCmed Innovations Co., Ltd. introduced Pulmogine to the China market.
  • January 2020: OMRON Corporation announced the opening of the Automation Center Tokyo (ATC-TOKYO) in Tokyo. With this center, customers can join the company to find solutions for any challenges arising during manufacturing.

Key Companies Profile:

The market for nebulizers is mature due to the presence of major players. However, the introduction of technologically advanced mesh nebulizers has created many opportunities for the companies such as Vectura Group and PARI Pharma.

Some prominent players in the global nebulizer market include:

  • Omron Corporation
  • GE Healthcare
  • Koninklijke Philips N.V.
  • Allied Healthcare
  • Vectura Group Plc.
  • PARI Respiratory Equipment, Inc.
  • Aerogen
  • DeVilbiss Healthcare LLC
  • Briggs Healthcare
  • Beurer GmBH

Order a sample PDF (free) of the Nebulizer Market Intelligence Study, published by Grand View Research.

About Grand View Research

Grand View Research, U.S.-based market research and consulting company, provides syndicated as well as customized research reports and consulting services. Registered in California and headquartered in San Francisco, the company comprises over 425 analysts and consultants, adding more than 1200 market research reports to its vast database each year. These reports offer in-depth analysis on 46 industries across 25 major countries worldwide. With the help of an interactive market intelligence platform, Grand View Research Helps Fortune 500 companies and renowned academic institutes understand the global and regional business environment and gauge the opportunities that lie ahead.


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The digital Kaia Health mobile app helped people with chronic obstructive pulmonary disease (COPD) to better adhere to a physical activity plan after completing an in-hospital pulmonary rehabilitation program, a study found.

Moreover, the patients who used the application for six months also saw increases in exercise performance, with an easing of shortness of breath and fatigue.

“The results show significantly higher physical activity over a period of six months by using the Kaia Health COPD app compared to the control group,” Stephan Huber, MD, chief medical officer at Kaia Health, and one of the study’s authors, said in a press release.

“The Kaia Health COPD app has been proven to be an innovative way of positively influencing the health status of COPD patients over a longer period of time,” Huber said.

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The company now is assessing the performance of its mobile app among those who have not yet completed a pulmonary rehab program.

“Our next goal is to demonstrate the effectiveness in patients with COPD without previous treatment in rehabilitation as part of an ongoing follow-up study,” said Huber.

The study, “Using a smartphone application maintains physical activity following pulmonary rehabilitation in patients with COPD: a randomised controlled trial,” was published in the journal Thorax.

People with COPD often undergo pulmonary rehabilitation as part of their treatment plan. This includes exercise training, health education classes, and psychological support. Several clinical trials have shown that such pulmonary rehabilitation programs boost health-related quality of life and exercise capacity.

However, evidence also suggests that COPD patients struggle to maintain physical activity and to adhere to exercise plans following the completion of these pulmonary rehabilitation programs.

Smartphone applications have been suggested as a way to help maintain access to rehab and structured exercises. But few studies have assessed whether their regular use helps patients to maintain physical activity.

“To our knowledge, this study is the first RCT [randomized controlled trial] to demonstrate the maintenance of PA [physical activity] after inpatient PR [pulmonary rehabilitation] using a digital structured programme,” the researchers wrote.

The team, from Switzerland and Germany, conducted the clinical trial (DRKS00017275) to assess whether regularly using the Kaia COPD app might help patients adhere to physical activity programs following pulmonary rehab.

The Kaia app consists of an exercise training program, breathing exercises, and an educational program. It was developed by healthcare professionals and pulmonary rehabilitation experts.

A total of 67 COPD patients, with a mean age of 64 and of whom 49.3% were women, were enrolled in the study. Each was randomly assigned to the Kaia COPD app — called the intervention group, with 33 patients — or to a control group (34 participants), in which patients received standard care. All were followed for six months after completing rehab.

COPD exercises included several daily whole-body exercises performed for 15 to 20 minutes. All exercises were explained in videos with detailed instructions.

The study’s main goal was to assess the effectiveness of the Kaia app in helping maintain physical activity, which was measured by the number of steps taken on a daily basis using an activity tracker.

Additional goals included assessing disease impact on the patient’s life, measured by the COPD assessment test (CAT) and the chronic respiratory disease questionnaire (CRQ), and changes in exercise capacity. Such changes were evaluated using the one-minute Sit-to-Stand test (STST).

CAT total scores range from zero to 40, in which higher scores reflect a more severe disease impact. STST assesses how many sit-to-stand actions a patient can perform in one minute.

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In total, 60 patients completed the study. The analysis showed that the number of steps was significantly higher for COPD patients in the intervention group compared with those in the control group after six months.

Also, while CAT scores decreased in the Kaia app group after six months — indicative of less severe disease — they increased in the control group by 3.7 points as compared with the study’s start (baseline).

Shortness of breath and fatigue were significantly eased in patients who used the app.

The number of sit-to-stand actions in the STST increased significantly in the intervention group after three months compared with the control group. However, no differences were seen after six months.

“Of course, we were very pleased with these positive study results, but were not surprised,” said Rembert  Koczulla, consultant pulmonologist at Kaia Health and a study co-author. “With Kaia Health, the success of the inpatient rehabilitation over six months was maintained to the greatest extent during the study.”

According to Koczulla, the findings highlight that, at the least, “slight improvements with symptoms can be achieved.”

Among participants, 13 (43%) were deemed frequent users, meaning they used the app at least four times a week for at least 70% of the study’s weeks.

A further analysis focused on this patient group alone showed an even higher difference in the main goal when compared with controls.

Overall, “this study reveals how a digital intervention can be used to supplement existing care by closing gaps in the existing healthcare landscape,” the researchers wrote.

 “We are excited about the potential the Kaia Health COPD app can bring to the U.S., which adds another layer of support to our mission to make clinically validated, cost effective digital therapies accessible anytime, anywhere and for anyone,” said Nigel Ohrenstein, president of Kaia Health.

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Multi-disciplinary post-COVID care centers have opened across the country to enable management of patients with lingering symptoms. Rehabilitation centers have developed physical therapy programs for patients with LC. 

There are no basic nor clinical research studies to support any treatment for the few months of lingering symptoms after COVID-19 nor for LC, but healthcare providers may be able to help reduce or manage symptoms through simpler measures of rehabilitation services, symptomatic medications, and coordinated care. Mild disease is more likely to resolve without aggressive therapy. Particularly with milder illness, it is important to consider other possible diagnoses masquerading as LC. Conventional interventions can be used to address issues such as pain, poor appetite, headache, nausea, and diarrhea. Specialists are needed for patients with chronic kidney disease who may need long-term dialysis after COVID-19 infection. Clotting abnormalities have been reported that require consultation and treatment by hematologists.

Although registries to assess LC are being launched, there is an absence of research on self-management practices among individuals with LC. Patients and patient advocacy groups have reported an absence of timely support and poor recognition and definition of LC, partly attributable to insufficient understanding of LC infection and overwhelmed healthcare systems. The lack of support for these patients has led to loss of faith and disappointment in healthcare service delivery, leading people with LC to seek alternative sources of support and treatment.

Exercise is currently being evaluated as early management of these patients with encouraging results.
 Specific treatment for defined organ involvement should include specialists such as cardiologists, pulmonologists, gastroenterogists, psychologists, neurologists, and physical therapists, as well as specialists in other fields of medicine.

The various presentations of LC are accounted for by variations in the effect of the virus on the immune system and other organs and the extent of the host inflammatory response. This interaction is currently being evaluated.

There are now published series of LC in children, although treatment data are lacking.
[12, 15]
 A major difference between LC in adults and children is that the percent of COVID-19 infected children developing LC is significantly lower and the duration of illness is shorter. Early symptoms appear to be similar to adults, with fatigue and difficulty concentrating being most common. Difficulty concentrating is of greatest concern because of the interference with optimal learning and school performance. One contrasting feature is that insomnia is much less common than in adults. Some series have suggested that in addition to the duration of illness being shorter, long-term outcome is better than for adults.

Some people with LC have symptoms of CFS/ME, postural orthostatic tachycardia syndrome (POTS), dysautonomia, fibromyalgia, autoimmune disease, mast cell activation syndrome (MCAS), and other health conditions that require management that has been shown to be effective in clinical trials. When someone suspected of having LC receives a new diagnosis of these other conditions, medical and rehabilitation specialists may then be able to apply the appropriate treatments and therapies.

For some patients, their LC symptoms improve over time. It is unclear which LC patients have symptoms that are likely to be permanent or are reversible with time. 

Cardiovascular therapies

In a retrospective study presented in February 2022 at the American College of Cardiology's virtual Cardiovascular Summit, scientists from Cleveland Clinic reviewed their data that used enhanced external counterpulsation (EECP).
 This intervention compresses the blood vessels in the lower limbs to increase blood flow to the heart. EECP uses contracting and relaxing pneumatic cuffs on the calves, thighs, and lower hip area to provide oxygen-rich blood to the heart muscle, brain, and the rest of the body. Each session takes 1 hour, and patients may undergo as many as 35 sessions over 7 weeks. The researchers evaluated the effect of the therapy in 50 COVID-19 survivors. Twenty patients had coronary artery disease (CAD), whereas 30 did not; average age was 54 years.

All patients completed the Seattle Angina Questionnaire-7 (SAQ7), Duke Activity Status Index (DASI), PROMIS Fatigue Instrument, Rose Dyspnea Scale (RDS), and the 6-minute walk test (6MWT) before and after they completed 15 to 35 hours of EECP therapy.

The analysis showed statistically significant improvements in all areas assessed, including 25 more points for health status on the SAQ7 (range, 0 to 100), 20 more points for functional capacity on DASI (range, 0 to 58.2), 6 fewer points for fatigue on PROMIS (range, 4 to 20), 50% lower shortness of breath score on the RDS, and 178 more feet on the 6MWT.

The change from baseline among participants who had LC but not CAD was significant for all end points, but there was no difference between LC patients with or without CAD. 

Registries and databases for LC 

Recover Initiative 

The United States National Institutes of Health has launched the RECOVER Initiative (Researching COVID to Enhance Recovery). The New York University Grossman School of Medicine will take the lead in building the RECOVER research consortium, harmonizing and coordinating data within the consortium, and developing methods for monitoring protocols, including recruitment, data quality, and safety measures to identify adverse events. Additionally, they will guide communication and engagement efforts with key stakeholders, including patients and healthcare providers. 

The Biostatistics Center at Massachusetts General Hospital will support the data resource core, which will help enable tracking and searchability of results across all sources of data, from clinical studies to electronic health records. In addition, they will provide expertise in statistical analyses and play a key role in ensuring data standardization, access, and sharing among RECOVER projects. 

Therapies for LC (TLC) study

The Therapies for LC study will begin to explore self-management practices through a central database that surveys people with LC.
This study aims to be a first step towards understanding this important and under-researched public health issue.

Finally as a warning: there are potential risks of self-prescription, such as harmful drug–drug interactions and use of inappropriate treatments. Research is needed to understand the self-management practices that are being used to manage LC symptoms; factors influencing their uptake; and the benefits, harms, and costs. There is also a need to assess the potential harmful effects of polypharmacy and drug–drug interactions in these individuals. 

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