Summary of Arietta’s thesis – Ma’ayan Dee, Neta Fibeesh & Abi Mincer

Systematic review and meta-analysis of health status questionnaires in bronchiectasis

A recent study regarding Bronchiectasis questionnaires was used to understand the quality of life of patients with a chronic lung disease called Bronchiectasis. These results were used to understand the connections between HRQOL (Health Related Quality of Life) and clinical measures, which are other tools we use to assess a disease. The aims of the study were to identify all the evidence and select the appropriate studies that can later be assessed in an unbiased and balanced way. The importance of collecting this data in this way is that it provides useful insights about the quality of life of patients from a personal point of view and helps the researchers understand the effectiveness of their clinical tools.

The searching and selection process using electronic databases were used to choose appropriate studies, for instance patients with cystic fibrosis (a genetic condition) were not chosen. The studies which were chosen were analysed to check for certain criteria that made sure their results were reliable. Then, a meta-analysis (a combination of various data assessments) was used to test how strong the connections between HRQOL and the clinical measures actually were. Out of the initial 1,918 studies first identified, 43 studies were used in the reviews and 38 ended up being chosen as suitable for the meta-analysis.

Results showed that there was a strong relationship between the HRQOL and subjective outcome measures such as fatigue (tiredness) in comparison to objective measures such as ability to exercise and how severe the Bronchiectasis was revealed to be on a CT scan.

 

Development and validation of the Bronchiectasis Health Questionnaire (BHQ): a new patient-reported outcome measure

There is an insufficient amount of questionnaires in relation to assessing the health status of someone with bronchiectasis. The questionnaires themselves are easy to understand and they give an idea of the patient’s perspective. A study was conducted to develop and confirm the value of the BHQ (Bronchiectasis Health Questionnaire). The BHQ is a new tool to measure the health status for patients with bronchiectasis. Questionnaires are needed for individual conditions due to the fact that every disease has its own causes and symptoms. This means that in order to help patients with different diseases questionnaires have to be adapted in order that the questions lead to suitable answers which can thus help those asking the questions to find answers that will lead to help for those taking part.

Patients who took part in the study were recruited from two outpatients clinics. The BHQ was developed by the introduction of item generation as well as item reduction. As well as this, the BHQ was developed by repeated testing and validation.

Two hundred and six patients took part in the study and completed a questionnaire with 65 questions. Fifty five of the questions were removed from the initial questionnaire to make the tool easy to use and more valid. The final version of the BHQ consisted of 10 items with a score between 0-100 with 100 being the best health status.

The BHQ generates a total score and general consensus. It can be used in clinical and research settings in order to assess the effect of bronchiectasis from the perspective of the patient who has the disease.

 

The objective assessment of cough frequency in bronchiectasis

Bronchiectasis is the abnormal widening of the bronchi or their branches, which causes a risk of infection. Cough is a common symptom of this condition and recent advances in technology in the monitoring of cough sound have enabled the assessment of cough frequency to be used to better understand various diseases. This study was aimed at quantifying cough frequency and by doing so investigating how the cough frequency affects the health status of individuals.

54 Bronchiectasis patients were assessed along with 35 healthy people (controls). The researchers measured their health status, cough severity, lung function and 24-hour cough. 24-hour cough was measured using a small portable audio recording device.

Data revealed that the cough frequency was high for patients suffering from Bronchiectasis meaning they coughed a significant amount more that healthy people. Additionally, patients with Bronchiectasis had impaired health status. Various factors associated with the objective cough frequency included sputum production (coughing up phlegm), the frequency of antibiotics for respiratory infections and older age. However, there was no good association between cough frequency and a common lung function test (spirometry).

 

Summary

Overall the studies revealed that questionnaires were a successful technique to provide results regarding the quality of life of those suffering from Bronchiectasis. This shows that a patient’s own perspective is very valuable in medical research and not only their physical condition!

This summarises the PhD research undertaken by Arietta Spinou, under the supervision of Surinder S Birring & Rachel Garrod. The summary was produced by Neta Fibeesh, Abi Mincer & Ma’ayan Dee, Year 12 student from JFS School, Harrow, as part of our departmental educational outreach programme.

Research summary – Morgan Walker

Airways Obstruction and Pulmonary Capillary Blood Volume in Children With Sickle Cell Disease

Catherine Wedderburn, David Rees, Susan Height, Moira Dick, Gerrard F. Rafferty, Alan Lunt, Anne Greenough

Published in the journal Pediatric Pulmonology, published online July 10th 2013

Children with Sickle Cell Disease (SCD) often face many obstacles due to the changes the condition causes in the body’s red blood cells. SCD results in anaemia, which is when there is less haemoglobin in the blood to help carry oxygen around the body. As a result, the heart has to pump much harder in order to ensure that the tissues of the body receive enough oxygen. This increased work by the heart also raises the amount of blood in the lungs, in order to allow sufficient oxygen is absorbed from the air. Children with SCD also frequently experience ‘airway obstruction’, which is the narrowing of the airways that makes it then harder to breathe. Airway narrowing can be caused by asthma, where muscles in the airways constrict, or by other causes.

This research was used to investigate whether the increased blood volume in lungs is associated with the ‘obstruction’ of the airways. The researchers tested this through testing the difference in the airways before and 30 minutes after using a medication called a bronchodilator (the blue asthma ‘reliever’ inhaler) which relaxes the airway muscles, widening the airways.   The study used measurements called spirometry, which tests the amount and speed of air that can be moved in and out of the lungs, and Impulse Oscillometry (IOS), which uses sound waves in order to assess the resistance of the airways (airway narrowing).

If the bronchodilator had a substantial effect, the researchers would be able to say that the airway obstruction was due to an asthma-type condition, as the inhaler would have relaxed the muscles and allowed air to move more easily through the airways. What the results showed, however, was that there was little change in the measurements of lung function after the inhaler was given. The researchers can therefore use this evidence to support the hypothesis that the airway obstruction in SCD may be due to increased blood volume in the lungs.

Therefore, this study suggests that treatment of non-asthma related airway obstruction in SCD patients could perhaps move away from bronchodilators and towards more effective treatments for the anaemia aspect of SCD such as blood transfusions. A great deal of further work is needed but this is a valuable insight into the a potential process underlying breathing problems in SCD.

This summary was produced by Morgan Walker, Year 13 student from Harris City Academy Crystal Palace, as part of our departmental educational outreach programme.

Research summary – Reef Ronel

Neuromuscular electrical stimulation to improve exercise capacity in patients with severe COPD: a randomised double-blind, placebo-controlled trial

Matthew Maddocks, Claire M. Nolan, William D-C. Man, Michael I. Polkey, Nicholas Hart, Wei Gao, Gerrard F. Rafferty, John Moxham, Irene J. Higginson

Published in the journal Lancet Respiratory Medicine, published online December 14th 2015

Patients with severe COPD often have weak legs as breathlessness can limit their ability to be active. Normally, to combat this and other symptoms of COPD, exercise classes called Pulmonary Rehabilitation (PR) are carried out. However, more severely affected patients may struggle to do PR.

An alternative therapy was introduced, neuromuscular electrical stimulation (NMES), to COPD patients with more severe symptoms. NMES is when electricity is used to create muscle contractions, in this case in the thigh muscles. While NMES has been used to strengthen muscles in previous research, this trial is the first to explore the impact on daily activities and the first to investigate the longer-term impact of the treatment.

52 participants with very severe COPD took part in this trial over two years. Participants received 30 minutes of NMES to both sets of thigh muscles daily for 6 weeks; 27 were placebo (‘sham’ stimulation) and 25 received active NMES. The aim: to assess the effectiveness of NMES, as a therapy to be conducted unsupervised at home, and at aiding daily activities. The main measure of effectiveness in this trial was a test of how far participants could walk in 6 minutes.

The results of the walk tests strongly support the use of NMES for severe COPD patients, with the patients who received the active NMES being able to walk substantially further. During interviews active NMES participants expressed a greater ease in everyday tasks (such as climbing the stairs) and stated that they could carry out physical activities for longer. No participants reported any negative views. Unfortunately, the improvement provided by NMES quickly waned after the treatment had stopped. Therefore, all existing evidence suggests that NMES should not be considered a replacement for PR. NMES can be used as an extension to PR, and could be used when patients are unable to take part in PR programmes. In addition, the short duration of effect suggests that longer programmes need to be investigated. Nonetheless, this trial has shown that NMES is a practical home-based therapy, suited to patients with more severe symptoms and has gives suggestions for future research.

This summary was produced by Reef Ronel, Year 12 student from JFS School, as part of our departmental educational outreach programme.

Research summary – David Launer

Pulmonary function, CT and echocardiographic abnormalities in sickle cell disease

Alan Lunt, Sujal Desai, Athol Wells, David Hansell, Sitali Mushemi, Narbeh Melikian, Ajay Shah, Swee Lay Thein, Anne Greenough

Published in the journal Thorax, August 2014

Sickle Cell Disease (SCD) is amongst the most prevalent genetic diseases worldwide. Only being inherited if both of one’s parents carry a ‘faulty’ gene in their DNA, SCD affects the Haemoglobin molecules that carry oxygen in the blood, distorting the shape of the red blood cells into so-called crescent shaped ‘sickles’.

It has been shown previously that the majority of adults with SCD have changes in their lungs that can be found on a CT scanner, a high powered X-ray scanner that can create a detailed 3D image of the lungs, including airways and blood vessels.

This study showed that findings like particularly large blood vessels in the lung were linked to reduced lung function. This study aimed to show a link between these changes in the lung and the resulting changes in heart function that one can view on an ‘echocardiogram’ in the same group of patients. An ‘echocardiogram’ is a scanner used to observe the way in which the heart functions, from ultrasound waves ‘bouncing’ off the heart. It can view the structure of the heart and vessels, as well as blood flow. In SCD the heart has to pump more blood through the lungs in order to deliver enough oxygen to the tissues.

Adults with SCD were assessed using CT, echocardiography, and other lung function tests such as lung capacity, between the years 2009-2013. This same group of adults had previously been shown to have lung changes on CT scans between 2003-2005.

Whilst there was a large variety in the lung function of the 28 patients with altered lung features, it was demonstrated that lung structure changes seen on CT scans was related to the patients’ decline in lung function, and changes in the function of the heart displayed on echocardiogram tests. Importantly, the results of the study suggest that some of the changes found in the blood vessels between the heart and lungs may be able to explain the differences in the lungs found on CT scan and the decline in lung function. The results of this study help us to understand the complex relationships between heart, lung and blood vessel function in SCD.

This summary was produced by David Launer, Year 12 student from JFS School, Harrow, as part of our departmental educational outreach programme.

Research summary – Ashleigh Francis

Airway and alveolar nitric oxide production, lung function and pulmonary blood flow in sickle cell disease
Alan Lunt, Na’eem Ahmed, Gerrard F. Rafferty, Moira Dick, David Rees, Sue Height, Swee Lay Thein, Anne Greenough
Published in the journal Pediatric Research, March 2016

Patients with Sickle Cell Disease (SCD) are often assumed to have asthma because they have ‘airflow obstruction’, which is when airways become narrowed and air is not able to move out of the lungs as quickly or easily as in healthy lungs.
Inflammation in the airways is one of the main features of asthma. Nitric Oxide (NO) is a substance that is produced by the airways when they are inflamed, so therefore can be used to measure the severity of asthma in a patient and find out how inflamed their airways are.
As well as being produced in the airways, NO is also produced in blood vessels, and helps to widen blood vessels.
People with SCD are anaemic, meaning they have less haemoglobin (a protein in the body that carries oxygen) so their cells cannot carry as much oxygen. In order to compensate for this, the heart beats faster and with more power to make sure enough oxygen is picked up from the lungs and delivered to the body.
This study looked at measurements of NO from the airways (representative of asthma) and the alveoli (representative of blood vessel widening), and compared it to lung function tests (to look at airway narrowing) and measures of pulmonary blood flow (how fast blood was circulating around the lungs).
The results showed that the airway NO was not raised, but that there was still airway narrowing occurring.  There was a relationship between how fast blood was circulating through the lungs and NO from the alveoli. This might suggest that previous findings of high NO and airway narrowing resulted in a false assumption that SCD patients’ airway narrowing was down to asthma. This study suggests that the changes in heart and blood vessel function in SCD may have an effect on the airways.
This study was relevant in terms of contributing to medical research because it shows the airway narrowing in SCD patients may not always be down to asthma, so it therefore allows us to target other root causes of the problem.

This summary was produced by Ashleigh Francis, Year 13 student from Harris City Academy Crystal Palace, as part of our departmental educational outreach programme.

Research paper summary – Casril Liebert

Ankle dorsiflexor muscle size, composition and force with ageing and chronic obstructive pulmonary disease

Matthew Maddocks, Matthew Jones, Thomas Snell, Bronwen Connolly, Susanne de Wolf-Linder, John Moxham, Gerrard F. Rafferty

Published in the journal Experimental Physiology, June 2014

Chronic obstructive pulmonary disease (COPD) is the name for a group of lung diseases that cause breathing problems. COPD patients often find it hard to do exercise because their muscles may be slightly weaker compared to a healthy person. The ankle dorsiflexor muscle, at the front of the shin, is used for balance and walking. This research looked at how the ankle dorsiflexor muscles were different between 20 young healthy people, 18 healthy elderly people and 17 people with COPD. This allows us to see how COPD affects the normal ageing process of the muscle.

Firstly, we took scans of the muscle to see what it is made of. We also measured the size of the muscle. The scans showed that the COPD patients had a lot of non-useful tissue in the muscle that doesn’t help the muscle work normally. The strength of the muscle was also measured. This was done by passing electricity into the nerve to the side of the knee that supplies the dorsiflexor muscle. This caused the nerves to react and tense the muscle.

The results showed that patients with severe COPD have ankle weakness. This means that their muscles are not as strong as a healthy person and it is harder to do certain tasks that require strength. The scans also revealed that a greater muscle size was associated with a greater muscle strength, and also that tissue in the muscle without a function is a major cause of muscle weakness. The muscle composition scan discovered that fat and fluid in the muscle was often found in COPD patients. This tissue that isn’t useful creates problems which affect exercise performance and postural control, causing impaired balance and walking abnormalities. The discoveries within this study have allowed us to better understand why muscle strength in COPD patients decreases much more than seen with normal ageing.

This summary was produced by Casril Liebert, Year 12 student from JFS School, Harrow, as part of our departmental educational outreach programme.

Research paper summary – David Launer

Longitudinal Assessment of Lung Function in Children With Sickle Cell Disease
Alan Lunt, Emily McGhee, Karl Sylvester, Gerrard F. Rafferty, Moira Dick, David Rees, Sue Height, Swee Lay Thein, Anne Greenough

Published in the journal Pediatric Pulmonology, December 2015

Sickle Cell Disease (SCD) is amongst the most prevalent genetic conditions worldwide. Only being inherited if both one’s parents carry a ‘faulty’ gene in their DNA, SCD affects the Haemoglobin molecules that carry Oxygen in the blood, changing the shape of the red blood cells into so-called crescent shaped ‘sickles’. Despite its commonness, with over 300,000 babies being born with SCD worldwide every year, a clear and consistent picture of how SCD affects the lungs of children with SCD had not yet been researched. This study aimed to research the lung function of children affected by the disorder over time, observing how this changed in early and later childhood, and how this was affected by episodes of ACS (Acute Chest Syndrome) in early childhood, when the sickle-shaped red blood cells can block blood vessels and lead to various different injuries.

Two groups of children were tested. The first, who were slightly younger on average, were
measured twice for their lung function over an average of 2 years, while the second group were measured twice over approximately 10 years. A number of methods were used to test each person’s lung function, including ‘spirometry’ in which the quantity of air one can force out the lungs is measured, among other values like lung capacity. These measurements were then compared to a ‘control’ group of healthy children without SCD at a similar age, to give a normal level of lung function to compare against the SCD patients’.

In both groups of children with SCD, a reduction in lung function over time was seen when compared to the groups of children without SCD. However, the lung function of those in the first, younger, group decreased at a faster rate.

The results suggest that the fastest period of deterioration in lung function takes place in early childhood. Indeed, having an episode of ACS in young childhood was the only factor found that increased the likelihood of worse overall lung function later on. This could explain the faster decline of the younger group, as ACS is more common in younger children. This would seem to conclude that a focus should be placed on preventing ACS in young children as a strategy to improve the general lung function later on of those with SCD.

This summary was produced by David Launer, Year 12 student from JFS School Harrow, as part of our departmental educational outreach programme.

Research paper summary – Lily Groom

Understanding Heroin Overdose: A Study of the Acute Respiratory Depressant Effects of Injected Pharmaceutical Heroin  Caroline J. Jolley, James Bell, Gerrard F. Rafferty, John Moxham, John Strang

Published in PLoS One, October 2015

Opioids are a class of drug which act by attaching to opioid receptors, found in the brain and spinal cord, reducing the perception of pain. For this reason, opioids are often prescribed for pain relief. When people misuse opioids, they are often unaware of the dangerous side effects that come with them. For example, they are respiratory depressants, meaning they can reduce the breathing rate, which can be fatal. Many of the current methods of measuring respiratory depression under-estimate the true effect these drugs have on the body (especially the breathing rate), which is why this study was undertaken. Respiratory depression is a major cause of overdose and if you cannot detect when it is happening effectively, you have less chance of helping someone suffering from it.

The participants in this study were monitored over a course of 150 minutes, after they had been given their usual opioid dose. This was done using EMGpara (a tool which assesses how hard the breathing muscles are working), pulse oximetry (measuring the blood’s oxygen levels), and measurement of carbon dioxide levels in exhaled breath. The participants were asked to rate how much they felt the drug’s effect at three minutes prior to the drug being given, and then at regular intervals afterwards. Staff ratings of intoxication and level of consciousness were also given. Pulse oximetry and observer ratings are the more commonly used methods of observing patients’ breathing currently.

However, this study found that there was an increase in the level of carbon dioxide per breath in eight of the ten participants and a low blood oxygen level in only four out of the ten patients. The difference in results shows that the traditional approach of measuring the blood’s oxygen level is not as sensitive a method to detect respiratory depression after taking an opioid. There were varying degrees of respiratory depression found in all patients. However, the pulse oximetry only picked up four of these. The study also found that just talking to a patient helped to mask episodes where they were breathing unusually slowly. This means that it is very easy to miss a potentially dangerous symptom.

The findings of this study therefore suggest that we should change the way we test for respiratory depression in clinical settings, to help identify, treat and prevent it in patients taking opioids.

This summary was produced by Lily Groom, Year 13 student from Graveney School, Tooting, as part of our departmental educational outreach programme.

Research paper summary – Lottricia Millett

Parasternal Intercostal Electromyography: a Novel Tool to Assess Respiratory Load in Children Victoria MacBean, Caroline J. Jolley, Timothy G. Sutton, Akash Deep, Anne Greenough, John Moxham, Gerrard F. Rafferty

Published in the journal Pediatric Research, May 11th 2016

Parasternal intercostal electromyography (EMGpara) is a new way to measure breathing difficulty. Research needs to be carried out because body parts used in breathing, like the lungs, need to be properly checked over for breathing problems to be managed, but the testing methods aren’t always suitable for children who are very young or ill. The parasternal intercostal muscles are muscles that move at the same time as the diaphragm (a thin sheet of muscle under the lungs) when you breathe in and out. EMGpara measures signals from the brain which are sent to these muscles without putting any instruments into the body, so it is ideal for children.

EMGpara was measured using stickers on the front of the chest while the participants (92 healthy, 20 wheezy and 25 with a machine (ventilator) to help them breathe) were breathing in and out in a resting state. For the wheezy children, measurements were taken before and after a substance to widen air passages (reliever inhaler, or bronchodilator) was used; for the critically ill children, these were taken during ventilator-assisted breathing, then with just mild air pressure to keep the airways open (continuous positive airways pressure).

It was found that as age, weight and height increased, EMGpara decreased. This is because when children are growing up, big changes take place in the respiratory system, decreasing the effort needed for breathing. EMGpara in the healthy children was the lowest; in the wheezy children it was higher before the bronchodilator was used, dropping to similar levels to the healthy children afterwards. In the critically ill children, EMGpara was higher than in the wheezy children when the ventilator was used, and even higher with continuous positive airways pressure when they were having to breathe without support.

This study has shown that measuring EMGpara is possible in children of a range of ages and levels of health. The results from the healthy children have shown important age-related changes in EMGpara, and those from the wheezy and critically ill children have shown that EMGpara is affected by changes in how hard the breathing muscles have to work because of different diseases and treatments. EMGpara could be a really helpful method in testing the breathing ability of patients who are usually difficult to assess.

This summary was produced by Lottricia Millett, Year 12 student from Burntwood School, Wandsworth, as part of our departmental educational outreach programme.

Upside-down research

Caroline spotted a new research article today that has just been published.  The study has been done by a group of scientists in Australia (and that’s not the reason it’s upside-down) who work on a very similar area of research to us, looking at how the breathing muscles work and how they respond to different situations.  One of the research team actually spent some time in our lab many years ago, so we know them quite well.

Normally, all of the breathing muscles (the main ones being the diaphragm, the muscles between the ribs and some small muscles in the neck) work together to make air move into the lungs.  If breathing becomes more difficult (like when people have lung disease), or if your body needs more oxygen (for example during exercise), the brain “drives” the muscles harder by sending more electrical signals down the nerves to those muscles and making them work harder.  What we don’t really know is whether the brain is able to decide to send different messages to the different breathing muscles at different times.

In this study, the researchers measured how much air was moving in and out of the lungs, how much the chest and tummy were moving with each breath, how much “drive” was going to the muscles (by measuring the electrical signals going to them), and how much pressure the diaphragm was making with each breath.  The measurements were very similar to the ones you can see in two of our videos, including the mouthpieces and the tubes going up the nose and down into the stomach.  They made these measurements with the person standing up, lying flat on a bed, and then hanging upside down!download

So, we would probably think it would be much harder to breathe when hanging upside down, because your all of your intestines would be pushing up against your lungs, so breathing would almost be like weightlifting.  The researchers did find that the pressure that the diaphragm muscle had to generate for each breath was increased (to push those intestines upwards).  You’d imagine then that the brain would have to send much more “drive” to the muscles.  But no – the researchers found that exactly the same amount of “drive” was going to the diaphragm, and in fact slightly less to the neck muscles than when the people were standing up, even though the people were moving the same amount of air in and out of their lungs with each breath and the diaphragm was doing more work.

So how does this make sense?  Well, we know that the diaphragm muscle is in fact stronger when it’s pushed up further into the chest, so actually being upside down makes the diaphragm more efficient.  This is why, for the same electrical “drive”, it was able to create more pressure.  We have shown this in previous studies in our lab some years ago, and we actually repeat these experiments each year for a group of students.  We do breathing muscle strength tests with relaxed lungs (at the end of a normal breath out), then again with completely full lungs (which makes the diaphragm flatten down), and then again after breathing all the way out (meaning the diaphragm is higher up in the chest and more ‘domed’).  We see that the best results come from the ‘breathing out’ position, then the relaxed position, and then the lowest strength values from the ‘deep breath’ position.

What’s also interesting about the results of this new study is that it seems the brain is able to work out how efficient the different breathing muscles are at any given time, and then work out where it needs to send its “drive” to.  This suggests to us that there might not just be one area of the brain that sends out all the breathing messages, but that it’s a more complicated process than we thought involving a lot more feedback loops.  This might be very relevant to many of our studies, so we will be reading this article closely and the findings may well be really useful to us.

But – really and truly – the best thing about this study is that they tipped people upside down!  Science really can be fun (though possibly not for the people being dangled over the end of a bed with tubes up their noses…).