NET Training Day: UCLH 09/03/18

In March we met at UCLH. Many thanks to Toby Hillman for co-ordinating a great day, looking beyond the basics.

Beyond Asthma – advanced assessment of wheeze and breathlessness

James Hull started the day with a case history of a patient with a 5year history of progressive breathlessness. CPEX revealed reduced breathing frequency. The flow volume loop showed attenuated inspiratory flow (always look at the loop!). Laryngoscopy revealed a posterior glottic web. Digging further into the history,  the patient had been intubated 20yrs prior (following an RTA). We were reminded that there are many causes of wheeze – in children and in adults. Think about other parts of the airway.

We moved on to consider the larynx. Dr Hull impressed upon us 3 must-know, never-miss conditions:

• ILO (inducible laryngeal obstruction)
• Large airway collapse with symptoms (LACS)
• Subglottic stenosis

This is not the domain of ENT surgeons, “we must reclaim the whole airway.”

• Christopher, Kent L., et al. “Vocal-cord dysfunction presenting as asthma.” New England Journal of Medicine 308.26 (1983): 1566-1570.

This paper from the archives shows that vocal cord dysfunction has been recognised for a long time. However, it uses problematic languages, and places a firm emphasis on psychiatric diagnoses and conversion disorder as the cause. On a positive note, patients had good outcomes following speech and language therapy.

The classic appearance is anterior closure, with a posterior chink. The is rarely seen but the same clinical problems occur with less dramatic examples, with abnormal movements and stridor. Is ‘brittle asthma’ largely VCD? Glottic closure can cause a sudden PEFR drop. PEFR is dependant on how much air you can get in before you perform a forced expiration. PEFR is unfortunately a waste of time diagnostically.

• Morris, Michael J., and Kent L. Christopher. “Diagnostic criteria for the classification of vocal cord dysfunction.” Chest138.5 (2010): 1213-1223.

Thankfully, perjorative historical terminology is now decreasing.  ILO is now the favoured terminology – it is a physiological description of the problem and much more appropriate.

It is important to distinguish EILO (exercise-induced laryngeal obstruction) from EIB (exercise induced bronchoconstriction). 8-10% of all adolescents may have EILO as at peak exercise they get wheeze. It is also possible to have inducible laryngeal obstruction not linked to exercise. An odour e.g. when exposed to perfume  on the tube. Direct provocation can clinch the diagnosis (available in the Occupational Lung Disease department at the Brompton).

• Traister, Russell S., et al. “A novel scoring system to distinguish vocal cord dysfunction from asthma.” The Journal of Allergy and Clinical Immunology: In Practice 2.1 (2014): 65-69.

The Pittsburgh VCD index is useful for screening patients for VCD. Remember, it is often a co-morbid condition – there is overlap between severe asthma and upper airway disorder. Therefore don’t cross off their asthma treatment straight away – de-escalate after therapy started.

Find out more at: http://www.laryngealobstruction.com/

Large Airway Collapse with symptoms (LACS) is the preferred current terminology for this group of conditions.

It includes excessive dynamic airway collapse (EDAC), which is often a benign phenomenon due to pressure changes and affects the posterior trachea. It may not be responsible for symptoms so don’t rush to operate/stent. Treatments are mainly physical therapy, cough assists, mucolytics +/- positive pressure support (CPAP). Portable CPAP may be an option – we expect a trial report soon. Early signals are it increases walking distance but it is not acceptable to patients to use in longterm. Relapsing polychondritis is a rare cause. ‘EDACS cough’ is a large airway centred problem, often associated with high BMI.

Tracheobronchomalacia can affect the anterior or lateral trachea and is a cartilaginous problem.

• Kalra A, Abouzgheib W, Gajera M, Palaniswamy C, Puri N, Dellinger RP. Dynamic airway collapse for the internist: New nomenclature or different entity? Postgrad Med J. 2011 Jul;87(1029):482-6.

In subglottic stenosis inspiratory flow may be as low as 10% predicted. There is an audible wheeze. We often see attenuation of inspiratory flow and less attenuation of the expiratory phase of the flow volume loop. This is not VCD as wheeze is there all the time including at night. A Bronchoscopy/laryngoscopy is needed ASAP. This is potentially life threatening as a mucus plug could lead to obstruction.

Should every asthma clinic have a laryngoscopy? Dr Hull says YES.

Management: remove irritants (treat nasal/sinus disease/reflux – give promotility agent + gaviscon), remove caffeine, regular clear fluid every 20min. Then find therapists -SLT/physio who understand the upper airway. Encourage diaphragmatic breathing, and nasal predominant patterns. There are a few potentially useful drugs. Anecdotally – spiriva/atrovent seems to work better for upper airway than LABAs. Neuronal hypersensitivity is part of the pathophysiology, therefore amitryptilline may be effective. Botox to the larynx is better for laryngeal spasm than VCD (2/52 loss of voice, cough OK but reduced airway secretion protection).

There is a higher prevalence of psychopathology in people with BPD – this is likely compounded by trauma due to delays to diagnosis and recurrent trips to ED. SLT usually have training in psych assessments in voice problems so are well placed to assess. For any queries about research opportunities, or to arrange a visit to the CPET lab at the Brompton contact j.hull@rbht.nhs.uk.

Beyond the Abstract – critical appraisal of a scientific paper

Neal Navani, Clinical lead for lung cancer, National lead for early diagnosis of lung cancer and Clinical chair NICE guidelines for lung cancer, took us through the The National Lung Screening Trial. He believes this to be ‘the most important trial done in respiratory medicine’.

RCTs are primary research that should influence patient management and change policies. They are expensive to carry out (TORCH cost $20million).

There are problems with trials. Failure to publish is a major problem, particularly as many industry trials are never published. Trial registries are aimed at addressing this – clinicaltrials.gov. Alltrials is a campaign to reduce non-reporting, and also hosts lots of useful resources. Trial registration reduces publication bias, prevents others producing similar work, and allows appraisal of results.

When reading a scientific paper ask:

1. What is the research question?

2. Can the results be trusted?

3. What are the results of the trial?

4. How can there results/conclusions be applied? (who are they generalisable to?)

How to define a research question:

P – participants

I – intervention

C – control

O – outcome

T – timeframe

The NLCST was published in the NEJM.

• National Lung Screening Trial Research Team. “Reduced lung-cancer mortality with low-dose computed tomographic screening.” New England Journal of Medicine 365.5 (2011): 395-409.

It cost half a billion dollars and was funded by NIH in USA. It undertook 5 years follow-up. NSLT criteria were 55-74yrs, 30pcyr smoking. The Supplementary appendix has lots more on methods e.g. scanner (low dose MDCT 1.5mSv). It used a threshold of 4mm nodule size, so that any non-calcified nodule >4mm was defined as suspicious for lung cancer. This is critical as this is different to what we are practicing in terms of BTS guidelines. It was based on a pilot study and affects whether we can apply the results to the UK.

Are the results valid?

Was the design valid? Was the conduct valid? Was the analysis valid?

Methods of randomisation are important for small numbers. Techniques such as stratification and minimisation make sure groups are matched at time of randomisation. When there are large numbers in the trial the method of randomisation less important. The trial was not blinded as it was a comparison between CXR vs CT. Could do sham? Lack of blinding may influence population recruited and bias investigators. May cause unconscious bias i.e. further followups etc. When it came to analysis, however, blinding did happen.

Table 1 in any trial is very important as it lays out the baseline characteristics and allows you to see whether this is relevant to your clinical practice. In this trial >50% participants 55-59yrs. There was a worry that it might be underpowered as the outcome is lung cancer mortality. Actually this was not a problem in this case, and in further analyses all the benefit is in the older people! It is important to scrutinise table 1 for other factors associated with the outcome.

Was the conduct of the trial valid?

How complete was follow-up of patients in each group? Apart form the intervention(s) itself were the groups treated equally? There is no CONSORT diagram in the NLCST paper – disappointing! They did report loss to follow-up in attendance at CT/CXR. But did not report loss to outcome follow-up in main paper. Not reported whether additional scans were different between groups. This is alluded to in subsequent health economic analyses. Importantly primary care were paid to facilitate recruitment in this trial.

What are the results?

How large was the effect of the intervention? Is it an absolute difference, a relative difference, or a relative risk? How precise was the effect estimate? (look at CIs not the p-value). Remember that p-value only tells you how likely the result is, not how strong the effect is. Doesn’t tell you about the degree of uncertainty.

In this trial 2000 cancers were diagnosed in 55000 people. The trial diagnosed 1/25 people with cancer in total. An additional 120 cancers were found by screening. Using person-years in each arm, and number of deaths from lung cancer in each arm the investigators worked out the rate of death and the relative reduction. There was a relative risk reduction of death from lung cancer of 20%. Inverse Kaplin-Meier curve showed a 6.7% relative risk reduction of all-cause mortality. These are phenomenal results. Can’t think of anything else that has this effect – except smoking cessation! Cost-effectiveness – v good!

BUT:

The rate of positive screening tests was 24.2%. A total of 96.4% of the positive screening results in the low-dose CT group and 94.5% in the radiography group were false positive results.

Limitations:

Results are likely to be more favourable than will be observed after implementation. The scanners used are already out of date. These were expert institutions for radiology/surgery etc. The control arm was not standard practice. Over diagnosis and radiation-induced cancers requires longer follow-up. Volume doubling time 400-600days intermediate risk >600 low risk. Uptake was high, but there was active paid recruitment from primary care – not likely to be funded/sustained outside of a trial.

Recommendations from AACP and US preventive services Task Force were that annual screening (not just for 3yrs) should be implemented, and paid for by medicaid – once per year from age 55-80 at start. The New York Times described this as “a new hope”. In the UK, the response was somewhat more subdued. Thorax – ‘several issues need to be resolved’. The so-called ‘European position statement on lung cancer screening’ is not in fact a European position statement but a statement by a group of self-selected people. The group excluded screening positive people.

Of note, the screening committee do not consider it screening, but instead case finding. Semantics?

Screening is coming, but will be slower to be implemented in the UK than elsewhere. There is lots of active work on faesability, acceptability and working out pathways. Watch this space!

Beyond smoking cessation, PR and triple therapy – hyperinflation in COPD

Melissa Heightman looked at a number of interventions for COPD. She reminded us of The Value Pyramid.  Where is oxygen and LVRS? She is increasingly being asked to deliver it. She reminded us that Pulmonary rehab is great and has an excellent evidence base. She encouraged us all to go to a session with a local team. How can you have a a conversation about it if you’ve never seen it? National COPD audit 2015 data showed great outcomes from PR in terms of QoL and hospital readmissions (real world data). However the completion rate was disappointing. Mel advised us to ask your patients: “Would you like to do more, breathe better and feel better? Yes, then we recommend PR.”

There is NICE guidance recommending LVRS and valves.

• www.nice.org.uk/guidance/ipg114 – LVRS
• www.nice.org.uk/guidance/ipg318 – bronchoscopic valves

NETT trial, VENT, STELVIO, BeLieVer, IMPACT, TRANSFORM – these trials show impressive outcomes.

Pneumothorax risk is around 15-25% therefore patients are usually admitted for 3-4 days. Pneumonia risk is <5%. There are some contraindications for valves: significant bronchiectasis, active microbiology, copious thick sputum, co-existent ILD, paraseptal disease, and giant bullae.

The best way to make treatment decisions is at a Hyperinflation MDT.

Inclusion criteria at the UCLH/Whittington MDT are:

• emphysema
• severe airflow obstruction (FEV1 <40%)
• limited by breathlessness, MRC 3-5 but >140m on 6MWT
• stopped smoking minimum 6/12 (use CO levels)
• hyper inflated RV >180%, TLCO >20% (or >15%)
• optimal medical management including recent PR ideally

Exclusions include:

• hypercapnia at baseline
• significant pulmonary hypertension
• TLCO <20%

The LVR academy run by pulmonex is very good training in just 1 day.

The minimum investigation set for LVRS/valves is: CT thorax, full lung function with volumes.

As part of MDT additional investigations will be discussed and recommended: ECHO, VQ Spect (gives V and Q for individual lobes which aids decision making), StratX analysis of imaging to look for intact fissures (£200 per go). The MDT occurs every 6 weeks and includes 2 consultants (across RFH, Whittington, UCLH), a Chest Radiologist, and a Thoracic Surgeon. It is a good mechanism for enhanced management of COPD and advice.

If fissure integrity is not clear on StratX then a further option is Chartis at bronchoscopy to directly measure flow.

Mel has had good experience so far – “It’s the first time I’ve made someone with COPD better!” As with so many things, Ii’s all about patient selection.

How do we reliably identify patients who may benefit?

• Train community respiratory teams
• Search PR databases
• upskill colleagues and GPs on update courses
• practice visits
• e-health records – opportunities for screening hospital COPD population.

In the future is is most likely this will become a specialist commissioning. It is around £7000/patient.

Other pearls of wisdom from Mel on COPD management:

• If reduced Cr Cl use increase ellipta rather than tiotropium
• 1/26th of carbon footprint DPI
• community pharmacist recycling scheme – make sure your patients know about it
• Inhalers are easy. Smoking cessation and PR are hard. Have you had motivational interviewing training?

Emerging therapies and science in mesothelioma

Dr Beth Sage started by reminding us of some asbestos basics:

• serpentine = white = chrysotile —> most common in UK
• amosite = brown
• crysidolite = blue

Exposure = environmental and occupational. Women were/are exposed in a number of ways – washing clothes, hairdryers in 1940s/1950s – asbestos lining. Hundreds of thousands of tons was released into environment at ground 0 of twin towers – a modern exposure event.

What is the pathogenesis of mesothelioma? Nature vs nurture?

Nature

Genetics – in 2001 researchers found familial clustering of MM. In 2011 they identified BAP1 as a causative gene. This gene is related to a cancer syndrome – melanocytic intradermal lessons, clear cell renal carcinoma, cholangiocarcinoma. BAP1 is a tumour suppressor and a potential target for therapy. NF2 encodes merlin protein on Chromose 22. It is a tumour suppressor and inhibits of oncogenes in the mTOR pathway.

Clinical trials are ongoing with everolimus. This is a combined mTOR and AKT inhibitors. Mainly phase 1 trials. Other targets may include FAK inhibitors and CDKN2A (cyclin dependant kinase inhibitor on Ch9). It is deleted in 50-100% mesothelioma tumours. There is also epigenetic silencing. These factors have a role in regulating apoptosis and cell cycle arrest.

Nurture

The cancer cell exists within a permissive microenvironment. Arginine forms part of the urea cycle. Arginosuccinate synthetase ASS1 is an enzyme silenced in 63% mesothelioma. At Barts researchers have developed pegylated arginine deaminase ADI-PEG20. The ADAM study is a phase 1 and 2 trial, an RCT with 2:1 randomisation. There was improved progression free survivial (PFS) and overall survival. The effect was greater in tumours with greater loss of ASS1. The treatment was well tolerated. There was a greater effect seen in sarcomatoid patients. They are now conducting the ATOMIC trial – enrolling for non-epitheloid mesothelioma. cis/pem vs cis/pem+ADI-PEG. NCT02029690. Get your patients into clinical trials!

The cancer microenvironment is increasingly being recognised as a relevant treatment target. There are many immunotherapy targets – yay! Key targets:  PD1/PD-L1, VEGF, PDGF, FGF.

VEGF is critical in tumour growth and is highly expressed in mesothelioma.

• Strizzi, Luigi, et al. “Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma.” The Journal of pathology 193.4 (2001): 468-475.

Bevacizumab is a monoclonal antibody. The MAPS trial (480 patients) was triple therapy 1st line, in combination with cis/pem. There was improved PFS at 2 months and Overall Survival (OS) 2.7 months. Approved in USA and Europe. Not approved by NICE on cost effectiveness grounds.

Nintedanib is being investigated in the LUME-meso trial – actively recruiting in UK for patients with histologically confirmed epithelioid mesothelioma which is unresectable. 1st line therapy cis/pem + nintadenib. 4/12 longer PFS in initial phase. Now gone onto larger phase 3 trial for those with PS 0-1.

Pembroluzimab is a further target. 20-70% mesos are PD-L1 positive. Trials include:\

• Checkmate-743 trial. Combined ipilimumab & nivolumab vs pemetrexed & platinum based drug.
• CONFIRM trial – nivolumab vs placebo for pts who have progressed on chemo
• PROMISE-meso – 2nd line treatment of mesothelioma for those who have progressed on chemo. 2nd line chemo (set by local guidelines) vs pembroluzimab. Cross-over trial.

What about surgery in mesothelioma?

• MARS1 – showed that unselected surgery is bad
• MARS2 – pleurectomy decortication vs no surgical intervention. Phase 3 trial
• MesoVATS – did not address trapped lung
• MesoTRAP – address issue of trapped lung. What is best way to manage? IPC vs VATS pleurectomy decortication.

Exciting times in mesothelioma research? Molecular stratification allows umbrella designs and personalised therapies.

There is a Mesothelioma stratification trial ongoing in Leicester. Umbrella trial design allows a common single entry point, then all tumours are pre-screened using nextgen sequencing (genetic/epigenetic). On basis of this the patient is enrolled into 1 of several trials – 4 at present. On postmortem or disease progression the tumour genetics are re-analysed. A major advantage of this trial design is that as new treatments come on line they can be added to another part of the umbrella design. Quicker throughput for new therapies. Bench to bedside!

Barts hosts the Regional MDT for mesothelioma and is research active. Get to an MDT soon!

Beyond ACBT

Rebecca Livingston, specialist Resp physio, at UCLH updated us on airway clearance, breathing pattern retraining, cough management, support with exercise, and stress incontinence support.

She started with some case studies. A patient with GvHD & bronchiectasis was finding ACBT and flutter ineffective. They had frequent exacerbations and a high symptom load. The Bird is a positive pressure device which augments Vt (tidal volume), and increases expiratory flow. It offsets work of breathing. The iSleep device is an NIV machine used to support cycles of clearance. In this case it reduced admissions 4—>1 a year. The patient no longer needs frequent courses of oral abx. It cost £1000 but is now off the market. ResMed and NIPPY cough assist devices are £5000 so less accessible for patients or NHS services. Pressures aimed for – 20-25/4.

Airway clearance techniques

• ACBT – works well with good technique.
• Autogenic drainage – breath at different lung volumes. Need to pick patients – difficult to learn but v effective.
• Accapella and flutter – oscillator devices. PEP device. Can combine devices.

What can you do? Prescribe mucolytics. Hypertonic saline in bronchiectasis – 3%. No evidence for Normal saline nebs. Calling an on call physio should only be used when really needed – they will be travelling in from home so can take 45mins (therefore not for urgent intervention). there are many times when this is absolutely appropriate – CF, recurrent plugging in Bronchiectasis, need for assist devices.

Afflovest? Effective in combination with ACBT or other active technique. ?worth the money – pricey. Used in USA a lot.

Chronic Cough can be tricky to manage. Need to consider pathophysiological, biomechanical, psychological. MDT therefore very useful! Chronic cough is often multifactorial. Factors that cause cough may be different to those that perpetuate it. Consider reflux, breathing pattern disorder (assoc hyperventilation and tingling in peripheries), tension in shoulders, poor sleep, stress. Mild asthma with low FeNO.

Breathing pattern disorder – Barker and Everard 2015 defined it as “alteration in the normal biomechanics of breathing that result in intermittent or chronic symptoms which may be respiratory and/or non-respiratory”. It is an umbrella term for breathing patterns that include hyperventilation, habitual or chronic cough, laryngeal dysfunction, ILO/EILO. Signs you should be looking out for in clinic: breathing apically, gasping, air hunger, noisy breathing.

Niemegan score is widely used but is limited – it is only validated for hyperventilation. A score of >23 is said to be diagnostic of VCD. Interpret with caution. The Brompton BPAT is a tool based on assessment features.

• Todd, Sarah, et al. “Novel assessment tool to detect breathing pattern disorder in patients with refractory asthma.” Respirology 23.3 (2018): 284-290.

It is not yet externally validated. A score >4 likely to have breathing pattern disorder. Usually 4-6 sessions with a specialist physiotherapst or SLT are needed for breathing pattern retraining. 1st appointment 1hr, follow-ups 45mins. But some success in just 2 sessions, whereas for some people despite 6 sessions they do not buy in and cannot see past physical aspects. Psychology interacts very strongly with treatment outcomes.

• Mitchell, Sarah AF Chamberlain, et al. “Physiotherapy, and speech and language therapy intervention for patients with refractory chronic cough: a multicentre randomised control trial.” Thorax 72.2 (2017): 129-136.

There is good evidence for physio interventions for cough. These include cough suppression techniques, education, laryngeal hygiene and hydration.

we should be supporting all patients to maintain and increase physical activity. Exercise advice remains important for patients who are high functioning or do not have COPD and therefore are not accepted for PR.

De-conditioning contributes to breathlessness – this is very common. Patients may need support and help to restart exercising/activity. Exercise testing eg 6MWT can be a good starting point. This test is simple, no equipment. However, if the patient is quite fit may need to do other test e.g. run up stairs. It is useful to check for desaturation, determine the level of functional impairment and activity limitation. CV and muscle strengthening are key. Work out target HR, and then aim for 60-80% peak exercise capacity. A target is very helpful for patients. The BORG scale for breathlessness is useful pre and during exercise. Modified 0-10 (0=no breathlessnes). There is evidence that 60-80% sits around 5-7 on BORG scale. This is a useful target for when patients exercise on their own.

Breathlessness – the Breathing Thinking Functioning clinical model by Spathis & Booth etc. is a very useful model for both clinicians and patients.

Stress incontinence should not be underestimated. About 50% resp patients experience this when coughing! It is not often addressed in clinic but is important for QoL. Physios can help by teaching basic pelvic floor exercises. 6wks regular training – should see effect. If not they refer on.

The app Squeezy is an NHS app that costs £3 – it talks through pelvic floor contractions, is motivating and useful.

When developing services, include therapists in business plan. Justify the need – e.g. use BPAT to screen all patents in outpatients clinic – what % of patients may benefit from physio?

Beyond the glottis – Tracheal interventions for benign and malignant disease

Dr Ricky Thakrar ended the day with a focus on central airway obstruction

– Intraluminal

– Extraluminal

– Combination

• Ost, David E., et al. “Complications following therapeutic bronchoscopy for malignant central airway obstruction: results of the AQuIRE registry.” Chest 148.2 (2015): 450-471

In thus analysis of the AQuIRE registry (US) 1039 procedures were technically successful. Improved to >50% potency. Does this mean clinical improvement? Treatments of central airway obstruction are mainly for malignant disease. Laser Nd:YAG and Brachytherapy.

Ricky showed a number of videos, including one of laser being delivered through a rigid bronchoscope – the carcinoid tumour vaporises. Jet ventilation is used. There are risks: fire, perforated airway wall, and adjacent structure… atrium. ET tubes will melt!

Other techniques include cry-extraction and cryotherapy and stents.

Stents

The Montgomery T-tube in 1965 for head and neck cancer was the first airway stent. Westaby J and Jackson pioneered the bifurcated silicon stent for airways. There are now lots of options on the market: Covered stents

Self-expanding nitinol stent etc.  Complications are mainly blockage by secretions, granulation tissue, stent migration, and wall perforation.

Bronchoplasty is used for benign disease e.g. sarcoid, TB, radiation, GPA – strictures. It emplots a cutting balloon (used in vascular/coronary artery disease).

AQuIRE registry summarises outcomes. Breathlessness – 50% had improvement on BORG score. Those with highest scores at start had greatest improvement. Procedure mortality was 0.5%. 30 day mortality 14.8%.

Those with PS >1 ardor ASA >3 more likely to have complications.

How to avoid missing central airway obstruction?

1. high index of suspicion (cancer, GPA, sarcoid)

2. Any patient unresponsive to asthma treatment

3. Monophonic/unilateral wheeze

4. Disproportionately low PEFR in relation to FEV1

@ricky_thakrar