LVR in Severe Emphysema Using Bronchoscopic Autologous Blood Instillation in Combination With Intra-bronchial Valves
LVR in Severe Emphysema Using Bronchoscopic Autologous Blood Instillation in Combination With Intra-bronchial Valves
A single arm pilot study of lung volume reduction in severe emphysema using bronchoscopic
 autologous blood instillation in combination with intra-bronchial valves.
Chronic obstructive pulmonary disease (COPD) is an umbrella term encompassing two entities
 causing progressive and ultimately disabling breathlessness. Emphysema is a process
 destructive of the airspaces distal to the terminal bronchioles, with loss of gas exchange
 tissue, of elastic recoil and of circumferential tethering of the small airways leading to
 their collapse on forced expiration. Chronic bronchitis is a disorder of the bronchi causing
 excess production and impaired mobilisation of mucus. Increased parasympathetic tone and
 progressive remodelling of airways impairs response to bronchodilators. Static and dynamic
 hyperinflation with a persistently expanded chest and flattened diaphragms despite increasing
 use of accessory respiratory muscles results in a disadvantaged respiratory pump.

 Patients with severe emphysema and hyperinflation may benefit from lung volume reduction
 techniques designed to reduce gas trapping and to improve airflow, chest wall and lung
 mechanics. The best evidence exists for lung volume reduction surgery (LVRS), which however
 is not without risk and there is increasing interest in the development of bronchoscopic lung
 volume reduction (BLVR) techniques including emplacement of intra-bronchial valves and
 bronchoscopic instillation of blood products, which have been shown individually to improve
 lung function, exercise capacity, and quality of life.

 Most of the experience in bronchoscopic lung volume reduction has been with endobronchial
 valves which were introduced in 2001. One-way valves are inserted into segmental airways to
 deflate the most emphysematous lobes of the lung, allowing compromised lesser diseased tissue
 to expand and regain its function. Reduction of hyperinflation and improved lung function,
 exercise capacity, and quality of life, have been observed using the intra-bronchial valve
 (IBV Valve System) by Olympus in patients with upper lobe-predominant emphysema. These
 improvements are most pronounced in those with radiologically intact lobar fissures, a
 surrogate observation thought to indicate an absence of collateral ventilation, which can be
 confirmed using the Chartis balloon catheter system. A combined approach of CT fissure
 analysis and Chartis measurement is suggested to ensure the appropriate selection of
 patients.

 Bronchoscopic instillation of biological agents such as fibrinogen, thrombin or autologous
 blood into the sub-segmental airways induces lung volume reduction initially by airway
 obstruction and resorption atelectasis followed by a localised inflammatory reaction leading
 to tissue remodelling at the alveolar level, with fibrosis and contraction of the target
 lobe. Unlike the intra-bronchial valve, collateral ventilation is not an issue, seeming not
 to influence the outcome. The cost compares favourably with that of prosthetic implants.
 Preliminary data from phase 1 and 2 trials using fibrinogen and thrombin in patients with
 upper lobe-predominant emphysema demonstrated improvements in lung function, exercise
 capacity, and quality of life scores up to 6 months with a trend towards better outcomes in
 those receiving 20mls (versus 10mls) to each of eight sub-segmental sites (four per upper
 lobe). Most patients experienced a self-limiting inflammatory reaction characterised by
 fever, malaise, shortness of breath, pleuritic chest pain and/or leucocytosis within 24
 hours. 11 of 50 patients (22%) in phase 2 experienced a procedure-related COPD exacerbation
 comparable to other forms of endoscopic lung volume reduction. Similar physiological and
 symptomatic outcomes were observed in patients with homogeneous emphysema with 20mls (versus
 10mls) per sub-segment instillation. Bakeer et al compared bronchoscopic lung volume
 reduction in patients with heterogeneous emphysema using autologous blood (n=7) with fibrin
 glue (n=8). At 12 weeks, statistically significant improvements in hyperinflation, lung
 function, exercise capacity (6MWT), and quality of life scores were observed in both groups.
 COPD exacerbations were fewer compared to earlier studies, which the authors suggest may be
 due to the use of a triple lumen balloon catheter protecting surrounding sub-segments from
 overspill and unintended inflammatory responses.

 The prospect of broadening the eligibility for intra-bronchial valve implantation to include
 those with collateral ventilation treated with autologous blood is attractive and not yet
 studied.

 Furthermore, the mechanisms of actions of intra-bronchial valves and of autologous blood
 instillation are not fully understood and may extend beyond lung volume reduction. In valve
 procedures where volume reduction has not been achieved, clinically meaningful improvements
 in quality of life independent of lung function have been described. Recruitment of
 compressed lung, restoration of elastic recoil and redirection of airflow are some of the
 postulated effects that are likely to involve the small airways. This may be investigated,
 for example, with multiple breath nitrogen washout (MBNW) which is a sensitive marker of
 small airways disease and can measure ventilation inhomogeneity, functional residual capacity
 and estimate trapped gas volumes. Impulse oscillometry (IOS) yields information on airway
 resistance and reactance (a measure of compliance) and distinguishes between large and small
 airway resistance.
Inclusion Criteria:

 1. Age 40 or older

 2. Diagnosis of severe COPD

 3. Stopped smoking for at least 6 months prior to entering the study.

 4. Completed a pulmonary rehabilitation program within 12 months prior to treatment
 and/or regularly performing maintenance respiratory rehabilitation if initial
 supervised therapy occurred more than 12 months prior to baseline testing.

 5. Received Influenza vaccination consistent with local recommendations and/or policy.

 6. Read, understood and signed the Informed Consent form.

 7. Dyspnea scoring ≥2 on mMRC scale of 0-4.

 8. FEV1%pred <45% and FEV1/FVC <60%.

 9. TLC%pred >100% AND RV%pred >175%.

 10. RV/TLC >55%

 11. CT thorax must demonstrate heterogeneous emphysema and a disrupted interlobar fissure
 (75-90% intact) in the treatment lobe. Scans will be analysed using in-house software
 to calculate a heterogeneity score and percentage fissure integrity.

 12. Chartis balloon catheter assessment confirms the presence of collateral ventilation in
 the target lobe.

 Exclusion Criteria:

 1. Patient unable to provide informed consent.

 2. Subject has a history of recurrent clinically significant respiratory infections,
 defined as 3 or more hospitalizations for respiratory infection during the year prior
 to enrolment.

 3. Subject has clinically significant bronchiectasis.

 4. Alpha-1 AT deficiency.

 5. Medical history of asthma.

 6. Subject has co-morbidities that may significantly reduce ability to improve exercise
 capacity (e.g., severe arthritis, planned knee surgery) or baseline limitation on 6MWT
 is not due to dyspnoea.

 7. Subject has evidence of other severe disease (such as, but not limited to, lung cancer
 or renal failure), which in the judgment of the investigator may compromise survival
 of the subject for the duration of the study.

 8. Subject is pregnant or lactating, or plans to become pregnant within the study
 timeframe.

 9. Subject has an inability to tolerate bronchoscopy under conscious sedation or general
 anaesthesia.

 10. Subject has severe gas exchange abnormalities as defined by: PaCO2 >8.0 kPa and/or
 PaO2 < 6.0 kPa (on room air).

 11. FEV1 <15% predicted and Total lung CO uptake (TLCO) <20% predicted.

 12. Subject has an inability to walk >140 meters in 6 minutes.

 13. Subject has severe pulmonary hypertension defined by right ventricular systolic
 pressure >45 mm Hg measured on transthoracic echocardiogram.

 14. Subject has giant bullae >1/3 lung volume.

 15. Lung nodule requiring surgery.

 16. Subject has had previous LVR surgery, lung transplantation or lobectomy.

 17. Subject has been involved in pulmonary drug or device studies within 30 days prior to
 this study.

 18. Subject is taking >10 mg prednisone (or equivalent dose of a similar steroid) daily.

 19. Subject requires high level chronic immunomodulatory therapy to treat a moderate to
 severe chronic inflammatory autoimmune disorder.

 20. Subject is on an antiplatelet (such as Plavix) or anticoagulant therapy (such as
 Warfarin or NOAC) which cannot be stopped prior to the procedure.

 21. Subject has a known sensitivity or allergy to Nickel.

 22. Subject has a known sensitivity to drugs required to perform bronchoscopy.

 23. Subject has any other disease, condition(s) or habit(s) that would interfere with
 completion of study and follow up assessments, would increase risks of bronchoscopy or
 assessments, or in the judgment of the investigator would potentially interfere.