Validating the Use of Disposable Bronchoscopes for Research Bronchoalveolar Lavage
Condition: Healthy
Study type: Observational

Summary: 
      Validation study to use the disposable bronchoscopes in healthy volunteer research
      bronchoscopies to ensure adequate sample and cell yield.
    

Detailed description: 
      Research bronchoscopies are traditionally performed using conventional flexible fibreoptic
      bronchoscopes. The technique for obtaining bronchoalveolar lavage fluid (BAL) from healthy
      volunteers for research purposes has been developed by our group since 1999 and has been
      performed in > 1,000 subjects in the UK and Malawi including healthy volunteers.

      Fibreoptic bronchoscopy with BAL using manual hand held suction enables the removal of
      non-adherent cells and lung lining fluid from the mucosal surface. In research environments,
      BAL allows sampling of innate (lung macrophage), cellular (B- and T- cells), and humoral
      (immunoglobulin) responses within the lung. Further applications include determining protein
      and drug levels, with the latter being a key parameter in early phase 'lung tissue active'
      drug development.

      The BAL technique uses gentle hand-held suction of instilled fluid; this is designed to
      maximize BAL volume returned, and to apply minimum shear force on ciliated epithelia in order
      to preserve the structure and function of cells within the BAL fluid. This technique is also
      intended to preserve viability to facilitate the growth of cells in ex vivo culture. The
      research technique therefore uses a larger volume of warmed normal saline instillate
      (typically in the order of 200 ml) and employs manual suction to reduce cell damage.

      At the Royal Liverpool Hospital (RLBUHT) ≥120 healthy volunteer BALs have been performed.
      Available data suggest that from 200 ml of instillate the following volume yields are
      retrieved: mean 100-120 ml, median 120 - 125 ml with ~ 19% of BALs returning <100 ml yield.
      The preferable BAL volume yield is >100 ml, a yield of >150 ml is considered excellent;
      yields >170 ml have not been recorded. There is no linear relationship between the cell yield
      and volume yield. Yields of <100 ml are in our experience, more likely to lead to side
      effects such as cough, chest pain and fever. Subjects with yields of <100 ml are advised to
      be recovered in the left lateral position to aid postural drainage of remaining instillate.
      There have been no serious adverse events (SAEs) reported; and notably there have been no
      post procedure hospitalisations or antibiotics required for suspected pneumonia.

      Single-use flexible intubation bronchoscopes are used throughout United Kingdom (UK) National
      Health Service (NHS) trusts. They are predominantly used within the intensive care and
      anaesthetic (theatre) setting for both emergency and elective airway intubation. The flexible
      fibreoptic bronchoscope with sterile single-use disposable-sheath endoscope system has the
      potential to be more cost-effective and reduce the risk, however negligible, of
      cross-infection during the sterilisation procedure. Eliminating the need for high-level
      disinfection processing between procedures reduces maintenance costs (equipment and staff),
      and scope downtime and provides the flexibility more suited for research in healthy
      volunteers.

      The content of this study proposal has been peer reviewed by two senior research associates
      based in Malawi and the UK who have deemed the scientific review criteria to be sound.

      Currently many new drug and therapeutics discovery and development projects are blighted by
      the absence of robust predictive pre-clinical models. For example, promising
      anti-tuberculosis (TB) drugs and drug combinations have been clinically trialled based on
      current in vitro and in vivo models, only to find that they lack clinical efficacy; and
      conversely effective anti-TB drugs such as linezolid had poor or modest efficacy in testing
      usingin vitro and in vivo models. To mitigate these issues we have therefore developed
      dynamic pharmacodynamic in vitro models based on high content imaging that are able to
      measure macrophage intracellular tubercular growth and killing rates. Pharmacodynamic (PD)
      and Pharmacokinetics (PK) modelling of these models more closely resemble clinical
      measurements for known first line anti-TB; therefore we now wish to further develop this
      platform into a more physiological model by using alveolar macrophages (AMs) obtained from
      human subjects.

      The purpose of using human AMs will be to compare the drug effects of known and new anti-TB
      compounds in human AMs to other in vitro models. This work will enable us to obtain better,
      more clinically relevant parameters to predict the outcome of drug dynamics. By using the
      AMswe can assess how reliable our current model systems are, and assess considerations of
      drug action in clinically relevant tissue samples. These cells can then be manipulated ex
      vivo to desired clinical scenarios e.g. dual TB and HIV-infections monitoring TB responses
      over time to a range of novel drugs and novel drug combinations. The outputs of these studies
      will be used directly to inform new clinical trials on drug regimens.
    

Intervention name(s): Bronchoalveolar Lavage validation study
Intervention type(s): Other
Intervention description(s): Bronchoalveolar lavage involved the washing out of the right middle lobe of the lung of a healthy volunteer with 200mls of warmed normal saline with or without sedation.
Intervention MeSH terms: Dimercaprol
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Healthy Volunteers, male and Non pregnant female, aged between 18-55 years old.
      
Biospecimen description: 
      Bronchoalveolar lavage cells Bronchoalveolar lavage supernatent
    
Keywords: Healthy volunteer; Respiratory; Bronchoalveolar lavage