Air Pollution and Children With Cystic Fibrosis
Condition: Cystic Fibrosis
MeSH terms: Cystic Fibrosis; Fibrosis
Study type: Observational

Summary: 
      1. To determine personal exposure to air pollution in children with cystic fibrosis;

        2. To determine airway macrophage uptake of inhaled particulate matter in cystic fibrosis
           children;

        3. To establish whether prostaglandin E2 affects particulate matter removal in airway.
    

Detailed description: 
      Background:

      Cystic fibrosis (CF) is the commonest hereditary life-shortening respiratory condition,
      resulting in premature death secondary to recurrent airway infections and inflammation,
      leading to irreversible lung damage. The screening programme in infancy has improved life
      expectancy but the lifespan of CF patients is still reduced by 20 years at present. Thus
      interventions to reduce inflammation, infection and lung damage in CF are still needed.

      One potential intervention is to reduce exposure of CF children to air pollution. Particulate
      matter (PM) are microscopic soot particles from petrol and diesel engine emissions; PM is
      linked to adverse respiratory health effects in children. Children with cystic fibrosis are
      particularly vulnerable to PM but, to date, no exposure-reduction advice is available, and
      the mechanism underlying this vulnerability is unclear.

      Personal exposure of CF children to PM is due to: i) locally-generated sources (relative to
      the proximity to busy roads) and ii) background concentrations (i.e. PM blown across the
      whole city from other areas). Although a link between air pollution and reduced lung function
      growth in healthy children is well established, the link with CF lung disease has only
      recently emerged. A recent study found that long-term exposure of CF children to PM increases
      risk of airway infection with Pseudomonas. Another study also found that short-term
      background pollution is associated with increased need for antibiotics in children and adults
      with CF. The need to reduce patients' personal exposure to PM has been recognised by Barts
      Health NHS Trust. Working with Global Action Plan, the Trust has developed tips on how to
      reduce adults' personal exposure to air pollution. These tips include traveling outside rush
      hours, taking low pollution routes (maps provided), and signing up to the airText air
      pollution warning App. Since travel outside rush hours is not feasible for school children,
      child-friendly tips are urgently needed.

      Recent research in asthma patients suggests a putative mechanism of impaired removal of
      inhaled PM. In the healthy lung, inhaled PM is quickly removed (phagocytosed) by airway
      macrophages (AM). AM patrol the surface of epithelial cells lining the airways; after taking
      up PM, they move up and out of the lung. Thus AM with normal phagocytic function act to both
      reduce PM exposure of other airway cells - including epithelial cells, and to ensure that PM
      does not accumulate in the lung. The amount of carbon particles in AM was previously used to
      assess the effects of long-term effects of exposure of healthy children and adults. The
      amount of black carbon (BC) in AM reflects the intrinsic capacity of AM to remove PM
      (phagocytic capacity). AM carbon is significantly lower in conditions such as severe asthma,
      where AM phagocytic capacity is impaired. Furthermore, a role for prostaglandin E2 (PGE2) in
      mediating impaired phagocytic function in asthma has been identified. First, PGE2 suppresses
      AM phagocytosis of urban PM in vitro; and second, children with severe asthma had increased
      urinary PGE2 metabolites. Shift of inhaled PM away from AM to other cells has the potential
      to stimulate interleukin-8 (IL-8) release by epithelial cells - a phenomenon observed in
      mouse, where inhalation of non-inflammatory particles produces significant airway
      neutrophilia when AM phagocytic function is impaired.

      The hypothesis is that impaired handling of inhaled PM by AM contributes to vulnerability of
      children with CF to air pollution. Specifically, increased vulnerability to inhaled PM in
      children with CF is due to PGE2-mediated impairment of AM phagocytosis. The corollary is that
      children with CF will have; i) reduced levels of AM carbon in vivo (reflecting reduced
      phagocytosis of inhaled PM in vivo), ii) reduced capacity of AM to phagocytose carbon PM in
      vitro, iii) increased metabolites of PGE2 in the airway and urine, and finally, iv) since
      PGE2 production is under the control of the enzyme cyclooxygenase (COX, especially COX-2), CF
      airway cells have increased COX-2 expression, v) COX inhibitors (e.g. Ibuprofen) should
      suppress PGE2 production, theoretically improving AM function.

      Non-cystic fibrosis bronchiectasis is a respiratory condition with multiple aetiology such as
      congenital pathology, immunodeficiency, and primary ciliary dyskinesia. Patients with non-CF
      bronchiectasis demonstrate similar clinical features to those with CF, patients with either
      conditions are managed with similar treatments, it is therefore hypothesised that the above
      also apply to children with non-CF bronchiectasis.

      There has been evidence that some organisms are capable of reproducing and residing within
      airway macrophages without being destroyed by the traditional phagocytic pathway. Often,
      unwell CF and non-CF bronchiectasis patients are admitted to the hospital for intensive
      antibiotic treatments but a proportion of their sputum samples yield no growth by routine
      hospital culture. This study will explore isolated airway macrophages and identify the
      organisms within - if any are present.

      Clinical Data:

      There is evidence to support this hypothesis; i) it was previously reported that phagocytosis
      of inert latex beads is impaired in AM from CF adults (71 + 15 % phagocytosis in controls vs.
      23 + 9 % in CF), ii), CF is associated with increased airway PGE2, and iii) in a pilot study,
      significantly (p<0.01) reduced AM carbon in 6 CF children compared with 6 healthy controls
      (mean 0 vs. 0.3 + .05, μm2 p<0.01) was found.

      Rationale:

      To date, the effect of impaired uptake of PM by AM on other airway cells has not been studied
      in vitro. The hypothesis is that in co-cultures of human AM and airway epithelial cells
      exposed to urban PM, PGE2-mediated impairment of macrophage phagocytosis increases epithelial
      release of IL-8. Furthermore, since AM are a major source of airway PGE2, it is speculated
      that there is increased COX-2 expression in AM from CF children. Thus suppression of AM
      phagocytic function in CF is an autocrine process; i.e. CF AM release more PGE2 - which in
      turn suppresses AM phagocytosis. In this study the evidence will be sought for abnormal
      handling of PM by AM from CF children, and model this using cultures of human airway cells
      and macrophages.
    

Intervention name(s): None. Not applicable
Intervention type(s): Other
Intervention description(s): None. Not applicable
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Inclusion Criteria:

          -  Age 1-17

          -  Diagnosis of Cystic Fibrosis

          -  Diagnosis of non-CF bronchiectasis

          -  Living in or around London With age matched healthy controls

        Exclusion Criteria:

          -  Current active smoker

          -  Receiving immunosuppressive drug therapy

          -  For children with CF not on regular nebulised hypertonic saline: drop in FEV1 of >15%
             post-bronchodilator (exclusion criterion for sputum induction)

          -  For healthy controls: Post-bronchodilator FEV1 <80% (standard exclusion criterion for
             sputum induction in healthy individuals)

          -  For participants currently or recently involved in other research study, they will be
             excluded if their current or recent research have any potential impact on our sampling
             or results.