RICERCA ITALIANA     

Research program

BRONCHIECTASIS IN COPD PATIENTS : PREVALENCE AND BACTERIAL COLONIZATION.

University Co-ordinator

Università degli Studi di PARMA - SCIENZE CLINICHE - PARMA(PR)

Research Unit Leader

Emilio MARANGIO

Description

Study Protocol
The study will be divided into two sections.
- Stable COPD patients
In these patients we intend to assess the prevalence of bronchiectasis using a CT spiral scanning. We will also detect the resting lung function and the exercise tolerance, assessed by the 6MWT and the CPET, by comparing patients with and without bronchiectasis.
- COPD patients with bronchiectasis:
In this population we will study the effect of different "prophylaxis" i.e. macrolide and inhaled steroids. The population will be followed for 12 months.
Details of the Interventions Proposed
- Stable COPD patients:
The patient will attend the clinic in the morning for enrolment, and provide written informed consent. During the visit medical history will be recorded and subjects will undergo a physical examination and lung function testing. CT scan, 6MWT and the CPET will also be performed on three different days.
- Resting Lung Function Testing
Pulmonary function will be measured by a flow-sensing spirometer and a body pletismograph connected to a computer for data analysis (Vmax 22 and 6200, Sensor Medics, Yorba Linda, US). Baseline total lung capacity (TLC), forced expiratory volume in the first second (FEV1), and FEV1/VC ratio will be recorded. Carbon monoxide transfer capacity (TLCO) will be also measured by the single breath method. All these variables will be expressed as percent of predicted value (10,11).
Reversibility of airflow obstruction will be assessed by spirometric tests after administration of inhaled salbutamol (200 mcg).
Resting respiratory muscle strength will be also assessed by maximal inspiratory pressure (PImax) and maximal expiratory pressure(PEmax). PImax and PEmax will be performed against a valve, which can be closed by turning a tap (12). PImax and PEmax will be measured in cm H2O from TLC and RV, respectively. The highest recorded pressures maintained for one second will be used for analysis.
- CT scan
Two radiologists will independently examine the same CT, every discrepancy will be solved by consensus. The following protocol will be followed:
1) CT in inspiration at TLC with slice of 1 mm every 10 + 3 expiratory slices at RV using three predetermined levels (aortic arch, tracheal carena, right basal common vein)
2) Technical parameters: 120 kV, 220 mA, filtro bone, FOV including both lung, lung parenchima window (-600/1600 HU)
3) All CT will be saved on CD rom
The diagnosis and evaluation of bronchiectasis will be performed according to Webb et al. (13). The evaluation will be performed lobe by lobe including lingula (total lobes= 6):
1) Bronchiectasis extension on lobar base: 0, 1 (< 25% of the lobe), 2 (25-50%), 3 (>50%) – MAX TOT 18
2) Severity and kind of bronchiectasis and semi-quantitative, comparing the diameter to that of the adiacent artery: 0, 1 (bronchial diameter equal to 100-200% artery diameter), 2 (200-300%), 3 (> 300%) – MAX TOT 18
3) Thickness of bronchial walls: 0, 1 (Thickness < 50% artery diameter), 2 (50-100%), 3 ( complete obliteration of lumen or Hydro-air levels) - MAX TOT 18
4) Evaluation of emphysema (visual score on three levels (inspiration) (aortic arch, carena, basal common vein)
5) Evaluation of air trapping in expiration (idem)
6) Bullae
7) Ground glass areas (estension by visual score)
8) Bronchiolites: prevalent site, lobar involvement, severity
(0,1,2,3)
9) Pulmonary artery diameter (pathol if > 2,9 cm)
10)Other features
- 6MWT
Patients will be perform two 6MWTs, according to a standard protocol (14). The 6MWTs are symptom limited, so patients are allowed to stop if necessary, though they will be instructed to resume walking as soon as possible. The second 6MWT will be performed in the same manner as the first, following a rest of at least 60 minutes. The walk distance will be recorded in meters and expressed as percent of predicted value (15). Results from the second walk only will be used for analysis to allow for any learning effect (16).
Before and immediately after 6MWT, patients will rate the magnitude of their perceived breathlessness on an interval scale, which was a 100-mm horizontal visual analogue scale (17). The visual analogue scale (VAS) consists of a horizontal ruler without any mark on the patient's side with the words "not at all breathless" and "extremely breathless" on the left and right end, respectively. Breathlessness perception ratings will be expressed in mm from 0 to 100 and will correspond to the distance of the marker from the left end of the VAS.
- CPET
Each patient will be perform a physician-supervised, standard, progressively increasing work rate (WR) CPET to maximum tolerance on an electromagnetically braked cycle ergometer. Gas exchange measurements (VMAX 229, Sensor Medics, and Yorba Linda, US) will be made during 3 minutes at rest, 3 minutes of unloaded leg cycling at 60 rpm followed by a progressively increasing WR exercise of 5 to 20 W • min -1 to maximum tolerance, and 2 minutes of recovery (18). Pulse oximetry (SpO2), heart rate (HR), 12-lead- ECG, and cuff blood pressure will be monitored and recorded.
Minute ventilation (VE), O2 uptake (V'O2), CO2 output (V'CO2), will be computer-calculated breath by breath, interpolated second by second, and averaged over 10-second intervals (18). The anaerobic threshold (AT), ratio of O2 uptake to WR increase (ΔV'O2/ΔWR), and oxygen pulse (O2 pulse) will be determined as previously described (18,19). Ventilatory efficiency during exercise will be expressed as the ratio of ventilation to CO output at AT (VE/V'CO2@AT) (7) and the slope of VE versus V'CO2 over the linear component of the plot of VE versus V'CO2 (20).
- Patients
We will enrol within the space of a year 120 consecutive COPD patients from the oupatient Clinic of the Lung Function Unit of the Department of Clinical Sciences of the Parma University. Patients must meet the conventional diagnostic criteria for COPD (21).
Inclusion Criteria :
1.Smokers or former smokers of at least 10 pack-years; 2.COPD demonstrated by forced spirometry with FEV1 > 0,7 L, FEV1 post-BD <60% and FEV1/FVC < 70%; 3.Bronchodilator test performed at inclusion or no more than 6 months before inclusion should have been negative (increase in FEV1 < 200 ml and 12%, 10 minutes after administration of 2 puffs of salbutamol); 4.Stable phase defined by clinical criteria of the attending investigator, but at least 6 weeks from the last exacerbation 5.Informed consent
Exclusion criteria:
1.Patients receiving oral corticosteroids at any dose or another immunosuppressor; 2.Formal contraindication for sputum collection or impossibility to obtain a sample of sputum valid for analysis.
- COPD Patients with Bronchiectasis:
In this population we will study the effect of different "prophylaxis" i.e. macrolide and inhaled steroids. The population will be followed for 12 months. The following procedure will be performed every 3 months and at each exacerbations:
Clinical assessment, Resting Lung Function testing, Serum Sampling, Sputum collection. On biological samples renal and hepatic function tests will be performed. Sputum culture will be performed to assess bacterial flora and resistance patterns. After 6 and 12 months of therapy, patients will undergo 6MWT and the CPET.
Design of the study
Patients will be randomized in 3 groups to receive :
1.Standard of care
2.azithromycin 500 mg OD 3 days a week (Monday, Wednesday, Friday) for 6 months and then inhaled steroids (fluticasone 500 ug bid) for 6 months
3.inhaled steroids (fluticasone 500 ug bid) for 6 months and then azithromycin 500 mg OD 3 days a week (Monday, Wednesday, Friday) for 6 months
End-points:
-effects of treatments on exacerbations frequency
-effects of treatments on resting pulmonary function
-effects of treatment on exercise tolerance