Doxycycline in a dose of 100 mg once a day for duration of 7 to 10 days has been used as an antimicrobial agent to treat acute exacerbations in COPD. The present study is first of its kind in which efficacy of 4 weeks doxycycline was assessed in patients of stable COPD. All the study participants were male patients because of inclusion of only those patients who had smoking history of more than 10 pack-years and the fact that smoking is much less common in females in India. Both the groups were comparable in terms of drop-outs and withdrawals during the study period.
Doxycycline demonstrated improvement in lung function parameters for which antimicrobial action of doxycycline is unlikely to be responsible. The present study excluded patients with acute exacerbation, as defined by Anthonisen et al
] This classification indicates likelihood of bacterial infection as cause of an exacerbation. The study also excluded patients who had moderate to severe exacerbations in last 4 weeks according to event-based definition given by Cazzola et al
] Patients having infective pathology were also excluded. A randomized controlled trial has provided evidence for significant beneficial effect of antibiotics only in those COPD patients who present with increase in all of the following cardinal symptoms: Dyspnea, increased sputum volume and sputum purulence[20
] or who present with sputum purulence, and at least one of other two cardinal symptoms.[23
] In conclusion, there is less possibility that antimicrobial action might have contributed to beneficial effect of doxycycline in improving lung function parameters in the present study.
Improvement in lung function parameters in present study might be the result of anti-inflammatory and MMP-inhibiting activity of doxycycline. A study demonstrated that the collagenase activity in tracheal aspirates from horses suffering from COPD was sensitive to doxycycline inhibition.[24
] Study by Nordstrom et al
] tested clinical response to 3 months doxycycline in concert with collagenase activity in patients of rheumatoid arthritis. Significant reduction in joint score and pain visual analogue scale was seen as early as 6 weeks. In the same study, saliva samples showed significant reduction in collagenase (MMP-8) activity at 12 weeks. Doxycycline has shown improvement in pulmonary disorders in which dysregulated MMP activity is held responsible. Maugban et al
] studied the effect of addition of doxycycline to immunosuppressive therapy in lung transplantation patients with recurrent acute rejections or obliterative bronchiolitis (OB/BOS). This was associated with improved lung functions in serial pulmonary function tests. OB/BOS is associated with elevated MMP- 9levels and the immunomodulatory effect of doxycycline might have been responsible for the beneficial effect. Long treatment with doxycycline in patient of idiopathic pulmonary fibrosis was associated with improvement in symptoms, physiological and radiological parameters.[26
] Doxycycline inhibits neutrophil collagenase (MMP-8) and MMP-9 at doses readily attainable by therapeutic doses. It achieves similar concentration in lungs and plasma.[27
Airway limitation and airway inflammation are separate and independent factors in pathophysiology of COPD. CRP reflects the total systemic burden of inflammation in patients of COPD.[29
] Eight-year follow-up study of large cohort with airway obstruction showed that the increased CRP levels are strong predictor of COPD hospitalization and deaths[30
] Increased serum CRP levels have been associated with all-cause mortality in patients with mild to moderate COPD, reduced lung function, and greater FEV 1
] The present study demonstrated significant difference in reduction of baseline serum CRP levels in doxycycline and standard group. The baseline serum CRP was higher in doxycycline group, though this was not significant. Anti-inflammatory agents like corticosteroids (inhaled fluticasone) for 2 weeks reduced baseline serum CRP levels by 50% in COPD patients who had stable symptoms in previous 3 months in a study.[32
] In MIDAS trial, subantimicrobial doses of doxycycline significantly reduced serum CRP level by 47% in patients with coronary artery disease.[27
] The study also demonstrated significant reduction in serum IL-6. The authors concluded that reduction in CRP due to doxycycline might be due to upstream inhibition of IL-6 or direct inhibitory effect on CRP synthesis in liver or both. IL-6 is a major signaling cytokine stimulant and induces CRP production and release by liver. Similar mechanism might be responsible for reduction in CRP in the present study.
Studies have demonstrated that dyspnea scores and lung function are distinct and separate in terms of their influence on health outcome.[33
] The lack of improvement in MRC dyspnea scale despite significant increase in FEV1
might be due to following reasons. First of all, the study intervention period might not be sufficiently long enough to change the perceived respiratory disability in patients of stable COPD. Second, association of FEV1
and MRC dyspnea scale has not been demonstrated.[34
] Lastly, there could be factors other than COPD which might have contributed to dyspnea in the study participants.
Limitations of the study include short study intervention period and lack of data on effect of doxycycline on long-term clinical outcomes in COPD like symptom scores, health status, exercise tolerance, and exacerbation rates. Alternate explanation for serum CRP reduction in doxycycline group could be resolution of mild or occult infection which was not recognized prior to study. The study did not address the problem of antimicrobial resistance.
In conclusion, the study demonstrates beneficial effect of short-term doxycycline in lung function parameters and systemic inflammatory marker, CRP in patients of stable COPD.