Clinical Utility of Doxycycline in Chronic Obstructive Pulmonary Disease (COPD) Infections: Review of Indian Experience

Chronic obstructive pulmonary disease (COPD) is a disease affecting the pulmonary airways with inflammation; pathologically characterized by its narrowing and remodeling, with or without mucus hypersecretion and/or destruction of the alveolar membrane (1). COPD is significantly associated with an increased risk of various respiratory tract infections (2). Upregulation of matrix metalloproteinases (MMPs) is related to the pathogenesis of COPD, and its inhibition has been regarded as a potential therapeutic target in influencing COPD outcomes (3). (reference updated) Doxycycline, an antimicrobial agent, and a known MMP inhibitor (4) have been used in several clinical studies in COPD. The scientific evidence bringing out the scope of Doxycycline in COPD infections, more specifically through some of the Indian data is reviewed.

Rationale for Consideration of Doxycycline in COPD Patients: Tackling the Matrix Metalloproteinases (MMPs) Pathway

Elevated levels of Matrix Metalloproteinases (MMPs) – a class of zinc-containing endopeptidases have been found to play an important role in the pathogenesis of COPD (5). MMPs are secreted by cells such as macrophages and neutrophils; and are associated with inflammation, mucus hypersecretion, and profibrotic pathways (6)  leading to matrix remodeling. The upregulation of MMPs among COPD patients in induced sputum, bronchoalveolar lavage lung tissue and exhaled breath condensate is cited in the scientific literature (7). Serum levels of Matrix Metalloproteinases-9 (MMP-9) and Tissue Inhibitors of Metalloproteinases (TIMP) levels are higher among COPD patients. Forced expiratory volume (FEV1) levels have been reported to be inversely correlated with MMP-9 levels in these patients (8). Therefore, inhibition of the MMPs pathway could be a potential therapeutic target in COPD. Doxycycline, a synthetic tetracycline derivative has demonstrated a significant reduction of MMP-9 production and concomitant elastin degradation (9).  Furthermore, doxycycline also possesses anti-inflammatory and antioxidant properties and thus can play a potential therapeutic role in improving the quality of life in COPD patients. 

Long Term Use of Doxycycline Improves Lung Function in COPD – An Indian Experience Published in 2021

Bhattacharyya P et al conducted a study to assess the tolerability and impact of long-term use of MMP inhibitor doxycycline in COPD. A cohort of COPD patients (n=88) was randomized to continue a uniform COPD treatment without (n=34) or with add-on long-term oral doxycycline (n=54) for a period of 12 months. The add-on doxycycline dosage was 100 mg once or twice daily, to be consumed after one hour of food. Pulmonary function parameters, health well-being estimations in the form of COPD Assessment Test scores, and adverse events were noted at 3, 6, 9, and 12 months of therapy. Measurement of serum Matrix Metalloproteinases (MMP-2, MMP- 9) and high-sensitive C-reactive protein (hs-CRP) levels were made at the initiation of the study and at three months, as feasible. The results of this study demonstrated significant improvement at 6 and 12 months for lung function parameters [forced expiratory volume in one second (FEV1), FEV1/forced vital capacity (FVC), and forced expiratory flow at 25-75% of FVC (FEF25-75)]. The universal health well-being measurements improved with an overall 26.69 % reduction in exacerbations. The concomitant reduction in serum MMP-9 (p=0.01), MMP-2 (p=0.01) and hs-CRP (p=0.0001) levels (n=21) at three months was also significant. The adverse reactions with add-on doxycycline appeared acceptable. It was thus inferred that long-term doxycycline treatment over 12 months seems to improve lung function, health status, and exacerbations in COPD, and was well-tolerated (10).

Doxycycline Improves Pulmonary Function & Inflammatory Markers in COPD Patients: Indian Study

Dalvi PS et al published a study intending to evaluate the effect of doxycycline in patients of moderate to severe COPD with stable symptoms. COPD patients (n=61) with stable symptoms were enrolled after a run-in period of 4 weeks in an interventional, randomized, observer-masked, parallel study. The intervention arm (n=31) received 4 weeks of doxycycline in a dose of 100 mg once a day. The study participants in the control group (n=30) did not receive doxycycline. The parameters measured were pulmonary functions, systemic inflammation marker C-reactive protein (CRP), and medical research council (MRC) dyspnea scale at baseline and at four weeks. The use of systemic corticosteroids or other antimicrobial agents was not allowed during the study period. The study results reported that, at 4 weeks, the pulmonary functions (change in FEV1 – doxycycline: +6.60% vs. control: -1.3%) significantly improved in the doxycycline group and the mean reduction in baseline serum CRP (CRP percent reduction – doxycycline: 45.59% vs. control: 15.78%)  was significantly greater in doxycycline group as compared with the reference group. It was concluded that the anti-inflammatory and MMP-inhibiting properties of doxycycline might have contributed to the improvement of pulmonary function indices in this study (11).

Anti-Inflammatory and Anti-Oxidant Effect of Doxycycline Corroborate with Lung Function Benefits among Indian COPD Patients

Singh B et al assessed the effect of doxycycline in COPD through a randomized prospective study. Oral doxycycline 100 mg was used once or twice daily, as an add-on to existing standard therapy. The study demonstrated that improvements in lung function and quality of life in COPD patients co-related with changes in antioxidant, anti-inflammatory markers, and anti-MMP activity of doxycycline (3).

Final Point of View

Chronic obstructive pulmonary disease (COPD) is significantly associated with an increased risk of various respiratory tract infections (2). While there are various antibiotic options available for the treatment of infections associated with COPD; due to the attribution of inflammatory pathophysiology in COPD, antimicrobial agents with specific anti-inflammatory activity inhibiting MMPs, like doxycycline may provide an additional advantage (4).  Based on studies published by Indian researchers, Doxycycline could improve lung function parameters, reduce inflammatory markers, improve quality of life and reduce exacerbations among COPD patients (11).

The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Doxycycline, click HERE

References

Adapted from: -

1) MacNee W. Pathology, pathogenesis, and pathophysiology. BMJ 2006; 332 : 1202–4.

2)Lange P. Chronic obstructive pulmonary disease and risk of infection. Pneumonol Alergol Pol. 2009;77(3):284-8. PMID: 19591100.

3)Singha B, Ghosh N, Saha D, Sarkar S, Bhattacharyya P, Chaudhury K. Effect of doxycyline in chronic obstructive pulmonary disease - An exploratory study. Pulm Pharmacol Ther 2019; 58 : 101831

4)Sorsa T, Ding Y, Salo T, Lauhio A, Teronen O, Ingman T, et al. Effects of tetracyclines on neutrophil, gingival, and salivary collagenases: A functional and Western-blot assessment with special reference to their cellular sources in periodontal diseases A. Ann N Y Acad Sci 1994; 732 : 112-31

5)Belvisi MG, Bottomley KM. The role of matrix metalloproteinases (MMPs) in the pathophysiology of chronic obstructive pulmonary disease (COPD): A therapeutic role for inhibitors of MMPs? Inflamm Res 2003; 52 : 95-100.

6)Loffek S, Schilling O, Franzke CW. Series "matrix metalloproteinases in lung health and disease:" Biological role of matrix metalloproteinases: A critical balance. Eur Respir J 2011; 38 : 191-208

7)Zdenka Navratilova Z, Kolek V, Petrek M. Matrix metalloproteinases and their inhibitors in chronic obstructive pulmonary disease. Arch Immunol Ther Exp 2016; 64 : 177-93

8)Gilowska I, Kasper Ł, Bogacz K, Szczegielniak J, Szymasek T, Kasper M, et al. Impact of matrix metalloproteinase 9 on COPD development in polish patients: genetic polymorphism, protein level, and their relationship with lung function. Biomed Res Int 2018; 2018 : 6417415

9)Boyle JR, McDermott E, Crowther M, Wills AD, Bell PR, Thompson MM. Doxycycline inhibits elastin degradation and reduces metalloproteinase activity in a model of aneurysmal disease. J Vasc Surg 1998; 27 : 354-61.

10)Bhattacharyya P, Singh B, Sarkar S, et al. Impact of long-term doxycycline on lung function & exacerbations: A real-world open, prospective pilot observation on chronic obstructive pulmonary disease. Indian J Med Res. 2021;153(4):465-474. doi:10.4103/ijmr.IJMR_1254_18

11)Dalvi PS, Singh A, Trivedi HR, Ghanchi FD, Parmar DM, Mistry SD. Effect of doxycycline in patients of moderate to severe chronic obstructive pulmonary disease with stable symptoms. Ann Thorac Med 2011;6:221-6.