ARROYO B 1, PALOT A 2, STEINBERG JG 3,CHARPIN D 2, GUIEU R 5 ,DELLIAUX S 1,3, JAMMES Y 3 and BREGEON F 1,4
1 Service des Explorations Fonctionnelles Respiratoires, Centre Hospitalo-Universitaire Nord, Pôle thoracique et cardio-vasculaire,
Assistance Publique Hôpitaux de Marseille, Marseille, France
2 Clinique des bronches, de l'allergie et du sommeil, Centre Hospitalo-Universitaire Nord, Pôle thoracique et cardio-vasculaire, Assistance
Publique Hôpitaux de Marseille, Marseille, France
3 Aix-Marseille Université, MD, DS-ACI, UMR 2, 13016, Marseille, France
4 Unité de Recherche sur les Maladies Infectieuses et Tropicales Émergentes (URMITE) UMR 63 CNRS 7278 IRD 3R198 INSERM U1095,
IHU Méditerranée Infection, Facultés de Médecine, Aix-Marseille Université, Marseille, France
5 Laboratoire de biochimie, Centre Hospitalo-Universitaire Timone, Assistance Publique Hôpitaux de Marseille, Marseille, France
Summary:
Background: The benefit of respiratory rehabilitation (RR) in the COPD patient is not explained by the improvement of the respiratory function. Some suggest that the observed benefit would be related to an improvement in the systemic inflammatory profile. The aim of our study was to evaluate in the COPD patient, the impact of RR on basal and post-exercise plasma levels of systemic cytokines. Methods: Monocentric prospective study including 15 stable COPD patients with preserved cardiac function, without neoplasia or chronic inflammatory disease or anti-inflammatory treatment. The 5- week pre- and postoperative RR assessment included a full-length spirometry, a 6-min walk test (6MWT), an exacerbative phenotype identification, and a peak ergometer exercise test with Vo2pic measurement, maximum power, evaluation of the metabolic threshold and resting assay at Vo2pic at 5 and then 10 minutes of recovery of blood gases, IL-1 , IL-6 and TNF-α. Results: A total of 11/15 patients were evaluated before and after RR. Before RR, the effort induced a significant increase in IL-1 with 1.73 ± 0.38 pg/mL vs 2.16 ± 0.52 pg / mL, p = 0.031. There is an inter-individual variation with only 7/15 IL6-producer profiles (all IL-1 producers). After RR, the basal IL-1 and IL-6 levels were lower than before RR with respectively 1.73 ± 0.38 pg / mL vs 0.49 ± 0.25 pg / mL, p <0.001 and 3.39 ± 1.26 μg / mL vs 4.4 ± 8.85 μg / mL, p = 0.017. No effects of RR and / or exercise were observed on TNF-α. No other parameters collected were significantly modified by the RR except for the distance traveled at 6MWT which increased by 37±52.90 meters, p = 0.042. The “exacerbator” phenotype could be revealed in 7/11 patients and γ/7 were frequent exacerbators. These patients corresponded to those with the basal IL-6 level and the most exacerbating patient was also the most IL6-producing at effort before and after RR. Conclusions: In the stable COPD patient, the RR seems to modulate the basal and post-exercise plasma levels of IL1- and IL-6.
27 Key Words: Chronic obstructive pulmonary disease, COPD, interleukins, cytokines, IL-1 , IL-6 and TNF-α, inflammation, systemic, respiratory rehabilitation, exercise re-training, stress test, EFFX, spirometry, 6 minutes walk test, 6MWT, exacerbation.
Chronic obstructive pulmonary disease (COPD) is the 4th leading death cause in the world, accounting for 5% of global deaths in 2005 according to the World Health Organization. 1 Its prevalence tends to increase over the years with 384 million global cases for the year 2010.2-4 Currently, we know that COPD is a chronic inflammatory disease starting at the epithelial bronchial level. It is initiated and mediated locally by interleukins (IL) such as IL-1 and TNF-α which stimulate B cells and T.5,6 This process could extend well beyond creating a real systemic disease involving particularly inflammatory, cardiovascular, metabolic and neuromuscular devices and systems.7,9 Indeed, compared to healthy subjects, significantly elevated levels of plasma fibrinogen, ultrasensitive C-reactive protein, leukocytes, TNF-α, IL- 6 and IL-1 have been reported in with COPD patients.10-17 Currently, from a pharmacological therapeutic point of view, immunotherapies are in full swing but must prove their benefit in COPD. Indeed, studies have focused on infliximab, an anti-TNF-α antibody, and have not shown to be effective in the COPD patient. 18 Canakinumab, an anti-IL-1 antibody, already having a Marketing Authorization in Periodic Syndrome, Rheumatoid Arthritis and Gout, has not shown clinical efficacy on respiratory function, quality of life and the rate of exacerbation at 56 weeks. 19 Benralisumab is an anti-IL5R antibody involved in the maturation of eosinophils. Its efficacy would be similar to that of mepolizumab on the exacerbation rate in severe asthma20 but in COPD patients, the benefit on the rate of exacerbations at 48 weeks has not been proved. However, a potential gain in subgroup data of COPD patients with hyper-eosinophilia was observed as evidenced by attenuation of the decline in FEV1 and an increase in quality of life from circulating eosinophil levels at baseline beyond 200 elements / mL. 21 Another track would reside in tocolizumab, an anti-IL6 antibody with Marketing Authorization in rheumatoid arthritis refractory to anti-TNF, but unfortunately this molecule has not yet been studied in the patient COPD. 22 Poor results in these studies may be an explanation from the variety of phenotypes found in COPD. 23 On the physio-therapeutic side, in COPD patients, it seems that respiratory rehabilitation (RR), which revolves around its central pivot, the physical training(PT), is recognized for its fundamental
28 role on reducing perceived symptoms, improving quality of life and reducing number of exacerbations in the first year following RR. 24-26 However, all works regarding this matter are consistent in saying that there is no significant benefit of RR in preventing the decline of FEV1. The benefits of physical exercise on the occurrence of exacerbations may imply immunoregulation as objectified in healthy subjects, but no data are yet available to support that hypothesis for COPD. 27,28 Thus, COPD appears as a chronic systemic disease with a significant inflammatory and metabolic component. Regular exercise, thanks to some of its effects on metabolism and native immunity, performed during RR, could interact with the disease and alter the basal or exercise-induced immune status of these patients, which remains
to be documented.
The main objective of this work was therefore to evaluate in the COPD patient, the impact of RR on the systemic inflammatory state, as represented by baseline plasma levels at rest and at the exercise of certain systemic cytokines (CTK): IL-1 , IL-6 and TNF-α. The secondary objective was to assess the effect of RR on spirometry, exercise capacity and adaptation, and exacerbation rate at 1 year.