asthma and exercise

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EXERCISE IN ASTHMA HARMFUL OR BENEFICIAL Ibrahim M El-Akkary, MD, PhD Professor, Clinical Physiology, Chairman, Bronchial Asthma Research Unit, Medical Research Institute, Alexandria University, Egypt

EXERCISE IN ASTHMA HARMFUL OR BENEFICIAL:

EXERCISE IN ASTHMA HARMFUL OR BENEFICIAL HARMFUL: EXERCISE – INDUCED BRONCHOCONSTRICTION (EIB) DEFINITION, INCIDENCE, STAGES • FACTORS THAT INFLUENCE EIB • MECHANISMS • MANAGEMENT BENEFICIAL: REHABILITATION TRAINING PROGRAM (EL-AKKARY et al, ERS 2003)

EXERCISE – INDUCED BRONCHOCONSTRICTION EIB:

EXERCISE – INDUCED BRONCHOCONSTRICTION EIB Transient airway narrowing that follows vigorous exercise. It is often incorrectly called exercise – induced asthma. A number of people who have not been diagnosed with asthma, exhibit breathing troubles after vigorous exercise. EIB: reduction ≥ 15% in FEV 1 after exercise (85-95% HR max ) Definition and incidence

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Canadian Lung Association, 2001

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STAGES: Early phase -the most severe stage. -peaks 5-15 min after exercise. -resolves 45-60 min. Refractory period: 30-90 min after EIB during which repetition of exercise results in little or no EIB. Late phase: -less severe. -12-16 h after exercise. -Resolves within 24 h. -In 35-50% of cases.

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FACTORS THAT INFLUENCE EIB LEVEL OF CONTROL OF ASTHMA. CONDITIONS: TEMPERATURE OF INSPIRED AIR (≤ 20 C) HUMIDITY OF INSPIRED AIR (≤ 50%) AIR BORN ALLERGENS AND POLLUTANTS. EXERCISE: TYPE: SWIMMING < RUNNING DURATION: ≥ 6 min at 85% or more HR max INTENISTY: ≥ 85% maximum aerobic capacity

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MECHANISMS THERMAL HYPOTHESIS: 1986 Increased ventilation AW cooling Rapid rewarming Vasoconstriction Reactive hyperemia edema AW NARROWING EIB

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MECHANISMS OSMOTIC HYPOTHESIS: 1992 Increased ventilation Evaporation of water from surface liquid Hyper-osmolarity Movement of water from nearby cells Cell shrinkage Mediator release Airway narrowing EIB

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MECHANISMS EIB Nitric Oxide hypothesis: McFadden et al, AJRCCM 2001 Impaired production of the constitutive (RELAXING) NO in response to exercise may play an intimate role in the development of EIB.

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MECHANISMS EIB Complement Activation El-Akkary et al, ERS 2002 Background Mast cell degranulation with mediator release, especially cysteinyl leukotrienes, has strongly implicated in the pathogenesis of EIA 2,3 . Complement activation products, activated either by allergic or non-allergic stimuli, can induce mast cell degranulation 4 .

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Aim Test the hypothesis that Complement activation plays a role in the pathogenesis of exercise – induced asthma. Is the protective effect of corticosteroid on exercise – induced asthma related to its ability to inhibit complement activation? Complement Activation El-Akkary et al, ERS 2002 EIB MECHANISMS

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Methodology Subjects: 31 atopic asthmatics: 20 Exercise Responders 11 Exercise non-responders 14 Control Study design: Complement activation: Baseline and 15 min after exercise Classical pathway: C4d Alternative pathway: Bb End products C5b-9 FEV 1 before and 15 min after exercise challenge . In exercise responders the above measurements were repeated 14 days after fluticasone propionate inhalation, FP (250 mgm twice daily). Complement Activation El-Akkary et al, ERS 2002

Results of complement activation and exercise – induced asthma:

Results of complement activation and exercise – induced asthma Control n = 14 ER n = 20 ER-FP n = 20 ENR n = 11 FEV 1 (L) before exer after exer % change 3.18 ±0.75 3.01 ±0.74 - 6.45 ±5.67 2.44 ± 0.64 1.71 ± 0.23 - 29.61 ±13.88 2.49 ± 0.73 2.29 ± 0.52 - 8.42 ±3.08 * 2.34 ± 0.71 2.11 ± 0.36 - 9.80 ±2.93 C4d ( μ g/ml) before exer after exer 16.73 ±5.27 16.10 ±4.50 18.33 ±5.45 18.99 ±5.23 17.95 ±4.79 18.76 ±5.20 22.25 ±6.92 22.22 ±5.72 Bb ( μ g/ml) before exer after exer 3.91 ±2.05 4.10 ±2.14 3.45 ±1.83 4.74 ±2.69 * 3.97 ±1.97 3.62 ±1.74 4.24 ±1.79 4.26 ±2.17 C5b-9 ( μ g/ml) before exer after exer 5.27 ±2.59 4.79 ±2.16 5.82 ±1.45 5.94 ±1.76 5.40 ±1.46 5.63 ±1.39 5.66 ±1.79 5.78 ±1.79

Fig 1: pre-exercise (pre-ex) and post-exercise (post-ex) FEV1 in control, exercise responder without treatment (ER) , and with fluticasone propionate (ER-FP) and exercise non-responder (ENR) asthmatic:

Fig 1: pre-exercise (pre-ex) and post-exercise (post-ex) FEV 1 in control, exercise responder without treatment (ER) , and with fluticasone propionate (ER-FP) and exercise non-responder (ENR) asthmatic

Fig 2: percent fall in FEV1 due to exercise in control subjects, exercise responder without treatment (ER) and with fluticasone propionate (ER-FP) and exercise non-responder (ENR) asthmatics.:

Fig 2: percent fall in FEV 1 due to exercise in control subjects, exercise responder without treatment (ER) and with fluticasone propionate (ER-FP) and exercise non-responder (ENR) asthmatics.

Fig 3: Serum C4d level pre- (Pre-Ex) and post- (post-Ex) exercise of control subjects, exercise responder without treatment (ER) and with fluticasone propionate (ER-FP) and exercise non-responder (ENR) asthmatics.:

Fig 3: Serum C4d level pre- (Pre-Ex) and post- (post-Ex) exercise of control subjects, exercise responder without treatment (ER) and with fluticasone propionate (ER-FP) and exercise non-responder (ENR) asthmatics.

Fig 4: Serum Bb level pre- (Pre-Ex) and post- (post-Ex) exercise of control subjects, exercise responder without treatment (ER) and with fluticasone propionate (ER-FP) and exercise non-responder (ENR) asthmatics.:

Fig 4: Serum Bb level pre- (Pre-Ex) and post- (post-Ex) exercise of control subjects, exercise responder without treatment (ER) and with fluticasone propionate (ER-FP) and exercise non-responder (ENR) asthmatics.

Fig 5: Serum SC5b-9 level pre- (Pre-Ex) and post- (post-Ex) exercise of control subjects, exercise responder without treatment (ER) and with fluticasone propionate (ER-FP) and exercise non-responder (ENR) asthmatics.:

Fig 5: Serum SC5b-9 level pre- (Pre-Ex) and post- (post-Ex) exercise of control subjects, exercise responder without treatment (ER) and with fluticasone propionate (ER-FP) and exercise non-responder (ENR) asthmatics.

Effects of complement in bronchial asthma:

Effects of complement in bronchial asthma Complement receptors are highly expressed on mast cells and eosinophils. Allergen – challenged mice deficient in C3 exhibit diminished AW hyper-responsiveness and lung eosinophilia ( Drouin et al, 2001 ). Increased levels of C3a and C5a in BAL of asthmatics after allergen challenge ( Krug, 2001 ). The increased level correlated with the degree of eosinophilia.

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Effects of complement in bronchial asthma One mechanism by which complement can mediate inflammation is through recruitment of inflammatory cells as eosinophils ( DiScipio et al, 1999). Other effects: Mediator release. Smooth muscle contraction Mucus secretion by goblet cells. Exercise may induce a sort of inflammation that leads to activation of complement.

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Drouin SM, Corry DB, Kildsgaard J, Wetsel RA. The absence of C3 demonstrates a role for complement in Th2 effector functions in a murine model of pulmonary allergy. J Immunol. 2001;167:4141-4145. Krug N, Tschernig T, Erpenbeck VJ, Hohlfeld JM, Kohl J. Complement factors C3a and C5a are increased in bronchoalveolar lavage fluid after segmental allergen provocation in subjects with asthma. Am J Respir Crit Care Med. 2001;164:1841-1843. DiScipio RG, Daffern PJ, Jagels MA, Broide DH, Sriramarao P. A comparison of C3a- and C5a-mediated stable adhesion of rolling eosinophils in postcapillary venules and transendothelial migration in vitro and in vivo. J Immunol. 1999;162:1127-1136.

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Conclusion Complement activation through the alternative pathway i.e. non antigen – antibody dependent activation, plays a role in the pathogenesis of exercise – induced asthma. prevention of complement activation by ICS represents a further mechanism of the protective effect of CS against EIA.

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MANAGEMENT OF EIB RELIEF: Short acting beta-2 PREVENT: Anti-inflammatory agents -DSCG: Effective in acute and chronic use -CS: Effective in chronic use -LTRA: Effective in acute and chronic use. LABA

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REHABILITATION TRAINING PROGRAM (EL-AKKARY et al, ERS 2003) OBJECTIVE: The effect of 12-weeks rehabilitation training program on clinical severity and airway reactivity scores pulmonary function response to exercise challenge

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MATERIAL Number: 150 children with mild to moderate asthma. Age: 6 – 12 years. Mean ± SD: 9.35 ± 1.82 Sex: 62 (40%) F, 88 (60%) M Weight (Kg): 18 – 80 (36.71 ± 11.68) Height (cm): 109 – 167 (139 ± 10.96)

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CHARACTERISTICS OF ASTHMA Age of onset (Year): 1 – 10 (3.92 ± 2.58) Duration of asthma (Year): 1 – 11 (5.48 ± 2.67) Type of asthma: seasonal 65 (43%) perennial 11 (7.3%) peren +S ex 74 (50%) Family hist. Asthma: YES 125 (83%) NO 25 (17%)

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Other allergy than asthma: YES 103 (69%) NO 47 (31%) Asthma mainly during: DAY 7 (5%) NIGHT 103 (69%) BOTH 40 (26%) Severity of asthma: Mild 94 (63%) Moderate 56 (37%) CHARACTERISTICS OF ASTHMA

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METHODS: Severity of asthma disease: Clinical severity score Airway reactivity score Socio-economic questionnaire Pulmonary function tests: FVC, FEV 1 , FEV 1 /FVC%, FEF 25-75% EXERCISE CHALLENGE: ATS 2000 warm-up, unloaded exercise 2min At 50-60% of HR Max 2min At 75-80% of HR Max 2min At target heart rate (=85-90% HR Max ) for 5 – 6 min

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CONDUCTION OF REHABILITATION PROGRAM DURATION 12 weeks FREQUANCY 3 sessions per week (one in water) INTERVAL 45 min each session Type active exercises at heart rate of 60-75% HR Mx for 4-5 min followed by 3-4 min active rest MEDICINES step-down according to the condition of the children METHODS:

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Socio-economic state

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Socio-economic state

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Socio-economic state

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Socio-economic state

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Socio-economic state

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relation to Socio-economic state 10.71±0.69 (SE) 8.20±1.85 P=0.021

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relation to Socio-economic state 22.12±1.08 (SE) 17.60±2.93 P=0.003

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Before After Number +ve 59 13 (78%) %reduction FEV1 15.27 ± 12.15 5.8 ± 5.7

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Response to exercise % protection= 58.88 ± 34.23 50% or more protection in 43 cases out of the 59 (73%)

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RELATIONSHIP BETWEEN FEV 1 /FVC% AND THE RESPONSE TO EXERCISE (BEFORE PROGRAM)

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RELATIONSHIP BETWEEN FEV 1 FVC% AND THE RESPONSE TO EXERCISE (AFTER PROGRAM)

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STUDIES CONCERNING REHABILITATION OF EGYPTIAN ASTHMATIC CHILDREN ARE NOT AVAILABLE IN LITERATURE. FEW STUDIES ON NON-EGYPTIAN PATIENTS ARE AVAILABLE. comment

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Material: 26 adult, mild asthmatics PROGRAM: 10-week rehabilitation PROGRAM Results: 3 only of the 17 still have EIA after the PROGRAM (82%). Significant increase in FEV 1 after the PROGRAM. Conclusion: Mild asthmatic persons benefit from the rehabilitation program. Emtner et al, 1996 Chest: comment

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comment Hallsdtrand et al, chest 2000 Material: 5 adult, mild asthmatics PROGRAM: 10-week Results: -Non-significant change in FEV 1 -Significant improvement in the ventilatory capacity. Conclusion: Rehabilitation program improves the ventilatory capacity in mild adult asthmatic patients.

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Neder et al, Thorax 1999 comment Material: 24 boys (8 – 16 Y) with moderate severe asthma. Program: 8-week. Result: - Significant reduction in the medication score. - Significant reduction in the daily use of both inhaled and oral steroids. - Non-significant change in the clinical score and the occurrence of EIA. Conclusion: Moderate-severe asthmatic children benefit from rehabilitation program in the form of significant reduction of daily use of both the inhaled and oral steroids

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REHABILITATION TRAINING PROGRAM PRELIMINARY DATA (EL-AKKARY et al) The observed improvement may be due to: 1-Cardio-respiratory conditioning to exercise i.e. lower heart rate, lower oxygen consumption and lower ventilation in response to a given work load. 2-Actual improvement in bronchial hyper-responsiveness due to changes in response of - or depletion of vaso-active mediators as leukotrienes with the subsequent affection on the inflammatory reaction induced by exercise.

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REHABILITATION TRAINING PROGRAM PRELIMINARY DATA (EL-AKKARY et al) STUDY 1: OBJECTIVE: Determine whether the 12-weeks training program - induced improvement is due to conditioning to exercise or to changes in bronchial hyper-responsiveness. MATERIAL: 25 asthmatic children aged 6 – 12 years METHOD QOL, asthma severity, PF, exercise test, cardio respiratory responses to exercise, and MIC.

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REHABILITATION TRAINING PROGRAM PRELIMINARY DATA (EL-AKKARY et al) STUDY 2: OBJECTIVE: To test the hypothesis that the RTP – induced improvement of asthmatics may be related to alteration in the level and behavior of mediators as leukotrienes. MATERIAL 25 asthmatic children 6 – 12 years age. METHODS The level of a mixture of lt in the induced sputum at PRE-PROGRAM POST-PROGRAM REST EXERCISE TEST

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SUMMARY SOCIO-ECONOMIC STATE: There is a relation between the severity of asthma and the family size i.e. the greater the family size the less the severity of asthma. The greater the number of persons sharing the same bed the less the severity of asthma, The less the ventilation of the bedroom the more the severity of asthma.

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SUMMARY REHABILITATION PROGRAM RESULTS IN: Significant improvement of baseline pulmonary functions Significant improvement of both clinical severity and airway re-activity scores. Significant reduction of the severity and the incidence of EIB.

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CONCLUSION The mild – moderate asthmatic children benefit from the rehabilitation training program.

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RECOMMENDATION: Rehabilitation program is recommended to be used in clinical practice as a supplement to the conventional pharmacologic treatment of asthma.

CONTRIBUTORS:

CONTRIBUTORS Prof. Anisa El-Hefny Prof. I. El-Akkary Prof. Mervat El-Seweify Prof. Maha Ibrahim Prof. Sally Ghabour Dr. Wedad Ismail Ms. Marwa Ezzat Mr. Samy Ezzat Ms.Manal Aly Ms.Nessren Ashour Dr. Eiman Younis Ms. Sabrien Badr Mr. Showki El-Dakrori Grand monitor Principle investigator Faculty associate Faculty associate Faculty associate Training leader Trainer Trainer Trainer Trainer Practical assisting Technical assisting Administration and financial affairs

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THANK YOU