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Broadbent & Coutts: Graded vs Intermittent Exercise Effects on Lymphocytes in CFS

mango

Senior Member
Messages
905
Graded vs Intermittent Exercise Effects on Lymphocytes in Chronic Fatigue Syndrome.

Broadbent, Suzanne; Coutts, Rosanne
School of Health and Human Sciences, Southern Cross University, Lismore NSW, Australia

Abstract
Purpose
: There is increasing evidence of immune system dysfunction in Chronic Fatigue Syndrome (CFS) but little is known of the regular exercise effects on immune cell parameters. This pilot study investigated the effects of graded and intermittent exercise on CD4+ lymphocyte subset counts and activation compared to usual care.

Methods: 24 CFS patients (50.2 +/- 10 yr) were randomised to Graded exercise (GE), Intermittent exercise (IE) or usual care (UC) groups; 18 sedentary non-CFS participants (50.6 +/- 10 yr) were controls (CTL) for blood and immunological comparisons. Outcome measures were pre- and post-intervention flow cytometric analyses of circulating lymphocyte subset cell counts, expression of CD3+, CD4+, CD25+ and CD134+, full blood counts and V[Combining Dot Above]O2peak

Results: Pre-intervention, CD3+ cell counts and expression of CD4+, CD25+, CD134+ and CD4+CD25+CD134+ were significantly lower in GE, IE and UC compared to CTL (f < 0.05). Total lymphocyte concentration was significantly lower in GE and IE groups compared to CTL. There were significant post-intervention increases in (i) expression of CD4+ and CD4+CD25+CD134+ for GE and IE, but CD25+ and CD134+ for IE only; (ii) circulating counts of CD3+ and CD4+ for GE, and CD3+, CD4+, CD8+, CD3+CD4+CD8+, CD3-CD16+CD56+, CD19+ and CD45+ for IE; (iii) neutrophil concentration for GE; (iv) V[Combining Dot Above]O2peak and elapsed test time for IE and GE, V[Combining Dot Above]Epeak for IE.

Conclusions: Twelve weeks of GE and IE training significantly improved CD4+ lymphocyte activation and aerobic capacity without exacerbating CFS symptoms. IE may be a more effective exercise modality with regard to enhanced CD4+ activation in CFS patients.

(C) 2016 American College of Sports Medicine

http://journals.lww.com/acsm-msse/A...s_Intermittent_Exercise_Effects_on.97534.aspx
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
I want to know about cohort selection. These results are not consistent with other work we have seen on exercise and aerobic capacity. However this might be due to a very different definition and application of GE, we cannot be sure at this point. We also need to know how exacerbation effects on CFS were determined.
 

Effi

Senior Member
Messages
1,496
Location
Europe
And this is not S Broadbent's first rodeo. She has done other CFS research http://www.biomedcentral.com/2052-1847/5/16
That looks like it's the protocol they used for this study.
90 patients aged between 16 to 60 years, who meet the diagnostic criteria for CFS and have been diagnosed by their medical practitioner, will be randomly recruited into groups consisting of Intermittent exercise, Graded exercise and usual care (Control). The outcomes will be measured pre-study (Week 0) and post-study (Week 13). Primary outcomes are VO2peak, anaerobic threshold, peak power, levels of fatigue, immune cell (CD3+CD4+, CD3+CD8+, CD19+, CD 16+CD56+) concentrations and activation. Secondary outcomes include onset of secondary CFS symptoms (e.g. fever, swollen lymph nodes), wellness, mood and sleep patterns.
A medical diagnosis is made when three of the following criteria from the Centre for Disease Control and Prevention’s modified case definition of CFS, have been met 3]:

(1) The individual has had severe chronic fatigue for 6 or more consecutive months and the fatigue is not due to ongoing exertion or other medical conditions associated with fatigue (these other conditions need to be ruled out by a doctor after diagnostic tests have been conducted).

(2) The fatigue significantly interferes with daily activities and work.

(3) The individual concurrently has 4 or more of the following 8 symptoms: post-exertion malaise lasting more than 24 hours; unrefreshing sleep; significant impairment of short-term memory or concentration; muscle pain; pain in the joints without swelling or redness; headaches of a new type, pattern, or severity; tender lymph nodes in the neck or armpit; a sore throat that is frequent or recurring.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Issues:
1. Fukuda - risk of heterogeneity in cohort.
2. No 2 day CPET.
3. How many patients in the study got worse? They claim it was without exacerbation, but can someone who has seen the full paper please comment on what they measured and actually wrote.
 

user9876

Senior Member
Messages
4,556
I think there is a big issue around what would be natural variability in these measures. I think they have a sample of 8 patients in each group and if there were a degree of variability then this would simply be noise and it would be hard to detect a signal. This result could simply be random. It may depend on the size of the changes but they are not given in the abstract.

There are also issues as to how they measured compliance to an exercise program. I would have expected some sort of scale as exercised increased if their hypothesis is correct.

They also do a lot of different tests so it is not clear that they deal with this.

There controls seem poor - as I understand it and its not clear in the abstract - they use sedentary controls initially but not as part of an exercise program. Hence it is unclear as to whether this would be an expected increase due to activity or something interesting about the way the immune system of people with ME reacts to exercise.
 

Hutan

Senior Member
Messages
1,099
Location
New Zealand
Yes, @user9876, really good points.

To illustrate the variability in the small samples, the abstract tells us that prior to the treatments:
Total lymphocyte concentration was significantly lower in GE and IE groups compared to CTL
So, prior to the treatments, the CFS patients randomly allocated to the 'activity as usual' group had total lymphocyte concentrations that weren't significantly lower than the control group, whereas the CFS patients randomly allocated to the exercise groups did.
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
Yes, @user9876, really good points.

To illustrate the variability in the small samples, the abstract tells us that prior to the treatments:

So, prior to the treatments, the CFS patients randomly allocated to the 'activity as usual' group had total lymphocyte concentrations that weren't significantly lower than the control group, whereas the CFS patients randomly allocated to the exercise groups did.

I totally missed that on the first reading - no difference in lymphocyte concentration between the healthy controls and the "usual care" group before the intervention. I've never seen any reason why there would be a meaningful difference in total lymphocyte concentration though...

Also, comparing post-intervention increases is a bit weird, shouldn't they be comparing the difference between the "usual care" group as the control and the intervention groups?
 

user9876

Senior Member
Messages
4,556
I totally missed that on the first reading - no difference in lymphocyte concentration between the healthy controls and the "usual care" group before the intervention. I've never seen any reason why there would be a meaningful difference in total lymphocyte concentration though...

Also, comparing post-intervention increases is a bit weird, shouldn't they be comparing the difference between the "usual care" group as the control and the intervention groups?

I think it is very hard to tell what they are doing from the abstract but yes I think they should be comparing all the groups.
 

Seven7

Seven
Messages
3,444
Location
USA
We need to organize a BIG study w Dr Nell (the 2 day cpet guy forgot his name) and put all exercise theories to rest. I would donate to that one.
 

Dolphin

Senior Member
Messages
17,567
CFS patients usually show a range of physiological responses to exercise indicative of fatigue and deconditioning, such as reduced exercise capacity, early onset of anaerobic threshold, increased lactate responses during incremental exercise, abnormal heart rate responses and an altered perception of physical effort with higher rates of perceived exertion compared to controls (13,20,39).
Minor point:
There are other interpretations for some of the findings apart from deconditioning. But I suppose it is not unreasonable to mention it has one possible reason for some findings.
 

Dolphin

Senior Member
Messages
17,567
UC participants were asked to follow the advice of their medical practitioner (rest, maintaining activity for daily activities) and not to engage in any other physical activity during the study. The non-CFS sedentary CTL group were also asked to maintain their current physical activity levels during the study.
 

Dolphin

Senior Member
Messages
17,567
Exercise Interventions

The 12-week program consisted of either IE or GE using a spin cycle ergometer (Keiser M3i, USA). The exercise sessions were conducted at the Southern Cross University fitness facility, three times per week. All sessions were supervised by an accredited Exercise Physiologist (EP) and post-graduate clinical exercise physiology students. The workloads (W) were determined from the baseline O2peak cycle test for each participant. Each exercise session consisted of a 5 minute gentle warm up of unloaded cycling, initially followed by a 10 to 15 minute block of either GE (load equivalent to 50% O2peak, RPE 3), or IE, of one minute of moderate intensity cycling (60% O2peak, RPE 4-5) alternated with one minute of unloaded or very low intensity cycling (30% O2peak, RPE 1-2). Recommended cadence was between 50 and 70 RPM. Exercise sessions were progressed by increasing the duration of the session only as tolerated for each participant. The workload was not increased until participants had achieved three consecutive exercise sessions of 30 min in total with no increase in symptoms, and the increase was 10% of the current workload. If participants reported any increase in fatigue or other symptoms during or post-exercise, the exercise intensity was reduced until participants felt able to manage a progression. HR and BP were monitored before and after each exercise session; RPE for each session was also recorded.
This contrasts with the more traditional graded exercise therapy programs which are partly about breaking the link between symptoms and activity levels. With such programmes you are expected to maintain the level of exercise/activity if symptoms increase for 1 week or more.
 

Dolphin

Senior Member
Messages
17,567
Participants were requested to abstain from physical activity for 24 hours prior to the blood draws to reduce the likelihood of leukocyte perturbation. Blood samples were de-identified and numerically coded with pathology staff blinded to the study.
 

Dolphin

Senior Member
Messages
17,567
Intervention compliance for each participant was calculated as the number of completed exercise sessions divided by the 36 sessions of the intervention; scores were totalled and expressed as a percentage.
Compliance and attrition Intervention compliance was 89% with the reasons for missing sessions including illness, joint pain, family and work commitments. Two participants from the GE group and one from the UC group withdrew from the study at six and two weeks respectively due to time constraints. Intention to treat process was followed for this data.

The success of the intervention may be due to ensuring that participants were not pushed to exercise at their set intensity on days when they were feeling more symptomatic; they were encouraged to either rest or reduce their duration and intensity of exercise if they felt more fatigued. Only three participants actually mentioned occasions where fatigue, joint pain or illness occurred that affected their ability to exercise during the 12 weeks. They either rested at home, on average for 2 days, or had their exercise levels decreased until such time as they felt better. They stated that symptoms were not due to the demands of the exercise intervention but to life stressors or illnesses circulating in the general community. Some previous GE and APT studies found that the exercise worsened CFS symptoms (34,42), possibly because participants felt they had to keep exercising at the same level even when they felt ill. There has been considerable robust discussion regarding the merits of GE/APT for CFS, but we can support previous studies where GE provided positive outcomes for individuals with no worsening of symptoms (15,16,21,39). Another contributing factor to the success of our interventions was that the participants were supervised by trained clinical exercise professionals who carefully monitored performance and symptoms, and who could reduce exercise intensity and duration if necessary.
The rates of compliance were high. However it is unclear to me whether the figure of 89% includes the people who withdrew.
 

Dolphin

Senior Member
Messages
17,567
Time since diagnosis for CFS participants was 2.9 ± 2.6 yr. Pre-intervention self-reported fatigue severity scores ranged between 15.8% (very low) to 100% (severe).
 

Dolphin

Senior Member
Messages
17,567
The pre-intervention GE, IE and UC mean fatigue severity scores were 84.5 ± 16.6%, 71.6 ± 23.7% and 85.1 ± 10.8% respectively (no difference between groups, P = 0.80), indicating high fatigue severity. The post-intervention GE, IE and UC mean fatigue severity scores were still high, (84.1 ± 14.1%, 73.1 ± 17.6%, 87.5 ± 10.1% respectively) with no significant difference between the groups (P = 0.75).
These findings were not mentioned in the abstract.

Interestingly, the self-reported fatigue severity in our cohort remained unchanged through the study, a similar finding to that of Karper and Stasik (2003) (21). The fatigue severity scores reflected the participants‟ perception of fatigue and tiredness, and the degree of fatigue-related impairment of daily activities, sleep, memory and cognition experienced. The fact that fatigue remained relatively unchanged for 12 weeks could indicate the need to trial a longer exercise intervention for participants to experience reduced tiredness or changes in their perception of fatigue and impairment. What is important is that despite their perceived fatigue, the participants were still able to gain physiological benefits without exacerbating their CFS symptoms.
 
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Dolphin

Senior Member
Messages
17,567
I have minimal knowledge of the immune system. One thing I noticed is that some of the immune measurements post the exercise programmes are a lot higher than those in the healthy controls. Increases are portrayed as a good thing but I wonder whether in any of these cases the now apparently high increases could be problematic?
 

Dolphin

Senior Member
Messages
17,567
Apparent increases in CD45+, CD8+ and B lymphocytes, and neutrophils, with exercise training sound promising but the results should be interpreted with caution because the group sizes were small, and because the assays did not measure cell activation and function. Therefore we cannot determine whether the increased cell counts correlated with enhanced cell function. The most likely explanation of the results is that regular exercise increased the recruitment of these cells into circulation through increased blood flow and shear stress, and release of catecholamines and chemokines (40), resulting in sustained higher circulating cell numbers. Although the exercise intervention intensities were relatively moderate, it is possible that training at 50% O2peak in the GE group was a sufficiently high stimulus for cortisol production, which would increase the release of neutrophils from bone marrow (40). The CFS participants had low exercise capacities, and even moderate-intensity exercise may have caused physiological stress resulting in cortisol release in the GE group. The reasons for increases in some lymphocyte subset cell counts in the IE group are less clear, and may be due to within-group variability. However, regular exercise training can increase CD3- CD16+CD56+ and CD45+ cell counts in general circulation, due to increased shear stress, and exercise-induced down-regulation of adhesion molecule expression (40). It is not clear whether a greater mobilization of CD3-CD16+CD56+ lymphocytes represents more activated cells and an enhanced ability to fight infection (6,40). Early exercise intervention studies with healthy adults reported modest increases in CD3-CD16+CD56+ cell counts after moderate-intensity training compared to sedentary controls, but other studies found conflicting results (40); it is unknown whether these findings are applicable to CFS individuals. Further research into the exercise effects on specific activation markers of lymphocyte subsets is warranted and would be more useful than measuring cell counts alone.
 

Dolphin

Senior Member
Messages
17,567
Consistent with other studies, we found that GE significantly increased aerobic capacity after 12 weeks (16,39,42). IE also significantly increased aerobic capacity, suggesting that the intermittent modality was as effective as GE in stimulating peripheral physiological adaptations (31). This is an important finding for CFS individuals because alternating periods of rest/lowintensity exercise may be also be more manageable in terms of symptoms which are usually a limiting factor in exercise participation (39).