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Two-day cardiopulmonary exercise test
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==Evidence== [[Mark VanNess]], [[Christopher Snell]] and [[Staci Stevens]] of the University of the Pacific, Stockton, CA, were the first to study the two-day CPET procedure in patients with ME/CFS. In a 2007 study published in the [[Journal of Chronic Fatigue Syndrome]], they compared six ME/CFS patients with six controls. At the first CPET there were no major differences between the two groups. At the second CPET however, ME/CFS patients reached significantly lower peak [[oxygen]] consumption (VO2Peak) and oxygen consumption at aerobic threshold.<ref name=":4">{{Cite journal | last = Vanness | first=J. Mark | last2 = Snell | first2 = Christopher R. | last3 = Stevens | first3=Staci R. | date = Jan 2007 | title = Diminished Cardiopulmonary Capacity During Post-Exertional Malaise|url=https://www.tandfonline.com/doi/abs/10.1300/J092v14n02_07|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=14|issue=2 | pages = 77–85|doi=10.1300/j092v14n02_07|issn=1057-3321}}</ref> In 2010, a Dutch research group including Ruud Vermeulen and [[Frans Visser]] used the 2-day CPET in a study with 15 female ME/CFS and 15 healthy controls. Patients reached the aerobic threshold and the maximal exercise at much lower oxygen consumption than controls, an effect that was magnified during the second-day exercise test. Since levels of creatine kinase in the blood and oxidative phosphorylation in mononuclear cells were normal in patients before and after exercise, Vermeulen et al. speculated that the lowered anaerobic threshold was not so much a result of [[mitochondrion|mitochondrial]] insufficiency, but of impaired oxygen transport to the [[Muscle|muscles]].<ref>{{Cite journal | last = Vermeulen | first = Ruud C. W. | last2 = Kurk | first2 = Ruud M. | last3 = Visser | first3=Frans C. | last4 = Sluiter | first4=Wim | last5 = Scholte | first5 = Hans R. | date = 2010-10-11 | title = Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity|url=https://www.ncbi.nlm.nih.gov/pubmed/20937116|journal=Journal of Translational Medicine|volume=8 | pages = 93|doi=10.1186/1479-5876-8-93|issn=1479-5876|pmc=2964609|pmid=20937116}}</ref> In 2013, [[Christopher Snell|Snell]], [[Staci Stevens|Stevens]] and [[Mark VanNess|VanNess]] tested the 2-day CPET procedure in a larger sample of 51 ME/CFS patients and 10 healthy controls. Once again, there were no sufficient differences between the groups at the first CPET. During the exercise test on the second day however, ME/CFS patients showed much lower oxygen consumption and workload at peak exercise and at aerobic threshold. Group differences were not due to lack of effort since most participants attained the ventilatory threshold and achieved a respiratory exchange ratio of greater than or equal to 1.1.<ref name=":0">{{Cite journal | last =Snell | first = C. R. | last2 = Stevens | first2 = S.R. | last3 = Davenport | first3=T.E. | last4 = Van Ness | first4=J.M. | date=2013-06-27 | title = Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome|url=https://academic.oup.com/ptj/article/93/11/1484/2735315|journal=Physical Therapy|language=en|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=0031-9023}}</ref> In 2014, the research group of [[Betsy Keller]] used the 2-day CPET protocol in a study involving 22 ME/CVS patient. A decline on several physiological measures was found (see table), while the respiratory exchange ratio indicated maximum efforts by participants during both exercise tests.<ref name=":1">{{Cite journal | last = Keller | first=Betsy A. | last2 = Pryor | first2=John Luke | last3 = Giloteaux | first3 = Ludovic | date = 2014-04-23 | title = Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO₂peak indicates functional impairment|url=https://www.ncbi.nlm.nih.gov/pubmed/24755065|journal=Journal of Translational Medicine|volume=12|pages=104|doi=10.1186/1479-5876-12-104|issn=1479-5876|pmc=4004422|pmid=24755065}}</ref> This group followed this research up with a study of a single pair of monozygotic twins in 2016.<ref>{{Cite journal | title = A Pair of Identical Twins Discordant for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Differ in Physiological Parameters and Gut Microbiome Composition|url=http://www.amjcaserep.com/abstract/index/idArt/900314|journal=American Journal of Case Reports | date = 2016-10-10|issn=1941-5923|pmc = 5058431|pmid=27721367 | pages = 720–729|volume=17|doi=10.12659/AJCR.900314|language=en | first = Ludovic | last =Giloteaux | first2 = Maureen R. | last2 = Hanson | first3=Betsy A. | last3 = Keller}}</ref> {| class="wikitable" ! colspan="8" |Physiological changes between first and second exercise test during 2-day CPET procedure in patients with ME/CFS (bold indicates statistical significance) |- | |Number of ME/CFS patients |VO2 peak |VO2 at VT |Workload peak |Workload at VT |HR peak |O2pulse at VT |- |VanNess et al. 2007. |6 |'''-22%''' |'''-26%''' |? |? |? |? |- |Vermeulen et al. 2010. |15 |'''-6.3%''' |'''-7.0%''' |'''-5.3%''' |'''-7.0%''' |<nowiki>-1.9%</nowiki> |'''-8.8%''' |- |Snell et al. 2013. |51 | -5% |'''-10.8%''' |'''-7.2%''' |'''-55.2%''' |? |? |- |Keller et al. 2014. |22 |'''-13.8%''' |'''-15.8%''' |'''-12.5%''' |'''-21.3%''' |'''-5.9%''' |'''-12.6%''' |- |Giloteaux et al. 2016. |1 (monozygotic twin) |0% | -13.4% |0% | -25% | +7.4% | -19% (calculated) |- |Hodges et al. 2017. |10 |<nowiki>+5.3%</nowiki> |<nowiki>+6.1%</nowiki> |<nowiki>-6.7%</nowiki> |'''-11.4%''' |<nowiki>-0.6%</nowiki> | +7% (calculated) |- |Nelson et al. 2019. |16 | +0.4% | -3.1% | -1.2% |'''-17.4%''' | -0.5% | +2% (calculated) |- |Lien et al. 2019. (numerical estimates) |18 | -5% | -6% | -2% |'''-7%''' | +1.5% |? |- |van Campen 2020.A (males) |25 |'''-10%''' |'''-22%''' |'''-10%''' |'''-30%''' |'''-5%''' | -16% (calculated) |- |van Campen 2020.B (females) |31 ("mild" cases) |'''-6%''' |'''-21%''' |'''-10%''' |'''-26%''' | -3% |? |- |van Campen 2020.B (females) |31 ("moderate" cases) |'''-11%''' |'''-21%''' |'''-16%''' |'''-31%''' | -6% |? |- |van Campen 2020.B (females) |20 ("severe" cases) |'''-12%''' |'''-19%''' |'''-19%''' |'''-33%''' | -7% |? |- |Davenport 2020. |51 | -5% | -10% | -9% |'''-11%''' | -3% | -7% (calculated) |- |van Campen 2021. (males) |25 |'''-12%''' |'''-27%''' |'''-10%''' |'''-27%''' | -7% | -17% (calculated) |- |van Campen 2021. (females) |50 |'''-10%''' |'''-23%''' |'''-11%''' |'''-30%''' | -4% | -15% (calculated) |} In 2017, a research team form [[New Zealand]] compared the physiological responses during a 2-day CPET, in ten patients with ME/CFS, seven patients with [[Multiple sclerosis|Multiple Sclerosis]] (MS) and seventeen healthy controls. Curiously peak oxygen increased at the second exercise test in ME/CFS patients, but there was a significant reduction noticeable in workload at aerobic threshold, a decline that was not seen in MS-patients or healthy controls. According to the authors: <blockquote>“differences between MS and CFS/ME responses only became evident after a second maximal exercise test, thus suggesting that a repeated protocol is required to not only distinguish CFS/ME from HC, but also from other fatigue-related conditions, who may not suffer from post-exertional malaise and have a differing delayed fatigue profile.”<ref name=":3">{{Cite journal | last =Hodges | first = L. D. | last2 = Nielsen | first2=T. | last3 = Baken | first3= D. | date = Jul 2018 | title = Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/28782878|journal=Clinical Physiology and Functional Imaging|volume=38|issue=4|pages=639–644|doi=10.1111/cpf.12460|issn=1475-097X|pmid=28782878}}</ref></blockquote>In 2019 the 2-day CPET procedure was tested by an Australian research team of Nelson and colleagues. They found a significant larger reduction in workload at the ventilatory threshold in patients with ME/CFS compared to healthy controls. A percentage change of −6.3% to −9.8% provided good sensitivity and specificity, indicating this test has the potential to become a biomarker for ME/CFS. However, the sample size of this study was small (16 ME/CFS patients), the control group consisted only of healthy persons (instead of patients with other chronic illnesses) and no significant difference was found in VO2 at the ventilatory threshold.<ref>{{Cite journal | last =Nelson | first = Maximillian J. | last2 = Buckley | first2 = Jonathan D. | last3 = Thomson | first3=Rebecca L. | last4 = Clark | first4 = Daniel | last5 = Kwiatek | first5 = Richard | last6 = Davison | first6 = Kade | date = 2019-03-14 | title = Diagnostic sensitivity of 2-day cardiopulmonary exercise testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://doi.org/10.1186/s12967-019-1836-0|journal=Journal of Translational Medicine|volume=17|issue=1 | pages = 80|doi=10.1186/s12967-019-1836-0|issn=1479-5876|pmc = 6417168|pmid=30871578}}</ref> A Norwegian study published in 2019 also reported a significant larger reduction in workload at the ventilatory threshold in 18 patients with ME/CFS compared to healthy controls, although this was not the case for peak values or VO2 measurement at the ventilatory threshold. The authors also measured arterial lactate concentrations, every 30 seconds during the exercise tests. Lactate was higher per power output per kg in patients than controls and the differences increased significantly at the second exercise test. In the healthy controls lactate concentration at the ventilatory threshold decreased while this was not the case in ME/CFS patients, suggesting a problem in lactate clearance ability.<ref>{{Cite journal | last =Lien | first = Katarina | last2 = Johansen | first2=Bjørn | last3 = Veierød | first3=Marit B. | last4 = Haslestad | first4=Annicke S. | last5 = Bøhn | first5 = Siv K. | last6 = Melsom | first6 = Morten N. | last7 = Kardel | first7 = Kristin R. | last8 = Iversen | first8 = Per O. | date = 2019 | title=Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome|url=https://physoc.onlinelibrary.wiley.com/doi/abs/10.14814/phy2.14138|journal=Physiological Reports|language=en|volume=7|issue=11| pages = e14138|doi=10.14814/phy2.14138|issn=2051-817X}}</ref> Researchers from the Workwell Foundation published in 2019, a case series of six women, who underwent the 2-day CPET. This study compared two healthy participants, one active, the other sedentary, two ME/CFS patients, one high functioning with high VO2peak, another with low VO2Peak, with a patient suffering from [[HIV/AIDS|human immunodeficiency virus]] (HIV) and another suffering from [[Multiple sclerosis|MS]].<ref>{{Cite journal | last =Larson | first = Benjamin | last2 = Davenport | first2=Todd E. | last3 = Stevens | first3=Staci R. | last4 = Stevens | first4=Jared | last5 = Van Ness | first5 = J. Mark | last6 = Snell | first6 = Christopher R. | date = Oct 2019 | title = Reproducibility of Measurements Obtained During Cardiopulmonary Exercise Testing in Individuals With Fatiguing Health Conditions: A Case Series|url=http://insights.ovid.com/crossref?an=01823246-201910000-00004|journal=Cardiopulmonary Physical Therapy Journal|language=en|volume=30|issue=4|pages=145–152|doi=10.1097/CPT.0000000000000100|issn=1541-7891|pmc=|pmid= | author-link = | author-link2 = Todd Davenport|access-date= | author-link3 = Staci Stevens | authorlink4 = | authorlink5 = Mark VanNess | authorlink6 = Christopher Snell|via=}}</ref> The healthy participants and the MS patient reproduced or improved their exercise parameters, namely VO2, workload, heart-rate and minute ventilation at both the ventilatory threshold and peak exercise. The HIV patient reproduced all of these findings except peak workload and peak minute ventilation. The ME/CFS patients were unable to reproduce VO2, workload, heart rate or minute ventilation at the ventilatory threshold. These results continue to suggest that the inability to reproduce workload at the ventilatory threshold is specific to ME/CFS patients, but patients with other fatiguing conditions will need to be tested to confirm this. This study was followed up in 2020 with 51 patients and 10 controls, focusing on additional statistical analysis and discussing the meaning of test-retest reliability in the context of ME/CFS. The main positive finding was a significant group*test (difference) in work rate at the ventilatory threshold. <ref>{{Cite journal | last =Davenport | first=Todd E. | last2 = Stevens | first2 = Staci R. | last3 = Stevens | first3=M. A. Jared | last4 = Snell | first4 = Christopher R. | last5 = Van Ness | first5 = J. Mark | date = 2020-06-16 | title = Properties of measurements obtained during cardiopulmonary exercise testing in individuals with myalgic encephalomyelitis/chronic fatigue syndrome|url=https://www.medra.org/servlet/aliasResolver?alias=iospress&doi=10.3233/WOR-203170 | journal = Work | pages=1–10|doi=10.3233/WOR-203170}}</ref> In 2020, researchers from Stichting Cardio Zorg, a cardiology clinic in the Netherlands published two studies of clinical 2-day CPET results for ME/CFS patients with exercise intolerance. The first study consisted of male patients, to see whether the results from previous studies which had predominantly female patients would be replicated.<ref>{{Cite journal | last =van Campen | first = C. (Linda) M. C. | last2 = Rowe | first2 = Peter C. | last3 = Visser | first3=Frans C. | date = 2020 | title=Validity of 2-Day Cardiopulmonary Exercise Testing in Male Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.scirp.org/journal/doi.aspx?doi=10.4236/ape.2020.101007|journal=Advances in Physical Education|volume=10|issue=01|pages=68–80|doi=10.4236/ape.2020.101007|issn=2164-0386}}</ref> A second study focused on female patients with differing severity, which were subgrouped according to: “Symptom severity impact must result in a 50% or greater reduction in a patient’s premorbid activity level for a diagnosis of ME. Mild: approximately 50% reduction in activity, moderate: mostly housebound, severe: mostly bedbound and very severe: bedbound and dependent on help for physical functions”.<ref>{{Cite journal | last =van Campen | first = C (Linda) MC | last2 = Rowe | first2 = Peter C. | last3 = Visser | first3=Frans C. | date = 2020-06-30 | title = Two-Day Cardiopulmonary Exercise Testing in Females with a Severe Grade of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Comparison with Patients with Mild and Moderate Disease|url=https://www.mdpi.com/2227-9032/8/3/192|journal=Healthcare|language=en|volume=8|issue=3|pages=192|doi=10.3390/healthcare8030192|issn=2227-9032}}</ref> This research was followed up in 2021 with a retrospective clinical comparison between 26 male idiopathic chronic fatigue (ICF) cases who did not suffer from PEM and 25 male ME/CFS patients who satisfied the 2011 ME International Consensus Criteria and the 1994 Center for Disease Control criteria for CFS. <ref name=":6">{{Cite journal | last =van Campen | first = C. (Linda) M. C. | last2 = Visser | first2=Frans C. | date = Jun 2021 | title = Comparing Idiopathic Chronic Fatigue and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Males: Response to Two-Day Cardiopulmonary Exercise Testing Protocol|url=https://www.mdpi.com/2227-9032/9/6/683|journal=Healthcare|language=en|volume=9|issue=6|pages=683|doi=10.3390/healthcare9060683|pmc=|pmid=|quote= | author-link = Linda van Campen | authorlink2 = Frans Visser|access-date=|via=}}</ref> Notably, most ME/CFS patients had a decline in VO2 and workload performance at peak and the ventilatory threshold on the second day, compared to all idiopathic chronic fatigue cases who were able to match or exceed their first day performance. The authors concluded that this decline in performance on the second day was disease-specific.<ref name=":6" /> A related comparison was performed for female patients with similar results.<ref>{{Cite journal | last =van Campen | first = C. (Linda) M. C. | last2 = Visser | first2=Frans C. | date = Jun 2021 | title = Female Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Idiopathic Chronic Fatigue: Comparison of Responses to a Two-Day Cardiopulmonary Exercise Testing Protocol|url=https://www.mdpi.com/2227-9032/9/6/682|journal=Healthcare|language=en|volume=9|issue=6|pages=682|doi=10.3390/healthcare9060682|pmc=|pmid=|quote= | author-link = Linda van Campen | authorlink2 = Frans Visser|access-date=|via=}}</ref> However there were several ICF patients that also had a reduction in peak workload and workload at the ventilatory threshold, despite the overall trend for an increase for ICF patients and a decrease for ME/CFS patients. Unpublished studies have reported negative results for the repeated CPET procedure. In her thesis, Tessa-Maree Nielsen<ref>Nielsen TM. [https://mro.massey.ac.nz/bitstream/handle/10179/14653/02_whole.pdf?sequence=2&isAllowed=y The Timeline of Post Exertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. 2018.]</ref> at the Massey University, [[New Zealand]], performed the second exercise test 48 hours and 72 hours later, instead of the usual 24 hours. The study did not find significant reductions of workload at the ventilatory threshold in ME/CFS patients compared to controls. The eight ME/CFS patients in the 72 hours group had a workload at ventilatory threshold that was slightly higher instead of lower than during the first test. In a 2018 presentation,<ref>[https://www.youtube.com/watch?v=xpyz9K62Izg Presentation Ruud Vermeulen (03-06-2018). Minute 34.00.]</ref> Ruud Vermeulen reported to have data on approximately 500 ME/CFS patients who performed the repeated CPET procedure. He stated the test on the second day did not show any difference in VO2max compared to the first day, as shown in the graphs he presented. Two-Day CPET studies have also considered other clinical groups, including [[Gulf War Illness|Gulf-War-Syndrome]]<ref>{{Cite journal | last =Lindheimer | first=Jacob B. | last2 = Alexander | first2=Thomas | last3 = Qian | first3=Wei | last4 = Klein‐Adams | first4=Jacquelyn C. | last5 = Lange | first5 = Gudrun | last6 = H. Natelson | first6 = Benjamin | last7 = Cook | first7 = Dane B. | last8 = Hill | first8 = Helene Z. | last9 = Falvo | first9 = Michael J. | date = Sep 2020 | title = An analysis of 2‐day cardiopulmonary exercise testing to assess unexplained fatigue|url=https://onlinelibrary.wiley.com/doi/abs/10.14814/phy2.14564|journal=Physiological Reports|language=en|volume=8|issue=17|doi=10.14814/phy2.14564|pmid=32889791|pages=|quote=|access-date= | author-link3 = | authorlink4 = | authorlink5 = Gudrun Lange | authorlink6 = Benjamin Natelson|via=|pmc= | authorlink7 = Dane Cook}}</ref> and Sarcoidosis.<ref>{{Cite journal | last =Braam | first = A.W.E. | last2 = de Haan | first2 = S.N. | last3 = Vorselaars | first3=A.D.M. | last4 = Rijkers | first4=G.T. | last5 = Grutters | first5 = J.C. | last6 = van den Elshout | first6 = F.J.J. | last7 = Korenromp | first7 = I.H.E. | date = Oct 2013 | title = Influence of repeated maximal exercise testing on biomarkers and fatigue in sarcoidosis|url=https://linkinghub.elsevier.com/retrieve/pii/S0889159113001967|journal=Brain, Behavior, and Immunity|language=en|volume=33|pages=57–64|doi=10.1016/j.bbi.2013.05.006|issue=|pmc=|pmid=|quote=|access-date=|via=}}</ref> The study of Gulf-War-Syndrome patients did not reveal any significant group by time effects and in particular, no time effects at VT1. The study of Sarcoidosis patients did not find any group by time effects, however they focused on peak performance and ignored differences in performance at sub-maximal thresholds such as VT1. In addition, the study of Sarcoidosis patients did find an exercise effect on several biomarkers, however changes in these markers were not related to self-reported fatigue. A 2023 conference abstract examined preliminary data from 2-day CPETs of LongCOVID patients <ref>{{cite journal |last1= Stringer | first1 = William |last2= Heffernan |first2= Carly |date= Oct 2023 |title=UTILITY OF 2-DAY CARDIOPULMONARY EXERCISE TESTING PROTOCOL IN LONG-HAUL COVID (LHC) PATIENTS: PRELIMINARY DATA |url=https://journal.chestnet.org/article/S0012-3692(23)04762-1/fulltext |journal=Chest|doi=10.1016/j.chest.2023.07.3724}}</ref> and found there was no difference in peak workrate and peak VO2 relative to day one. However the key finding across all ME/CFS studies is a reduction in workrate at VT1, and it is uncertain if that study analysed such data.
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