{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T23:04:54Z","timestamp":1784761494368,"version":"3.55.0"},"reference-count":52,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004564","name":"Ministry of Education, Science, and Technological Development of the Republic of Serbia","doi-asserted-by":"crossref","award":["451-03-68\/2020-14\/200156"],"award-info":[{"award-number":["451-03-68\/2020-14\/200156"]}],"id":[{"id":"10.13039\/501100004564","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100016047","name":"Science Fund of the Republic of Serbia","doi-asserted-by":"crossref","award":["COVANSA"],"award-info":[{"award-number":["COVANSA"]}],"id":[{"id":"10.13039\/501100016047","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Autonomic nervous system (ANS) dysfunction has emerged as a central feature of post-infectious syndromes, including post-COVID syndrome (PCS), chronic fatigue syndrome (CFS), and late-stage Lyme disease. This cross-sectional study included 1036 patients evaluated in the Neurocardiological Laboratory of the Institute for Cardiovascular Diseases \u201cDedinje,\u201d divided into four groups: PCS, CFS after COVID-19, CFS of insidious onset, and Lyme disease. All patients underwent head-up tilt testing (HUTT), and serological testing was performed in accredited institutions. The Lyme disease group demonstrated the highest prevalence of positive HUTT responses and a significantly greater frequency of orthostatic hypotension and syncope. Approximately 50\u201365% of patients in the PCS and Lyme groups were positive for IgM antibodies against at least one microorganism, with more than 10% showing positivity for three or more pathogens. Logistic regression analysis revealed that, beyond classical hemodynamic parameters, antibody status served as a significant predictor of HUTT outcomes, with specific associations identified for HSV-1, HHV-6, Coxiella burnetii, Toxoplasma gondii, and Borrelia spp. Multinomial regression further indicated that negative IgG antibodies, particularly to HSV-1 and VZV, predicted Lyme disease group membership. These findings support the hypothesis that ANS dysfunction in post-infectious syndromes may be driven by persistent or prior infections, highlighting the need for integrative diagnostic approaches.<\/jats:p>","DOI":"10.3390\/v17111430","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T13:59:36Z","timestamp":1761659976000},"page":"1430","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Relationship Between Hemodynamic Responses During Head-Up Tilt Testing and Parameters of Infection in Post-COVID Syndrome, Chronic Fatigue Syndrome, and Late-Stage Lyme Disease"],"prefix":"10.3390","volume":"17","author":[{"given":"Branislav","family":"Milovanovic","sequence":"first","affiliation":[{"name":"Institute for Cardiovascular Diseases \u201cDedinje\u201d, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5090-6029","authenticated-orcid":false,"given":"Nikola","family":"Markovic","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Diseases \u201cDedinje\u201d, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1709-8449","authenticated-orcid":false,"given":"Masa","family":"Petrovic","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Diseases \u201cDedinje\u201d, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smiljana","family":"Stojanovic","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Diseases \u201cDedinje\u201d, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasko","family":"Zugic","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Diseases \u201cDedinje\u201d, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milijana","family":"Ostojic","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Diseases \u201cDedinje\u201d, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milovan","family":"Bojic","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Diseases \u201cDedinje\u201d, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,28]]},"reference":[{"key":"ref_1","unstructured":"Daroff, R.B., Jankovic, J., Mazziotta, J.C., Pomeroy, S.L., and Bradley, W.G. (2016). Bradley\u2019s Neurology in Clinical Practice, Elsevier."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/0735-1097(91)90714-K","article-title":"Methodology of head-up tilt testing in patients with unexplained syncope","volume":"17","author":"Fitzpatrick","year":"1991","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1136\/bmj.285.6346.916","article-title":"Diagnosis and management of diabetic autonomic neuropathy","volume":"285","author":"Ewing","year":"1982","journal-title":"Br. Med. J. (Clin. Res. Ed.)"},{"key":"ref_4","first-page":"e2502","article-title":"Quantitative autonomic testing","volume":"53","author":"Novak","year":"2011","journal-title":"J. Vis. Exp."},{"key":"ref_5","first-page":"226","article-title":"Quantitative Scale for Grading of Cardiovascular Autonomic Reflex Tests and Small Fibers from Skin Biopsies (QASAT)","volume":"3","author":"Novak","year":"2015","journal-title":"J. Neurol. Disord."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.mayocp.2012.10.013","article-title":"COMPASS 31: A refined and abbreviated Composite Autonomic Symptom Score","volume":"87","author":"Sletten","year":"2012","journal-title":"Mayo Clin. Proc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1212\/WNL.0b013e3182120147","article-title":"Assessing autonomic dysfunction in early diabetic neuropathy: The Survey of Autonomic Symptoms","volume":"76","author":"Zilliox","year":"2011","journal-title":"Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Shaffer, F., and Ginsberg, J.P. (2017). An Overview of Heart Rate Variability Metrics and Norms. Front. Public Health, 5.","DOI":"10.3389\/fpubh.2017.00258"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"814","DOI":"10.36660\/abc.20200420","article-title":"Dysautonomia: A Forgotten Condition\u2014Part 1","volume":"116","author":"Rocha","year":"2021","journal-title":"Arq. Bras. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.ncl.2022.08.002","article-title":"Dysautonomia: Diagnosis and Management","volume":"41","author":"Hovaguimian","year":"2023","journal-title":"Neurol. Clin."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0306-9877(03)00331-1","article-title":"Dysautonomia in chronic fatigue syndrome: Facts, hypotheses, implications","volume":"62","author":"Naschitz","year":"2004","journal-title":"Med. Hypotheses"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Nicolini, P., Ciulla, M.M., Malfatto, G., Abbate, C., Mari, D., Rossi, P.D., Pettenuzzo, E., Magrini, F., Consonni, D., and Lombardi, F. (2014). Autonomic dysfunction in mild cognitive impairment: Evidence from power spectral analysis of heart rate variability in a cross-sectional case-control study. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096656"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/ana.25807","article-title":"COVID-19: A Global Threat to the Nervous System","volume":"88","author":"Koralnik","year":"2020","journal-title":"Ann. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.pmr.2023.04.003","article-title":"Autonomic Dysfunction Related to Postacute SARS-CoV-2 Syndrome","volume":"34","author":"Haloot","year":"2023","journal-title":"Phys. Med. Rehabil. Clin. N. Am."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"S\u0142omko, J., Est\u00e9vez-L\u00f3pez, F., Kujawski, S., Zawadka-Kunikowska, M., Tafil-Klawe, M., Klawe, J.J., Morten, K.J., Szrajda, J., Murovska, M., and Newton, J.L. (2020). Autonomic Phenotypes in Chronic Fatigue Syndrome (CFS) Are Associated with Illness Severity: A Cluster Analysis. J. Clin. Med., 9.","DOI":"10.3390\/jcm9082531"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/neurolint15010001","article-title":"ME\/CFS and Post-Exertional Malaise among Patients with Long COVID","volume":"15","author":"Jason","year":"2023","journal-title":"Neurol. Int."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Chu, L., Valencia, I.J., Garvert, D.W., and Montoya, J.G. (2019). Onset patterns and course of myalgic encephalomyelitis\/chronic fatigue syndrome. Front. Pediatr., 7.","DOI":"10.3389\/fped.2019.00012"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wong, T.L., and Weitzer, D.J. (2021). Long COVID and Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome (ME\/CFS)\u2014A Systemic Review and Comparison of Clinical Presentation and Symptomatology. Medicina, 57.","DOI":"10.3390\/medicina57050418"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Shor, S., Green, C., Szantyr, B., Phillips, S., Liegner, K., Burrascano, J.J., Bransfield, R., and Maloney, E.L. (2019). Chronic Lyme Disease: An Evidence-Based Definition by the ILADS Working Group. Antibiotics, 8.","DOI":"10.3390\/antibiotics8040269"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Adler, B.L., Chung, T., Rowe, P.C., and Aucott, J. (2024). Dysautonomia following Lyme disease: A key component of post-treatment Lyme disease syndrome?. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1344862"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1111\/anec.12158","article-title":"A tale of two syndromes: Lyme disease preceding postural orthostatic tachycardia syndrome","volume":"20","author":"Noyes","year":"2015","journal-title":"Ann. Noninvasive Electrocardiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"158","DOI":"10.2174\/1874205X01206010158","article-title":"Chronic Lyme Disease and Co-infections: Differential Diagnosis","volume":"6","author":"Berghoff","year":"2012","journal-title":"Open Neurol. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"108427","DOI":"10.1016\/j.clim.2020.108427","article-title":"COVID-19 pathophysiology: A review","volume":"215","author":"Yuki","year":"2020","journal-title":"Clin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Tian, S., Chang, Z., Wang, Y., Wu, M., Zhang, W., Zhou, G., Zou, X., Tian, H., Xiao, T., and Xing, J. (2020). Clinical characteristics and reasons for differences in duration from symptom onset to release from quarantine among patients with COVID-19 in Liaocheng, China. Front. Med., 7.","DOI":"10.3389\/fmed.2020.00210"},{"key":"ref_25","unstructured":"National Institute for Health and Care Excellence (2021). Myalgic Encephalomyelitis (or Encephalopathy)\/Chronic Fatigue Syndrome: Diagnosis and Management, National Institute for Health and Care Excellence (NICE). Available online: https:\/\/www.nice.org.uk\/guidance\/ng206."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"102828","DOI":"10.1016\/j.autneu.2021.102828","article-title":"Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Institutes of Health Expert Consensus Meeting\u2014Part 1","volume":"235","author":"Vernino","year":"2021","journal-title":"Auton. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1093\/eurheartj\/ehy037","article-title":"2018 ESC guidelines for the diagnosis and management of syncope","volume":"39","author":"Brignole","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e23","DOI":"10.1016\/j.jemermed.2023.04.002","article-title":"SYNCOPE: A RARE PRESENTATION OF LYME DISEASE","volume":"65","author":"Pence","year":"2023","journal-title":"J. Emerg. Med."},{"key":"ref_29","first-page":"e49803","article-title":"Third-Degree Atrioventricular Block Secondary to Lyme Disease: A Case Report","volume":"15","author":"Ivey","year":"2023","journal-title":"Cureus"},{"key":"ref_30","unstructured":"Jameson, J.L., Fauci, A., Kasper, D., Hauser, S., Longo, D., and Loscalzo, J. (2017). Harrison\u2019s Principles of Internal Medicine 19th Edition and Harrison\u2019s Manual of Medicine 19th Edition VAL PAK, McGraw-Hill Medical."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/joa3.13001","article-title":"Postural orthostatic tachycardia syndrome and other autonomic dysfunctions following COVID-19: Incidence, characteristics, and associated factors","volume":"40","author":"Tanking","year":"2024","journal-title":"J. Arrhythm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/S0002-9343(00)00704-X","article-title":"Chronic fatigue syndrome symptoms common in patient with vasovagal syncope","volume":"110","author":"Kenny","year":"2001","journal-title":"Am. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1001\/jama.1995.03530120053041","article-title":"The relationship between neurally mediated hypotension and the chronic fatigue syndrome","volume":"274","author":"Rowe","year":"1995","journal-title":"JAMA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s10286-002-0014-1","article-title":"Hemodynamic and neurohumoral responses to head-up tilt in patients with chronic fatigue syndrome","volume":"12","author":"Timmers","year":"2002","journal-title":"Clin. Auton. Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"van Campen, C.M.C., and Visser, F.C. (2022). Orthostatic Intolerance in Long-Haul COVID after SARS-CoV-2: A Case-Control Comparison with Post-EBV and Insidious-Onset Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome Patients. Healthcare, 10.","DOI":"10.3390\/healthcare10102058"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1093\/europace\/eup338","article-title":"Blood pressure oscillations during tilt testing as a predictive marker of vasovagal syncope","volume":"11","author":"Hausenloy","year":"2009","journal-title":"Europace"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.cnp.2020.01.003","article-title":"Cerebral blood flow is reduced in ME\/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography","volume":"5","author":"Verheugt","year":"2020","journal-title":"Clin. Neurophysiol. Pract."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jns.2010.11.018","article-title":"Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling","volume":"301","author":"Biswal","year":"2011","journal-title":"J. Neurol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.nicl.2012.12.006","article-title":"Cerebral vascular control is associated with skeletal muscle pH in chronic fatigue syndrome patients both at rest and during dynamic stimulation","volume":"2","author":"He","year":"2013","journal-title":"Neuroimage Clin."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1068000","DOI":"10.1155\/2023\/1068000","article-title":"Epstein Barr Virus Reactivation during COVID-19 Hospitalization Significantly Increased Mortality\/Death in SARS-CoV-2(+)\/EBV(+) than SARS-CoV-2(+)\/EBV(\u2212) Patients: A Comparative Meta-Analysis","volume":"2023","author":"Manoharan","year":"2023","journal-title":"Int. J. Clin. Pract."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Milovanovic, B., Djajic, V., Bajic, D., Djokovic, A., Krajnovic, T., Jovanovic, S., Verhaz, A., Kovacevic, P., and Ostojic, M. (2021). Assessment of Autonomic Nervous System Dysfunction in the Early Phase of Infection With SARS-CoV-2 Virus. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.640835"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Vojdani, A., Vojdani, E., Saidara, E., and Maes, M. (2023). Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID. Viruses, 15.","DOI":"10.3390\/v15020400"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1136\/bmj.38933.585764.AE","article-title":"Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: Prospective cohort study","volume":"333","author":"Hickie","year":"2006","journal-title":"BMJ"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Gravelsina, S., Vilmane, A., Svirskis, S., Rasa-Dzelzkaleja, S., Nora-Krukle, Z., Vecvagare, K., Krumina, A., Leineman, I., Shoenfeld, Y., and Murovska, M. (2022). Biomarkers in the diagnostic algorithm of myalgic encephalomyelitis\/chronic fatigue syndrome. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.928945"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"102253","DOI":"10.1016\/j.ttbdis.2023.102253","article-title":"Enteroviral central nervous system infections in patients with Lyme neuroborreliosis","volume":"14","author":"Perlejewski","year":"2023","journal-title":"Ticks Tick Borne Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"66","DOI":"10.3121\/cmr.2018.1419","article-title":"Infectious Mononucleosis and Lyme Disease as Confounding Diagnoses: A Report of 2 Cases","volume":"16","author":"Koester","year":"2018","journal-title":"Clin. Med. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1080\/0036554021000026972","article-title":"Activation of latent Lyme borreliosis concurrent with a herpes simplex virus type 1 infection","volume":"34","author":"Gylfe","year":"2002","journal-title":"Scand. J. Infect. Dis."},{"key":"ref_48","first-page":"e60213","article-title":"Diagnostic Challenges of Lyme Co-infections: Lessons From a Lyme and Herpes Simplex Virus-1 (HSV-1) Cocktail","volume":"16","author":"Bhatia","year":"2024","journal-title":"Cureus"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Hannestad, U., Apostolou, E., Sj\u00f6gren, P., Brag\u00e9e, B., Polo, O., Bertilson, B.C., and Ros\u00e9n, A. (2023). Post-COVID sequelae effect in chronic fatigue syndrome: SARS-CoV-2 triggers latent adenovirus in the oral mucosa. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1208181"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Ch\u00e9mali, K., and Sandefer, A. (2022). Mycoplasma pneumoniae infection associated with autoimmune small fiber neuropathy and postural orthostatic tachycardia syndrome (POTS) (P18-1.007). Neurology, 98.","DOI":"10.1212\/WNL.98.18_supplement.3892"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/BF01314882","article-title":"Herpes simplex virus infection of isolated autonomic neurons in culture: Viral replication and spread in a neuronal network","volume":"71","author":"Price","year":"1982","journal-title":"Arch. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/257686a0","article-title":"Latent infection of the peripheral ANS with herpes simplex virus","volume":"257","author":"Price","year":"1975","journal-title":"Nature"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/11\/1430\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T05:20:20Z","timestamp":1761801620000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/11\/1430"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,28]]},"references-count":52,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["v17111430"],"URL":"https:\/\/doi.org\/10.3390\/v17111430","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,28]]}}}