Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Post-COVID dysautonomias: what we know and (mainly) what we don’t know

Nature Reviews Neurology volume 20, pages 99–113 (2024)Cite this article

Subjects

Abstract

Following on from the COVID-19 pandemic is another worldwide public health challenge that is referred to variously as long COVID, post-COVID syndrome or post-acute sequelae of SARS-CoV-2 infection (PASC). PASC comes in many forms and affects all body organs. This heterogeneous presentation suggests involvement of the autonomic nervous system (ANS), which has numerous roles in the maintenance of homeostasis and coordination of responses to various stressors. Thus far, studies of ANS dysregulation in people with PASC have been largely observational and descriptive, based on symptom inventories or objective but indirect measures of cardiovascular function, and have paid little attention to the adrenomedullary, hormonal and enteric nervous components of the ANS. Such investigations do not consider the syndromic nature of autonomic dysfunction. This Review provides an update on the literature relating to ANS abnormalities in people with post-COVID syndrome and presents a theoretical perspective on how the ANS might participate in common features of PASC.

Key points

  • The diverse nature of post-COVID syndrome suggests involvement of the autonomic nervous system (ANS), which plays numerous roles in homeostasis and coordinates responses to essentially all stressors.

  • The ANS concept was promulgated before the discoveries of neuroendocrine systems, immune and inflammatory systems, and the central autonomic network; the extended autonomic system theory is a necessary update.

  • Publications on post-COVID dysautonomias have not considered the syndromic nature of autonomic dysfunctions.

  • Such studies have been largely observational and descriptive, based on symptom inventories or objective but indirect cardiovascular measures; the hormonal and enteric components of the ANS have generally been ignored.

  • Understanding of multisystem disorders of regulation, such as post-COVID syndrome, requires a shift towards consideration of the feedback-regulated, plastic networks that, via the extended autonomic system, determine homeostasis and allostasis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Components and chemical messengers of the autonomic nervous system.
Fig. 2: Organization of the autonomic nervous system in the body and some dysautonomia syndromes.
Fig. 3: Evidence of PASC.
Fig. 4: The extended autonomic system.
Fig. 5: Mechanisms that might link features of post-COVID syndrome to the extended autonomic system.

Similar content being viewed by others

References

  1. Anand, H. et al. Nervous system-systemic crosstalk in SARS-CoV-2/COVID-19: a unique dyshomeostasis syndrome. Front. Neurosci. 15, 727060 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Nagai, M., Kato, M. & Keigo, D. Anxiety and hypertension in the COVID-19 era: how is the central autonomic network linked? Hypertens. Res. 45, 922–923 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Goldstein, D. S. Stress and the “extended” autonomic system. Auton. Neurosci. 236, 102889 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Goldstein, D. S. Adrenaline and the Inner World: An Introduction to Scientific Integrative Medicine (Johns Hopkins University Press, 2006).

  5. Davis, H. E., McCorkell, L., Vogel, J. M. & Topol, E. J. Long COVID: major findings, mechanisms and recommendations. Nat. Rev. Microbiol. 21, 133–146 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Langley, J. N. The autonomic nervous system. Brain 26, 1–26 (1903).

    Article  Google Scholar 

  7. Cannon, W. B. & de la Paz, D. Emotional stimulation of adrenal gland secretion. Am. J. Physiol. 28, 64–70 (1911).

    Article  CAS  Google Scholar 

  8. Dale, H. H. & Feldberg, W. The chemical transmission of secretory impulses to the sweat glands of the cat. J. Physiol. 82, 121–128 (1934).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. von Euler, U. S. A specific sympathomimetic ergone in adrenergic nerve fibres (sympathin) and its relations to adrenaline and noradrenaline. Acta Physiol. Scand. 12, 73–96 (1946).

    Article  Google Scholar 

  10. Goldstein, D. S. Principles of Autonomic Medicine v. 4.0 https://research.ninds.nih.gov/staff-directory/david-s-goldstein-md-phd (2020).

  11. Goldstein, D. S. et al. Sympathoadrenal imbalance before neurocardiogenic syncope. Am. J. Cardiol. 91, 53–58 (2003).

    Article  PubMed  Google Scholar 

  12. Wallin, B. G. & Sundlof, G. Sympathetic outflow to muscles during vasovagal syncope. J. Auton. Nerv. Syst. 6, 287–291 (1982).

    Article  CAS  PubMed  Google Scholar 

  13. Meck, J. V. et al. Mechanisms of postspaceflight orthostatic hypotension: low α1-adrenergic receptor responses before flight and central autonomic dysregulation postflight. Am. J. Physiol. Heart Circ. Physiol. 286, H1486–H1495 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Davis, H. E. et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine 38, 101019 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Erdal, Y. et al. Autonomic dysfunction in patients with COVID-19. Acta Neurol. Belg. 122, 885–891 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Goldstein, D. S. The possible association between COVID-19 and postural tachycardia syndrome. Heart Rhythm. 18, 508–509 (2021).

    Article  PubMed  Google Scholar 

  17. Miglis, M. G., Stiles, L. E. & Raj, S. R. POTS may be underestimated in Post-COVID assessments. J. Am. Coll. Cardiol. 80, e103 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Raj, S. R. et al. Long-COVID postural tachycardia syndrome: an American Autonomic Society statement. Clin. Auton. Res. 31, 365–368 (2021).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  19. Stahlberg, M. et al. Post-COVID-19 tachycardia syndrome: a distinct phenotype of post-acute COVID-19 syndrome. Am. J. Med. 134, 1451–1456 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ormiston, C. K., Swiatkiewicz, I. & Taub, P. R. Postural orthostatic tachycardia syndrome as a sequela of COVID-19. Heart Rhythm. 19, 1880–1889 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Mallick, D. et al. COVID-19 induced postural orthostatic tachycardia syndrome (POTS): a review. Cureus 15, e36955 (2023).

    PubMed  PubMed Central  Google Scholar 

  22. Miglis, M. G. et al. A case report of postural tachycardia syndrome after COVID-19. Clin. Auton. Res. 30, 449–451 (2020).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  23. Blitshteyn, S. & Whitelaw, S. Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID-19 infection: a case series of 20 patients. Immunol. Res. 69, 205–211 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gall, N. P., James, S. & Kavi, L. Observational case series of postural tachycardia syndrome (PoTS) in post-COVID-19 patients. Br. J. Cardiol. 29, 3 (2022).

    PubMed  PubMed Central  Google Scholar 

  25. Johansson, M. et al. Long-haul post-COVID-19 symptoms presenting as a variant of postural orthostatic tachycardia syndrome. The Swedish experience. J. Am. Coll. Cardiol. Case Rep. 3, 573–580 (2021).

    Google Scholar 

  26. Parker, W. H. et al. COVID-19 and postural tachycardia syndrome: a case series. Eur. Heart J. Case Rep. 5, ytab325 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Bosco, J. & Titano, R. Severe post-COVID-19 dysautonomia: a case report. BMC Infect. Dis. 22, 214 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Drogalis-Kim, D., Kramer, C. & Duran, S. Ongoing dizziness following acute COVID-19 infection: a single center pediatric case series. Pediatrics 150, e2022056860 (2022).

    Article  PubMed  Google Scholar 

  29. Hanson, J., Richley, M., Hsu, J. J., Lin, J. & Afshar, Y. Postural orthostatic tachycardia syndrome and orthostatic hypotension in post-acute sequelae of COVID-19 during pregnancy: a case report. Eur. Heart J. Case Rep. 6, ytac453 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Fanciulli, A. et al. Impact of the COVID-19 pandemic on clinical autonomic practice in Europe. A survey of the European Academy of Neurology (EAN) and the European Federation of Autonomic Societies (EFAS). Eur. J. Neurol. https://doi.org/10.1111/ene.15787 (2023).

  31. Seeley, M. C., Gallagher, C., Langdon, A., Ong, E. & Lau, D. H. Postural orthostatic tachycardia syndrome is prevalent in postacute sequela of COVID-19? Clin. Auton. Res. 32, 368 (2022).

    Google Scholar 

  32. Varma-Doyle, A., Freeman, R., Mandeville, R. & Gibbons, C. Neuromuscular and autonomic features in Long COVID-19: a single-center retrospective review of clinical and objective findings. Clin. Auton. Res. 32, 370 (2022).

    Google Scholar 

  33. Hastie, C. E. et al. Outcomes among confirmed cases and a matched comparison group in the Long-COVID in Scotland study. Nat. Commun. 13, 5663 (2022).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sharma, V., Pattnaik, S., Ahluwalia, H. & Kaur, M. Pre-pandemic autonomic function as a predictor of the COVID clinical course in young adults. Clin. Exp. Pharmacol. Physiol. 87, 594–603 (2023).

    Article  Google Scholar 

  35. Sletten, D. M., Suarez, G. A., Low, P. A., Mandrekar, J. & Singer, W. COMPASS 31: a refined and abbreviated composite autonomic symptom score. Mayo Clin. Proc. 87, 1196–1201 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Buoite Stella, A. et al. Autonomic dysfunction in post-COVID patients with and without neurological symptoms: a prospective multidomain observational study. J. Neurol. 269, 587–596 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Eldokla, A. M. et al. Prevalence and patterns of symptoms of dysautonomia in patients with long-COVID syndrome: a cross-sectional study. Ann. Clin. Transl. Neurol. 9, 778–785 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ser, M. H. et al. Autonomic and neuropathic complaints of long-COVID objectified: an investigation from electrophysiological perspective. Neurol. Sci. 43, 6167–6177 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Larsen, N. W. et al. Characterization of autonomic symptom burden in long COVID: a global survey of 2,314 adults. Front. Neurol. 13, 1012668 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Rinaldi, L. et al. Incidence of post-COVID-19 autonomic syndrome in working-age patients within 6 months from hospital discharge. Clin. Auton. Res. 32, 367 (2022).

    Google Scholar 

  41. Bryarly, M., Cabrera, J., Tarpara, K., Barshikar, S. & Vernino, S. Minimal objective autonomic dysfunction in long-COVID. Clin. Auton. Res. 32, 362 (2022).

    Google Scholar 

  42. Jamal, S. M. et al. Prospective evaluation of autonomic dysfunction in post-acute sequela of COVID-19. J. Am. Coll. Cardiol. 79, 2325–2330 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Oakley, J. C. & Hendrickson, R. C. Central and peripheral hyperadrenergic symptoms significantly contribute to symptom burden in people with post-acute sequela of COVID-19. Clin. Auton. Res. 32, 366 (2022).

    Google Scholar 

  44. Townsend, L. et al. Fatigue following COVID-19 infection is not associated with autonomic dysfunction. PLoS One 16, e0247280 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chung, T. H. & Azar, A. Autonomic nerve involvement in post-acute sequelae of SARS-CoV-2 syndrome (PASC). J. Clin. Med. 12, 73 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Shouman, K. et al. Autonomic dysfunction following COVID-19 infection: an early experience. Clin. Auton. Res. 31, 385–394 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Low, P. A. Autonomic nervous system function. J. Clin. Neurophysiol. 10, 14–27 (1993).

    Article  CAS  PubMed  Google Scholar 

  48. Acanfora, D. et al. Impaired vagal activity in long-COVID-19 patients. Viruses 14, 1035 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Asarcikli, L. D. et al. Heart rate variability and cardiac autonomic functions in post-COVID period. J. Interv. Cardiovasc. Electrophysiol. 63, 715–721 (2022).

    Article  Google Scholar 

  50. Marques, K. C. et al. Reduction of cardiac autonomic modulation and increased sympathetic activity by heart rate variability in patients with long COVID. Front. Cardiovasc. Med. 9, 862001 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Menezes Junior, A. D. S., Schroder, A. A., Botelho, S. M. & Resende, A. L. Cardiac autonomic function in long COVID-19 using heart rate variability: an observational cross-sectional study. J. Clin. Med. 12, 100 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Mohammadian, M. & Golchoobian, R. Potential autonomic nervous system dysfunction in COVID-19 patients detected by heart rate variability is a sign of SARS-CoV-2 neurotropic features. Mol. Biol. Rep. 49, 8131–8137 (2022).

    Article  CAS  PubMed  Google Scholar 

  53. Shah, B. et al. Heart rate variability as a marker of cardiovascular dysautonomia in post-COVID-19 syndrome using artificial intelligence. Indian Pacing Electrophysiol. J. 22, 70–76 (2022).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  54. Solinski, M. et al. Heart rate variability comparison between young males after 4-6 weeks from the end of SARS-CoV-2 infection and controls. Sci. Rep. 12, 8832 (2022).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wekenborg, M. K., Schwerdtfeger, A., Aust, F. & Verkuil, B. High-frequency variability in heart rate is related to COVID-19-associated worries six years later. Biol. Psychol. 173, 108404 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Salem, A. M. et al. Post-acute effect of SARS-CoV-2 infection on the cardiac autonomic function. Int. J. Gen. Med. 15, 7593–7603 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Kurtoglu, E. et al. Altered cardiac autonomic function after recovery from COVID-19. Ann. Noninvasive Electrocardiol. 27, e12916 (2022).

    Article  PubMed  Google Scholar 

  58. Skow, R. J. et al. Impact of COVID-19 on cardiac autonomic function in healthy young adults: potential role of symptomatology and time since diagnosis. Am. J. Physiol. Heart Circ. Physiol. 323, H1206–H1211 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mina, Y. et al. Deep phenotyping of neurologic postacute sequelae of SARS-CoV-2 infection. Neurol. Neuroimmunol. Neuroinflamm. 10, e200097 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Stute, N. L. et al. COVID-19 is getting on our nerves: sympathetic neural activity and haemodynamics in young adults recovering from SARS-CoV-2. J. Physiol. 599, 4269–4285 (2021).

    Article  CAS  PubMed  Google Scholar 

  61. Aranyo, J. et al. Inappropriate sinus tachycardia in post-COVID-19 syndrome. Sci. Rep. 12, 298 (2022).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  62. Liviero, F. et al. Persistent increase of sympathetic activity in post-acute COVID-19 of paucisymptomatic healthcare workers. Int. J. Environ. Res. Public Health 20, 830 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Dell’Acqua, C., Mura, F., Messerotti Benvenuti, S., Patron, E. & Palomba, D. Reduced heart rate variability and expressive suppression interact to prospectively predict COVID-19 pandemic-related post-traumatic stress symptoms. Sci. Rep. 12, 21311 (2022).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  64. Oikonomou, E. et al. Impaired left ventricular deformation and ventricular-arterial coupling in post-COVID-19: association with autonomic dysregulation. Heart Vessel. 38, 381–393 (2023).

    Article  Google Scholar 

  65. Chan, J., Senior, H., Homitz, J., Cashin, N. & Guers, J. J. Individuals with a previous symptomatic COVID-19 infection have altered heart rate and blood pressure variability during acute exercise. Front. Physiol. 14, 1052369 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Goldstein, D. S. & Cheshire, W. P. Jr Beat-to-beat blood pressure and heart rate responses to the Valsalva maneuver. Clin. Auton. Res. 27, 361–367 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Barizien, N. et al. Clinical characterization of dysautonomia in long COVID-19 patients. Sci. Rep. 11, 14042 (2021).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bristow, J. D., Gribbin, B., Honour, A. J., Pickering, T. G. & Sleight, P. Diminished baroreflex sensitivity in high blood pressure and ageing man. J. Physiol. 202, 45P–46P (1969).

    CAS  PubMed  Google Scholar 

  69. Mortara, A. et al. Arterial baroreflex modulation of heart rate in chronic heart failure: clinical and hemodynamic correlates and prognostic implications. Circulation 96, 3450–3458 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Virtanen, R. et al. Anxiety and hostility are associated with reduced baroreflex sensitivity and increased beat-to-beat blood pressure variability. Psychosom. Med. 65, 751–756 (2003).

    Article  PubMed  Google Scholar 

  71. Norcliffe-Kaufmann, L. et al. Autonomic findings in takotsubo cardiomyopathy. Am. J. Cardiol. 117, 206–213 (2016).

    Article  PubMed  Google Scholar 

  72. Elkholey, K. et al. Post-COVID-19 afferent baroreflex failure. Hypertension 80, 895–900 (2023).

    Article  CAS  PubMed  Google Scholar 

  73. Kingwell, B. A. et al. Heart rate spectral analysis, cardiac norepinephrine spillover, and muscle sympathetic nerve activity during human sympathetic nervous activation and failure. Circulation 90, 234–240 (1994).

    Article  CAS  PubMed  Google Scholar 

  74. Goldstein, D. S., Bentho, O., Park, M. Y. & Sharabi, Y. Low-frequency power of heart rate variability is not a measure of cardiac sympathetic tone but may be a measure of modulation of cardiac autonomic outflows by baroreflexes. Exp. Physiol. 96, 1255–1261 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Moak, J. P. et al. Supine low-frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation. Cleve. Clin. J. Med. 76, S51–S59 (2009).

    Article  PubMed  Google Scholar 

  76. Rahman, F., Pechnik, S., Gross, D., Sewell, L. & Goldstein, D. S. Low frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation. Clin. Auton. Res. 21, 133–141 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Sleight, P. et al. Physiology and pathophysiology of heart rate and blood pressure variability in humans: is power spectral analysis largely an index of baroreflex gain? Clin. Sci. 88, 103–109 (1995).

    Article  CAS  Google Scholar 

  78. Duan, Y. F., Kopin, I. J. & Goldstein, D. S. Stimulation of the paraventricular nucleus modulates firing of neurons in the nucleus of the solitary tract. Am. J. Physiol. 277, R403–R411 (1999).

    CAS  PubMed  Google Scholar 

  79. Jimeno-Almazan, A., Pallares, J. G., Buendia-Romero, A., Martinez-Cava, A. & Courel-Ibanez, J. Chronotropic incompetence in non-hospitalized patients with post-COVID-19 syndrome. J. Clin. Med. 10, 5434 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Inanc, I. H. & Sabanoglu, C. Autonomic dysfunction and metabolic disorders as the possible sequelae of COVID-19 infection. Eur. Rev. Med. Pharmacol. Sci. 26, 5587–5595 (2022).

    CAS  PubMed  Google Scholar 

  81. Zanoli, L. et al. Vascular dysfunction of COVID-19 is partially reverted in the long-term. Circ. Res. 130, 1276–1285 (2022).

    Article  CAS  PubMed  Google Scholar 

  82. Nandadeva, D. et al. Cardiovascular and cerebral vascular health in females with postacute sequelae of COVID-19. Am. J. Physiol. Heart Circ. Physiol. 324, H713–H720 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Chadwick, R. S., Goldstein, D. S. & Keiser, H. R. Pulse-wave model of brachial arterial pressure modulation in aging and hypertension. Am. J. Physiol. 251, H1–H11 (1986).

    CAS  PubMed  Google Scholar 

  84. Gonzalez-Hermosillo, G. J. et al. Exaggerated blood pressure elevation in response to orthostatic challenge, a post-acute sequelae of SARS-CoV-2 infection (PASC) after hospitalization. Auton. Neurosci. 247, 103094 (2023).

    Article  Google Scholar 

  85. Haffke, M. et al. Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS). J. Transl. Med. 20, 138 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Serviente, C., Decker, S. T. & Layec, G. From heart to muscle: pathophysiological mechanisms underlying long-term physical sequelae from SARS-CoV-2 infection. J. Appl. Physiol. 132, 581–592 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Araujo, C. et al. Endothelial function, arterial stiffness and heart rate variability of patients with cardiovascular diseases hospitalized due to COVID-19. Heart Lung 58, 210–216 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Mejia-Renteria, H. et al. In-vivo evidence of systemic endothelial vascular dysfunction in COVID-19. Int. J. Cardiol. 345, 153–155 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Sykes, R. A. et al. Vascular mechanisms of post-COVID-19 conditions: rho-kinase is a novel target for therapy. Eur. Heart J. Cardiovasc. Pharmacother. 9, 371–386 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Varma-Doyle, A., Villemarette-Pittman, N. R., Lelorier, P. & England, J. Demonstrating new-onset or worsened sudomotor function post-COVID-19 on comparative analysis of autonomic function pre-and post-SARS-CoV-2 infection. eNeurologicalSci 30, 100445 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Bocci, T. et al. Not myopathic, but autonomic changes in patients with long-COVID syndrome: a case series. Neurol. Sci. 44, 1147–1153 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Papadopoulou, M. et al. Autonomic dysfunction in long-COVID syndrome: a neurophysiological and neurosonology study. J. Neurol. 269, 4611–4612 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Esposito, G. et al. Can the enteric nervous system be an alternative entrance door in SARS-CoV2 neuroinvasion. Brain Behav. Immun. 87, 93–94 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Deffner, F. et al. Histological evidence for the enteric nervous system and the choroid plexus as alternative routes of neuroinvasion by SARS-CoV2. Front. Neuroanat. 14, 596439 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gray-Rodriguez, S. et al. Multisystem screening reveals SARS-CoV-2 in neurons of the myenteric plexus and in megakaryocytes. J. Pathol. 257, 198–217 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Clerbaux, L. A. et al. Gut as an alternative entry route for SARS-CoV-2: current evidence and uncertainties of productive enteric infection in COVID-19. J. Clin. Med. 11, 5691 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Jammoul, M. et al. Investigating the possible mechanisms of autonomic dysfunction post-COVID-19. Auton. Neurosci. 245, 103071 (2023).

    Article  PubMed  Google Scholar 

  98. Novak, P. et al. Network autonomic analysis of post-acute sequelae of COVID-19 and postural tachycardia syndrome. Neurol. Sci. 43, 6627–6638 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Jacob, G. et al. The neuropathic postural tachycardia syndrome. N. Engl. J. Med. 343, 1008–1014 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Agnihotri, S. P., Luis, C. V. S. & Kazamel, M. Autonomic neuropathy as post-acute sequela of SARS-CoV-2 infection: a case report. J. Neurovirol. 28, 158–161 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Vogel, E. R., Sandroni, P. & Low, P. A. Blood pressure recovery from Valsalva maneuver in patients with autonomic failure. Neurology 65, 1533–1537 (2005).

    Article  PubMed  Google Scholar 

  102. Novak, P. et al. Multisystem involvement in post-acute sequelae of coronavirus disease 19. Ann. Neurol. 91, 367–379 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Novak, P. QASAT-quantitative scale for grading cerebral blood flow, autonomic testing, and skin biopsies. Neurol. Sci. 43, 4821–4828 (2022).

    Article  PubMed  Google Scholar 

  104. Marks, D. F. Converging evidence of similar symptomatology of ME/CFS and PASC indicating multisystemic dyshomeostasis. Biomedicines 11, 180 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Wirth, K. J. & Scheibenbogen, C. Dyspnea in post-COVID syndrome following mild acute COVID-19 infections: potential causes and consequences for a therapeutic approach. Medicina 58, 419 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Yong, S. J. & Liu, S. Proposed subtypes of post-COVID-19 syndrome (or long-COVID) and their respective potential therapies. Rev. Med. Virol. 32, e2315 (2022).

    Article  CAS  PubMed  Google Scholar 

  107. Astin, R. et al. Long COVID: mechanisms, risk factors and recovery. Exp. Physiol. 108, 12–27 (2023).

    Article  PubMed  Google Scholar 

  108. Ryabkova, V. A., Gavrilova, N. Y., Fedotkina, T. V., Churilov, L. P. & Shoenfeld, Y. Myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID Syndrome: a common neuroimmune ground? Diagnostics 13, 66 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Sherif, Z. A. et al. Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC). eLife 12, e86002 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Mahroum, N. & Shoenfeld, Y. Autoimmune autonomic dysfunction syndromes: potential involvement and pathophysiology related to complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant-related symptoms and post-COVID syndrome. Pathophysiology 29, 414–425 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Malkova, A. M. & Shoenfeld, Y. Autoimmune autonomic nervous system imbalance and conditions: chronic fatigue syndrome, fibromyalgia, silicone breast implants, COVID and post-COVID syndrome, sick building syndrome, post-orthostatic tachycardia syndrome, autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants. Autoimmun. Rev. 22, 103230 (2023).

    Article  CAS  PubMed  Google Scholar 

  112. Sotzny, F. et al. Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in post COVID syndrome correlate with symptom severity. Front. Immunol. 13, 981532 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Chang, P. C., Grossman, E., Kopin, I. J. & Goldstein, D. S. On the existence of functional β-adrenoceptors on vascular sympathetic nerve endings in the human forearm. J. Hypertens. 12, 681–690 (1994).

    Article  CAS  PubMed  Google Scholar 

  114. Grossman, E., Chang, P. C., Hoffman, A., Tamrat, M. & Goldstein, D. S. Evidence for functional α2-adrenoceptors on vascular sympathetic nerve endings in the human forearm. Circ. Res. 69, 887–897 (1991).

    Article  CAS  PubMed  Google Scholar 

  115. Augustin, M. et al. Immunological fingerprint in coronavirus disease-19 convalescents with and without post-COVID syndrome. Front. Med. 10, 1129288 (2023).

    Article  Google Scholar 

  116. Ginty, A. T. et al. Heart rate reactivity to acute psychological stress predicts higher levels of PTSD symptoms during the COVID-19 pandemic. Psychosom. Med. 83, 351–357 (2021).

    Article  CAS  PubMed  Google Scholar 

  117. Gordon, I. et al. Pre-pandemic autonomic nervous system activity predicts mood regulation expectancies during COVID-19 in Israel. Psychophysiology 58, e13910 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Novak, P. Post COVID-19 syndrome associated with orthostatic cerebral hypoperfusion syndrome, small fiber neuropathy and benefit of immunotherapy: a case report. eNeurologicalSci 21, 100276 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Biswas, S. et al. COVID-19 induced Miller Fisher syndrome presenting with autonomic dysfunction: a unique case report and review of literature. Neurohospitalist 12, 111–116 (2022).

    Article  PubMed  Google Scholar 

  120. Younger, D. S. Post-acute sequelae of SARS-CoV-2 infection (PASC): peripheral, autonomic, and central nervous system features in a child. Neurol. Sci. 42, 3959–3963 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Suresh, K., Alam, M. D. U. & Satkovich, E. COVID-19-associated dysautonomia. Cureus 13, e17156 (2021).

    PubMed  PubMed Central  Google Scholar 

  122. Desai, A. D. et al. Autonomic dysfunction post-acute COVID-19. Infect. Heart Rhythm. Case Rep. 8, 143–146 (2022).

    Google Scholar 

  123. Dani, M. et al. Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies. Clin. Med. 8, e63–e67 (2020).

    Google Scholar 

  124. Messinger-Rapport, B. & Grubb, B. Patient-centered paradigm for managing autonomic long COVID symptoms during sports and exercise. Clin. J. Sport Med. 33, e14–e15 (2023).

    Article  PubMed  Google Scholar 

  125. Wright, J., Astill, S. L. & Sivan, M. The relationship between physical activity and long COVID: a cross-sectional study. Int. J. Environ. Res. Public Health 19, 5093 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Corrado, J. et al. HEART rate variability biofeedback for long COVID symptoms (HEARTLOC): protocol for a feasibility study. BMJ Open. 12, e066044 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Tracey, K. J. Physiology and immunology of the cholinergic antiinflammatory pathway. J. Clin. Invest. 117, 289–296 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Correa, F. I. et al. Transcutaneous auricular vagus nerve stimulation improves inflammation but does not interfere with cardiac modulation and clinical symptoms of individuals with COVID-19: a randomized clinical trial. Life 12, 1644 (2022).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  129. Uehara, L. et al. Transcutaneous auricular vagus nerve stimulation effects on inflammatory markers and clinical evolution of patients with COVID-19: a pilot randomized clinical trial. Exp. Rev. Med. Devices 19, 915–920 (2022).

    Article  CAS  Google Scholar 

  130. Zolotovskaia, I. A., Shatskaia, P. R., Davydkin, I. L. & Shavlovskaya, O. A. Post-COVID-19 asthenic syndrome. Neurosci. Behav. Physiol. 52, 191–195 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Chauhan, G., Upadhyay, A., Khanduja, S. & Emerick, T. Stellate ganglion block for anosmia and dysgeusia due to long COVID. Cureus 14, e27779 (2022).

    PubMed  PubMed Central  Google Scholar 

  132. Khan, M. H., Kirkpatrick, K. P., Deng, Y. & Shah, K. B. Stellate ganglion block for long COVID symptom management: a case report. Cureus 14, e32295 (2022).

    PubMed  PubMed Central  Google Scholar 

  133. Liu, L. D. & Duricka, D. L. Stellate ganglion block reduces symptoms of Long COVID: a case series. J. Neuroimmunol. 362, 577784 (2022).

    Article  CAS  PubMed  Google Scholar 

  134. Allendes, F. J. et al. Cardiovascular and autonomic dysfunction in long-COVID syndrome and the potential role of non-invasive therapeutic strategies on cardiovascular outcomes. Front. Med. 9, 1095249 (2022).

    Article  Google Scholar 

  135. Chandan, J. S. et al. Non-pharmacological therapies for post-viral syndromes, including long COVID: a systematic review. Int. J. Environ. Res. Public Health 20, 3477 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Eslami, M. et al. Postural orthostatic tachycardia syndrome and orthostatic hypotension post COVID-19. Infect. Disord. Drug Targets 23, e100622205846 (2023).

    Article  CAS  PubMed  Google Scholar 

  137. Goldstein, D. S. The extended autonomic system, dyshomeostasis, and COVID-19. Clin. Auton. Res. 30, 299–315 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Sterling, P. What is Health? Allostasis and the Evolution of Human Design (MIT Press, 2020).

  139. Norcliffe-Kaufmann, L., Palma, J. A., Martinez, J., Camargo, C. & Kaufmann, H. Fear conditioning as a pathogenic mechanism in the postural tachycardia syndrome. Brain 145, 3763–3769 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Stewart, J. M., Medow, M. S., Glover, J. L. & Montgomery, L. D. Persistent splanchnic hyperemia during upright tilt in postural tachycardia syndrome. Am. J. Physiol. Heart Circ. Physiol. 290, H665–H673 (2006).

    Article  CAS  PubMed  Google Scholar 

  141. Stewart, J. M. & Montgomery, L. D. Regional blood volume and peripheral blood flow in the postural tachycardia syndrome. Am. J. Physiol. Heart Circ. Physiol. 287, H1319–H1327 (2004).

    Article  CAS  PubMed  Google Scholar 

  142. Stewart, J. M. et al. Postural hyperventilation as a cause of postural tachycardia syndrome: increased systemic vascular resistance and decreased cardiac output when upright in all postural tachycardia syndrome variants. J. Am. Heart Assoc. 7, e008854 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Engel, G. L. Psychologic distress, vasodepressor (vasovagal) syncope, and sudden death. Ann. Int. Med. 89, 403–412 (1978).

    Article  CAS  PubMed  Google Scholar 

  144. Goldstein, D. S. & Kopin, I. J. Adrenomedullary, adrenocortical, and sympathoneural responses to stressors: a meta-analysis. Endo. Regul. 42, 111–119 (2008).

    Google Scholar 

  145. Hasser, E. M., Bishop, V. S. & Hay, M. Interactions between vasopressin and baroreflex control of the sympathetic nervous system. Clin. Exp. Pharmacol. Physiol. 24, 102–108 (1997).

    Article  CAS  PubMed  Google Scholar 

  146. Baily, R. G., Prophet, S. A., Shenberger, J. S., Zelis, R. & Sinoway, L. I. Direct neurohumoral evidence for isolated sympathetic nervous system activation to skeletal muscle in response to cardiopulmonary baroreceptor unloading. Circ. Res. 66, 1720–1728 (1990).

    Article  CAS  PubMed  Google Scholar 

  147. Zinn, M. A. & Jason, L. A. Cortical autonomic network connectivity predicts symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Int. J. Psychophysiol. 170, 89–101 (2021).

    Article  PubMed  Google Scholar 

  148. Ilanges, A. et al. Brainstem ADCYAP1+ neurons control multiple aspects of sickness behaviour. Nature 609, 761–771 (2022).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  149. Chaskiel, L., Paul, F., Gerstberger, R., Hubschle, T. & Konsman, J. P. Brainstem metabotropic glutamate receptors reduce food intake and activate dorsal pontine and medullar structures after peripheral bacterial lipopolysaccharide administration. Neuropharmacology 107, 146–159 (2016).

    Article  CAS  PubMed  Google Scholar 

  150. Valenzuela-Arzeta, I. E. et al. LPS triggers acute neuroinflammation and parkinsonism involving NLRP3 inflammasome pathway and mitochondrial CI dysfunction in the rat. Int. J. Mol. Sci. 24, 4628 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Nagashima, T. et al. Parabrachial-to-parasubthalamic nucleus pathway mediates fear-induced suppression of feeding in male mice. Nat. Commun. 13, 7913 (2022).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  152. Browne, C. A. et al. Distinct post-sepsis induced neurochemical alterations in two mouse strains. Brain Behav. Immun. 104, 39–53 (2022).

    Article  CAS  PubMed  Google Scholar 

  153. Veit, C. et al. The effect of LPS and ketoprofen on cytokines, brain monoamines, and social behavior in group-housed pigs. Front. Vet. Sci. 7, 617634 (2020).

    Article  PubMed  Google Scholar 

  154. Cheshire, W. P. The grand challenge of autonomic disorders. Front. Neurol. 13, 1052137 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Wang, L. et al. Applying systems thinking to unravel the mechanisms underlying orthostatic hypotension related fall risk. Geroscience 104, 2743–2755 (2023).

    Article  Google Scholar 

  156. Tsilingiris, D. et al. Laboratory findings and biomarkers in long COVID: what do we know so far? insights into epidemiology, pathogenesis, therapeutic perspectives and challenges. Int. J. Mol. Sci. 24, 10458 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Baker, A. M. E. et al. Neural dysregulation in post-COVID fatigue. Brain Commun. 5, fcad122 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Hira, R. et al. Objective hemodynamic cardiovascular autonomic abnormalities in post-acute sequelae of COVID-19. Can. J. Cardiol. 104, 767–755 (2022).

    Google Scholar 

  159. Anaya, J. M. et al. Post-COVID syndrome. A case series and comprehensive review. Autoimmun. Rev. 20, 102947 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Oliver-Mas, S. et al. Transcranial direct current stimulation for post-COVID fatigue: a randomized, double-blind, controlled pilot study. Brain Commun. 5, fcad117 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Stute, N. L. et al. Longitudinal observations of sympathetic neural activity and hemodynamics during 6 months recovery from SARS-CoV-2 infection. Physiol. Rep. 10, e15423 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Grenon, S. M. et al. Why is orthostatic tolerance lower in women than in men? Renal and cardiovascular responses to simulated microgravity and the role of midodrine. J. Investig. Med. 54, 180–190 (2006).

    Article  CAS  PubMed  Google Scholar 

  163. Convertino, V. A. Gender differences in autonomic functions associated with blood pressure regulation. Am. J. Physiol. 275, R1909–R1920 (1998).

    CAS  PubMed  Google Scholar 

  164. Fu, Q., Witkowski, S., Okazaki, K. & Levine, B. D. Effects of gender and hypovolemia on sympathetic neural responses to orthostatic stress. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R109–R116 (2005).

    Article  CAS  PubMed  Google Scholar 

  165. Diaz-Canestro, C., Pentz, B., Sehgal, A. & Montero, D. Sex differences in orthostatic tolerance are mainly explained by blood volume and oxygen carrying capacity. Crit. Care Explor. 4, e0608 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Jarvis, S. S., Florian, J. P., Curren, M. J. & Pawelczyk, J. A. Sex differences in vasoconstrictor reserve during 70 deg head-up tilt. Exp. Physiol. 95, 184–193 (2010).

    Article  CAS  PubMed  Google Scholar 

  167. Blitshteyn, S. et al. Multi-disciplinary collaborative consensus guidance statement on the assessment and treatment of autonomic dysfunction in patients with post-acute sequelae of SARS-CoV-2 infection (PASC). PMR 14, 1270–1291 (2022).

    Article  Google Scholar 

  168. Ladlow, P. et al. Dysautonomia following COVID-19 is not associated with subjective limitations or symptoms but is associated with objective functional limitations. Heart Rhythm. 19, 613–620 (2022).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

D.S.G. is supported (in part) by the Division of Intramural Research of the US National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS).

Author information

Authors and Affiliations

  1. Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    David S. Goldstein

Authors
  1. David S. Goldstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David S. Goldstein.

Ethics declarations

Competing interests

The author declares no competing interests.

Peer review

Peer review information

Nature Reviews Neurology thanks Artur Fedorowski and Kamal Shouman for their contribution to the peer review of this work.

Additional information

Disclaimer

The views and opinions expressed here are those of the author and do not necessarily represent the views of the National Institute of Neurological Disorders and Stroke, the National Institutes of Health, the Department of Health and Human Services, or the United States Government.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Review criteria

PubMed literature searches yielded a total of 165 potentially relevant publications. The abstracts of these publications were reviewed and full articles with abstracts of interest were obtained and read (103 articles). Of these, 53 reported relevant original research data. In addition, weekly Web of Science searches were performed to identify newly published articles with titles containing any of the following search terms: “allostasis”; “allostatic load”; “autonomic nervous system”; “catecholamine”; “dysautonomia”; “dyshomeostasis”; “adrenaline”; “norepinephrine”; “orthostatic hypotension”; “post-COVID”; “postural orthostatic tachycardia syndrome”; “postural tachycardia syndrome”; and “sympathetic nervous system”.

Related links

ClinicalTrials.gov: https://clinicaltrials.gov/

Supplementary information

Glossary

Baroreflex

A rapid reflex in which stretching of distortion receptors in blood vascular walls evokes an increase in cardiovagal outflow, a decrease in heart rate, and a decrease in sympathetic noradrenergic outflows that relaxes blood vessels and decreases the rate and force of cardiac contractions, thereby decreasing blood pressure.

Expressive suppression

A response-focused strategy that consists of inhibiting emotions once they have already been generated.

Negative mood regulation expectancy

A belief that one can use behaviours and cognitions to alleviate unpleasant emotional states.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Goldstein, D.S. Post-COVID dysautonomias: what we know and (mainly) what we don’t know. Nat Rev Neurol 20, 99–113 (2024). https://doi.org/10.1038/s41582-023-00917-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-023-00917-9

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing