Article

Orthostatic intolerance associated with decreased levels of circulating growth hormone was found in long COVID patients under 20 years of age

 

Orthostatic intolerance (OI) is a cardiovascular autonomic disorder defined as having difficulty tolerating the upright posture because of symptoms that abate when returned to supine. Loss of consciousness or a sense of impending loss of consciousness, cognitive deficits (memory loss and decreased reasoning and concentration), dizziness or lightheadedness, headache, exhaustion, orthostatic hypotension and occasionally hypertension, weakness, nausea, abdominal pain, sweating, tremulousness, and intolerance to exercise are typical symptoms. Chronic orthostatic intolerance, present for at least 3 months although symptoms may wax and wane, has been recorded in a significant proportion of patients with long COVID. In this study, Japanese authors investigated the prevalence of a positive standing test (ST) and related autonomic manifestations in patients diagnosed with long COVID syndrome.

The central nervous system (CNS) symptoms of OI are related to reduced brain perfusion during orthostatic stress. The common forms of OI include orthostatic hypotension (both neurogenic and nonneurogenic), vasovagal syncope, and postural tachycardia syndrome (POTS). Neurogenic orthostatic hypotension is caused by autonomic failure attributable to inadequate release of norepinephrine from sympathetic vasomotor neurons leading to vasoconstrictor failure. Autonomic failure can be primary, caused by preganglionic, postganglionic, or both forms of sympathetic failure; it can be genetic, as in dopamine beta-hydroxylase deficiency; autoimmune, or acquired as a secondary aspect of systemic disease. (Stewart JM. Mechanisms of sympathetic regulation in orthostatic intolerance. J Appl Physiol 113: 1659–1668, 2012.)  https://journals.physiology.org/doi/full/10.1152/japplphysiol.00266.2012

OI is common in pediatrics. Approximately 40% of people faint during their lives, half faint during adolescence, and the peak age for first fainting is 15 years. Evidence of partial autonomic denervation in some patients with POTS and preceding viral syndrome supports an underlying immune system-related cause. This is further supported by the detection of nicotinic ganglionic acetylcholine receptor autoantibodies in a small percentage of patients with OI, or autoantibodies that cross-react with a wide range of cardiac proteins and α- and β-adrenergic receptors. Stewart JM, et al. Pediatric Writing Group of the American Autonomic Society. Pediatric Disorders of Orthostatic Intolerance. Pediatrics. 2018 Jan;141(1):e20171673.   https://pmc.ncbi.nlm.nih.gov/articles/PMC5744271/ It is interesting that the study of Yapici-Eser et al. (2021), which investigated a mimicry between human proteins and SARS-CoV-2 proteins using a computational methodology (Host-Microbe Interaction PREDiction Algorithm), showed that SARS-CoV-2 proteins mimic 5 proteins linked with the α-adrenergic receptor signaling pathway, 9 proteins linked with the β1-adrenergic receptor signaling pathway, 9 proteins linked with the β2-adrenergic signaling pathway, and 6 proteins linked with the beta3-adrenergic receptor signaling pathway. (Yapici-Eser H et al. Neuropsychiatric Symptoms of COVID-19 Explained by SARS-CoV-2 Proteins’ Mimicry of Human Protein Interactions. Front. Hum. Neurosci, 23 March 2021.)   https://www.frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2021.656313/full  Moreover, higher levels of autoantibodies against six receptors involved in autonomic regulation, including the angiotensin II type 1 receptor, endothelin-1 type A receptor, M2 and M3 muscarinic acetylcholine receptors, β2 adrenergic receptor, and MAS1 receptor were detected in individuals with post-COVID-19 vaccination syndrome than in healthy controls. https://discovermednews.com/autoantibodies-against-elements-of-autonomic-regulation-post-covid-vaccination-syndrome/ 

The secretion of growth hormone (GH), like other anterior pituitary hormones, is regulated through a complex neuroendocrine control system that comprises two main hypothalamic regulators: growth hormone-releasing hormone (GHRH), which stimulates GH synthesis and secretion to a large extent, and somatostatin, which inhibits GH secretion from the anterior hypophysis. Extensive pharmacologic studies in man and animals indicate a stimulatory effect of central norepinephrine and dopamine on GH secretion. Stimulation of CNS α-adrenergic receptors elicits GH release in men. (Terry LC, et al. Regulation of episodic growth hormone secretion by the central epinephrine system. Studies in the chronically cannulated rat. J Clin Invest. 1982; 69(1): 104-12.)  https://pmc.ncbi.nlm.nih.gov/articles/PMC371173/  It should be noted that immunohistochemical analysis of the endocrine organ samples (pituitary, thyroid, and adrenal gland), taken at autopsy from deceased individuals with antemortem SARS-CoV-2 infection, revealed that SARS-CoV-2 proteins were abundantly expressed in the cells of the adenohypophysis. In contrast, the cells of the neurohypophysis did not express viral proteins. Using computational methods, the authors also found that human coronaviruses share 117 immune pentapeptide epitopes with 18 autoantigens expressed by human endocrinocytes. (Kolobov VE et al. Post-COVID Endocrine Disorders: Putative Role of Molecular Mimicry and Some Pathomorphological Correlates. Diagnostics 2023, 13, 522.)  https://doi.org/10.3390/diagnostics13030522

Since cardiovascular morbidity is associated with GH, previous studies have investigated the relationship between GH levels and the occurrence of POTS. In the study by Johansson M et al. (2021), POTS patients were found to have lower median plasma GH levels and higher supine heart rate (HR) and diastolic blood pressure (but not systolic blood pressure) than control subjects. (Johansson M et al. Circulating levels of growth hormone in postural orthostatic tachycardia syndrome. Scientific Reports 2021; 11:8575).  https://doi.org/10.1038/s41598-021-87983-5  In contrast, a previous study that used a proteomics approach reported elevated GH plasma levels in patients with POTS. (Medic Spahic, J. et al. Proteomic analysis reveals sex-specific biomarker signatures in postural orthostatic tachycardia syndrome. BMC Cardiovasc. Disord. (2020) 20, 190.)  https://doi.org/10.1186/s12872-020-01465-6

 

About the study

The study was conducted on outpatients diagnosed with long COVID syndrome, which lasts for more than one month following the onset of COVID-19. The majority of patients were infected during the Omicron phase (70%). The patients had undergone a standing test due to the symptoms of OI such as palpitation and syncope. The patients who had undergone the ST had not received any drug for long COVID treatment. 49% of participants in the ST-positive group, and 64% in the ST-negative group received at least 2 doses of COVID vaccines.

Information on age, gender, body mass index, smoking/alcohol drinking habits, severity of the acute phase of COVID-19, viral variants, history of COVID vaccination, clinical symptoms of long COVID, and results of ST were obtained from medical records.

In the active standing test, an individual lies supine for 5 minutes during which time their baseline blood pressure and HR were measured, and then stands up actively for 10 minutes. The monitoring of systolic and diastolic blood pressures and HR was conducted every two minutes for up to 10 minutes in a standing position. Symptoms such as fatigue, nausea, lightheadedness, shortness of breath, headache, pain, and impaired concentration were recorded while the individuals were supine and standing. The increase in HR from the basal HR of 30 beats per minute (bpm) or more, the increase to 120 bpm or more over the same period, and the decrease in systolic blood pressure of 25 mmHg or more were all considered positive indicators for the ST.

 

Results

The most frequent daily symptoms in the long COVID patients were fatigue, headache, sleep disturbance, dizziness, dyspnea, nausea, and poor concentration.

Of 86 patients with long COVID suspected of OI, 38% (33 patients) were positive for ST. The ST-positive patients with long COVID were significantly younger than the ST-negative patients (median age was 20 years vs. 40 years). 49% of the ST-positive patients were under 20 years of age, while the proportion of patients under 20 years of age in the ST-negative patients was only 21%. There was no significant difference in the gender ratio between the ST-positive and ST-negative groups.

There were no significant differences in the clinical symptoms between the ST-positive and ST-negative groups with long COVID. In ST-positive patients, there was an insignificant tendency for accompanying symptoms, such as nausea and tachycardia, to occur.

The ST-positive patients and ST-negative patients did not differ in body mass index, habits of smoking and drinking, the severity of COVID-19, viral variants, vaccination history, peripheral blood counts, and biochemical laboratory data showing liver and kidney functions, electrolytes, and inflammatory factors. 

 

A standing test (ST)

Both ST-positive and ST-negative patients experienced a significant increase in HR after standing up from the supine position. However, the initial increment in HR in the ST-positive patients was twice as high (25 bpm) as in the ST-negative patients (14 bpm). Also, the ST-positive patients showed a greater initial increase in HR during a 10-minutes after standing up than the ST-negative patients.

Systolic and diastolic blood pressures showed moderate increases in both groups. The increase in systolic blood pressure compared to the baseline value after 5 minutes was not significantly different between the two groups. However, diastolic blood pressure immediately after standing up was higher in the ST-positive group (+14 mmHg) than in the ST-negative group (+9 mmHg), suggesting that an acute rise in diastolic blood pressure immediately after standing up is characteristic of ST-positive patients. The authors emphasized that this phenomenon of an initial increase in diastolic blood pressure was also found in a previous study in POTS patients, unrelated to COVID.

 

Laboratory parameters

The patients were divided into two age groups: under 20 years and 20 years or older because the ST-positive group included a large proportion of younger patients. Between the ST-positive and ST-negative patients under 20 years of age, there was no significant difference in thyroid hormones (free thyroxine (FT4), thyrotropin (TSH), and the ratio of TSH/FT4) or adrenocortical hormones (cortisol, adrenocorticotropin (ACTH), and the ratio of ACTH/cortisol). However, ST-positive long COVID patients under 20 years of age had lower serum growth hormone levels than the ST-negative group of the same age. These findings are consistent with those of the aforementioned study, which found lower plasma GH levels and higher diastolic blood pressure (but not systolic blood pressure) in POTS patients unrelated to COVID.

In the ST-positive long COVID patients aged 20 years or older, serum cortisol levels were higher than in the ST-negative group of the same age. 

 

Conclusion

This study showed a high rate (38%) of positive standing tests in patients with long COVID and symptoms of orthostatic intolerance. The ST-positive patients with long COVID were significantly younger than the ST-negative patients, and 49% of them were under 20 years of age.

The ST-positive patients with long COVID had an acute increase in diastolic blood pressure with increasing HR during active standing. The ST-positive patients with long COVID under 20 years of age had decreased circulating growth hormone levels. This was not the case in the ST-positive long COVID patients aged 20 years or older who were found to have elevated cortisol levels.

This article was published in Scientific Reports.

 

Journal Reference

Kato, A., Tokumasu, K., Yamamoto, K. et al. Clinical and endocrine features of orthostatic intolerance detected in patients with long COVID. Sci Rep 14, 17025 (2024).  https://www.nature.com/articles/s41598-024-67815-y

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