USU Study Found Severity of Infection, Co-Morbidities, Demographics Had an Effect
BETHESDA, MD — Because a significant proportion of patients presenting with post-acute sequelae of COVID-19 (PASC) have met diagnostic criteria for certain disorders of the autonomic nervous system, a study team set out to evaluate demographic and medical factors associated with PASC dysautonomia in active-duty U.S. servicemembers (ADSM).
The researchers from the Uniformed Services University of the Health Sciences in Bethesda, MD, and colleagues also assessed for risk factors in those diagnosed with COVID-19 for PASC dysautonomia and determined the differences in those with PASC dysautonomia and non-PASC dysautonomia.
One conclusion reported in Frontiers in Neurology was that increased severity of COVID-19 infection appeared to be a key driver in elevated risk for PASC dysautonomia. Also strongly correlated, the researchers found, were comorbid depression and anxiety.
The study team used a case-control dataset of nearly 1.4 million ADSM, including those diagnosed with COVID-19 matched with ADSM with no evidence of COVID-19, to assess any associations of demographic and clinical factors with PASC dysautonomia. Of the military personnel, 619,983 COVID-19 cases were determined. Those included 158 PASC dysautonomia cases compared to 747,978 controls with 219 non-PASC dysautonomia cases.
“Among COVID-19 cases, factors positively associated with PASC dysautonomia were white, non-Hispanic race/ethnicity, female sex, younger age, Northeast region, more severe COVID-19 infection and comorbid depression or anxiety,” the authors pointed out. “Among those with dysautonomia, those with PASC dysautonomia were more likely to be of female sex, younger, in the Northeast region, and less likely to have comorbid anxiety.”
The researchers concluded that PASC dysautonomia is rare in ADSM “but associated with increased care utility and often prolonged diagnostic pathways. Important demographic and COVID-19 specific risk factors are associated with the development of PASC dysautonomia. PASC dysautonomia has significant differences in risk factors as compared to non-PASC dysautonomia, warranting further examination. These findings may support clinician awareness and prognostication and prompt further research on the pathophysiology and management of these conditions.”
Background information in the article advised that the COVID-19 pandemic has resulted in significant harm to the health of the world’s population and economy, involving more than 750 million diagnoses of COVID-19, resulting in more than 7 million deaths. “While recent strains of the SARS-COV-2 virus which causes COVID-19 has been associated with less virulent infections, there is still substantial morbidity and mortality from this now endemic pathogen,” according to the study team.
They recounted how, early in the COVID-19 pandemic, reports began to identify patients with persistent symptoms and/or symptoms developing after resolution of acute disease related to their COVID-19 infection. Called long COVID, long-haul COVID, post COVID condition and post-acute sequelae of COVID (PASC), “symptoms associated with this condition appear widely variable, and encompass sustained symptoms similar to those seen in the acute phase of infection including cough, fatigue, alterations in sensation of taste and smell, as well as other atypical symptoms that typically onset after the acute phase of COVID-19 has ended including cognitive and psychological problems (‘brain fog’), palpitations and other cardiac symptoms, and neurologic symptoms,” according to the report.
For PASC in general, some risk factors that have been identified include female sex, Hispanic ethnicity, older age, underlying health conditions, including depression and anxiety, more severe acute COVID-19 infection and being unvaccinated for COVID-19.
In some studies of PASC patients, a significant proportion meet diagnostic criteria for dysautonomia, conditions that affect the function of the autonomic nervous system, which controls involuntary systems including heart rate and blood flow. Those recently have become increasingly identified following the onset of the COVID-19 pandemic, the authors noted.
“While the underlying pathophysiology of COVID-19 induced dysautonomia (‘PASC dysautonomia’) remains uncertain, several hypotheses have been proposed,” the authors explained. “These include direct viral effects on the autonomic nervous system potentiating disordered regulation of neurotransmitters including serotonin, dysregulated inflammatory responses affecting the autonomic nervous system, and viral induced endothelial dysfunction impairing vascular function. The interplay between serotonin and other neurotransmitters with PASC, dysautonomia, and PASC dysautonomia are of particular interest as these conditions are frequently comorbid with anxiety and depression.”
They added, “There are several major gaps in our understanding of PASC dysautonomia. First, the prevalence of PASC dysautonomia is unclear, including in the Military Health System (MHS). Second, it is unclear whether PASC dysautonomia has distinct risk factors and pathophysiological mechanisms than dysautonomia not associated with COVID-19 (‘non-PASC-dysautonomia’), and if differing approaches to clinical prediction and management are warranted for these individuals.
With the 158 individuals identified as having probable PASC dysautonomia diagnosed with COVID-19, as well as the 219 individuals with probable non-PASC dysautonomia in those without evidence of COVID-19 infection, “factors that appeared to place individuals infected with COVID-19 at higher risk of PASC dysautonomia included female sex, age 35-44, service in the Marine Corps, residing in the Northeast, severity of infection, infection with COVID-19 prior to the delta variant era of SARS-CoV-2, comorbid depression or anxiety, and prescription of beta blockers, stimulants, selective serotonin reuptake inhibitors, or alpha agonists prior the time of their COVID-19 infection. Individuals with PASC dysautonomia as compared to those with non-PASC dysautonomia also were more likely to be residing in the Northeast, and were less likely to be above age 45, and to have comorbid anxiety. These risk factors may assist clinicians predict those more likely to develop this complication,” the study team described.
In addition, while an uncommon complication, the researchers noted that those with PASC dysautonomia had much higher medical utilization after their COVID-19 diagnosis as compared to those diagnosed with COVID-19 without a PASC dysautonomia diagnosis, with the lowest medical utilization seen in those without documented COVID-19 infection without dysautonomia.
“These findings support that PASC dysautonomia is a risk for increased medical utilization within the MHS, and additionally that COVID-19 diagnosis in general also has some impact on increasing medical utilization rates after diagnosis,” they wrote. “Those diagnosed with PASC dysautonomia had a median time from COVID-19 infection to dysautonomia diagnosis of approximately 6 months, contrasting to a previous study of individuals with a specific form of dysautonomia (postural orthostatic tachycardia syndrome), who reported a median time from symptom onset to diagnosis of 24 months. The relatively faster diagnoses of the individuals in our sample could be due to the increased visibility and attention to PASC syndromes during the height of the COVID-19 pandemic. Time to diagnosis may be further reduced with augmented messaging to MHS providers to raise awareness of this significant COVID-19 complication.”
The authors suggested that next steps for future research might integrate direct clinical evaluation and management of research participants to better understand underlying pathophysiologic mechanisms of PASC dysautonomia and identify potential treatment algorithms for management of these often-complex patients.
- Pierson BC, Craig-Kuhn MC, Stewart L, Sercy E, et. Al. . Evaluating the risk and risk factors of dysautonomia as a post-acute sequelae of COVID-19: a secondary analysis of a matched case-control dataset. Front Neurol. 2025 Oct 14;16:1653175. doi: 10.3389/fneur.2025.1653175. PMID: 41164396; PMCID: PMC12558787.