Autonomic dysfunction in SARS-COV-2 infection acute and long-term implications COVID-19 editor's page series.

The autonomic nervous system (ANS) is a complex network of nerves originating in the brain, brain stem, spinal cord, heart and extracardiac organs that regulates neural and physiological responses to internal and external environments and conditions. A common observation among patients with the 2019 Coronavirus (CoV) (SARS-severe acute respiratory syndrome CoV-2) (SARS-CoV-2) or COVID-19 [CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019)] in the acute and chronic phases of the disease is tachycardia, labile blood pressure, muscular fatigue and shortness of breath. Because abnormalities in the ANS can contribute to each of these symptoms, herein a review of autonomic dysfunction in SARS-COV-2 infection is provided to guide diagnostic testing, patient care and research initiatives. The autonomic nervous system is a complex network of nerves originating in the brain, brain stem, spinal cord, heart and extracardiac organs that regulates neural and physiological responses to internal and external environments and conditions. A common collection of signs and symptoms among patients with the 2019 Coronavirus (CoV) (SARS-severe acute respiratory syndrome CoV-2) (SARS-CoV-2) or COVID-19 [CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019)] is tachycardia, labile blood pressure, muscular fatigue and shortness of breath. Abnormalities in the autonomic nervous system (ANS) can contribute to each of these identifiers, potentially offering a unifying pathobiology for acute, subacute and the long-term sequelae of SARS-CoV-2 infection (PASC) and a target for intervention.

Preparing for the long-haul: Autonomic complications of COVID-19.

As global numbers of COVID-19 grow, chronic neurological symptoms, including those of autonomic dysfunction, are being reported with increasing frequency. Mounting evidence suggests that many patients experience chronic and sometimes debilitating symptoms long after their acute infectious period, leading to the new diagnostic category of post-acute COVID syndrome. Many symptoms of post-acute COVID syndrome appear autonomic in nature, suggesting that autonomic impairment may play a central role in the underlying pathophysiology. In this review, we discuss the autonomic symptoms and manifestations of post-acute COVID syndrome, potential mechanisms involved, and future directions for a better understanding of this novel condition.

A Case Series of Parechovirus Encephalopathy: Apnea and Autonomic Dysregulation in Critically Ill Infants.

This article aims to describe a rare cause of severe encephalitis in 2 cases of infants with signs of intracranial hypertension and severe autonomic dysregulation. The authors conclude that human parechoviruses are becoming a more recognized cause of encephalitis because of the increasing use of rapid detection methods. With early recognition of this clinical entity, improved care can be administered.

Autonomic deficit not the cause of death in West Nile virus neurological disease.

INTRODUCTION: Some West Nile virus (WNV)-infected patients have been reported to manifest disease signs consistent with autonomic dysfunction. Moreover, WNV infection in hamsters causes reduced electromyography amplitudes of the gastrointestinal tract and diaphragm, and they have reduced heart rate variability (HRV), a read-out for the parasympathetic autonomic function. METHODS: HRV was measured in both hamsters and mice using radiotelemetry to identify autonomic deficits. To identify areas of WNV infection within the medulla oblongata mapping to the dorsal motor nucleus of vagus (DMNV) and the nucleus ambiguus (NA), fluorogold dye was injected into the cervical trunk of the vagus nerve of hamsters. As a measurement of the loss of parasympathetic function, tachycardia was monitored contiguously over the time course of the disease. RESULTS: Decrease of HRV did not occur in all animals that died, which is not consistent with autonomic function being the mechanism of death. Fluorogold-stained cells in the DMNV were not stained for WNV envelope protein. Fourteen percent of WNV-stained cells were co-localized with fluorogold-stained cells in the NA. These data, however, did not suggest a fatal loss of autonomic functions because tachycardia was not observed in WNV-infected hamsters. CONCLUSION: Parasympathetic autonomic function deficit was not a likely mechanism of death in WNV-infected rodents and possibly in human patients with fatal WN neurological disease.

Autonomic dysfunction is common in HIV and associated with distal symmetric polyneuropathy.

Neurologic complications of HIV are well characterized in the central and peripheral nervous systems but not in the autonomic nervous system, perhaps due to the complexities of measuring autonomic function in medically ill populations. We hypothesized that autonomic dysfunction is common in HIV, can be meaningfully measured with an autonomic reflex screen, and is associated with distal symmetric polyneuropathy (DSP) but not with signs of CNS disease. We also sought to characterize immunovirologic and medical factors associated with autonomic dysfunction. We assessed 102 HIV-infected adults for autonomic dysfunction with a laboratory-based autonomic reflex screen summarized as the composite autonomic severity score (CASS). The total neuropathy score (TNS) was used to quantify DSP based on neurologic interview/examination, quantitative sensory testing, and nerve conduction studies. Autonomic dysfunction was common, with a CASS ≥ 3 in 61 % of participants, of whom 86 % were symptomatic. Greater CASS abnormalities demonstrated univariate association with increasing TNS, age, viral load, hypertension, and use of medications (particularly anticholinergics), but not with antiretrovirals, current/nadir CD(4+) count, HIV duration, metabolic factors, or signs of CNS disease. The TNS was the only significant predictor of the CASS in multivariate analysis; anticholinergic medications were marginally significant. This study demonstrates that autonomic dysfunction is common and frequently symptomatic in HIV and that an autonomic reflex screen, adjusted for anticholinergic medication, is useful in its assessment. Association of autonomic dysfunction with DSP suggests common factors in their pathogenesis, and autonomic neuropathy may be part of the spectrum of HIV-associated peripheral nerve pathologies.

Acute autonomic sensory and motor neuropathy associated with parvovirus B19 infection.

We report a 9-year-old girl with acute autonomic sensory and motor neuropathy (AASM) associated with human parvovirus B19 (HPV-B19) infection. The patient presented with fever, erythema of the entire body, and abdominal pain with vomiting. The titer of HPV-B19 IgM antibody was significantly elevated. Symptoms such as muscle weakness, severe hyperesthesia, dyshidrosis, and neurogenic bladder associated with autonomic disturbance developed over several days. Intravenous immunoglobulin therapy gave no obvious improvement of her symptoms. Motor and sensory impairment improved slowly without medical treatment, but dysautonomia persisted for a long time. Sural nerve biopsy revealed axonal degeneration of small fibers, involving both myelinated and unmyelinated fibers, which is compatible with the autonomic sensory and motor neuropathy. AASM is very rare in pediatric populations, and there is no report of AASM associated with HPV-B19 infection.

Influenza A induced acute autonomic neuropathy in an adolescent.

Influenza A may cause serious neurologic complications, but an autoimmune autonomic ganglionopathy has rarely been reported. Autoantibodies that impair synaptic transmission in the autonomic ganglia may cause orthostatic hypotension, gastrointestinal dysmotility, and sudomotor dysfunction. A 15-year-old girl developed severe and persisting orthostatic hypotension during influenza A infection. Removal of circulating antibodies by a single course of intravenous immunoglobulin resulted in rapid and complete recovery.

Evaluation of autonomic malfunction in HTLV-1 associated myelopathy (HAM).

HTLV-1 associated myelopathy (HAM) has been known to reveal various clinical manifestations of autonomic dysfunction; thus the focus of the present study was to investigate whether or not thoracic spinal cord injury frequently observed in HAM patients leads to cardiovascular autonomic dysfunction. The subjects consist of 18 patients in the chronic phase of HAM (group HAM) and 29 normal subjects (group C). They were examined for CVR-R and total heart rate. A power spectral analysis of R-R interval variability of their 24-hour Holter ECGs was also done. High frequency (HF) was an indicator of parasympathetic activity, while the low to high frequency ratio (L/H) was used as an indicator of sympathetic activity. Nominated HAM patients were evaluated by neurological examination using clinical indicators of HAM (EDSS, OMDS and FIM). To examine the degree of atrophy of the upper thoracic spinal cord, we performed individual MR (magnetic resonance) imaging of HAM spinal cords. Correlations between the above indicators and clinical indicators of HAM were examined. The L/H ratio was significantly lower in group HAM (1.67+/-0.79) than in group C. Significant reduction in the L/H ratio was observed in 8 (88.9%) of 9 patients in group HAM with orthostatic hypotension. The L/H ratio was significantly low in HAM patients with thoracic cord atrophy, strongly suggesting that the coexistence of a thoracic cord lesion is associated with a reduction of cardiovascular sympathetic activity. In conclusion, cardiovascular autonomic dysfunction in HAM patients is mainly associated with cardiac sympathetic efferent abnormalities in the upper thoracic segments.

Alphafoetoprotein and acetylcholinesterase in amniotic fluid as a factor suggesting fetal skin and nerve lesions in a case of congenital varicella syndrome.

BACKGROUND: Prenatal care of pregnant women exposed to varicella skin rash during the first half of pregnancy remains a frequent concern in countries that do not have access to systematic vaccination. The frequency of maternofetal transmission is low. Ultrasound is the usual tool for prenatal survey of exposed fetuses. But many anomalies due to VZV infection are not accessible to ultrasound alone. CASE REPORT: We review a case in which the diagnosis of fetal infection suspected due to transient fetal bowel hyperechogenicity was confirmed in amniotic fluid by molecular biology (PCR). RESULTS: An unusual elevation of alphafoetoprotein in maternal blood and in amniotic fluid was associated with inguinal skin, muscular and nerve destruction. CONCLUSION: In fetuses diagnosed with in utero varicella infection, in addition to a precise diagnosis and follow-up, we suggest that elevated AFP levels in maternal blood and amniotic fluid together with the presence of acetylcholinesterase in amniotic fluid may be related to lesion of fetal skin and nerves.

Modulation of autonomic balance by tumors and viruses.

Autonomic balance, a function generally under host control, is subject to modulation by other signalers. In some cases, modulation of host autonomic function through behavioral and physical stressors exerted by another individual may have negative consequences for the stress recipient by inducing sympathetic bias. Modulation of autonomic function may sometimes benefit one party at the expense of another. Tumors and HIV are examples of illegitimate signalers who may induce host sympathetic bias to promote their own growth and evade host immune surveillance. Paraneoplastic and paraviral syndromes such as hypertrophic osteoarthopathy, QTc prolongation, insomnia, and cachexia could be viewed as epiphenomena related to the tumoral and viral manipulation of host autonomic balance. In a more general framework, other paraneoplastic and paraviral syndromes may represent epiphenomena related to modulation of endocrine, cytokine, and autonomic functions by tumors and viruses to promote their own survival. Spatial distribution of cancers and viruses within the host may reflect affinity for strategic locations that facilitate manipulation of a variety of host functions including autonomic, endocrine, and cytokine regulation. A more general for understanding spatial distribution of diseases based on gradients of autonomic balance in the body are explored. Darwinian perspectives are discussed.

Modulation of host immunity by HIV may be partly achieved through usurping host autonomic functions.

Modulation of host immunity has been observed in human immunodeficiency virus (HIV) infections. HIV is believed to influence host immunity through a variety of mechanisms including direct effects on host T cell survival, indirect effects on cytokine profile through modulation of immune cells, and modulation of endocrine functions that affect immunity such as steroids. We hypothesize that HIV infection may also alter host immunity through modulation of host sympatho-vagal balance. Specifically, we propose that HIV drives autonomic balance towards sympathetic bias, which can contribute to a T helper (Th)2 type immunity. A variety of paraviral syndromes associated with HIV infection such as QT prolongation, cachexia, cardiomyopathy, and lipodystrophy are consistent with evidence of autonomic dysfunction. Immunomodulatory effects of autonomic dysfunction toward Th2 bias are presented. A plausible mechanism by which HIV can influence autonomic balance through hypothalamic manipulation is offered. Shift to Th2 dominance is associated with HIV disease progression and can be viewed as a viral adaptation to promote its own survival. Autonomic remodeling by HIV may exemplify this phenomenon. Our hypothesis has implications for treatment of HIV and its associated syndromes.

Sympathetic nerve destruction in spleen in murine AIDS.

In susceptible strains of mice, the LP-BM5 mixture of murine retroviruses induces the fatal immunodeficiency disease known as murine acquired immunodeficiency syndrome (murine AIDS or MAIDS). We have previously reported that murine AIDS produces a profound depletion of splenic norepinephrine (NE). Here, we demonstrate that NE depletion is limited to the spleen, a major site affected by LP-BM5 infection. NE depletion in the spleen is first observed at two weeks following LP-BM5 inoculation, concurrent with the onset of splenomegaly, and continues through 12 weeks post-infection. Neuroanatomical studies revealed that the reduction in NE is due to destruction of splenic sympathetic nerve fibers. Administration of the NE reuptake blocker desipramine did not prevent LP-BM5-induced NE depletion, suggesting that destruction is not caused by excess release and reuptake of NE. Elucidating the mechanism of MAIDS-induced sympathetic nerve destruction may provide insight into autonomic and peripheral neuropathies reported in people with AIDS.

Cardiovascular autonomic dysfunction in Africans infected with human immunodeficiency virus.

The effects of human immunodeficiency virus (HIV) on cardiovascular autonomic function have been little investigated in African patients. We performed standard heart-rate and blood pressure tests on 75 consecutive consenting patients referred for an HIV test in Yaounde, Cameroon. 54 patients proved to be HIV-infected (30 having progressed to AIDS). Cardiovascular autonomic dysfunction was present in 8 (28%) patients with AIDS and in 1 (4%) HIV-positive patient without AIDS; no HIV-negative individuals had abnormal results. If borderline results are included, over 80% of HIV-positive patients had cardiovascular autonomic dysfunction. In HIV-infected patients, simple tests such as blood pressure responses to standing or handgrip can warn of cardiovascular autonomic dysfunction, thus signalling the need for added precautions when invasive procedures are proposed.