Post-COVID-19 Afferent Baroreflex Failure.

HomeHypertensionVol. 80, No. 5Post–COVID-19 Afferent Baroreflex Failure Free AccessCase ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessCase ReportPDF/EPUBPost–COVID-19 Afferent Baroreflex Failure Khaled Elkholey, Amr Wahba, Sachin Y. Paranjape, Mohammad Saleem, Annet Kirabo, Karen M. Joos, André Diedrich, Cyndya A. Shibao and Italo Biaggioni Khaled ElkholeyKhaled Elkholey Divisions of Clinical Pharmacology, Department of Medicine (K.E., A.W., S.P., M.S., S.K., A.D., C.A.S., I.B.), Vanderbilt University Medical Center, Nashville, TN. Autonomic Dysfunction Center (K.E., A.W., S.Y.P., A.D., C.A.S., I.B.), Vanderbilt University Medical Center, Nashville, TN. Search for more papers by this author , Amr WahbaAmr Wahba Divisions of Clinical Pharmacology, Department of Medicine (K.E., A.W., S.P., M.S., S.K., A.D., C.A.S., I.B.), Vanderbilt University Medical Center, Nashville, TN. Autonomic Dysfunction Center (K.E., A.W., S.Y.P., A.D., C.A.S., I.B.), Vanderbilt University Medical Center, Nashville, TN. Search for more papers by this author , Sachin Y. ParanjapeSachin Y. Paranjape Divisions of Clinical Pharmacology, Department of Medicine (K.E., A.W., S.P., M.S., S.K., A.D., C.A.S., I.B.), Vanderbilt University Medical Center, Nashville, TN. Autonomic Dysfunction Center (K.E., A.W., S.Y.P., A.D., C.A.S., I.B.), Vanderbilt University Medical Center, Nashville, TN. Search for more papers by this author , Mohammad SaleemMohammad Saleem https://orcid.org/0000-0001-8091-8361 Divisions of Clinical Pharmacology, Department of Medicine (K.E., A.W., S.P., M.S., S.K., A.D., C.A.S., I.B.), Vanderbilt University Medical Center, Nashville, TN. Search for more papers by this author , Annet KiraboAnnet Kirabo https://orcid.org/0000-0001-8580-9359 Search for more papers by this author , Karen M. JoosKaren M. Joos https://orcid.org/0000-0002-6210-4126 and Vanderbilt Eye Institute (K.M.J.), Vanderbilt University Medical Center, Nashville, TN. Search for more papers by this author , André DiedrichAndré Diedrich Divisions of Clinical Pharmacology, Department of Medicine (K.E., A.W., S.P., M.S., S.K., A.D., C.A.S., I.B.), Vanderbilt University Medical Center, Nashville, TN. Autonomic Dysfunction Center (K.E., A.W., S.Y.P., A.D., C.A.S., I.B.), Vanderbilt University Medical Center, Nashville, TN. Search for more papers by this author , Cyndya A. ShibaoCyndya A. Shibao https://orcid.org/0000-0002-4518-6801 Divisions of Clinical Pharmacology, Department of Medicine (K.E., A.W., S.P., M.S., S.K., A.D., C.A.S., I.B.), Vanderbilt University Medical Center, Nashville, TN. Autonomic Dysfunction Center (K.E., A.W., S.Y.P., A.D., C.A.S., I.B.), Vanderbilt University Medical Center, Nashville, TN. Search for more papers by this author and Italo BiaggioniItalo Biaggioni Correspondence to: Italo Biaggioni, MD, Divisions of Clinical Pharmacology, Department of Medicine and Autonomic Dysfunction Center, Vanderbilt University Nashville, TN. Email E-mail Address: [email protected] https://orcid.org/0000-0001-7667-7083 Divisions of Clinical Pharmacology, Department of Medicine (K.E., A.W., S.P., M.S., S.K., A.D., C.A.S., I.B.), Vanderbilt University Medical Center, Nashville, TN. Autonomic Dysfunction Center (K.E., A.W., S.Y.P., A.D., C.A.S., I.B.), Vanderbilt University Medical Center, Nashville, TN. Search for more papers by this author Originally published20 Feb 2023https://doi.org/10.1161/HYPERTENSIONAHA.123.20316Hypertension. 2023;80:895–900Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: February 20, 2023: Ahead of Print A 47-year-old male with a history of psoriatic arthritis and type II diabetes contracted COVID-19 in 2020 complicated by pneumonia and acute hypoxic respiratory failure requiring hospitalization. He received supplemental oxygen, convalescent plasma, Remdesivir, and dexamethasone. He started to develop significant blood pressure (BP) variability with BP ranging from 223/124 to 72/43 mm Hg beyond 4 weeks of the initial infection. Hypertension episodes were usually associated with nausea, vomiting, and retching. Hypotension episodes were associated with blurred vision, dizziness, lightheadedness, and confusion and were not related to position changes but to BP changes. His ocular history was significant for observed small lagophthalmos of the right eyelid while sleeping, which reportedly started after his COVID-19 infection. His blurred vision was associated with changes in his BP. His eye exam when alert with BP 129/57 was significant for equal small pupils (3 mm) but reactive to light exposure (2 mm) with no relative afferent pupillary defect. His near vision was normal J1+ in each eye. Extraocular motility was full, 1 mm lagophthalmos right eyelid, equal lid strength, and sensation, no lid lag, no lid fatigue, visual fields full to confrontation, normal portable slit-lamp anterior segment exam, normal 5-minute Schirmers with 0.5% proparacaine at 18 and 20 mm, Tonopen intraocular pressure 12 and 13 mm Hg, dilated exam with normal retinal vascularity and no evidence of diabetic retinopathy. He had a cup-to-disc ratio of 0.7 with healthy rims similar to historical ophthalmic examination reports. The patient was examined during one of his hypotensive spells. His BP and heart rate (HR) changed while remaining supine from 88/52 mm Hg and 53 bpm to 66/32 mm Hg and 40 bpm. Also, his intraocular pressure decreased from 11 and 12 mm Hg to 7 and 8 mm Hg over this 5-minute interval.His hospitalization course was complicated by recurrent episodes of urinary retention that required catheterization, alternating with episodes of increased urinary frequency. He had a urodynamic study that showed severe high-amplitude detrusor overactivity with some incomplete emptying, and the underlying cause for his bladder symptoms was attributed to autonomic dysfunction. Also, bladder manipulation occasionally triggered precipitous hypotension.Initial ancillary tests including complete blood count, basic metabolic panel were normal. There was no clinical or biochemical evidence of secondary causes for hypertension, with normal renal function, plasma aldosterone–renin ratio, and cortisol levels at baseline and after ACTH stimulation. Plasma norepinephrine levels paralleled BP changes and were excessively elevated during a hypertension crisis (1012 pg/mL) and normal in between the episodes (323 pg/mL). Adrenal tumors and renal artery stenosis were ruled out. Brain imaging was normal with no identifiable brainstem lesions.During a 10-minute head-up tilt, the patient’s supine BP was 98/63 mm Hg with HR of 65 BPM; by the end of 5 minutes of up-tilt, his standing BP was 101/69 with HR of 102 but the test was aborted after 7 minutes because of development of AV block associated with severe presyncopal symptoms. Cardiovagal function was impaired, as assessed by analysis of variability of heart rate during slow deep breathing, with reduction of respiratory sinus arrhythmia ratio to 1.12. Valsalva maneuver showed an excessive phase-II BP drop, a lack of phase IV BP overshoot, indicating impaired sympathetic vasoconstrictor reflexes (Figure 1). Absence of appropriate compensatory reciprocal changes in heart rate indicated baroreflex failure. On the contrary, there was a paradoxical parallel increase in both BP and heart rate during phase IV. Cold pressor testing produced an excessive unmodulated sympathetic increase in SBP (+33 mm Hg) and heart rate (+20 BPM; Figure 1); intraocular pressure increased in parallel by 7 mm Hg, as seen in autonomic failure patients.1 Altogether, the test showed autonomic dysfunction with impaired baroreflex-mediated sympathetic activation but intact efferent responses, consistent with afferent baroreflex failure.Download figureDownload PowerPointFigure 1. Cardiovascular responses to physical and mental stimuli. Blood pressure (BP) and heart rate (HR) changes associated with forced expiration against pressure (PRE) during the Valsalva maneuver (A) and cold pressor test (B). See text for details.Severe COVID-19 has been associated with pronounced changes in peripheral immune activity and cytokine release including IL (interleukin)-1beta, IL-6, TNF (tumor necrosis factor)-alpha, and others.2,3 Macrophages, monocytes, and dendritic cells form the mononuclear phagocyte system. Mononuclear phagocytes are professional antigen-presenting cells (APCs); they sense and phagocytose pathogens, mediate leukocyte recruitment, initiate and shape immune responses, and control inflammation.4 Flow cytometric data analyses of peripheral blood mononuclear cells showed a reduction in classical monocytes but a marked increase in the number of proinflammatory macrophages (Supplemental Figure S1). A reduced number of immune cells in severe COVID-19 has been reported previously.2,4–6 Dendritic cells and macrophages exhibited increased accumulation of the product of lipid oxidation gamma ketoaldehydes known as isolevuglandins (Figure 2). Isolevuglandins are highly immunogenic and function as neoantigens after making adducts with proteins.7 This was associated with a profound increase in the production of proinflammatory cytokine IL-1beta in dendritic cells and macrophages (Figure 2). Although the total number of monocytes was reduced, we found the activation of the classical monocytes in this patient (Figure 2). The patient received plasmapheresis for a possible underlying autoimmune process, but there was no improvement in his symptoms.Download figureDownload PowerPointFigure 2. Cytokine expression in circulating immune cells. Expression of isolevuglandins (IsoLG) and interleukin (IL)-1 beta in dendritic cells (DCs, A and B) and in macrophages (C and D). Expression of activation markers CD83 and CD86 in classical monocytes (E and F). Results in the patient (red) are juxtaposed to those in healthy control (blue).Clonidine helped controlled hypertensive episodes, but worsening hypotension required treatment with intravenous norepinephrine. He was then treated with the longer-acting central sympatholytic guanfacine in combination with the norepinephrine precursor droxidopa as a rescue to avoid symptomatic hypotension. This autonomic BP clamp resulted in a more stable BP. Systolic BP variability (coefficient of variation) decreased from 31% to 18 % (Figure 3).Download figureDownload PowerPointFigure 3. Blood pressure (BP) variability in response to autonomic clamp. BP and heart rate measurements done on admission (left) and during treatment with the long-acting central sympatholytic guanfacine combined with the norepinephrine precursor droxidopa (right). Coefficient of variation of systolic BP (SBP) decreased from 31% to 18 %. DBP indicates diastolic BP.Despite adequate BP control the patient continued to have repeated hospitalizations for episodes of intractable nausea and volume depletion, and ultimately refused further medical treatment and died in hospice.DiscussionWe here report a case report for a labile BP after COVID-19 infection due to afferent baroreflex failure. Since the beginning of the COVID-19 pandemic, several reports have identified the association between dysautonomia and COVID-19 illness.8 Most reports deal with patients developing postural tachycardia. Only a few cases have been reported with BP fluctuations after COVID-19. Eshak et al,9 described a case of acute dysautonomia and labile BP, in a critically ill old age male with COVID-19 severe pneumonia, but autonomic function evaluation was not done due to the patient’s critical condition. Kakumoto et al10 described a 22-year-old male patient with Guillain-Barré syndrome (GBS) with fluctuating BP and heart rate with evidence of bilateral facial nerve involvement based on contrast enhancement findings on the brain magnetic resonance imaging. Furthermore, Abdelnabi et al11 reported another case of a 58-year-old female who developed transient episodes of severe hypertension with BP reaching 180/110 mm Hg and a heart rate of 130 BPM after testing positive for COVID-19 and was managed by short-acting calcium channel blockers for a short duration of time with complete resolution of symptoms over the follow-up and discontinuation of medications.Carotid sinus baroreceptors reflex is a negative-feedback circuit, which consists of carotid sinus stretch receptor’s sensing of BP, transmission through a branch of the glossopharyngeal nerve to interneurons of the nucleus tractus solitarius, synapse of the interneurons with caudal ventrolateral medulla neurons, which inhibit preganglionic fibers of the rostral ventrolateral medulla (which provide basal sympathetic tone to the heart, blood vessels and kidneys) causing decrease of central sympathetic outflow.12 Most cases of afferent baroreflex failure result from late complications of neck radiation13 and are characterized by extreme BP lability with severe hypertensive crises, hypotensive episodes, and orthostatic hypotension, making it the most difficult form of hypertension to manage.14 Acute afferent baroreflex failure, seen after bilateral neck surgery from paragangliomas is characterized by severe vomiting during hypertensive crises, as seen in this patient.15 The diagnosis of afferent baroreflex failure is based on the clinical picture of extreme BP lability, parallel BP and heart rate changes, absence of the normal reciprocal changes in heart rate in response to BP changes elicited by the Valsalva maneuver but exaggerated efferent pressor response to central stressor like the cold pressor test.12,16The exact mechanism by which COVID-19 can cause afferent baroreflex failure is unknown. Direct viral central nervous system invasion and neuroinflammation can be one of possible mechanisms; In a recent study, evidence of SARS-CoV-2 viral proteins and neuroinflammatory changes were reported in the brainstem and cranial nerves of postmortem brain autopsies of COVID-19 patients.14 However, the authors hypothesized that neuropathological changes and neurological manifestations were not associated with the presence of the viral proteins themselves but were attributed to be mostly due to cytokine-mediated neuroimmune stimulation.17 Indirect immune-mediated viral effects via cytokine release associated with the peripheral inflammatory response could be another possible mechanism by which COVID-19 can affect the central nervous system.18 Also, cytokines could affect the interplay between the immune system and autonomic nervous system. Previous studies have found that cytokines can modulate the activity of sympathetic and parasympathetic nervous systems, innervating multiple organs.19 Flow cytometry data from our patient and published reports2,4–6 showed elevated inflammatory markers which support this hypothesis. Involvement of other afferent nerves has been proposed in COVID-19 and has been proposed as an explanation for the lack of hypoxia sensing.20 One striking finding in this patient is the profound reduction in monocytes with increased activated dendritic cells expressing CD83. We previously found that proinflammatory milieu such as excess dietary salt result in increased conversion of monocytes to activated dendritic cells with increased expression of activation markers and cytokines including CD83 and IL-1β.21Autonomic dysfunction after viral infections has been previously reported22 and in most cases in association with Guillain-Barré syndrome (GBS). Unlike most of the previously published cases, our patient developed acute autonomic dysfunction without evidence of associated GBS. Noteworthy, acute pan-dysautonomia has been reported to be an uncommon variant of GBS,23 but these patients are characterized by efferent autonomic failure. BP fluctuations with hypertension alternating with hypotension were reported to be the most disabling symptoms associated with post-viral dysautonomia.23 Tuck et al24 did a detailed autonomic function testing in a group of patients with GBS and autonomic dysfunction and they documented impaired baroreflex sensitivity in some of these patients which may explain the BP fluctuations, also they hypothesized that glossopharyngeal nerve lesions could be the underlying mechanisms that could be contributing to BP fluctuations. Moreover, Ropper et al,25 performed a detailed hemodynamic assessment in a patient with GBS and severe dysautonomia and showed that BP fluctuations were due to changes in systemic vascular resistance associated with parallel (paradoxical) changes in heart rate, consistent with sympathetically driven hypertension. They reported elevated plasma catecholamines during both hypertension and hypotension episodes, but in our patient, we were able to document elevated plasma catecholamines level during the hypertensive episodes with normalization in between the episodes.Management of BP fluctuations in these patients is challenging and literature review showed no consistent data about management. We used the sympathetic clamp approach, which was described by our group previously for management of BP in baroreflex failure.12 The patient was started on a longer-acting central sympatholytic (guanfacine), to control the hyperadrenergic mediated hypertensive episodes, in combination with a rescue vasopressor (droxidopa) to prevent symptomatic hypotension, as a way to replace the baroreflex by clamping BP.In this case report, we suggest that labile hypertension after COVID-19 infection is caused by afferent baroreflex failure and the diagnosis can be established by detailed cardiovascular autonomic function testing. Further studies are required to explain the pathophysiological mechanisms of baroreflex arc involvement associated with COVID- 19 infection.SummaryWe report a case of COVID-19 infection associated with documented afferent baroreflex failure characterized clinically by extremely labile BP with episodes of hypertension and hypotension with parallel heart rate changes and documented by autonomic reflex testing showing absence of baroreflex function but exaggerated efferent pressor responses to cold stimulation. This case expands on the spectrum of autonomic dysfunction reported with COVID-infection which heretofore has been associated mostly with postural tachycardia syndrome, and suggest the involvement of sensory afferents which may also explain the lack of hypoxia sensing. The underlying pathophysiology is unclear, but in this case, there was evidence of abnormal inflammatory response. Labile hypertension was managed with a sympathetic BP clamp approach, combining the long-acting central sympatholytic guanfacine to prevent hypertensive episodes with the norepinephrine precursor droxidopa.Article InformationAcknowledgmentsThe authors would like to thank the house staff and many other health professionals involved in the care of this patient.Sources of FundingThis work was supported by the American Heart Association grant 967054 (Cardiovascular Autonomic and Immune Mechanism of Post-COVID-19 Tachycardia Syndrome); by the National Institutes of Health grants HL149386, HL161095, HL157584, HL155041, HL142583, and HL144941; by the Overton and Jeannette Smith Fund; and by the Joseph Ellis and Black funds and Research to Prevent Blindness GrantDisclosures None.FootnotesFor Sources of Funding and Disclosures, see page 899.The opinions expressed in this article are not necessarily those of the editors nor the American Heart Association.Presented in part at the Clinical-Pathological Conference chaired by Aletta E. Schutte and David G. Harrison at the Hypertension Scientific Sessions 2022 in San Diego, CA September 9, 2022. Khaled Elkholey and Italo Biaggioni presented the case and led the discussion.Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/HYPERTENSIONAHA.123.20316.Correspondence to: Italo Biaggioni, MD, Divisions of Clinical Pharmacology, Department of Medicine and Autonomic Dysfunction Center, Vanderbilt University Nashville, TN. Email italo.biaggioni@vumc.orgReferences1. Singleton CD, Robertson D, Byrne DW, Joos KM. Effect of posture on blood and intraocular pressures in multiple system atrophy, pure autonomic failure, and baroreflex failure.Circulation. 2003; 108:2349–2354. doi: 10.1161/01.CIR.0000097114.11038.26LinkGoogle Scholar2. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, Xie C, Ma K, Shang K, Wang W, et al. 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Blood pressure fluctuations in the dysautonomia of guillain-barre syndrome.Arch Neurol. 1990; 47:706–708. doi: 10.1001/archneur.1990.00530060120029CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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