Sex: M
Vaccine: COVID19
Symptoms: Histamine level, Investigation, Leukotriene test, Magnetic resonance imaging head, Metabolic function test
Clinical narrative: Postural orthostatic  tachycardia syndrome; This is a literature report for the following literature source(s).  Postural orthostatic tachycardia syndrome (POTS) is a condition primarily affecting females between the ages of 12 and 50 years; it is most commonly triggered by viral infections, pregnancy, fever, surgery, or trauma.1 Symptoms of POTS include dizziness/lightheadedness, fatigue, palpitations, visual disturbance, headache, nausea, and difficulty concentrating. While there are likely several underlying mechanisms and etiologies of POTS, an autoimmune basis of POTS has been postulated.2,3 Since the start of the COVID-19 pandemic, several case reports have documented the onset of POTS following SARS-CoV-2 infection4-6; in fact, our group published one of the first documented cases of POTSfollowing SARS-CoV-2 infection in a pediatric patient.7 The development of POTS following SARSCoV-2 is not entirely surprising considering that prior to the pandemic, roughly 50% of patients reported a history of infection closely preceding the onset of their POTS symptoms. The authors report a case of POTS in combination with another cause of dizziness, persistent postural perceptual dizziness (PPPD), following mRNA COVID-19 vaccination; to our knowledge, this is one of the first documented cases of POTS and PPPD co-occurring. The authors aim to bring more attention to both POTS and PPPD as 2 distinct causes of chronic dizziness that can coexist. The co-occurrence of POTS and PPPD may indicate a common etiology of the 2 conditions, or, perhaps, one may directly or indirectly cause the other.   Case Report A 15-year-old male reported general malaise in the hours following administration of his second dose of the Pfizer-BioNTech mRNA COVID-19 vaccine. He went on to develop symptoms of dizziness, headache, fatigue flushing, and nausea over the next few days. Prior to vaccination, he had been running daily and was overall healthy, with no chronic medical problems besides mild anxiety and depression, which had been well controlled on 20 mg of fluoxetine daily. Interestingly, the patient tolerated the first vaccine without incident. Over the next year and a half, his symptoms fluctuated but persisted, with dizziness being his most debilitating symptom. His dizziness, described as if the room were spinning, was exacerbated by standing up quickly, motion, and exertion, and was often accompanied by nausea, visual changes, and worsening headache. In light of persistent symptoms, the patient was evaluated by several pediatric neurologists; multiple neurological examinations were documented as reassuring and nonfocal. Magnetic resonance imaging of the brain revealed a few faint punctate foci scattered in cerebral white matter, deemed a normal variant, and was otherwise unremarkable. Of note, punctate foci are more often seen in patients with migraine headaches than in the general population.9 A complete blood count and complete metabolic panel were unremarkable, with a C-reactive protein = 0.1, erythrocyte sedimentation rate = 5, vitamin D = 45, vitamin B12 = 987, thyroid-stimulating hormone = 0.8, Epstein-Barr virus (EBV) IgM antibody = 0.2, EBV IgG antibody = <0.2, Borrelia burgdorferi antibody test negative, and ferritin = 60. Trials of meclizine 25 mg as needed, sumatriptan 50 mg as needed, zonisamide 5 mg daily, and topiramate 50 mg twice daily (BID) for headaches did not result in symptomatic improvement. Six months after the onset of symptoms, the patient underwent cardiac testing; his cardiac examination, echocardiogram,and electrocardiogram (ECG) were unremarkable. A 10-minute passive standing test revealed an increase in heart rate (HR) of 45 beats per minute (bpm) from 54 bpm supine to a peak of 99 bpm standing, associated with worsening orthostatic symptoms, and in the absence of orthostatic hypotension, consistent with the criteria proposed by the 2019 agency to diagnose POTS.1 He was subsequently trialed on various interventions commonly used to treat POTS, including both non-pharmacological and pharmacological measures. Initially, he saw some improvement in symptoms after increasing his daily fluid and salt intake, but the improvement was not sustained. He also tried several medications commonly used for POTS; some, like fludrocortisone 1 mg daily and propranolol 10 mg 3 times daily (TID), appeared to exacerbate his symptoms, while others, like midodrine 7.5 mg TID and pyridostigmine 60 mg BID, resulted in only very mild improvement. He also started physical therapy (PT) twice weekly; he followed a POTS protocol, focusing on recumbent physical activity, and   was able to work up to 50minutes at a time on a recumbent bike. At the same time, he was working with a pediatric psychologist twice a month on pain-coping strategies for headaches. After completing several months of PT and therapy services, he noted some improvement in functioning but not in symptom burden. Due to the presence of flushing, mild dermatographia, and pruritus upon standing, the possibility of mast cell activation syndrome (MCAS) was investigated; testingwas ordered and revealed a normal tryptase, urine N-methylhistamine, chromogranin A, and PGF2 alpha, but elevated plasma histamine level of 3.7 (<1.8) and urine leukotriene E4 level of 193 (<104). Based on these results, the patient met Consensus-2 criteria for MCAS, including 1 major criterion (clinical complaints) and 2 minor criteria (presence of elevated mast cell mediators: histamine and leukotriene E4).10 Various pharmacological agents aimed at MCAS, including a combination of H1 (cetirizine 10 mg daily) and H2 blockers (famotidine 20 mg BID), cromolyn sodium 200 mg 4 times daily, and quercetin 500 mg daily, proved ineffective. Considering the patient's lack of response to multiple MCAS-targeted treatments, it is possible that MCAS was an overdiagnosis in this case.11 Despite various interventions for chronic headaches, POTS, and MCAS, the patient saw little improvement and remained functionally impaired over a year following the onset of his symptoms. He was unable to return to in-person school and struggled to complete even asynchronous virtual school due to his symptom burden. Finally, the patient underwent vestibular testing, which showed gaze-evoked right-beating nystagmus and left unilateral weakness on caloric testing. These results were interpreted as mild left vestibular hypofunction, possibly resulting from vestibular neuritis. Persistent postural perceptual dizziness is a condition typically precipitated by another event or disorder that causes dizziness or vertigo, which can include vestibular neuritis. Patients with PPPD therefore sometimes have abnormalities on vestibular testing related to the precipitating or comorbid disorder. The authors' patient's clinical picture, in particular the severity and chronicity of his symptoms, was overall consistent with a diagnosis of PPPD, possibly triggered by vestibular neuritis.12 Treatment recommendations for PPPD included cognitive behavioral therapy (CBT), vestibular PT, and migraine diet and lifestyle modifications. The patient was then referred and accepted into a monthlong pediatric day rehabilitation program, which provides daily, intensive rehabilitation services consisting of PT, occupational therapy (OT), and CBT services. After completing the program, the patient's symptoms improved enough that he was able to start a gradual return to in-person school. Two months later, he described himself as 100% functional albeit not completely symptom-free. He remains on target to graduate on time with his classmates. Discussion Although several case reports have suggested a temporal relationship between vaccination and POTS, a causal association has never been established.13,14 According to the Vaccine Adverse Event Reporting System (VAERS), a total of 29 case reports worldwide from June 1, 2006, through August 31, 2015, described the onset of POTS following administration of the human papillomavirus (HPV) vaccine.15 The VAERS review concluded that POTS following HPV vaccination was relatively rare, accounting for just 0.4% of all HPV reports during the study period. As the incidence of POTS is highest in teens and young adults, which is the predominant demographic receiving the HPV vaccination series, it was hypothesized that the occurrence of POTS following HPV vaccination is most likely due to chance alone. Two recent review articles, including one from the Society, have similarly concluded that there is insufficient evidence to support a causal relationship between POTS and the HPV vaccine. With regard to the COVID-19 mRNA vaccine specifically, a recent cohort study of 284,592 COVID-19 -vaccinated individuals demonstrated that the odds of developing POTS were higher in the 90 days after vaccination compared with the 90 days prior.18 Nevertheless, the authors caution that these results should not be interpreted as a causal link due to the observational design of the study. While there are several case reports describing a temporal association between POTS and COVID vaccination in adults,19-21 the only published pediatric case report describing this association is convoluted by several factors, including an imprecise timeline and a concomitant diagnosis of myocarditis.22 Although autoimmunity is a potential key mechanism underlying vaccine-induced and infection-induced POTS, it is important to note that very little conclusive evidence has emerged for autoimmune mechanisms in POTS.23 Persistent postural perceptual dizziness (PPPD) is a newly recognized disorder by the World Health Organization, caused by chronic dysfunction of the vestibular system and characterized by at least 3 months of persistent dizziness, nonspinning vertigo, and/or unsteadiness.24,25 PPPD typically develops in response to an insult or other condition(s) that cause dizziness; this insult is thought to induce an overreliance on postural control strategies and visual stimuli for spatial orientation. 25 Symptoms of PPPD are exacerbated by upright posture, active or passive movement (eg, walking or riding in a vehicle), and exposure to complex visual stimuli (eg, wallpaper with an intricate pattern). 24,25 Symptoms tend to cause the patient significant distress, especially in the modern world with its increasing fascination with multimedia stimulation.24 While there are similarities between POTS and PPPD, for example, in both conditions, patients experience dizziness that increases upon standing, there are also differences. An important distinction is that sensitivity to complex or moving visual stimuli from a seated position is specific to PPPD as POTS is a purely orthostatic condition. Furthermore, PPPD does not cause abnormal changes in HR as seen in POTS. It is important to distinguish between these two conditions as medications targeted to POTS are unlikely to be useful in PPPD (see Table). Our patient remained debilitated for over a year following vaccination despite trying various treatments for POTS, MCAS, and chronic daily headache; he finally experienced significant improvement in symptoms and functioning when his treatment plan was targeted to PPPD. In his case, the PPPD may have been triggered by vestibular neuritis, headache syndrome, anxiety, and/or POTS itself, which can all occur after vaccination and cause dizziness.26,27 Alternatively, it is possible that the patient first developed PPPD, which caused dizziness upon standing; this dizziness, in turn, may have produced discomfort and/or anxiety, resulting in a tachycardia mimicking POTS.While it is known that benign paroxysmal positional vertigo and vestibular migraines can trigger PPPD and then coexist with it,24 our literature search found no reports linking POTS with PPPD; thus, this is one of the first reported case describing POTS co-occurring with PPPD. The co-occurrence of POTS and PPPD may indicate a common etiology of the 2 conditions or, perhaps, as we suggest, one may directly or indirectly cause the other. Our primary aim is to bring attention to both POTS and PPPD as distinct and, importantly, treatable causes of chronic dizziness that may co-occur. The authors believe further research is needed to determine the prevalence of both POTS and PPPD as separate but also coexisting conditions in adult and pediatric patients alike.; Sender's Comments: The impact of this report on the benefit/risk profile of the Pfizer product is evaluated as part of Pfizer procedures for safety evaluation, including the review and analysis of aggregate data for adverse events. Any safety concern identified as part of this review, as well as any appropriate action in response, will be promptly notified to Regulatory Authorities, Ethics Committees and Investigators as appropriate.