Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency.

The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.

Spatial Morphoproteomic Features Predict Uniqueness of Immune Microarchitectures and Responses in Lymphoid Follicles.

Multiplex imaging technologies allow the characterization of single cells in their cellular environments. Understanding the organization of single cells within their microenvironment and quantifying disease-status related biomarkers is essential for multiplex datasets. Here we proposed SNOWFLAKE, a graph neural network framework pipeline for the prediction of disease-status from combined multiplex cell expression and morphology in human B-cell follicles. We applied SNOWFLAKE to a multiplex dataset related to COVID-19 infection in humans and showed better predictive power of the SNOWFLAKE pipeline compared to other machine learning and deep learning methods. Moreover, we combined morphological features inside graph edge features to utilize attribution methods for extracting disease-relevant motifs from single-cell spatial graphs. The underlying subgraphs were further analyzed and associated with disease status across the dataset. We showed that SNOWFLAKE successfully extracted significant low dimensional embedding from subgraphs with a clear separation between disease status and helped characterize unique cellular interactions in the subgraphs. SNOWFLAKE is a generalizable pipeline for the analysis of multiplex imaging data modality by extracting disease-relevant subgraphs guided by graph-level prediction.

Exploring Mental Health in a Pediatric Paradoxical Vocal Fold Motion Sample Using Patient-Reported Outcomes.

OBJECTIVE: Paradoxical vocal fold motion (PVFM) is characterized by inappropriate adduction of vocal folds during inspiration causing dyspnea. While anxiety is suspected to be a predisposing factor, incidence has been understudied. STUDY DESIGNS: Retrospective review. SETTING: Multidisciplinary PVFM hospital clinic. METHODS: We used patient-reported outcome measures to examine anxiety and depression in consecutive patients aged 10 to 17 years using Pediatric SFv1.1 Anxiety 8b and Level 2-Depression inventories (parents completed proxy forms). T-scores were classified as normal (none to slight <55) or elevated (mild 55-59.9, moderate 60-69.9, severe >70). RESULTS: Twenty-three pediatric patients and 20 parents completed surveys. Mean age was 13.74 years. For anxiety, 69.6% of patients and 40% of parents identified elevated levels. For depression, 30.4% of patients and 15% of parents identified elevated levels. Therapy need for the sample was 65.2% (34.8% active in services and 30.4% referred). Child anxiety scores were significantly higher in the therapy need group, U = 17, P = .004. CONCLUSION: This study of adolescents with PVFM confirmed elevated anxiety and depression scores in 2/3 of the participants. Anxiety likely precedes diagnosis and is a predisposing factor. Referral for individualized intervention targeting anxiety and depression is indicated.

Protein phosphatase 2A propels follicular T helper cell development in lupus.

Follicular helper T (Tfh) cells are important for generating humoral immune responses by helping B cells form germinal centers (GCs) and the production of high-affinity antibodies. However, aberrant Tfh cell expansion also contributes to the generation of self-reactive autoantibodies and promotes autoantibody-mediated autoimmune diseases such as systemic lupus erythematosus (SLE). Protein phosphatase 2A catalytic subunit alpha isoform (PP2A Cα) expression levels are elevated in peripheral T cells of SLE patients and positively correlate with autoantibody titers and disease activity. Here, we demonstrate a critical role of PP2A in Tfh differentiation by using T cell restricted PP2A Cα deficient mice. We observed impaired Tfh differentiation and GC response in two different classical Tfh induction models. Mechanistic studies revealed that downregulation of protein translation of the Tfh lineage transcription factor BCL6 in PP2A deficient T cells. Importantly, we found that PP2A deficiency by either gene knockout or chemical inhibition alleviated lupus severity in mice. Lastly, we confirmed a positive correlation between PP2A Cα and BCL6 protein levels in human CD4+ T cells from patients with SLE. In summary, our study revealed a critical role of PP2A in regulating Tfh cells and suggests it is a potential therapeutic target for lupus.

Examining the pediatric subglottic airway by ultrasound: A systematic review.

OBJECTIVE: The purpose of this review was to determine the ability of ultrasound (US) to assess the subglottic airway in pediatric patients to estimate the appropriate size of endotracheal tube (ETT). DATA SOURCES: Pubmed, Scopus, and Embase databases. METHODS: A search of the literature was performed for studies that utilized ultrasonography to examine the minimal transverse diameter of the subglottic airway (MTDSA) in the pediatric (age < 18) population to estimate endotracheal tube (ETT) size. Articles were excluded if they involved adults or non-humans, had no comparison method, or were case reports. The primary outcome was the successful use of ultrasound compared to the reference standard defined by the study. RESULTS: Sixteen studies were included, for a total of 1,633 pediatric subjects in whom transcervical laryngeal ultrasound was used prospectively to examine the MTDSA to estimate ETT size prior to intubation. Ultrasound reliably predicted the clinically best fit endotracheal tube by air leak test in 48-100% of subjects, while age-based formulas were accurate 24-95% of the time. Ultrasound was highly predictive of proper size, with R2 ranging between 0.684 to 0.980. Of those reintubated (n = 104), 86 (83%) required larger-sized tubes, while 18 (17%) required smaller-sized tubes. Both methods tended to underestimate ETT size, but the age-based formulas accounted for most of these differences. CONCLUSION: Transcervical laryngeal ultrasound appears to be a reliable predictor of endotracheal tube size in children undergoing elective surgery, which has implications for preventing intubation-related trauma and ensuring adequate ventilation for those who may require prolonged intubation.

A Nearly Obstructive Intratracheal Mass in a Pediatric Patient.

A 12-year-old girl presented to the clinic with a 3-month history of intermittent stridor; her symptoms were initially most prominent while playing sports and were suspected to be due to asthma or seasonal allergies. What is your diagnosis?

Adaptive immune responses to SARS-CoV-2 persist in the pharyngeal lymphoid tissue of children.

Most studies of adaptive immunity to SARS-CoV-2 infection focus on peripheral blood, which may not fully reflect immune responses at the site of infection. Using samples from 110 children undergoing tonsillectomy and adenoidectomy during the COVID-19 pandemic, we identified 24 samples with evidence of previous SARS-CoV-2 infection, including neutralizing antibodies in serum and SARS-CoV-2-specific germinal center and memory B cells in the tonsils and adenoids. Single-cell B cell receptor (BCR) sequencing indicated virus-specific BCRs were class-switched and somatically hypermutated, with overlapping clones in the two tissues. Expanded T cell clonotypes were found in tonsils, adenoids and blood post-COVID-19, some with CDR3 sequences identical to previously reported SARS-CoV-2-reactive T cell receptors (TCRs). Pharyngeal tissues from COVID-19-convalescent children showed persistent expansion of germinal center and antiviral lymphocyte populations associated with interferon (IFN)-γ-type responses, particularly in the adenoids, and viral RNA in both tissues. Our results provide evidence for persistent tissue-specific immunity to SARS-CoV-2 in the upper respiratory tract of children after infection.

Managing the Destructive Foreign Body: Water Beads in the Ear (A Case Series) and Literature Review.

OBJECTIVE: To characterize our experience with super-absorbent polymer beads placed in the external auditory canal to better understand the damage caused and subsequent management required. METHODS: Retrospective chart review of pediatric patients at 2 separate tertiary referral centers. RESULTS: Seven patients were identified as having placed super-absorbent polymer beads in the external auditory canal, 6 of whom required removal under general anesthesia. Three patients did not suffer otologic trauma or hearing loss (average foreign body duration <72 hours). Four patients experienced severe otologic complications (average foreign body duration >1 week), all of whom were treated with otologic drops prior to bead identification. Of this severe complication group, 3 patients had restored hearing after surgical intervention, while 1 patient suffered profound hearing loss secondary to labyrinthitis ossificans. CONCLUSION: Early recognition of otologic foreign bodies is important, particularly if expansile water-bead is suspected. Depending on timeframe, water beads are highly destructive to the middle ear structures, and most patients will require surgical intervention.

Association of anosmia and neutralizing antibody production in adolescents with SARS-CoV-2.

BACKGROUND: To monitor olfactory/gustatory dysfunction and its relationship to SARS-CoV-2 IgG antibody responses in an adolescent population. METHODS: Adolescents with changes in olfactory/gustatory functions were enrolled in a 15-month study. The patients were evaluated with 1) SNOT-22, 2) pediatric smell wheel, and 3) SARS-CoV-2 antibody testing. The relationship between these scores and length of anosmia, and the amount of SARS-CoV-2 IgG antibodies were assessed. A brain MRI was performed in cases of persistent special sensory symptoms. RESULTS: Eighteen patients were identified with smell and/or taste complaints. Most of the patients were female (67%) and median age was 15 years (range 11-17). Twelve patients had prior SARS-CoV-2 PCR testing, with only five patients with a positive result. The median SNOT-22 score was 16 (range 0-52) and the median smell wheel score was 6.5 (range 1-11). Patients with taste difficulty were more likely to have a score less than eight. 78% of the patients tested positive for antibodies and there was a strong negative correlation between smell wheel score and antibody level (Spearman, ρ = -0.798, p = 0.002). Five patients underwent MRI scan, and all resulted as normal olfactory bulb structures. 66% received nasal corticosteroids. 11 patients presented in follow up. CONCLUSIONS: Adolescents presenting to a pediatric ENT clinic during the SARS-CoV-2 pandemic were likely to have prolonged (>6 weeks) symptoms of SARS-CoV-2. The majority do not report positive PCR testing result but do report systemic symptoms including anosmia. This suggests that anosmia may be both a late and prolonged symptom of SARS-CoV-2.

Multi-Institutional Study of Patient-Reported Outcomes of Paradoxical Vocal Fold Motion.

OBJECTIVE: To explore patient-reported outcome measures of pediatric paradoxical vocal fold motion through a multi-institutional study of geographically diverse United States medical facilities to assess long-term management and outcomes. METHODS: Eligible participants >8 years of age diagnosed with PVFM over a 10-year period from 7 tertiary pediatric hospitals were invited to complete a survey addressing study objectives. RESULTS: 65 participants completed the survey, of whom 80% were female, 75% reported a 3.5 grade point average or better, and 75% identified as competitive athletes or extremely athletic individuals. Participants rated their perceived efficacy of 13 specific treatments. Only five treatments were considered effective by a majority of the participants who tried them. The treatments that participants tried most often were breathing exercises (89.2%), bronchodilator treatments (45%), and allergy medications (35.4%). 78.8% of participants reported receiving more than one treatment and 25% reported receiving a combination of bronchodilators, anticholinergics, and steroids. At the time of PVFM diagnosis, 38% of participants had no idea when their symptoms would completely resolve. 23.3% of participants did not experience symptom resolution until greater than 1 year after diagnosis. CONCLUSIONS: Traditional management tools such as breathing exercises and biofeedback treatments may not provide the long-term benefit that providers anticipate. In addition to these commonly used management strategies, highly efficacious techniques such as counseling and lifestyle management should be incorporated into the long-term management of patients whose symptoms are refractory to traditional care. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:970-976, 2023.

Examining multi-level immune response to determine prevalence of COVID-19 in pediatric tonsillectomy.

OBJECTIVE: To determine the prevalence of COVID-19 in a cohort of children undergoing tonsillectomy through assessment of B cell immune responses to SARS-CoV-2 in both peripheral blood and tonsil tissue. METHODS: In this cohort study at a tertiary pediatric hospital (Children's National Hospital) in Washington, DC, we recruited 100 children undergoing tonsillectomy from late September 2020 to January 2021. Serum, peripheral blood cells, and tonsil tissue were collected and examined for immune reactivity to SARS-CoV-2. Parent-reported clinical histories were compared to antibody and B-cell responses. RESULTS: Among 100 children undergoing tonsillectomy, 19% had evidence of immune responses to SARS-CoV-2 (CoV2+), indicating prior COVID-19. In all seropositive participants, we detected SARS-CoV-2 specific B cells in both peripheral blood mononuclear cells and tonsils, providing evidence for tissue-specific immunity in these children. Of the 19, 63% reported no known history of COVID-19, and an additional 3 were asymptomatic or unaware of an acute infection when detected on pre-surgery screen. Hispanic children represented 74% of CoV2+ subjects compared to 37% of the full cohort. 100% of CoV2+ children lived in a zip code with poverty level >10%. CONCLUSIONS: Nearly one-fifth of children undergoing tonsillectomy at an urban U.S. hospital had evidence of prior COVID-19 during the early pandemic, with the majority unaware of prior infection. Our results underscore the ethnic and socio-economic disparities of COVID-19. We found concordant evidence of humoral immune responses in children in both blood and tonsil tissue, providing evidence of local immune responses in the upper respiratory tract. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1993-1999, 2023.

Robust, persistent adaptive immune responses to SARS-CoV-2 in the oropharyngeal lymphoid tissue of children.

SARS-CoV-2 infection triggers adaptive immune responses from both T and B cells. However, most studies focus on peripheral blood, which may not fully reflect immune responses in lymphoid tissues at the site of infection. To evaluate both local and systemic adaptive immune responses to SARS-CoV-2, we collected peripheral blood, tonsils, and adenoids from 110 children undergoing tonsillectomy/adenoidectomy during the COVID-19 pandemic and found 24 with evidence of prior SARS-CoV-2 infection, including detectable neutralizing antibodies against multiple viral variants. We identified SARS-CoV-2-specific germinal center (GC) and memory B cells; single cell BCR sequencing showed that these virus-specific B cells were class-switched and somatically hypermutated, with overlapping clones in the adenoids and tonsils. Oropharyngeal tissues from COVID-19-convalescent children showed persistent expansion of GC and anti-viral lymphocyte populations associated with an IFN-γ-type response, with particularly prominent changes in the adenoids, as well as evidence of persistent viral RNA in both tonsil and adenoid tissues of many participants. Our results show robust, tissue-specific adaptive immune responses to SARS-CoV-2 in the upper respiratory tract of children weeks to months after acute infection, providing evidence of persistent localized immunity to this respiratory virus.

Ultrasound of the vocal cords in infants.

Vocal cord paralysis is a common cause of respiratory and feeding problems in the pediatric population. While the causes of vocal cord paralysis are multiple, iatrogenic injury of the recurrent laryngeal nerve after cardiovascular surgery is the most frequent cause. Vocal cord paralysis increases the risk of swallowing dysfunction, tracheal aspiration and pneumonia. It also increases the need for nasoenteric feeds and gastrostomy tube placement. Flexible nasopharyngolaryngoscopy is considered the gold standard for diagnosing vocal cord paralysis, but it has significant drawbacks: it is uncomfortable, it can trigger a cardiovascular event in children with unstable cardiovascular status, it can be challenging to perform, and it can be difficult to interpret. Laryngeal US has become a popular imaging modality to evaluate the function of the vocal cords. Laryngeal US is well-tolerated, easy to perform, simple to interpret and has a lower physiological impact compared to flexible nasopharyngolaryngoscopy. Laryngeal US is an accurate and low-cost diagnostic test for vocal cord paralysis. In this review, we describe the anatomy of the larynx and recurrent laryngeal nerve; the causes, symptoms and pathophysiology of vocal cord paralysis; laryngeal US technique; diagnostic criteria for vocal cord paralysis; and a reporting system.

Pediatric tracheostomy surveillance.

We report an unusual case of a 14-month-old ex-28 week, ventilator-dependent male with a history of bronchopulmonary dysplasia and tracheostomy at 2 months of age. Lost to follow-up, at age 9 months, he presented to the emergency department with worsening respiratory distress. The patient was taken to the operating room at which time direct visualization of the airway demonstrated a mass filling the entire glottic inlet without supraglottic or pharyngeal mucosal attachments. The solid, nonvascular, mass appeared to be emanating from a suprastomal site. Excision proved to relieve the airway obstruction and postoperatively the patient has thrived.

Systemic Bevacizumab for Treatment of Respiratory Papillomatosis: International Consensus Statement.

OBJECTIVES/HYPOTHESIS: The purpose of this study is to develop consensus on key points that would support the use of systemic bevacizumab for the treatment of recurrent respiratory papillomatosis (RRP), and to provide preliminary guidance surrounding the use of this treatment modality. STUDY DESIGN: Delphi method-based survey series. METHODS: A multidisciplinary, multi-institutional panel of physicians with experience using systemic bevacizumab for the treatment of RRP was established. The Delphi method was used to identify and obtain consensus on characteristics associated with systemic bevacizumab use across five domains: 1) patient characteristics; 2) disease characteristics; 3) treating center characteristics; 4) prior treatment characteristics; and 5) prior work-up. RESULTS: The international panel was composed of 70 experts from 12 countries, representing pediatric and adult otolaryngology, hematology/oncology, infectious diseases, pediatric surgery, family medicine, and epidemiology. A total of 189 items were identified, of which consensus was achieved on Patient Characteristics (9), Disease Characteristics (10), Treatment Center Characteristics (22), and Prior Workup Characteristics (18). CONCLUSION: This consensus statement provides a useful starting point for clinicians and centers hoping to offer systemic bevacizumab for RRP and may serve as a framework to assess the components of practices and centers currently using this therapy. We hope to provide a strategy to offer the treatment and also to provide a springboard for bevacizumab's use in combination with other RRP treatment protocols. Standardized delivery systems may facilitate research efforts and provide dosing regimens to help shape best-practice applications of systemic bevacizumab for patients with early-onset or less-severe disease phenotypes. LEVEL OF EVIDENCE: 5 Laryngoscope, 131:E1941-E1949, 2021.

Decrease in Respiratory Related Hospitalizations in Tracheostomy-Dependent Children Who Tolerate Passy-Muir Valve Use.

OBJECTIVE: To assess the effect of Passy-Muir® Valve (PMV) tolerance on respiratory illness and respiratory related hospital admissions in tracheostomy-dependent children. METHODS: Retrospective cohort study of 262 patients who underwent tracheostomy placement between 2012 and 2018 at a tertiary free-standing children's hospital. Outcome measures studied were number of reported upper respiratory infections and respiratory related hospitalizations per year (RRH/year). RESULTS: About 135 (51.5%) tracheostomy-dependent children underwent PMV trials, and 106 (78.5%) of these children were able to tolerate PMV for at least 1 hour daily. When comparing children who tolerated PMV versus those who did not, the latter group had significantly higher rates of subglottic stenosis but no significant differences in RRH/year or average age. In those children who tolerated PMV and achieved routine use of PMV > 1 hour/day, an average of 1.14 RRH/year occurred prior to PMV tolerance, as compared with 0.57 RRH/year after PMV tolerance (P = .003). Multivariate analysis shows that in patients <2 years, there is a significant decrease in RRH/year after PMV tolerance is attained (1.53 vs 0.76, P = .001), independent of indication for tracheostomy. CONCLUSION: In tracheostomy-dependent children who tolerate PMV use routinely >1 hour/day there are decreased rates of respiratory related hospitalizations (RRH). Children <2 years of age have the most impact of RRH, with rates that are significantly lower with routine use of the PMV.

Presenting Symptom as a Predictor of Clinical course in Juvenile Onset Recurrent Respiratory Papillomatosis.

OBJECTIVE/HYPOTHESIS: Determine if the presentation of voice versus airway symptoms at the time of diagnosis of juvenile recurrent respiratory papillomatosis (JORRP) correlates with treatment and outcomes. STUDY DESIGN: Original report, Retrospective review. METHODS: Twenty year retrospective review of all patients with JORRP presenting at any time in treatment to a single tertiary children's hospital between 1997 and 2017. RESULTS: Fifty-four patients presented with a diagnosis of JORRP during the 20 year study period. Of these, 32 were female and 22 were male. African American children made up the majority of the patients (65%), with 19% identifying as Caucasian, 9% Hispanic, and 7% Asian. Fifteen of the children presented initially to the ENT clinic (87% with hoarseness), 12 to the emergency department (92% with airway concerns), 11 to the voice clinic, and the remaining 12 at outside hospitals or clinics and care were transferred. Voice symptoms, namely hoarseness, was the presenting symptom in 31 (57%), airway symptoms, namely respiratory distress or stridor was predominate in 17 (32%), and the presenting symptom was unknown in six cases (11%). Children presenting with airway symptoms were younger at presentation (median 2.1 years, range 0.38-8.77 years) than those presenting with voice symptoms (median 6.7 years, range 0.98-15.13 years), and after adjusting for age underwent a greater number of surgeries in the first year to control disease. CONCLUSIONS: Patients who present with airway symptoms present younger and have an increased number of surgeries in the first year compared to those presenting with voice complaints. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1670-1675, 2021.

Common genetic susceptibility loci link PFAPA syndrome, Behçet's disease, and recurrent aphthous stomatitis.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the pathogenesis is unknown. We queried two European-American cohorts and one Turkish cohort (total n = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behçet's disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of IL12A (rs17753641) is strongly associated with PFAPA (OR 2.13, P = 6 × 10-9). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ and LPS stimulation than those from individuals without the risk allele. We also found that variants near STAT4, IL10, and CCR1-CCR3 were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behçet's disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet's disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet's spectrum disorders to highlight their relationship. HLA alleles may be factors that influence phenotypes along this spectrum as we found new class I and II HLA associations for PFAPA distinct from Behçet's disease and recurrent aphthous stomatitis.

Outcomes of Paradoxical Vocal Cord Motion Diagnosed in Childhood.

OBJECTIVES: To explore long-term patient reported outcome (PRO) measures of pediatric paradoxical vocal cord motion (PVCM) including ease of diagnosis, management, symptom duration and effect on quality of life. METHODS: All children >8 years of age diagnosed with PVCM at a tertiary pediatric hospital between 2006 and 2017 were invited to complete a survey addressing study objectives. RESULTS: 21/47 eligible participants could be contacted and 18/21 (86%) participated. 78% were female with a mean age at diagnosis of 11.6 and 15.0 years at survey completion. Common PVCM symptoms reported were dyspnea (89%), globus sensation (56%), and stridor (50%). The median time to diagnosis was 3 months (IQR 2-5 months). Nearly all reported being misdiagnosed with another condition, usually asthma, until being correctly diagnosed usually by an otolaryngologist. Participants reported undergoing 3.7 diagnostic studies (range 0-8); pulmonary function testing was most common. Of numerous treatments acknowledged, breathing exercises were common (89%) but only reported helpful by 56%. Use of biofeedback was recalled in 1/3 of subjects but reported helpful in only 14% of them. Anti-reflux, allergy, anticholinergics, inhalers and steroids were each used in >50%, but rarely reported effective. PVCM was reportedly a significant stressor when initially diagnosed but despite 2/3 of participants still reporting ongoing PVCM symptoms, the perceived stress significantly decreased over time (Z = 3.26, P = 0.001). CONCLUSIONS: This first PVCM PRO study endorses that diagnosis is often delayed and prescribed treatments often viewed as ineffective. While biofeedback and breathing exercises may be critical for short-term control of PVCM episodes, lifestyle changes and stress reduction are likely necessary for long-term management. Increased awareness and improvements in management are needed for this condition.