Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis.

BACKGROUND: Ivacaftor (IVA) has been shown to be safe and efficacious in children aged ≥4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF. METHODS: In this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements. RESULTS: Seven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received ≥1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (-40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed. CONCLUSIONS: In this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age.

Dobutamine-Induced Myoclonus in a Patient With Advanced Heart Failure and Chronic Kidney Disease.

Dobutamine is a positive inotropic agent often used in treatment of cardiogenic shock. Although there are well-documented adverse effects, dobutamine-induced myoclonus is a rarely reported phenomenon. Our case offers a direct and temporally related description of myoclonus, with onset observed within hours of dobutamine initiation and complete resolution within minutes of discontinuation.

Disparities in Huntington Disease Severity: Analysis Using the ENROLL-HD Dataset.

Background and Objectives: Social and structural determinants of health (SDOH) have been associated with disability in neurologic diseases. However, the association between these factors and disability in Huntington disease (HD) has not been studied. This study aimed to evaluate the association of racial and sociodemographic factors with disease severity in patients with HD in North America. Methods: We conducted a cross-sectional study of genetically confirmed participants with HD (36+ CAG repeats) in the North American region using the ENROLL-HD 2020 periodic dataset. In this analysis, our exposure variable was the participant's race/ethnicity. The main outcome measure was disease severity, as measured by the Total Functional Capacity Score (TFC), which measures the level of disability of patients with HD. We used multivariate regression models to adjust for sociodemographic factors that may mediate or moderate a causal effect between race/ethnicity and disease severity. Results: Among 4,717 gene-positive participants in the North American region, 89.5% identified as White, 3.4% as Hispanic or Latino, and 2.3% as African American/Black. The average TFC score was 10.22 (SD 3.22); 48% of participants completed either secondary education (including college) or a professional degree, and 55% lived in a city and not in a town, village, or rural location. In multivariate regression models, we found that Black participants and those with less than a high school degree entered the ENROLL-HD study with lower TFC scores than White participants. We also found that compared with those with at least a high school degree, those who completed some form of higher education or professional degree had higher TFC scores (p < 0.001). This multivariate analysis did not find an association between geographic location and TFC score. Discussion: Our study found that Black participants in North America presented to ENROLL-HD with more advanced disease than White patients. We also found that higher education was associated with less advanced disease when entering the ENROLL-HD study. The role of race/ethnicity and education in HD symptom severity warrants further investigation. These findings underscore the importance of further studying the role of social and structural determinants of health in patients with HD, particularly those from historically marginalized communities.

Adolescent e-cigarette or vaping product use-associated lung injury: A case series and review of the literature.

BACKGROUND: Adolescent e-cigarette or vaping product use-associated lung injury (EVALI) has increased in prevalence, and while cases describing various pulmonary manifestations have been reported, reports on the presentations and outcomes in teenage patients are sparse. METHODS: We retrospectively describe eight EVALI patients with different presentations, laboratory and imaging findings, treatment, and concomitant diagnoses. We review the literature and describe how our analysis adds to the literature. FINDINGS: Eight males, aged 15-18 years of age presented with various symptoms. Four patients were Caucasian while four were of Hispanic origin. All patients presented with respiratory symptoms; six also had GI symptoms; five were hypoxemic; all but one patient admitted to using products containing tetrahydrocannabinol (THC). All patients had changes on imaging with ground-glass opacities. One patient underwent lung biopsy and bronchoscopy showing eosinophilic pneumonia. All patients received antimicrobial therapies without improvement until systemic steroids were administered. Six patients underwent pulmonary function testing, and five required medications for newly diagnosed persistent asthma. One patient developed pulmonary hypertension, which resolved after treatment. One patient required noninvasive ventilation. No patients were positive for SARS-CoV2. Two had coinfections with other microbes. Five patients required escalation of asthma therapies at follow-up with pulmonology. CONCLUSION: This analysis of eight adolescent males hospitalized for EVALI highlights the unpredictable spectrum of disease presentation and management. These patients can be misdiagnosed without proper screening and may have residual respiratory complications necessitating outpatient management by a pulmonologist.

A commentary on adolescent electronic cigarette use and nicotine addiction.

Adolescent electronic cigarette (e-cigarette) use has continued due to the ongoing struggle with nicotine addiction affecting teenagers. By briefly discussing the timeline of the emergence of e-cigarettes and nicotine addiction in adolescents, this author hopes to shed some light on mitigation strategies to curtail this ongoing epidemic of youth e-cigarette use and nicotine addiction through public health education and advocacy.

A Rare Case of Steroid-Resistant Neurosarcoidosis of the Cavernous Sinus With Optic Neuropathy: A Case Report.

Sarcoidosis is an inflammatory disease that presents with nervous system involvement in 5-10% of cases, commonly known as neurosarcoidosis.1 While there are no randomized controlled trials for the treatment of neurosarcoidosis, expert opinion supports initial treatment with corticosteroids and the use of steroid-sparing or anti-TNF agents in refractory or severe cases. We report a case of a 48-year-old African American male with a past medical history of biopsy-proven hepatic and renal sarcoidosis and progressive headache, dizziness, and blurry vision for 5 months, presenting with an acute exacerbation of right-sided vision loss over one day. MRI of the brain revealed a dural-based mass extending into the right cavernous sinus and compressing the right optic nerve. Given the pathological confirmation of systemic granulomatous disease consistent with sarcoidosis, clinical manifestations, bilateral hilar and mediastinal lymphadenopathy, MRI findings typical of central nervous system inflammation, and exclusion of other possible etiologies, the patient was diagnosed with probable neurosarcoidosis. Corticosteroids initially resolved his symptoms; however, he suffered an acute relapse. Combination therapy with corticosteroids plus mycophenolate mofetil (MMF) led to the eventual resolution of his symptoms. Only 8 cases of neurosarcoidosis involving the cavernous sinus have been reported. Our patient represents the only reported case of probable neurosarcoidosis of the cavernous sinus with optic neuropathy successfully treated with corticosteroid plus MMF combination therapy. We highlight the need to consider early, aggressive treatment in cases of neurosarcoidosis with optic neuropathy and to develop criteria to guide treatment strategy based on neurolocalization and the degree of neurological disability.

Correlating objective echocardiographic parameters in patients with pulmonary hypertension due to bronchopulmonary dysplasia.

OBJECTIVE: Echocardiographic parameters assessing left and right heart function were evaluated in children with established pulmonary hypertension (PH) from bronchopulmonary dysplasia (BPD) to look for correlations with each other, and pulmonary artery pressure (PAPs) from right heart catheterizations (RHC). STUDY DESIGN: Data were retrospectively collected on patients with BPD and PH and correlations were performed between various objective echocardiographic and RHC measurements. RESULTS: A total of 31 patients with BPD were found to have PH by echocardiogram and RHC after chart review. Median age of evaluation was 0.58 years. Correlations were noted between measurements of right heart function, indirect measures of pulmonary artery pressures and left ventricular dimensions. A trend was noted between the tricuspid annular plane systolic excursion obtained at echocardiography and systolic pulmonary artery pressure, obtained during RHC. CONCLUSION: Significant correlations were found between objective echocardiographic measurements of left and right heart function, in patients with PH from BPD.

Obstructive Sleep Apnea and Pulmonary Hypertension in Children.

Obstructive sleep apnea (OSA) is a common pediatric breathing disorder, affecting 1-5% of all children. Pulmonary hypertension (PH), a severe complication of OSA, is associated with significant morbidity and mortality. Despite this important relationship between OSA and PH, there is sparse literature addressing this subject in children. This review will examine the putative relationship between OSA and PH, synthesize the available literature in children, and suggest a reasonable approach, despite limited data, for clinicians. We conclude that available evidence suggests many children with OSA have evidence of PH (estimates ranging from 0% to 85%) and vice versa (estimates ranging from 6% to 24%). Furthermore, previous studies demonstrate that treatment of the OSA, either with surgery or non-invasive ventilation, ameliorates pulmonary artery pressures to the extent of cure in a substantial number of cases. Future studies are required to better delineate the true co-occurrence of these diseases and help predict which patients are at greater risk for this serious complication. Clinicians who maintain a healthy vigilance for this important interaction of disease states will likely recognize opportunities to intervene and improve prognoses in these patients.