Sequencing of idiopathic pulmonary fibrosis-related genes reveals independent single gene associations

BACKGROUND: Previous studies investigating a genetic basis for idiopathic pulmonary fibrosis (IPF) have focused on resequencing single genes in IPF kindreds or cohorts to determine the genetic contributions to IPF. None has investigated interactions among the candidate genes. OBJECTIVE: To compare the frequencies and interactions of mutations in six IPF-associated genes in a cohort of 132 individuals with IPF with those of a disease-control cohort of 192 individuals with chronic obstructive pulmonary disease (COPD) and the population represented in the Exome Variant Server. METHODS: We resequenced the genes encoding surfactant proteins A2 (SFTPA2), and C (SFTPC), the ATP binding cassette member A3 (ABCA3), telomerase (TERT), thyroid transcription factor (NKX2-1) and mucin 5B (MUC5B) and compared the collapsed frequencies of rare (minor allele frequency <1%), computationally predicted deleterious variants in each cohort. We also genotyped a common MUC5B promoter variant that is over-represented in individuals with IPF. RESULTS: We found 15 mutations in 14 individuals (11%) in the IPF cohort: (SFTPA2 (n=1), SFTPC (n=5), ABCA3 (n=4) and TERT (n=5)). No individual with IPF had two different mutations, but one individual with IPF was homozygous for p.E292V, the most common ABCA3 disease-causing variant. We did not detect an interaction between any of the mutations and the MUC5B promoter variant. CONCLUSIONS: Rare mutations in SFTPA2, SFTPC and TERT are collectively over-represented in individuals with IPF. Genetic analysis and counselling should be considered as part of the IPF evaluation

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Abstract Number ‐ 223: Spontaneous Revascularization of Completely Occluded Internal Carotid Artery: Case Report

Introduction Occlusion of the internal carotid artery (ICA), caused by atherosclerotic thrombosis, arterial embolism, or dissection, is associated with high morbidity and mortality of acute stroke. Commonly, these lesions are managed with aggressive medical treatment due to their chronic and usually irreversible nature. Spontaneous recanalization of the occluded ICA has been described in rare instances. Methods We present a report here on three cases with spontaneous recanalization of complete occluded carotid arteries. Results Our first patient was a 62‐year‐old male with a history of hypertension, who presented with transient left eye vision loss. CT angiography of the head and neck (CTA HN) demonstrated left ICA complete occlusion while the left middle cerebral artery (MCA) and anterior cerebral arteries (ACA) were patent. He was treated with apixaban. At the two‐month follow‐up, the repeat CTA HN demonstrated complete recanalization of the left ICA. The etiology of the occlusion remained cryptogenic. Our second patient was a 71‐year‐old male with a prior history of right carotid endarterectomy, peripheral vascular disease, coronary artery disease, hypertension, and dyslipidemia, who presented with acute right MCA stroke. Work‐up with CTA HN demonstrated right ICA complete occlusion. He was treated medically with aspirin and clopidogrel. Six months later, he presented with a two‐week history of intermittent confusion and left‐sided weakness. His MRI brain was negative foracute stroke. Interestingly, CTA HN demonstrated that the right ICA had complete recanalization. The cause of carotid thrombosis remained cryptogenic. Our third patient was a 46‐year‐old female with a history of hypertension, hyperlipidemia, remote low‐speed vehicle collision, and cervical spine chiropractic treatment (the last neck manipulation was about two years prior), presenting with sudden onset dizziness, right‐sided neck pain, and left homonymous hemianopia. Brain MRI showed acute right posterior cerebral artery (PCA) stroke. CTA HN revealed occlusion of the right ICA with a flare‐up appearance suggestive of a carotid dissection. She also had a right fetal PCA. She was treated medically with rivaroxaban. Four months later, a follow‐up MR angiogramof the neck showed a fully revascularized right ICA. Her hypercoagulable workup revealed that she had a rare form of breast cancer. Conclusions Although ICA occlusion is generally considered chronic and irreversible, our case series suggests that the lesion can have spontaneous recanalization with medical treatment. Further studies of characterizing carotid occlusion to predict recanalization are warranted

Abstract Number ‐ 148: Emergent Carotid Artery Stenting On Acute Stroke Patients With Carotid Occlusion: Benefit Or Harm?

Introduction Almost one out of four patients with acute middle cerebral artery occlusion also have ipsilateral internal carotid artery occlusion (ICAO). The interventions for acute stroke due to extracranial ICAO with or without intracranial occlusions are still a challenge. Case series reported early revascularization reduced stroke recurrence and improved outcomes. The benefits of this intervention on hyperacute ischemic strokes (within 6 hours) were much less known. We reported here two hyperacute stroke patients who emergent CAS on ICAO. Methods Electronic medical charts were reviewed, assessing intracranial hemorrhage (ICH) in two hyperacute stroke patients resulting from emergent carotid artery stenting (CAS) on the occluded internal carotid artery (ICA). Results Case description:The first patient was a 60‐year‐old male who had acute right hemiparesis, aphasia, and left gaze deviation with NIHSS12. The last known normal was five hours ago. Head and neck CT angiography (CTA) showed left anterior M2 branch artery occlusion and left ICAO. Head CT perfusion (CTP) showed a small core infarct with a large perfusion mismatch. Emergent CAS was performed without distal embolic protection (DEP) and followed by distal mechanical thrombectomy (MT). TICI 2B recanalization was achieved. After CAS, aspirin and clopidogrel were administrated. He had a large left MCA and PCA stroke from fetal PCA. A few days later, the patient developed large intraparenchymal hemorrhage (IPH) and intraventricular hemorrhage (IVH). He expired shortly. The second was a 52‐year‐old male had acute right facial droop, aphasia, dysarthria, and decreased consciousness (NIHSS 8). CTA showed left ICAO but patent intracranial arteries. CT perfusion showed a large mismatch without core infarction. He received intravenous tPA and had emergent CAS with a DEP. Aspirin 600 mg was administrated afterward. A few hours later, he had worsened weakness. Head CT showed left IPH, IVH, and subarachnoid hemorrhages with cerebral edema, and midline shift. He was medically managed for a prolonged stay and was discharged to a rehabilitation facility. Conclusions We presented two consecutive cases of emergent revascularization of ICAO in hyperacute stroke carried a high risk of ICH with poor outcome. Our online database search found that only a few case series of emergent CAS on ICAO were reported. Overall, emergent CAS carried about 20% risk of ICH and high mortality. Other series reported angioplasty on stenotic or occluded cervical ICA lesions with MT on distal occlusions had less hemorrhagic risk because there was no need fordual antiplatelet treatment. Most emergent CAS cases were performed on tandem occlusions for faster direct access and better efficacy of distal recanalization. A futurestudy comparing hemorrhagic risk betweenemergent CAS versus angioplasty of ICAO in patients with tandem occlusions can help to establish a standard MT protocol. For isolated ICAO with patent intracranial arteries from good collaterals, CTP may not be a good guidance tool for decision‐making of emergent CAS as it can falsely show mismatch from existing collaterals due to occlusion. A randomized clinical trial of comparison of medical management versus emergent CAS on those patients is warranted

Abstract Number ‐ 233: Vaccine‐Induced Thrombotic Thrombocytopenia presenting as Massive Stroke: Case Report and Literature Review

Introduction Vaccines have been pivotal for the COVID‐19 pandemic. Rare adverse effects of the vaccines such as thrombosis have been observed. Here we report a case of an acute malignant ischemic stroke in a young healthy patient caused by thrombosis due to Vaccine‐Induced Thrombotic Thrombocytopenia (VITT). Methods Electronic chart review for a case report. Results A 43‐year‐old Caucasian female with a medical history of hypertension was found unresponsive on the morning of presentation. Her Last known normal was the night before. On arrival in the emergency department, she was globally aphasic, with left eye deviation, right‐sided neglect, right facial droop, and right‐side hemiplegia. Pupils were equal and reactive to light. NIHSS was 23. Head CT showed large left middle cerebral artery and anterior cerebral artery strokes with significant cerebral edema and midline shift. Head and neck CTA showed left ICA and left MCA occlusions. She was taken for decompressive craniectomy immediately. Ten days prior to the stroke, she received her first COVID vaccination. She smoked but did not take oral contraceptives. She did not have a family history of hypercoagulability. Stroke workup showed LDL 141, A1C 4.8%, and a negative COVID test. She had normal white and red blood cell counts but low platelet counts at 73,000, which was 233,000 one month prior. 2D echocardiogram showed an ejection fraction of 54% and no patent foramen ovale or thrombus. Lower extremity doppler showed deep vein thrombosis. Because of arterial and venous thrombosis with new thrombocytopenia, hematology was consulted. She was found to have positive anti–PF4–heparin antibody, leading to a VITT diagnosis. She received IVIG, rituximab, and steroid treatments, and her platelets gradually returned to the baseline. She was later transferred to a rehabilitation facility. Conclusions VITT is characterized by thrombosis and thrombocytopenia with positive PF4 antibodies after a median of 14 days post‐vaccination. It was reported in COVID vaccines from all manufacturers. The mechanism remains unclear. The current hypothesis describes a two‐hit process through which the vaccine triggers neoantigen formation (the first hit) followed by a systemic inflammatory response (the second hit). Incidence of VITT from COVID vaccinations is unknown but the reported cases were rare. VITT‐caused acute stroke, especially malignant strokes, is even rarer.Although the COVID vaccines can cause rare life‐threatening adverse events, they are essential for controlling the pandemic. When encountering an ischemic stroke patient with thrombocytopenia, we should consider VITT. Further study with post‐vaccination registration and monitoring is warranted