Characteristics of Patients With Pulmonary Arterial Hypertension in a Pulmonary Hypertension Association-Accredited Comprehensive Care Center: A Contrast in Features When Compared With US National Registry Data.

Background Since the initial description in the 1980s, our understanding of the diversity of pulmonary arterial hypertension (PAH) has continued to evolve. In this study, we report the characteristics of patients seen in an academic medical center for PAH from August 2020 through November 2021 and contrast those with nationally reported data from the United States Pulmonary Hypertension Scientific Registry (USPHSR).  Study Design Investigators at the University of Utah Pulmonary Hypertension Program prospectively enrolled adult patients diagnosed with WHO Group 1 PAH, who were evaluated between August 2020 and November 2021 in a program-specific registry. Patient exposure and health histories were collected through structured interviews and questionnaires, along with clinical data and medication use. A total of 242 patients were enrolled in the University of Utah Pulmonary Hypertension Registry (UUPHR).  Results Of the 242 enrolled patients, the most common etiology was associated PAH (APAH), accounting for 71.1% of the population. The second largest etiology was idiopathic PAH (IPAH) at 26.4%. The remaining patients were distributed between familial PAH (FPAH), pulmonary veno-occlusive disease (PVOD), and others. Of the total population classified as APAH, 39% of cases were noted as secondary to connective tissue disease (CTD) and 33% as toxin-induced. These represented 28% and 24% of the total population, respectively.  Conclusions In this US-based accredited academic medical center, the etiology of PAH in our patient population contrasts with national registry data. In the UUPHR, APAH, specifically CTD-PAH and toxin-associated PAH, accounts for the majority of patients with PAH. This contrasts with IPAH, which nationally is the most reported cause of PAH. Differences in our population may reflect the regional variation of the referral site, but it is noteworthy for its contrast with historically reported phenotypes.

Imaging in Pulmonary Vascular Disease-Understanding Right Ventricle-Pulmonary Artery Coupling.

The right ventricle (RV) and pulmonary arterial (PA) tree are inextricably linked, continually transferring energy back and forth in a process known as RV-PA coupling. Healthy organisms maintain this relationship in optimal balance by modulating RV contractility, pulmonary vascular resistance, and compliance to sustain RV-PA coupling through life's many physiologic challenges. Early in states of adaptation to cardiovascular disease-for example, in diastolic heart failure-RV-PA coupling is maintained via a multitude of cellular and mechanical transformations. However, with disease progression, these compensatory mechanisms fail and become maladaptive, leading to the often-fatal state of "uncoupling." Noninvasive imaging modalities, including echocardiography, magnetic resonance imaging, and computed tomography, allow us deeper insight into the state of coupling for an individual patient, providing for prognostication and potential intervention before uncoupling occurs. In this review, we discuss the physiologic foundations of RV-PA coupling, elaborate on the imaging techniques to qualify and quantify it, and correlate these fundamental principles with clinical scenarios in health and disease. © 2022 American Physiological Society. Compr Physiol 12: 1-26, 2022.

A pilot trial of human amniotic fluid for the treatment of COVID-19.

OBJECTIVE: Vertical transmission from SARS CoV-2-infected women is uncommon and coronavirus has not been detected in amniotic fluid. Human amniotic products have a broad immune-mediating profile. Observing that many COVID-19 patients have a profound inflammatory response to the virus, we sought to determine the influence of human amniotic fluid (hAF) on hospitalized patients with COVID-19. RESULTS: A 10-patient case series was IRB-approved to study the impact of hAF on hospitalized patients with documented COVID-19. Nine of the 10 patients survived to discharge, with one patient succumbing to the disease when enrolled on maximal ventilatory support and severe hypoxia. The study design was altered by the IRB such that the last 6 patients received higher dose of intravenous hAF. In this latter group, patients that had observed reductions in C-reactive protein were associated with improved clinical outcomes. No hAF-related adverse events were noted. Acknowledging some of the inherent limitations of this case series, these results inform and catalyze a larger scaled randomized prospective trial to further investigate hAF as a therapy for COVID-19. Trial Registration ClinicalTrials.gov: NCT04319731; March 23, 2020.

Management of Pulmonary Arterial Hypertension.

PURPOSE OF REVIEW: This review focuses on the therapeutic management and individualized approach to Group 1 pulmonary arterial hypertension (PAH), utilizing Food and Drug Administration-approved PAH-specific therapies and various interventional and surgical options for PAH. RECENT FINDINGS: The paradigm for the optimal management of PAH has shifted in recent years. Upfront combination therapy with an endothelin receptor antagonist and a phosphodiesterase 5 inhibitor is now widely accepted as standard of care. In addition, there is increasing emphasis on starting prostanoids early in order to delay time to clinical worsening. However, less is known regarding which prostanoid agent to initiate and the optimum time to do so. In order to facilitate shared decision-making, there is an increasing need for decision tools based on guidelines and collective clinical experiences to navigate between pharmacologic and interventional treatments, as well as explore innovative, therapeutic pathways for PAH. SUMMARY: The management of PAH has become increasingly complex. With a growing number of PAH-specific therapies, intimate knowledge of the therapeutics and the potential barriers to adherence are integral to providing optimal care for this high-risk patient population. While current PAH-specific therapies largely mediate their effects through pulmonary vasodilation, ongoing research efforts are focused on ways to disrupt the mechanisms leading to pulmonary vascular remodeling. By targeting aberrations identified in the metabolism and proliferative state of pulmonary vascular cells, novel PAH treatment pathways may be just on the horizon.

SARS-CoV-2 innate effector associations and viral load in early nasopharyngeal infection.

COVID-19 causes severe disease with poor outcomes. We tested the hypothesis that early SARS-CoV-2 viral infection disrupts innate immune responses. These changes may be important for understanding subsequent clinical outcomes. We obtained residual nasopharyngeal swab samples from individuals who requested COVID-19 testing for symptoms at drive-through COVID-19 clinical testing sites operated by the University of Utah. We applied multiplex immunoassays, real-time polymerase chain reaction assays and quantitative proteomics to 20 virus-positive and 20 virus-negative samples. ACE-2 transcripts increased with infection (OR =17.4, 95% CI [CI] =4.78-63.8) and increasing viral N1 protein transcript load (OR =1.16, CI =1.10-1.23). Transcripts for two interferons (IFN) were elevated, IFN-λ1 (OR =71, CI =7.07-713) and IFN-λ2 (OR =40.2, CI =3.86-419), and closely associated with viral N1 transcripts (OR =1.35, CI =1.23-1.49 and OR =1.33 CI =1.20-1.47, respectively). Only transcripts for IP-10 were increased among systemic inflammatory cytokines that we examined (OR =131, CI =1.01-2620). We found widespread discrepancies between transcription and translation. IFN proteins were unchanged or decreased in infected samples (IFN-γ OR =0.90 CI =0.33-0.79, IFN-λ2,3 OR =0.60 CI =0.48-0.74) suggesting viral-induced shut-off of host antiviral protein responses. However, proteins for IP-10 (OR =3.74 CI =2.07-6.77) and several interferon-stimulated genes (ISG) increased with viral load (BST-1 OR =25.1, CI =3.33-188; IFIT1 OR =19.5, CI =4.25-89.2; IFIT3 OR =245, CI =15-4020; MX-1 OR =3.33, CI =1.44-7.70). Older age was associated with substantial modifications of some effects. Ambulatory symptomatic patients had an innate immune response with SARS-CoV-2 infection characterized by elevated IFN, proinflammatory cytokine and ISG transcripts, but there is evidence of a viral-induced host shut-off of antiviral responses. Our findings may characterize the disrupted immune landscape common in patients with early disease.

A Pathway for Community-Acquired Pneumonia With Rapid Conversion to Oral Therapy Improves Health Care Value.

BACKGROUND: Evidence supports streamlined approaches for inpatients with community-acquired pneumonia (CAP) including early transition to oral antibiotics and shorter therapy. Uptake of these approaches is variable, and the best approaches to local implementation of infection-specific guidelines are unknown. Our objective was to evaluate the impact of a clinical decision support (CDS) tool linked with a clinical pathway on CAP care. METHODS: This is a retrospective, observational pre-post intervention study of inpatients with pneumonia admitted to a single academic medical center. Interventions were introduced in 3 sequential 6-month phases; Phase 1: education alone; Phase 2: education and a CDS-driven CAP pathway coupled with active antimicrobial stewardship and provider feedback; and Phase 3: education and a CDS-driven CAP pathway without active stewardship. The 12 months preceding the intervention were used as a baseline. Primary outcomes were length of intravenous antibiotic therapy and total length of antibiotic therapy. Clinical, process, and cost outcomes were also measured. RESULTS: The study included 1021 visits. Phase 2 was associated with significantly lower length of intravenous and total antibiotic therapy, higher procalcitonin lab utilization, and a 20% cost reduction compared with baseline. Phase 3 was associated with significantly lower length of intravenous antibiotic therapy and higher procalcitonin lab utilization compared with baseline. CONCLUSIONS: A CDS-driven CAP pathway supplemented by active antimicrobial stewardship review led to the most robust improvements in antibiotic use and decreased costs with similar clinical outcomes.

Transitioning Between Prostanoid Therapies in Pulmonary Arterial Hypertension.

Background: New oral prostacyclin therapies and prostacyclin agonists have become available for the treatment of pulmonary arterial hypertension (PAH). However, methods for transitioning between oral, inhaled, and parenteral formulations are not well-established, except in the form of case reports and case series. Collectively, these emphasize the lack of a standardized process and approach in transitioning patients between PAH prostanoid therapies. In this case series, we report our experience at an accredited Pulmonary Hypertension center in transitioning between various oral, inhaled, and parenteral prostanoids to offer additional guidance on safe transitions in therapy. Methods: All cases of prostanoid transitions at an accredited Pulmonary Hypertension center from March 2018 to September 2019 were included in this report. The transition approach for each case was developed through a review of the literature, extrapolation of available pharmacokinetic data, and collaboration between pharmacists and clinicians. Results: This case series describes the transition of 3 patients from selexipag to parenteral treprostinil; 1 patient transitioning from parenteral treprostinil to selexipag; 1 patient transitioning from oral treprostinil to parenteral treprostinil; and 1 patient transitioning from inhaled treprostinil to selexipag. Four of the 6 patients presented here were transitioned to an alternate prostanoid on account of clinical worsening, while the remaining 2 patients transitioned due to intolerance of parenteral therapy and poor medication adherence. This case series includes patients with various etiologies of PAH including idiopathic PAH, methamphetamine-associated PAH, and scleroderma-associated PAH. All patients successfully completed each transition without serious adverse events. Conclusions: With the increasing utilization and availability of prostanoids, there is a critical need for a standardized approach in transitioning safely between different formulations without compromising treatment efficacy. In this case series, we present our clinical experiences, guided by available pharmacokinetic data, in transitioning between various prostanoid formulations.

Reducing Diabetic Ketoacidosis Intensive Care Unit Admissions Through an Electronic Health Record-Driven, Standardized Care Pathway.

Diabetic ketoacidosis (DKA) is a common condition, with wide variation in admission location and clinical practice. We aimed to decrease intensive care unit (ICU) admission for DKA by implementing a standardized, electronic health record-driven clinical care pathway that used subcutaneous insulin, rather than a continuous insulin infusion, for patients with nonsevere DKA. This is a retrospective, observational preintervention to postintervention study of 214 hospital admissions for DKA that evaluated the effect of our intervention on clinical, safety, and cost outcomes. The primary outcome was ICU admission, which decreased from 67.0% to 41.7% (p < .001). Diabetes nurse educator consultation increased from 45.3% to 63.9% (p = .006), and 30-day Emergency Department (ED) return visit decreased from 12.3% to 2.8% (p = .008). Time to initiation of basal insulin increased from 18.19 ± 1.25 hours to 22.47 ± 1.76 hours (p = .05) and reopening of the anion gap increased from 4.7% to 13.9% (p = .02). No changes in ED length of stay (LOS), hospital LOS, hypoglycemia, treatment-induced hypokalemia, 30-day hospital readmission, or inpatient mortality were observed. The implementation of a standardized DKA care pathway using subcutaneous insulin for nonsevere DKA resulted in decreased ICU use and increased diabetes education, without affecting patient safety.

SARS-CoV-2 Innate Effector Associations and Viral Load in Early Nasopharyngeal Infection.

To examine innate immune responses in early SARS-CoV-2 infection that may change clinical outcomes, we compared nasopharyngeal swab data from 20 virus-positive and 20 virus-negative individuals. Multiple innate immune-related and ACE-2 transcripts increased with infection and were strongly associated with increasing viral load. We found widespread discrepancies between transcription and translation. Interferon proteins were unchanged or decreased in infected samples suggesting virally-induced shut-off of host anti-viral protein responses. However, IP-10 and several interferon-stimulated gene proteins increased with viral load. Older age was associated with modifications of some effects. Our findings may characterize the disrupted immune landscape of early disease.

Right-to-left ventricular end diastolic diameter ratio in severe sepsis and septic shock.

PURPOSE: The ratio of right ventricular end-diastolic diameter (EDD) to left ventricular EDD (RV/LV) is a measure predictive of right ventricular failure. We hypothesized that an increase in RV/LV would be associated with poor prognosis in severe sepsis and septic shock. MATERIALS AND METHODS: This is a retrospective chart review of patients with severe sepsis and septic shock admitted to a medical intensive care unit (ICU) at a single tertiary care hospital. Patients were identified by ICD-9 codes: 995.92 for severe sepsis and 785.52 for septic shock; and had to have an echocardiogram within 48 h of ICU admission. Increased RV/LV was defined as RV/LV ≥ 0.9. Left and right-sided chamber dimensions were measured according to American Society of Echocardiography guidelines. RESULTS: We included 146 consecutive ICU patients admitted with septic shock (72) or severe sepsis (74). There was no significant difference in ICU mortality in patients with RV/LV ≥ 0.9 versus RV/LV < 0.9 (p = .49). CONCLUSIONS: An increased RV/LV does not predict mortality in severe sepsis or septic shock.

Right ventricular adaptation and failure in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy, characterized by excess proliferation, apoptosis resistance, inflammation, fibrosis, and vasoconstriction. Although PAH therapies target some of these vascular abnormalities (primarily vasoconstriction), most do not directly benefit the right ventricle (RV). This is suboptimal because a patient's functional state and prognosis are largely determined by the success of the adaptation of the RV to the increased afterload. The RV initially hypertrophies but might ultimately decompensate, becoming dilated, hypokinetic, and fibrotic. A number of pathophysiologic abnormalities have been identified in the PAH RV, including: ischemia and hibernation (partially reflecting RV capillary rarefaction), autonomic activation (due to G protein receptor kinase 2-mediated downregulation and desensitization of ß-adrenergic receptors), mitochondrial-metabolic abnormalities (notably increased uncoupled glycolysis and glutaminolysis), and fibrosis. Many RV abnormalities are detectable using molecular imaging and might serve as biomarkers. Some molecular pathways, such as those regulating angiogenesis, metabolism, and mitochondrial dynamics, are similarly deranged in the RV and pulmonary vasculature, offering the possibility of therapies that treat the RV and pulmonary circulation. An important paradigm in PAH is that the RV and pulmonary circulation constitute a unified cardiopulmonary unit. Clinical trials of PAH pharmacotherapies should assess both components of the cardiopulmonary unit.

Phanerochaete chrysosporium and granulomatous lung disease in a mulch gardener.

A 50-year-old woman who gardens regularly with rotting bark mulch presented with exertional dyspnea, diffusion impairment, and radiographic abnormalities (centrilobular nodules, tree-in-bud and ground glass opacities, calcified mediastinal and hilar lymph nodes) on a computed tomogram. Moderate lymphocytosis was noted on bronchoalveolar lavage. Surgical biopsy of her lung revealed granulomatous changes, and biopsies grew Phanerochaete chrysosporium, a fungus that causes white rot in tree bark. She was treated with voriconazole and instructed to avoid gardening, which led to radiographic and symptomatic improvement. She had recurrence of symptoms when she started doing yard work again. P. chrysosporium has been demonstrated to cause hypersensitivity pneumonitis in animal models. This case is the first documented report of P. chrysosporium associated with granulomatous lung disease in a human.