The ALPHA phase 1 study: pulmonary ArteriaL hypertension treated with CardiosPHere-Derived allogeneic stem cells.

BACKGROUND: Pulmonary Arterial Hypertension (PAH) is a progressive condition with no cure. Even with pharmacologic advances, survival remains poor. Lung pathology on PAH therapies still shows impressive occlusive arteriolar remodelling and plexiform lesions. Cardiosphere-derived cells (CDCs) are heart-derived progenitor cells exhibiting anti-inflammatory and immunomodulatory effects, are anti -fibrotic, anti-oxidative and anti-apoptotic to potentially impact several aspects of PAH pathobiology. In preclinical trials CDCs reduced right ventricular (RV) systolic pressure, RV hypertrophy, pulmonary arteriolar wall thickness and inflammation. METHODS: The ALPHA study was a Phase 1a/b study in which CDCs were infused into patients with Idiopathic (I)PAH, Heritable (H) HPAH, PAH-connective tissue disease (CTD) and PAH-human immunodeficiency virus (HIV). The study was IRB approved and DSMB monitored. Phase 1a, was an open label study (n = 6). Phase 1b was a double-blind placebo-controlled study (n = 20) in which half received 100 million CDCs (the maximum feasible dose from manufacturing perspective) and half placebo (PLAC) infusions. Right heart catheterization (RHC) and cardiac MR imaging (cMR) were performed at baseline and at 4 months post infusion. Patients were followed over a year. FINDINGS: No short-term clinical safety adverse events (AE) were related to the IP, the primary outcome measure. There were no adverse hemodynamic, gas exchange, rhythm or other clinical events following infusion and in the 1st 23 h monitored in hospital. There were no long-term AEs over 12 months noted, including unrelated limited hospitalizations. No immunologic short or long-term AEs were noted. We examined exploratory outcomes across multiple domains to determine encouraging signals to motivate future advanced phase testing. Phase 1a data showed encouraging observations for both 50 and 100 million CDC doses. Several encouraging findings favouring CDCs (n = 16) compared to placebo (n = 10) were noted. On cMR, the RV end diastolic volume (RVEDV) and index (RVEDVI) decreased with CDCs with a rise in the PLAC group. The 6-min walk distance was increased 2 months post infusion in the CDC group compared with PLAC. With PLAC, diffusing capacity (DLCO) decreased at 4 months but was unchanged with CDCs. Serum creatinine decreased with CDCs at 4 months. Encouraging observations favouring CDCs were also noted for RV fractional area change on echo and RV ejection fraction (RVEF) on cMR at 4 months. No differences were observed for mean pulmonary artery pressures or pulmonary vascular resistance. Review of long-term data to 12 months showed continued decline in DLCO for the PLAC cohort at 6 months with no change through 12 months. By contrast, CDC subjects showed an unchanged DLCO over 12-months. For parameters exhibiting early encouraging exploratory findings in CDC subjects, no further improvement was noted in long-term follow up through 12 months. INTERPRETATION: Intravenous CDCs were safe in both the short and long term in PAH subjects and thus may be safe in larger cohorts, in line with our extensive track record of safety in clinical trials for other conditions. Further, CDCs exhibited encouraging exploratory findings across several domains. Repeat dosing (quarterly, over one year) of intravenous CDCs has been reported to yield highly significant sustained disease-modifying bioactivity in subjects with advanced Duchenne muscular dystrophy. Because only single CDC doses were used here, the findings represent a lower limit estimate of CDC's potential in PAH. Upcoming phase 2 studies would logically use a repeat dosing paradigm. FUNDING: California Institute for Regenerative Medicine (CIRM). Project Number: CLIN2-09444.

Long term recovery of right ventricular function after treatment of intermediate and high risk pulmonary emboli.

INTRODUCTION: Pulmonary embolism (PE) is a common and significant source of mortality and morbidity worldwide. A subset of patients with PE, particularly those who have intermediate and high risk events, are at increased risk for long-term right ventricular (RV) dysfunction; however, the impact of novel advanced therapies used for acute PE, including catheter-directed intervention, on long-term RV function remains uncertain. We sought to determine whether use of advanced therapies (catheter-directed intervention or systemic thrombolysis) is associated with improved long-term RV function. MATERIALS AND METHODS: Retrospective, single-center cohort study of adult (≥18 year old) patients admitted and discharged alive with a diagnosis of acute PE, who fell under the category of intermediate or high risk, with available follow-up echocardiograms at least 6 months after the index, seen at a single quaternary referral center in Los Angeles, CA between 2012 and 2021. RESULTS: There were 113 patients in this study (58 (51.3 %) treated with anticoagulation alone, 12 (10.6 %) treated with systemic thrombolysis, and 43 (38.1 %) treated with catheter-directed intervention), with approximately equal gender and racial distribution. Patients treated with advanced therapies were significantly more likely to have moderate-severe RV dysfunction (100 % for those treated with thrombolysis, 88.3 % for those treated with catheter-directed intervention, vs 55.2 % for those treated with anticoagulation alone; p < 0.001). At a follow-up of about 1.5 years, patients treated with advanced therapy (systemic thrombolysis or catheter-directed intervention) were more likely to have normalization of RV function (93-100 % vs 81 % for anticoagulation alone, p = 0.04). The subgroup of patients with intermediate-risk PE was significantly more likely to have normalization of RV function (95.6 % vs 80.4 % for anticoagulation alone, p = 0.03). Use of advanced therapy was not associated with substantial short-term adverse events among patients who survived to hospital discharge. CONCLUSION: Patients with intermediate and high risk PE were more likely to have recovery in RV function long-term if treated with catheter-directed intervention or systemic thrombolysis, as compared to anticoagulation alone, without substantial safety issues, despite having worse RV function at baseline. Further data is needed to verify this observation.

Perception of interdisciplinary collaboration between ICU nurses and resident physicians during the COVID-19 pandemic.

Multidisciplinary collaboration is the hallmark of quality critical care. Prior studies have shown that nurses and physicians have different perceptions on communication and collaboration in the ICU. The Covid-19 pandemic has served to both strain and strengthen relationships between nurses and resident physicians in the ICU. This study used a survey-based approach sought to identify the similarities and differences between perception of collaboration between ICU nurses and resident physicians taking care of patients during the pandemic, and to identify whether they felt that the pandemic impacted the collaborative spirit of critical care. Although findings from this study suggest that overall residents and nurses perceive collaboration similarly, the COVID-19 pandemic may be differentially affecting the interdisciplinary dynamics of the ICU.

Chronic Thromboembolic Pulmonary Hypertension: the Bedside.

PURPOSE OF REVIEW: Chronic thromboembolic pulmonary hypertension (CTEPH), included in group 4 PH, is an uncommon complication of acute pulmonary embolism (PE), in which emboli in the pulmonary vasculature do not resolve but rather form into an organized scar-like obstruction which can result in right ventricular (RV) failure. Here we provide an overview of current diagnosis and management of CTEPH. RECENT FINDINGS: CTEPH management is complex with treatments that range from surgery, percutaneous interventions, to medical therapies. Current CTEPH medical therapies have largely been repurposed from pulmonary arterial hypertension (PAH). The diagnosis of CTEPH can be challenging, requiring a multimodality approach to differentiate from disease mimics. While these treatments improve symptoms, they may not reverse the underlying pathology of CTEPH.

Radiologic mimics of pulmonary embolism.

The diagnosis of pulmonary embolism (PE) is often made more challenging by the presence of diseases that can mimic thromboembolic disease. There is no specific or sensitive constellation of clinical signs or symptoms that can be used to diagnose PE. Ventilation/perfusion scans can have false-positive findings related to mediastinal conditions that can compress the pulmonary arteries, and pulmonary hemorrhage can resemble PE on V/Q scanning with potentially devastating consequences if anticoagulation is started. CT-scan related issues l eading to potential false-positive diagnoses range from inadequate imaging technique, to systemic-pulmonary shunting, to non-thrombotic occlusion of pulmonary arteries by tumor, septic emboli, and emboli of fat, air, and foreign material, as well as vasculitic processes. Careful assessment of the patient and consideration of these potential mimickers is imperative to correct diagnosis of this potentially life-threatening condition.

Progesterone in Addition to Standard of Care vs Standard of Care Alone in the Treatment of Men Hospitalized With Moderate to Severe COVID-19: A Randomized, Controlled Pilot Trial.

BACKGROUND: Severity of illness in COVID-19 is consistently lower in women. A focus on sex as a biological factor may suggest a potential therapeutic intervention for this disease. We assessed whether adding progesterone to standard of care (SOC) would improve clinical outcomes of hospitalized men with moderate to severe COVID-19. RESEARCH QUESTION: Does short-term subcutaneous administration of progesterone safely improve clinical outcome in hypoxemic men hospitalized with COVID-19? STUDY DESIGN AND METHODS: We conducted a pilot, randomized, open-label, controlled trial of subcutaneous progesterone in men hospitalized with confirmed moderate to severe COVID-19. Patients were randomly assigned to receive SOC plus progesterone (100 mg subcutaneously twice daily for up to 5 days) or SOC alone. In addition to assessment of safety, the primary outcome was change in clinical status on day 7. Length of hospital stay and number of days on supplemental oxygen were key secondary outcomes. RESULTS: Forty-two patients were enrolled from April 2020 to August 2020; 22 were randomized to the control group and 20 to the progesterone group. Two patients from the progesterone group withdrew from the study before receiving progesterone. There was a 1.5-point overall improvement in median clinical status score on a seven-point ordinal scale from baseline to day 7 in patients in the progesterone group as compared with control subjects (95% CI, 0.0-2.0; P = .024). There were no serious adverse events attributable to progesterone. Patients treated with progesterone required three fewer days of supplemental oxygen (median, 4.5 vs 7.5 days) and were hospitalized for 2.5 fewer days (median, 7.0 vs 9.5 days) as compared with control subjects. INTERPRETATION: Progesterone at a dose of 100 mg, twice daily by subcutaneous injection in addition to SOC, may represent a safe and effective approach for treatment in hypoxemic men with moderate to severe COVID-19. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04365127; URL: www.clinicaltrials.gov.

Pupillary Light Reflex Is Not Abolished by Epinephrine and Atropine Given During Advanced Cardiac Life Support in Patients Who Achieve Return of Spontaneous Circulation.

INTRODUCTION: Absence of pupillary light reflex (PLR) is a well-studied indicator of poor neurologic recovery after cardiac arrest. Interpretation of absent PLR is difficult in patients with hypothermia or hypotension, or who have electrolyte or acid-base disturbances. Additionally, many studies exclude patients who receive epinephrine or atropine from their analysis on the basis that these drugs are thought to abolish the PLR. This observational cohort study assessed for presence or absence of PLR in in-hospital cardiac arrest patients who received epinephrine with or without atropine during advanced cardiac life support and achieved return of spontaneous circulation (ROSC). METHODS: Pupil size and reactivity were assessed in adult patients who had an in-hospital cardiac arrest, received epinephrine with or without atropine, and achieved ROSC. Measurements were taken using a NeurOptics NPi-200 infrared pupillometer. RESULTS: Forty patients had pupillometry performed within 1 hour (median: 6 minutes) after ROSC. Of these only 1 (2.5%) patient had nonreactive pupils at first measurement after ROSC. The remaining 39 (97.5%) had reactive pupils. Of the 19 patients who had pupils checked within 3 minutes of ROSC, 100% had reactive pupils. Degree of pupil responsiveness was not correlated with cumulative dose of epinephrine. Ten patients received atropine in addition to epinephrine, including the sole patient with nonreactive pupils. The remaining 9 (90%) had reactive pupils. CONCLUSION: Epinephrine and atropine do not abolish the PLR in patients who achieve ROSC after in-hospital cardiac arrest. Lack of pupillary response in the post-arrest patient should not be attributed to these drugs.

Cell-Type-Specific Immune Dysregulation in Severely Ill COVID-19 Patients.

Recent studies have demonstrated immunologic dysfunction in severely ill coronavirus disease 2019 (COVID-19) patients. We use single-cell RNA sequencing (scRNA-seq) to analyze the transcriptome of peripheral blood mononuclear cells (PBMCs) from healthy (n = 3) and COVID-19 patients with moderate disease (n = 5), acute respiratory distress syndrome (ARDS, n = 6), or recovering from ARDS (n = 6). Our data reveal transcriptomic profiles indicative of defective antigen presentation and interferon (IFN) responsiveness in monocytes from ARDS patients, which contrasts with higher responsiveness to IFN signaling in lymphocytes. Furthermore, genes involved in cytotoxic activity are suppressed in both natural killer (NK) and CD8 T lymphocytes, and B cell activation is deficient, which is consistent with delayed viral clearance in severely ill COVID-19 patients. Our study demonstrates that COVID-19 patients with ARDS have a state of immune imbalance in which dysregulation of both innate and adaptive immune responses may be contributing to a more severe disease course.

Cell type-specific immune dysregulation in severely ill COVID-19 patients.

Coronavirus disease 2019 (COVID-19) has quickly become the most serious pandemic since the 1918 flu pandemic. In extreme situations, patients develop a dysregulated inflammatory lung injury called acute respiratory distress syndrome (ARDS) that causes progressive respiratory failure requiring mechanical ventilatory support. Recent studies have demonstrated immunologic dysfunction in severely ill COVID-19 patients. To further delineate the dysregulated immune response driving more severe clinical course from SARS-CoV-2 infection, we used single-cell RNA sequencing (scRNAseq) to analyze the transcriptome of peripheral blood mononuclear cells (PBMC) from hospitalized COVID-19 patients having mild disease (n = 5), developing ARDS (n = 6), and recovering from ARDS (n = 6). Our data demonstrated an overwhelming inflammatory response with select immunodeficiencies within various immune populations in ARDS patients. Specifically, their monocytes had defects in antigen presentation and deficiencies in interferon responsiveness that contrasted the higher interferon signals in lymphocytes. Furthermore, cytotoxic activity was suppressed in both NK and CD8 lymphocytes whereas B cell activation was deficient, which is consistent with the delayed viral clearance in severely ill COVID-19 patients. Finally, we identified altered signaling pathways in the severe group that suggests immunosenescence and immunometabolic changes could be contributing to the dysfunctional immune response. Our study demonstrates that COVID-19 patients with ARDS have an immunologically distinct response when compared to those with a more innocuous disease course and show a state of immune imbalance in which deficiencies in both the innate and adaptive immune response may be contributing to a more severe disease course in COVID-19.

Pre-existing traits associated with Covid-19 illness severity.

IMPORTANCE: Certain individuals, when infected by SARS-CoV-2, tend to develop the more severe forms of Covid-19 illness for reasons that remain unclear. OBJECTIVE: To determine the demographic and clinical characteristics associated with increased severity of Covid-19 infection. DESIGN: Retrospective observational study. We curated data from the electronic health record, and used multivariable logistic regression to examine the association of pre-existing traits with a Covid-19 illness severity defined by level of required care: need for hospital admission, need for intensive care, and need for intubation. SETTING: A large, multihospital healthcare system in Southern California. PARTICIPANTS: All patients with confirmed Covid-19 infection (N = 442). RESULTS: Of all patients studied, 48% required hospitalization, 17% required intensive care, and 12% required intubation. In multivariable-adjusted analyses, patients requiring a higher levels of care were more likely to be older (OR 1.5 per 10 years, P<0.001), male (OR 2.0, P = 0.001), African American (OR 2.1, P = 0.011), obese (OR 2.0, P = 0.021), with diabetes mellitus (OR 1.8, P = 0.037), and with a higher comorbidity index (OR 1.8 per SD, P<0.001). Several clinical associations were more pronounced in younger compared to older patients (Pinteraction<0.05). Of all hospitalized patients, males required higher levels of care (OR 2.5, P = 0.003) irrespective of age, race, or morbidity profile. CONCLUSIONS AND RELEVANCE: In our healthcare system, greater Covid-19 illness severity is seen in patients who are older, male, African American, obese, with diabetes, and with greater overall comorbidity burden. Certain comorbidities paradoxically augment risk to a greater extent in younger patients. In hospitalized patients, male sex is the main determinant of needing more intensive care. Further investigation is needed to understand the mechanisms underlying these findings.

Use of the Bedside-Placed Angel Catheter IVC Filter for Venous Thromboembolic Disease in Critically Ill Medical Patients.

Venous thromboembolic disease is a major problem among critically ill patients, with significant associated morbidity and mortality. Many critically ill patients have contraindications to systemic anticoagulation, and inferior vena cava (IVC) filters are an important alternative in preventing pulmonary emboli (PE) in this population. The Angel Catheter (Mermaid, Stenlose, Denmark) is a novel percutaneous and removable IVC filter attached to the end of a triple lumen central venous catheter which has been demonstrated to reduce PE in surgical and trauma patients. This case series describes 18 critically ill medical patients who had an Angel catheter placed either for diagnosed PE or due to high risk for PE; over half had at least submassive PE at the time of Angel catheter placement. None of the patients had a recurrence of PE during Angel catheter use, 29.4% had clot found in the filter via cavogram upon removal, and only one had a minor complication which had no clinical consequence. In 2 patients, the placement of the Angel Catheter resulted in the prevention of PE during catheter-directed thrombolysis of extensive deep vein thrombosis. This case series demonstrates that in a population of critically ill, elderly, and obese medical patients the bedside placement of the Angel IVC filter is feasible, safe, and may be effective for preventing PE.

Use of pressure-regulated volume control in the first 48 hours of hospitalization of mechanically ventilated patients with sepsis or septic shock, with or without ARDS.

PURPOSE: To evaluate the impact of pressure-regulated volume control (PRVC/VC+) use on delivered tidal volumes in patients with acute respiratory distress syndrome (ARDS) or at risk for ARDS. MATERIALS AND METHODS: Retrospective study of mechanically ventilated adult patients with severe sepsis or septic shock. RESULTS: A total of 272 patients were divided into patients with recognized ARDS, patients without ARDS, and patients with unrecognized ARDS. Over 90% of patients were ventilated with PRVC on admission, resulting in delivered tidal volumes significantly higher than set tidal volumes among all groups at all time points, even after ARDS recognition (p < 0.001). Tidal volumes were lower for patients with pulmonary sepsis as compared to those with a nonpulmonary origin (p < 0.001). CONCLUSIONS: Using PRVC promotes augmented delivered tidal volumes, often in excess of 6 mL/kg ideal body weight. Correct recognition of ARDS and having pulmonary sepsis improves compliance with low-stretch protocol ventilation.

A retrospective review of the frequency and nature of acute hypersensitivity reactions at a medium-sized infusion center: comparison to reported values and inconsistencies found in literature.

PURPOSE: To evaluate acute hypersensitivity reactions at the UCSD Moores Cancer Center in San Diego, compare our findings to those reported previously in the literature, and examine the effectiveness of the objective grading scale as represented by the Common Terminology Criteria for Adverse Events (CTCAE). PATIENTS AND METHODS: Using the available pharmacy and electronic medical record data from 2006-2010, we examined our reported hypersensitivity reactions (HSRs) using the CTCAE v.3.0 and v.4.0. A thorough literature review was also performed to compare our findings with those previously reported. RESULTS: We found 222 cases of HSRs, of which 50% were due to immunotherapeutics. Most were grade 1 or 2 by any CTCAE criteria. The clinical presentation of HSRs varied between drug classes. Using different versions of grading schema led to inconsistencies in ~50% of all HSRs. Fifty-two percent of all cases not due to blood products were rechallenged on the same day. The reported literature HSR frequencies for each causative agent showed a striking variability, possibly indicating that previous studies used a wide variety of grading and reporting systems for adverse events. CONCLUSION: HSRs are common in clinical practice, and most are mild or moderate. There are inconsistencies in reporting HSRs between studies. The existence of several grading schema and subjective definitions of hypersensitivity could be contributing to poor clinical generalizability. Along with an improved system of reporting HSRs to minimize underreporting, a standard system of objectively assessing HSRs is necessary for purposes of research and clinical practice.