Thoracic Ultrasound in COVID-19: Use of Lung and Diaphragm Ultrasound in Evaluating Dyspnea in Survivors of Acute Respiratory Distress Syndrome from COVID-19 Pneumonia in a Post-ICU Clinic.

INTRODUCTION: Dyspnea is a common symptom in survivors of severe COVID-19 pneumonia. While frequently employed in hospital settings, the use of point-of-care ultrasound in ambulatory clinics for dyspnea evaluation has rarely been explored. We aimed to determine how lung ultrasound score (LUS) and inspiratory diaphragm excursion (DE) correlate with patient-reported dyspnea during a 6-min walk test (6MWT) in survivors of COVID-19 acute respiratory distress syndrome (ARDS). We hypothesize higher LUS and lower DE will correlate with dyspnea severity. STUDY DESIGN AND METHODS: Single-center cross-sectional study of survivors of critically ill COVID-19 pneumonia (requiring high-flow nasal cannula, invasive, or non-invasive mechanical ventilation) seen in our Post-ICU clinic. All patients underwent standardized scanning protocols to compute LUS and DE. Pearson correlations were performed to detect an association between LUS and DE with dyspnea at rest and exertion during 6MWT. RESULTS: We enrolled 45 patients. Average age was 61.5 years (57.7% male), with average BMI of 32.3 Higher LUS correlated significantly with dyspnea, at rest (r = + 0.41, p = < 0.01) and at exertion (r = + 0.40, p = < 0.01). Higher LUS correlated significantly with lower oxygen saturation during 6MWT (r = -0.55, p = < 0.01) and lower 6MWT distance (r = -0.44, p = < 0.01). DE correlated significantly with 6MWT distance but did not correlate with dyspnea at rest or exertion. CONCLUSION: Higher LUS correlated significantly with patient-reported dyspnea at rest and exertion. Higher LUS significantly correlated with more exertional oxygen desaturation during 6MWT and lower 6MWT distance. DE did not correlate with dyspnea.

Recurrent Meningitis.

PURPOSE OF REVIEW: Recurrent meningitis is a rare clinical scenario that can be self-limiting or life threatening depending on the underlying etiology. This review describes the causes, risk factors, treatment, and prognosis for recurrent meningitis. As a general overview of a broad topic, the aim of this review is to provide clinicians with a comprehensive differential diagnosis to aide in the evaluation and management of a patient with recurrent meningitis. RECENT FINDINGS: New developments related to understanding the pathophysiology of recurrent meningitis are as scarce as studies evaluating the treatment and prevention of this rare disorder. A trial evaluating oral valacyclovir suppression after HSV-2 meningitis did not demonstrate a benefit in preventing recurrences. The data on prophylactic antibiotics after basilar skull fractures do not support their use. Intrathecal trastuzumab has shown promise in treating leptomeningeal carcinomatosis from HER-2 positive breast cancer. Monoclonal antibodies used to treat cancer and autoimmune diseases are new potential causes of drug-induced aseptic meningitis. Despite their potential for causing recurrent meningitis, the clinical entities reviewed herein are not frequently discussed together given that they are a heterogeneous collection of unrelated, rare diseases. Epidemiologic data on recurrent meningitis are lacking. The syndrome of recurrent benign lymphocytic meningitis described by Mollaret in 1944 was later found to be closely related to HSV-2 reactivation, but HSV-2 is by no means the only etiology of recurrent aseptic meningitis. While the mainstay of treatment for recurrent meningitis is supportive care, it is paramount to ensure that reversible and treatable causes have been addressed for further prevention.

EGFR activation suppresses respiratory virus-induced IRF1-dependent CXCL10 production.

Airway epithelial cells are the primary cell type involved in respiratory viral infection. Upon infection, airway epithelium plays a critical role in host defense against viral infection by contributing to innate and adaptive immune responses. Influenza A virus, rhinovirus, and respiratory syncytial virus (RSV) represent a broad range of human viral pathogens that cause viral pneumonia and induce exacerbations of asthma and chronic obstructive pulmonary disease. These respiratory viruses induce airway epithelial production of IL-8, which involves epidermal growth factor receptor (EGFR) activation. EGFR activation involves an integrated signaling pathway that includes NADPH oxidase activation of metalloproteinase, and EGFR proligand release that activates EGFR. Because respiratory viruses have been shown to activate EGFR via this signaling pathway in airway epithelium, we investigated the effect of virus-induced EGFR activation on airway epithelial antiviral responses. CXCL10, a chemokine produced by airway epithelial cells in response to respiratory viral infection, contributes to the recruitment of lymphocytes to target and kill virus-infected cells. While respiratory viruses activate EGFR, the interaction between CXCL10 and EGFR signaling pathways is unclear, and the potential for EGFR signaling to suppress CXCL10 has not been explored. Here, we report that respiratory virus-induced EGFR activation suppresses CXCL10 production. We found that influenza virus-, rhinovirus-, and RSV-induced EGFR activation suppressed IFN regulatory factor (IRF) 1-dependent CXCL10 production. In addition, inhibition of EGFR during viral infection augmented IRF1 and CXCL10. These findings describe a novel mechanism that viruses use to suppress endogenous antiviral defenses, and provide potential targets for future therapies.

The Evolution of Cardiovascular Ultrasound: A Review of Cardiac Point-of-Care Ultrasound (POCUS) Across Specialties.

The use of cardiac point-of-care ultrasound (POCUS) is now widespread in clinics, emergency departments, and all areas of the hospital. Users include medical trainees, advanced practice practitioners, and attending physicians in many specialties and sub-specialties. Opportunities to learn cardiac POCUS and requirements for training vary across specialties, as does the scope of the cardiac POCUS examination. In this review, we describe both a brief history of how cardiac POCUS emerged from echocardiography and the state of the art across a variety of medical fields.

A Non-Resolving "Hematoma" Diagnosed as an Arteriovenous Malformation by POCUS.

Point-of-care ultrasound (POCUS) is a useful tool for the evaluation of soft tissue masses. We present the case of a patient with a mass on his forehead initially thought to be a slowly resolving hematoma. POCUS examination of the mass revealed a vascular structure more consistent with a post-traumatic arteriovenous malformation (AVM). This case illustrates how POCUS can be utilized to rapidly assess soft tissue masses and even identify unexpected vascularity.

Natural mucosal barriers and COVID-19 in children.

BACKGROUNDCoronavirus disease 2019 (COVID-19) is more benign in children compared with adults for unknown reasons. This contrasts with other respiratory viruses where disease manifestations are often more severe in children. We hypothesize that a more robust early innate immune response to SARS coronavirus 2 (SARS-CoV-2) protects against severe disease.METHODSClinical outcomes, SARS-CoV-2 viral copies, and cellular gene expression were compared in nasopharyngeal swabs obtained at the time of presentation to the emergency department from 12 children and 27 adults using bulk RNA sequencing and quantitative reverse-transcription PCR. Total protein, cytokines, and anti-SARS-CoV-2 IgG and IgA were quantified in nasal fluid.RESULTSSARS-CoV-2 copies, angiotensin-converting enzyme 2, and TMPRSS2 gene expression were similar in children and adults, but children displayed higher expression of genes associated with IFN signaling, NLRP3 inflammasome, and other innate pathways. Higher levels of IFN-α2, IFN-γ, IP-10, IL-8, and IL-1ß protein were detected in nasal fluid in children versus adults. Children also expressed higher levels of genes associated with immune cells, whereas expression of those associated with epithelial cells did not differ in children versus adults. Anti-SARS-CoV-2 IgA and IgG were detected at similar levels in nasal fluid from both groups. None of the children required supplemental oxygen, whereas 7 adults did (P = 0.03); 4 adults died.CONCLUSIONThese findings provide direct evidence of a more vigorous early mucosal immune response in children compared with adults and suggest that this contributes to favorable clinical outcomes.FUNDINGNIH grants R01 AI134367, UL1 TR002556, T32 AI007501, T32GM007288, P30 AI124414; an Albert Einstein College of Medicine Dean's COVID-19 Pilot Research Award; and the Eric J. Heyer, MD, PhD Translational Research Pilot Project Award.

Natural Mucosal Barriers and COVID-19 in Children.

COVID-19 is more benign in children compared to adults for unknown reasons. This contrasts with viruses such as influenza where disease manifestations are often more severe in children1. We hypothesized that a more robust early innate immune response to SARS-CoV-2 may protect against severe disease and compared clinical outcomes, viral copies and cellular gene and protein expression in nasopharyngeal swabs from 12 children and 27 adults upon presentation to the Emergency Department. SARS-CoV-2 copies were similar, but compared to adults, children displayed higher expression of genes associated with interferon signaling, NLRP3 inflammasome, and other innate pathways. Higher levels of IFN-alpha2, IFN-gamma, IP-10, IL-8, and IL-1beta were detected in nasal fluid in children versus adults. Anti-SARS-CoV-2 IgA and IgG were detected in nasal fluid from both groups and correlated negatively with mucosal IL-18. These findings suggest that a more robust innate immune response in children compared to adults contributes to favorable clinical outcomes.

Clinical characteristics of acute lower extremity deep venous thrombosis diagnosed by duplex in patients hospitalized for coronavirus disease 2019.

OBJECTIVE: Little is known about coronavirus disease 2019 (COVID-19)-associated hypercoagulability. We sought to characterize patients with deep venous thrombosis (DVT) identified after admission for COVID-19. METHODS: All adult patients admitted to Montefiore Medical Center from March 1, 2020, to April 10, 2020, and undergoing lower extremity venous duplex for DVT evaluation were included. Patients admitted with suspicion of COVID-19 were divided into severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive and SARS-CoV-2 negative groups based on in-hospital test results. Patients without clinical suspicion for COVID-19 were not tested. A retrospective case-control study design was used to identify potential risk factors for DVT in patients with COVID-19. Demographic, radiographic, and laboratory values were abstracted and analyzed. RESULTS: During the study period, 3404 patients with confirmed COVID-19 were admitted to the hospital. Of the 135 SARS-CoV-2 patients who underwent duplex scanning, there were 18 (13.3%) noted to have DVT compared with 72 of the 711 patients (10.1%) who were either SARS-CoV-2 negative or untested. The odds ratio for DVT in COVID-19 was 1.35 (95% confidence interval, 0.78-2.34; P = .289). Baseline characteristics for COVID-19 patients with and without DVT were overall similar. COVID-19 patients with DVT had an elevated median first d-dimer (18.88 µg/mL [interquartile range (IQR), 7.79-20.00] vs 2.55 µg/mL [IQR, 1.45-6.28]; P = .002; reference value, <0.5 µg/mL), average in-hospital d-dimer (median, 11.93 µg/mL [IQR, 8.25-16.97] vs 3.54 µg/mL [IQR, 2.05-8.53]; P < .001) and median fibrinogen level (501.0 [IQR, 440.0-629.0] vs 654.5 [IQR, 535.8-780.0]; P = .002; reference range, 187-502 mg/dL). There was a trend to significance for COVID-19 patients with DVT compared with without DVT in median d-dimer levels at the time of the duplex (13.61 µg/mL [IQR, 4.04-19.97] vs 3.58 µg/mL [IQR, 2.51-9.62]; P = .055) and median ferritin levels (1679.0 ng/mL [IQR, 1168.0-2577.0] vs 1103.0 ng/mL [IQR, 703.5-2076.5]; P = .055; reference range, 25-270 ng/mL). Twelve of the 18 patients with COVID who developed DVT did so despite chemical thromboprophylaxis, and 2 developed DVT despite therapeutic anticoagulation CONCLUSIONS: We found only a modestly increased risk of DVT in patients with COVID-19, likely underestimated owing to limitations in duplex testing early in the epidemic. Elevated d-dimer and a less elevated fibrinogen are associated with DVT in patients with COVID-19 who seem to form thrombus despite conventional chemical thromboprophylaxis. Additionally, an increasing d-dimer over time may be a reflection of the development of DVT in patients with COVID-19.

The Use of Point-of-Care Ultrasound (POCUS) in the Diagnosis of Deep Vein Thrombosis.

Acute lower extremity proximal deep venous thrombosis (DVT) requires accurate diagnosis and treatment in order to prevent embolization and other complications. Point-of-care ultrasound (POCUS), a clinician performed, and clinician interpreted bedside ultrasound examination has been increasingly used for DVT evaluation mainly in the urgent and critical care setting, but also in the ambulatory clinics and the medical wards. Studies have demonstrated that POCUS has excellent diagnostic accuracy for acute proximal DVT when performed by well-trained users. However, there is significant heterogeneity among studies on the necessary extent of training and universally acceptable standardized education protocols are needed. In this review, we summarize the evidence that supports the use of POCUS to diagnose acute proximal DVT and focus on methodology and current technology, sensitivity and specificity, pre-test probability and the role of D-dimer, time and resources, education, limitations, and future directions.

The Focused Assessment with Sonography in Cancer (FASC) Examination.

Malignant effusions occur frequently in patients with cancer and are important to diagnose and treat. In this report, we describe a novel point-of-care ultrasound (POCUS) protocol to rapidly identify pleural effusion, pericardial effusion, and ascites: The Focused Assessment with Sonography in Cancer (FASC). This protocol utilizes six standard sonographic positions to identify the presence of fluid in common anatomic spaces. The FASC examination is intended for widespread use by oncologists and other clinicians who treat patients with cancer.

Internal Medicine Resident Work Absence During the COVID-19 Pandemic at a Large Academic Medical Center in New York City.

BACKGROUND: Montefiore Medical Center (MMC) is a large tertiary care center in the Bronx, New York City, with 245 internal medicine residents. Beginning on February 29, 2020, residents became ill with COVID-19-like illness (CLI), which required absence from work. There was initially a shortage of personal protective equipment and delays in SARS-CoV-2 testing, which gradually improved during March and April 2020. OBJECTIVE: We evaluated the relationship between CLI-related work absence rates of internal medicine residents and MMC's COVID-19 hospital census over time. METHODS: Data on resident work absence between February 29 and May 22 were reviewed along with MMC's COVID-19 hospital census data. To determine the effect of patient exposure on resident CLI incidence, we compared the mean incidence of CLI per patient exposure days (PED = daily hospital census × days pre- or post-peak) before and after peak COVID-19 hospital census. RESULTS: Forty-two percent (103 of 245) of internal medicine residents were absent from work, resulting in 875 missed workdays. At the peak of resident work absence, 16% (38 of 245) were out sick. Residents were absent for a median of 7 days (IQR 6-9.5 days). Mean resident CLI incidence per PED (CLI/PED) was 13.9-fold lower post-peak compared to pre-peak (P = .003). CONCLUSIONS: At the beginning of the COVID-19 pandemic in New York City, a large portion of internal medicine residents at this single center became ill. However, the incidence of CLI decreased over time, despite ongoing exposure to patients with COVID-19.

Reducing peripherally inserted central catheters and midline catheters by training nurses in ultrasound-guided peripheral intravenous catheter placement.

BACKGROUND: Training nurses in ultrasound-guided peripheral intravenous catheter placement might reduce the use of more invasive venous access devices (peripherally inserted central catheters (PICC) and midline catheters). METHODS: We implemented an abbreviated training in ultrasound-guided peripheral intravenous catheter placement for nurses on an inpatient medical unit and provided a portable ultrasound device for 10 months. RESULTS: Nurses on this unit placed 99 ultrasound-guided peripheral intravenous catheters with a high level of success. During the implementation period, PICC and midline catheter placement decreased from a mean 4.8 to 2.5 per month, meeting criteria for special cause variation. In the postimplementation period, the average catheter use reverted to 4.3 per month on the intervention unit. A comparison inpatient medical unit without training or access to a portable ultrasound device experienced no significant change in PICC and midline catheter use throughout the study period (mean of 6.0 per month). CONCLUSIONS: These results suggest that an abbreviated training in ultrasound-guided peripheral intravenous catheter placement for nurses on an inpatient medical unit is sufficient to reduce PICC and midline catheters.

HVEM signaling promotes protective antibody-dependent cellular cytotoxicity (ADCC) vaccine responses to herpes simplex viruses.

Herpes simplex virus (HSV) glycoprotein D (gD) not only is required for virus entry and cell-to-cell spread but also binds the host immunomodulatory molecule, HVEM, blocking interactions with its ligands. Natural infection primarily elicits neutralizing antibodies targeting gD, but subunit protein vaccines designed to induce this response have failed clinically. In contrast, preclinical studies demonstrate that an HSV-2 single-cycle strain deleted in gD, ΔgD-2, induces primarily non-neutralizing antibodies that activate Fcγ receptors (FcγRs) to mediate antibody-dependent cellular cytotoxicity (ADCC). These studies were designed to test the hypothesis that gD interferes with ADCC through engagement of HVEM. Immunization of Hvem-/- mice with ΔgD-2 resulted in significant reduction in HSV-specific IgG2 antibodies, the subclass associated with FcγR activation and ADCC, compared with wild-type controls. This translated into a parallel reduction in active and passive vaccine protection. A similar decrease in ADCC titers was observed in Hvem-/- mice vaccinated with an alternative HSV vaccine candidate (dl5-29) or an unrelated vesicular stomatitis virus-vectored vaccine. Unexpectedly, not only did passive transfer of immune serum from ΔgD-2-vaccinated Hvem-/- mice fail to protect wild-type mice but transfer of immune serum from ΔgD-2-vaccinated wild-type mice failed to protect Hvem-/- mice. Immune cells isolated from Hvem-/- mice were impaired in FcγR activation, and, conversely, addition of gD protein or anti-HVEM antibodies to in vitro murine or human FcγR activation assays inhibited the response. These findings uncover a previously unrecognized role for HVEM signaling in generating and mediating ADCC and an additional HSV immune evasion strategy.